º º: - ºffl --- º - - --- º: º - * # - - º --- - - - Hä - º #.ºffli º | ºffli --- - º ºffl º: Häß. # H + - # - º #: - # - º - º: -------- º º: --------- - ºfflº --- ºffli ºffl # - ºffl º º: --- #: - º º º: ####### - ºfflº - ºffli º --- - # Hä ########### #: # # º º ºffl º --- º # ºffl - --------------- - - - -- ################# º ########### ºffl ºffl ############################# H º # ºffl ºffli --- º: # º ºffl --~~~~ º: - # º - - º º # º º º:#º --- - º - ------------------ # - Häß #. ############ --- - ºffli --- - º: º: # - - ºffl --- --~~~~ º ºffl ########### - ºffl ºfflº ºffl º -------- - ºffl º --- - =# ºffl - ºffl - - - - - - - - - - ####### ################## - ########## （º - - - - --- - --- - - -------- ------ ºfflº º - - º # º - ºffli E - - º º - ºffl º º º - º º: º º - º: º - º - -- - - º: º: --- - - --- º: º - - ºffl - ------------- ############### sº -- ºffl ºffl ºffl --- ºffl - - # ºffli ºffl º - - - º - - º --- º - - - ºffl --- # # # - --- --- --- - - # - ºffl - ------ - - ºffl - º ºfflº - - - =ºffli = - --~~~~ --~~~~ T - TEMPOROMANDIBULAR DISORDERS AND OROFACIAL PAIN: SEPARATING CONTROVERSY FROM CONSENSUS This volume includes the proceedings of the Thirty-Fifth Annual Moyers Symposium March 1–2, 2008 Ann Arbor, Michigan Editors James A. McNamara, Jr. Sunil D. Kapila Associate Editor Kristin Y. Van Riper Volume 46 Craniofacial Growth Series Department of Orthodontics and Pediatric Dentistry School of Dentistry; and Center for Human Growth and Development The University of Michigan Ann Arbor, Michigan ©2009 by the Department of Orthodontics and Pediatric Dentistry, School of Dentistry and Center for Human Growth and Development The University of Michigan, Ann Arbor, MI 48109 Publisher’s Cataloguing in Publication Data Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development Craniofacial Growth Series Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus Volume 46 ISSN 0.162 7279 ISBN 0-929921-00-3 ISBN 0-929921–42-9 No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the Editor-in- Chief of the Craniofacial Growth Series or designate. CONTRIBUTORS STEVE ABRAMSON, Division of Rheumatology, NYU Hospital for Joint Diseases, New York, NY. LARS ARENDT-NIELSEN, Professor, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark. MUKUNDAN ATTUR, Division of Rheumatology, NYU Hospital for Joint Diseases, New York, NY. TIZIANO BACCETTI, Associate Professor, Department of Orthodontics, University of Florence, Florence, Italy; Thomas M. Graber Visiting Scholar, Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI. BRIAN E. CAIRNS, Associate Professor, Canada Research Chair in Neuropharmacology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. CHARLES R. CARLSON, Professor of Psychology and Dentistry, University of Kentucky, Lexington, KY. DANIEL S. CASSANO, Fellow, Department of Oral and Maxillofacial Surgery, Texas A&M University Health Science Center Baylor College of Dentistry and Baylor University Medical Center, Dallas, TX. EDUARDO E. CASTRILLON, Research Assistant Professor, Orofacial Pain Laboratory, Center for Sensory–Motor Interaction, Aalborg University, Aalborg, Denmark; Clinical Teacher, Department of Clinical Oral Physiology, School of Dentistry, University of Aarhus, Aarhus, Denmark. LUCIA H. CEVIDANES, Assistant Professor, Department of Orthodontics, School of Dentistry, University of North Carolina, Chapel Hill, NC. JING CHEN, Department of Craniofacial Sciences, Division of Orthodontics, University of Connecticut Health Center, School of Dental Medicine, Farmington, CT. R. SCOTT CONLEY, Clinical Associate Professor, University of Michigan School of Dentistry, Department of Orthodontics and Pediatric Dentistry, Ann Arbor, MI. MARINA D’ANGELO, Center for Chronic Disorders of Aging, Philadelphia College of Osteopathic Medicine, Philadelphia, PA. MALIN ERNBERG, Associate Professor, Department of Clinical Oral Physiology, Institute of Odontology, Kariolinska Institutet, Stockholm, Sweden. JOAO FERREIRA, Department of Orthodontics, Applied and Materials Sciences Program, University of North Carolina, Chapel Hill, NC; School of Dentistry, University of North Carolina, Chapel Hill, NC. DEBRA F. FINK, private practice, St. Louis, MO. JAMES FRICTON, Professor, Department of Diagnostic and Surgical Services, School of Dentistry, University of Minnesota, Minneapolis, MN. LUIGI M. GALLO, Clinic for Masticatory Disorders and Complete Dentures, Center for Oral Medicine, Dental and Maxillo-facial Surgery, University of Zurich, Zürich, Switzerland. JOAO ROBERTO GONCALVES, Assistant Professor of Orthodontics, Pediatric Dentistry Department, Araraquara Dental School, Sao Paulo State University, Araraquara, SP, Brazil; Former Fellow, Department of Oral and Maxillofacial Surgery, Texas A&M University Health Science Center Baylor College of Dentistry and Baylor University Medical Center, Dallas, TX. TINA GUPTA, Department of Craniofacial Sciences, Division of Orthodontics, University of Connecticut Health Center, School of Dental Medicine, Farmington, CT. ANNA-KARI HAJATI, Department of Clinical Oral Physiology, Institute of Odontology, Karolinska Institutet, Huddinge, Sweden. HIROSHI INOUE, Department of Removeable Prosthodontics, Osaka Dental University, Osaka, Japan. LAURA R. IWASAKI, Associate Professor and Chair, Division of Orthodontics and Dentofacial Orthopedics, Department of Oral Biology School of Dentistry, University of Missouri-Kansas City, Kansas City, MO. SHANTI KAIMAL, School of Dentistry, University of Minnesota, Minneapolis, MN. ZANA KALAJZIC, Department of Craniofacial Sciences, Division of Orthodontics, University of Connecticut Health Center, School of Dental Medicine, Farmington, CT. SUNIL D. KAPILA, Professor and Chair, Department of Orthodontics and Pediatric Dentistry, School of Dentistry, The University of Michigan, Ann Arbor, MI. MICHELLE KINNEY, private practice, St. Louis, MO. CHING-CHANG KO, Associate Professor, Department of Orthodontics, Applied and Materials Sciences Program, University of North Carolina, Chapel Hill, NC; School of Dentistry, University of North Carolina, Chapel Hill, NC. LINDA LERESCHE, Professor, Department of Oral Medicine, University of Washington, Seattle, WA. PEI FENG LIM, Assistant Professor, Department of Diagnostic Sciences, School of Dentistry, University of North Carolina, Chapel Hill, NC. JOHN LOOK, School of Dentistry, University of Minnesota, Minneapolis, MN. TERUTA MAEDA, Department of Removeable Prosthodontics, Osaka Dental University, Osaka, Japan. DAVID B. MARX, Department of Statistics, University of Nebraska, Lincoln, NE. LAURIE K. McCAULEY, Chair, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI. MARY KATE McDONNELL, Assistant Professor, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO. CHARLES McNEILL, Professor Emeritus and Director, Center for Orofacial Pain, University of California, San Francisco, CA. SANDRA MYERS, School of Dentistry, University of Minnesota, Minneapolis, MN. JEFFREY C. NICKEL, Associate Professor, Departments of Orthodontics & Dentofacial Orthopedics and Oral Biology School of Dentistry, University of Missouri-Kansas City, Kansas City, MO. CHAD M. NOVINCE, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI. GIOVANNI OBERTI, Assistant Professor, Department of Orthodontics, CES University, Medellin, Colombia. JEFFREY P. OKESON, Chair, Department of Oral Health Science; Director, Orofacial Pain Program, University of Kentucky College of Dentistry, Lexington, KY. SANDRO PALLA, Clinic for Masticatory Disorders and Complete Dentures, Center for Oral Medicine, Dental and Maxillo-facial Surgery, University of Zurich, Zürich, Switzerland. GLYN PALMER, Division of Rheumatology, NYU Hospital for Joint Diseases, New York, NY. HANS PANCHERZ, Professor Emeritus, Department of Orthodontics, University of Giessen, Giessen, Germany. DIEGO REY, Professor, Department of Orthodontics, CES University, Medellin, Colombia. NELSON RHODUS, School of Dentistry, University of Minnesota, Minneapolis, MN. PATRICIA A. RUDD, Assistant Clinical Professor, Center for Orofacial Pain, University of California, San Francisco, CA. SHIRLEY SAHRMANN, Professor, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO. ERIC SCHIFFMAN, Associate Professor, Department of Diagnostic and Biologic Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN. BARRY J. SESSLE, Professor and Canada Research Chair, Faculty of Dentistry, The University of Toronto, Toronto, Ontario, Canada. JENNIFER SPRINGSTEEN, School of Dentistry, University of Minnesota, Minneapolis, MN. CHRISTIAN S. STOHLER, Dean, Dental School, University of Maryland, Baltimore, MD. MARTIN STYNER, Assistant Professor, Department of Computer Sciences, School of Dentistry, University of North Carolina, Chapel Hill, NC. PETER SVENSSON, Professor and Chairman, Department of Clinical Oral Physiology, School of Dentistry, Aarhus, Denmark; Clinical Consultant, Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, Aarhus, Denmark; Adjunct Professor, Orofacial Pain Laboratory, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark. CRISTINA C. TEIXEIRA, Department of Basic Science & Craniofacial Biology, New York University College of Dentistry, New York, NY. LWIN MON THANT, Department of Basic Science & Craniofacial Biology, New York University College of Dentistry, New York, NY. LORIN TRETTEL, Department of Craniofacial Sciences, Division of Orthodontics, University of Connecticut Health Center, School of Dental Medicine, Farmington, CT. SHINJI UCHIDA, Department of Removeable Prosthodontics, Osaka Dental University, Osaka, Japan (deceased). LINDA VAN DILLEN, Associate Professor, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO. ANA M. VELLY, School of Dentistry, University of Minnesota, Minneapolis, MN. SUNIL WADHWA, Department of Craniofacial Sciences, Division of Orthodontics, University of Connecticut Health Center, School of Dental Medicine, Farmington, CT. DAVID G. WALKER, School of Dentistry, University of North Carolina, Chapel Hill, NC. KELUN WANG, Associate Professor, Orofacial Pain Laboratory, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark. LARRY M. WOLFORD, Clinical Professor, Dept. of Oral and Maxillofacial Surgery, Texas A&M University Health Science Center, Baylor College of Dentistry; Private Practice at Baylor University Medical Center, Dallas, TX. YORITAKA YOTSUI, Department of Oral Maxillofacial Radiology, Osaka Dental University, Osaka, Japan. PREFACE It has been 20 years since the so-called “Michigan case,” in which a clinician was accused of causing temporomandibular joint problems in one of his patients. The resultant judgment of one million dollars against the orthodontist rocked the dental profession, putting to rest the popular belief that “dentists do not get sued.” With the increased emphasis on evidence-based dentistry, much has been learned about the etiology of temporomandibular disorders (TMDs) and orofacial pain since the late 1980s. For the 2008 Moyers Symposium, we have brought together nine well-known experts from various disciplines to address what is known and what is not concerning contemporary management of temporomandibular and other orofacial pain conditions. An in-depth discussion of TMD and orofacial pain as well as their clinical management was addressed during the 35" Annual Moyers Symposium, which was held in Rackham Auditorium on The University of Michigan campus on Saturday, March 1 and Sunday, March 2, 2008. As in previous years, the Symposium honored the late Dr. Robert E. Moyers, Professor Emeritus of Dentistry and Fellow Emeritus and Founding Director of the Center for Human Growth and Development. The meeting was co-sponsored by the School of Dentistry and the Center for Human Growth and Development. In addition, the 34" International Annual Conference on Cranio- facial Research (the so-called “Presymposium”) was held on the Friday before the Symposium (February 29) in the Ballroom of the Michigan League. The Presymposium Conference featured papers relevant to Orthodontics and craniofacial biology that were presented by an international group of investigators. The majority of presentations focused on TMD and orofacial pain; these topic-related papers are included within this volume as well, making Volume 46 of the Craniofacial Growth Monograph Series one of the largest ever. We are fortunate to have a skilled individual who has worked tirelessly in putting together this volume. Kris Van Riper has assumed the role of Associate Editor of the Craniofacial Growth Series this year, facilitating the publication of this book through editing, manipulating a Variety of figure formats, interacting with the authors and formatting the entire layout. We thank Kris for working so hard in producing this Volume in a timely manner. We also thank Lauren Sigler, our research assistant and future dental student, for thoroughly checking the references and also for her work on improving some of the submitted figures. Further, we thank Dr. Sunil Kapila, who as Chair of the Department of Orthodontics and Pediatric Dentistry has provided the financial resources to underwrite partially the publication of this book. We also must recognize Dr. Dan Keating from the Center for Human Growth and Development for his continued financial and moral support of the Moyers Symposium. We thank Debbie Montague, Michelle Jones, and Karel Barton from the Office of Continuing Dental Education for organizing and running the Presymposium and Symposium in such an efficient fashion. Their year-to-year support is appreciated greatly. It is wonderful to interact with the same crew year after year. Finally, we thank the participants of the Symposium and Presymposium and those that buy the volumes of the Craniofacial Growth Series, without whose support none of this would exist. All Volumes still in print are available online (www.needhampress.com) or by phone (734.668.6666). James A. McNamara DDS MS PhD Ann Arbor, Michigan November 2008 FRIENDS OF THE SYMPOSIUM Edward Bayleran Chester S. Handelman Thomas A. Herberger James Isaacson New Conn Orthodontic Foundation John O. Nord William Patchak Michael W. Paulus William D. Paulus Terry Tippin Howard L. Tingling Philip Williamson TABLE OF CONTENTS Contributors Preface Friends of the Symposium Temporomandibular Joint Diseases and Disorders: The Future is Now Christian Stohler Orthodontic Therapy and Temporomandibular Disorders: Should the Orthodontist Even Care? Jeffrey P. Okeson Management of Jaw Disorders (TMD) Charles McNeill and Patricia A. Rudd Psychological Factors in TMD and Orofacial Pain Charles R. Carlson Gender and Hormonal Effects on Clinical TMJD Pain Linda LeResche CBCT (3D Imaging): Application for Selected Articular Disorders and Associated Facial Growth David Hatcher Condylar Resorption in Patients with TMD Lucia H. Cevidanes, David G. Walker, Martin Styner, Pei Feng Lim Common TMJ Disorders: Orthodontic and Surgical Management Larry M. Wolford, Daniel S. Cassano, João Roberto Goncalves The Modified Condylotomy for TMJD Patients: A Good Solution or Just Another Surgery? R. Scott Conley Temporomandibular Joint Adaptations in Adolescents and Adults Treated with the Herbst Appliance Hans Pancherz 15 31 91 107 125 147 159 199 217 An Appraisal of Temporomandibular Disorders in Class III Patients Treated with Mandibular Cervical Headgear and Fixed Appliances Diego Rey, Giovanni Oberti, Tiziano Baccetti Temporomandibular Muscle and Joint Disorders: Progress in Research with NIDCR’s TMJ Implant Registry and Repository Ana M. Velly, John Look, Sandra Myers, Ching- Chang Ko, Shanti Kaimal, João Ferreira, Jennifer Springsteen, Eric Schiffman, Nelson Rhodus, James Fricton Current and Future Innovations in Diagnostics and Therapeutics of TMJ Diseases * Sunil D. Kapila Developing Future Bioceramics for Temporomandibular Joint Tissue Engineering Ching-Chang Ko, João Ferreira, Sandra Myers F-spondin: A New Regulator of Cartilage Maturation in Development and Osteoarthritis Marina D'Angelo, Lwin Mon Thant, Glyn Palmer, Mukundan Attur, Steve Abramson, Cristina C. Teixeira Early Signs of Bone Tissue Resorption in the TMJ of Patients with Recent Diagnosis of Rheumatoid Arthritis Ana-Kari Hajati Peripheral NMDA Receptors and TMD Pain Mechanisms Eduardo E. Castrillon, Brian E. Cairns, Malin Ernberg, Kelun Wang, Barry J. Sessle, Lars Arendt- Nielsen, Peter Svensson Ipsilateral and Contralateral Human TMJ Loads Compared via Validated Numerical Models Laura R. Iwasaki, Shinji Uchida, David B. Marx, Yoritaka Yotsui, Teruta Maeda, Hiroshi Inoue, Jeffrey C. Nickel 255 265 283 3.11 353 367 383 405 Tractional Forces, Work and Energy Densities in the Human TMJ Jeffrey C. Nickel, Laura R. Iwasaki, Luigi M. Gallo, Sandro Palla, David B. Marx Altered Temporomandibular Joint Loading Jing Chen, Lorin Trettel, Zana Kalajzic, Tina Gupta, Sunil Wadhwa A Movement System Impairment Treatment of TMD Debra F. Fink, Mary Kate McDonnell, Michelle Kinney, Shirley Sahrmann, Linda Van Dillen Toward a Better Understanding of Bisphosphonates and Their Potential for Impacting Orthodontic Therapy Chad M. Novince and Laurie K. McCauley 427 451 465 475 TEMPOROMANDIBULAR JOINT DISEASES AND DISORDERS: THE FUTURE IS NOW Christian S. Stohler ABSTRACT The field of temporomandibular joint diseases and disorders (TMJDs) has reached a juncture where the prevailing models of causation will fall by the wayside rapidly, making room for exciting new understanding that promises critical advances for the care of patients. This chapter introduces the reader to the future possibilities for treatment of TMJDs. It examines what is known and what should be established science by now if our conceptual framework is cor- rect, placing emphasis on the bigger picture and the road ahead. Contemporary science calls for an entirely new way to view the field of temporomandibular diseases and disorders (TMJDs). Most nota- bly, it is the introduction of the working draft of the human genome that forces scientists, clinicians and patients to study, treat and experience disease in a completely new theoretical framework. DNA sequence variations affect the gene product and, in turn, may have functional relevance with respect to disease. From this per- Spective, genetics and genomics have emerged as the conceptual frontier by which to advance the understanding and care of all 12,000 diseases that affect the human race. The idea that an error in the DNA predicts our fate, including the risk to suffer from TMJDs, has become common knowledge. Not surprisingly, the first wave of systematic genetic studies of TMJDS and their related pain conditions already has appeared in the literature. Inspired by the prevailing trends in science at-large, the field of TMJD has reached a juncture where traditional, mostly unicausal models of TMJD causation will fall rapidly by the wayside, making room for exciting new paradigms that promise much needed advances in the care of patients. Although this newly found enthusiasm is boundless, road- blocks remain. The purpose of this chapter is to introduce the reader to the future possibilities of TMJD treatment, i.e., to examine what is The Future is NOW known and what should be established science by now if our conceptual framework is correct, placing emphasis on the bigger picture and the road ahead. A TAXONOMICALLY UNTENABLE SITUATION From a diagnostic point of view, TMJDs are anything but clear- cut, with the traditional subsets – muscle, joint or disk – overlapping in terms of symptoms and many of their clinical features. Although disci- plinary entitlements, professional stakeouts, scope of practice and pre- Vailing diagnostic taxonomies force these musculoskeletal orofacial pain conditions into a narrowly defined topographic domain, these conditions often are not limited to a single anatomical region (e.g., the face). Neither is the case assignment to a particular TMJD subset stable over the course of the TMJD disease. In fact, painful involvement of comorbid features outside the topographical domain of the masticatory apparatus is com- mon and occurs with greater frequency and severity among those patients for whom therapeutic intervention leaves much to be desired (Dworkin et al., 1990; Huggins et al., 1997; Türp et al., 1998a). In addition, poorly defined symptoms that suggest dysregulation of autonomic, endocrine, antinociceptive and immune systems are not depicted as critical, taxonomic features of TMJD disease. This observa- tion raises further concern that the existing narrowly casted scope of as- sessment and management of TMJD cases, centering on the orofacial complex, may be detrimental to those affected. Of further concern is the current state of case definition that is based solely on historically relevant clinical features with no reference to the underlying pathogenetic, often systemic, mechanisms in effect. TMJD causation, which appeared to be clearly understood until about 15 years ago, is now under much needed investigation. With generations of practitioners having been taught a cer- tain way, however, a false sense of security about the validity and use- fulness of current diagnostic systems seems to be counteracting the much needed refreshment of the discipline in terms of its scientific foundation and the resultant clinical protocols. DOES THE TYPE OF TREATMENT REALLY MATTER.? Between 75-95% of patients seeking care for the first time re- ceive treatment benefits, even lasting resolution of their pain condition, from a range of different treatments that are founded on a host of widely different explanations for their respective modes of action. This observa- Stohler tion is in stark contrast to that of patients encountered in academic healthcare centers who are desperate to obtain relief or, at best, receive comfort – again, from a wide range of treatment management modalities (Türp et al., 1998b). Although providers have their preferred modes of treatment and often justify and defend their favorite approaches in emo- tionally charged terms, no significant and consistent response differences have been established (from study to study) between various treatment modalities for close to two decades. In fact, it appears that the patient’s preference for a specific mode of treatment often plays a more important role in: 1. Choosing a practitioner; and in 2. The outcome of the preferred modality of treatment. The absence of data to the contrary speaks volumes and no longer can be ignored. These observations beg for an explanation, as the type of treat- ment seems to be of less importance than the patient’s preferences and expectations of receiving a beneficial outcome from a specific mode of treatment. For example, does a patient who is desperate to find relief and who believes that such relief will be obtained from treatment with an occlusal appliance find greater benefit from this type of intervention than from an alternative form of treatment that the patient believes is ques- tionable? What distinguishes the various treatment modalities in terms of efficacy in a research context, if anything? Are these treatments nothing but just credible or non-credible placebos with the only difference being that a favorable placebo response is boosted in biologically stressed pa- tients by: 1. Their firm expectations and strong beliefs regarding the expected outcome; and 2. The comfort provided by a specialized clinical setting within which the practitioner is confident and exqui- sitely trained and equipped to administer a most credible product? It is not surprising that properly designed and executed clinical trials demonstrate little or no difference among diverse types of credible interventions, even between those situations with and those without the presumably active ingredient that the administered placebo is believable. The absence of significant and consistent (from study to study) response differences between diverse modalities of treatment in experimental con- texts – treatments harvesting presumably very different modes of action The Future is Now – raises concern about the validity of the widely cited underlying theories in support of these therapies. Such therapies include: 1. Repositioning the articular condyle in glenoid fossa to achieve condylar concentricity; 2. Repositioning anteriorly displaced disks to normalize the function of the condyle-disk complex; 3. Adjusting the dental occlusion to eliminate the man- dibular slide from centric relation contact to centric occlusion; 4. Increasing the vertical dimension of the dental occlu- sion to harmonize the masticatory force distribution; and 5. Stabilizing splints to eliminate harmful tooth contact and/or bruxism. * The fact that these treatments produce similar benefits – although at sub- stantially varying risks – is now a topic of discussion for patient advo- cacy groups. These treatments all work as long as patients expect to benefit from them. Why are we dismissing out of hand the possible im- pact of spirituality, prayer, empathy and love and their associated bio- logical processes in the human brain, that are linked to better health out- comes in over 130 trials? While the prevailing thinking assumes that the difference be- tween a primary and tertiary care patient lies solely in the fact that the tertiary care patient was “unlucky to get the right treatment” the very first time, alternative explanations should not be dismissed. Do patients that climb the health care ladder from the first encounter in the primary care setting into the tertiary care environment exhibit an endophenotype that determines their fate irrespective of the type and manner by which the first treatment was rendered? If so, what are these endophenotypes? Are these patients biologically deficient in that they are unable to harvest the brain’s placebo machinery – nocebo responders? Rather than being obsessed with the controversy regarding the importance of “my” treatment, the scientific and practicing community should examine new explanatory models of causation that offer better concurrence between epidemiological data, clinical reality and theoreti- cal predictions than current constructs permit today. When will we ac- knowledge that we have enough trials showing the absence of a differ- ence? Any useful model of TMJDs has to be founded on biologically plausible, established or hypothesized mechanisms that explain the Stohler demographics of those affected, including the differences in treatment response observed among patients in the primary and tertiary care set- tings. In the mindset of the Genomic Age, the question that should be asked is “do these patients present with unique constellations of gene variants, risk-conferring behaviors and environmental factors that deter- mine their fate?” Advanced biotechnologies inspire the chase for Vulner- ability genes with exciting prospects for TMJD Science and treatment, paving the way from “my” one-fits-all management regimens to predic- tions and treatments based on molecular fingerprinting. BEING AWOMAN OF CHILD-BEARING AGE There are well-known risk factors for TMJDs, notably age and gender that apply to a majority of patients. Both biological characteristics and differences in social and life expectations influence their role in the TMJD symptomatology. The ratio of female patients increases from 1.1- 1.4 to 1 in community-based and primary care environments to 9:1 in tertiary care centers, the setting in which the forms of TMJDs most tax- ing to patients are encountered. Sex and gender are established modifiers in all matters of functioning in pain in general, not just discomfort asso- ciated with TMJDs (Greenspan et al., 2007). Although not widely ac- knowledged, brain regions that exhibit the greatest differences in func- tion between the sexes coincide with those involved in processing pain. Besides being almost exclusively female, tertiary care patients exhibit a greater likelihood of disease involvement outside of the orofa- cial domain; only about 15% of these patients’ complaints regarding pain are restricted to the face (Türp et al., 1998b). Beyond the high level of comorbidity with other pain conditions, TMJDs also are linked statisti- cally to other Somatic and/or mood changes, notably depressive preoccu- pation. Depressive preoccupation is a condition that shows a striking similarity in prevalence with respect to gender and onset to TMJDs (LeResche et al., 2005, 2007). With regard to age, the overwhelming majority of TMJD cases for both men and women are associated with the reproductive ages, with increases in case numbers occurring in the later part of puberty tempo- rally linked to gonadal maturation. However, TMJDs does occur in the aged and elderly, but at much lower prevalence rates (Hiltunen et al., 1995). Similar case distribution patterns with respect to age and gender also are found in other pain conditions (Unruh, 1996). The Future is NOW Overall, case demographics suggest that the mechanisms under- lying the majority of TMJD cases are not associated with degenerative processes or dental/occlusal conditions that would have to show an in- crease in case frequency with age as the risk must be considered as being cumulative. Because gender and age represent the strongest predictors of the worst-case scenario of persistent pain and dysfunction, support for the once popular, unicausal models of the causation of TMJDs (e.g., oc- clusal features, condyle-fossa relationship) is fading rapidly. Instead, the mechanisms responsible for the generation of TMJD signs and symp- toms, notably pain and allodynia (i.e., pain from stimuli that are not nor- mally painful), appear to be enhanced by the female endophenotype en- countered during the reproductive years. In this respect, hormonal mi- lieus interacting with vulnerable genotypes are and increasingly will be subject to examination regarding their effects on symptom severity. TAXONOMIC TUNNEL VISION Comorbid conditions, the presence of one or more ailments occurring at the same time as a TMJD condition, manifest themselves in terms of sensory, motor, autonomic and affective symptoms. Regarding comorbid pain conditions, diagnostic labels, such as myofascial pain syndrome, fibromyalgia, irritable bowel syndrome, tension-type head- ache, interstitial cystitis and vulvadynia often are cited. For some of these conditions (e.g., fibromyalgia) the overlap is significant and well documented (Plesh et al., 1996). Taxonomic rigidity, including territorial focus and/or profes- sional stakeouts, has a direct bearing on what becomes classified as being a comorbid condition. With respect to TMJDs, any condition outside of the taxonomic focus automatically becomes a comorbid condition, irre- spective of whether it is artifactual due to our inability to assign a single diagnosis within a rigid disease concept limited by hard boundaries of the assigned disease domain. While some co-occurring conditions may be mutually exclusive, others may become recognized as either genuine or spurious. As the prevailing TMJD construct changes, conditions may become declassified as being comorbid. As gene variants become known to produce signs and/or symptoms in tissues outside of the primary field of taxonomic focus, diagnostic systems with a tight anatomical focus will fall by the wayside due to their inability to acknowledge distant effects that are based on shared pathogenetic mechanisms. Stohler Besides the overlap of TMJDs with other pain conditions, there are many symptoms that are not captured adequately by current TMJD taxonomies such as sleep disturbances, cardiovascular, gastrointestinal and reproductive system complaints, weight loss or weight gain, Swel- ling, numbness, sweating, flushing, and concerns regarding loss of libido, drive, attention and memory. These symptoms seem to occur more fre- quently among patients affected by TMJDs than would be expected due to chance. For some of these symptoms, there are convincing data re- garding their effect on TMJDs. For example, widespread pain represents a risk for the persistence of TMJDs (John et al., 2003). Furthermore, changes in mood such as depressive preoccupation are predictive of poor outcomes (Grossi et al., 2001) or the escalation of TMJDs with respect to severity and impact (Wright et al., 2004). Regrettably, such factors, which are quantitative in nature, con- tinue to have little impact on patient management planning or on the al- location of patients into treatment groups in clinical research trials. Rather than being forced into a strict anatomical domain by imposed ter- ritorial stakeouts (e.g., medical vs. dental), a useful model and sensible taxonomic classification of TMJDs should provide a plausible frame- work for explaining the broad disease patterns in terms of comorbid con- ditions that are believed to impact the course and treatment of TMJDs. SYMPTOMS RE-CONCEPTUALIZED Past thinking explained local symptoms as the result of compensatory strain, misuse, or overwork of the masticatory apparatus due to mechanical factors at the level of the dental occlusion and/or TMJ biomechanics. The consequences of discrepancies from textbook ideals Supposedly forced the jaw system into dysfunction, resulting in the initia- tion and maintenance of pain. Emerging theories, however, make persua- sive arguments in support of alternative, broader explanations. More and different genotypes are being implicated in the ampli- fication of clinical symptoms and the susceptibility of a patient to a spe- cific clinical course of disease and/or treatment response, including the development of complications. Complications might include, for exam- ple, the unfavorable response to an environmental or behavioral stressor, intolerable side effects from the exposures to foreign body materials, or drug toxicity due to metabolic variation. The Future is Now Unique genetic individuality is attributed to either an amplified or attenuated, case-specific system response that is translated into titrated Sensory, motor, affective and/or autonomic body messages known as symptoms. In this broader view of the TMJD phenotype, symptoms en- tail subject-specific information that does not fall within the confines of the historically defined TMJD case attributes (e.g., pain, problems with the ability to move the jaw and joint sounds). Traditional definitions of TMJDs are skewed toward capturing features in support of the comfort- able idea that the cause of TMJDs pain and dysfunction is attributable only to jaw biomechanics, which makes them mechanically correctable. Today, distinct gene variants are assumed to mediate vulnerabil- ity to the development of key attributes of the TMJD phenotype, includ- ing those symptoms and signs that are being looked upon as comorbid features. With gender or sex being the strongest predictor of a bad treat- ment outcome of TMJDs and many of the related, overlapping pain con- ditions, causation cannot be explained by a single biomechanical factor. This leaves little room for a biologically plausible explanation of the greater susceptibility of women to TMJDs in their childbearing ages. Viewing TMJDs as a “black and white” issue – “you have it, or you don’t’” – also is overly simplistic. Rather than being a “yes/no” dis- ease, it comes in many shades of grey. This is an important fact in ad- vancing the understanding of the genetic underpinnings of the TMDs. Most human traits are quantitative in nature. Pain is no exception, even at the level of its sensory, affective and cognitive dimensions. Instead, symptoms are re-conceptualized as the individually titrated, exaggerated response caused by the interplay of the patient’s unique genetic makeup, the impact of risk-conferring behaviors and environmental exposures, and the effect of developmental variations that modulate a subject’s vul- nerability to disease throughout his/her lifespan. With respect to comorbid phenomena, shared genetic influences linked to gene variants, which are expressed in and affect different tis- sues, seem to account for the co-occurring complaints in parts of the body outside the anatomical domain of interest. It must be recognized that the effect of environmental influences and risk conferring behaviors, including their timing, are heavily tissue-specific. Exposure to an envi- ronmental pathogen may be conditional, depending upon a person’s genotype or, alternatively, gene variants can modulate the effect of envi- ronmental exposures. Stohler CRACKING THE DISEASE CODE Increasingly, specific genotypes are reported to augment the Sus- ceptibility to disease, the course of disease and/or treatment response, including the development of complications during treatment. In parallel with the trends in science at-large and consistent with the emerging theme of accepting TMJDs as conditions with a genetic underpinning, research conducted in recent years has produced the first insight into TMJD genetics (Zubieta et al., 2003; Diatchenko et al., 2005, 2006; Zhou et al., 2008). As with most human diseases, TMJDs do not demonstrate the classical Mendelian patterns of inheritance, excluding the possibility of a rare gene exerting a large effect on the clinical TMJD phenotype. On the contrary, the pattern of disease suggests that TMJD genetics is complex with multiple genes contributing in a quantitative fashion to the pheno- typic variance observed clinically and experimentally. When examining the genetic code, most of the genetic variations among humans occur in non-coding regions and produce no phenotypic consequences. However, genetic variations that occur in coding regions can produce consequences ranging from immeasurable to consequences powerful enough to cause mutations. Assuming a complex, multigenic disease construct, the risk at- tributable to a single gene variant may be small in terms of the predictive power for the disease in question. Through the collective action of many genes (possibly ten or more), however, the combined risk explained by genetic factors may become substantial. As mentioned above, there also exists a need for sex- and age-corrected morbid risks in any experimental design and data analysis. Furthermore, in that suffering from TMJDs is a stressful matter by the very nature of the disease, particularly if nothing Seems to help relieve pain, genetic loci that modulate the body’s stress response systems always are linked. Regarding the discovery of genes important in TMJDs, one ap- proach involves the study of gene candidates suspected to influence the clinical and experimental TMJD phenotype or the corresponding molecu- lar endophenotype. The candidacy of a gene is derived from the under- standing of the: 1. Known function of the gene in question; and/or 2. Underlying disease process believed to regulate the clinical picture for which the respective gene variants The Future is NOW are hypothesized as mediating either vulnerability or resiliency. Linkage analyses, a second method used in gene discovery, tra- ditionally have employed a categorical, “yes/no” approach to case as- signment, using somewhat arbitrary cutoff points as implemented by cur- rent TMJD taxonomies. A quantitative rather than a qualitative approach to phenotyping clinic cases, however, increasingly has gained appeal in the study of the genetic underpinning of complex diseases that are im- pacted by gene variants involving many genes. A compelling argument in support of this methodology rests with the fact that symptom severity occurs on a continuum, allowing the identification of so-called quantitative trait loci that explain a statistically significant portion of the variation of the trait/symptom in the population. An appealing advantage of this method is the fact that a quantitative trait association analysis (in contrast to a traditional linkage study) can be car- ried out on a random sample of unrelated subjects (certain caveats apply) using simple linear regression models with the trait/symptom as depend- ent and the genotype as independent variables. With TMJDs being re-conceptualized as complex conditions influenced by genetic susceptibility, environmental factors and risk- conferring behaviors, the challenge not only will be the identification of the gene variants, but also the discovery of the environmental drivers that interactive with a subject’s genotype and contribute to the initiation and maintenance of the disease. Regarding the effect of environmental fac- tors and gene–environment interactions, the research field remains wide open. The absence of established low- and high-risk geographic regions for TMJDs, however, points to the fact that the genetic underpinning must be viewed as important. THE RIDE AHEAD Leveraging the Human Genome project, available 21st century biotechnologies enable fresh new thinking and research directions for the field of TMJDs. Rather than viewing TMJDs as “yes/no” conditions, they seem to be better captured as a collection of quantitative traits, both individually as symptoms and collectively as a symptom complex. Be- cause case attributes outside the face domain are significant phenome- nologically, the biased description of TMJDs with respect to scope and historical case criteria, which endorse old concepts of disease, is no longer tenable. Vulnerability to express TMJD symptoms is linked con- 10 Stohler ceptually to unique gene variants and the effect of risk-conferring behav- iors and environmental factors. This new conceptual framework for TMJDs, aligned with the trends in science at-large, permits the harvest- ing of modern biotechnologies to advance the understanding and care of those affected. It is disturbing that the clinical research of the past 15 years has been unable to establish a meaningful utility for any of the current TMJD taxonomies with respect to assigning cases to subsets for which a spe- cific form of treatment yields a better outcome over all other types of interventions and produces benefits large enough to be clinically impor- tant and consistent from study to study. Given the wide range of pre- sumed modes of action of all treatments rendered to TMJD patients (there are too many), we can no longer dismiss the following questions. Do available treatment modalities differ only: 1. With respect to their perceived credibility in the mind of the patient and the biological processes initiated by his/her expectation of benefit; and/or 2. Relative to the practitioner’s ability to offer a believ- able placebo and what it does in terms of changing the brain’s potential for a treatment to become bene- ficial? For those unable to harvest the brain’s machinery to produce a favorable treatment response (also referred to as the nocebo responders), Science needs to establish the individually applicable mechanisms, which includes the genetic underpinning that prohibits such favorable responses in the first place. Last, but not least, we need to determine why it all hap- pens in the face and why both the occurrence and severity of TMJD is greater in women. REFERENCES Diatohenko L, Anderson AD, Slade GD, Fillingim RB, Shabalina SA, Higgins TJ, Sama S, Belfer I, Goldman D, Max MB, Weir BS, Maixner W. Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for devel- opment of a common musculoskeletal pain disorder. Am J Med Ge- net B Neuropsychiatr Genet 2006;141B:449-462. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov 11 The Future is Now SS, Maixner W. Genetic basis for individual variations in pain per- ception and the development of a chronic pain condition. Hum Mol Gen 2005; 14:135-143. Dworkin SF, Von Korff M, LeResche L. Multiple pains and psychiatric disturbance: An epidemiologic investigation. Arch Gen Psychiatry 1990:47:239-244. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ; Consensus Working Group of the Sex, Gender and Pain SIG of the IASP. Studying sex and gender dif- ferences in pain and analgesia: A consensus report. Pain 2007; 132 S1:26-45. Grossi ML, Goldberg MB, Locker D, Tenenbaum HC. Reduced neuro- psychologic measures as predictors of treatment outcome in patients with temporomandibular disorders. J Orofac Pain 2001; 15:329-339. Hiltunen K, Schmidt-Kaunisaho K, Nevalainen J, Närhi T, Ainamo A. Prevalence of signs of temporomandibular disorders among elderly inhabitants of Helsinki, Finland. Acta Odontol Scand 1995:53:20–23. Huggins KH, Dworkin SF, Saunders K, Von Korff M, Barlow W. Five- year course for temporomandibular disorders using RDC/TMD. J Dent Res 1997;75(Special Issue):352. John MT, Miglioretti DL, LeResche L, Von Korff M, Critchlow CW. Widespread pain as a risk factor for dysfunctional temporomandibu- lar disorder pain. Pain 2003;102:257-263. LeResche L, MancllA, Drangsholt MT, Huang G, Von Korff M. Pre- dictors of onset of facial pain and temporomandibular disorders in early adolescence. Pain 2007;129:269-278. LeResche L, Mancl LA, Drangsholt MT, Saunders K, Korff MV. Rela- tionship of pain and symptoms to pubertal development in adoles- cents. Pain 2005; 118:201-209. Plesh O, Wolfe F, Lane N. The relationship between fibromyalgia and temporomandibular disorders: Prevalence and symptom severity. J Rheumatol 1996:23:1948–1952. Türp JC, Kowalski CJ, O'Leary TJ, Stohler CS. Pain maps from facial pain patients indicate a broad pain geography. J Dent Res 1998a;77: 1465–1472. 12 Stohler Türp JC, Kowalski CJ, Stohler CS. Treatment-seeking patterns of facial pain patients: Many possibilities, limited satisfaction. J Orofac Pain 1998b;12:61-66. Unruh AM. Gender variations in clinical pain experience. Pain 1996;65:123-167. Wright AR, Gatchel RJ, Wildenstein L, Riggs R, Buschang P, Ellis E III. Biopsychosocial differences between high-risk and low-risk patients with acute TMD-related pain. JAm Dent Assoc 2004; 135:474-483. Zhou Z, Zhu G, Hariri AR, Enoch MA, Scott D, Sinha R, Virkkunen M, Mash DC, Lipsky RH, Hu XZ, Hodgkinson CA, Xu K, Buzas B, Yuan Q, Shen PH, Ferrell RE, Manuck SB, Brown SM, Hauger RL, Stohler CS, Zubieta JK, Goldman D. Genetic variation in human NPY expression affects stress response and emotion. Nature 2008; 452:997-1001. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003:299:1240–1243. 13 ORTHODONTIC THERAPY AND TEMPOROMANDIBULAR DISORDERS: SHOULD THE ORTHODONTIST EVEN CARE” Jeffrey P. Okeson ABSTRACT It has been over 20 years since the “Michigan Case” suggested that Orthodontic therapy was a risk factor for the development of a temporomandibular disorder (TMD). This chapter explores the relationships between orthodontic therapy, occlusion and TMDs. The available scientific literature is reviewed and concepts of how occlusion may affect TMD are presented. Although scientific studies do not strongly link orthodontic therapy with the development or prevention of TMD, it is difficult to imagine a specialty that routinely and significantly changes a patient’s occlusal condition would not have a powerful affect on the masticatory structures and their functions. Orthodontists need to establish their treatment goals by considering both the occlusal position and the stable joint position. This chapter emphasizes the importance of establishing orthopedic stability in the masticatory through orthodontic therapy. These goals are impor- tant for maintaining a healthy masticatory system for a lifetime. The term “temporomandibular disorder” (TMD) stirs up much interest and debate in the profession of dentistry and it has for many years. By definition, TMD is a collective term embracing a number of clinical problems that involve the masticatory musculature, the TMJ and associated structures, or both (Okeson, 1996). Therefore, TMDs are musculoskeletal pain disorders of the masticatory system. Dentistry has become interested in these disorders because the occlusion of the teeth can influence masticatory function greatly. Over the years, there has been much professional debate regarding how the dental occlusion influences jaw function and ultimately how this relationship may lead to TMD. Many dentists feel that the occlusion of the teeth is the primary etiology of TMD symptoms, while others feel it has little effect. This debate remains an important discussion in that dentists are the only healthcare providers who alter the occlusion. Therefore, if occlusion does 15 Orthodontic Therapy and TMJD play a significant role in the etiology of TMD, the dentist can and should play an important role in the management of these disorders. On the other hand, if occlusion plays no role in TMD, than any attempt by the dentist to alter the occlusal condition is misdirected and should be avoided. It is obvious that this question is very important to the dental profession. So where does the orthodontist fit into the debate? The Orthodon- tist, like any dentist, is brought in to the debate any time she or he changes the patient’s occlusion. It is obvious that most, if not all, ortho- dontic therapies alter the patient’s occlusion. In fact, from a prosthodon- tic viewpoint, the orthodontist performs a full mouth reconstruction in the natural dentition for every patient. Therefore, it is obvious that the orthodontist needs to be interested in this debate. Orthodontists’ interest in this debate was emphasized further in 1987 when a young patient sued an orthodontist for causing her TMD. The jury found in her favor for an original judgment of over one million dollars. This case caught the orthodontists’ attention and brought the specialty soundly into the debate. The question that needs to be answered is whether the scientific data support such a decision. This chapter will attempt to review the science and opinions that prevail at this time. STUDIES INVESTIGATING ORTHODONTIC THERAPY AND TMD After the “Michigan Case,” orthodontists became interested in documenting the relationship between orthodontic therapy and TMD. In fact, three significant studies (Larsson and Ronnerman, 1981; Sadowsky and Polson, 1984; Sadowsky et al., 1988) already had been published but seemed to be ignored in the courtroom. Since these studies, seven more studies (Dahl et al., 1988; Smith and Freer, 1989; Hirata et al., 1992; Kremenak et al., 1992b; Rendell et al., 1992; Wadhwa et al., 1993; Hen- rikson and Nilner, 2000) have attempted to investigate this relationship. These studies are highlighted in Table 1 and suggest that subjects who received orthodontic therapy have no greater incidence of developing TMD than a group of control subjects who never received orthodontic therapy. There were some in the dental community who felt that the ex- traction of premolars produced risk factors that would lead to increased TMD. Five studies (Janson and Hasund, 1981; Sadowsky et al., 1991; 16 Okeson Table 1. TMD signs and symptoms: post-ortho vs. controls. AUTHORS # PAT | # CONTROLS YEARS RESULTS Sadowsky & BeGole, 1980 75 75 10 No significant differences Sadowsky & Polson, 1984 96 103 10 No significant differences Larsson & Ronnerman, 1981 23 HI 10 No significant differences Dahl et al., 1988 51 47 5 No significant differences (-pat) Smith & Freer, 1989 87 28 4 No significant differences (+pat) Rendell et al., 1992 462 HI 1.5 No significant differences Hirata et al., 1992 102 41 2 No significant differences Kremenak et al., 1992 109 HI 1-6 No significant differences Wadhwa et al., 1993 31 71 4 No significant differences Henrikson et al., 2000 65 60 , 2 No significant differences Dibbets and van der Weele, 1992; Kremenak et al., 1992a; Luppan- apornlarp and Johnston, 1993) investigated this concept; they are high- lighted in Table 2. The data do not imply that the extraction of premolars is a significant contributor to TMD. Another argument that has been made is that the extraction of the premolars leads to a posterior displacement of the condyles in the fossa. This has been investigated in five studies (Gianelly et al., 1989; Artun et al., 1992; Luecke and Johnston, 1992; O’Reilly et al., 1993; Beattie et al., 1994) listed in Table 3. Although some differences were reported, there was no strong evidence that the condyles assume a more posterior position in the fossa following premolar extractions and orthodontic therapy. In fact, one study found the condyles positioned more anteriorly after the completion of orthodontic therapy. Table 2. Extraction vs. non-extraction and various TMD symptoms. AUTHORS # EX PAT | # NON-EX | YEARS RESULTS Janson & Hasund, 1981 30 30 5 No significant differences Sadowsky et al., 1991 87 68 3 No significant differences Luppanapornlarp, 1993 33 29 15 No significant differences Kremenak et al., 1992 39 26 1-2 No significant differences Dibbets et al., 1992 73 38 20 No significant differences Table 3. Extraction vs. non-extraction and posterior displacement of the condyle. AUTHORS # EX PAT | # NON-EX RESULTS Gianelly et al., 1988 30 37 No significant differences Luecke et al., 1992 42 tº º 70% more forward after tx Beattie et al., 1994 33 30 No significant differences Mixed: right middle & lateral Annaa, 1992 29 34 All other areas, no significant differences O'Reilly et al., 1993 60 60 No significant differences 17 Orthodontic Therapy and TMJD These reported studies do not suggest that orthodontic therapy is a significant risk factor for the development of TMD. Although this ob- servation has been a positive finding for many orthodontists, a reverse statement also must be recognized. Orthodontic therapy does not seem to reduce the risk of TMD. Therefore, orthodontists who tell their patients that orthodontic therapy is needed to prevent TMD have no data to sup- port their claim. INTERPRETING THE DATA Most orthodontists who review these studies breathe a sigh of re- lief. Certainly the outcome of the “Michigan Case” was not based on sci- entific evidence. Perhaps, however, we need to reconsider the interpreta- tion of the results. The concept that orthodontic therapy has nothing to do with TMD is like stating that moving the teeth anywhere will not influ- ence how the patient functions. Certainly that is not the case in prostho- dontics. Perhaps some additional factors need to be considered. For ex- ample, all these studies investigated populations in which very controlled orthodontic therapy had been performed (most in teaching environ- ments). Can poorly completed orthodontics be a greater risk factor? If orthodontic therapy is carried out with no consideration for joint func- tion, will this increase TMD risk factors? Clinical sense says yes but studies have not investigated this variable. Most prosthodontists would be greatly concerned with developing a permanent occlusal position with no regard to joint position. It may be that the orthodontist has a significant advantage over the prosthodontist. Prosthodontists normally are rebuilding the mouths of mature adults who already have developed TMJ anatomy and function. Orthodontists often are working in an environment in which the struc- tures of the TMJs are not matured fully. In many instances, the orthodon- tist completes treatment before full maturation of the condyles and fossa has occurred and therefore takes advantage of nature’s adaptability. The concept that “form follows function” is evident in the growing young adult and may contribute to the success of orthodontic therapy and the low risk factors of developing TMD. Another consideration in interpreting the data is that the relation- ship between TMD and orthodontics is based on the fact that orthodontic therapy changes the patient’s occlusion; occlusal factors, however, may not be a major contributor to TMD. If the relationship between occlusion and TMD is strong, the influence of orthodontics may be strong. If this 18 Okeson relationship is weak, orthodontics may play very little role in either con- tributing or preventing TMD symptoms. Therefore a sound appreciation of the etiology of TMD is needed to understanding the orthodontist role in TMD. THE ETIOLOGY OF TMD It is critical for the dentist attempting to manage a TMD patient to appreciate the major etiologic factors that may be associated with the condition. Such knowledge is essential for selecting proper and effective therapy. A review of the scientific literature reveals at least five major factors that may be associated with TMD. These factors are the occlusal condition, trauma, emotional stress, deep pain input, and parafunctional activity (Fig. 1). The importance of any of these factors may vary greatly from patient to patient. Since this chapter is discussing only the role of occlusion, the other factors will not be elaborated. During this discus- Sion, however, the reader should be aware that the most important etiol- Ogy may not be the occlusal condition. Assuming occlusion to be the ma- jor etiology for every TMD patient is common with dentists because this is our training. Automatically making this assumption, however, can lead to major treatment failures. A full description of how each of these fac- tors may influence TMD can be found in another text (Okeson, 2008a). THE ROLE OF OCCLUSION IN TMD When evaluating the relationship between occlusal factors and TMD, the occlusal condition may need to be considered both statically and dynamically. To date, most occlusal studies only have assessed the Static relationship of the teeth (e.g., the Angle molar classification in the intercuspal position). Some studies do investigate slides from a certain Condylar position to the intercuspal position, while others investigate eccentric tooth contacts. The findings certainly are not impressive re- garding any single factor consistently being associated with a TM disor- der. Some authors have suggested that the relationship between oc- clusal factors and TM disorders may be appreciated better when combi- nation of factors are investigated. Pullinger and colleagues (1993) at- tempted to do this by using a blinded multifactorial analysis to determine the weighted influence of each factor, acting in combination with the other factors. The interaction of 11 occlusal factors was considered in randomly collected but strictly defined diagnostic groups compared to 19 Orthodontic Therapy and TMJD Adaptability of the individual Genetic factors Biologic factors The asymptomatic Etiologic Factors Hormonal factors individual Others 2 Occlusal Factors Trauma Adaptability Normal functioning Emotional Stress TMD masticatory system Deep Pain Input Parafunction Figure 1. A model depicting etiologic factors and how they may contribute to TMD. When an asymptomatic individual is exposed to one of the five etiologic factors, the musculoskeletal system may be affected. Each individual has a cer- tain amount of adaptability that protects him or her from developing a TMD. If one of these factors is great or if the patient’s adaptability is small, a TMD may develop. It is important for the orthodontist to appreciate that occlusion is the only factor that is influenced by orthodontic therapy. If this is not the significant reason for the patient’s TMD, orthodontic therapy should not be expected to help the TMD. asymptomatic controls. These investigators concluded that no single oc- clusal factor was able to differentiate patients from healthy subjects. There were four occlusal features, however, that occurred mainly in TMD patients and rarely were seen in normals. These factors were: the presence of a skeletal anterior open bite; RCP-ICP slides of greater than 3 to 4 mm; overjets greater than 4 mm; and five or more missing and un- replaced posterior teeth. Unfortunately all of these signs not only are rare in healthy individuals, but also in patient populations as well, indicating limited diagnostic usefulness of these features. Pullinger and coworkers (1993, 2000) concluded that many oc- clusal parameters that traditionally were believed to be influential con- tribute only minor amounts to the change in risk in the multiple factor analysis used in their study. They reported that although the relative odds 20 Okeson for disease were elevated with several occlusal variables, clear definition of disease groups was evident only in selective extreme ranges and in- Volved only a few subjects. Thus they concluded that the occlusion can- not be considered the most important factor in the definition of TMD. The multifactorial analysis of Pullinger and colleagues (1993, 2000) suggests that, except for a few defined occlusal conditions, there is a relatively minor relationship between occlusal factors and TMDs. It should be noted, however, that these studies report on the static relation- ship of the teeth as well as the contact pattern of the teeth during various eccentric movements. This represents the traditional approach to evaluat- ing occlusion. Perhaps these static relationships can provide only limited insight into the role of occlusion and TMD. When considering the dynamic functional relationship between the mandible and the cranium, it appears that the occlusal condition can impact on some TM disorders in at least two ways. The first relates to how the occlusal condition effects orthopedic stability of the mandible as it loads against the cranium. The second is how acute changes in the oc- clusal condition can influence mandibular function thus leading to TMD Symptoms. Each of these conditions will be discussed separately. The Effects of Occlusal Factors on Orthopedic Stability Orthopedic stability in the masticatory structures exists when the stable intercuspal position of the teeth is in harmony with the muscu- loskeletally stable position of the condyles in the fossae (Okeson, 2008b). When this condition exists, functional forces can be applied to the teeth and joints without tissue injury. However, when there is a lack of harmony between the musculoskeletally stable position of the con- dyles and the intercuspal position of teeth, the condition is known as or- thopedic instability. When this condition exists, there are opportunities for overloading and injury. When orthopedic instability is present and the teeth are not in Occlusion, the condyles are maintained in their musculoskeletally stable positions by the elevator muscles (Fig. 2A). However, when teeth are brought into occlusion, maximum intercuspation cannot be achieved with the condyles maintained in their stable position (Fig. 2B). This results in a Very unstable occlusal position, even though each condyle remains in a Stable joint position. The individual now has a choice either to maintain the stable joint position and only occlude on a few teeth, or bring the teeth into a more stable occlusal position, which may compromise joint 21 Orthodontic Therapy and TMJD → Figure 2. A. With the teeth apart, the elevator muscles maintain the condyles in their musculoskeletally stable positions (superoanterior, resting against the posterior slopes of the articular eminences). In this situation there is joint stabil- ity. B: When the mouth is closed, a single tooth contact does not allow the entire dental arch to gain full intercuspation. At this moment there is occlusal instabil- ity but still joint stability. Because the condyles and teeth do not fit in a stable relationship at the same time, this represents orthopedic instability. C. To gain the occlusal stability necessary for functional activities, the mandible is shifted and the intercuspal position is achieved. At this moment the patient achieves occlusal stability, but the condyles may no longer be orthopedically stable. This orthopedic instability may not pose a problem unless unusual loading occurs. If loading begins, the condyles will seek out stability and the unusual movement can lead to strains on the condyle/disc complex resulting in a risk factor for an intracapsular disorder. (Reprinted with permission; Okeson JP. Management of Temporomandibular Disorders and Occlusion. 6" ed. St Louis. Mosby Co., 2008: 142.)”. stability. In that occlusal stability is basic to function (chewing, swal- lowing and speaking), the priority is to achieve occlusal stability and the mandible is shifted to a position that maximizes occlusal contacts (the intercuspal position). When this occurs, this shift can force one or both condyles from its musculoskeletally stable position, resulting in orthope- dic instability (Fig. 2C). What this means is that when the teeth are in a stable position for loading, the condyles are not, or vice versa. When orthopedic instability exists, however, merely bringing the teeth into occlusion may not create a problem because loading forces are minimal. Problems arise when such an orthopedically unstable condition is loaded by the elevator muscles or by extrinsic forces (trauma). Since the intercuspal position represents the most stable position for the teeth, loading is accepted by the teeth without consequence. If the condyles also are in a stable relationship in the fossae, loading occurs with no ad- verse effect to the joints structures. If, however, loading occurs when a joint is not in a stable relationship with the disc and fossa, unusual movement can occur in an attempt to gain stability. This movement, al- though small, often is a translatory shift between disc and condyle. Movement such as this can lead to strain to the discal ligaments and eventually elongation of the discal ligaments and thinning of the disc. These changes can lead to an intracapsular TMD. It should be remembered that there are two factors that determine whether an intracapsular disorder will develop: the degree of orthopedic 22 Okeson iſ W. Kºſſº) instability; and the amount of loading. Orthopedic instabilities with dis- Crepancies of 1 or 2 mm are not likely significant enough to create a problem. However, as the discrepancy between the musculoskeletally Stable position of the condyles and the maximum intercuspation of the teeth becomes greater, the risk of intracapsular disorders increases (Pull- inger and Seligman, 1993, 2000). 23 Orthodontic Therapy and TMJD The second factor that determines whether the patient will de- velop a TMD is the amount of loading. Bruxing patients with orthopedic instability, therefore, represent a greater risk for developing problems then non-bruxers with the same orthopedic instability. Also, forceful uni- lateral chewing can provide the mechanics that lead to sudden intracap- sular disorders. These variables may help explain why patients with simi- lar occlusal conditions may not develop similar disorders. In fact, when the static occlusal relationships of two patients are compared, the patient with the more significant malocclusion may not always be the patient who develops the disorder. Considering the dynamic functional aspect of the occlusion as it relates to the joint position is likely to provide more important information regarding the relative risk of developing a TMD. In considering the relationship between occlusion and TMD, an- other factor needs to be considered. The term “dental malocclusion” re- fers to the specific relationship of the teeth to each other, but does not necessarily reflect any risk factors for the development of functional dis- turbances in the masticatory system (TMD). Dentists have recognized and described dental malocclusions such as open bites and Angle Class II molar relationships for years. The literature, however, does not convinc- ingly relate these dental malocclusions to TMD. These dental malocclu- sions are important only when viewed in relationship to the joint posi- tion. Therefore, merely looking in the mouth or viewing hand held study casts does not provide insight as to the relative risk factor for TMD. Only by observing the occlusal relationship with respect to the stable joint position can one appreciate the degree of orthopedic instabil- ity that is present. Orthopedic instability is the critical factor that needs to be considered when accessing relative risk factors for TMD. Also re- member, a small discrepancy of 1 to 3 mm is normal epidemiologically and apparently not a risk factor. Small discrepancies appear to be well within the individual’s ability to physiologically adapt. Shifts of greater than 3 to 4 mm present more significant risk factors for TMD (Nilner, 1986; Seligman and Pullinger, 1989, 1991, 2000; Wanman and Ager- berg, 1991; Pullinger et al., 1993; McNamara et al., 1995). An Acute Change in the Occlusal Condition A second manner by which the occlusal condition can affect TMD symptoms is through a sudden or acute change. The occlusal con- tact patterns of the teeth can influence the activity of masticatory muscles 24 Okeson significantly (Williamson and Lundquist, 1983; Miralles et al., 1988, 1989; Manns et al., 1989). It also has been demonstrated that introducing a slightly high contact between the teeth can induce masticatory muscle pain in some individuals (Ingervall and Carlsson, 1982; Rugh et al., 1984; Sheikholeslam et al., 1993). An acute change in the occlusal con- dition such as a high crown often will precipitate a protective response of the muscle known as protective co-contraction. This protective response may produce muscle symptoms. Most dentists will recognize this acute disruption in normal occlusion and quickly adjust the crown to fit, re- Solving the symptoms. If the crown is not adjusted, the chronic occlusal interference may affect muscle activity in one of two ways. The most common is to alter muscle engrams so as to avoid the potentially damaging contact and get on with the task of function. This is an example of adaptation of the masticatory system and likely the most common response the body to accommodate to the altered sensory input. Another form of adaptation relates to tooth movement to accommodate the heavy loading. Dentists should be thankful that most patients can adapt to change and do not show prolonged signs of dysfunction. If the masticatory system cannot adapt sufficiently, however, continued muscle co-contraction can lead to a more significant masticatory muscle disorder that needs to be recog- nized and managed (Fig. 1). HOW OCCLUSION RELATES TO TMDS In summary, the occlusal condition can affect TMDs by way of two mechanisms. One mechanism relates to the introduction of acute changes in the occlusal condition. Although acute changes can create a protective muscle co-contraction response leading to a muscle pain con- dition, most often new muscle engrams are developed and the patient adapts with little consequence. The second manner in which the occlusal condition can affect TMDs is in the presence of orthopedic instability. The degree of orthopedic instability must be considerable and it must be combined with significant loading forces. A simple way to remember these relationships is as follows: problems with bringing the teeth into occlusion are answered by the muscles. However, once the teeth are in occlusion, problems with load- ing the masticatory structures are answered in the joints. These relation- 25 Orthodontic Therapy and TMJD ships are, in fact, how dentistry relates to TMD. Therefore, if one of these two conditions exists, dental therapy may be indicated. Conversely, if neither of these conditions exists, dental therapy is contraindicated. CONCLUSIONS Scientific studies do not link orthodontic therapy with the devel- opment or prevention of TMDs. However, it is difficult to imagine a spe- cialty that routinely and significantly changes a patient’s occlusal condi- tion would not have a powerful affect on the masticatory structures and their functions. Perhaps the relationship between orthodontics and TMD is not great because orthodontic therapy only influences one of at least five different etiologic factors that are linked to TMD. Perhaps orthodon- tists are fortunate to be carrying out their therapies on young healthy populations that routinely have the ability to adapt to the treatment changes. To think that orthodontic therapy could never create risk factors for TMD is a naïve clinical thought. Orthodontists need to establish their treatment goals by considering both the occlusal position and the stable joint position. Establishing orthopedic stability in the masticatory is an important concept for maintaining a healthy masticatory system for a lifetime. REFERENCES Artun J, Hollender LG, Truelove EL. Relationship between orthodontic treatment, condylar position, and internal derangement in the tem- poromandibular joint. Am J Orthod Dentofacial Orthop 1992; 101:48–53. Beattie JR, Paquette DE, Johnston LE Jr. The functional impact of ex- traction and nonextraction treatments: A long-term comparison in patients with borderline, equally susceptible Class II malocclusions. Am J Orthod Dentofacial Orthop 1994;105:444-449. Dahl BL, Krogstad BS, Ogaard B, Eckersberg T. Signs and symptoms of craniomandibular disorders in two groups of 19-year-old individuals, one treated orthodontically and the other not. Acta Odontol Scand 1988:46:89-93. Dibbets JM, van der Weele LT. Long-term effects of orthodontic treat- ment, including extraction, on signs and symptoms attributed to CMD. Eur J Orthod 1992:14:16-20. 26 Okeson Gianelly AA, Petras JC, Boffa J. Condylar position and Class II deep- bite, no-overjet malocclusions. Am J Orthod Dentofacial Orthop 1989:96:428-432. Henrikson T, Nilner M. Temporomandibular disorders and the need for stomatognathic treatment in orthodontically treated and untreated girls. Eur J Orthod 2000:22:283-292. Hirata RH, Heft MW, Hernandez B, King GJ. Longitudinal study of signs of temporomandibular disorders (TMD) in orthodontically treated and nontreated groups. Am J Orthod Dentofacial Orthop 1992; 101:35-40. Ingervall B, Carlsson GE. Masticatory muscle activity before and after elimination of balancing side occlusal interference. J Oral Rehabil 1982;9:183-192. Janson M, Hasund A. Functional problems in orthodontic patients out of retention. Eur J Orthod 1981:3:173-179. Kremenak CR, Kinser DD, Harman HA, Menard CC, Jakobsen JR. Or- thodontic risk factors for temporomandibular disorders (TMD): I. Premolar extractions. Am J Orthod Dentofacial Orthop 1992; 101:13- 20. Kremenak CR, Kinser DD, Melcher TJ, Wright GR, Harrison SD, Ziaja RR, Harman HA, Ordahl JN, Demro JG, Menard CC. Orthodontics as a risk factor for temporomandibular disorders (TMD): II. Am J Orthod Dentofacial Orthop 1992; 101:21–27. Larsson E, Ronnerman A. Mandibular dysfunction symptoms in ortho- dontically treated patients ten years after the completion of treat- ment. Eur J Orthod 1981;3:89-94. - Luecke PE, Johnston LE Jr. The effect of maxillary first premolar extrac- tion and incisor retraction on mandibular position: Testing the central dogma of "functional orthodontics.” Am J Orthod Dentofacial Or- thop 1992; 101:4-12. Luppanapornlarp S, Johnston LE Jr. The effects of premolar-extraction: A long-term comparison of outcomes in clear-cut extraction and nonextraction Class II patients. Angle Orthod 1993;63:257-272. Manns A, Miralles R, Valdivia J, Bull R. Influence of variation in an- teroposterior occlusal contacts on electromyographic activity. J Pros- thet Dent 1989;61:617-623. 27 Orthodontic Therapy and TMJD McNamara JA Jr, Seligman DA, Okeson JP. Occlusion, orthodontic treatment, and temporomandibular disorders: A review. J Orofac Pain 1995;9:73-90. Miralles R, Bull R, Manns A, Roman E. Influence of balanced occlusion and canine guidance on electromyographic activity of elevator mus- cles in complete denture wearers. J Prosthet Dent 1989;61:494-498. Miralles R, Manns A, Pasini C. Influence of different centric functions on electromyographic activity of elevator muscles. Cranio 1988;6:26-33. Nilner M. Functional disturbances and diseases of the stomatognathic system: A cross-sectional study. J Pedod 1986; 10:21 1-238. O'Reilly MT, Rinchuse DJ, Close J. Class II elastics and extractions and temporomandibular disorders: A longitudinal prospective study. Am J Orthod Dentofacial Orthop 1993;103:459–463. Okeson JP. Management of Temporomandibular Disorders and Occlu- sion. St Louis: Mosby Year Book Pub 2008a; 139-156. Okeson JP. Management of Temporomandibular Disorders and Occlu- sion. St Louis: Mosby Year Book Pub 2008b;95-1 10. Okeson J. Orofacial Pain: Guidelines for Classification, Assessment, and Management. Chicago: Quintessence Pub Co., 1996. Pullinger AG, Seligman DA. Quantification and validation of predictive values of occlusal variables in temporomandibular disorders using a multifactorial analysis. J Prosthet Dent 2000;83:66-75. Pullinger AG, Seligman DA, Gornbein JA. A multiple logistic regression analysis of the risk and relative odds of temporomandibular disorders as a function of common occlusal features. J Dent Res 1993;72:968– 979. Rendell JK, Norton LA, Gay T. Orthodontic treatment and temporoman- dibular joint disorders. Am J Orthod Dentofacial Orthop 1992; 101:84–87. Rugh JD, Barghi N, Drago C.J. Experimental occlusal discrepancies and nocturnal bruxism. J Prosthet Dent 1984:51:548–553. Sadowsky PL, Bernreuter W, Lakshminarayanan AV, Kenney P. Ortho- dontic appliances and magnetic resonance imaging of the brain and temporomandibular joint. Angle Orthod 1988:58:9-20. 28 Okeson Sadowsky C, Polson AM. Temporomandibular disorders and functional occlusion after orthodontic treatment: Results of two long-term stud- ies. Am J Orthod 1984;86:386–390. Sadowsky C, Theisen TA, Sakols EI. Orthodontic treatment and tem- poromandibular joint sounds: A longitudinal study. Am J Orthod Dentofacial Orthop 1991;99:441-447. Seligman DA, Pullinger AG. Association of occlusal variables among refined TM patient diagnostic groups. J Craniomandib Disord 1989;3:227–236. Seligman DA, Pullinger AG. The role of intercuspal occlusal relation- ships in temporomandibular disorders: A review. J Craniomandib Disord 1991; 5:96-106. Sheikholeslam A, Holmgren K, Riise C. Therapeutic effects of the plane occlusal splint on signs and symptoms of craniomandibular disorders in patients with nocturnal bruxism. J Oral Rehabil 1993:20:473–482. Smith A, Freer T.J. Post-orthodontic occlusal function. Austral Dent J 1989:34:301-309. Wadhwa L., Utreja A, Tewari A. A study of clinical signs and symptoms of temporomandibular dysfunction in subjects with normal occlu- sion, untreated, and treated malocclusions. Am J Orthod Dentofacial Orthop 1993; 103:54–61. Wanman A, Agerberg G. Etiology of craniomandibular disorders: Evaluation of some occlusal and psychosocial factors in 19-year- olds. J Craniomandib Disord 1991;5:35-44. Williamson EH, Lundquist DO. Anterior guidance: Its effect on electro- myographic activity of the temporal and masseter muscles. J Prosth Dent 1983:49:816-823. 29 MANAGEMENT OF JAW DISORDERS (TMD) Charles McNeill and Patricia A. Rudd ABSTRACT Articular and muscular jaw disorders, often termed temporomandibular disor- ders (TMD) rarely occur in isolation, but rather as a cluster of problems with overlapping symptoms. The multi-factorial nature of these musculoskeletal problems demands identifying interrelated diagnoses and rendering a multidisci- plinary management approach. To properly manage TMD, the health provider must be able to appreciate the underlying principles of basic pain mechanisms in order to understand cause and effect. In order to fulfill this important responsi- bility, the health provider must have a working knowledge of functional neuro- anatomy, peripheral and central nervous system pain pathways including the descending pain modulating system and appreciate the affective or emotional aspects of persistent pain. Further, in order to differentiate pain conditions properly, the health provider must be knowledgeable regarding the various head, neck and face pain classifications and be aware of the operational diagnostic criteria for the various conditions that can cause, result from, or are coincidental to TMD. Diagnostic- specific management of musculoskeletal disorders affecting the jaw including risk management strategies before, during and after orthodontic treatment is critical. Management of the at-risk TMD patient includes patient education, symptomatic care, medications, behavior modification and relaxation strategies and a comprehensive physical medicine approach. The goal of the multidiscipli- nary management program is to reduce pain, promote tissue repair and improve function with minimal risk for the patient. Lastly, when orthodontic treatment is being contemplated for the at-risk jaw patient, special emphasis will be placed on the importance of establishing and maintaining a healthy, functional equilib- rium between the compromised tissues of the masticatory system. The multitude of disease entities that can present with similar pain patterns in the head, face and neck region mandate that orthodontists consider diseases unrelated to the masticatory system in their differential diagnosis of orofacial pain. A thorough diagnostic process using vali- dated diagnostic criteria is critical because an incorrect or omitted diag- nosis is one of the most frequent causes of treatment failure (Slavkin, 1997). In fact, it becomes a daunting task to correctly identify all of the 31 Management of Jaw Disorders possible sources of pain that may be the cause, the effect or are coinci- dental to a patient’s orofacial pain complaints. In order to help differenti- ate all the possible head, face, jaw, intraoral and neck pain conditions, it is essential to have a systematic approach. Internationally established pain classifications with operational diagnostic criteria for the various possible orofacial pain conditions serve as useful guides. Differential diagnoses can be based on universally accepted inclusion and exclusion criteria, even though the mechanism causing the pain may not fully be known (Maixner, 2008; Matthews and Sessle, 2008; Sessle et al., 2008; Stohler, 2008). In 1988, the International Headache Society (IHS) published its landmark diagnostic system, the Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain (IHS, 1988). This classification system, with specific operational diagnostic criteria, was updated and improved in 2004 and was titled the Interna- tional Classification of Headache Disorders II (ICHD-II; Headache Clas- sification, 2004). Two years after the publication of the second edition, the IHS launched a website edition of the International Classification of Headache Disorders (www.ICHDII.org; Table 1). In support of and in conformity with this major effort, the American Academy of Orofacial Pain (known as the American Academy of Craniomandibular Disorders at the time) published a diagnostic classification for temporomandibular disorders (TMD; McNeill, 1990). The American Academy of Orofacial Pain (AAOP) improved this classification in 1993 with the addition of more specific inclusion and exclusion diagnostic criteria (McNeill, 1993). In both 1996 and 2008, the AAOP diagnostic classification has been expanded, based on the IHS classification, to include all head, face and neck conditions that could be associated with orofacial pain (Okeson, 1996; de Leeuw, 2008). This classification is, as is the IHS’s genitor classification, a work-in-progress with plans to publish updated editions as new research mandates a timely transfer of science. This chapter presents an overview of the differential diagnosis of orofacial pain, emphasizing the diagnosis and management of TMD. Part I of the chapter will cover the diagnostic range of orofacial pain involv- ing: 1. The typical intraoral pain conditions well-known to dentists; and 2. Medical conditions that either directly cause, refer pain to the region, or masquerade as orofacial pain. 32 McNeill and Rudd Table 1. The International Classification for Headache Disorders (Second Edi- tion: ICHD-II). Part 1 PRIMARY HEADACHES IHS 1 Migraine Headache IHS 2 Tension-type Headache IHS 3 Cluster Headache and Other Trigeminal Autonomic Cephalgias IHS 4 Other Primary Headaches Part 2 SECONDARY HEADACHES IHS 5 Headache Attributed to Head and/or Neck Trauma IHS 6 Headache Attributed to Cranial or Cervical Vascular Disorder IHS 7 Headache Attributed to Nonvascular Intracranial Disorders IHS 8 Headache Attributed to a Substance or Its Withdrawal IHS 9 Headache Attributed to Infection IHS 10 Headache Attributed to Disorder of Homeostasis IHS 11 Headache Attributed to Extracranial Pain Disorders IHS 12 || Headache Attributed to Psychiatric Disorder Part 3 CRANIAL NEURALGIAS, CENTRAL AND PRIMARY FACIAL PAIN IHS 12 || Cranial Neuralgias and Central Causes of Facial Pain IHS 12 || Other Headache, Cranial Neuralgia, Central or Primary Facial Pain Part II of the chapter will emphasize the classification, assessment and management of musculoskeletal cervical and TMDS (Table 2). DIFFERENTIAL DIAGNOSIS: PART I Intraoral Pain Disorders Intraoral pain disorders include odontogenic pain and pain condi- tions associated with mucogingival tissues, tongue and salivary glands. Odontogenic pain is defined as pain associated with the teeth and periodontium. Tooth pain includes reversible and non-reversible pulpitis and pulpal necrosis. Teeth often refer pain to other teeth as well as to distant areas in the head, neck and jaw. Pain conditions associated with the Supporting tissues of the teeth include acute apical periodontitis, acute apical abscess and acute periodontal abscess. Mucogingival and glossal pain disorders may be localized or generalized throughout the mouth. Burning mouth syndrome (BMS), also known as stomatodynia or oral dysesthesia, is characterized by burning mucosal, glossal and/or palatal pain sometimes with associated taste sensations (Eliav et al., 2007). 33 Management of Jaw Disorders Table 2. Management of orofacial pain: diagnostic range. PART I: NON-MUSCULOSKELETAL PAIN DISORDERS A. Intraoral Pain Disorders (Routine Dental Diagnoses) 1. Teeth and Periodontal Disorders 2. Mucogingival, Tongue, Salivary Gland Disorders B. Medical Conditions Masquerading as Orofacial Pain 1. Intracranial and Vascular Pain Disorders 2. Neurovascular Headache Disorders a. Primary Headache b. Secondary Headache 3. Neuropathic Pain Disorders a Paroxysmal Pain Disorders b. Continuous Pain Disorders 4. Headache Attributed to Associated Extracranial Pain Disorders (Eye, Ear, Nose, Sinuses, and Throat Disorders) PART II: MUSCULOSKELETAL PAIN DISORDERS A. Cervical Disorders B. Temporomandibular Disorders 1. Articular Disorders 2. Muscular Disorders Intraoral pain disorders are familiar to and routinely screened for by dental health professionals. However, atypical odontalgia, a persistent neuropathic pain, is not familiar to orthodontists. Even though the preva- lence of atypical odontalgia is not known, studies suggest 3-5% of endo- dontically treated teeth may develop this persistent pain condition (Campbell et al., 1990; Melis et al., 2003; Baad-Hansen, 2008). Due to the lack of understanding of central nervous system pain mechanisms and the complexities of persistent pain syndromes, atypical odontalgia is a commonly mistreated diagnosis (Fig. 1). Imaging studies and clinical examination of the tissues appear normal, with no obvious source of lo- cal pathology. The constant pain, however, continues at the site for months and years (List et al., 2007). The condition occurs subsequent to dental treatment and is thought to be both peripherally and centrally gen- erated, with alterations in the descending inhibitory pathways. The sym- pathetic nervous system also might be involved in the maintenance of this continuous pain condition (Vickers and Cousins, 2000). Atypical ondontalgia (OA) is defined as a continuous, variable, diurnal tooth or tooth site pain of greater than four months with no obvi- ous source of local pathology. It often is described as an aching, burning 34 McNeill and Rudd E. Figure 1. Panoramic radiograph revealing multiple unnecessary endodontic procedures for persistent neuropathic intraoral (atypical odontalgia, or OA) pain. and/or pressure sensation with a history of dental treatment, or trauma resulting in deafferentation of peripheral nocioceptive nerve endings. The pain is located in a region where a tooth has been endodontically or Surgically treated. Local provocation with temperature or loading and local diagnostic anesthetic injections are equivocal. Most OA patients have other co-morbid pain conditions and higher scores for depression and somatization. Significantly lower scores on quality of life measures also are found (Baad-Hansen et al., 2008). Unfortunately, this diagnosis often is mistreated with repeated root canal therapies, apicoectomies and even extractions. The result is worsening pain and irreversible harm to the patient. Treatment typically consists of tricyclic antidepressants, Gabapentin (Neurontin) and other membrane stabilizers, Tramadol and topical Lidocaine. Medical Conditions Masquerading as Orofacial Pain Medical conditions that can be associated or confused with oro- facial pain include intracranial non-vascular and vascular disorders, Dºurovascular pain conditions (primary and secondary headache), neuro- genic (neuropathic) pain conditions and extracranial pain disorders (e.g., Car, nose, sinus, throat conditions). Intracranial Disorders. Disorders of the intracranial structures, Such as neoplasia, aneurysm, abscess, hemorrhage or hematoma and edema usually can be differentiated from orofacial pain easily (de 35 Management of Jaw Disorders Leeuw, 2008). They should be considered first in the diagnostic process because they can be life threatening and require immediate attention. The characteristics of serious intracranial disorders include new or abrupt onset of pain, pain that increases in severity, interruption of sleep by pain, pain precipitated by exertion or positional change, and neurologic deficits. Referred pain from primary and metastatic tumors in particular can be extremely difficult to separate from symptoms related to TMDS in a timely manner (Aniceto et al., 1990). One vascular pain disorder, tem- poral arteritis, may be misdiagnosed as myofascial pain involving the temporalis muscle. The temporal and possibly the facial arteries are swollen, torturous and extremely tender. Arteritis is associated with a significantly elevated erythrocyte sedimentation rate; a biopsy of the temporal artery confirms the diagnosis. Treatment consists of the appro- priate corticosteriod therapy for the autoimmune inflammatory process. If treatment is delayed, temporal arteritis can lead quickly to a loss of vision due to acute ischemic optic neuropathy due to inflammation of the ciliary artery (Solomon and Cappa, 1987). Neurovascular Headache Disorders. Headache is a common complaint reported by patients suffering from musculoskeletal jaw disor- ders. Neurovascular headache disorders and jaw disorders can share common nociceptive pathways; dentists, therefore, must be aware of the characteristics of primary and secondary headache and their potential association with orofacial pain (Mitrirttanakul and Merrill, 2006; Ram- ero-Reyes and Graff-Radford, 2007; de Leeuw, 2008; Widmer, 2008). Primary headache disorders associated with orofacial pain include mi- graine headaches, migraine-variant headaches, cluster headaches and tension-type headaches. Migraine headache is divided into migraine with aura (classic) and migraine without aura (common migraine) headache. Migraine with aura headaches are characterized by unilateral (60% of the time), throbbing or pulsating pain lasting 4-72 hours with frequent accompanying nausea and/or vomiting, phonophobia and pho- tophobia. Migraine without aura is similar to classic migraine but pro- ceeds into headaches without a prodromal phase. Tension-type head- aches are believed to be a type of chronic or episodic migraine-like head- ache. They are bilateral, mild to moderate in intensity and characterized by a nonpulsating, pressing or tightening feeling in the head. The head- aches are not related to the use of the jaw (such as chewing hard foods) and may or may not be associated with pericranial muscle tenderness. 36 McNeill and Rudd Thus, it is important to distinguish between tension-type headaches and localized myofascial pain of the temporalis muscles. Secondary headache disorders are defined as headaches that de- velop secondary to another condition or mechanism. These could include physical exertion, cold stimuli, trauma, infection, metabolic disorders or substances or substance withdrawal. Orofacial pain can be associated commonly with rebound headache. Patients who have misused or abused medications, including over-the-counter analgesics and non-steroidal anti- inflammatory drugs, can suffer from rebound headache. When prescription medications are either prescribed or taken inappropriately, or when pa- tients develop tolerances to the medications, breakthrough pain can be- come a major problem. There usually is a history of daily or near-daily headache and medication use, associated depression and sleep disturbance, and occasional severe migraine-like attacks (Trucco et al., 2005). Neuropathic Pain Disorders. Neuropathic pain is a disorder re- Sulting from injury, peripheral and/or central, in the pain transmission System; it usually is present in the absence of an ongoing primary source for the pain (Maixner, 2008). Neuropathic pain disorders are divided into either paroxysmal (episodic) or continuous painful conditions (de Leeuw, 2008). The common paroxysmal conditions associated with orofacial pain include either trigeminal or glossopharyngeal neuralgia. The pain sensations follow the distribution of these different nerves and are char- acterized by brief electric shock-like pains (lancinating or jabbing) last- ing only seconds to minutes with pain-free intervals. One of the distinguishing aspects of trigeminal neuralgia and glossopharyngeal neuralgia is that the pain is evoked by trivial stimuli including use of the jaw (e.g., talking, swallowing or even brushing the teeth) as well as just lightly touching the face or mouth. The unilateral pain is severe, with remissions lasting for days to years. Glossopharyn- geal neuralgia pain also is a severe, transient, stabbing or burning pain located in the ear, base of the tongue, tonsillar fossa or beneath the angle of the mandible. The paroxysms of pain are provoked by swallowing, chewing, talking and/or yawning. The continuous neuropathic pain disorders associated with oro- facial pain primarily are deafferentation pain syndromes related to com- pression or distortion, demyelination, infarction or inflammation of the cranial nerves. Acute herpes zoster, chronic post-herpetic neuralgia, dia- betic neuropathy and neuromas are examples of continuous neuropathic pain syndromes. Burning mouth syndrome is considered a neuropathic 37 Management of Jaw Disorders pain. The pain is persistent without major visible signs of spontaneous onset. Idiopathic persistent facial pain, historically referred to as atypical facial pain, likely is related to partial or complete deafferentation (Jensen and Baron, 2003). The previously mentioned OA or idiopathic odontal- gia (historically referred to as phantom tooth pain) is a continuous, but variable, dull ache that sometimes also is described as a burning pain that typically follows dental treatment (Graff-Radford and Solberg, 1992). Headache Attributed to Extracranial Pain Disorders. Extracra- nial pain disorders associated with orofacial pain include pain related to the eyes, ears, nose, sinuses, throat, intraoral structures, neck, jaw and cranial bones (Table 3; de Leeuw, 2008). Extracranial musculoskeletal cervical and TMDs will be discussed in more detail in Part II of the chap- ter. Referral of pain from one extracranial structure to seemingly another site is very common and is explained in part by the convergence of nox- ious input in the subnucleus caudalis (Gear, 1997). Pain in and around the eyes is relatively common but seldom is it a result of noxious stimuli originating in the eye, extraocular muscles or optic nerve. Rather, pain commonly is referred to the eye from other structures. Pain perceived to be emanating from the ear also is very common. Although the source of the pathology may be from the ear (e.g., otitis externa and media, mas- toiditis, eustachian tube disorders, neoplasia such as acoustic neuroma; Fig. 2), the majority of ear pain is referred from another source. Pain in the nose and paranasal sinuses can arise from inflammation, infection and malignant disease. As with the above extracranial structures, the nose and sinuses commonly refer pain to adjacent structures such as the teeth. Table 3. IHS 11 headache or facial pain attributed to extracranial disorders. IHS 11.1 Headache Attributed to Disorders of Cranial Bones IHS 11.2 Headache Attributed to Disorders of the Neck IHS 11.3 Headache Attributed to Disorders of the Eyes IHS 11.4 Headache Attributed to Disorders of the Ears IHS 11.5 Headache Attributed to Rhinosinusitis IHS 11.6 Headache Attributed to Disorders of Teeth, Jaws or Related Structures IHS 11.7 Headache or Facial Pain Attributed to TMD IHS 11.8 Headache Attributed to Other Extracranial Structures 38 McNeill and Rudd - --------- Figure 2. Acoustic neuroma initially can present as face and jaw pain. DIFFERENTIAL DIAGNOSIS: PART II Musculoskeletal Disorders Musculoskeletal conditions affecting the jaw (TMD) and neck are the major cause of non-odontogenic pain in the orofacial region (Lip- on et al., 1993). They include cervical spine and temporomandibular joint (TMJ: articular) and cervical and masticatory muscle (non-articular) disorders. As with other musculoskeletal disorders, both neck and jaw Symptoms wax and wane. Even though they are not life threatening, they “an affect the quality of life significantly. They are defined as a collec- 39 Management of Jaw Disorders tion of disparate musculoskeletal disorders, articular or nonarticular, that affect the neck and jaw often with similar signs and symptoms. Cervical Spine Disorders. Pain disorders associated with the cer- Vical spine can involve the muscles, ligaments, facet joints, bones, discs and neural tissues (de Leeuw, 2008). The traditional classification of these soft tissue and articular disorders includes diagnostic terms such as myositis, cervical sprain/strain, fibrositis, facet syndrome, osteoporosis, spondylosis, and osteoarthritis, articular hypo- and hypermobility, discogenic disease and cervical nerve disorders. Eight percent of the US population seeks treatment for cervical spine disorders. Prevalence gen- erally increases in frequency and intensity up to the fifth decade of life and is higher among women than men (de Leeuw, 2008). A common traumatic cause of cervical symptoms is the damage that occurs during acceleration-deceleration (extension-flexion) injuries to the neck referred to as “whiplash” injuries (Spitzer et al., 1995; Bur- gess et al., 1996). As with the various TMDs, the etiology of many of the cervical disorders is not well understood. In the absence of fracture and disease, therefore, another classification has been proposed. It is modeled after the guidelines for low back pain and focuses on signs and symp- toms to facilitate better communication among health professionals (Ta- ble 4). Symptomatically, the cervical region overlaps with the cranio- facial region because the upper cervical nerves, discs, facet (zygapophy- seal) joints and muscles are potential sources of referred pain. The sec- ond and third cervical nerves innervate the angle of the jaw, the region inferior to the TMJ and parts of the ear, neck and back of the head. Any irritation and/or dysfunction of these nerves, therefore, can be associated with facial pain. As was discussed previously, sensory input from the upper cervical nerves (C1, C2 and C3) can converge with input from the trigeminal nerve in the subnucleus caudalis. This trigeminocervical con- vergence within the brainstem often results in incorrect cortical discrimi- nation of the actual source of the pain (Sessle et al., 1986). The patient may not be able to determine whether the source of the pain is in their neck, head or jaw. Additionally, the upper cervical discs (Slip et al., 2005), as in discogenic disease and facet joints (Aprill et al., 1990; Dwyer et al., 1990; Cooper et al., 2007) as well as spondylosis and os- teoarthritis are other common sources of referred pain to the craniofacial region. Lastly, trigger points (tight bands) in cervical myofascial pain can 40 McNeill and Rudd Table 4. Cervical spine subclassification scheme. Category | | Neck Symptoms without Musculoskeletal and Neurologic Signs Category 2 Neck Symptoms without Neurological Signs; Musculoskeletal Signs are Present with a Decrease in Cervical Range of Motion T and/or Tension, Plus Pain on Palpation of the Cervical Muscles Category 5 TNeck Symptoms with Musculoskeletal and Neurologic signs That May Include Decreased or Absent Deep-Tendon Reflexes, - Weakness. and Sensory Deficits - Category 4 Radiation of Symptoms or Cephalic Symptoms in Addition to Symptoms of Category 1, 2 or 3; Cephalic Symptoms May In- clude Headaches, Dizziness/Unsteadiness, Nausea/Vomiting, Tinnitus, Visual Problems, Dysphagia, Memory/Cognitive Prob- lems, and Reduced/Painful Jaw Movements site of Pain Figure 3. Noxious input from the upper cervical nerves (C2 and C3) converges With noxious input from the trigeminal nerve primarily in subnucleus caudalis and can result in incorrect cortical discrimination of the actual source of the palm. be another confusing source of referred pain to other cervical regions as Well as the craniofacial region (Fig. 3; Travell and Simons, 1983). 41 Management of Jaw Disorders Cervical findings are prevalent in university-based orofacial pain centers. In a recent study at the University of California San Francisco Center for Orofacial Pain, 86% of all patients seeking treatment had cervical findings and 42% had moderate to severe cervical muscle ten- derness (Fig. 4; Rudd et al., 2008). It is the responsibility of the dentist to determine if the cervical findings are a primary source of the patient’s orofacial pain complaint or a concomitant finding. A simple Screening question can help with this differentiation. If chewing or other uses of the jaw do not change the patient’s primary orofacial pain complaint, the dentist should be suspicious of a cervical spine disorder. The dentist should screen the cervical region for proper range of motion and Soft- tissue tenderness. If there is any significant mobility dysfunction or soft- tissue tenderness, it needs to be investigated by a medical colleague with orthopedic training. Unfortunately in many cases, cervical diagnoses go undetected by the community dentist and orthodontist, and patients are treated improperly. 126 140 120 100 80 60 40 20 O - No Pain mMild Pain (13.70%) | EModeratelSevere Pain ; Total Patients (n=283) Figure 4. Cervical muscle tenderness in orofacial pain patients seeking treatment at a university-based orofacial pain center. Temporomandibular Disorders (TMD). In the past, TMDs were referred to as “TMJ,” “TMJ Syndrome,” or “TMJ Pain-Dysfunction Syndrome.” Presently they are considered a collection of various distinct articular or muscular conditions affecting the jaw, often with similar signs and symptoms but different underlying mechanisms. The common clinical presentation is any combination of: r 42 McNeill and Rudd 1. Jaw, face, head or ear pain; 2. TMJ noises such as clicking, popping, crepitus or grating; and /or 3. Limited jaw opening, jaw catching and locking (Dworkin et al., 1990). Related symptoms without proven cause and effect include global head- aches, neck pain, tinnitus, ear fullness or perceived hearing loss and diz- ziness. Pain in the TMJ region is reported in approximately 10% of the population over 18 years of age (8-15% for women and 3-10% for men; LeResche, 1997). Recent studies have shown that these reported symp- toms and clinical signs rarely become progressively more severe or dis- abling, TMD-related pain, however, is the most common persistent oro- facial pain, with a prevalence of about 10-15% worldwide. Epidemiol- ogical studies reveal that females seek treatment more than males. The gender ratio varies between cross-sectional studies from anywhere from 4:1 to 2:1 female to male. The peak age is approximately 35–45 years (the child-bearing years of females; LeResche, 2008). Although the etiology of the various subsets of TMD was thought to relate directly to occlusal discrepancies and improper jaw rela- tionships in the past, the number of related contributing factors for each specific diagnosis presently is uncertain and many times unknown. Re- cent systematic reviews of randomized controlled trials (RCTs) have concluded that malocclusion is not correlated directly with the various subsets of TMD (Forssell et al., 1999). Contributing etiologic factors include: trauma, possibly oral parafunction; gender and hormonal fac- tors; systemic factors; overuse of the masticatory system; and psychoSo- cial and behavioral factor (Greene et al., 1995). Recent evidence sug- gests a specific gene expression, primarily in females, is implicated as a risk factor for persistent orofacial pain (Stohler, 2007). The number of co-morbid conditions is substantial in a number of patients seeking treatment, especially when the orofacial pain condition has become persistent (Bartsch and Goadsby, 2003). CLASSIFICATION OF ARTICULAR DISORDERS The American Academy of Orofacial Pain's 2008 classification of TMDS includes a disparate group of articular and nonarticular condi- tions (de Leeuw, 2008). TMJ disorders include congenital, developmen- tal or acquired disorders, disc derangement disorders, condylar disloca- 43 Management of Jaw Disorders Table 5. TMJ Disorders (modified from the American Academy of Orofacial Pain’s Classification). Congenital, Developmental Disorders and Acquired Disorders Disc Derangement Disorders * Disc Displacement with Reduction * Disc Displacement without Reduction Temporomandibular Dislocation Inflammatory Disorders * Synovitis and Capsulitis * Polyarthritides Osteoarthritis (Non-inflammatory Disorders) * Active * Stable Ankylosis Condylar Fracture tion, inflammatory disorders, non-inflammatory disorders, ankylosis and fracture of the condylar process (Table 5). Developmental and Acquired Disordersz Developmental disorders of the TMJ include: 1. 2. 3. 4. Agenesis (lack of development); Aplasia (faulty development); - Hypoplasia (incomplete or under-development of the condyle); and Hyperplasia (non-neoplastic over-development of the condyles; Fig. 5; Behrents et al., 1977; Brecht and Johnson, 1985). Acquired disorders include benign (e.g., osteoma, chondromas, synovial chondromatosis; Mendoca-Caridad and Schwartz, 1994), malignant or metastatic neoplasms (e.g., Squamous cell carcinomas, primary na- sophyarngeal tumors; White et al., 1992). Approximately 3% of malig- nant neoplasia metastasizes to the mandible, usually to the body or ramus (D’Silva et al., 2006). Disc Derangements. Disc derangement disorders represent an abnormal anatomical relationship or misalignment of the articular disc and condyle. Although recent studies are revealing that there is a great deal of variation in the disc position even in individuals without joint 44 McNeill and Rudd Figure 5. Cone-beam CT (CBCT) revealing hyperplasia of left condyle and subtle dengenerative changes in the right condyle. pain, joint noise, or jaw dysfunction, MRI studies of asymptomatic vol- unteers have revealed that about one third of these individuals had dis- placed discs (Larheim et al. 2001). Most of the volunteers had a partial disc displacement that reduced on opening with a small number not re- ducing on opening (Katzberg et al., 1996; Ribeiro et al., 1997). Stretched Or torn collateral discal ligaments are thought to be the reason why discs become displaced. although there still is uncertainty regarding the natural history of these derangement conditions (Nitzan, 2003). Articular discs typically are displaced anteriorly and medially, but also can be posi- . laterally (Kurita et al., 1992) or even posteriorly (Westesson et al., 998). 45 Management of Jaw Disorders Derangement disorders occur as disc displacement with reduc- tion, disc displacement without reduction and disc adhesion. The most common disc disorders are disc displacements with reduction. The reduc- tion occurs when the condyle moves into a more normal position with an unstable disc during translation, usually creating a joint Sound (i.e., click- ing or popping) at the time of the improved relationship of the condyle with the disc. On closing, the condyle moves posterior to the disc, result- ing in a closing click. The incidence of disc displacement with reduction occurs in 50–55% of the adult population, representing a relatively com- mon biologic variation. Disc displacement can be either asymptomatic (non-painful) or symptomatic (painful) at the time of the click. When a momentary hesitation or locking (catching) occurs analogous to a shoul- der impingement, the displacement is referred to as a disc impingement disorder. The symptomatic disc displacement and impingement disorders require management. Disc displacement without reduction (disc fails to reestablish an improved anatomical relationship) either can be acute (less than three months duration) or chronic (three months or greater duration; Fig. 6). The acute condition often is painful with marked reduction in condylar translation; it can on occasion, however, be painless. The chronic condi- tion usually is less painful with a normal or near-normal range of condy- lar translation over time. In the chronic stage, as the tissues adapt, pain- free range of motion increases, but articular changes may be seen on im- aging due to the change in force loading (Sato et al., 1997; Kurita et al., 1998). Lastly, disc adhesion is a disc disorder created by the disc adher- ing to the temporal component of the fossa, creating a static disc position and altered joint mechanics. With disc adhesion, the condyle translates under the posterior band of the disc, causing a click and then continues to move beyond the anterior band of the disc resulting in a second click. During jaw closure, the clicking occurs at the same two places as it did during opening (Laskin, 2006). Condylar Dislocation. Condylar dislocation or open lock is a hy- permobility condition of the jaw (Bucking et al., 1991). It occurs when the condyle inadvertently becomes positioned anterior and superior to the articular eminence, during jaw opening or protrusion, and is unable to return to a closed position. It can be caused by trauma, extended periods of mouth opening such as a long dental appointment, or can be a mani- festation of joint hypermobility. This condition requires the condyle to be distracted manually below the crest of the articular eminence so the con- 46 McNeill and Rudd Auditory Meatus Biconcave Disc Condyle Figure 6. MRI sagittal view of an anterior disc displacement without reduction. dyle can return freely to a closed position in the fossa. It is called an open lock or dislocation if a health provider has to reduce the anterior- positioned condyle. This same condition is referred to as subluxation When the patient is able to self-manipulate the jaw back to a closed posi- tion. Inflammatory and Non-inflammatory Disorders. Inflammatory joint disorders can occur as an inflammation of the synovium (synovitis) and/or joint capsule (capsulitis). This disorder may be the result of trauma, infection or cartilage degeneration or the sequelae of a systemic polyarthritic or collagen disease (rheumatoid arthritis, lupus, Reiters syn- drome; Klasser et al., 2007). Inflammatory joint conditions typically pre- Sent with localized joint pain that limits jaw movements. Non- inflammatory joint disorders include primary and secondary osteoarthri- tis. Osteoarthritis is defined as a non-inflammatory degenerative condi- tion of the joint characterized by deterioration and abrasion of articular tissue and concomitant remodeling of the underlying subchondral bone due to overload of the remodeling mechanism (Stegenga et al., 1991; de Leeuw et al., 1994; Zarb and Carlsson, 1999; Dijkgraaf et al., 2003; Mi- lam, 2006). In Susceptible individuals, mechanical overload can involve the production or release of free radicals, cytokines, fatty acid catabo- 47 Management of Jaw Disorders lites, neuropeptides and matrix-degrading enzymes resulting in a degen- erative disease state (Fig. 7; Milam, 2005). Osteoarthritis (OA) is classified as primary osteoarthritis when the etiology is unknown and secondary osteoarthritis when an etiologic event or factor can be identified (e.g., gout, Cushing’s disease, osteone crosis, infections, Charcot's neuropathic pain). It can be categorized fur- º º - | | º | º | º T - º | = º-- Figure 7. CBCT reveals significant degenerative joint disease in the left TMJ. The condyle and the articulareminence are flattened markedly compared to the 48 McNeill and Rudd ther into active osteoarthritis or stable osteoarthritis, sometimes referred to as osteoarthrosis. Active OA is related to an active change or degen- eration in the articular tissues, whereas stable OA refers to the recortica- tion of the articular osseous structure with a lack of any further structural change (Fig. 8). | | º | º º º | | ºl- = D. Hºs (Figure 7 Continued) right joint. There also is evidence of an osteophyte on the anteriosuperior aspect of the left condyle. 49 Management of Jaw Disorders Ankylosis and Fracture. Ankylosis is a hypomobility condition of the jaw in which either fibrous or bony adhesions restrict condylar translation, thus limiting jaw mobility and function (Fig. 9). Ankylosis often is the sequelae of trauma including condylar fracture, infection, significant inflammation or adhesions resulting from surgical interven- tion. The last articular diagnosis is fracture of the condyle. This condition usually results from direct trauma to the mandible. Fracture can be idio- pathic or even iatrogenic when secondary to another pathologic process (Fig. 10). Ankylosis, condylar degeneration and osteoarthritis are possi- ble sequelae (Block et al., 1990). MUSCULAR DISORDERS The underlying mechanisms that cause masticatory muscle pain are similar to those that cause skeletal muscle disorders throughout the rest of the body. Some mechanisms thought to be related to muscle pain include overuse, localized ischemia, spontaneous activity of deep noci- ceptors, sympathetic nervous system hemodynamic perfusion changes and changes in descending anti-nociceptive modulation (Mense, 1993, 2003; Sessle, 1995). Endogenous substances such as bradykinin, sero- tonin, prostaglandins, neuropeptides, substance P and others are thought to sensitize the peripheral nociceptive nerve endings, resulting in pain in the muscle (Bellamy et al., 2006). Deep tissue inflammation can upregu- late nociceptive behaviors that may not be modulated effectively by a neuropeptide antagonists, resulting in more pain (Ambalavanar et al., 2006). The concept that bruxism is a major cause of masticatory muscle pain is being questioned, in that most subjects who brux do not have muscle tenderness (Lund et al., 1991). Also, the historic dental view that masticatory muscle pain is related to occlusal interferences no longer is a viable concept. Systemic conditions that can produce muscle pain in- clude polymyalgia rheumatica, polymyositis, lupus erythematosus and fibromyalgia. It also is important to distinguish between the cranial mus- cle tenderness associated with the various headache types and primary masticatory muscle tenderness, because even though the symptoms of these conditions can be very similar, the source of the pain is quite dif- ferent, requiring very different management strategies (Rogers and Rogers, 1991). Masticatory muscle disorders include local myalgia, myo- fascial pain, centrally mediated myalgia, myospasm or trismus, myositis and tendonitis, myofibrotic contracture and neoplasia (Table 6). 50 McNeil/ and Rudd A. B Figure 8. Active osteoarthritis (A) is an active change or degeneration in the articular hard tissues. The cortical outline no longer is intact, and there are erosions and Subchondral bone cyst formation. Stable osteoarthritis (B) is a recortication (smooth Surface) of the articular hard tissues and a probable end to any further structural change. _g Fºº-ºº: ºº:: H -- . . In: 13 |- s. ºr EIH = A. ºld. || || Fºº. ºf Figure 9. Computerized tomography of bilateral TMJ bony ankylosis following temporomandibular surgery. 51 Management of Jaw Disorders Figure 10. CBCT reveals bilateral con- dylar fracture of the TMJ. The condyles are displaced infer- iorly and medially in these coronal views. - Zºrn […mm. 52 McNeill and Rudd Table 6. Masticatory Muscle Disorders (modified from the American Academy of Orofacial Pain’s Classification). Local Myalgia Myofascial Pain Centrally-Mediated Myalgia Myospasm Myositis and Tendonitis Myofibrotic Contracture Neoplasia Local Myagia Local myalgia is characterized by localized (or regional) dull aching and stiffness in the masticatory muscles. There typically is little to no pain at rest. The pain increases with jaw function and often results in a decreased active jaw opening that increases with passive stretch. The patient often reports muscle weakness, fatigue and increased pain when eating hard foods, yawning and prolonged opening. Local myalgia can include such conditions as protective muscle splinting as a result of TMJ pain, muscle fatigue and delayed-onset muscle Soreness. Delayed-onset muscle Soreness or post-exercise muscle Soreness is a painful muscle condition related to intense or unaccustomed use of a muscle (Lieber and Friden, 2002). The overuse results in interstitial inflammation and a de- layed pain in the muscles 8-24 hours later. Myofascial Pain Myofascial pain is characterized by a regional (or local) dull ach- ing muscle pain that increases during function. Clinically, there are local- ized tender sites or trigger points in the muscle, tendon or fascia. Palpa- tion of the trigger point provokes pain referral to a distant site such as the teeth, ear or head and must be present to meet the criteria for myofascial pain (Fig. 11; Travell and Simons, 1983; Fricton and Awad, 1990). Pa- tients also may report muscle stiffness, ear symptoms such as tinnitus, decreased mouth opening that can be passively stretched by more than 4mm, and hyperalgesia in the region of the referred pain. Myofascial pain is not considered an inflammatory process, whereas tendinitis is an inflammation and/or soreness in the tendinous attachments of mastica- tory muscles. 53 Management of Jaw Disorders Figure 11. Localized tender sites, or trigger points, in the muscle (red dot), tendon or fascia with referral to a distant site such as the teeth. Centrally Mediated Myalgia Fibromyalgia, a type of general or global muscle pain involved with central nervous system upregulation, can be confused with local or regional muscle pain if the dentist is not comprehensive with both the history-taking and physical assessment process (Lund et al., 1993). Fi- bromyalgia is characterized by a continuous, aching pain in many areas of the body. It is associated with generalized fatigue, chronic headache, irritable bowel syndrome, sleep disturbance and emotional distress in- cluding anxiety, depression and somatization. The American College of Rheumatology has developed a screening exam for fibromyalgia. They have identified 18 points (nine pairs) on the body that are normally non- painful with palpation. If 11 or more of these points are painful to palpa- tion and there is pain in three out of four quadrants of the body for at least three months, this suggests a positive fibromyalgia screening 54 McNeill and Rudd (Wolfe et al., 1990). Fibromyalgia patients should be referred to a rheu- matologist for further evaluation. Centrally mediated muscle pain is thought to be associated with the up-regulation in central mechanisms. The pain may result from prolonged nociceptive input to the central nervous system, resulting in antidromic effect on the afferent peripheral neurons. This can lead to the release of pain-modulating substances such as bradykinin and substance P that cause pain. Chronic exposure to emo- tional stress and other sources of deep pain input such as chronic upregu- lation in the autonomic nervous system are thought to be possible under- lying sources of the centrally mediated pain. Myospasm Myospasm or trismus is an acute muscle disorder characterized by a sudden, involuntary, tonic contraction (fasciculation) of a muscle. Acute pain is present at rest as well as during function, and function is significantly limited. The jaw cannot be stretched manually to open be- yond the patient’s voluntary opening (hard end-feel), unlike local myal- gia or myofascial pain. Myospasm involves the entire muscle and pro- duces a dramatic increase in EMG activity in the muscle similar to maximum Voluntary clench, again unlike the slight increase associated with myalgia or myofascial pain (Lund, 2006). Myospasm is a relatively rare muscle disorder of the masticatory muscles. One common cause of myospasm of the medial pterygoid is a mandibular nerve block. The risk of myospasm increases when the injection is repeated several times to achieve profound anesthesia. This intervention inadvertently may cause local trauma, bleeding or the introduction of intraoral organisms into the muscle resulting in myospasm. Myositis and Tendonitis Myositis is defined as a true inflammation of muscle usually due to direct trauma and/or infection. Swelling, erythema and increased tem- perature over the entire muscle are common. Continuous severe pain and diffuse tenderness result in increased pain with function leading to a sig- nificant limitation in the range of motion. Ossification of a muscle can occur secondary to inflammation that leads to myositis ossificans (Kim et al., 2002). The inflammation may occur in the tendinous attachments of the muscle referred to as tendonitis or tendomyositis. When the tendon- ous attachments become inflamed, there is severe pain with use and pal- pation. This inflammatory condition often requires aggressive anti- inflammatory management. 55 Management of Jaw Disorders Muscle Contracture Muscle contracture or myofibrotic contracture is a painless shortening of a muscle as a result of fibrosis or scarring of the supporting tendons, ligaments or muscle fibers. Jaw opening is limited and usually is not painful except when the muscle is extended beyond its functional length. When the opening is stretched, there is an unyielding firmness or hard end-feel. This muscle disorder can occur following a long period of limited range of motion such as with extended use of intermaxillary fixa- t1On. Muscle Neoplasia Muscle neoplasia is defined as a new, abnormal or uncontrolled malignant or benign growth of muscle tissue that may or may not be as- sociated with pain. The tumors can be present within the muscle or more commonly are extensions from adjacent structures or metastases from remote sites. Swelling, trismus, paresthesias and possibly pain are com- mon features of these rare tumors. Confirmation with imaging and bi- opsy is required when a tumor is suspected (Hashizume et al., 2000; Mizen et al., 2004). ASSESSMENT OF MUSCULOSKELETAL DISORDERS Screening History and Examination The collection of baseline records and indicated diagnostic tests is fundamental to the proper management of jaw disorders. The extent to which any or all of the elements of evaluation are pursued depends upon the magnitude of the presenting complaints and the potential for the problem progressing physically and psychologically. Screening for jaw disorders is an essential part of all routine dental and orofacial pain ex- aminations (Goulet and Palla, 2008). Basic assessment of all patients also should include behavioral and psychosocial screening by the orthodontist during the history-taking process. The history should include questions to evaluate behavioral, social, emotional and cognitive factors that may ini- tiate, sustain or result from the patient's condition. If significant findings are identified and recorded, a comprehensive history and examination should be conducted (de Leeuw, 2008). Appropriate imaging studies of the jaw and craniofacial structure, as well as other diagnostic tests in- cluding blood and urine chemical analyses are important diagnostic tools in specific cases. Also, diagnostic Somatic and sympathetic nerve blocks, 56 McNeill and Rudd intra-articular TMJ injections and triggerpoint injections are extremely valuable as diagnostic aids. Comprehensive History and Examination The gold standard for diagnosis of TMD still is the interpretation of findings from a comprehensive history and comprehensive physical examination (Dworkin et al., 1990; De Wijer et al., 1995). The compre- hensive history parallels the traditional medical history and review of systems, and consists of the: Chief complaint(s); History of the complaints; Medical history; 4. Dental history; and 5. Personal history (social and family). : It is important for the orthodontist to not get lost in multiple complaints. The history of the present illness should include a chronological history for each complaint. The comprehensive physical examination consists of 1. A general inspection of the head and neck, including a visual inspection and palpation; 2. Cursory evaluation of the cranial nerves; 3. A comprehensive orthopedic evaluation of the TMJ (Fig. 12) and cursory evaluation of the cervical spine (Fig. 13): 4. A masticatory and cervical muscle evaluation (Figs. 14 and 15); and 5. An intra-oral evaluation. Figure 12 A: Assessment of the TMJs for tenderness with endoral palpation of the posterior *Spect of the joint and, atthe same time, assessing for jointnoises during mandibular movements. B. Use of abiaural stethoscope to further assessforjointnoises, especially for crepitus. 57 Management of Jaw Disorders Figure 13. Cervical range of motion is assessed for quality, range and pain with movement. Normal range of cervical rotation is 80-90° (A and B), side-bending (D and E); flexion (C) is 45° and extension (F) is 80°. Figure 14. A: Extraoral palpation of masseter. B: Extraoral palpation of temporalis muscles. 58 McNeill and Rudd Behavioral and Psychosocial Assessment With pain being defined at the beginning of this chapter as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage, it is read- ily apparent that a biopsychosocial model is required to manage orofacial pain. This assessment becomes especially important when these pain conditions become persistent. It long has been established that persistent pain disorders result in a number of biologic and psychologic changes. Persistent pain patients exhibit significant anxiety, depression, somatiza- tion, high utilization of health services and frequent use of pain medica- tions (Keefe et al., 2004). Because patients develop maladaptive patterns that prolong suffering and prevent effective symptom management, the comprehensive history needs to include an evaluation of the behavioral, Social, emotional and cognitive factors that either can sustain or result from their pain complaints. Psychological and psychosocial assessment can be incorporated effectively as part of the pain history with standardized self-report ques- tionnaires. A dual-axis system for physical and psychological assessment for TMD referred to as the Research Diagnostic Criteria for TMD (RDC) was developed by an international team of clinicians and researchers (Dworkin and LeResche, 1992). In 2005 they established a website with Axis I physical diagnoses, viable for research diagnostic classification standardization and Axis II for psychological assessment (International Consortium). The psychological assessment measures include: 1. A visual analog pain scale; 2. Mandibular function questionnaire; 3. Depression and somatization system checklists; and 4. A psychosocial functions graded chronic pain scale. Self-report questionnaires are numerous and can include the Holmes and Rahe Scale for life changes (Moody et al., 1982), the Inter- active Microcomputer Patient Assessment Tool for Health (IMPATH; Fricton et al., 1987) and the TMJ Scale (Spiegel and Levitt, 1991) as screening devices. These tests may indicate the need for a more extensive evaluation from a psychologist or psychiatrist. They may consider the <- Figure 15. A: Bilateral palpation of the SCM muscle. B: Bilateral palpation of the posterior deep cervical muscles. 59 Management of Jaw Disorders need for other psychological inventories such as the Symptom Checklist- 90-Revised (SCL-90-R), Post-traumatic Stress Disorder (PTSD) Civilian Checklist, Minnesota Multiphasic Personality Inventory (MMPI), Hamil- ton Depression Scale, West-Haven-Yale Multidimensional Pain Inven- tory, McGill Pain Questionnaire and the Million Behavioral Question- naire (Rugh, 1992; Bertoli et al., 2007). Imaging Imaging of the TMJ and orofacial structures may be necessary to rule out structural disorders of the jaw and other medical conditions that may be masquerading as a jaw disorder (Lareim and Westesson, 2006). Imaging primarily should be ordered after a comprehensive examination suggests some form of joint pathology or when there is a suspicion of some other serious non-musculoskeletal pathology such as an infection or tumor. Corrected tomography has been the choice of imaging for hard tissue pathology in the TMJ (Hussain et al., 2008). CBCT is the most accurate method for radiographically examining patients with suspected TMJ degenerative disease or other osseous pathology and structural aber- rations (Fig. 16; Honda et al., 2008). Magnetic resonance imaging (MRI) has diverse capabilities for the examination of suspected TMJ soft tissue disorders and pathology, e.g., disc displacement, effusion and tumors. As the resolution improves and technical advancement occurs, MRI clearly is becoming the study of choice for complex problem solving. The MRI studies on autopsy series of oblique sagittal and coronal views have been found to be approxi- mately 95% accurate in determining disc position (Tasaki and Westes- son, 2008). For the study of routine jaw disorders, MRI is indicated rarely for non-surgical TMD management because the study usually does not change the treatment approach. If surgical intervention is a consid- eration, however, a MRI study can be a critical diagnostic aid for surgical treatment planning. Additional Diagnostic Tests A variety of additional diagnostic studies are available for use in select cases to assist in confirming a physical diagnosis. Diagnostic tests may include laboratory tests (blood chemistries) for systemic arthritides; neural blockade, somatic and sympathetic nerve blocks; diagnostic spe- cific injections of TMJ and trigger point injections of the cervical and masticatory muscle; spray and stretch to determine if a soft-tissue trigger point is a source of pain. A physical therapy evaluation is useful 60 McNeill and Rudd | urº ºl - ººº-ºº- crº-ºrdinal view -Tº-Lº- Panuronic view - - - - | | | || Dººlau - - - - - ºn - º º: Image lº celled and Figure 16. CBCT of the right TMJ revealing significant degenerative joint disease of the condyle, including a large anteriorly fractured osteophyte in Sagittal, horizontal, coronal and 3D views. in order to determine the appropriateness of case-specific rehabilitation program, to evaluate the cervical spine as a source of orofacial pain and to perform a fibromyalgia screening examination to determine the com- plexity of the pain presentation (Fig. 17). Adjunctive Diagnostic Devices - There are a number of electronic devices marketed to diagnose Jaw disorders (TMD) including electromyography (EMG) testing, jaw tracking, thermography, sonography and vibration analysis. Peer- reviewed articles, however, have questioned the sensitivity (percentage of correctly diagnosed patients) and reliability (percentage of correctly diagnosed normals) of these technical diagnostic “TMD" tests. Many of the devices lack research support and are subject to great biologic Variability (Mohl et al., 1990a,b,c, Suvinen and Kemppainen, 2007). 61 Management of Jaw Disorders Figure 17. Palpation of the lateral epicondyle region by a physical therapist is part of the evaluation of the 18 control points assessed in the fibromyalgia screening process. Jaw tracking instrumentation that provides additional measure- ment data regarding mandibular movements does not justify treatment of the occlusion for TMD patients. The “high-tech electronic devices” that record jaw relationships and jaw movements often are recording biologic variations that can be misleading. Jaw tracking, however, can have tech- nical benefit for the orthodontist who wants to use a semi-adjustable or fully adjustable articulator when comprehensive restorative, orthodontic. 62 McNeill and Rudd prosthodontic or implant dentistry is being contemplated for dental treatment. The literature to date on the use of thermography for the diagno- sis of orofacial pain, also, has revealed conflicting evidence (Fikackova and Ekberg, 2004). Furthermore, there is insufficient evidence that vibra- tion analysis of the temporomandibular joint can diagnosis disc dis- placement with reduction any more accurately than the use of the stetho- scope and palpation (Motoyoshi et al., 1995). The US Food and Drug Administration (FDA) and the American Dental Association (ADA) used the term “adjunctive diagnostic devices” when they approved jaw tracking, EMG and sonography devices only for the measurement of clinical jaw signs (Greene et al., 1995). Both organi- zations did not approve the devices for having the ability to make a diag- nosis (Council on Scientific Affairs, 1997; FDA, 2003) and the ADA stated that “the interpretation of the test results rests with the dentist.” The interpretation that these data is supportive evidence that treatment is required to prevent TMD or that the occlusion needs to be altered from a TMD management standpoint is not in agreement with evidenced-based research. The primary concern with using these adjunctive devices is their low degree of diagnostic specificity resulting in a high number of false positive diagnoses. The risk of an incorrect diagnosis often based on over-interpretation of insignificant or normative physiological data can result in unnecessary treatment (Greene et al., 1995). Dental Casts Due to the many variables involved, it has been difficult to estab- lish significant cause and effect correlations between the occlusion and TMD (Sessle, 2003). Based on the literature, treatment involving the oc- clusion rarely is appropriate for treating TMD specifically. Because TMD is not correlated directly to the occlusion or specific jaw relation- ship, therefore, diagnostic casts to study the occlusion have little value in the assessment of TMD. Casts can be an important assessment aid for identifying wear patterns from sleep and awake bruxism, longitudinal comparisons of jaw relationship and/or occlusion changes due to an ar- ticular or muscular TMD condition. They also are extremely beneficial during the treatment planning process for complex restorative, prostho- dontic and orthodontic therapy including orthognathic surgery. Cast sur- gery on mounted diagnostic casts prior to surgery is helpful for both the Surgeon and the orthodontist. 63 Management of Jaw Disorders MANAGEMENT OF MUSCULOSKELETAL DISORDERS The majority of patients with jaw disorders achieve good symp- tomatic relief with a medical model using noninvasive management (Hodges, 1990). Long-term follow-up studies show that 85% to more than 90% of patients have few or no symptoms after conservative treat- ment (Garefis et al., 1994). A recent meta-analysis of TMD treatment need reports an approximate 16% need for adults (Al-Jundi et al., 2008). Jaw disorders are similar to other musculoskeletal disorders, but cur- rently not enough is known about the natural course of most jaw disor- ders and which signs and symptoms will progress to more serious condi- tions. As in other musculoskeletal conditions, the TMD signs and symp- toms vary and may be transient and self-limiting, resolving without seri- ous long-term effects. Recent reports on the course of untreated non- reducing disc displacement without reduction suggest that a natural reso- lution of symptoms occurs over time. The research from investigators in the Netherlands (Stegenga et al., 1991; de Leeuw et al., 1994) also sug- gests a natural course for not only some disc disorders but osteoarthritis as well. The peer-reviewed literature strongly supports that a special ef- fort should be made to avoid aggressive, irreversible therapy for the ar- ticular and non-articular jaw disorders (Randolph et al., 1990; Stohler and Zarb, 1999). As mentioned previously, treatment of the occlusion rarely is ap- propriate for specifically treating the subsets of TMD, based on the re- cent systematic reviews of randomized controlled trials (RCTs; Gesch et al., 2004). There are many testimonials and belief systems that claim that occlusion or incorrect jaw relationship is the primary etiologic factor for TMD, but scientifically, a direct correlation is largely unproven (Pullin- ger et al., 1993; McNamara et al., 1995; Clark and Tsukiyama, 1999; Kahn et al., 1999; Seligman and Pullinger, 2000). Thus, based upon the efficacy of the non-invasive medical model for the treatment of TMD and the lack of evidence that the occlusal therapy is necessary, the old concept of Phase I and Phase II treatment is obsolete. As a patient’s TMD signs and symptoms improve with the conservative medical man- agement model described in this chapter (“Phase I treatment”), there is no scientific evidence to support the need for subsequent definitive treatment of the occlusion (“Phase II treatment”; De Boever et al., 2000a,b; Koh and Robinson, 2003). When TMD signs and symptoms resolve, the only compelling reasons to proceed with treatment of the occlusion would be based on dental (tooth and/or periodontal) pathology, 64 McNeill and Rudd mobility, discomfort or esthetic reasons. Even then, great care should be taken with this “at-risk” patient relative to minimizing trauma to the pa- tient’s jaw including minimal appointments, limited jaw opening, and reduced force loading. Less rather than more complex dental procedures should be contemplated, especially when considering making changes in the occlusion. Open TMJ surgery rarely is indicated and, when indicated, only for selected cases. Open surgery is indicated for structural joint deformi- ties and disease including extreme developmental discrepancies, neopla- sia, bony or fibrous ankylosis and displaced condylar fractures resulting in significant functional problèms (Nickerson and Veaco, 1989). Arthrocentesis has been shown to be as effective as arthroscopic surgery and is less invasive. Both surgical procedures can be indicated for acute disc displacement without reduction and, on rare occasion, for extreme joint inflammatory and pain (Nitzan et al., 1990; Al-Belasy and Dolwick, 2007; Schiffman et al., 2007). A multidisciplinary medical model that includes patient educa- tion and self-care, cognitive behavioral intervention, pharmacologic ther- apy, physical rehabilitation and/or orthopedic appliance therapy is en- dorsed for the management of nearly all patients (Table 7; NIH, 1996). Management goals should be diagnosis specific. Common goals are: 1. Reduction of pain; 2. Reduction of adverse loading; 3. Improvement of mobility and function, and 4. Restoration of activities of daily living. Emphasis should be placed on conservative therapy that facilitates the musculoskeletal system's natural healing capacity. Proper management requires the patient to assume responsibility for the physical and behav- ioral management of his or her own problem. There are a small number of TMJ disorders that require surgical intervention, e.g., developmental conditions resulting in significant structural, functional and/or esthetic problems, tumors, ankylosis or fracture that will be discussed elsewhere in this publication (Reston and Turkelson, 2003; Dolwick, 2007). Table 7. Multidisciplinary management model. Patient Education and Self-Care Cognitive Behavioral Interventions Pharmacologic Therapy Physical Rehabilitation Orthopedic Appliance Therapy 65 Management of Jaw Disorders Patient Education and Self-Care The success of a self-care program depends on patient motiva- tion, cooperation and adherence. A successful program begins with a thorough explanation of the patient’s diagnosis/diagnoses and a discus- sion about the patient’s prognosis. Once the patient understands his or her condition, the self-care program is more meaningful and patient ad- herence is higher. When the jaw disorder is mild, patient education and instructions in a self-care program may be all that is required (Truelove et al., 2006; Riley et al., 2007). Self-care instructions should be specific for the patient’s diagno- sis and clinical presentation and should be directed toward achievable goals. These instructions typically include resting the masticatory system through correct relaxed jaw posture awareness with an emphasis on not contacting opposing teeth unless swallowing, i.e., preventing awake clenching and grinding of the teeth. Patients need to be mindful of any other oral habits that delay their recovery such as jaw protrusion, cheek sucking or tongue bracing behaviors. Patients generally benefit from a soft diet and slower mastication. If they need joint protection, as with joint inflammation or disc instability, patients benefit from chewing on the affected side, limiting incising their food, and avoiding prolonged opening (Wright et al., 1995). The instructions also may include palliative recommendations such as moist heat to increase circulation and relax muscles for local my- algia and myofascial pain. Ice is the preferable thermal modality to de- crease pain and inflammation when there is an acute joint inflammation. Self-massage of the affected muscles is another method to relax tight muscles and improve local circulation. Gentle range of motion exercises sometimes are appropriate to lubricate the joint, reducing joint pain and increasing range of motion. Other instructions may focus on head and neck posture, ergonomics and sleep positioning, general suggestions for improved health habits, cardiovascular exercise and sleep hygiene. Cognitive Behavioral Intervention Behavioral intervention is an important part of the overall medi- cal management program for patients with jaw disorders (Dworkin, 2008). Simply making patients aware of their jaw habits often is enough to improve jaw relaxation skills, but changing persistent habits may re- quire a structured program with a clinician trained in behavior modifica- tion strategies. Comprehensive stress management and counseling pro- 66 McNeill and Rudd grams using a combination of EMG biofeedback, progressive relaxation, diaphragmatic breathing and self-directed changes in lifestyle appear to be more effective than any one behavioral treatment procedure in isola- tion. Unfortunately, biofeedback generally is not effective for treatment of sleep bruxism (Pierce and Gale, 1988). Patients with persistent pain or who have experienced multiple treatment failures typically require in- depth psychological evaluation and treatment by a mental health profes- sional such as a psychologist or psychiatrist. Pharmacologic Therapy The indicated classes of pharmacologic agents include analge- sics, nonsteroidal anti-inflammatory agents, corticosteroids, anxiolytics, muscle relaxants, low-dose (pain-dosing) antidepressants and nerve membrane stabilizers. The non-opiate analgesics, such as Acetamino- phen (Tylenol), are effective for mild to moderate pain, whereas the opioid narcotics, such as Codeine, Ultram, Hydrocodone and Demerol, only should be used short term for controlling more severe acute pain (Stohler, 2008). Opioid narcotics produce tolerance and dependence and should be used on a time-contingent basis (Dionne, 2006). Nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., Ibuprofen [Motrin], Naproxen [Naprosyn] or Nabumetone [Relafen]) are effective analgesics and anti- inflammatory agents. They are prescribed for painful articular inflamma- tory disorders, usually not for muscle disorders. They must be prescribed at therapeutic levels over a significant period of time to achieve the de- sired anti-inflammatory effects. Caution should be exercised when pre- scribing these medications, as they can cause gastrointestinal irritation and bleeding. When nonsteroidal anti-inflammatory medications are con- traindicated or ineffective, corticosteroids can be considered for persis- tent localized moderate to severe joint inflammation. These medications can be delivered orally, e.g., Methyprednisolone (Medrol) dosepak or can be injected directly into the TMJ, e.g., Prednisolone (Depomedrol). The benzodiazepines, such as Alprazolam (Xanax), Lorazepam (Ativan) and Diazepam (Valium), are prescribed most commonly for their anti-anxiety effects. These drugs act as depressants and should be used only for short-term for acute muscle pain/spasm (trismus), to relax patients prior to jaw manipulation for acute disc displacement without reduction and/or for sleep disturbances associated with anxiety (Dellemijn and Fields, 1994; Huynh et al., 2006). Muscle relaxants such as Cyclobenzaprine (Flexeril), Metaxolone (Skelaxin) and Tizanidine (Zanaflex) are useful for acute and especially chronic muscle pain. Cy- 67 Management of Jaw Disorders clobenzaprine, which is quite similar chemically to the tricyclic antide- pressants, is one of the drugs of choice by rheumatologists and pain spe- cialists for generalized persistent muscle pain (Brown and Womble, 1978; Toth and Utis, 2004). Cyclobenzaprine (5-10 mg at bedtime) is reported to improve sleep architecture and reduce sleep bruxism. Tri- cyclic antidepressants such as Nortriptyline (Pamelar), Doxepin (Sine- quan) and Desipramine (Norpramin), when used in low dosages (10–75 mg) have been shown to act on central nervous system neurotransmitters improving the patient’s pain regulation. They are prescribed for persis- tent pain patients who have neuropathic pain, persistent myofascial pain and poor restorative sleep (Tura and Tura, 1990; Benbouzid et al., 2008). Studies suggest that they also may reduce sleep bruxism. Membrane stabilizers or anti-seizure drugs, such as Carba- mazepine (Tegretol) and Phenytoin (Dilantin), have been replaced with improved medications like Gabapentin (Neurontin) and Pregablin (Lyrica) for persistent pain conditions including neuropathic atypical odontalgia pain. These second generation medications have less signifi- cant side-effect profiles than the former drugs (Kimos et al., 2007). Re- cently botulinum toxin has been used as a treatment for head and neck pain including tension-type headache and migraine headaches. The theo- ries related to the mechanisms of action include direct effects at the neu- romuscular junction and direct antiproprioceptive effects and the inhibi- tion of the release of neuropeptides including substance P and CGRP and various neuromodulators. Reportedly, botulinum toxin provides signifi- cant relief of facial pain and reduces the intensity, frequency and dura- tion of recurrent episodes. It is strongly suggested, however, that it be used after standard conservative therapy fails and prior to surgical inter- vention. Adverse effects from botulinum toxin are mild, transient and reportedly limited to adjacent muscle weakness (Song et al., 2007). Physical Therapy Physical therapy is recognized as an effective and conservative approach for patients with jaw disorders (Clark et al., 2007). A physical therapy consultation should be performed by a physical therapist involv- ing a comprehensive head, neck, upper quarter orthopedic evaluation and fibromyalgia screening. Based on these findings, a rehabilitation program is designed to restore optimal masticatory, cervical and upper quarter function as appropriate. The rehabilitation strategies are based on the patient’s diagnoses, clinical findings and the patient’s personal treatment goals. Treatment goals commonly include: 68 McNeill and Rudd Pain control; Optimizing joint biomechanics and range of motion; Restoring functional muscle strength and endurance; . Restoring the ability to perform activities of daily liv- ing of the jaw such as talking, chewing, yawning, and singing; or of the 5. Cervical and upper quarter regions such as sitting, reading, driving, lifting and reaching. The management begins with patient education and instructions in a structured self-care program. The next goal is to reduce pain as effi- ciently as possible so the patient can begin exercising his or her jaw, neck and upper quarter as appropriate. Physical agents such as moist heat, cold packs, transcutaneous electrical nerve stimulators (TENS), iontophoresis, ultrasound and vapocoolants initially may be used for pain control. Moist heat increases local circulation and relaxes muscles, im- proving the nutrition to the tissue and removes the inflammatory by- products from the area. Cold packs anesthetize the area reducing pain, initially decreasing the circulation reducing an inflammatory response. TENS inhibits “c” fibers, thereby reducing the propagation of pain. Ion- tophoresis uses an electric galvanic stimulator to deliver corticosteroids through the tissues. Ultrasound is a thermal device that produces sound waves. The sound waves penetrate the skin at a depth of up to 5 cm, vi- brating the tissue and creating a mechanical heat that results in increased local circulation and muscle relaxation (Fig. 18). Vapocoolants anesthe- tize the skin so that a muscle with tight bands (trigger points) can be stretched, deactivating the referred pain from the trigger points (Fig. 19). Soft-tissue mobilization and myofascial release techniques commonly are used to increase local circulation, restore normal muscle tone and deactivate myofascial trigger points (Fig. 20). Once the patient has better pain control, the therapist can mobilize the joints as needed and begin a range of motion and muscle conditioning program. Joint mo- bilization is essential for the acute disc displacement without reduction. The therapist manually distracts and translates the condyle under the pos- terior band of the displaced disc, restoring full condylar translation and the former condition of disc displacement with reduction. Joint mobiliza- tion also is indicated when jaw mobility is limited for other reasons. Mo- bilization techniques to restore rotation and translation for optimal joint biomechanics are performed before muscle stretching is initiated. 69 Management of Jaw Disorders º Figure 18. Ultrasound application to the right masseter region. Figure 19. Spray and Stretch technique to eliminate a masseter muscle trigger point that is referring pain to the head and teeth. This same philosophy is applied to other joints of the upper quar- ter. Once improved joint mechanics are achieved, range of motion and stretching exercises are introduced to facilitate normal movement of the joint and muscles. For more persistent hypomobility conditions such as in post-operative rehabilitation, a Therabite exercise device is helpful. 70 McNeil/ and Rudd making stretching more comfortable for the patient so exercise compli- ance is higher (Fig. 21). For hypomobility of shorter duration, simple active-assisted exercises for opening and laterotrusion are prescribed (Fig. 22). Lastly, muscle strengthening and conditioning ensures the safe return to previous levels of function without re-injury. Patients who only do palliative treatments are likely to re-aggravate their tissues when they advance their diet, attempt to use their jaw normally or resume other ac- tivities of daily living. Figure 20. Soft tissue mobilization of the left masseter. - A - Figure 21. Assisted opening using a Therabite exercise device. A: Therabite placement. B. Patient gently squeezing the device to assist mandibular opening. 71 Management of Jaw Disorders Figure 22. A. The patient performing an active-assisted opening exercise. B. Actively assisted laterotrusion exercise. Physical therapy for persistent pain conditions requires less periph- eral (local) management and involves strategies to influence the central nervous system. The therapist must address sleep positioning and sleep hy- giene to enhance restorative sleep (Fig. 23). It also is essential to motivate patients to be more active, establishing realistic and achievable exercise goals to improve general strength and endurance. Education about dia- phragmatic breathing and relaxation training is another important compo- nent in the rehabilitation program. Lastly, stressing the proper pacing of activities is important, so as not to overdo on a better day only to relapse and have increased pain the following day. Better restorative sleep, in- creased activity, improved relaxation skills and improved pacing with ac- tivities of daily living improve the patient’s central pain modulation system. Figure 23. A. Proper side-lying positioning using a memory foam pillow and a second traditional pillow to achieve a neutral cervical posture and mandibular support. B. Proper supine positioning with the cervical lordosis (concavity) supported with a medium height pillow. 72 McNeill and Rudd Throughout physical therapy, the patient should be reassessed frequently by the physical therapist and the referring orthodontist. The patient should be achieving their management goals and requiring fewer treatments with the therapist. If the patient is not improving as expected, additional diagnostic testing and or consults must be considered. Ulti- mately, the patient should be discharged from treatment with an inde- pendent home management program. Orthopedic Appliance Therapy Orthopedic appliances (also referred to as orthoses, occlusal splints, bite splints, bite plates, night guards or bruxism appliances) commonly have been used in the management of jaw disorders (Carraro and Caffesse, 1978). There is general agreement that some patients with myofascial pain, articular disc instability and joint inflammation either exacerbate or sustain their symptoms when they brux their teeth at night. These patients may benefit from appliances worn during sleep. Appli- ances also have dental benefits with regard to protecting the teeth and/or restorations from wear and fracture, as well as decreasing tooth sensitiv- ity and mobility. Appliances should be worn only during sleep in order to limit the amount of time the appliance masks the periodontal propriocep- tive input that allows the patient to return to their intercuspal position (ICP) when the appliance is removed. There still is great debate about how to design an appliance for the greatest efficacy (Clark, 1984). Systematic reviews of randomized controlled trials (RCTs) suggest that appliance design (i.e., specific types of occlusal interfaces and/or jaw positions) are not a very critical factor for the management of bruxism or masticatory muscle pain. Most den- tists agree, however, that orthopedic appliances should cover all the teeth on either the maxillary or mandibular arch in order to prevent irreversible changes in the occlusion (Fig. 24). Partial coverage appliances can allow teeth to extrude or intrude and/or cause condyles to reposition within the articular fossae. The type of material, whether hard acrylic or soft vinyl, also is no longer an important consideration. The efficacy of soft vinyl appliances, which were questioned in the past, have been reported to be comparable to hard acrylic appliances in recent studies for the manage- ment of masticatory muscle pain (Wright et al., 1995). Even though vinyl appliances are effective for most TMD diagnoses, tooth sensitivity, minimal-to-moderate tooth wear and hard acrylic appliances should be considered for severe tooth wear and increased tooth mobility. Jaw stabi- lizing and test appliances for re-establishing the jaw and occlusion rela- 73 Management of Jaw Disorders Figure 24. Frontal and occlusal view of a processed acrylic maxillary orthosis. tionships are best fabricated with hard acrylic in order to establish spe- cific and more precise relationships. The interocclusal appliance flow chart in this section (Fig. 25) attempts to strategize the use of the appliances based on the individual patient’s specific problem (case-specific management). Interocclusal ap- pliances are used primarily to manage conditions related to sleep or even awake bruxism or as a provisional appliance to stabilize the jaw relation- ship and test a new jaw and interocclusal treatment relationship. The ef- fects of sleep bruxism can be related to an exacerbation of TMD signs and symptoms and create multiple dental problems to the teeth, restora- tions and supporting tissues. Bruxism, including clenching and grinding of the teeth, can exacerbate existing TMD signs and/or symptoms (e.g., symptomatic disc displacements, osteoarthritis, local myalgia or myofas- cial pain). Bruxism also can result in tooth sensitivity, mobility, fracture and tooth and/or restoration wear from abrasion or attrition. Because a definite cause and effect relationship has not been es- tablished between bruxism and TMD, bruxism is thought to be a contrib- uting or secondary etiological factor rather than the primary factor. Thus, appliances used for the treatment of the effects of bruxism generally are fabricated in an intercuspal position (ICP) or maximum intercuspation (MI), based on the lack of evidence that occlusal relationships cause bruxism or TMD. An alteration or re-establishment of the occlusion is not indicated unless the occlusion needs to be re-established from a den- tal health standpoint. If a change in the vertical dimension of occlusion (VDO) and/or new reference position (i.e., retruded contact position [RCP) or centric relation [CR]) technically is required to perform com- plex dental treatment such as prosthodontics, orthodontics or orthog- nathic surgery, a test appliance should be considered prior to the treat- 74 McNeil/ and Rudd INTEROCCLUSAL APPLIANCES (Orthoses INightguards vs. Occlusal Stabilizing Splints) | Bruxism Related | New Reference Conditions Position (Maintain ICP/M) (Estab Rcºcº) Rºſaw Sn & SX | Tooth sm & sy Tooth Wear - Stabilize & Test TMJ & Mast Ms. | Pain/Fractſmobility | Abrasion/Attrition | Occi. 8. Jaw Rel. - (Vinyl- Acrylic) (vinyl = Acrylic, (Severe- Acrylic) || ||(Mt. Casts - Acrylic). Figure 25. Interocclusal appliances are used primarily for two main reasons: (1) to manage conditions related to sleep bruxism; or (2) as a provisional appliance to stabilize the jaw relationship and test a new jaw and interocclusal treatment relationship. In the first condition, the effects of sleep bruxism can be related to an exacerbation of TMD signs and symptoms and/or create multiple dental problems to the teeth, restorations and supporting tissues. In the second, a new reference position can be established with an appliance prior to orthodontic treatment, including orthognathic surgery, or prosthodontic treatment when the existing intercuspal position is not acceptable or the jaw relationship is not stable. ment. The appliance is fabricated to both stabilize the existing structural JaW relationships and to test the contemplated new structural changes to the occlusion. Currently, an appliance called the Nociceptive Trigeminal Inhi- bition Splint (NTI) is being marketed widely to the dental profession and the public (Fig. 26). The appliance covers the maxillary central incisors allowing contact on jaw closure with only the lower incisors based on the old concept of the Lucia Jig and the Leaf Gauge (Lucia, 1960; Long, 1973). The anterior contact reportedly decreases jaw elevator muscle activity and associated muscle pain and headache. However, a recent Study reported that the decrease in postural EMG activity in a myofascial 8Toup was short lasting and should not be considered as evidence that the appliance has a long-term muscle relaxation effect (Bodere and Woda, 2008). 75 Management of Jaw Disorders | There are two primary disadvantages of this appliance. First, an- terior tooth contact only increases TMJ loading, possibly resulting in an exacerbation of an existing articular condition. Secondly, the appliance can cause a significant irreversible repositioning of the condyle and/or disc resulting in an irreversible change in the occlusion. Studies have revealed no significant differences in muscle pain between a full- coverage stabilization appliance or a NTI appliance after three months (Jokstad et al., 2005). At six-month follow-up, the stabilization splint was favored over the NTI splint by a number of the patients with an added advantage of less risk for occlusal changes (Magnusson et al., 2004). Figure 26. Container and Nociceptive Trigeminal Inhibition (NTI) anterior guide-plane that fits over the maxillary central incisors. The appliance allows contact only with the mandibular central incisors creating disclusion or separation of the posterior teeth. There are two primary disadvantages of this appliance. First, anterior tooth contact only, increases TMJ loading possibly resulting in an exacerbation of an existing articular condition. Secondly, the appliance can cause a significant irreversible repositioning of the condyle and/or disc resulting in an irreversible change in the occlusion. 76 McNeill and Rudd Recent scientific reviews and RCTs find no difference in effi- cacy between active full-occlusal coverage appliances vs. palatal cover- age placebo appliances for the treatment of bruxism (Macedo et al., 2007). They also have found that full occlusal coverage stabilization ap- pliances performed no better than non-occluding palatal coverage appli- ances for the treat of masticatory muscle pain (Dao et al., 1994; Turp et al., 2004; Al-Ani et al., 2005). In recent studies, the effectiveness of oc- clusal appliance therapy vs. conservative medical treatment for mastica- tory muscle pain is comparable. One systematic review concluded that there was insufficient evidence to suggest that stabilization appliances are more effective than other treatments such as self-care, acupuncture, biofeedback, relaxation and exercises for treatment of TMD pain (Nilner, 2004). CONCLUSION Managing pain and relieving suffering should be at the core of the health professional’s commitment to patients. Proper pain manage- ment is mandated in order to prevent the consequences of unrelieved pain. Recent scientific and clinical advances have recognized that unre- lieved pain can cause delayed healing, an altered immune system, an al- tered stress response, vegetative symptoms and permanent alterations in the peripheral and central nervous systems resulting in persistent pain syndromes. Therefore, every medical and ethical reason to treat pain, including orofacial pain, in a timely manner with every resource is avail- able. In doing so, when at all possible, we need to provide irreversible, non-invasive treatment that facilitates the natural healing process and that also helps to sufficiently alleviate pain. As health providers, we al- ways must remember the axiom: physician, do no harm! REFERENCES Al-Ani Z, Gray RJ, Davies SJ, Sloan P, Glenny AM. Stabilization splint therapy for the treatment of temporomandibular myofascial pain: A systematic review. J Dent Educ 2005;69;1242–1250. Al-Belasy FA, Dolwick MF. Arthrocentesis for the treatment of tem- poromandibular joint closed lock: A review article. Int J Oral Maxil- lofac Surg 2007:36:773-782. Al-Jundi MA, John MT, Setz JM, Szentpétery A, Kuss O. Meta-analysis of treatment need for temporomandibular disorders in adult nonpa- tients. J Orofac Pain 2008:22:97-107. 77 Management of Jaw Disorders Ambalavanar R, Moritani M, Moutanni A, Gangula P, Yallampalli C, Dessem D. Deep tissue inflammation upregulates neuropeptides and evokes nociceptive behaviors which are modulated by a neuro- peptide antagonist. Pain 2006; 120:53-68. Aniceto GS, Peñín AG, de la Mato Pages R, Moreno JJM. Tumors me- tastatic to the mandible: Analysis of nine cases and review of the lit- erature. J Oral Maxillofac Surg 1990:48:246-251. Aprill C, Dwer A, Bogduk N. Cervical zygapophyseal joint pain patterns. II: A clinical evaluation. Spine 1990; 15:458–461. Baad-Hansen L. Atypical odontalgia: Pathophysiology and clinical man- agement. J Oral Rehabil 2008:35: 1-11. Baad-Hansen L, Leijon G, Svensson P, List T. Comparison of clinical findings and psychosocial factors in patients with atypical odontalgia and temporomandibular disorders. J Orofac Pain 2008:22:7-14. Bartsch T, Goadsby PJ. The trigeminocervical complex and migraine. Current concepts and synthesis. Curr Pain Headache Rep 2003;7:371-376. Behrents RG, McNamara JA Jr, Avery JK. Prenatal mandibulofacial dysostosis (Treacher Collins syndrome). Cleft Palate J 1977; 14:13- 34. Bellamy J, Bowen EJ, Russo AF, Durham PL. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neursci 2006:23:2057-2066. Benbouzid M, Gavériaux-Ruff C, Yalcin I, Waltisperger E, Tessier LH, Muller A, Kieffer BL, Freund-Mercier MJ, Barrot M. Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuro- pathic allodynia. Biol Psychiatry 2008;63:633-636. Bertoli E, de Leeuw R, Schmidt JE, Okeson JP, Carlson CR. Prevalence and impact of post-traumatic stress disorder symptoms in patients with masticatory muscle or temporomandibular joint pain: Differ- ences and similarities. J Orofac Pain 2007:21:107-119. Block MS, Provenzano J, Neary JP. Complications of mandibular frac- tures. Oral Maxillofac Surg Clin North Am 1990:2:525-550. Bodere C, Woda A. Effect of a jig on EMG activity in different orofacial pain conditions. Int J Prosthod 2008;21:253–258. Brecht K, Johnson CM III. Complete mandibular agenesis: Report of a case. Arch Otolaryngol 1985; 11.1:132-134. 78 McNeill and Rudd Brown BR Jr, Womble J. Cyclobenzaprine in intractable pain syndromes with muscle spasm. JAMA 1978:240: 1151-1 152. Buckingham RB, Braun T, Harinstein DA, Oral K, Bauman D, Bartynski W, Killian PJ, Bidula LP. Temporomandibular joint dysfunction syndrome: A close association with systemic laxity (the hypermobile joint syndrome). Oral Surg Oral Med Oral Pathol 1991;72:514-519. Burgess JA, Kolbinson DA, Lee PT, Epstein JB. Motor vehicle accidents and TMDs: Assessing the relationship. J Am Dent Assoc 1996; 127:1767–1772. Campbell RL, Parks KW. Dodds RN. Chronic facial pain associated with endodontic therapy. Oral Surg Oral Med Oral Pathol 1990;69:287- 290. Carraro JJ, Caffesse RG. Effect of occlusal splints on TMJ symptomol- ogy. J Prosthet Dent 1978;40:563-566. Clark GT. A critical evaluation of orthopedic interocclusal appliance therapy: Design, theory, and overall effectiveness. J Am Dent Assoc 1984;108:359-364. Clark GT, Adashi NY, Dornan MR. Physical medicine procedures affect temporomandibular disorders: A review. J Am Dent Assoc 1990; 121:151 – 162. Clark GT, Tsukiyama Y, Baba K, Watanabe T. Sixty-eight years of ex- perimental occlusal interference studies: What have we learned? J Prosthet Dent 1999;82:704–713. Cooper G, Bailey B, Bogduk N. Cervical zygapophysial joint maps. Pain Med 2007;8:344–353. Council on Scientific Affairs, American Dental Association. Acceptance Program Guidelines: Devices for Evaluation of Temporomandibular Musculoskeletal Complex (TMSC). Adopted May 1997. Dao TT, Lavigne GJ, Charbonneau A, Feine JS, Lund JP. The efficacy of oral splints in the treatment of myofascial pain of the jaw muscles: A controlled clinical trial. Pain 1994:56:85-94. De Boever JA, Carlsson GE, Klineberg IJ. Need for occlusal therapy and prosthodontic treatment in the management of temporomandibular disorders. Part I: Occlusal interferences and occlusal adjustment. J Oral Rehabil 2000a:27:367–379. De Boever JA, Carlsson GE, Klineberg IJ. Need for occlusal therapy and prosthodontic treatment in the management of temporomandibular 79 Management of Jaw Disorders disorders. Part II: Tooth loss and prosthodontic treatment. J Oral Re- habil 2000b:27:647–659. de Leeuw R, Boering G, Stegenga B, de Bont, LGM. Clinical signs of TMJ osteoarthrosis and internal derangement 30 years after nonsur- gical treatment. J Orofacial Pain 1994;8:18-24. de Leeuw R, ed. Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management. 4" ed. Chicago: Quintessence Publishing Co., 2008. de Wijer A, Lobbezoo-Scholte AM, Steenks MH, Bosman F. Reliability of clinical findings in temporomandibular disorders. J Orofac Pain 1995;9:181-191. Dellemiji PL, Fields HL. Do benzodiazepines have a role in chronic pain management? Pain 1994:57:137-152. Dijkgraaf LC, Zardeneta G, Cordewener FW, Liem RS, Schmitz JP, de Bont LG, Milam SB. Crosslinking of fibrinogen and fibronectin by free radicals: A possible initial step in adhesion formation in os- teoarthritis of the temporomandibular joint. J Oral Maxillo Surg 2003;61:101-111. Dolwick MF. Temporomandibular joint surgery for internal derange- ment. Dent Clin North Am 2007:51:195-208. D’Silva NJ, Summerlin DJ, Cordell KG, Abdelsayed RA, Tomich CE, Hanks CT, Fear D, Meyrowitz S. Metastatic tumors in the jaws: A retrospective study of 114 cases. J Am Dent Assoc 2006; 137:1667- 1672. Dworkin SF, Huggins KH, LeResche L, Von Korff M, Howard J, True- love E, Sommers E. Epidemiology of signs and symptoms in tem- poromandibular disorders: Clinical signs in cases and controls. J Am Dent Assoc 1990;120:273-281. Dworkin SF, LeResche L. Research diagnostic criteria for temporoman- dibular disorders: Review, criteria, examinations and specifications, critique. J Craniomand Disord 1992;6:301-355. Dworkin SF, LeResche L, DeRouen T, Von Korff M. Assessing clinical signs of temporomandibular disorders: Reliability of clinical exam- iners. J Prosthet Dent 1990;63:574-579. Dwyer A, Aprill C, Bogduk N. Cervical zygapophyseal joint pain pat- terns. I: A study in normal volunteers. Spine 1990;15:453-457. 80 McNeill and Rudd Eliav E, Kamran B, Schaham R, Czerninski R, Gracely RH, Benoliel R. Evidence of corda tympani dysfunction in patients with burning mouth syndrome. J Am Dent Assoc 2007;138:628–633. Fikackova H, Ekberg E. Can infrared thermography be a diagnostic tool for arthralgia of the temporomandibular joint? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:643-650. Food and Drug Administration. Department of Health and Human Serv- ices. Medical Devices: Classification of the Dental Sonography De- vice and Jaw Tracking Device. Final Rule. Fed Regist 2003;68:67365-67367. Forssell H, Kalso E. Koskela, Vehmanen R, Puukka P, Alanen P. Occlu- sal treatments in temporomandibular disorders: A qualitative system- atic review of randomized trials. Pain 1999;83:549–560. Fricton JR, Awad E.A. Myofacial pain syndrome: Characteristics and epidemiology. In: Advances in Pain Research and Therapy, Vol. 17, Myofacial Pain and Fibromyalgia. New York: Raven Press 1990; 107-127. Fricton JR, Nelson A, Monsein M. IMPATH: Microcomputer assessment of behavioral and psychosocial factors in craniomandibular disor- ders. Cranio 1987:5:372-381. Garefis P, Grigoriadou E, Zarifi A, Koidis PT. Effectiveness of conserva- tive treatment for craniomandibular disorders: A 2-year longitudinal study. J Orofac Pain 1994;8:309-314. Gear RW. Neural control of oral behavior and its impact on occlusion. In: McNeill C, ed. Science and Practice of Occlusion. Chicago: Quintessence Publishing Co., 1997:50-68. Gesch D, Bernhardt O, Kirbschus A. Association of malocclusion and functional occlusion and temporomandibular disorders (TMD) in adults: A systematic review of population based studies. Quintes- sence Int 2004:35:211-221. Graff-Radford SB, Solberg WK. Atypical odontalgia. J Craniomandib Disord 1992;6:260-265. Greene CS, Lund JP, Widmer CG. Clinical diagnosis of orofacial pain: Impact of recent FDA ruling on electronic devices. J Orofac Pain 1995;9:7-8. 81 Management of Jaw Disorders Hashizume A, Nakagawa Y, Nagashima H, Ishibashi K. Rectal adeno- carcinoma metastatic to the masseter muscle. J Oral Maxillofac Surg 2000:58:324-327. Headache Classification Committee of the International Headache Soci- ety. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8: 1-96. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia 2004:24:S9-160. Hodges JM. Managing temporomandibular joint syndrome. Laryngo- scope 1990; 100:60-66. Honda K, Larheim TA, Maruhashi K, Matsumoto K, Iwai K. Osseous abnormalities of the mandibular condyle: Diagnostic reliability of cone beam computed tomography compared with helical computed tomography based on an autopsy material. Dentomaxillofac Radiol 2008:35:152-157. Hussain AM, Packota G, Major PW, Flores-Mir C. Role of different im- aging modalities in assessment of temporomandibular joint erosions and osteophytes: A systematic review. Dentomaxillofac Radiol 2008:37:63-71. Huynh N, Lavigne GJ, Lanfranchi PA, Montplaisir JY, De Champlain J. The effect of 2 sympatholytic medications – propranolol and clonidine – on sleep bruxism: Experimental randomized controlled studies. Sleep 2006:29:307-316. International Consortium for RDC/TMD-Based Research (www.rdc- tmainternational.org). International Headache Society website (www.ICHDII.org). Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 2003;102:1-8. Jokstad A, Mo A, Krogstad BS. Clinical comparison between two differ- ent splint designs for temporomandibular disorder therapy. Acta Odontol Scand 2005;63:218–226. Kahn J, Tallents RH, Katzberg RW, Ross ME, Murphy WC. Prevalence of dental occlusal variables and intraarticular temporomandibular disorders: Molar relationship, lateral guidance and nonworking side contacts. J Prosthet Dent 1999;82:410–415. 82 McNeill and Rudd Katzberg RW, Westesson PL, Tallents RH, Drake CM. Anatomic disor- ders of the temporomandibular joint disc in asymptomatic subjects. J Oral Maxillofac Surg 1996:54: 147-153. Keefe FJ, Rumble ME, Scipio CD, Giordano LA, Perri LM. Psychologi- cal aspects of persistent pain: Current status of the science. J Pain 2004;5:195-211. Kim DD, Lazow SK, Har-El G, Berger JR. Myositis ossificans trau- matica of masticatory musculature: A case report and literature re- view. J Oral Maxillofac Surg 2002;60:1072–1076. Kimos P, Biggs C, Mah J, Heo G, Rashiq S, Thie NM, Major PW. Anal- gesic action of gabapentin on chronic pain in the masticatory mus- cles: A randomized controlled trial. Pain 2007;127:151-160. Klasser GD, Balasurbramaniam R, Epstein J. Topical review – Connec- tive tissue diseases: Orofacial manifestations including pain. J Oro- fac Pain 2007:21:171-184. Koh H, Robinson PG. Occlusal adjustment for treating and preventing temporomandibular joint disorder. Cochrane Database Syst Rev 2003;1:CD003812. Kurita K, Westesson PL, Tasaki M, Liedberg J. Temporomandibular joint: Diagnosis of medial and lateral disc displacement with anterio- posterior arthrography. Correlations with cryosections. Oral Surg Oral Med Oral Pathol 1992;73:364-368. Kurita K, Westesson PL, Yuasa H, Toyama M, Machida J, Ogi N. Natu- ral course of untreated symptomatic temporomandibular joint disc displacement without reduction. J Dent Res 1998;77:361-365. Larheim TA, Westesson PL, Sano T. Temporomandibular joint disk dis- placement: Comparison in asymptomatic volunteers and patients. Radiology 2001:218:428-432. Laskin DM, Greene CS, Hylander WL. Temporomandibular Disorders: An Evidenced-based Approach to Diagnosis and Treatment. Chi- cago: Quintessence Publishing Co., 2006:249-253. LeResche L. Epidemiology of temporomandibular disorders: Implica- tions for the investigation of etiologic factors. Crit Rev Oral Biol Med 1997:8:291-305. Lieber RL, Friden J. Morphologic and mechanical basis of delayed-onset muscle Soreness. J Am Acad Orthop Surg 2002;10:67–73. 83 Management of Jaw Disorders Lipton JA, Ship JA, Larach-Robinson D. Estimated prevalence and dis- tribution of reported orofacial pain in the United States. J Am Dent Assoc 1993;124; 115-121. List T, Leijon G, Helkimo M, Oster A, Dworkin SF, Svensson P. Clinical findings and psychosocial factors in patients with atypical odontal- gia: A case-control study. J Orofac Pain 2007:21:89-98. Long JH. Locating centric relation with a leaf gauge. J Prosthet Dent 1973:29:608-610. Lucia VO. Centric relation: Theory and practice. J Prosthet Dent 1960; 10:849-856. Lund JP, Donga R, Widmer CG, Stohler CS. The pain-adaptation model: A discussion of the relationship between chronic musculoskeletal pain and motor activity. Can J Physiol Pharmacol 1991;69:683-694. Lund JP, Lavigne G, Sessle BJ, Dubner R, eds. Orofacial Pain: From Basic Science to Clinical Management. 2nd ed. Chicago: Quintes- sence Publishing Co., 2008. Macedo CR, Silva AB, Machado MA, Saconato H, Prado GF. Occlusal splints for treating sleep bruxism (tooth grinding). Cochrane Data- base of Syst Rev 2007;4:CD005514. Magnusson T, Adiels AM, Nilsson HL, Helkimo M. Treatment effect on signs and symptoms of temporomandibular disorders: Comparison between stabilisation splint and a new type of splint (NTI). A pilot study. Swed Dent J 2004:28:11-20. McNamara JA Jr, Seligman DA, Okeson JP. Occlusion, orthodontic treatment, and temporomandibular disorders: A review. J Orofacial Pain 1995;9:73-90. McNeill C, ed. Craniomandibular Disorders: Guidelines for Evaluation, Diagnosis and Management. Chicago: Quintessence Publishing Co., 1990. McNeill C, ed. Temporomandibular Disorders: Guidelines for the Clas- sification, Assessment and Management. 2nd ed. Chicago: Quintes- sence Publishing Co., 1993. Melis M, Lobo SL, Ceneviz C, Zawawi K, Al-Badawi E, Maloney E, Mehta N. Atypical odontalgia: A review of the literature. Headache 2003:43:1060–1074. 84 McNeill and Rudd Mendoca-Caridad JJ, Schwartz HC. Synovial chondromatosis of the temporomandibular joint: Arthroscopic diagnosis and treatment of a case. J Oral Maxillofac Surg 1994:56:624–625. Mense S. Nociception from skeletal muscle in relation to clinical muscle pain. Pain 1993:54:241-289. Mense S. The pathogenesis of muscle pain. Curr Pain Headache Rep 2003;7:419–425. Milam SB. Pathogenesis of degenerative temporomandibular joint arthri- tides. Odontology 2005:93:7-15. Mitrirttanakul S, Merrill RL. Headache impact in patients with orofacial pain. JAm Dent Assoc 2006; 137: 1267-1274. Mizen KD, Loukota RA, Addante RR. Mass in the masseter muscle. J Oral Maxillofac Surg 2004;62:607-610. Mohl ND, Lund JP, Widmer CG, McCall WD Jr. Devices for the diagno- sis and treatment of temporomandibular disorders. Part II: Electro- myography and sonography. J Prosthet Dent 1990a;63:332–336. Mohl ND, McCall WD Jr, Lund JP, Plesh O. Devices for the diagnosis and treatment of temporomandibular disorders. Part I: Introduction, scientific evidence and jaw tracking. J Prosthet Dent 1990b;63:198– 201. Mohl ND, Ohrbach RK, Crow HC, Gross A.J. Devices for the diagnosis and treatment of temporomandibular disorders. Part III: Thermogra- phy, ultrasound, electrical stimulation, and electromyographic bio- feedback. J Prosthet Dent 1990c;63:472-477. Moody PM, Kemper JT, Okeson JP, Calhoun TC, Packer MW. Recent life changes and myofascial pain syndrome. J Prosthet Dent 1982:48:328-330. Motoyoshi M, Hayashi A, Arimoto M, Ohnuma M, Namura S. Studies of temporomandibular joint sounds. Part 3: The clinical usefulness of TMJ Doppler. J Nihon Univ Sch Dent 1995:37:209-213. National Institutes of Health Technology Assessment Conference State- ment. Management of temporomandibular disorders. J Am Dent As- Soc 1997;127:1595–1606. Nickerson JW Jr, Veaco NS. Condylotomy in surgery of the temporo- mandibular joint. Oral Maxillofac Surg Clin North Am 1989;1:303– 327. 85 Management of Jaw Disorders Nilner M. Does splint therapy work for temporomandibular pain? Evid Based Dent 2004;5:65-66. Nitzan D.W. ‘Friction and adhesive forces’: Possible underlying causes for temporomandibular joint derangement. Cells Tissues Organs 2003; 174:6–16. Nitzan DW, Dolwick MF, Heft MW. Arthroscopic lavage and lysis of the temporomandibular joint: A change in perspective. J Oral Maxillofac Surg 1990;48:798-801. Okeson JP, ed. Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management. 3rd ed. Chicago: Quintessence Publishing Co., 1996. Pierce CJ, Gale EN. A comparison of different treatments for nocturnal bruxism. J Dent Res 1988;67:597–601. Pullinger AG, Seligman DA, Gornbein JA. A multiple logistic regression analysis of the risk and relative odds of temporomandibular disorders as a function of common occlusal features. J Dent Res 1993;72:968- 979. Randolph CS, Greene CS, Moretti R, Forbes D, Perry HT. Conservative management of temporomandibular disorders: A post-treatment comparison between patients from a university clinic and from pri- vate practice. Am J Orthod Dentofacial Orthop 1990;98:77-82. Reston JT, Turkelson CM. Meta-analysis of surgical treatments for tem- poromandibular articular disorders. J Oral Maxillofac Surg 2003; 61:3-10. Ribeiro RF, Tallents RH, Katzberg RW, Murphy WC, Moss ME, Magal- haes AC, Tavano O. The prevalence of disc displacement in symp- tomatic and asymptomatic volunteers aged 6 to 25 years. J Orofacial Pain 1997; 11:37-47. Riley JL III, Myers CD, Currie TP, Mayoral O, Harris RG, Fisher JA, Gremillion HA, Robinson ME. Self-care behaviors associated with myofascial temporomandibular disorder pain. J Orofac Pain 2007:21:194-202. Rogers EJ, Rogers RJ. Tension-type headaches, fibromyalgia, or myo- fascial pain. Headache Q 1991;2:273-277. Romero-Reyes M, Graff-Radford S. Is there hope for chronic pain and headache? Headache 2007;47;1262–1271. 86 McNeill and Rudd Rudd PA, Shen Y, McNeill C. Prevalence of cervical muscle tenderness in patients seeking treatment in a university-based orofacial pain cen- ter. AAOP Scientific Meeting Poster Presentation: May 2008. Rugh JD, Association between bruxism and TMD. In: McNeill C, ed. Current Controversies in Temporomandibular Disorders. Chicago: Quintessence Publishing Co., 1992:29-31. Sato S, Goto S, Kawamura H, Motegi K. The natural course of nonreduc- ing disc displacement of the TMJ: Relationship of clinical findings at initial visit to outcome after 12 months without treatment. J Orofacial Pain 1997; 11:315-320. Schiffman EL, Look JO. Hodges JS, Swift JQ, Decker KL, Hathaway KM, Templeton RB, Fricton JR. Randomized effectiveness study of four therapeutic strategies for TMJ closed lock. J Dent Res 2007;86:58–63. Seligman DA, Pullinger AG. Analysis of occlusal variables, dental attri- tion, and age for distinguishing healthy controls from female patients with intracapsular temporomandibular disorders. J Prosthet Dent 2000;84:114-115. Sessle B.J. Biological adaptation and normative values. Int J Prosthod 2003;S16:72-73. Sessle, B.J. Masticatory muscle disorders: Basic science perspectives. In: Sessle BJ, Bryant PS, Dionne RA, eds. Temporomandibular Disor- ders and Related Pain Conditions. Seattle: IASP PreSS 1995:47-61. Sessle BJ, Hu JW, Amano N, Zhong G. Convergence of cutaneous, tooth pulp, visceral, neck and muscle afferents onto nociceptive and non- nociceptive neurons in trigeminal subnucleus caudalis (medullary dorsal horn) and its implications for referred pain. Pain 1986:27:219– 235. Slavkin HC. Chronic disabling diseases and disorders: The challenges of fibromyalgia. J Am Dent Assoc 1997;128:1583–1589. Slipman CW, Plastaras C, Patel R, Isaac Z, Chow D, Garvan C, Pauva K, Furman M. Provocative cervical discography symptom mapping. Spine J 2005:5:381-388. Solomon S, Cappa KG. The headache of temporal arteritis. J Am Geriatr Soc 1987:35:163–165. 87 Management of Jaw Disorders Song PC, Schwartz J, Blitzer A. The emerging role of botulinum toxin in the treatment of temporomandibular disorders. Oral Dis 2007:13:253–260. Spiegel EP, Levitt SR. Measuring symptom severity with the TMJ scale. J Clin Orthod 1991:25:21–26. Spitzer WO, Skovron ML Salmi LR, Cassidy JD, Duranceau J, Suissa S, Zeiss E. Scientific monograph of the Quebec Task Force on Whip- lash-Associated Disorders: Redefining “whiplash” and its manage- ment. Spine 1995:20:S1-73. Stegenga B, de Bont LG, Boering G, van Willigen JD. Tissue responses to degenerative changes in the temporomandibular joint: A review. J Oral Maxillofac Surg 1991:49:1079–1088. Stohler CS. The end of an era: Orofacial pain enters the genomic age. In Türp JC, Sommer C, Hugger A, eds. Puzzle of Orofacial Pain. New York: Karger 2007:236-247. Stohler CS, Zarb GA. On the management of temporomandibular disor- ders: A plea for a low-tech, high-prudence therapeutic approach. J Orofac Pain 1999; 133:255-261. Suvinen TI, Kemppainen P. Review of clinical EMG studies related to muscle and occlusal factors in healthy and TMD subjects. J Oral Re- habil 2007:34:631-634. Tasaki MM, Westesson PL. Temporomandibular joint: Diagnostic accu- racy with sagittal and coronal MR imaging. Radiology 1993;186:723-729. Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back pain: A review of carisoprodol, cyclobenzaprine hydrochloride, and metaxalone. Clin Ther 2004:26:1355–1367. Travell JG, Simons DG. Myofascial Pain and Dysfunction: The Trigger Point Manual. Baltimore: Williams and Wilkins 1983. Trucco M, Meineri P, Ruiz L. Preliminary results of a withdrawal and detoxification therapeutic regimen in patients with probable chronic migraine and probable medication overuse headache. J Headache Pain 2005;6:334-337. Truelove E, Huggins KH, Mancll, Dworkin SF. The efficacy of tradi- tional, low-cost and nonsplint therapies for temporomandibular dis- order: A randomized controlled trial. J Am Dent Assoc 2006; 1.37:1099-1 107. 88 McNeill and Rudd Tura B, Tura SM. The analgesic effect of tricyclic antidepressants. Brain Res 1990:518:19-22. Türp JC, Komine F, Hugger A. Efficacy of stabilization splints for the management of patients with masticatory muscle pain: A qualitative systematic review. Clin Oral Investig 2004;8:179-195. Westesson PL, Larheim TA, Tanaka H. Posterior disc displacement in the temporomandibular joint. J Oral Maxillofac Surg 1998:56:1266- 1273. White RD, Makar J Jr, Steckler RM. Synovial sarcoma of the temporo- mandibular joint. J Oral Maxillofac Surg 1992:50: 1227-1230. Wolfe F, Smythe HA, Yunus MB, Bennett EM, Bombardier C, Golden- berg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin M, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, McCain GA, Reynolds WJ, Romano TJ, Russell IJ, Sheon RP. The American College of Rheumatology crite- ria for the classification of fibromyalgia. Arthritis Rheum 1990:33:160-172. Wright E, Anderson G, Schulte J. A randomized clinical trial of intraoral Soft splints and palliative treatment of masticatory muscle pain. J Orofac Pain 1995;9:192-199. Vickers ER, Cousins MJ. Neuropathic orofacial pain. Part 1: Prevalence and pathophysiology. Austr Endod J 2000:26:19–26. Zarb GA, Carlsson GE. Temporomandibular disorders: Osteoarthritis. J Orofac Pain 1999; 13:295-306. 89. PSYCHOLOGICAL FACTORS IN TMD AND OROFACIAL PAIN Charles R. Carlson ABSTRACT This chapter presents an overview of important psychological factors influenc- ing the development and maintenance of chronic orofacial pain. The biopsycho- social model is presented first as the general frame of reference guiding treat- ment of persistent orofacial pains. Then a discussion of foundational principles for clinical practice is presented with a special emphasis on the potential role of post-traumatic stress disorder within this population. Basic screening strategies for psychological distress are described for the practitioner, as well as the chal- lenges associated with managing the classic clinical triad of fatigue, pain, and sleep dysfunction. The chapter concludes with a discussion of key practice per- spectives the dental practitioner may incorporate into the evaluation and effec- tive management of chronic orofacial pains. For the past 20 years, the field of orofacial pain has addressed the challenges associated with developing a science-based approach to patient care. One of the major milestones influencing the development of this field was a National Institutes of Health consensus conference held in 1996 to discuss the diagnosis and treatment of trigeminally mediated pain conditions. What emerged from this conference was the professional consensus that patient care needed to be informed by more randomized controlled clinical trials, as well as by a clinical approach emphasizing reversible and non-iatrogenic therapies. Fortunately, the cases where ir- reversible treatments have been applied systematically to orofacial pain disorders have diminished in the last decade. The field now is benefiting substantially from the contributions of dentists, neuroscientists, behav- ioral scientists, physicians and physical therapists to name but a few of the many specialties with interests in science-based understandings of trigeminally mediated pain conditions. Recent advances in the neurosciences, for example, have helped improve the understanding of burning mouth disorder (BMD; Albuquer- que et al., 2006). This disorder, primarily experienced by women over 91 Psychological Factors in TMD the age of 50, previously has been described as a disorder of excessive brain activation. Current functional magnetic resonance imaging (fMRI) data from Albuquerque and coworkers (2006), however, indicate brain activity in persons with BMD is diminished relative to normal controls rather than being overactive, as many once had believed. Furthermore, these data suggest that strategies such as cognitive behavior therapy may have their therapeutic effects via pathways that increase brain activity necessary for promoting inhibitory control in those pain circuits involved in BMD. Another example of the use of fMRI to study trigeminally medi- ated pain involves exploring the effects of anger on the perception of heat pain (Davis, 2003). In this project, participants who were experienc- ing heat pain stimulation while also experiencing anger demonstrated greater activity in a variety of brain regions known to be influenced by pain as compared to when experiencing pain alone. These findings dem- onstrate the important role that emotions may play in an individual’s re- port of pain experience. Taken together, these findings from neurosci- ence studies indicate that there are a variety of potential pathways for clinicians to explore with patients to influence pain experience. There also have been recent advances in our understanding of trigeminally mediated pain from genetic studies. Nackley and colleagues (2006) found that variants of the catechol-O-methyltransferase (COMT) gene regulated pain sensitivity. These data provide early evidence that genetic factors may be playing a significant role in pain perception dif- ferences among individuals. Another recent investigation has linked post-traumatic stress disorder (PTSD) to temporomandibular (TM) pain in twin pairs (Afari et al., 2008). These findings also suggest that Vulner- ability to pain experience can be influenced by genetic factors. While both of these studies demonstrate that genetic factors play a role in pain experience, it is important to recognize that genetic influences are mod- est at best, and environmental and other host factors (e.g., cognitions, learned experiences) contribute significantly to pain experience. Recent behavioral science studies also have fostered our under- standing of trigeminally mediated pain conditions affecting the mastica- tory system, particularly in the area of symptom management. For exam- ple, Dworkin and colleagues (2002a) reported that effective TM pain management could be obtained using a brief three-session cognitive- behavioral treatment program along with appropriate follow-up. Gatchel’s research group (2006) also has demonstrated effective long- term intervention for pain with a six-session cognitive behavioral ap- 92 Carlson proach to pain management. Using an approach that focuses on the ac- quisition of specific behavioral skills for addressing the physical changes seen in TM disorders (TMD) primarily affecting the muscles of mastica- tion, Carlson and coworkers (2001) demonstrated significant and lasting (six months) reductions in self-reports of pain. This approach was de- scribed as “physical self-regulation” and involved: 1. Providing an explanation for the presenting com- plaints and developing patient ownership of the prob- lem; 2. Establishing rest positions of structures in the tri- geminal region; p 3. Monitoring head position and avoiding prolonged tilt- ing of the head to one side or the other; 4. Easing upper back muscle tension with gentle flex- ion-extension exercises; 5. Taking brief relaxation breaks using a relaxation strategy, involving placement of the body in positions of rest; 6. Beginning sleep in a relaxed position; 7. Exercising and drinking fluids regularly; and 8. Entraining a diaphragmatic breathing pattern. Results of these behavioral science studies have demonstrated that self- regulation strategies can be effective low-cost approaches to the long- term management of TMDs. GENERAL MODEL FOR INTEGRATION Engle (1977) first introduced a general model for understanding the integration of biological, psychological and social factors important for the management of medical conditions. He described this model as the biopsychosocial model. The biological component of this model in- cludes the genetic predispositions of an individual that influence the course of development and adaptation to the environment. It also in- cludes the central processes of the brain that regulate both biological and psychological processes, as well as peripheral processes such as those associated with providing feedback information to central control sys- tems. The psychological domain of the biopsychosocial model involves both cognitive and affective processes necessary for the regulation of human behavior. The social domain includes: activities in daily living; environmental stressors that may emerge in the course of routine activi- 93 Psychological Factors in TMD ties; relationships; family environment; social support one might receive, or the lack thereof that might result in isolation; culture; medicolegal is- sues; previous treatment; and work history. The biopsychosocial model emphasizes the integrative nature of these interacting systems and forms the overall foundation for understanding the multiple factors influencing the patient’s clinical presentation. MODEL FOR OROFACIAL PAIN DEVELOPMENT Twenty years ago, data from a variety of sources indicated that approximately 5% of the general population would experience chronic TMDS (Solberg et al., 1979; Greene and Marbach, 1982; Von Korff et al., 1988). Data currently indicate that 10% of women and 6% of men will experience TMDS (Gatchel et al., 2006). It also is estimated that to- tal lost productive time due to pain in the United States is $62 billion (Bates et al., 1994), with total overall costs ranging upwards of $125 bil- lion (Sessle, 2008). These findings suggest that the frequencies of chronic pain conditions have not diminished as sophistication in medical management has increased. Additionally, these findings indicate the con- tinued need for the refinement of models to help guide treatment inter- ventions for improved patient care. One model that has emerged from research and clinical practice with orofacial pain patients at the University of Kentucky suggests that if one is trying to go from some event as a starting point to the endpoint that is the perception of pain, there are multiple factors contributing to the development of the pain endpoint. Bear in mind that pain can be de- fined as the perception of a disturbance or disturbances signaling a need for change. One factor that already has been reviewed briefly is the role of genetic contributions. There is no question based on emerging data that genetic factors play an important role in the onset and maintenance of certain pain conditions. These genetic factors, however, also are influ- enced by physiologic parameters that may be altered by such things as sleep, medications, physical activity level, and nutritional intake. So, when one moves from an event to the development of pain, particularly chronic pain, genetic factors interact with physiologic factors as well as cognitive, affective, and behavioral factors. Figure 1 depicts the model that has been described as an interactive, multi-directional, multi- component model for the development of chronic orofacial pain. 94 Carlson Physiological Cognitive Affective Behavioral Pain Figure 1. Model for orofacial pain development. Perception of disturbance(s) signaling the need for change. Another important factor to consider in the development of long- term pain conditions is that along with nerves that convey information regarding tissue damage (or nociception), there are nerves used to con- Vey information about metabolism. The fact that nociceptors are co- located with metaboreceptors and that both convey information to central modulatory systems suggests that one cannot focus exclusively on the role of nociception for the interpretation of pain. Indeed, when sensory Summation of either nociception or metaboreception or some combina- tion of the two exceeds endogenous anti-nociception capacity, the brain Will interpret these signals as pain and/or anxiety. This pathway has been described and documented elegantly by Bertrand in the opening chapter of the American Academy of Orofacial Pain’s recently released guide- lines for the management of orofacial pain (Bertrand, 2008). Clinicians, therefore, must be aware that when there is minimal tissue change, no *ute injury, no tumor, no infection, or no neuropathy, pain should be Viewed as a perception of disturbance in physiology, signaling a need for 95 Psychological Factors in TMD something to change. Pain is a protective mechanism, and managing the summative effects of activation is important for effective pain manage- ment. Figure 2 graphically presents the relationships among metabore- ceptors, nociceptors, and brain interpretation of pain and/or anxiety that comes when endogenous anti-nociception capacity is exceeded. Behavior Metaboreceptors (-) Nociceptors (metabolic products) same nerves (tissue damage) Summation exceeds - endogenous anti-nociception Pain and Anxiety Brain interpretations Figure 2. Relationship of metaboreceptors and nociceptors. Minimal detectable tissue change, no acute injury, tumor, infection, or neuropathy; think of pain as perception of disturbance in physiology signaling the need for change. Pain is a protective mechanism; managing the summative effects of arousal is important to pain management. Model courtesy of P.M. Bertrand (2008). FOUNDATIONS FOR PRACTICE BASED ON CLINICAL DATA For the past 10 years, the orofacial pain clinic at the University of Kentucky has seen approximately 400-450 new patients each year. Between 1997-1999, 51% of the patients were found to have primarily muscle-related disorders. In that same time frame, 24% of patients were diagnosed with primarily joint-related problems. Neuropathic pain condi- tions comprised approximately 10% of the patients who presented at the clinic. From 2006-2007, 45% of the patients were found to have primar- ily muscle-related disorders, 31% of patients were diagnosed with pri- marily joint-related problems, and 11% of patients were found to have neuropathic pain conditions. The data regarding psychological symptoms for these patients indicated that psychological symptoms were more common in patients with muscle-related disorders as compared to either joint-related problems or neuropathic conditions. Clinical findings from the University of Kentucky indicate there is a greater likelihood for psy- 96 Carlson chological issues to be more relevant for persons with muscle-related disorders than for persons with joint or neuropathic pain conditions. Problems of a psychological nature are not unusual in orofacial pain settings. The diagnosis of depression is common, and Korszun and coworkers (1996) have noted that 28% of patients reporting to their clinic met the criteria for diagnosis of depression. Anxiety disorders are also present in the orofacial pain population. Kight and colleagues (1999) found that 31% of the patients in their clinic could be diagnosed with anxiety disorders. These disorders can include generalized anxiety disor- der, obsessive-compulsive disorder (OCD) and PTSD. The problems associated with OCD often are manifested in pa- tients who have an unusual interest in their occlusions. While occlusal awareness is important – in fact, it has been said that “occlusion is every- thing and occlusion is nothing” – one must be careful to assume that oc- clusion is at the basis of every orofacial pain condition. For example, there are any number of patients who have come to the UK Orofacial Pain Clinic with complaints of orofacial pain, yet their occlusion is as perfect as possible. Occlusion may not be the critical factor in the devel- opment of orofacial pain. On the other hand, it is possible that a person may develop pain as a result of occlusal factors. One example of this is the individual who has a restoration or crown with a slight elevation so that s/he engages in excessive parafunctional activity that may lead to pain and discomfort. There also is the possibility that an individual may have an inordinate focus of attention or “occlusal awareness” that is not warranted. Such a person may reflect recurrent and persistent thoughts that are intrusive or cause distress when thinking about their occlusion. This pattern of behavior would meet the criteria for diagnosis of an OCD. The so-called “occlusal neurotic” is likely such an individual. Such an individual, however, is rare at the UK Clinic, with less than 1% presenting with such symptoms. One of the more significant anxiety disorders that presents in the UK Orofacial Pain Center is PTSD. Data from a recent study conducted at UK (Sherman et al., 2005) indicated that 15% of patients who present for treatment of their orofacial pain conditions meet diagnostic criteria for PTSD. Upon careful inquiry, it was found that 24% of patients meet the criteria for a lifetime diagnosis of PTSD. PTSD is diagnosed using five criteria (American Psychiatric Association, 1994). These criteria include first an exposure to a threat to oneself or others in which there is a response of fear, helplessness or horror. The second component of the 97 Psychological Factors in TMD diagnosis is persistently re-experiencing the threat through memories, dreams, flashbacks and/or symbolic events. Third, there also is an endur- ing avoidance of stimuli and numbing that develops in response to the events that have occurred or memories of such events. The fourth symp- tom cluster that characterizes PTSD involves behavioral changes due to increased arousal including sleep disturbances, problems falling asleep or problems with frequent sleep awakenings, outbursts of anger and hyper- vigilance. Finally, in order for PTSD to be diagnosed, the full set of symptoms must last for greater than one month and cause significant dis- trust or impairment in functioning. One way to understand the problem of PTSD is to think about it as a problem associated with an inability to recover normal functioning. In other words, it represents a problem whereby an individual is not able to exercise inhibitory control over thoughts and physiological respond- ing. Research has demonstrated recently that the development of PTSD is linked to social contexts. One of the childhood risk factors for the de- velopment of PTSD involves an individual being exposed to an environ- ment in which there were limited opportunities to exercise control and experiences that produced significant disruptions in normal activities. This can happen if a child experiences significant chaos in his/her family of origin and does not develop a sense of control over her/his world. In- terestingly, a recent study of orofacial pain patients found that as a group they reported a less supportive family environment than did a group of normal controls (Anders et al., 2000). The environment of one's family during childhood can play a significant role in helping the child learn to cope with stressful life events. When the family of origin has not pro- vided the scaffolding for managing significant stressors, the individual is vulnerable to developing stress-related disorders. Furthermore, it also is the case that current, ongoing Social support plays an important role in helping an individual cope with stressful life events. In fact, Schmidt (2006) found that persons currently experiencing orofacial pain reported receiving more negative feedback from family members and lower levels of support for talking about problems than did normal controls. These findings again suggest that social contexts are important for the effective processing of stressful life events. While it is very useful to understand the influence of social con- texts on how significant life events are interpreted and managed, it is equally valuable to appreciate the influence of PTSD on other symptoms of psychological distress. Using a large sample of orofacial pain patients, de Leeuw and colleagues (2005) found that persons reporting PTSD 98 Carlson symptoms also were the ones who reported clinically significant levels of other symptoms related to psychopathology like depression. These find- ings suggest that PTSD is an important dimension of an orofacial pain patient’s clinical presentation that can have far-ranging consequences. Clinicians, therefore, must be prepared to explore the possibility that PTSD is a factor in the orofacial pain patient’s presentation during the initial evaluation. Recent data from several laboratories indicate that a significant percentage of orofacial pain patients report a history of significant life trauma. Curran and colleagues (1995) found that 69% of orofacial pain patients anonymously reported a history of physical or sexual abuse. In- terestingly, that same cohort of patients reported this history to the den- tists conducting the initial examination only 8% of the time. Fillingim and coworkers (1997) found that 45% of patients with TMDS recruited from a general population reported a history of abuse, either physical or sexual. In a related study, Campbell and colleagues (2000) found that a history of physical abuse was associated with greater pain, anxiety and depression as compared to persons who had no abuse history or who re- ported a history of sexual abuse. Clearly, it is essential that orofacial pain clinicians have the ability to assess a patient's experiences with abuse, as such a history may play an important role in an individual’s ability to manage his/her pain condition. There is one other important psychological dimension to con- sider at this point in the discussion of psychological factors influencing orofacial pain conditions. A personality disorder is defined as an endur- ing pattern of thought and behavior that deviates markedly from the ex- pectations of the culture. Several examples of personality disorders in- clude antisocial, borderline, dependent and histrionic personality disor- ders. The antisocial personality disorder is represented by an individual who has little regard for following social rules and norms. Such an indi- vidual is likely to violate laws in order to satisfy his/her own needs. A person with borderline personality disorder has difficulty with maintain- ing appropriate boundaries in human relationships; S/he may harbor in- terests in developing a more personal relationship with a health provider than is appropriate ethically or may engage in manipulative behaviors. An individual with a dependent personality makes excessive demands on the clinician’s time and thinks little of making multiple visits for care. Finally, the histrionic personality disorder tends to magnify symptoms and may over-interpret their importance. Interestingly, when a structured clinical interview was given to patients in an orofacial pain clinic, it was 99 Psychological Factors in TMD found that 29% of the patients met diagnostic criteria for a personality disorder (Kight et al., 1999). It is important to note that the diagnosis of a personality disorder requires an extensive structured clinical interview. There is no simple way to screen for the presence of a personality disor- der in orofacial pain settings. Unfortunately, many clinicians only dis- cover the existence of a personality disorder in a patient through painful experience in their practices. SCREENING FOR PSYCHOLOGICAL DISTRESS It is possible to screen for general psychological distress in the orofacial pain setting. There are several good paper and pencil psycho- logical screening instruments currently available, including the SCL-90- R, Beck Depression Inventory, SF-36 and the Post Traumatic Stress Dis- order Checklist. Based on the literature, it also is possible to use two screening questions during the initial interview to determine whether a patient should be referred to a mental health professional for further evaluation (Rugh et al., 1993). The two questions are: “How depressed are you?” and “Do you consider yourself more tense than calm, or more calm than tense?” A positive response to either question indicates a refer- ral should be made. CHALLENGE OF PAIN-FATIGUE-SLEEP One of the common complaints from orofacial pain patients is that the pain they experience also is accompanied by problems of fatigue and sleep. Fatigue can be defined as a state of increased discom- fort/tiredness and decreased ability to respond. It has been demonstrated that orofacial pain patients who are experiencing primarily muscle- related pain report greater fatigue than do matched normal controls (Carlson et al., 1998). Furthermore, it also has been reported that orofa- cial pain patients experience greater difficulty sleeping (Carlson et al., 1998). Sleep difficulties include delayed sleep onset (greater than 20-30 minutes) and frequent awakenings. These data involving sleep difficul- ties and fatigue underscore the importance of conducting a comprehen- sive initial evaluation covering all aspects of an individual patient's life history. Moreover, problems with fatigue and sleep may be understood as suggesting an inability for orofacial pain patients to quiet themselves or exercise inhibitory control effectively. An inability to quiet oneself physiologically can be described as a failure of inhibitory control. Physiologic systems are designed to main- 100 Carlson tain a homeostatic balance. When there is an increase in sympathetic ac- tivity, there is an immediate response by the parasympathetic nervous system and the endogenous opioid system to return the individual to a normal state. The capacity for an individual to recover from sympathetic activation or to exercise inhibitory control now can be indexed easily by a physiologic measure called heart rate variability, a construct that de- scribes the change in time between each individual heartbeat. In a normal individual, the time between each individual heartbeat is changing con- stantly. If the inter-beat interval should become constant, it is a sign of significant concern and ill health of the individual. High heart rate vari- ability, therefore, is an indication of a healthy, well-functioning physiol- ogic System. The variability of heart rate can be evaluated by examining the frequency range in which the variability occurs. Low-frequency variabil- ity involves both sympathetic and parasympathetic functioning. On the other hand, high frequency variability in heart rate functioning is under parasympathetic control primarily. Thus, one would expect to find in individuals who are not able to exert inhibitory control over heart rate function greater low-frequency variability and reduced high-frequency Variability. Recent data indicate that this is exactly the case (Schmidt and Carlson, 2008). Persons reporting long-term orofacial pain conditions were found to have greater low-frequency variability than normal matched controls, as well as lower high-frequency activity when com- pared to normal controls. These findings suggest one of the characteris- tics of chronic orofacial pain is a failure of inhibitory control mecha- nisms enabling an individual to quiet physiologic systems when stressors have resolved. It is important to note at this point that one of the common views among dentists is that the rest position of the tongue is on the roof of the mouth (Fricton and Schiffman, 2001). It has been shown, however, that placing the tongue on the roof of the mouth involves increased activity in the temporalis and suprahyoid muscle groups (Carlson et al., 1997). Fur- thermore, in a recently completed study it was found that tongue position on the roof of the mouth will reduce a standard measure of heart rate variability (Schmidt et al., 2008). These data suggest that caution should be exercised when giving orofacial pain patients instructions to “relax” muscles of mastication by placing the tongue on the roof of the mouth. Such instructions may result in increased levels of physical functioning inadvertently and not promote inhibitory control or achieving rest needed for tissue repair and effective pain management. 101 Psychological Factors in TMD PRACTICE PERSPECTIVES FOR DENTAL PRACTITIONERS The dental practitioner who is interested in treating orofacial pain patients should have a working understanding of how people change, particularly if s/he believes it is important to provide information and to promote opportunities for behavior change in their patients. Pro- chaska and colleagues (1992) have described a five-step model for how people change. The first step is described as pre-contemplation. In this stage, an individual is not aware of the need for change. There is no rea- son at this stage for an individual to be concerned about change and to consider the possibility of making lifestyle changes. One of the roles of a clinician working with a patient at this stage is to introduce information that may help them move to the next stage: contemplation. In the phase of contemplation, an individual is considering whether or not s/he should make changes. If an individual comes to the conclusion that change should occur, S/he will engage in the next stage: preparation. In the preparation phase, the individual is putting together the information and resources necessary for enabling change to occur. The fourth step is ac- tually implementing change or action. This stage is the point in the proc- ess of change where new ways of thinking and acting are implemented. One of the most important factors influencing this stage is the individ- ual’s goals and expectations. Finally, the last stage in the process of change is maintaining those changes that were initiated during the action phase. It is important for the orofacial pain clinician to appreciate the challenge and difficulty associated with patients making changes in their behavior. The use of a “stages of change” model can assist the clinician in modifying her/his behaviors with the patient to foster the possibilities for meaningful changes to occur. The practitioner’s role in facilitating the process of patient change involves providing the structure, direction and support for the patient to change. The practitioner provides information that is wanted by the patient. It also is important to have the skills to elicit the patient's views and aspirations; in other words, a practitioner must help negotiate change with the patient by making the patient an active decision-maker in the change process. In fact, the goal for the clinician is to help the pa- tient become the primary healthcare provider for the long-term manage- ment of the chronic orofacial pain condition. Helping the patient ulti- 102 Carlson mately become a team player/manager will result in improved outcomes for the patient, it will save the practitioner future time and effort, and will also help the patient understand and embrace who is ultimately responsi- ble for outcomes: the patient him/herself. Helping patients change is a critical role for the orofacial pain practitioner. It is important to remember that relatively brief interven- tions focusing on the patient engaging in self-directed care have been demonstrated to be effective over long periods of time. One does not have to have an elaborate set of strategies for effective management of long-term pain conditions. Several recent examples introduced at the be- ginning of this chapter illustrate this point nicely. Carlson and colleagues (2001) demonstrated in a randomized, controlled clinical trial that effec- tive reductions in pain could be accomplished within a brief period of time among persons with chronic masticatory muscle pain using a treat- ment program that consisted of two 50-minute training sessions. Dworkin and colleagues (2002a, b) likewise have developed a brief self- care program involving three sessions along with phone contact for man- aging TMDs. Self-care programs enable patients to manage their pain conditions in an effective manner such that at follow-up patients reported less pain, less life interference from the pain, and fewer office visits for care, compared with persons who received standard care from their den- tists for orofacial pain. In summary, there is a growing database from randomized, controlled clinical trials that self-care strategies can be ef- fective for the long-term management of chronic orofacial pain condi- tlOnS. Long-term care of chronic orofacial pain conditions is best in- formed by the use of treatment strategies that focus on pain management. The central philosophy behind this approach focuses on the word man- age. The word manage comes from the Latin root meaning “to train or to School” and was used in the context of training animals such as horses. Patients need to be schooled or trained in the effective application of skills that will help them return to normal levels of functioning and de- Velop control over their pain conditions. It is not about curing the chronic orofacial pain problem, but rather about helping patients learn to manage their pain condition and moving forward in their lives. This overall ap- proach involves teaching patients to become their own primary healthcare providers for the effective long-term management of their chronic pain conditions. 103 Psychological Factors in TMD SUMMARY This chapter described foundational principles from the field of psychology that can help improve the quality of care given by dental practitioners to patients with chronic orofacial pain conditions. Long- term pain in structures mediated by the trigeminal nerve can be difficult for both the patient and the practitioner to manage unless both parties come to an agreement about treatment philosophy and approach. When faced with non-acute pain in trigeminally mediated structures, the princi- ples described in this chapter can provide the dental practitioner with an informed approach for enabling patients to begin the process of manag- ing chronic orofacial pain levels effectively. REFERENCES Afari N, Wen Y, Buchwald D, Goldberg J, Plesh O. Are post-traumatic stress disorder symptoms and temporomandibular pain associated? Findings from a community-based twin registry. J Orofac Pain 2008; 22:41–49. Albuquerque RJC, de Leeuw R, Carlson CR, Okeson JP, Miller CS, An- dersen AH. Cerebral activation during thermal stimulation of patients who have Burning Mouth Disorder: An fMRI study. Pain 2006; 122:223–234. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4" ed. Washington DC, 1994. Bates RE Jr, Gremillion HA, Stewart CM. Degenerative joint disease. Part II: Symptoms and examination findings. Cranio 1994;12:88-92. Bertrand, PM. Introduction to orofacial pain. In: de Leeuw R, ed. Orofa- cial Pain: Guidelines for Assessment, Diagnosis, and Management. 4th ed. Chicago: Quintessence Publishing Co., 2008:1-24. Campbell LC, Riley JL III, Kashikar-Zuck S, Gremillion H, Robinson ME. Somatic, affective, and pain characteristics of chronic TMD pa- tients with sexual versus physical abuse histories. J Orofac Pain 2000; 14:112-119. Carlson CR, Bertrand PM, Ehrlich AD, Maxwell AW, Burton RG. Physical self-regulation training for the management of temporo- mandibular disorders. J Orofacial Pain 2001:15:47-55. 104 Carlson Carlson CR, Reid KI, Curran SL, Studts J, Okeson JP, Falace D, Nitz A, Bertrand PM. Psychological and physiological parameters of masti- catory muscle pain. Pain 1998;76:297-307. Carlson CR, Sherman JJ, Studts JL, Bertrand PM. The effects of tongue position on mandibular muscle activity. J Orofac Pain 1997; 11:291- 297. Curran SL, Sherman JJ, Cunningham LL, Okeson JP, Reid KI, Carlson CR. Physical and sexual abuse among orofacial pain patients: Link- ages with pain and psychologic distress. J Orofac Pain 1995;9:340- 346. Davis CE. A functional magnetic resonance imaging study of pain and emotion. Unpublished thesis, Department of Psychology, The Uni- versity of Kentucky, Lexington 2003. de Leeuw R, Bertoli A, Schmidt JE, Carlson CR. Prevalence of post traumatic stress disorder symptoms in orofacial pain patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:558-568. Dworkin SF, Huggins KH, Wilson L, Mancll, Turner J, Massoth D, LeResche L, Truelove E. A randomized clinical trial using research diagnostic criteria for temporomandibular disorders-axis II to target clinic cases for a tailored self-care TMD treatment program. J Orofac Pain 2002; 16:48–63. Dworkin SF, Turner JA, Manci L, Wilson L, Massoth D, Huggins KH, LeResche L, Truelove E. A randomized clinical trial of a tailored comprehensive care treatment program for temporomandibular dis- orders. J Orofac Pain 2002:16:259-276. Engel GL. The need for a new medical model: A challenge for biomedi- cine. Science 1977; 196: 129-136. Fillingim RB, Sexual and physical abuse history in subjects with tem- poromandibular disorders: Relationship to clinical variables, pain sensitivity, and psychologic factors. J Orofac Pain 1997; 11:48-57. Fricton JR, Schiffman E. Management of masticatory myalgia and ar- thralgia. In: Lund JP, Lavigne GL, Dubner R, Sessle BJ, eds. Orofa- cial Pain: From Basic Science to Clinical Management. Chicago, London: Quintessence 2000:235–248. Gatchel RJ, Stowell AW, Wildenstein L, Riggs R, Ellis E. Efficacy of an early intervention for patients with acute temporomandibular disor- der-related pain: A one-year outcome study. JAm Dent Assoc 2006; 137:339–347. 105 Psychological Factors in TMD Greene CS, Marbach JJ. Epidemiologic studies of mandibular dysfunc- tion: A critical review. J Prosthet Dent 1982:48: 184-190. Kight M, Gatchel RJ, Wesley L. Temporomandibular disorders: Evi- dence for significant overlap with psychopathology. Health Psychol 1999; 18:177-182. Korszun A, Hinderstein B, Wong M. Comorbidity of depression with chronic facial pain and temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:496-500. Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L. Human catechol-O- methyltransferase haplotypes modulate protein expression by alter- ing mRNA secondary structure. Science 2006;314:1930-1933. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change: Applications to addictive behaviors. Am Psychol 1992:47:1102-1114. Rugh JD, Woods BJ, Dahlström L. Temporomandibular disorders: As- sessment of psychological factors. Adv Dent Res 1993;7:127-136. Schmidt JE. A controlled comparison of emotional reactivity and physio- logical response in chronic orofacial pain patients. Unpublished the- sis, Department of Psychology, The University of Kentucky, Lexing- ton, 2006. Schmidt J, Carlson CR. A controlled comparison of emotional reactivity and physiological response in chronic masticatory pain patients. J Orofac Pain 2008:in press. Schmidt J, Carlson CR, Usery A, Quevido A. The effects of tongue posi- tion on mandibular muscle activity and heart rate function. Submit- ted for publication, 2008. Sessle B.J. Pain costs. J Orofac Pain 2008:22:5-6. Sherman JJ, Carlson CR, Wilson JF, Okeson JP, McCubbin JA. Post- traumatic stress disorder among patients with orofacial pain. J Oro- fac Pain 2005;19:309-317. Solberg WK, Woo MW, Houston, JB. Prevalence of mandibular dys- function in young adults. J Am Dent Assoc 1979;98:25-34. Von Korff M, Dworkin SF, Le Resche L, Kruger A. An epidemiologic comparison of pain complaints. Pain 1988:32:173-183. 106 GENDER AND HORMONAL EFFECTS ON CLINICAL TMJD PAIN Linda LeResche ABSTRACT Temporomandibular muscle and joint disorder (TMJD) pain is about twice as common in women as in men; peak prevalence occurs during the reproductive years. Although the majority of common pain conditions show higher female prevalence, the peak seen in TMJD pain prevalence during the reproductive years does not occur for most other pain conditions. This suggests that, in addition to generic factors affecting pain in women, TMJD pain may be influenced by fac- tors specific to this time of life. Studies of the association of TMJD with hormone replacement therapy, as well as changes in clinical TMJD pain across the men- Strual cycle and during pregnancy, have found an association between the occur- rence and severity of TMJD pain and the presence and level of estrogen. Specifi- cally, estrogen appears to be a pain modulator, such that high pain occurs at times of lowest estrogen, whereas higher levels of estrogen are associated with lower pain report. However, TMJD pain prevalence does not increase dramatically in girls until three to five years after menarche, suggesting that repeated exposure to estrogen fluctuations may be necessary to trigger onset. Studies also indicate that psychological distress and pain are strongly related and show similar patterns in relation to hormones. These data are supportive of the hypothesis that these hor- monal influences act at the level of the central nervous system. If the influences are central, hormones may influence other pain conditions in women as well, but TMJD pain presents a particularly dramatic example of this phenomenon. It long has been known that the majority of people seeking treat- ment for temporomandibular muscle and joint disorders (TMJD) in orofacial pain clinics are women of reproductive age. This chapter re- views epidemiologic and clinical research addressing the possible rea- Sons for this pattern, specifically, the effects of gender and hormones on TMJD pain. TMJD is a collective term for a group of conditions affect- ing the masticatory muscles and the temporomandibular joint. Although these disorders are associated with signs and symptoms other than pain, e.g., joint sounds or abnormalities in mandibular movement, pain is overwhelmingly the symptom for which people seek treatment. 107 Gender and Hormonal Effects EPIDEMIOLOGY OF TMJD PAIN In looking at age and gender differences in TMJD, an initial question to ask is whether the age and sex pattern of TMJD pain seen with clinic patients also occurs in the general population. A related ques- tion is whether the age and sex pattern of TMJD pain is unique, or is similar to patterns of other chronic/recurrent pain conditions. Most of the available data on TMJD and on other pain conditions are data on prevalence. Prevalence is simply the proportion of the popu- lation with a particular condition at a given point or period of time. Inci- dence, on the other hand, is the proportion of the population at risk who develop a condition over a specific time period, usually one year. Inci- dence is the equivalent of an onset rate. As might be expected, preva- lence and incidence are related. How many cases there are in the popula- tion at a given point in time (i.e., prevalence) is a function of the rate of onset of a condition and how long it typically lasts (Lilienfeld and Lilien- feld, 1980). PREVALANCE PATTERNS OF TMJD AND OTHER COMMON PAIN PROBLEMS Figure 1 shows the age and sex distribution of TMJD pain among adults in a population-based study conducted in an integrated health care delivery system in Seattle (Von Korff et al., 1988). The popu- lation of the healthcare delivery system is representative of the general population in the Seattle area. The peak prevalence of TMJD pain is in the 25- to 44-year-old age group; at all ages shown, TMJD pain is more common in women than in men. Overall, the prevalence ratio is about two females for every male. Similar age and sex patterns have been found in several other epidemiologic studies (e.g., Locker and Slade, 1988; Goulet et al., 1995), although absolute prevalence rates vary somewhat from study to study depending on the definition of TMJD pain. TMJD pain is not unique in being more prevalent in women than in men. In fact, the majority of pain conditions show higher prevalence in women (Berkley, 1997). However, focusing only on the higher overall prevalence rates in women does not do justice to the diversity of age- and sex-specific prevalence patterns for different pain conditions. In particu- lar, although most common pain conditions are, like TMJD, more com- mon in women than in men, many of these pain conditions do not show 108 LeResche Prevalence (%) 20 – Males 15 – Females 18–24 25-44 45-64 65+ Age (years) Figure 1. Age- and sex-specific six-month prevalence of TMJD pain in 1,016 subjects randomly selected from a prepaid health plan; Seat- tle, WA. (Data from Von Korff et al., 1988.) the peak prevalence in the 25- to 44-year age group that is apparent for TMJD pain (LeResche, 1999, 2000). Fibromyalgia, for example, like facial pain is more common in Women than in men. However, community studies of fibromyalgia Sug- gest that, unlike the pattern for facial pain, the prevalence of fibromyal- gia continues to increase past the reproductive years, dropping only in persons over 80 years of age (Wolfe et al., 1995). Neck and shoulder pain also show higher prevalence in women than in men, but the age- related prevalence patterns for TMJD and for neck and shoulder pain appear very different since neck and shoulder pain tend to increase with age (e.g., Hasvold and Johnsen, 1993). Gastrointestinal pain shows a female predominance, but preva- lence decreases substantially with age (Agréus et al., 1994; Kay et al., 1994, Adelman et al., 1995). Tension type headache, although thought to share many characteristics with facial pain, especially pain of muscular origin, has a somewhat different prevalence pattern than TMJD (Scher et al., 1999). Again, there is a female predominance, but the rates are level or decline slightly as people age. Migraine headache, however, shows a pattern similar to TMJD, although perhaps even more dramatic – a bell-shaped curve over the adult lifespan, with a large female predominance in the middle 109 Gender and Hormonal Effects years (e.g., rates in women of over 25% and in men of only 8% at age 40; Stewart et al., 1992). Data from children indicate that prevalence rates of migraine are similar in girls and boys before puberty, with possi- bly a somewhat higher prevalence rate in boys (Scher et al., 1999). It is important to consider whether the higher prevalence of TMJD pain in women is due to higher incidence rates or longer duration – that is, are women more likely to experience a initial onset TMJD pain, do they experience pain of longer duration, or are both incidence and duration higher for women than for men? Although there are few pro- spective studies that allow us to estimate TMJD incidence rates, it ap- pears that the rate of onset of TMJD pain is about 1.5 times higher in women than in men (Von Korff et al., 1993). If duration of TMJD was similar in the two sexes, this would result in a prevalence rate in women 1.5 times that in men, so incidence alone is not enough to account for the prevalence differences. Although population-based data on duration are not available, several factors point to slightly longer duration of TMJD pain in women as well. Among treated cases, women report earlier onset of TMJD pain. In addition, men who are treated appear to have a higher probability of pain offset than women receiving similar treatment (Dworkin et al., 1997). Thus, it appears that both incidence and pain du- ration are higher for women than for men. POSSIBLE EXPLANATIONS FOR GENDER DIFFERENCES IN PAIN Given that gender differences in TMJD incidence and duration exist, how might they come about? The experience of pain is complex and multidimensional, with factors acting at multiple levels. In theory, gender differences in pain experience could be due to differences in: 1. The biological substrates that transmit and modulate pain signals; 2. The organism’s ability to detect and discriminate stimuli (that is, pain perception); 3. Pain appraisal, that is, the cognitive and emotional re- sponse to pain, including how one copes with a pain condition; 4. Gender differences may occur in pain-related behav- iors including pain report, nonverbal expressiveness and use of medications and health care; and/or 5. Finally, men and women with pain may assume or be expected to assume different social roles. 110 LeResche In fact, there is evidence that biological sex and/or psychosocial gender differences at all these levels influence pain (LeResche, 2006). Another consideration is that individuals are different organisms biologically, psychologically and socially at different points in the life cycle. Biological changes, including puberty for both sexes and meno- pause for women, occur rather predictably, although the specific ages at which these events take place can vary from individual to individual. In US society, most individuals spend the time from ages 6 to 16 years in primary and secondary school, the majority of people marry and are em- ployed as adults. These common experiences, as well as unique individ- ual differences in biology, diseases and disorders, personal stressors and changing social circumstances may influence the risk for and presenta- tion of pain in a given individual at a specific point in the life cycle. For this reason, it is interesting to consider what points in the life cycle seem to be associated with changes in the rates of TMJD pain. Rates of TMJD pain are low and very similar for girls and boys before puberty (Drangholt and LeResche, 1999). Rates of TMJD pain also ap- pear to decline in those over 45 years and rates for women approach those for men after age 65 (Von Korff et al., 1988). This prevalence pat- tern, showing peak pain prevalence during the reproductive years, led us to consider that hormonal factors may play a role in TMJD pain. HORMONAL INFLUENCES ON TMJD PAIN Theoretically, hormones could operate in the periphery, influenc- ing inflammation in the temporomandibular joint (Milam, 1995). Estro- gen receptors have been found in the TMJs of a number of species (Auf- demorte et al., 1986; Yamada et al., 2003). Joints become lax during pregnancy under the influence of hormones (possibly both estrogen and relaxin), and it has been suggested (Westling, 1992) that joint laxity could be associated with TMJD. In theory, hormones also could influ- ence muscle pain, although mechanisms of muscle pain are as yet un- clear. Centrally, hormones may act as neurotransmitters or pain modula- tors in the central nervous system (Craft, 2007). Hormone Replacement Therapy Our research group began a systematic epidemiologic investiga- tion of hormonal influences on clinical TMJD pain by examining whether the use of hormone replacement therapy (HRT) influenced the probability of experiencing TMJD pain in women over age 40 (LeResche 111 Gender and Hormonal Effects et al., 1997). Specifically, we compared rates of HRT use in 1,388 women over age 40 referred for TMJD care at Group Health Coopera- tive, an integrated health care delivery system in Seattle, over a 10-year period and 5,164 age-matched female controls who had not had a referral for TMJD. We reasoned that if hormones played a role in TMJD pain, older women who took hormone replacement and thus were hormonally more like younger women, would be at higher risk for TMJD. Pharmacy records were used to identify prescriptions filled and doses of various estrogen and progestin medications. Usage rates of both estrogens and progestins were higher in our sample of TMJD cases (for estrogen, 28% in cases vs. 19% in controls; for progestins, 10% in cases vs. 8% in con- trols). When analyses were controlled for the number of health care vis- its, a factor that could be associated both with TMJD and with use of hormones, the relationship between use of progestins and TMJD pain no longer was significant. However, the odds ratio (OR) for the use of es- trogens remained significant (OR = 1.32, p = 0.002) after controlling for use of health services and, interestingly, the risk of TMJD increased with increasing exposure to estrogen over the year prior to referral. For women who had used the equivalent of 220 mg or more of estrogen es- tradiol, the risk was almost double that of women using no estrogen. Following this initial study, other investigators also examined this question. Wise and colleagues (2000) found higher levels of pain reported among orofacial pain patients using HRT vs. those who did not use HRT. Hatch and coworkers (2001), on the other hand, found no rela- tionship between recent HRT use and the severity of a range of TMJD signs and symptoms in a community study; Macfarlane and colleagues (2002) found that HRT was a risk factor for orofacial pain (including, but not limited to TMJD pain) in a community sample. Despite the somewhat differing findings of these studies, taken together the results suggested that the hormone-TMJD connection was a hypothesis worthy of further investigation. However, the decision to use exogenous hormones, such as oral contraceptives and hormone replace- ment therapy, may be influenced by a number of factors including age, education and the presence of symptoms. Therefore, rather than continu- ing to investigate the role of exogenous hormones, we designed a series of studies to evaluate the possible relationship between naturally occur- ring, or endogenous, hormones and TMJD pain. 112 LeResche TMJD Pain Across the Menstrual Cycle The first study in the series (LeResche et al., 2003b) examined whether levels of TMJD pain vary systematically across the menstrual cycle. The study subjects were three groups of TMJD patients, all of whom met Research Diagnostic Criteria (RDC/TMD) criteria (Dworkin and LeResche, 1992) for both facial muscle and temporomandibular joint pain disorders (i.e., myalgia plus either arthralgia or arthritis). TMJD pain was recorded daily over three menstrual cycles in normally cycling Women and in women using oral contraceptives, and over a three-month period in men. All subjects completed daily diaries including measures of pain and somatic symptoms. Women also recorded whether they were having their menstrual period. In normally cycling women, ovulation prediction kits were used to estimate time of ovulation and mid-luteal saliva samples were assayed for progesterone to confirm that ovulation did, in fact, occur. In order to examine menstrual cycle-related changes, we controlled for the overall trend in pain over the course of the study for each subject. We found that TMJD pain was highest for all women during the first few days of the menstrual cycle, and that there was a pattern of ris- ing pain toward the end of the cycle – a time of dropping estradiol for naturally cycling women and a time of withdrawal of synthetic estrogen for women taking oral contraceptives. Interestingly, we also found a peak around the time of ovulation for normally cycling women – again a time of rapid fluctuation in estradiol. There was no mid-cycle peak for the women on oral contraceptives who do not have estradiol peaks mid-cycle and usually do not ovulate. No discernible pattern was found for men. We found patterns similar to the pain patterns across the men- strual cycle for other, non-pain symptoms, especially symptoms tradi- tionally labeled as premenstrual (PMS) symptoms. In general, TMJD pain levels rise at the end of the menstrual cycle and peak during menses. Fluctuations in pain also occur around ovulation. These findings suggest that low or, possibly, rapidly fluctuating levels of estrogen are associated with increased pain. The cyclic patterns are similar for other somatic Symptoms. One hypothesis to explain the pattern of pain we saw is that es- tradiol may be a pain modulator in women, as it is in some strains of 113 Gender and Hormonal Effects mice (Sternberg and Wachterman, 2003). There also is some human ex- perimental evidence supporting this hypothesis (Smith et al., 2006). If estradiol were a pain modulator, we would expect highest pain when es- tradiol is low and lowest pain when estradiol is high. Initial pilot data (LeResche et al., 2003a) using daily saliva samples to monitor estradiol levels and diaries to monitor pain levels suggests that this pattern holds at least for some women. In this small pilot study of four women, the corre- lation between salivary levels of estradiol and pain was always negative, and one woman showed a remarkable correlation (r = -0.77) between estradiol levels and pain. We currently are investigating how strong this relationship is in a larger sample of women with TMJD pain. TMJD Pain During Pregnancy In the normal reproductive life of women, the highest levels of estradiol, as well as other estrogens and progesterone, occur during preg- nancy. The levels of all hormones are low at conception, but rise throughout pregnancy. The rise for progesterone is fairly steady across pregnancy, whereas the estradiol curve initially rises slowly and then becomes much steeper during the second and third trimesters. We evalu- ated the relationship of hormone levels to pain in a sample of 19 preg- nant women who were TMJD patients at the start of their pregnancies (LeResche et al., 2005c). Self-report and examination data, as well as saliva samples, were collected four times – during the first, second and third trimesters of pregnancy, as well as one-year post-partum. With clinical TMJD pain during pregnancy, we found a pattern parallel to that of pain across the menstrual cycle, that is, lower pain dur- ing the later months of pregnancy, when estradiol (and progesterone) levels are high. Pain rose again one-year post-partum when these levels are very low, compared to those during pregnancy. For example, worst pain intensity levels averaged 6.7 on a 0-10 scale during month 3, 5.0 at month 6, 4.8 at month 9 and had risen to 6.3 at one-year post-partum. Again, there was a negative correlation (on the order of -0.4) between levels of salivary estradiol and pain within each woman over time, which supports the hypothesis that estradiol is a pain modulator. Thus, the pregnancy and menstrual cycle studies suggest that in women who have TMJD, high pain is associated with low levels of es- tradiol. The initial hormone replacement study, however, found that the use of exogenous estradiol was associated with increased risk of experi- encing TMJD pain. As shown in Figure 2, these findings can be recon- ciled, in that the serum levels of estradiol in HRT are actually very low, 114 LeResche Effective dose of estradiol in HRT = 41-45 pg/ml (serum) Progesterone Estradiol _ 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Day of Cycle Figure 2. Patterns of estradiol and progesterone across a prototypical menstrual cycle. Circulating levels of estradiol in women on hormone replacement therapy correspond to those of the early follicular phase of the cycle (arrow). on the order of 41-45 pg/ml (Gavaler, 2002), and thus similar to those levels found at the beginning of the menstrual cycle – the time of greatest pain susceptibility. Puberty and TMJD Pain A major opportunity to study the relationship between endoge- nous hormonal changes and pain occurs around ages 11 to 14 in girls, when estradiol levels rise steeply (Fig. 3). There is wide variability among individuals in terms of pubertal development, such that at any given age during the pre-teen and teenage years, individual girls (and boys) are at differing stages of sexual maturity. Nevertheless, for the ma- jority of girls, the time from ages 11 to 14 capture the period surrounding the start of menstrual periods (menarche) as estrogen levels rise sharply and then plateau. Data from a large population-based study in Sweden (Nilsson et al., 2005) indicate a sharp rise in the prevalence of TMJD pain for girls between the ages of 12 and 16. However, this Swedish study did not ex- amine the association of TMJD to puberty. Because of the substantial Variability in when pubertal development begins, adolescents of a given age may be in a wide range of stages of puberty. For example, a 13-year- old boy has about an equal probability of being in early, mid or late pu- berty, as well as a reasonable probability of not having started puberty at 115 Gender and Hormonal Effects Estradiol (pg/ml) menarche 100 — ! 80 – 60 — 40 – 20 — O I i I I I I I I l 10 11 12 13 14 15 Age (years) Figure 3. Modal estradiol levels by age in girls. (Data from: McAnamey ER, Kreipe RE, Orr DP, Comerci GD. Text- book of Adolescent Medicine. Philadelphia: WB Saunders, 1992.) all or having completed the process altogether. Thus, although there is a positive relationship between age and pubertal status, an analysis of dis- ease risk by pubertal status might yield substantially different results than an analysis by age. To assess the possible relationship of pain and puberty, we con- ducted two studies. The first was a cross sectional telephone survey of a population based sample of approximately 3,100 eleven- to 17-year-olds. The sample included almost 2,000 eleven-year-olds and about 1,100 ado- lescents aged 12 to 17 years. We assessed demographic factors, the pres- ence of four pain conditions (back pain, headache, stomach pain and fa- cial pain/TMJD), pubertal status, depressive and somatic symptoms, and a range of other factors that might influence the probability of having TMJD pain (LeResche et al., 2005a). All the eleven-year-olds from this survey then were followed every three months for three years (LeResche et al., 2007). The frequent data collection allowed us to determine pain onsets and changes in SuS- pected risk factors with much more precision than usually is the case in longitudinal studies. Subjects who reported an onset of facial pain at any 116 LeResche time during the three-year period were examined for clinical signs of TMJD by a trained calibrated dental hygienist examiner, using the stan- dardized RDC/TMD examination. In the cross sectional study (LeResche et al., 2005a), the pattern of prevalence of pain by pubertal development stage in girls was similar for all four pain conditions, with prevalence increasing across pubertal development. The steepness of the curves varied somewhat, but the trend was always upward. For boys, the pattern differed by pain condition, with some pain problems increasing in prevalence and some either stay- ing stable or decreasing somewhat. For both boys and girls, the probabil- ity of experiencing at least one pain condition rose with progressing pu- berty (from 28% pre-puberty to 49% for boys who had completed puber- tal development, and from 28% to almost 60% over the same period for girls). The percentage of girls who experienced two or more pain prob- lems also rose with increasing development (from about 11% for those who had not begun puberty to almost 30% in those whose pubertal de- Velopment was complete). The rise was not as steep for boys (from about 11% to about 16%). Interestingly, the percent of girls who experienced high levels of depressive symptoms and the percent of girls who experienced high lev- els of non-pain somatic symptoms also followed the pattern of increasing risk with increasing pubertal development; “high level” was defined as being above the 90" percentile for the entire sample. For girls, rates of high depression rose from 5% pre-puberty to 23% among those who had completed pubertal development. The rates for high levels of somatic Symptoms rose from 6% before puberty to about 17% after puberty. Again for boys, the increase in risk was not as great, with rates of high depression rising from 6% to 11% and rates of high levels of somatic Symptoms ranging only from 9% to 11% across pubertal development. As with the other pain conditions, facial/TMJD pain (defined as pain in the muscles of the face, the joint in front of the ear, or inside the ear, other than an ear infection) rose in prevalence across puberty in girls. The rate of rise, however, was virtually the same for boys as for girls (about 4% pre-puberty in both sexes, and 13% in boys and 14% in girls who had completed puberty). Thus, the 2:1 ratio of TMJD pain preva- lence seen in adults was not present by the end of puberty in this sample. As shown in Figure 4, however, we found that the prevalence of TMJD pain increased dramatically with time since menarche in girls, such that about a quarter of the girls who were five or more years past their first menstrual period had TMJD pain (LeResche et al., 2005b). 117 Gender and Hormonal Effects Prevalence (%) 30 — 25 — 20 – 15 – 10 — Pre-menarche 0-1 yr >1-3 yrs >3-5 yrs >5 yrs Time Since Menarche Figure 4. TMJD pain prevalence by time since menarche. Girls 11-17 years old (n = 1548). In summary, as boys passed through puberty, the prevalence of back pain and facial pain increased, headache prevalence was un- changed, and stomach pain prevalence declined; the rate of multiple pains remained fairly stable and rates of high depression and non-pain Somatic symptoms increased slightly. As girls passed through puberty, prevalence rates of each pain, multiple pains, depression and somatic symptoms all increased. Importantly, multivariate statistical analyses revealed that puberty is a better predictor of pain prevalence than is age. The longitudinal study that followed children from ages 11 to 14 years (LeResche et al., 2007) aimed to identify factors at age 11 that would predict an onset of TMJD pain between the ages of 11 and 14 years. Specifically, the outcome was the presence of an initial onset of facial pain that met criteria, on examination, for an RDC/TMD diagnosis of myalgia, arthralgia or both. We found that female gender was, as ex- pected, an important predictor of onset of TMJD pain, with an odds ratio (OR) of about 2.01 (p < 0.005) in a multivariate logistic regression analysis, an analysis that separates out the effect of each variable while controlling for all other variables in the analysis. Other significant pre- dictors were the number of existing pain complaints at baseline (OR = 3.22, p < 0.0001) and the presence and severity of other non-pain So- matic symptoms (OR = 1.80, p < 0.05). Another important predictor of TMJD onset was life dissatisfaction. Children who were dissatisfied or even neutral with life in general at age 11 – as opposed to positive about life – had a four-fold risk for an onset of TMJD pain over the next three 118 LeResche years, compared with those children who declared that they were satis- fied or very satisfied with life in general (OR = 4.12, p < 0.0001). Thus, the studies of pain and puberty have shown that the com- bination of being female and becoming sexually mature puts adolescent girls at higher risk for experiencing both physical and psychological symptoms. TMJD pain is one symptom that seems to develop a bit later in the maturation process than some of the other pain conditions, but it definitely is linked closely to pubertal development and more closely linked to puberty than to age. SUMMARY The data discussed in this chapter can be summarized as a series of working hypotheses to be investigated in further research: 1. Because the vast majority of pain conditions are re- ported more frequently by women than by men (al- though the age-related patterns are different for dif- ferent pain conditions), it seems likely that societal factors influence the reporting of all types of pain. 2. From our studies of hormone replacement therapy and pain across the menstrual cycle, it appears that TMJD pain likely is associated with exposure to es- trogen. However, the menstrual cycle and pregnancy studies suggest that hormonal changes may be more important than absolute levels, and that estrogen may be a pain modulator. It is interesting to specu- late that this pain modulation system may be an evo- lutionary adaptation that could be very useful during labor pain. 3. From our studies on TMJD pain in adolescents, we hypothesize that there may be an “incubation pe- riod” between onset of hormone exposure and onset of TMJD pain in women. 4. Finally, it appears from both the menstrual cycle study and the adolescent study that psychological distress and pain are strongly related and that both may be influenced by hormones. 5. From our own work and from other evidence, it ap- pears that these hormonal influences most likely are central (although peripheral influences cannot be 119 Gender and Hormonal Effects ruled out at this point), and thus the phenomena we observe with TMJD pain may generalize to at least some other pain conditions. ACKNOWLEDGEMENTS This work was supported by a series of research grants from the Na- tional Institute of Dental and Craniofacial Research and the NIH Office of Research on Women’s Health (Grant Nos. P01 DE 08773, R01 DE 12470 and R01 DE 16212). REFERENCES Adelman AM, Revicki DA, Magaziner J, Hebel R. Abdominal pain in an HMO. Family Med 1995:27:321-325. Agréus L., Svardsudd K, Nyren O, Tibblin, G. The epidemiology of ab- dominal symptoms: Prevalence and demographic characteristics in a Swedish adult population. Scand J Gastroenterol 1994:29:102-109. Aufdemorte TB, Van Sickels JE, Dolwick MF, Sheridan PJ, Holt GR, Aragon SB, Gates GA. Estrogen receptors in the temporomandibular joint of the baboon (Papio cynocephalus): An autoradiographic study. Oral Surg Oral Med Oral Pathol 1986;61:307-314. Berkley K.J. Sex differences in pain. Behav Brain Sci 1997:20:371-380. Craft RM. Modulation of pain by estrogens. Pain 2007;132 S1:S3-12. Drangsholt M, LeResche L. Temporomandibular disorder pain. In: Crombie IK, Croft PR, Linton SJ, LeResche L, Von Korff M, eds. Epidemiology of Pain. Seattle: IASP Press 1999:203-233. Dworkin SF, LeResche L. Research diagnostic criteria for temporoman- dibular disorders: Review, criteria, examinations and specifications, critique. J Craniomandib Disord 1992;6:301-355. Dworkin SF, LeResche L, Truelove E, Saunders K. Gender differences in onset and duration of TMD and headache. Orlando, FL: Interna- tional Association for Dental Research, March, 1997. Gavaler JS. Oral hormone replacement therapy: Factors that influence the estradiol concentrations achieved in a multiracial study popula- tion. J Clin Pharmacol 2002:42:137-144. Goulet JP, Lavigne GJ, Lund JP. Jaw pain prevalence among French- speaking Canadians in Quebéc and related symptoms of temporo- mandibular disorders. J Dent Res 1995;74:1738–1744. 120 LeResche Hasvold T, Johnsen R. Headache and neck or shoulder pain: Frequent and disabling complaints in the general population. Scand J Prim Health Care 1993; 11:219–224. Hatch JP, Rugh JD, Sakai S, Saunders MJ. Is the use of exogenous estro- gen associated with temporomandibular signs and symptoms? J Am Dent ASSOc 200 l ; 132:3:19–326. Kay L, Jorgensen T, Jensen KH. Epidemiology of abdominal symptoms in a random population: Prevalence, incidence, and natural history. Eur J Epidemiol 1994; 10:559-566. LeResche L. Epidemiologic perspectives on sex differences in pain. In: Fillingim RB, ed. Sex, Gender and Pain: Progress in Pain Research and Management. Vol. 17. Seattle: IASP Press 2000:233-249. LeResche L. Gender considerations in the epidemiology of chronic pain. In: Crombie IK, Croft PR, Linton SJ, LeResche L. Von Korff M, eds. Epidemiology of Pain. Seattle: IASP Press 1999:43–52. LeResche L. Sex, gender and clinical pain. In: Flor H, Kalso E, Dos- trovsky JO, eds. Proceedings of the 11" World Congress on Pain. Seattle: IASP Press 2006:543–554. LeResche L, Dworkin SF, Gandara B, Mancl L, Sherman J.J. Relation- ship between salivary hormone levels and temporomandibular disor- der (TMD) Pain. Abs. No. 2861. J Dent Res 82 (Special Issue B), 2003a. LeResche L, MancllA, Drangsholt MT, Huang G, Von Korff M. Pre- dictors of onset of facial pain and temporomandibular disorders in early adolescence. Pain 2007;129:269-278. LeResche L, Mancll/A, Drangsholt MT, Saunders K, Von Korff M. Re- lationship of pain and symptoms to pubertal development in adoles- cents. Pain 2005a;118:201-209. LeResche L, Mancl LA, Drangsholt M, Von Korff, MR. Dating the onset of gender differences in TMD pain prevalence. J Dent Res 84 (Spe- cial Issue A), Abs. No. 2728, 2005b. LeResche L, Mancl L, Sherman JJ, Gandara B, Dworkin SF. Changes in temporomandibular pain and other symptoms across the menstrual cycle. Pain 2003b;106:253-261. LeResche L, Saunders K, Von Korff M, Barlow W, Dworkin SF. Use of exogenous hormones and risk of temporomandibular disorder pain. Pain 1997;69:153-160. 121 Gender and Hormonal Effects LeResche L, Sherman JJ, Huggins KH, Saunders K, ManclDA, Lentz G, Dworkin SF. Musculoskeletal orofacial pain and other signs and symptoms of temporomandibular disorders during pregnancy: A pro- spective study. J Orofac Pain 2005c. 19:193-201. Lilienfeld AM, Lilienfeld DE. Foundations of Epidemiology. 2nd ed. New York: Oxford University Press 1980. Locker D, Slade G. Prevalence of symptoms associated with temporo- mandibular disorders in a Canadian population. Community Dent Oral Epidemiol 1988;16:310-313. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J, Worthington HV. Association between female hormonal factors and orofacial pain: Study in the community. Pain 2002;97:5-10. Milam SB. Articular disk displacements and degenerative temporoman- dibular joint disease. In: Sessle BJ, Bryant PS, Dionne RA, eds. Temporomandibular Disorders and Related Pain Conditions. Seat- tle: IASP PreSS 1995:89–1 12. Nilsson IM, List T, Drangsholt M. Prevalence of temporomandibular pain and subsequent dental treatment in Swedish adolescents. J Oro- fac Pain 2005; 19: 144-150. Scher AI, Stewart WF, Lipton RB. Migraine and headache: A meta- analytic approach. In: Crombie IK, Croft PR, Linton SJ, LeResche L, Von Korff M, eds. Epidemiology of Pain. Seattle: IASP Press 1999: 159–170. - Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta JK. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J Neurosci 2006; 26:5777-5785. Sternberg WF, Wachterman MW. Experimental studies of sex-related factors influencing nociceptive responses: Nonhuman animal re- search. In: Fillingim RB, ed. Sex, Gender and Pain: Progress in Pain Research and Management. Vol 17. Seattle: IASP Press 2000:71-88. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of mi- graine headache in the United States: Relation to age, income, race, and other sociodemographic factors. J Am Med Assoc 1992;267:64- 69. Von Korff M, Dworkin SF, LeResche L, Kruger A. An epidemiologic comparison of pain complaints. Pain 1988:32:173-183. 122 LeResche Von Korff M, LeResche L, Dworkin SF. First onset of common pain symptoms: A prospective study of depression as a risk factor. Pain 1993:55:251-258. Westling L. Temporomandibular joint dysfunction and systemic joint laxity. Swed Dent J 1992;S81:1-79. Wise EA, Riley JL III, Robinson ME. Clinical pain perception and hor- mone replacement therapy in postmenopausal women experiencing orofacial pain. Clin J Pain 2000;16:121-126. Wolfe F, Ross K, Anderson J, Russell IJ, Herbert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995:38:19-28. Yamada K, Nozawa-Inoue K, Kawano Y, Kohno S, Amizuka N, Iwanaga T, Maeda T. Expression of estrogen receptor alpha (ER al- pha) in the rat temporomandibular joint. Anat Rec A Discov Mol Cell Evol Biol 2003:274:934-941. 123 CBCT (3D IMAGING): APPLICATION FOR SELECTED ARTICULAR DISORDERS AND ASSOCIATED FACIAL GROWTH David Hatcher ABSTRACT Orthodontists have a fundamental interest in facial form, facial growth patterns, occlusion and any pathologic conditions that may alter them. Current three- dimensional (3D) imaging techniques available for routine imaging provide the opportunity to utilize a “systems approach” in order to visualize and evaluate the functional and developmental relationships between proximal craniofacial regions. A develop-mental insult to the temporomandibular joints (TMJs) may have a regional effect on the growth of the ipsilateral side of the face including the mandible, maxilla and base of skull. Similarly it has been suggested that there is a direct relationship between jaw growth and airway development. The notion that there are functional and growth relationships between adjacent anatomic regions creates the desire for a robust method to visualize and analyze them. This chapter will discuss the use of 3D imaging (cone beam CT; CBCT) to evaluate the developmental and functional inter-relationships between TMJ, occlusion, facial growth, facial profile and airway. The specialty of orthodontics has an abiding interest in facial form, facial growth patterns, occlusion and any pathologic conditions that may alter them. Current three-dimensional (3D) imaging techniques available for routine imaging provide the opportunity to utilize a “systems approach” in order to visualize and evaluate the functional and developmental relationships between proximal craniofacial regions. It has been reported that a developmental insult to the temporomandibular joints (TMJs) may have a regional effect on the growth of the ipsilateral side of the face including the mandible, maxilla and base of skull (Legrell and Isberg, 1998, 1999; Legrell et al., 1999; Nebbe et al., 1999; Nebbe and Major, 2000; Bryndahl et al., 2006; Flores-Mir et al., 2007a,b). Similarly it has been suggested that there is a direct relationship between jaw growth and airway development (Stratemann et al., 2008). The notion that there are functional and growth relationships between adjacent anatomic regions creates the desire for a robust method 125 CBCT Imaging to visualize and analyze them. This chapter will discuss the use of 3D imaging (cone beam CT; CBCT) to evaluate the developmental and functional inter-relationships between TMJ, occlusion, facial growth, facial profile and airway. CBCT and Imaging Protocols Advancements in imaging technology are paralleled by the development of imaging protocols and diagnostic strategies. Imaging technology milestones for visible light and x-ray imaging include 2D film imaging, 2D digital imaging and 3D digital imaging. Volumetric imaging is synonymous with 3D imaging because the information has depth as well as length and width. The 3D domain includes both x-ray (CT and CBCT) and MRI technologies. The two principle differences that distinguish CBCT from traditional CT are the type of imaging source-detector complex and the method of data acquisition. The x-ray source for CT is a high output rotating anode generator, while that for CBCT can be a low-energy fixed anode tube similar to that used in dental panoramic machines. CT employs a fan-shaped x-ray beam emitted from its source to acquire images and records data on Solid-state image detectors arranged in a 360° array around the patient. On the other hand, CBCT technology uses a cone-shaped x-ray beam with a special image intensifier and a solid-state sensor or an amorphous silicon plate for capturing the image (Mozzo et al., 1998). Conventional medical CT devices image patients in a series of axial plane slices that are captured either as individual stacked slices or from a continuous spiral motion over the axial plane. Conversely, CBCT presently uses one rotation sweep of the patient similar to that used for panoramic radiography. Image data can be collected for either a com- plete dental/maxillofacial volume or a limited regional area of interest. Scan times for these vary from 10–40 seconds for the complete volume. The progression of imaging protocols and diagnostic strategies includes deconstruction of the anatomy in 2D, deconstruction of anatomy in 3D, and reconstruction and analysis of anatomy in 3D. All imaging technologies allow for the capture and display of anatomy. The capture and display variables of interest for this chapter are point of view (POV), field of view (FOV) and anatomic accuracy. These are important variables when discussing the differences in 2D and 3D imaging. 126 Hatcher Point of View (POV) POV refers to the visualization perspective. For example, a cephalometric projection usually refers to a lateral or postero-anterior POV. Using 2D techniques, the visualization and capture POVs are identical. Conversely using 3D techniques, the capture POV does not necessary match the display POV. A 3D CBCT capture may occur by circling a central ray around the head, but the display angle can be user defined and is infinite. There is, therefore, an infinite number of viewing angle. In addition, a 3D volume (CBCT), using software tools, can be reformatted or sliced along any plane, oblique plane or curved plane to reveal the internal anatomy. p Field of View (FOV) FOV refers to the dimensions and the anatomy captured by the imaging sensor. The variables related to the FOV include sensor size and spatial relationships between imaging source, anatomy and sensor. It often is the goal of imaging to have the FOV match the region of interest (ROI) by collimating the x-ray beam and the sensor in order to minimize the radiation burden. To select the FOV appropriately requires imaging objectives that are designed to answer the clinical question being investigated. Matching the FOV with the ROI has the added advantages of controlling the radiation burden and improving the quality of the exam by reducing scatter radiation. Anatomic Accuracy An ideal imaging goal is to represent the anatomy as it exists in nature accurately, i.e., the anatomic truth. The projection geometry asso- ciated with 2D techniques does not produce accurate anatomic images. 3D digital techniques using back-projection algorithms create the opportunity to produce anatomically accurate images. Imaging the craniofacial structures using 2D film and digital acquisition techniques occurs with multiple POVs, multiple FOVs and Variable resultant accuracy. This method deconstructs the anatomy into a collection of 2D images. For the clinician to understand the anatomy using the 2D deconstruction method requires a virtual reconstruction that attempts to reassemble disparate POVs, FOVs and variables of differing accuracy. This is a difficult if not an impossible task. 127 CBCT Imaging Current 3D imaging techniques allow an anatomically accurate capture of the surface and subsurface structures (Stratemann et al., 2008). One measure of image quality is the ability to detect small anatomic features. The variables that have significant influence on quality of a CBCT include voxel size (smallest element in a 3D digital image), dynamic range (number of gray levels), signal and noise. In general, the best quality image is comprised of small voxels, large number of gray levels, high signal and low noise. CBCT voxels are isotropic (equal size in all dimensions x, y and Z) and range in size from 0.1 to 0.4 mm. The captured FOV can be scaled to match the regions of interest (ROI). The ROI can include the entire craniofacial region or a selected sub-section of the craniofacial anatomy. The display of the captured FOV has a variable POV and a variable ROI. For example, the entire craniofacial skeleton may be captured using a CBCT scan; using software tools, a ROI, such as the TMJs, may be selected and displayed. Deconstruction of the anatomy using 3D occurs by capturing and displaying a series of small 3D FOVs using various POVs or by capturing a large 3D FOV then using the software tools to limit the display to a series of anatomic subsets. Modeling 3D imaging creates the opportunity for 3D anatomic re- construction and analysis. A 3D image Volume has a global reference or coordinate system (Cartesian coordinates) that is displayed as three orthogonal planes (axial, coronal and Sagittal). The coordinate system often is assigned to the anatomic volume by the acquisition device but can be modified later by the user with specialized software tools. Multiple image sets can be combined into the same 3D matrix. The process of combining these images into the same coordinate matrix is called fusion or registration. For instance, a 3D surface acquired using visible light or laser scan can be fused onto a common coordinate matrix with a 3D volume acquired using CBCT. Following fusion of the two objects (surface and volume), they can be displayed, analyzed and visualized together. Fusion of objects onto a common coordinate system can improve the accuracy and completeness of the anatomic repre- sentation. A process called anatomic segmentation also can add value to the image set. Segmentation creates an anatomic object that can be used for morphometric analysis, simulation and biomechanical testing. For example, segmented objects may include individual teeth, mandible, 128 Hatcher maxilla, skin and airway. The objects are displayed and managed as rendered iso-surfaces. Each object may be assigned a local coordinate system. The global or original coordinate system monitors the position of each object using six degrees of freedom (DOF). The six DOF for each object are x, y, z, yaw, pitch and roll. Fusion also can occur in 4D. Fusion in 4D occurs by spatially managing the object coordinate systems in a timed sequence of 3D images. For instance, the position of mandible, including the TMJs, relative to the maxilla and temporal bone can be tracked and displayed by managing the local and global coordinate systems over time. This would allow for the creation of a virtual articulator (Fig. 1). Anatomic reconstructions can be used to create patient specific models that can be analyzed. These models provide a visual repre- sentation of the patient and also can be used to measure size and shape of the selected attributes. The analysis data can be stored in a database for future reference. The database can be analyzed later to determine outcomes values and develop prediction tables. Multi-object models can be used for treatment simulations. Treatment simulations allow the operator to iterate treatment options or rehearse a treatment. Anatomic reconstructions create the opportunity for a systems or integrated diagnostic approach. This approach allows for the analysis and consideration of anatomically related structures. A developmental disturbance of the TMJ (i.e., arthritis, fracture) may have a local effect on the ipsilateral joint and a regional effect on that side of the face. The joint pathology may limit or stop growth of the effected condyle. In addition, there may be a growth reduction in the vertical dimensions of the neck, ramus and body of the mandible. The occlusal plane may be elevated on the effected side. The lateral development of the mandible may be reduced and the cranial base (fossa) may be depressed on that side. The limited growth of the mandible may alter the occlusion, maxillomandibular spatial relationships, facial profile, facial growth pattern and the airway shape and size. Mandibular Growth The mandible forms using a combination of endochondral and intramembranous processes for bone formation. The condyles do not control growth of the entire mandible, but condylar growth contributes to the process of mandibular growth – primarily the condylar processes and rami and secondarily the body and alveolar ridges. Mesenchymal cell differentiation into articular cartilage followed by endochondral 129 CBCT Imaging Modeling 3D 5D Skeleton Roots Muscles Light Attributes Face Crown E º º É E 3 º º E. E. # Patient Specific Model Meta T Morphometrics - Data Data .. D Base Size N-ºil- Simulation Outcomes | Predictions Therapy Figure 1. This figure illustrates the anatomic reconstruction of a 3D patient specific model using disparate imaging sources and fusing them on the same 3D Cartesian coordinate system. The patient specific model can evolve to a 4D model by fusing a timed sequence of 3D images onto the same 3D coordinate system. 4D systems can be used to evaluate change over time, 4D modeling includes monitoring growth, development, jaw movement, facial expression and treatment outcomes. 5D modeling allows for the fusion of biomechanical attributes into the coordinate system and testing the biomechanical relationships between the structures. Information can be collected from the 3D, 4D and 5D models and stored in a database for retrieval and analysis. The data pool can be used for diagnostic evaluation, treatment simulation, outcomes analysis. outcome predictions and therapy (Usui et al., 2003). ossification contributes to condylar growth. There are several mandib- ular growth sites (growth fields); these include the condyles, alveolar process, rami, body and coronoid process. These growth sites have genetic potential for growth through mesenchymal cell differentiation and cell division, but the growth can be modulated through external or 130 Hatcher environmental factors (epigenetic). These external factors include neighboring growth sites, hormones, tissues stress and strain and tissue damage. The craniofacial complex generally grows in harmony. Changes occurring in one area of the craniofacial complex induce a response in adjacent areas. A model proposed by Petrovic and coworkers (1994) Suggests that distant craniofacial changes (such as maxillary growth) are transformed into local (mandibular) growth signals by a complex interplay of muscle adaptation, neural input, connective tissue response, blood supply, biochemical growth activation and suppression. Condylar fibrocartilage during growth is responsive to growth stimuli from a Variety of systemic and local influences. Ideally, condylar growth is modulated to keep pace with facial growth. Fibrocartilage in the adult condyle has adaptive function to maintain the mandible in its functional role. Reduced adaptive capacity of the fibrocartilage, such as degenerative joint disease (DJD), during growth and development has been shown to limit growth of the ispilateral half of the mandible. DJD in adulthood that results in significant hard tissue loss may be associated with a change in mandibular posture, occlusion and condyle/fossa spatial relationships. Degenerative Joint Disease DJD, also known as degenerative arthritis, degenerative arthrosis, osteoarthritis and osteoarthrosis, affects all joints including the TMJ. There are several factors that can initiate the pathologic and imaging features associated with DJD. These factors create a situation where the articular structures no longer can resist the applied forces to the joint. DJD involves the destruction of the hard and soft articular tissues and occurs when the remodeling capacity of those tissues has been exceeded by the functional demands. Scenarios that modulate and increase joint loads and/or diminish the strength or adaptive capacity of the articular tissues, therefore, are of interest in discovering the pathogenesis of TMJ DJD. The understanding of DJD has evolved significantly over the past 30 years. Until recently, DJD of the TMJ was considered a wear-and-tear phenomenon that occurred in individuals over the age of 40, as observed in other synovial joints. Recent investigations and clinical observations have discovered significant differences in the occurrence and behavior of TMJ DJD, however, when compared to other joints. TMJ DJD has been recognized to have a predilection for females, can be identified at all 131 CBCT Imaging ages following puberty, and is not limited to individuals over the age of 40. It has been suggested that sex hormones and hormone receptors may play a role in the early age onset and sex predilicection of this phenomenon. DJD onset and the associated complaints in females occur from puberty through menopause. The TMJ is a diarthrodial joint, like other synovial joints; however, the expression of DJD differs from other joints. Key distinctions between the TMJ anatomy and other synovial joints include the predominance of fibrocartilage in lieu of hyaline cartilage and motion mechanics that include rotation and translation. The TMJ is a loaded joint and it has been estimated that the joint loads or stress concentrations (force/area) may be equal to other load bearing joints (Hatcher et al., 1997). The functional movement of the condyle over the disc creates a contact force (F) applied in a direction (cosine Theta) over a distance (d) during a specific time (t) interval. The disc/condyle interactions can be expressed in terms of work (W) or Power (P). W=F x d x cosine Theta and P = W/t (Mah et al., 1997; Nickel et al., 2004, 2006; Gallo et al., 2006). Current investigations are examining the mechanobiology or single cell biomechanics, that is, how physical forces influence biological processes in the TMJ (Carter et al., 2004; Huang et al., 2004; Lammi, 2004; Turner, 2004). Single cell biomechanics depend on their material properties relative to the surrounding matrix. The TMJ disc cells are a heterogenous mixture of fibroblasts and fibrochondrocytes. The TMJ disc is a fibro-cartilaginous tissue but it is not a homogeneous tissue. The disc is composed mostly of collagen (type I), proteoglycans (glycosaminoglycan chains that primarily are chondroitin sulfate and dermaten sulfate) and water. The distribution and arrangement of the disc components are not uniform. This disc has been divided in three areas or zones: the anterior band, intermediate zone and the posterior band. The zone-like anatomic regions create material property differences, and therefore the single cell biomechanics between these zones may vary. Anatomic variations between the zones ideally reflect a structural relationship in response to the functional demands in terms of work and power. The work imparted on the tissues (cells) initiates a mechanotransduction pathway (mechanism by which cells convert a mechanical stimulus into a chemical activity) that results in gene expression. Gene expression initiates several pathways to produce: 132 Hatcher 1. Extracellular matrix proteins; 2. Matrix metalloproteinases; 3. Proinflammatory cytokines; or 4. Apoptosis regulators. Extracellular matrix protein synthesis creates extracellular matrix and tissue regeneration. Production of matrix metalloproteinases and proinflammatory cytokines result in extracellular matrix degradation. Extracellular matrix degradation and apoptosis are pathways that can result in DJD. Variations in mechanotransduction pathways may be related to the tissue anatomy, tissue quality and power (work/time). Several variables affect work including peak forces, force vectors, Velocity and work cycles. Tissues anatomy and quality will relate to the adaptive capacity of those tissues. Both mechanotransduction and signal transduction by hormones (beta-estradiol, relaxin, progesterone) currently are being explored (Naqvi et al., 2005; Hashem et al., 2006). Using in vivo testing of disc explants in rabbits, it has been demonstrated that increased serum levels of relaxin, beta-estradiol and relaxin and beta-estradiol result in loss of glycosaminoglycans and collagen from fibrocartilaginous sites, i.e., TMJ and pubic symphysis, but not from hyaline cartilaginous sites. Relaxin and beta-estradiol induced the matrix metalloproteinase expression of collagenase-1 and stromelysin-1. It also was shown that progesterone prevented loss of matrix molecules. This hormone-induced targeted matrix degradation may be the key to understanding why TMJ DJD is observed most commonly in females during their reproductive years. There likely is interplay between mechanotransduction and hormonal transduction of matrix degradation proteinases during the onset and progression of DJD. DJD: Imaging Observations Current imaging modalities have revealed several stages associated with DJD that progress along a continuum from normal, failure, repair and stability (Mah et al., 1997). In general, it has been observed that soft tissue changes occur first and this progresses to involvement of the hard tissues in a small percentage of individuals. It has been proposed that DJD progresses until the functional forces (work and power) are modulated by tissues changes to be within adaptive capacity of targeted tissues. When the progressive stages of DJD are evaluated a pattern of TMJ forms (size and shape) and structural changes can be identified (Figs. 2-6). 133 CBCT Imaging Continuum of Hard & SoftTissue Changes: Clinical Findings in the Degenerative Joint Disease Process Osteophytes & Subchondra BoneCyst Disc Bones Adolescent Interrupted Decreased Facial Growth - - Figure 2. A continuum showing the progression of TMJ hard and soft tissues changes and a summary of associated clinical signs and symptoms that range from normal to end stage degenerative joint disease (DJD). The horizontal axis of this graph represents time and the vertical axis represents the severity of associated signs and symptoms. The color bands indicate the following: purple - normal; yellow = remodeling; red = active DJD; and blue = stable DJD. (From Hatcher et al., 1997.) Figure 2 shows the normal progression of hard and soft tissue changes that occur with degenerative joint disease. The normal osseous components of the TMJs exhibit smooth, rounded articular surfaces without evidence of subchondral defects (purple color code) and has a normally positioned articular disc in the closed and open mouth positions. Early soft tissue changes include tissue thinning (proteoglycan depletion) and possibly a reducing anteriorly displaced disc (yellow color code). In this early stage, it is possible to identify minor changes in osseous shape (flattening) and cortical thickening (sclerosis) primarily in the areas of joint loading (anterosuperior surfaces of the condyle and the posterior slope of the articular eminence). This early stage is not associated with a reduction in size or volume of the osseous components. The next stage shown in Figure 2 is characterized by a non- reducing displaced disc (red/blue code). An increase in the clinical signs 134 Hatcher and Symptoms (i.e., pain, limited open and cessation of a clicking) corresponds with the onset of the non-reducing displaced disc. The disc displacement seems to be a risk factor for the onset of hard tissues DJD. When the hard tissue changes occur (red color code), they are characterized by the onset of erosive lesions that occur in the functional (loaded) areas. These erosions begin as small cortical defects but can progress to be cavitation defects, followed by a reduction in condylar size, flattening of the articular surface and re-cortication. Ultimately, the recorticated condylar surface often has a radius of curvature that nearly matches the opposing eminence. Late stage changes shown in Figure 2 that are observed in some individuals with DJD include the formation of osteophytes and subchondral bone cysts. Osteophytes most often extend from the anterior surface of a condyle, form in low stress areas, adapt the available space (do not displace the condyle) and increase the functional contact area. Subcondrondal bone cysts are thought to be a result of functional impaction of synovial fluid through an un-corticated surface (erosion) thus cavitating the subchondral bone. The cavitations fill with connective tissue; therefore, they appear lucent with skeletal imaging. It is interesting to note that this is a self-limiting process and that despite the progression DJD there is a point at which the degenerative process becomes stable (adapted) and the signs and symptoms reduce to level associated with normal. In the adolescent patient, the joint status has a local effect (epigenetic) on TMJ development and a regional effect on facial growth (Fig. 3). Figure 3 (next page). This chart illustrates a spectrum of form (size and shape) and structural changes observed in the osseous components of the TMJs as they extend progress from normal through end stage DJD. The progression of change is color-coded the match the graph shown in Chart 1 (purple = normal; yellow = remodeling; red = active DJD; and blue = stable DJD). The joint images are arranged vertically and progress from normal (top) to end stage DJD (normal, Sclerosis, flattening, erosions, osteophyte and subchondral bone cysts). The images are sorted horizontally so that severity of a feature increases toward the right side of the image set. 135 CBCT Imaging Sclerosis - Osteophytes - Subchondra Bone Cyst 136 Hatcher Mandibular Growth Normal Disc Displacement º DºD Figure 4. This graph describes the mandibular growth effects associated with TMJ hard and soft tissue changes. The horizontal axis represents time, showing age milestones of puberty, post-puberty and adult. The vertical axis shows an accumulation of mandibular growth. Normal mandibular growth is illustrated by the white line. A disc displacement (reducing and non-reducing) has been associated with an interruption in mandibular growth (blue-green line) so that the net growth on the affected side was less than the normal. If DJD occurs prior to the completion of skeletal growth then there can be a severe reduction in or cessation of growth. The earlier the onset of DJD and the severity of the DJD have a proportional relationship with the severity of the mandibular growth defect. Figure 5 (next page). This image collage illustrates an adolescent with end stage DJD. The condyles are small, having been reduced in size from their superior Surfaces. The Superior surfaces of the condyles showed signs of flattening, Sclerosis and erosions. The erosive process was at a more stable stage in the right TMJ. The posterior slopes of the articular eminentia were flat, sclerotic and formed relatively shallow inclines. This individual has a convex facial profile, Crowded dentition, steep mandibular plane, obtuse gonial angle, steep occlusal plane and limited lateral (transverse) development of the mandible and maxilla. There is a clockwise facial growth pattern. The size, form and facial growth Pattern are characteristic of individuals with a developmental onset of DJD. 137 CBCT Imaging Hatcher Figure 6. A 22-year-old female with a facial asymmetry and a left side cross bite. The individual illustrates the region effects of a developmental onset of left side TMJ DJD. Since the DJD is unilateral, the right side can be used as a Control side for comparison. The left condyle was small and showed signs of flattening, sclerosis and erosions. The posterior slope of the left articular eminence showed signs of flattening and sclerosis. The right condyle has a normal size and form, but has a mildly thickened cortex. The frontal view of the Skeleton illustrates the following features: the osseous midline of the mandible Was shifted to the left side, the occlusal plane was elevated on the left side 139 CBCT Imaging (Figure 6 Continued) (includes maxillary compensations), the left ascending ramus was shorter than the right, the vertical height of the left body of the mandible was less than the right and the lateral development of the mandible was less than the right. The coronal CT scan showed that the cranial base (TMJ) was inferior to the right side (illustrates cranial base compensations). It is of interest to note that a facial asymmetry can occur for many reasons (differential diagnosis) and 3D imaging (CBCT) is a valuable tool for investigating (forming and navigating a diagnostic decision tree) the etiology a facial asymmetry (Hatcher et al., 1997; courtesy of Dr. Martin Fine, Sydney, Australia). FACIAL GROWTH AND THE AIRWAY The airway extending from tip of the nose to the epiglottis can be visualized on a conventional CBCT scan. Because the scan also includes the jaws, teeth, cranial base, spine and facial soft tissues, there is an opportunity to evaluate the functional and developmental relationships between these structures. The skeletal support for the airway is provided by the cranial base (superiorly), spine (posteriorly), nasal septum (anterosuperiorly) and jaws and hyoid bone (anteriorly). The airway valves include the soft palate, tongue and epiglottis. - Airway obstructions or encroachments are of interest and therefore visualization and calculation of the airway dimensions are important. Common airway encroachments include turbinates, adenoids, long Soft palate, large tongue and pharyngeal and lingual tonsils. Uncommon airway encroachments include polyps and tumors. The anteroposterior dimensions of the airway have been shown to have a proportional relationship to jaw growth and facial growth pattern (Aboudara et al., 2003; Stratemann, 2005). The airway is largest when there is normal mandibular and maxillary growth and when facial growth 140 Hatcher Figure 7. A CBCT has been rendered. The maxilla, mandible and airway Were segmented as individual objects and displayed from the frontal, posterior and lateral sides. This individual has a mandibular asymmetry with the right side smaller than the left. The vertical heights of the right condylar process, ascending ramus and body of the mandible were less than the left side. The occlusal plane was elevated on the right side, the osseous midline of the mandible was shifted to the right, and lateral development of the right side of the mandible was less than the left. The right side demonstrated an obtuse gonial angle and clockwise facial growth pattern. The airway was not Symmetrical. The right side of the airway was smaller than the left in bone anteroposterior and transverse dimensions (Aboudara et al., 2003; Stratemann, 2005). Interpretation of the CBCT showed that there was a stable stage of right TMJ DJD that initiated prior to skeletal growth. (Courtesy of Dr. Scott Stratemann.) Pattern occurs with a counter-clockwise rotation. Conversely, the airway is smaller with deficient maxillary and mandibular growth and when there is a clockwise facial growth pattern. Since mandibular growth has been linked to condylar growth and DJD effects condylar growth, it Sºems reasonable to postulate that a developmental onset of DJD may limit airway dimensions (Figs. 7 and 8). 141 CBCT. Imaging 0-0 CSA 43-53-mm- 100 CSA 37.53 mºm- º 150 CSA 45-54 mm- 20-0--SA-5-12-mm- - - - 142 Hatcher <- Figure 8. This individual was scanned using a CBCT and displayed using multi and curved planar sections and Volume rendering (courtesy of Anatomage and 3dMD Vultus). The images demonstrate the following: the condyles were small secondary to a now stable DJD process. There was a small anterior open bite. The condyles were located in the anteroinferior regions of their fossa and the resultant posterosuperior joint spaces were large. The airway was very small with the smallest cross sectional area measuring 24.57 mm. The forward position of the mandible is an acquired position that needs to be maintained for a patent airway. It is not unusual for an acquired reduction in condylar size to be followed by a clockwise rotation of the mandible around molar fulcrums thus “seating” the condyles. Selective muscle recruitment is required to resist the clockwise rotation of the mandible and maintain airway patency. CONCLUSION The dynamic processes of craniofacial growth and function have been very difficult to monitor because of the inability to acquire spatially accurate anatomic volumes. The introduction and availability of CBCT has created the opportunity to serially examine individuals and acquire accurate 3D anatomic information. Fusing the timed sequence of images onto a common Cartesian coordinate system creates the opportunity to detect changes (position, size, shape) over time. The “systems approach” of observing and testing the interactions and influence that adjacent regions have on each other will be a key to understanding the biomechanical influences on craniofacial form. REFERENCES Aboudara CA, Hatcher D, Nielsen IL, Miller A. A three-dimensional evaluation of the upper airway in adolescents. Orthod Craniofac Res 2003;6,S1:173–175. Bryndahl E, Eriksson L, Legrell PE, Isberg A. Bilateral TMJ disk displacement induces mandibular retrognathia. J Dent Res 2006:85:1 118-1123. Carter DR. Beaupré GS, Wong M, Smith RL, Andriacchi TP, Schurman DJ. The mechanobiology of articular cartilage development and degeneration. Clin Orthop Relat Res 2004;427:69-77. Flores-Mir C, Nebbe B, Heo G, Major PW. Longitudinal study of temporomandibular joint disc status and craniofacial growth. Am J Orthod Dentofacial Orthop 2006;130:324-330. 143 CBCT Imaging Flores-Mir C, Akbarihamed L, Nebbe B, Heo G, Major PW. Longitudinal study on TMJ disk status and its effect on mandibular growth. J Orthod 2007:34:194-199. Gallo LM, Chiaravalloti G, Iwasaki, LR, Nickel JC, Palla S. Mechanical work during stress-field translation in the human TMJ. J. Dent Res 2006:85:1006–1010. Hashem G, Zhang Q, Hayami T, Chen J. Wang W, Kapila S. Relaxin and beta-estradiol modulate targeted matrix degradation in specific synovial joint fibrocartilages: Progesterone prevents matrix loss. Arthritis Res Ther 2006:8:R98. Huang H, Kamm RD, Lee RT. Cell mechanics and mechanotransduction: Pathways, probes, and physiology. Am J Physiol Cell Physiol 2004:287:C1-11. Lammi M.J. Current perspectives on cartilage and chondrocyte mechanobiology. Biorheology 2004:41:593-596. Legrell PE, Isberg A. Mandibular height asymmetry following experimentally induced temporomandibular joint disk displacement in rabbits. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:280–285. Legrell PE, Isberg A. Mandibular length and midline asymmetry after experimentally induced temporomandibular joint disk displacement in rabbits. Am J Orthod Dentofacial Orthop 1999; 115:247-253. Legrell PE, Reibel J, Nylander K, Hörstedt P, Isberg A. Temporomandibular joint condyle changes after surgically induced non-reducing disk displacement in rabbits: A macroscopic and microscopic study. Acta Odontol Scand 1999:57:290–300. McNeill C, ed. Science and Practice of Occlusion. Chicago: Quintes- sence Publishing Co., 1997;153-164. Mozzo P, Procacci C, Tacconi A, Martini PT, Andreis IA. A new volumetric CT machine for dental imaging based on the cone-beam technique: Preliminary results. Eur Radiol 1998;8:1558-1564. Naqvi T, Duong TT, Hashem G, Shiga M, Zhang Q, Kapila S. Relaxin's induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in Synovial joint fibrocartilaginous explants. Arthritis Res Ther 2005;7:R1-11. Nebbe B, Major PW. Prevalence of TMJ disc displacement in a pre- orthodontic adolescent sample. Angle Orthod 2000;70:454-463. 144 Hatcher Nebbe B, Major PW, Prassad N. Female adolescent facial pattern associated with TMJ disk displacement and reduction in disk length: Part I. Am J Orthod Dentofacial Orthop 1999; 116:168-176. Nickel JC, Iwasaki LR, Beatty MW, Marx DB. Laboratory stresses and tractional forces on the TMJ disc surface. J Dent Res 2004;83:650– 654. Nickel JC, Iwasaki LR, Beatty MW, Moss MA, Marx DB. Static and dynamic loading effects on temporomandibular joint disc tractional forces. J Dent Res 2006:85:809–813. Petrovic A. Auxologic categorization and chronobiologic specification for the choice of appropriate orthodontic treatment. Am J Orthod Dentofac Orthop 1994;105:192-205. Stratemann S. 3D Craniofacial imaging: Airway and craniofacial morphology. Unpublished Master’s thesis, Department of Growth and Development, University of California, 2005. Stratemann SA, Huang JC, Maki K, Miller AJ, Hatcher DC. Comparison of cone beam computed tomography imaging with physical measures. Dentomaxillofac Radiol 2008:37:80–93. Turner CH. Biomechanical Aspects of Bone Formation In: Bronner F, Farrach-Carson M, eds. Bone Formation. New York: Springer Press 2004;79-105. Usui T, Maki K, Toki Y., Shibasaki Y, Takanobu H, Takanishi A, Hatcher D, Miller A. Measurement of mechanical strain on mandibular surface with mastication robot: Influence of muscle loading direction and magnitude. Orthod Craniofac Res 2003;6 S1:163–167. 145 CONDYLAR RESORPTION IN PATIENTS WITH TMD Lucia H. Cevidanes, David G. Walker, Martin Styner, Pei Feng Lim ABSTRACT The objective of this study is to determine the nature of the difference between condyle morphology of osteoarthritic temporomandibular joint (TMJ) and non- osteoarthritic TMJ, using 3D surface models constructed from cone-beam CT (CBCT) images. Three-dimensional Shape Correspondence was used to localize and quantify condylar morphological differences of 20 patients with RDC/TMD group III (arthralgia, arthritis, arthrosis) compared to 40 asymptomatic subjects. Three-dimensional models of right and left condyles for each subject were con- structed from CBCT images and shape analysis performed using the publicly available SPHARM-PDM software. The right and left condyles were normalized using rigid Procrustes alignment to an overall mean condylar surface per group. The mean differences between groups were compared using the Hotelling T2 analysis with permutation-test derived p-values, corrected for False Discovery Rate. The differences between the group mean surfaces were visualized with color-coded magnitude and difference vectors. The condylar morphology of the TMD group was statistically significantly different from the asymptomatic group (p = 0.05, average surface distance differences of 1.9 mm for the right condyles and 2.3 mm for the left condyles). The average condylar morphology in the TMD patients showed resorption of the anterior surface of the lateral pole and flattening of the articular surface compared to the mean morphology in as- ymptomatic subjects. The condylar morphology and condylar dimensions of the TMD patients were different, on average, from those of the asymptomatic sub- jects. The preliminary findings in this cross-sectional study will lead to future investigations to elucidate osteoarthritic changes in TMD and their role in the pathophysiology of TMD. Supported by NIDCR DE017727. Temporomandibular disorder (TMD) is a common craniofacial condition involving the temporomandibular joints (TMJ), muscles of mastication, or both (AADR Policy Statement, 1996). It affects approxi- mately 10% of the population, being more prevalent in women and caus- ing pain and functional limitations (Rugh and Solberg, 1985; Helenius et 147 Condylar Resorption al., 2006). A comprehensive history, physical examination, and relevant investigations (such as radiographs) are currently used to diagnose TMD. This paper will focus on Research Diagnostic Criteria for TMD (RDC/TMD) Group 3 patients with arthralgia, arthritis, and arthrosis (Dworkin and LeResche, 1992). Radiographic limitations previously have made quantifying the extent of condylar remodeling in TMD patients difficult (Limchaichana et al., 2007). However, utilizing current cone-beam computed tomogra- phy (CBCT) technology and new three-dimensional (3D) surface map- ping techniques, we present a novel visualization and analysis method that has made quantification of osteoarthritic changes in the TMJ possi- ble (Bailey et al., 2004; Cevidanes et al., 2005a,b; Walker et al., 2008a,b). The goals of this study are to: 1. Assess 3D condylar morphology and evaluate condy- lar remodeling in patients with history of TMD; and 2. Determine the nature of the difference between con- dyle morphology of osteoarthritic TMJ and non- osteoarthritic TMJ, using 3D surface models con- structed from CBCT images. A comparative analysis was performed using surface mapping of 3D models generated from the CBCT scans of RDC/TMD Group III patients and a composite “asymptomatic model” (Walker et al., 2008a). Specifi- cally, we have analyzed the condylar morphology in a group of 20 fe- male patients using 3D surface models and compared them to the asymp- tomatic model generated from 40 subjects. METHODS This retrospective cross-sectional study utilized 3D virtual sur- face models of the mandible from CBCT images of 20 patients (85% female, mean age = 36.9 years) with RDC/TMD group III (arthralgia, arthritis, arthrosis) diagnosis to 40 asymptomatic subjects (78.1% female, mean age = 31.4 years). Biomedical Institutional Review Board approval was obtained for secondary data analysis of the CBCTs. Image analysis consisted of the following steps: 148 Cevidanes et al. Construction of 3D Models from CBCT Datasets Segmentation of anatomic structures, i.e., outlining the shape of structures visible in the cross-sections of a volumetric dataset with the NewTom CBCT-3D images, is performed with ITK-SNAP (Yushkevich et al., 2006). Three-dimensional virtual models to be used were built from a set of ~300 axial cross-sectional slices for each image with the voxels reformatted for an isotropic of 0.5 x 0.5 x 0.5 mm. This resolution was used because higher spatial resolution with smaller slice thickness in- creases image file size and requires greater computational power and user interaction time. After the segmentation with ITK-SNAP tool, a 3D graphical rendering of the volumetric object allowed navigation between Voxels in the Volumetric image and the 3D graphics with zooming, rotat- ing and panning. Quantification of Osteoarthritic Changes Using Shape Correspondence After construction of 3D models of the right and left condyles of each subject, shape analysis was performed using the publicly available SPHARM-PDM software. The right and left condyles were normalized using rigid Procrustes alignment to an overall mean condylar surface per group. Three-dimensional surface models were converted into a corre- sponding spherical harmonic description (SPHARM software), which then was sampled into a triangulated surface (SPHARM-PDM; Styner et al., 2003). A mean model of asymptomatic subjects with two standard deviations was used to compare surface differences to a mean condylar morphology for TMD subjects, using the established SPHARM corre- spondence. The mean differences between groups were compared using the Hotelling T2 analysis with permutation-test derived p-values, cor- rected for False Discovery Rate. RESULTS Three-dimensional virtual surface models allowed clear visuali- zation of 3D shape as well as surface erosions, osteophytes and surface flattening. For the group of patients with TMD symptoms, 19 subjects showed either flattening and/or osteoarthritic changes. Condylar flatten- ing was observed in 60% of the subjects, and osteoarthritic changes were found in 95% of the cases. Osteoarthritic changes varied from surface 149 Condylar Resorption irregularities to erosions (present in 40% of the right and left condyles). Different degrees for surface remodeling were observed and varied from partial surface to whole condylar head remodeling (five out of 40 right and left condyles). Condyles with incipient surface remodeling displayed a characteristic morphology with the long axis of the condyle forming an unusually large angle to the transmeatal line (Figs. 1 and 2). Degenerative-mºmºsº remodeling - osteophytes Figure 1. The 3D morphological distribution of condylar shapes associated with the continuum of change is shown. The right of the vertical axis describes the progres- sion (flattening, erosions and osteophytes) of degenerative change, while the hori- zontal axis represents severity. Note that cases with severe degenerative process of ten include all three manifestations with presence of flattening, erosions, and osteo- phytes. Although 15% of asymptomatic subjects presented some degree of condylar flattening, erosions and osteophytes were not observed in this group. The comparison of a composite “asymptomatic model” to a composite TMD model illustrated the magnitude and location of differ- ences. These differences between the group mean surfaces were visual- ized with color-coded magnitude and difference vectors on the combined mean surface. On average, the condylar morphology of the TMD group was statistically significantly different from the asymptomatic group (p → 150 Cevidanes et al. * i Recall Figure 2. Patient showing marked remodeling between the be- ginning of orthodontic-surgical treatment and one year after completion of orthodontics. This patient received maxillary im- paction for correction of open bite. A. Frontal view of condylar morphology prior to surgery through recall. Note that condylar flattening was present in both right and left condyles before sur- gery and was more severe on the right condyle. B. Condylar flat- tening progressed during post-surgery orthodontics and C. after treatment was completed. D. Superimposition shows remarkable condylar remodeling between pre-surgery (transparent mesh lines) and recall (surface models). E. Superimposition shows progression of condylar remodeling after the completion of orthodontic treatment. 0.05, average surface distance differences of 1.9 mm for the right con- dyles and 2.3 mm for the left condyles). The average condylar morphol- Ogy in the TMD patients showed resorption of the anterior surface of the lateral pole and flattening of the articular surface, compared to the mean morphology in asymptomatic subjects. The condylar morphology and condylar dimensions of the TMD patients were different, on average, from those of the asymptomatic subjects (Figs 3-5). - 151 Condylar Resorption Figure 3 (previous page). A mean model of asymptomatic subjects (shown in orange) with 2 standard deviations was used to compare surface differences to a mean condylar morphology for TMD subjects (shown in blue). Figure 4. The comparison of a composite asymptomatic model to a composite TMD model illustrated the magnitude and location of differences. These differ- ences between the group mean surfaces were visualized with color-coded mag- nitude and difference vectors on the combined mean surface. 152 Cevidanes et al. Figure 5. Color maps JFTmºn diſºn. Tº groups using the Ho- telling T2 analysis with permutation-test derived p-values, corrected for False Discovery Rate. DISCUSSION TMD patients are likely to exhibit pain in the TMJ area, clicking or locking of the joint, functional limitations, stiffness of the TMJ, head- aches, and auricular pain (Helenius et al., 2005). Treatment of TMD has focused primarily on alleviating the symptoms of the disease with pre- Scription anti-inflammatory and pain medications. Radiographic indica- tions of TMD have included the observation of erosion of the condyles, Osteophytes, condylar flattening, abnormal condylar shape, abnormal disc perforation and anterior position (Helenius et al., 2005, 2006; Walker et al., 2008a). Physical examination for TMD involves palpating the TMJ and masticatory muscles, listening for clicking or popping noises in the joint and assessing joint mobility (Ardic et al., 2006). These diagnostic methods have not allowed for the quantification of os- coarthritic change or attempted to relate those changes to the symptoms of TMD. Koyama and colleagues (2007) suggest that CBCT imaging is the modality of choice for classification of condylar bone changes be- *ause of its lower radiation dose compared to CT, MRI generally has the disadvantage against CT for the display of the detailed contour of the °ondyle because of the limited spatial resolution and the magnetic sus- 153 Condylar Resorption ceptibility of bone (Hu and Fox, 1996). It also has been noted that some changes in bone structure, which are not identifiable on radiographs, are much more easily noticed using tomosynthesis, CTs and CBCTs (Ardic et al., 2006; Cevidanes et al., 2006; Gomi et al., 2007; Koyama et al., 2007). CBCT imaging systems have the clinical benefit of providing de- tailed multi-planar TMJ imaging with lower radiation and lower cost than CT (Cevidanes et al., 2006). Yale and coworkers (1963) classified the shape of the condyle into five types: flat, convex, angled, round or others. They did not con- side, however, the influence of TMD on the occurrence of condylar bone change. Recent studies have proposed criteria for bone change of the TMJ using multi-planar images from helical CT Volume data (Anker et al., 1990; Schellhas et al., 1993; Nebbe et al., 1997; Hayashi et al., 1999; Yamada et al., 1999, 2001). Koyama and colleagues (2007) have re- ported that multi-planar (axial, coronal and Sagittal images) represent an advantage for the investigation of Osseous changes of the condyle, such as erosive Osseous change, osteophyte and sclerosis, that often have not been detected by previous studies using conventional tomography, axial CT, or MR images. They excluded sclerosis from the criteria for condy- lar bone change, however, as there is no specific definition as to width of thickened cortex (Koyama et al., 2007). While multi-planar images allow assessment of cross-sectional slices in the axial, sagittal and coronal planes of space, the current study is the first to investigate the 3D condy- lar morphology of symptomatic TMD patients compared to non- symptomatic subjects. The findings in this pilot study suggest the need for future inves- tigations to elucidate osteoarthritic changes in TMD and their role in the pathophysiology of TMD, assessing larger samples in a prospective study with careful determination of inclusion and exclusion criteria for TMD patients and controls, and comparison of osteoarthritic changes to the severity of TMD symptoms. CONCLUSIONS Three-dimensional virtual surface models can aid diagnosis of even small bone remodeling changes. This pilot study reveals that condy- lar remodeling was a common finding and that condylar morphology might be a factor indicative of the onset of pathological remodeling in TMD patients. 154 Cevidanes et al. REFERENCES American Association of Dental Research. Policy Statement. Temporo- mandibular Disorders (TMD). Vol 18, No 4, Sept 1996. Anker AH, D'Rozario RH, Li S. Computerized axial tomography in the diagnosis of internal derangements of the temporomandibular joint. Aust Dent J 1990:35:253–257. Ardic F, Gokharman D, Atsu S, Guner S, Yilmaz M, Yorgancioglu R. The comprehensive evaluation of temporomandibular disorders seen in rheumatoid arthritis. Aust Dent J 2006:51:23-28. Bailey LJ, Cevidanes LH, Proffit WR. Stability and predictability of or- thognathic surgery. Am J Orthod Dentofacial Orthop 2004;126:273- 277. Cevidanes LH, Bailey LJ, Tucker GR Jr, Styner MA, Mol A, Phillips CL, Proffit WR, Turvey T. Superimposition of 3D cone-beam CT models of orthognathic surgery patients. Dentomaxillofac Radiol 2005:34:369-375. Cevidanes LH, Franco AA, Gerig G, Proffit WR, Slice DE, Enlow DH, Yamashita HK, Kim YJ, Scanavini MA, Vigorito JW. Assessment of mandibular growth and response to orthopedic treatment with 3- dimensional magnetic resonance images. Am J Orthod Dentofacial Orthop 2005;128:16-26. Cevidanes LHS, Motta A, Styner MA, Proffit WR. Superimposition of 3Dimensional cone-beam computed-tomography models. American Association of Dental Maxillofacial Radiographic Technicians, Fall 2006;1:20-25. - Dworkin SF, LeResche L. Research diagnostic criteria for temporoman- dibular disorders: Review, criteria, examinations, and specifications, critique. J Craniomandib Disord 1992;6:301-355. Gomi T, Yokoi N, Hirano H. Evaluation of digital linear tomosynthesis imaging of the temporomandibular joint: Initial clinical experience and evaluation. Dentomaxillofac Radiol 2007:36,514-521. Hayashi T, Ito J, Koyama J, Hinoki A, Kobayashi F, Torikai Y, Hiruma Y. Detectability of anterior displacement of the articular disk in the temporomandibular joint on helical computed tomography: The value of open mouth position. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88: 106-111. 155 Condylar Resorption Helenius LM, Hallikainen D, Helenius I, Meurman JH, Könönen M, Leirisalo-Repo M, Lindqvist C. Clinical and radiographic findings of the temporomandibular joint in patients with various rheumatic dis- eases: A case control study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005:99:455-463. Helenius LM, Tervahartiala P, Helenius I, Al-Sukhun J. Kivisaari L, Suuronen R, Kautiainen H, Hallikainen D, Lindqvist C, Leirisalo- Repo M. Clinical, radiographic and MRI findings of the temporo- mandibular joint in patients with different rheumatic diseases. Int J Oral Maxillofac Surg 2006:35:983–989. Hu H, Fox SH. The effect of helical pitch and beam collimation on the lesion contrast and slice profile in helical CT imaging. Med Phys 1996:23:1943-1954. Koyama J, Nishiyama H, Hayashi T. Follow-up study of condylar bony changes using helical computed tomography in patients with tem- poromandibular disorder. Dentomaxillofac Radiol 2007:36:472-477. Limchaichana N, Nilsson H, Ekberg EC, Nilner M, Petersson A. Clinical diagnoses and MRI findings in patients with TMD pain. J Oral Re- habil 2007:34:237-245. Nebbe B, Major PW, Prasad NG, Grace M, Kamelchuk LS. TMJ internal derangement and adolescent craniofacial morphology: A pilot study. Angle Orthod 1997;67:407-414. Rugh JD, Solberg WK. Oral health status in the United States: Tem- poromandibular disorders. J Dent Educ 1985;49:398-406. Schellhas KP, Pollei SR, Wilkes CH. Pediatric internal derangements of the temporomandibular joint: Effect on facial development. Am J Orthod Dentofacial Orthop 1993;104:51–59. Styner MA, Rajamani KT, Nolte LP, ZSemlye G, Székely G, Taylor CJ, Davies RH. Evaluation of 3D correspondence methods for model building. Inf Process Med Imaging 2003;18:63-75. Walker D, Cevidanes LHS, Lim PF. Condylar remodeling in temporo- mandibular disorder using 3D surface models analysis of condylar. J Dent Res 2008a;87 (Special Issue A):#082. Walker D, Cevidanes LHS, Lim PF, Styner M, Phillips C. Condylar morphology in temporomandibular disorder using 3D shape analysis. J Dent Res 2008b;87 (Special Issue B): #022. 156 Cevidanes et al. Yale SH, Ceballos M, Kresnoff CS, Hauptfuehrer JD. Some observations of the classification of mandibular condyle types. Oral Surg Oral Med Oral Pathol 1963; 16:572-577. Yamada K, Hanada K, Hayashi T, Ito J. Condylar bony change, disc dis- placement, and signs and symptoms of TMJ disorders in orthog- nathic surgery patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:603–610. Yamada K, Hiruma Y, Hanada K, Hayashi T, Koyama J, Ito J. Condylar bony change and craniofacial morphology in orthodontic patients with temporomandibular disorders (TMD) symptoms: A pilot study using helical computed tomography and magnetic resonance imag- ing. Clin Orthod Res 1999;2:133-142. Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, Gerig G. User-guided 3D active contour segmentation of anatomical struc- tures: Significantly improved efficiency and reliability. Neuroimage 2006:31:11 16-1128. 157 COMMON TMJ DISORDERS: ORTHODONTIC AND SURGICAL MANAGEMENT Larry M. Wolford, Daniel S. Cassano, João Roberto Goncalves ABSTRACT The temporomandibular joints (TMJs) are the foundation and support for jaw position, function, occlusion, and facial balance necessary for quality treatment outcomes in dentistry, orthodontics, and orthognathic surgery. If the TMJs are not stable and healthy (non-pathological), treatment outcomes in these dental disciplines may be unsatisfactory relative to function, esthetics, occlusal and skeletal stability, and pain. There are many temporomandibular joint disorders that can affect the TMJ adversely. The most common of these conditions include: Articular disc dislocation; Reactive arthritis; Adolescent internal condylar resorption; Condylar hyperplasia; Osteochondroma or osteoma; and End-stage TMJ pathology. These conditions often are associated with dentofacial deformities, malocclusion, TMJ pain, headaches, myofascial pain, TMJ and jaw functional impairment, ear symptoms, sleep apnea, etc. Patients with these conditions may benefit from corrective surgical intervention. This chapter will discuss the most common TMJ pathologies and present the orthodontic and surgical management considerations to correct the specific TMJ conditions and associated jaw deformities to obtain predictable outcomes. Improvements in TMJ diagnostics and surgical procedures have contributed to improved treatment and rehabilitation of the pathological, dysfunctional and painful TMJ disorders. Research has demonstrated that TMJ and orthognathic Surgery can be performed safely and predictably at the same operation, but it does necessitate the correct diagnosis and treatment plan, as well as requires the surgeon to have expertise in both TMJ and orthognathic surgery. 159 Common TMJ Disorders There are many temporomandibular joint (TMJ) conditions that can cause pain, TMJ and jaw dysfunction and disability. The most com- mon of these conditions include: Articular disc dislocation; Reactive arthritis; Adolescent internal condylar resorption (AICR): Condylar hyperplasia; Osteochondroma or osteoma; and End-stage TMJ pathology (e.g., connective tissue/ autoimmune diseases, advanced reactive arthritis and osteoarthritis, multiply operated joints, failed al- loplastic TMJ implants, absence of the joint, trau- matic injuries and ankylosis). These conditions often are associated with dentofacial deformities, mal- occlusion, TMJ pain, headaches, myofascial pain, TMJ and jaw func- tional impairment, ear symptoms and sleep apnea. Patients with these conditions may benefit from corrective surgical intervention. The diffi- culty for many clinicians may lie in identifying the presence of a TMJ condition, diagnosing the specific TMJ pathology and selecting the proper treatment for that condition. This chapter will discuss the most common TMJ pathologies and present the orthodontic and surgical man- agement considerations to correct the specific TMJ conditions and asso- ciated jaw deformities. WHY CONSIDER TMJ SURGERY2 The TMJs are the foundation and support for jaw position, func- tion, occlusion and facial balance necessary for quality treatment out- comes in dentistry, orthodontics and orthognathic surgery. If the TMJs are not stable and healthy (non-pathological), treatment outcomes for patients may be unsatisfactory relative to function, esthetics, occlusal and skeletal stability, and pain. Contrary to popular belief, orthognathic sur- gery to correct a malocclusion and jaw deformity will not “fix” or elimi- nate co-existing TMJ pathology and symptoms. Our studies (Fuselier et al., 1998; Wolford et al., 2003; Goncalves et al., 2008) and other studies (Arnett and Tamborello, 1990; Kerstens et al., 1990; Moore et al., 1991; Crawford et al., 1994; DeClercq et al., 1994) demonstrate that perform- ing only orthognathic surgery on patients with co-existing TMJ pathol- ogy can result in unsatisfactory treatment outcomes. 160 Wolford et al. The above listed TMJ conditions, when occurring with or with- out dentofacial deformities, can be treated predictably by performing the appropriate TMJ and orthognathic surgical procedures at one operation. These TMJ conditions also can be treated by performing the TMJ and orthognathic surgery at separate operations, but the TMJ Surgery should be done at the first operation for best quality outcomes. Patient history as well as clinical, radiographic, dental model, MRI and/or CT scan evalua- tions and when indicated laboratory tests are very important for accurate diagnosis of the TMJ pathology and treatment planning. With appropri- ate selection and execution of the surgical procedures and proper post- Surgical management, good outcomes usually can be achieved. Our research studies (Fuselier et al., 1998; Wolford et al., 2003) evaluated 25 consecutive patients with jaw deformities and anteriorly displaced discs treated with orthognathic surgery only. All but one pa- tient had the mandible advanced. Pre-surgery, 36% of the patients had pain or discomfort. At an average of 2.2 years post-surgery, 84% of the patients had TMJ-related pain, with a 70% increase in pain severity. In addition, 25% of the patients developed anterior open bites from condy- lar resorption. New onset/aggravation of TMJ symptoms occurred at an average of 14 months post-surgery. Twelve patients (48%) required TMJ surgery and repeat orthognathic surgery. Nine additional patients (36%) required long-term medications and/or splint therapy for pain control. These studies clearly demonstrate the problems associated with perform- ing orthognathic surgery only on patients with co-existing TMJ disc dis- locations. Goncalves and coworkers (2008) evaluated 72 patients (59 fe- males, 13 males) with an average age of 30 years (range, 15 to 60 years) who had double-jaw orthognathic surgery with counter-clockwise rota- tion of the maxillo-mandibular complex. The patients were divided into three groups. Group 1 (G1; n = 21) with healthy TMJs (Fig. 1) received orthognathic surgery only; Group 2 (G2; n = 35) with bilateral articular disc dislocation (Fig. 2) received articular disc repositioning with the Mitek anchor technique concomitantly with orthognathic surgery; and Group 3 (G3; n = 16) with bilateral articular disc dislocation received orthognathic surgery only. Average post surgical follow-up was 31 months. At surgery, the occlusal plane angle decreased significantly in all three groups G1 (-6.3 + 5.0°), G2 (-9.6 + 4.8%), and G3 (-7.1 + 4.8%). The maxillomandibular complex advanced and rotated counter-clockwise similarly in all three groups, with advancement at menton in G1 (12.4 + 161 Common TMJ Disorders 5.5 mm), G2 (13.5 + 4.3 mm), and G3 (13.6 + 5.0 mm); Point B in Gl (9.5 + 4.9 mm), G2 (10.2 + 3.7 mm), and G3 (10.8 + 3.7 mm); and lower incisor edge in G1 (7.1 + 4.6 mm), G2 (6.6 + 3.2 mm), and G3 (7.9 + 3.0 mm). Post-surgery, the occlusal plane angle increased in G3 (37% re- lapse) while G1 and G2 remained stable. Mandibular post-surgical changes demonstrated a significant anteroposterior relapse in G3 at men- ton (28%), Point B (28%), and lower incisor edge (34%) while G1 and G2 remained stable. This study clearly demonstrated that maxilloman- dibular advancement with counter-clockwise rotation of the occlusal plane is a stable procedure for patients with healthy TMJs and for pa- tients with simultaneous TMJ disc repositioning using the Mitek anchor technique. Patients with preoperative TMJ articular disc displacement who underwent double-jaw surgery and no TMJ intervention experienced significant relapse. Figure 1. MRI of a TMJ shows good A-P position of the articular disc as well as good shape of the disc, condyle and eminence. On opening, the disc remains in good position as the condyle demonstrates good translation (C = condyle, arrows denote the disc). TMJ Surgery (e.g., disc repositioning, arthroplasties, high con- dylectomies) can alter the position of the mandible and the occlusion significantly. Therefore, the surgical sequencing for performing TMJ and orthognathic surgery at one operation or divided into two operations (the TMJ and orthognathic procedures performed separately) is important to achieve good outcomes and includes TMJ surgery first, followed by mandibular ramus Sagittal split osteotomies with rigid fixation and then. if indicated, maxillary osteotomies with rigid fixation. With the man- dibular osteotomies being performed after the TMJ surgery, the mandible will be positioned into its predetermined position regardless of the amount of mandibular displacement resulting from the TMJ surgery. The jaws are not wired together post-surgery because rigid fixation (bone plates and screws) is used to stabilize the maxillary and mandibular OS- teotomies. Light vertical elastics (3.5 oz) with a slight Class III vector 162 Wolford et al. usually are used post-surgery to control the occlusion and minimize the TMJ intercapsular edema. Closely monitoring and managing the occlu- sion in the post-surgery period, as well as controlling the parafunctional habits (i.e., clenching, bruxism), are very important to provide high qual- ity outcomes. When end-stage TMJ pathology requires reconstruction with total joint prostheses, then the mandible can be advanced, counter- clockwise rotated if indicated, and asymmetries corrected with custom- fitted total joint prostheses without requiring additional mandibular os- teotomies. BENEFITS OF ONE-STAGE TMJ AND ORTHOGNATHIC SURGERY The benefits of one-stage TMJ and orthognathic surgery include: 1. It requires one operation and general anesthetic; 2. It balances the occlusion, TMJs, jaws and neuromus- cular structures at the same time; and 3. It decreases overall treatment time. Our research studies (Wolford et al., 1994, 1995, 2002, 2003; Wolford, 1997; Wolford and Karras, 1997; Wolford and Cardenas, 1999; Mehra and Wolford, 2000: Downie et al., 2001; Garcia-Morales et al., 2001; Freitas et al., 2002; Mehra and Wolford, 2002; Morales–Ryan et al., 2002) have shown that simultaneous surgical correction of TMJ pathol- ogy and co-existing dentofacial deformities performed in one operation provides high quality treatment outcomes for patients relative to func- tion, esthetics, elimination or significant reduction in pain, and patient Satisfaction. Equivalent results also can be achieved by separating the TMJ and orthognathic surgical procedures into two operations; the TMJ surgery must be performed first, with at least six months before perform- ing the orthognathic surgery procedures. ARTICULAR DISC DISLOCATION The most common TMJ pathology is an anterior and/or medial displaced disc (Fig. 2). This condition can initiate a cascade of events leading to arthritis and TMJ-related symptoms (Nickerson and Boring, 1989). Simultaneous surgical treatment would include repositioning the TMJ disc into a normal anatomical, functional position and stabilizing it using the Mitek anchor (Mitek Surgical Products Inc., Westwood, MA) 163 Common TMJ Disorders Figure 2. MRI of a TMJ shows a significantly anterior displaced ar- ticular disc (C = con- dyle, arrow denotes the disc). technique (Wolford et al., 1995, 2002; Wolford, 1997; Wolford and Cardenas, 1999: Downie et al., 2001; Mehra and Wolford, 2001) and then performing the indicated orthognathic surgery. The Mitek anchor technique uses a bone anchor that is placed into the lateral aspect of the posterior head of the condyle and the anchor will subsequently osseoin- tegrate. Two 0–Ethibond sutures (Ethicon Inc., Somerville, NJ) are at- tached to the anchor and are used as artificial ligaments to secure and stabilize the disc to the condylar head (Fig. 3). Our study (Wolford et al., 2002) using this treatment protocol on 70 patients showed that pre-surgery, 80% of the patients had preopera- tive TMJ pain, but at longest follow-up, 60% had complete relief of pain and an additional 33% had significant reduction in pain. All but one par tient had stable orthognathic surgery outcomes. Using the criteria of in- cisal opening greater than 35 mm, stable skeletal and occlusal relation- ships and significant reduction in pain, the success rate was 91%. The success rate was significantly better (95%) if the TMJ discs were reposi- tioned surgically within the first four years of onset of the TMJ dysfunc- tion. After four years, the progression of irreversible TMJ degenerative changes may result in a lower success rate. Another of our studies (Downie et al., 2001) evaluated 88 different patients with simultaneous TMJ disc repositioning with the Mitek anchor and orthognathic surgery that likewise demonstrated a very similar statis- tically significant decrease in TMJ pain and headaches, while improving jaw function and providing stable occlusal and skeletal results. Patients with systemic conditions that affect joints (e.g., rheumatoid arthritis, pSO- riatic arthritis, Sjogren's syndrome, scleroderma, ankylosing spondylitis. lupus), previously operated TMJs, or with multiple other joint involve- ment, generally will not do well with the Mitek anchor technique or 164 Wolford et al. Posterior band Anterior discal attachment º, º --- Lateral pterygoid m. Freeing Anterior Disc Attachment (lateral view) Placing Sutures Through Disc A B (posterior 3/4 view) Repaired bilaminartissue Superior joint space Anchor suture - Repositioned Disc C Bilaminar Tissue Closed D (lateral view) (posterior 3/4 view) Figure 3. A. In the use of the Mitek anchor to stabilize the articular disc, the joint first is exposed and the excessive bilaminar tissue excised. To mobilize the disc, the anterior attachment of the disc to the articular eminence is released so the disc can be positioned over the condyle passively. B and C. The Mitek Mini Anchor (insert) has an eyelet that will support two 0–Ethibond sutures that can function as artificial ligaments. The anchor is inserted into the posterior head of the condyle lateral to the mid-sagittal plane and 5 to 8 mm below the top. One Suture is placed in a mattress fashion through the medial aspect of the posterior Part of the posterior band. The other suture is placed more lateral through the Posterior band. D. Cross-sectional sagittal view shows the Mitek anchor posi- tioned in the condyle with the artificial ligaments attached to the disc to stabilize it to the condylar head. attempts to use autogenous tissues to reconstruct the TMJs. TMJ total Joint prostheses may be indicated for TMJ reconstruction with these pathological conditions. Case / This 41-year-old female presented with bilateral TMJ anteriorly displaced articular discs (confirmed by MRI, Fig. 6) and a Class II skele- |al and occlusal dentofacial deformity (Figs. 4A and C, 5A-C, 7A). She- had moderate to severe TMJ pain, headaches and myofascial pain as 1.65 Common TMJ Disorders Figure 4. Case 1. A and C. A 41-year-old female is seen with bilaterally dis- placed articular discs, TMJ dysfunction and severe TMJ pain and headaches. The mandible is retruded significantly with a high occlusal plane angle and as- sociated facial morphology. B and D. The patient is seen three years post- surgery following bilateral TMJ articular disc repositioning with Mitek anchors and simultaneous double-jaw orthognathic surgery. Figure 5. Case 1. A c. The pre-surgical occlusion demonstrates an anterior open bite and Class II occlusal relationship. D-F. The Class I occlusion achieved by the Surgery remained stable three years post-surgery. well as clicking in the TMJs and difficult eating. Following orthodontic preparation, Surgery was performed in one operation including: 1. Bilateral TMJ disc repositioning with Mitek anchors; 2. Mandibular counter-clockwise advancement of 20 mm at pogonion; and 3. Multiple maxillary osteotomies to downgraft the pos- terior aspect and upright the incisors (Fig. 7B). 166 Wolford et al. --> --> Figure 6. Case 1. A. MRI of a TMJ shows a significantly anterior displaced articular disc (arrows). B: On opening, the disc remains anteriorly displaced and non-reducing with degenerative changes (C = condyle; arrows denote the disc). The patient was evaluated three years post-surgery, showing good stabil- ity (Figs. 4B and D; 5D-F, 7C and D) with elimination of TMJ pain, headaches, myofascial pain and TMJ noises. Her jaw function and facial esthetics were improved as well. REACTIVE ARTHRITIS Reactive Arthritis (also called seronegative spondyloarthropathy) is an inflammatory process in joints commonly related to bacterial and/or Viral factors. This condition usually occurs during the third to fourth dec- ade of life, but it can develop at any age. In the TMJ, Reactive Arthritis Commonly is seen in conjunction with a displaced TMJ articular disc, but it also can develop with the disc in position. Our studies (Henry et al., 2000, 2001) have confirmed that at least 73% of patients with articular disc displacements have bacteria in the bilaminar tissues of the TMJ. The bacterial species we have identified include: Chlamydia trachomatis and psittaci, as well as Mycoplasma genitalium and fermentans (Henry et al., 2000, 2001; Hudson et al., 2000; Wolford et al., 2001). Other bacteria that have been found in other joints but also may infect the TMJ creating Reactive Arthritis include: Borrelia burgdorferi (Lymes disease), Salmonella species, Shigella spe- Cies, Yersina enterocolitica and Campylobacter jejuni. 167 Common TMJ Disorders —immediate Post-op -3 years Post-op ſus Figure 7. Case 1. A. The pre-treatment cephalometric analysis shows a retruded mandible, anterior open bite, steep occlusal and mandibular plane angles, and proclined lower incisors. B. The Surgical Treatment Objective (STO prediction tracing) demonstrates the orthognathic procedures required to achieve a good functional and esthetic result, including disc repositioning as well as maxillary and mandibular osteotomies with counterclockwise rotation of the occlusal plane. C. Cephalometric analysis at three years post-surgery demonstrates good facial balance. D. Superimposition of the immediate post-surgery (red lines) and three years follow-up (black lines) cephalometric tracings demonstrate the treatment stability achieved for this patient. 168 Wolford et al. We suspect that other bacterial/viral species also may cause Re- active Arthritis in joints, including Chlamydia pneumoniae, Mycoplasma pneumoniae, Ureaplasma, Herpes virus, Epstein-Barr virus, Cy- tomegalovirus and Varicella zoster. The bacteria we identified (Chlamy- dia and Mycoplasma species) were found in the bilaminar tissues. They live and function like viruses and, therefore, antibiotics may not be effec- tive in eliminating the bacteria from joints and the body. Antibiotics may affect the extracellular organisms but will not affect the intracellular bac- teria, although they may be placed into a dormant state. These bacteria are known to stimulate the production of Substance P, cytokines, and tissue necrosis factor, which are all pain modulating factors (Henry et al., 2002). In addition, these bacterial species have been associated with Re- iter’s syndrome, destructive arthritis and dysfunction of the immune sys- tem. Although we have identified the bacteria, the specific affect for each patient is difficult to quantify. We also have identified specific genetic factors, Human Leukocyte Antigen (HLA) markers that occur at a sig- nificant greater incidence in TMJ patients than the normal population (Henry et al., 2002). These same markers also may indicate an immune dysfunctional problem for these bacterial species allowing the bacteria to have a greater affect on patients with these markers compared to people without these same markers. Patients with localized TMJ Reactive Arthritis usually will have displaced discs, pain, TMJ and jaw dysfunction, ear symptoms and head- aches. As the disease progresses, condylar resorption and/or bony depo- sition can occur, causing changes in the jaw and occlusal relationships. Patients with moderate to severe Reactive Arthritis may have other body systems involvement, including the genitourinary, gastrointestinal, re- productive, respiratory, cardiopulmonary, ocular, neurological, Vascular, hemopoietic and immune systems as well as involvement of other joints (Wolford et al., 2004). Most patients with mild to moderate TMJ Reactive Arthritis, without significant involvement of other body systems or other joints, usually respond well to articular disc repositioning using the Mitek an- chor System and the appropriate orthognathic surgery procedures, provid- ing the discs are salvageable and within four years of the onset of the TMJ problems. It is possible that the resection and removal of a large portion of the bilaminar tissue (where it is known that these bacteria re- side) during surgery may result in a major reduction of the source of the inflammation. In more advanced Reactive Arthritis cases, particularly 1.69 Common TMJ Disorders those with involvement of other body systems and other joints, the best TMJ treatment may be reconstruction with a total joint prostheses (TMJ Concepts Inc., Ventura, CA). Case 2 This 27-year-old female presented with Reactive Arthritis, bilat- eral TMJ involvement with articular disc displaced in the left side (Fig. 10A) and significant right TMJ condylar destruction and resorption (Fig. 10B), Class II skeletal and occlusal dentofacial deformity, left side poste- rior open bite, significant asymmetry of the mandible, decreased oro- pharyngeal airway with sleep apnea symptoms (Figs. 8A and C; 9A-C, 11A), TMJ symptoms, pain and headaches. Following orthodontic prepa- ration, surgery was performed that consisted of: 1. Unilateral right TMJ reconstruction and mandibular counter-clockwise advancement with custom-made TMJ total joint prosthesis (TMJ Concepts system; Fig. 12); 2. Unilateral right TMJ fat graft placement (harvested from abdomen); Unilateral right coronoidectomy; 4. Unilateral left TMJ disc repositioning with Mitek an- chor; 5. Sagittal split osteotomy of the left mandibular ramus with counter-clockwise rotation of occlusal plane an- gle; and 6. Multiple maxillary osteotomies to down graft the pos- terior aspect and upright the incisors (Fig. 11B and C). Pogonion advanced 17 mm. The patient was evaluated one year post- surgery, showing good stability (Figs. 8B and D; 9D-F; 11D), free from TMJ pain, headaches and myofascial pain; as well as improved facial esthetics and increased orpharyngeal airway, eliminating her sleep apnea. 3 → Figure 10. Case 2. A: MRI of left TMJ shows the anteriorly displaced articu- lar disc (C = condyle, arrows denote the disc). B: MRI of right TMJ shows Re- active Arthritis with severe degenerative and resorptive changes. 170 Wolford et al. B Cº- D. Figure 8. Case 2. A and C. A 27-year-old female is seen with a unilaterally left TMJ displaced articular disc and Reactive Arthritis of the right TMJ with sig- nificant condylar resorption. The mandible is retruded significantly, shifted off to the right side, with a high occlusal plane angle and associated facial morphol- Ogy. B and D. The patient is seen one year post-surgery, following unilateral left TMJ articular disc repositioning with Mitek anchor, unilateral right TMJ recon- struction and mandibular advancement with custom-made TMJ total joint pros- thesis (TMJ Concepts system), unilateral right coronoidectomy, unilateral right TMJ fat graft, left mandibular ramus sagittal split osteotomy and multiple maxil- lary osteotomies. D E. F. Figure 9. Case 2. A-C. The pre-surgical occlusion demonstrates Class II occlusal relationship and left side posterior open bite. D-F. The occlusion remained sta- ble one year post-surgery. 171 Common TMJ Disorders BB STO Left Side Age 27 years BB STO Right Side Figure 11. Case 2. A. The pre-treatment cephalometric analysis shows a retruded mandible, asymmetry of mandibular base and level of teeth, steep occlusal and mandibular plane angles, and proclined lower incisors and a significant de- creased oropharyngeal airway. B: The Surgical Treatment Objective (prediction tracing) of the left side demonstrates the TMJ disc repositioning with a Mitek anchor and orthognathic procedures required to achieve a good functional and esthetic result including maxillary and mandibular osteotomies with counter- clockwise rotation of the occlusal plane. C. The STO of the right side demon- strates right TMJ reconstruction and mandibular advancement with custom- made TMJ total joint prosthesis (TMJ Concepts system), unilateral right coronoidectomy, unilateral right TMJ fat graft (harvest from the abdomen). maxillary osteotomies for counter-clockwise rotation of the maxillomandibular complex and occlusal plane angle. D. Cephalometric analysis at one year post- surgery demonstrates good facial balance and a normal oropharyngeal airway. 172 Wolford et al. Figure 12. A. The TMJ Concepts total joint prosthesis is a custom-made de- Vice fitted to each patient’s specific anatomical requirements. The fossa Component is made of titanium (T) and ultra high molecular weight poly- ethylene (P). The mandibular component shaft (M) is made of titanium al- loy and the head is chromium-cobalt alloy, B. Case 2. The 3D polymer model was prepared with the mandible advanced to the predetermined posi- tion relative to the unoperated maxilla. The TMJ Concepts custom-made to- tal joint prosthesis was constructed on the prepared model. C. The Panograph shows the TMJ Concepts total joint prosthesis of the right side, Mitek anchor in the left mandibular condyle and bone plates and screws in the maxilla and left mandibular body. Ramus area shows good healing one year post-surgery. 173 Common TMJ Disorders ADOLESCENT INTERNAL CONDYLAR RESORPTION (AICR) AICR is a pathological, hormonally mediated condition primar- ily affecting teenage females (ratio 9:1, females to males), usually initi- ated as they enter their pubertal growth phase. In AICR, it is postulated that the female hormones stimulate hyperplasia of the synovial tissues that then produce chemical substrates that destroy the ligaments that nor- mally stabilize the disc to the condyle. The disc becomes displaced anteriorly, and the condyle then is surrounded by the hyperplastic syno- vial tissue that continues to release chemical substrates which penetrate the condylar head, causing internal condylar resorption and creating a slow but progressive decrease in size of the condyle and retrusion of the mandible. In AICR, condylar resorption is internal with inward collapse of the overlying thinned outer cortical bone and fibrocartilage. Other TMJ resorptive pathologies resorb the condyle from the outside. Interestingly, 25% of the patients with AICR are asymptomatic relative to pain and joint noises. The only treatment protocol proven to eliminate the TMJ pathology and allow optimal correction of the associ- ated dentofacial deformity was developed by the senior author (Wolford and Cardenas, 1999; Morales–Ryan et al., 2002; Wolford et al., 2002) and includes: 1. Removal of the hyperplastic bilaminar and synovial tissues around the condyle; - 2. Repositioning and stabilizing the disc to the condyle with the Mitek anchor technique (Fig. 3); and 3. Performing the indicated orthognathic surgery. Our initial study (Wolford and Cardenas, 1999) involved 12 pa- tients with active AICR (formerly called idiopathic condylar resorption) who underwent simultaneous TMJ and orthognathic surgery. The aver- age post-surgical follow-up was 33 months with stable results, excellent jaw and masticatory function, and elimination or significant reduction in pain in all patients. Our more recent study (Wolford et al., 2002) evaluated 44 pa- tients with active AICR who were divided into two groups. Group 1 (n = 10) underwent orthognathic surgery only, with no TMJ surgical treat- ment. Group 2 (n = 34) underwent TMJ disc repositioning with the Mitek anchor technique, and simultaneous orthognathic surgery. In Group 1, AICR continued in all 10 patients post-surgery resulting in statistically 174 Wolford et al. significant skeletal and occlusal instability and relapse with redevelop- ment of Class II occlusion and anterior open bite as well as continued pain. Group 2 patients all maintained stable Class I skeletal and occlusal outcomes, with statistically significant reduced pain and improved jaw function compared to Group 1. Case 3 This 15-year-old female presented with bilateral TMJ AICR, an- teriorly displaced articular discs, internal condylar resorption with de- crease in size of the condyle (confirmed by MRI, Fig. 15A and B) and a Class II skeletal and occlusal déntofacial deformity that was slowly be- coming progressively worse (Figs. 13A and C, 14A-C; 16A). She had headaches, myofascial pain, as well as clicking in the TMJs. Following Orthodontic preparation, surgery was performed in one operation includ- Ing. 1. Bilateral TMJ disc repositioning with Mitek anchors; 2. Bilateral sagittal split osteotomy with mandibular counter-clockwise rotation and advancement of 6.5 mm at pogonion; and, 3. Multiple maxillary osteotomies to move the anterior aspect of the maxilla upward, decrease the occlusal plane angle, as well as upright the incisors (Fig. 16B). The patient was evaluated 13 months post-surgery showing good stabil- ity (Figs. 13B and D, 14D-F; 16C and D), with elimination of headaches, myofascial pain and TMJ noises; as well as improved facial esthetics. Figure 13, Case 3, 4 and C. A 15-year-old female is seen with bilaterally dis- placed articular discs, AICR and TMJ dysfunction. The mandible is retruded With a high occlusal plane angle, and the maxilla shows vertical excess. B and D. The patient is seen 13 months post-surgery following bilateral TMJ articular disc repositioning with Mitek anchors and simultaneous double-jaw orthog- nathic surgery. 175 Common TMJ Disorders Figure 14. Case 3. A-C. The pre-surgical occlusion demonstrates a Class II oc- clusal relationship. D-F, the occlusion remained stable 13 months post-surgery. Figure 15. Case 3. MRIs of the TMJs show a significantly anterior displaced articular discs (left and right side) and significant internal condylar resorption (C = condyle, arrows denote the disc). CONDYLAR HYPERPLASIA (CH) Normal facial and jaw growth usually is 98% complete in fe- males at age 15 years, and in males at age 17 to 18 years. CH is an ab- normal growth condition affecting the mandibular condyles, creating ac- celerated and excessive overgrowth of the mandible (prognathism) that often continues into the patient’s mid-20s. Bilateral active CH causes progressive and worsening prognathism and occlusion, but relatively a- symptomatic for TMJ symptoms. Unilateral CH can cause progressive deviated prognathism, facial asymmetry, disc dislocations, TMJ pain. headaches and masticatory dysfunction. Not all prognathic mandibles are caused by CH; only those demonstrating accelerated, excessive mandibu- lar growth and/or growth continuing beyond the normal growth years. 176 Wolford et al. CF Age 15 years A CF CF 13 months Post-op Superimposition - Immediate Post-op - 13 months Post-op (U9. Figure 16. Case 3, 4: The pre-treatment cephalometric analysis shows a retruded mandible, high occlusal and mandibular plane angles, anterior vertical excess of the maxilla, and proclined lower incisors. B. The Surgical Treatment Objective (prediction tracing) demonstrates the orthognathic procedures required to achieve a good functional and esthetic result including disc repositioning as well *S maxillary and mandibular osteotomies with counterclockwise rotation of the Occlusal plane. C. Cephalometric analysis at 13 months post-surgery demon- Strates good facial balance. D. Superimposition of the immediate post-surgery (red lines) and 13 months follow-up (black lines) cephalometric tracings demon- ºrate the treatment stability achieved for this patient. 177 Common TMJ Disorders The treatment protocol developed by the senior author (Garcia-Morales et al., 2001; Wolford et al., 2002) for these patients includes: 1. High condylectomy to arrest condylar growth; 2. TMJ disc repositioning (Fig. 3); and 3. Simultaneous orthognathic surgery. This protocol predictably stops mandibular growth and provides stable outcomes with normal jaw function and good esthetics. Our study (Wolford et al., 2002) evaluated 54 patients (32 fe- males, 22 males) with confirmed active CH, average age 17 years, fol- lowed for five-years post-surgery and divided into two groups. Group 1 patients (n = 12) were treated with orthognathic surgery only, and Group 2 patients (n = 42) were treated with simultaneous high condylectomies, discs repositioned over the remaining condyle, and orthognathic surgery. All patients in Group 1 redeveloped skeletal and occlusal Class III relationships. In Group 2, all 42 patients remained in a stable Class 1 skeletal and occlusal relationship with normal jaw function. Case 4 This female patient presented with bilateral CH with the right side worse than the left side, creating a deviated mandibular prog- nathism, maxilla retrusion and a Class III skeletal and occlusal dentofa- cial deformity (Figs. 17A and C, 18A-C, 20A). Active CH caused wors- ening of a deviated prognathism. This patient had displaced discs, TMJ pain, headaches and myofascial pain. Following orthodontic preparation, the surgical treatment indicated for this type of patient with active CH included: 1. Bilateral high condylectomy to arrest the condylar growth (Fig. 19A and B); 2. Bilateral TMJ disc repositioning with Mitek anchors (Fig. 19B); 3. Bilateral sagittal split osteotomy with mandibular counterclockwise rotation and setback; and, 4. Multiple maxillary osteotomies to downgraft the pos- terior aspect and upright the incisors (Fig. 20B). The patient was evaluated 25 months post-surgery showing good stabil- ity (Fig. 17B and D, 18D-F, 200 and D), improved facial esthetics, and elimination of TMJ pain, headaches and myofascial pain. 178 Wolford et al. A Figure 17. Case 4. A and C. This female patient is seen with bilateral condylar hy- perplasia (CH: right side worse than left side) and a Class III skeletal and occlusal dentofacial deformity. The mandible is prognathic and deviated toward the left side with a high occlusal plane angle and a retruded maxilla. The occlusion and jaw de- formity will get progressively worse with active CH, B and D. The patient is seen 25 months post-surgery following TMJ surgery including articular disc repositioning with Mitek anchors and simultaneous double-jaw orthognathic surgery. Figure 18. Case 4. A-C. The pre-surgical intraoral views demonstrate Class III oc- ºlusal relationship and mandibular dental midline deviated significantly off to the left side, D-F. The occlusion remained stable 25 months post-Surgery. MANDIBULAR CONDYLAR OSTEOCHONDROMA/OSTEOMA Condylar osteochondromas or osteomas are unilateral pathologi- cal processes that cause enlargement of the mandibular condyle and neck, creating a progressive, asymmetric dentofacial deformity that can result in TMJ disc dislocation (usually on the opposite side from the tu- mor), TMJ pain, headaches and masticatory dysfunction. An osteochon- 179 Common TMJ Disorders Figure 19. Case 4. The illustration demonstrates the level of the high condylec- tomy to arrest active CH growth (4 to 5 mm below the top of the condylar head) and disc repositioning with Mitek anchor. The condylectomy includes the lateral and medial poles to ensure removal of the mandibular growth center. droma is a tumor in the condylar head producing excessive bone and car. tilage that enlarges the condyle. An osteoma can have a similar growth pattern, but produces only excessive bone in the condyle and usually is not as fast growing as an osteochondroma. Both of these tumors can be- come very large and cause severe dentofacial and occlusal deformities. This pathological process usually creates increased vertical height of the ipsilateral mandibular body, ipsilateral posterior open bite and downward development of the ipsilateral maxilla creating a transverse cant to the occlusal plane. These pathologies can be treated predictably with a low con- dylectomy, preserving the condylar neck, that is recontoured to function as a “new condyle,” and the disc is stabilized to it with a Mitek anchor. Simultaneous orthognathic surgery can be performed including mandibu- lar ramus osteotomics, maxillary osteotomies, as well as vertical reduc- tion of the ipsilateral inferior border of the mandible with preservation of the inferior alveolar nerve to provide optimal functional and esthetic re- sults as well as maintain neurological sensibility to the lower lip and chin. Our study (Wolford et al., 1994) on six patients treated by this pro- tocol showed at four years post-surgery, no recurrence of the tumors Was observed, jaw structures and occlusions were stable, jaw function was good and patients were pain-free. Case 5 This 16-year-old female presented with unilateral osteochon- droma of left TMJ, significant asymmetry with vertical elongation of the mandibular body, ramus, and chin, vertical maxillary asymmetry and a Class I skeletal and occlusal dentofacial deformity (Figs. 21A and C. 180 Wolford et al. SHY SHY --- Initial - 25 months Post-o /US aſºvº ------ Figure 20, Case 4 4. The pre-treatment cephalometric analysis shows a prog- nathic mandible, high occlusal and mandibular plane angles, long condylar heads and necks and proclined lower incisors. B. The STO (prediction tracing) demonstrates the maxillary and mandibular orthognathic surgical procedures including counterclockwise rotation of the maxilla mandibular complex and Occlusal plane. C. Cephalometric analysis at 25 months post-surgery demon- Strates good facial balance. D. Superimposition of the pre-surgery (red lines) and 25 months follow-up (black lines) cephalometric tracings demonstrate the surgical changes achieved for this patient. |8 || Common TMJ Disorders - A (e C. Figure 21. Case 5. A and C. A 16-year-old female is seen with a unilateral os- teochondroma of left TMJ, significant vertical asymmetry with elongation of the left mandibular ramus, body, and chin, and a Class I skeletal and occlusal dento- facial deformity. B and D. The patient is seen nine years post-surgery following unilateral left low condylectomy, and TMJ articular disc repositioning with Mitek anchor, left mandibular inferior border ostectomy preserving the inferior alveolar nerve and simultaneous double-jaw orthognathic surgery. Figure 22. Case 5. A-C. The pre-surgical occlusion demonstrates Class I occlu- sal relationship, posterior open bite of the left side and transverse cant to the occlusal plane. D-F. The occlusion remained stable nine years post-surgery. 22A-C; 23A; 24A and B). This pathological process created progressively increasing vertical height of the mandibular body, ipsilateral posterior open bite and increased ipsilateral vertical maxillary compensatory growth creating a transverse cant to the occlusal plane. Following ortho- dontic preparation, Surgery was performed in one operation including: 1. Low condylectomy preserving the condylar neck (Figs. 23B and C, 24C); 2. Unilateral TMJ disc repositioning with Mitek anchor (Figs. 23B; 24C); 182 Wolford et al. Figure 23. A and B: The illustration demonstrates the level of the low con- dylectomy to preserve the condylar neck and articular disc repositioning With a Mitek anchor (5 to 8 mm below the top of the remaining condylar head in the posterolateral aspect). C. The tumor in the condylar head was sent for histopathologic analysis. D. Microscopic description of the osteo- chondroma: cartilaginous tumor formatting a cap over area of lamellar bone. There is a transition from cartilage to bone; cartilaginous islands are present within the bone structures. 3. Bilateral mandibular ramus sagital split osteotomy (Fig. 23B); 4. Left mandibular inferior border ostectomy (Fig. 23B); and 5. Multiple maxillary osteotomes. The resected condylar head was sent for histopathologic analysis, and it Was diagnosed as an osteochondroma (Fig. 23D). The patient was evalu- ºted nine years post-surgery, showing good stability (Figs. 21.B and D, 22D-F, 24C) with improved facial esthetics, good jaw function and pain free. END-STAGE TMJ PATHOLOGY The TMJ can become end-stage, non-salvageable (not amend- able to autogenous tissue reconstruction) as a result of the following Conditions: 183 Common TMJ Disorders Figure 24. Case 5. A and B: A pre-surgical panograph and MRI shows an en- larged and deformed left mandibular condyle and neck (osteochondroma). C. The post-surgical panograph shows the Mitek anchor in position and the recon- toured condylar neck to function as the head. The screws seen in the ramus and body were used to fixate the mandibular sagittal split osteotomy. 1. Connective tissue/autoimmune diseases (e.g., rheu- matoid arthritis [RA], psoriatic arthritis, lupus, Scleroderma, Sjogren’s Syndrome, ankylosing spon- dylitis; Figs. 25–30); Reactive Arthritis (i.e., Reiter’s syndrome); Osteoarthritis; Neoplasms; Multiple operated joints; Failed TMJ alloplastic implants; Traumatic injuries (Figs. 31-34); Absence of the TMJ (i.e., hemifacial microsomia); or 9. Ankylosis (Figs. 35–39). Some patients with these conditions may have severe pain, severe TMJ and jaw dysfunction, severe facial deformities and major disability is: sues. Patients with these TMJ pathologies, regardless of the severity, may benefit from TMJ reconstruction and mandibular repositioning with total joint prosthesis, as well as simultaneous maxillary orthognathic Sur- gery, if necessary, to achieve the best outcome results relative to funct tion, stability, esthetics and reduction of pain (Wolford and Karras, 1997. Mehra and Wolford, 2000; Freitas et al., 2002; Mercuri et al., 2002; Wolford et al., 2003). 184 Wolford et al. Figure 25. A. MRI sagittal view shows condylar resorption in a rheumatoid ar- thritic (RA) TMJ. The thick white arrows show the top of the condyle and the roof of fossa. The thin white arrows identify the articular disc. The light gray tissue surrounding the disc is the reactive pannus. B. Further progression of RA in the Sagittal view shows destruction of the condyle, articular eminence, and the articular disc with only pannus remaining between the condyle and fossa. Ar- rows show the top of the condyle and fossa roof. Figure 26. A. RA and particularly Juvenile Rheumatoid Arthritis (JRA) can Cause significant condylar resorption, severe retrusion of the mandible, de- °reased vertical dimension of the posterior maxilla and a high occlusal plane angle. B. In severe RA and JRA cases, the articular eminence may be resorbed, and the remaining condylar stump may function on the articular eminence. The black arrows outline the fossa and white arrows the condylar stump and remain- ing articular eminence. Our studies (Mehra and Wolford, 2000; Freitas et al., 2002) show good outcomes in treating connective tissue/autoimmune diseases affecting the TMJ with custom-made total joint prostheses (TMJ Con- ºpts system) for TMJ reconstruction and mandibular advancement, as Well as simultaneous maxillary orthognathic surgery. The average man- 185 Common TMJ Disorders dibular advancement was 15 mm with stable results and significant re- duction in pain levels and improvement in jaw function. Other studies (Wolford et al., 1994, 2003; Wolford, 1997) demonstrated good out- comes using these custom-made total joint prostheses and orthognathic surgery in treating other TMJ disorders including multiply operated joints and those having failed alloplastic TMJ implants. However, the quality of results decreases as the number of previous TMJ surgeries in- creases, particularly in reference to pain relief. When the TMJ Concepts total joint prostheses system is used as the first or second TMJ Surgery, the success rate is good relative to jaw function, stability, facial balance and pain relief. A common complication of TMJ total joint prostheses is the de- velopment of heterotopic (reactive) bone and fibrosis around the prosthe- sis causing limited jaw function and pain. An important factor in the suc- cess of total joint prostheses is the placement of fat grafts around the functional area of the devices. Following placement of the joint prosthe- sis, fat is harvested from the abdomen or buttocks and packed around the fossa and condylar head area to eliminate dead space and prevent in- growth of pluripotent cells that could differentiate into fibroblasts or os- teoblasts generating bone and fibrotic tissues. Our initial study (Wolford and Karras, 1997) demonstrated sig- nificant improvement in function and decrease in pain in 15 patients when using the fat grafts as compared to 20 patients who did not receive fat grafts. Other studies (Wolford and Morales–Ryan, 2001; Wolford et al., 2008) evaluated post-surgery outcomes of 115 patients that received fat grafts around the prostheses with an average post-surgery follow-up of 31 months. There was significant improvement in jaw opening and function post-surgery with no radiographic or clinic evidence of hetero- topic bone or significant fibrosis. Case 6 This 18-year-old female presented with juvenile rheumatoid ar- thritis (JRA), bilateral TMJ involvement with significant and progressive condylar resorption, Class II skeletal and occlusal dentofacial deformity, anterior open bite, and decreased oropharyngeal airway with sleep apnea symptoms (Figs. 27A and C; 28A-C; 30A), but no significant TMJ symp- toms, pain or headaches. Following orthodontic preparation, surgery was performed which consisted of: 186 Wolford et al. A - B C D Figure 27. Case 6. A and C. This 18-year-old girl had bilateral TMJ JRA, sig- nificantly retruded mandible, high occlusal plane angle and associated facial morphology. B and D. The patient is seen one year post-surgery following bilat- eral TMJ reconstruction and mandibular advancement with custom-made TMJ total joint prostheses (TMJ Concepts system), bilateral coronoidectomies, bilat- eral TMJ fat grafts, simultaneous maxillary osteotomies and chin augmentation demonstrating a good stable, functional and esthetic outcome. Figure 28. Case 6. A-C. The pre-surgical occlusion demonstrated an anterior open bite and Class II end-on canine relationship. D-F. The occlusion remained stable one year post-Surgery. 1. Bilateral TMJ reconstruction and mandibular counter- clockwise advancement with custom made TMJ total joint prostheses (TMJ Concepts system; Fig. 29); 2. Bilateral TMJ fat grafts (harvest from abdomen) packed around the functional component of the pros- theses: Bilateral coronoidectomies: 4. Multiple maxillary osteotomies to down graft the pos- terior aspect and upright the incisors (Fig. 30B); and 5. Chin augmentation with an HTR implant (Walter Lo- renz Co., Jacksonville, FL). 3 187 Common TMJ Disorders T06-260 Figure 29. The mandible was repositioned on the plastic model relative to the unoperated maxilla. Custom-fitted TMJ Concepts total joint prostheses were manufactured to fit the patient’s specific anatomical requirements. Pogonion advanced 24 mm (Fig. 30B). The patient was evalu- ated one year post-surgery, showing good stability (Figs. 27B and D. 28D-F, 30C and D), free from TMJ pain, headaches and myofascial pain; as well as improved facial esthetics and increased oropharyngeal airway eliminating her sleep apnea. Case 7 This 52-year-old female was four years post-trauma that in- volved multiple mandibular fractures including bilateral subcondylar fractures (Fig. 33A). She presented with bilateral TMJ severe arthritis, displaced condyles and a Class II skeletal and occlusal dentofacial de- formity (Figs. 31A and C: 32A-C, 34A). She had severe TMJ pain, head- aches, myofascial pain difficulty eating and chewing as well as severe sleep apnea. Following orthodontic preparation, surgery was performed in one operation including: - Figure 30. Case 6. A. The pre-treatment cephalometric analysis shows a retruded maxilla and mandible, anterior open bite, steep occlusal and mandibular plane angles, proclined lower incisors, severe decreased oropharyngeal airway and significant degenerative changes of the condyles (JRA). B. The STO (pre- diction tracing) demonstrates the TMJ and orthognathic procedures required to achieve a good functional and esthetic result including bilateral TMJ reconstruct tion and mandibular advancement with custom-made TMJ total joint prostheses 188 Wolford et al. AM Age 18 years A 1 yº. ---. Initial — 1 year follow-up ſlig sºs TOTſ. : º P --- - --- |\\ º *Pººl. , ſº ſº? 13-> %). º --- -- -- (Figure 30 Continued, TMJ Concepts system), bilateral coronoidectomies, maxillary osteotomies for counter-clockwise rotation of the maxillomandibu- lar complex and occlusal plane angle, and chin augmentation with an HTR im- plant. C: Cephalometric analysis at one year post-surgery demonstrates good facial balance. D. Superimposition of the immediate pre-surgery (red lines) and *-year follow-up (blue lines) cephalometric tracings demonstrates the treat- "ent changes achieved for this patient with a normal oropharyngeal airway. 189 Common TMJ Disorders - A. B C. L Figure 31. Case 7. A and C. A 52-year-old female is seen four years post-trauma with bilateral TMJ severe arthritis and displaced condyles. The mandible is retruded significantly with a high occlusal plane angle and associated facial morphology. She has severe pain and severe sleep apnea. B and D. The patient is seen one year post-surgery following bilateral TMJ reconstruction and man- dibular advancement with custom-made TMJ total joint prostheses (TMJ Con- cepts system), bilateral coronoidectomies, bilateral TMJ fat grafts, left mandibu- lar body osteotomy and simultaneous maxillary osteotomies. - Figure 32. Case 7. A-C. The pre-surgical occlusion demonstrates anterior open bite, Class II occlusal relationship and posterior crossbite. D-F. The occlusion remained stable post-surgery. Figure 33. Case 7. A. The pre-surgical panograph shows subcondylar fractures in both TMJs and bone plates, screws and wires used to fixate the mandibular fractures. B. The immediate post-surgery panograph shows the TMJ total joint 190 Wolford et al. 1. Bilateral TMJ reconstruction and mandibular counter- clockwise advancement (28 mm at pogonion) with custom-made TMJ total joint prostheses (TMJ Con- cepts system; Fig. 33B); 2. Bilateral coronoidectomies; 3. Bilateral TMJ fat grafts (harvested from the abdo- men) placed around the functional aspect of the pros- theses; and 4. Multiple maxillary osteotomes to down graft the pos- terior aspect and upright the incisors (Fig. 34B). The patient was evaluated one year post-surgery showing good stability (Figs. 31B and D, 32D-F, 34C and D), with elimination of TMJ pain, headaches and myofascial pain; improved jaw function and facial esthet- ics, as well as increased orpharyngeal airway eliminating the sleep apnea. Case 8 This 45-year-old male had 14 previous right TMJ surgeries, in- cluding procedures using devices that contained Proplast/Teflon. He was two years post-TMJ reconstruction with total joint prosthesis (Osteomed Inc., Dallas, TX). There was massive bony ankylosis surrounding the right TMJ (Fig. 37A), a foreign body giant cell reaction secondary to the previous Proplast/Teflon materials and severe limitation of incisal open- ing of 20 mm with no translation of the right condyle. He had severe TMJ and myofascial pain, headaches and difficulty eating. He presented with the Class I skeletal and occlusal relationship on the left side and Class II canine relationship on the right side. (Figs. 35A and C, 36A-C). The surgery was performed in one operation including: - 1. Unilateral right TMJ debridement and removal of the heterotopic bone formation around the old prosthesis (Fig. 37B); 2. Removal of Osteomed prosthesis; 3. Unilateral TMJ reconstruction with custom-made TMJ total joint prosthesis (TMJ Concepts system) (Fig. 39A); and 4. Unilateral TMJ fat graft placement (Fig. 39B and C) harvested from the abdomen (Fig. 38). *— (Figure 33 Continued) prostheses (TMJ Concepts system), bone plates and screws in the maxilla and mandible, and hydroxyapatite graft in the maxilla. 191 Common TMJ Disorders Ps Ps Age 52 years Sto PS – Immediate Post-op – 1 yr Post-op PS 1 yr Post-op | D Figure 34. Case 7. A. The pre-treatment cephalometric analysis shows a retruded mandible, anterior open bite, steep occlusal and mandibular plane angles, Over- angulated lower incisors, severely decreased oropharyngeal airway and signifi. cant degenerative changes of the displaced condyles. B. The STO (prediction tracing) demonstrates the TMJ and orthognathic procedures required to achieve a good functional and esthetic result including bilateral TMJ reconstruction and mandibular advancement with custom made TMJ total joint prostheses (TM) Concepts system), bilateral coronoidectomies and maxillary osteotomies for counter-clockwise rotation of the maxillo-mandibular complex and occlusal plane angle. C. Cephalometric analysis at one year post-surgery demonstrates 192 Wolford et al. Figure 35. Case 8. A and C. A 45-year-old male is seen two years post-right TMJ reconstruction with total joint prosthesis (Osteomed system). There was massive bony ankylosis of the right TMJ and significant limitation of incisal opening (20 mm) with no translation of the right condyle. He had severe TMJ and myofascial pain, headaches and difficulty eating. B and D. The patient is Seen two years post-surgery following unilateral right TMJ debridement and removal of heterotopic bone, unilateral right TMJ reconstruction with custom- made TMJ total joint prosthesis (TMJ Concepts system) and unilateral right TMJ fat graft. Figure 36. Case 8. A-C. The pre-surgical occlusion demonstrates Class I canine relationship on the left side and Class II canine relationship on the right side. D- F. The occlusion remained stable two years post-Surgery. - . (Figure 34 Continued) good facial balance. D. Superimposition of the imme- diate post-surgery (red lines) and one-year follow-up (black lines) cephalometric racings demonstrate the treatment stability achieved for this patient. 193 Common TMJ Disorders Figure 37. Case 8. A. The pre-surgical panograph shows the heterotopic bone formation around the prosthesis and ankylosis of the mandible and cranial base. B. The heterotopic bone was removed in sections. A L. Figure 38. Case 8. A and B. The fat grafts usually are harvested from the abdo- men. The incision is usually 1-1/2 to 2 inches in length and made in the Su- prapubic area. C. Abdominal fat graft has been harvested from the abdomen. D. 3–0 Vicryl sutures were used to close the deep fat layers so no depression in the harvest area will be evident. The skin is closed with subcuticular suturing. - - | || 194 Wolford et al. The patient was evaluated two years post-Surgery showing good stability (Figs. 35B and D: 36D-F) with elimination of TMJ pain, head- aches, myofascial pain; and improved jaw function. At 10 years post- Surgery, his incisal opening was 42 mm with 2 to 3 mm of translation of the right condyle. CONCLUSIONS During the past two decades, major advancements have been made in TMJ diagnostics and the development of surgical procedures to treat and rehabilitate the pathological, dysfunctional and painful TMJ. Research has demonstrated clearly that TMJ and orthognathic surgery can be performed safely and predictably at the same operation, but it does necessitate the correct diagnosis and treatment plan, as well as re- quires the surgeon to have expertise in both TMJ and orthognathic sur- gery. The surgical procedures can be separated into two or more surgical stages, but the TMJ surgery should be done first. Poor TMJ surgery out- comes usually are related to wrong diagnosis, wrong surgical procedure, poorly executed Surgery, Surgical complications, inadequate follow-up care and/or unrecognized or untreatable local and/or systemic factors. With the correct diagnosis and treatment plan, simultaneous TMJ and Orthognathic surgical approaches provide complete and comprehensive management of patients with co-existing TMJ pathology and dentofacial deformities. REFERENCES Arnett GW, Tamborello J.A. Progressive Class II development: Female idiopathic condylar resorption. Oral Maxillofac Surg Clin North Am 1990:2:699-716. Crawford JG, Stoelinga PJ, Blijdrop PA, Brown JJ. Stability after reop- eration for progressive condylar resorption after orthognathic sur- gery: Report of seven cases. J Oral Maxillofac Surg 1994;52:460- 466. *— Figure 39. Case 8. A: The TMJ Concepts total joint prosthesis was custom- made for this patient’s specific anatomical requirements. B: The fossa compo- nent of the TMJ Concepts total joint prosthesis was placed through an endaural incision. The mandibular component was placed through a submandibular inci- sion. C. The abdominal fat graft was packed into the joint space to prevent het- erotopic bone formation and fibrosis. 195 Common TMJ Disorders DeClercq CA, Neyt LF, Mommaerts MY, Abeloos JV, DeMot BM. Condylar resorption in orthognathic surgery: A retrospective study. Int J Adult Orthod Orthognath Surg 1994;9:233-240. Downie MJ, Wolford LM, Morales–Ryan CA. Outcome assessment following simultaneous orthognathic and TMJ surgery. J Oral Maxillofac Surg 2001;S1,59:51. Freitas RZ, Mehra P, Wolford LW. Autogenous versus alloplastic TMJ reconstruction in rheumatoid-induced TMJ Disease. J Oral Maxillo- fac Surg 2002;S1,58:43. Fuselier C, Wolford LM, Pitta M, Talwar R. Condylar changes after or- thognathic surgery with untreated TMJ internal derangement. J Oral Maxillofac Surg 1998;Sl 4,56:61. Garcia-Morales P, Wolford LM, Mehra P, Reiche-Fischel O. Morales- Ryan CA. Efficacy of high condylectomy for management of condy- lar hyperplasia. J Oral Maxillofac Surg 2001;S1,59:106. Goncalves JR, Cassano DS, Wolford LM, Santos-Pinto A, Marquez IM. PostSurgical stability of counterclockwise maxillomandibular ad- vancement surgery: Effect of articular disc repositioning. J Oral Maxillofac Surg 2008; in press. Henry CH, Hudson AP, Gerard HC, Franco PF, Wolford LM. Identifica- tion of Chlamydia Trachomatis in the human temporomandibular joint. J Oral Maxillofac Surg 1999:57:683-688. Henry CH, Hughes CV, Gerard HC, Hudson AP, Wolford LM. Reactive arthritis: Preliminary microbiologic analysis of the human temporo- mandibular joint. J Oral Maxillofac Surg 2000:58: 1137-1142. Henry CH, Nikaein A, Wolford LM. Analysis of human leukocyte anti- gens in patients with internal derangement of the temporomandibular joint. J Oral Maxillofac Surg 2002;60:778-783. Henry CH, Pitta MC, Wolford LM. Frequency of chlamydial antibodies in patients with internal derangement of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:287–292. Henry CH, Wolford LM. Substance P and Mast Cells: Preliminary his- tologic analysis of the human temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:384-389. Hudson AP, Henry C, Wolford L., Gerard HC. Chlamydia psittaci infec- tion may influence development of temporomandibular joint dys- function. J Arthritis Rheumatism 2000:43:S174. 196 Wolford et al. Kerstens HC, Tuinzing DB, Golding RP, Van der Kwast WA. Condylar atrophy and osteoarthrosis after bimaxillary surgery. Oral Surg Oral Med Oral Pathol 1990:69:274-280. Mehra P, Wolford LM. Custom-made TMJ reconstruction and simulta- neous mandibular advancement in autoimmune/connective tissue diseases. J Oral Maxillofac Surg 2000;S1,58:95. Mehra P, Wolford LM. The Mitek mini anchor for TMJ disc reposition- ing: Surgical technique and results. Int J Oral Maxillofac Surg 2001:30:497-503. Mercuri LG, Wolford LM, Sanders B, White RD, Giobbie-Hurder A. Long-term follow-up of the CAD/CAM patient fitted total temporomandibular joint reconstruction system. J Oral Maxillofac Surg 2002;60: 1440–1448. Moore KG, Gooris PJ, Stoelinga PJ. The contributing role of condylar resorption in orthognathic surgery: A retrospective study. J Oral Maxillofac Surg 1991;49:448-460. Morales–Ryan CA, Garcia-Morales P, Wolford LM. Idiopathic condylar resorption: Outcome assessment of TMJ disc repositioning and or- thognathic surgery. J Oral Maxillofac Surg 2002;S1,60:53. Nickerson JW, Boring G. Natural course of osteoarthrosis as it relates to internal derangement of the temporomandibular joint. Oral Maxillo- fac Surg Clin North Am 1989;1:27-45. Wolford LM. Temporomandibular joint devices: Treatment factors and outcomes. Oral Surg Oral Med Oral Pathol Oral Radiol Endo 1997;83: 143-149. Wolford LM, Cardenas L. Idiopathic condylar resorption: Diagnosis, treatment protocol, and outcomes. Am J Orthod Dentofacial Orthop 1999; 116:667-676. Wolford LM, Cottrell DA, Henry CH. Temporomandibular joint recon- struction of the complex patient with the Techmedica custom-made total joint prosthesis. J Oral Maxillofac Surg 1994;52:2-10. Wolford LM, Cottrell DA, Karras SC. Mitek mini anchor in maxillofa- cial surgery. Proceedings of SMST-94, First International Confer- ence on Shape Memory and Superelastic Technologies, 1995, Mon- terey, CA. MIAS:477-482. Wolford LM, Gerard HC, Henry CH, Hudson AP. Chlamydia psittaci infection may be involved in development of temporomandibular joint dysfunction. J Oral Maxillofac Surg 2001;S59:30. 197 Common TMJ Disorders Wolford LM, Henry CH, Goncalves JR. TMJ and systemic effects asso- ciated with Chlamydia psittaci. J Oral Maxillofac Surg 2004;62:S50- 51. Wolford LM, Karras SC. Autologous fat transplantation around tem- poromandibular joint total joint prostheses: Preliminary treatment outcomes. J Oral Maxillofac Surg 1997:55:245-251. Wolford LM, Karras SC, Mehra P. Concomitant temporomandibular joint and orthognathic surgery: A preliminary report. J Oral Maxillo- fac Surg 2002:60:356-362. Wolford LM, Mehra P, Franco P. Use of conservative condylectomy for treatment of osteochondroma of the mandibular condyle. J Oral Maxillofac Surg 2002;60:262-263. Wolford LM, Mehra P, Reiche-Fischel O, Morales–Ryan CA, Garcia- Morales P. Efficacy of high condylectomy for management of con- dylar hyperplasia. Am J Orthod Dentofacial Orthop 2002; 121:136- 151. Wolford LM, Morales–Ryan CA. The use of autologous fat grafts in the temporomandibular joint reconstruction. J Oral Maxillofac Surg 2001;S59:121. Wolford LM, Morales–Ryan CA, Garcia-Morales P, Cassano DS. Auto- logous fat grafts placed around temporomandibular joint total joint prostheses to prevent heteroteopic bone formation. Baylor University Medical Center Proceedings 2008:21:248-254. - Wolford LM, Pitta MC, Reiche-Fischel O, Franco PF. TMJ Concepts/Techmedica Custom-made TMJ total joint prosthesis: 5- year follow-up. Int J Oral Maxillofac Surg 2003:32:268-274. Wolford LM, Reiche-Fischel O, Mehra P. Changes in TMJ dysfunction after orthognathic surgery. J Oral Maxillofac Surg 2003;61:655-660. 198 THE MODIFIED CONDYLOTOMY FOR TMJD PATIENTS: A GOOD SOLUTION OR JUST ANOTHER SURGERY2 R. Scott Conley ABSTRACT Several treatment options are available to patients with temporomandibular joint dysfunction (TMJD). Before initiating treatment, accurate diagnosis is essential to assure that the treatment is individualized to the patient’s symptoms and un- derlying disease process. For patients with appropriately diagnosed internal de- rangement of the one or both temporomandibular joints (TMJ), conservative therapy always should be attempted initially. For the few patients who fail con- servative therapy, surgical options must be considered, including their risks and benefits. The modified condylotomy has the unique advantage in that it is an extra-capsular procedure that has been shown to have a high degree of success, with low morbidity and low re-operation rates. In addition, patients with mild Class III skeletal malocclusion with joint discomfort can undergo this procedure to address both their concerns. While successful, the modified condylotomy is not a panacea. Proper diagnosis and patient selection are critical for success. For patients in whom conservative therapy has failed, the modified condylotomy can be an excellent form of treatment. Multiple investigations have been performed to examine the in- cidence and prevalence of temporomandibular joint dysfunction (TMJD) in various patient populations. One of the more difficult aspects of TMJ care includes distinguishing the difference between patients who per- ceive a joint dysfunction and those patients with signs and symptoms of dysfunction. In the early 1990s, de Kanter and colleagues performed a large meta-analysis. After examining 23 randomized studies with over 15,000 patients, the investigators concluded that 30% of the study popu- lation reported a perceived dysfunction of one or both TMJs. To assess clinical signs and symptoms, a second group of 22 randomized studies with over 16,000 patients was examined. A 44% incidence of clinical signs and symptoms was observed. Unfortunately, perceived dysfunction with or without signs and Symptoms of clinical dysfunction is not sufficient. The severity of the 199 Modified Condylotomy perceived or clinical dysfunction ultimately is what motivates patients to seek care. To help address this component, following their meta-analysis, de Kanter and colleagues (1993) performed a severity assessment on a sample of over 6,000 Dutch patients. Slightly over 21% of the patient group reported a perceived TMJD. Of the patients reporting a dysfunc- tion, the majority (75%) reported a mild dysfunction while the remainder reported moderate-to-severe dysfunction. For the overall sample, 17% of patients reported mild dysfunction and 5% reported moderate-to-severe dysfunction. The clinical follow-up of these same patients revealed a similar incidence of signs and symptoms as their previous meta-analysis with 45% of the patient population demonstrating one or more signs and symptoms of clinical dysfunction. Among the patients demonstrating clinical dysfunction, 95% fell into the mild category while only 5% (or 3% of the entire population studied) demonstrated moderate-to-severe clinical signs and symptoms of dysfunction. The most common clinical signs and symptoms included pain on function, pain on movement, dislo- cation, and locking. Using a variety of joint imaging modalities, other investigators have attempted to define objective signs of TMJD. Katzberg and col- leagues (1996, 2005) performed an MRI study on healthy subjects and subjects reporting to the orofacial pain clinic due to TMJ pain and dys- function. The control group was observed to have approximately 33% prevalence of TMJ disc displacement. Significant gender differences were observed between the control and study groups; nearly 40% of the female control patients demonstrated a disc displacement while male control subjects only had a 24% disc displacement. The study group had an overall disc displacement of 77%, with 80% of the females and 58% of the males demonstrated disc displacement on MRI. Due to the large percentage of patients with disc displacement in the asymptomatic con- trol group, the investigators questioned whether disc displacement alone constituted a pathologic condition or whether it was a variation of normal anatomy. When the disc was displaced, the most likely disc position was directly anterior to the head of the condyle. Other common displacement locations were anterior displacement with a component of medial or lat- eral displacement (Katzberg et al., 1996). Unfortunately, while clinical signs may be observed radiographically or with other image modalities, the amount of disc displacement does not necessarily correlate with the level of pain patients report. 200 Conley TREATMENT OPTIONS Several treatment modalities exist as first line treatment of TMJD. These include splint therapy, diet modification, non-steroidal anti-inflammatory medications, and various combinations of all the pre- viously mentioned therapy (McNeill, 1997; Aaron et al., 2006). For most patients, conservative treatment and time will work synergistically to improve their symptoms thereby enabling them to return to normal func- tion (deBont et al., 1997). For some small percentage of patients, at- tempts at conservative therapy do not succeed. Others are unable to tol- erate the continued symptoms and seek a surgical treatment modality. Dolwick and Wilson (1999) examined the percentage of patients that were most likely to pursue surgical therapy. Their investigation reported that 75% of the population has symptoms of TMJD at some point in their life. Only one third of the population was reported to have signs of TMJD, with only 5% of the population requiring treatment for this dys- function. Ninety-five percent of the patients who need treatment receive conservative therapy and do well; however, 5% of the treated population was reported to have refractory symptoms that ultimately required sur- gery. As a result, only about 0.25% of the general population reportedly need surgery in the TMJ region. Within the surgical realm, several options are available. Patients may undergo surgical procedures that enter the joint capsule (intracapsu- lar); other surgical protocols may attempt to address the dysfunction without entering the joint capsule itself (extracapsular). Intracapsular procedures include arthocentesis, arthroscopy, meniscectomy or discec- tomy, disc placation, disc replacement, joint reconstruction, and artificial total joint replacement. Of the intracapsular procedures, arthrocentesis generally is considered the most conservative approach (Okeson, 1998). With arthrocentesis, the surgeon enters the joint to perform lavage. Ef- forts are made to flush the inflammatory mediators from the joint cap- Sule, reduce pain, and enable the patient a rapid return to function. Ar- throscopy is similar, though a camera also is inserted into the joint space for visual inspection of the condylar head. Small joint adhesions that oth- erwise are undetectable may be observed, removed, and followed by lav- age. The success of the two procedures is similar. When the joint space is entered and the interposing disc is deformed grossly, some surgeons will advocate an open-joint procedure to remove the disc entirely. While pain 201 Modified Condylotomy → Figure 1. Costochondral graft harvested from a patient and reshaped. The cartilaginous portion is at the top of the photograph and will serve as the new condylar head when placed in the patient. (Photo courtesy of SJ McKenna.) → Figure 2. Clinical demonstration of the costochondral graft fixated to the mandible using rigid internal fixation. The cartilaginous portion is not visible but has been positioned within the glenoid fossa to function as the new condylar head. (Photo courtesy of SJ McKenna.) is reduced, the patient now functions entirely with bone-to-bone contact between the condylar head and the glenoid fossa. Due to the bone-to- bone contact, some surgeons have advocated replacement of the disc with other tissues or alloplastic materials. Due to the high and occasion- ally catastrophic results of alloplastic grafts (e.g., Proplast), most of the disc replacements now utilize autogenous temporalis flaps rather than artificial material. In severe cases in which all of these attempts have been per- formed and the patient has refractory TMJ pain and dysfunction, joint reconstruction or total joint replacement with artificial joints has been suggested (Wolford, 2009). Joint reconstruction methods include costo- chondral grafts and sternoclavicular grafts (Figs. 1 and 2). These typi- cally are performed on patients who were born without a TMJ, patients following trauma and joint ankylosis, patients with condylar hyperplasia, or patients with tumors in the joint. With the costochondral graft, a rib is harvested from the patient and reshaped. The cartilaginous portion of the rib is fashioned as the new condylar head, while the rest of the rib simu- lates the condylar process and ascending ramus. A similar reshaping process is performed during sternoclavicular grafts as well. Significant donor site as well as recipient site morbidity is associated with both of these procedures. A final surgical option includes the use of artificial joints, which typically are made of stainless steel and either can be stock appliances or custom made joint reconstructions (Figs. 3 and 4). All of the previously mentioned surgical procedures are intra- capsular procedures. Unfortunately, even the most conservative will have a negative effect on the joint ligaments, causing increased laxity within the joint. Condylotomy, however, is an extracapsular surgical procedure that does not have the same limitations and potential negative sequelae. 202 º º º º : - º 203 Modified Condylotomy Figure 3. Total joint replacement can be performed with both stock and custom-made joint prostheses. The panoramic radiograph dem- ‘onstrates the components being replaced, namely the glenoid fossa, the condylar head, the condylar process, and a portion of the posterior mandible. (Photo courtesy of SB Boyd.) Figure 4. Well-positioned total joint replacements, though aggressive, can serve patients well. This particular patient now has poor function, as the patient does not have vertical overlap of the teeth anteriorly and is unable to incise food. (Photo courtesy of SB Boyd.) 204 Conley HISTORY AND SUCCESS OF THE MODIFIED CONDYLOTOMY PROCEDURE The procedure was described first in 1898 to address a dentofa- cial deformity, but as such really consisted of a high condylectomy or removal of the condyle from the mandible (Caldwell and Lowry, 1984). Ward (1961) was the first to describe the procedure to address joint pain specifically. The procedure was described as a blind surgery utilizing a Gigli saw to cut through the neck of the condylar process, separating the condylar head from the rest of the mandible. No attempts were made to position the freed condyle. Essentially, the procedure can be described more accurately as a condylectomy (removal of the condyle) rather than a condylotomy. Ward reported 100% success in relieving pain with the procedure. Six patients were reported to have complete initial success while the other eight reported that they continued to improve after sur- gery (Ward, 1961). While this report indicates a high degree of success, it is unclear what the end result was for the eight patients who continued to improve. Campbell (1965), in a report analyzing Ward’s cases, also found high success. Patients demonstrated a sustained increase in joint space 84% of the time. Multiple other groups reported similarly high success rates. Many of the other reports of the procedure come from two surgical centers, Vanderbilt University and the University of Michigan, with both groups performing multiple studies. The Vanderbilt investiga- tions demonstrated both a high degree of clinical success (i.e., pain re- duction). In their series of reports, they demonstrated varying degrees of disc position improvement. In less severe cases, disc recapture (both short-term and long-term) was observed. In the more severe cases, some disc improvement was noted, but the disc was not necessarily recaptured. Their attempts at long-term follow-up are among the only reports found in the literature (Hall and McKenna, 1993; Hall et al., 1993; Wer- ther et al., 1995; Hall, 1996a,b, 1997, 1999; McKenna et al., 1996; Hall and Werther, 1997; Hall et al., 2000a, b, 2005; McKenna, 2006). Due to the difficulties inherent in following a series of surgical patients long term, clear interpretation and application of their data are difficult to as- Sess. While a large number of patients underwent the procedure, more limited numbers of patients were available for follow-up. As stringent as the investigators were, the sample may have been subject to an inadver- tent selection bias. As a result, one must be cautious in applying these results to the general population. 205 Modified Condylotomy SURGICAL INDICATIONS AND TECHNIQUE Indications for condylotomy include debilitating TMJ pain, failed conservative therapy, anteriorly displaced discs with reduction and compliant patients. Though less successful, some authors suggest the modified condylotomy also can be used for patients with anteriorly dis- placed discs without reduction (Hall, 1996a, Albury, 1997). These authors suggest that successful disc recapture is most likely to occur with recently disc displacement. With chronically displaced discs, condy- lotomy can successfully reduce the pain but has limited success in recap- turing the disc. Patients with long-term anteriorly displaced discs without reduction have been observed to have discs that undergo degenerative changes. As a result, even if the disc is reduced, because of the degenera- tive changes, it does not stay reduced. These correspond to Wilkes Stage II – Wilkes Stage III. The Wilkes stages were developed to classify and group TMJ internal derangements by clinical radiographic and surgical findings (Wilkes, 1989). This was expanded to include more radio- graphic analysis by Schellhas (1989). Current surgical technique for the modified condylotomy has been described more accurately as a variation to the intraoral vertical ramus osteotomy (IVRO). With the modified condylotomy, the osteot- omy is performed on the buccal aspect of the mandible, starting superi- orly at the sigmoid notch and continuing inferiorly to the angle of the mandible (Fig. 5). When viewed from the lingual aspect, the osteotomy is proximal to the lingula to avoid severing the inferior alveolar neurovascular bundle. As a result, a very low incidence of infection, Vas- cular compromise, and nerve damage is observed with this procedure. The distal (tooth-bearing) segment is placed in intermaxillary fixation, while the proximal (non-tooth bearing) segment that contains the condyle is repositioned. Because nearly all of the TMJD patients demonstrated a decrease in joint space, early condylotomy procedures focus on inten- tionally repositioning the proximal segment inferiorly. This inferior seg- ment positioning is maintained with wire osteosynthesis. The technique has been demonstrated to be more successful with a unilateral surgical approach. Patients demonstrating the most consistent increase in joint space on post-surgical follow-up had the modified con- dylotomy performed on a single side. Surgeons theorize that the healthy side maintains a stable vertical dimension during healing. When condy- lotomy is performed on both sides, the surgeon must rely on the dentition and intermaxillary fixation to hold the vertical position. 206 Conley Figure 5. The osteotomy design for the modified condylotomy shown from the buccal (A) and lingual (B) aspects. Note the osteotomy is be- hind or proximal to the lingula to preserve the inferior alveolar neurovascular bundle. Because the modified condylotomy represents a variation of the IVRO, this surgical technique has the advantage that it also can be used in patients with Class III malocclusion and TMJ discomfort to address both problems simultaneously. Unfortunately, because there is no oppor- tunity for bony overlap in a mandibular advancement patient (the distal Segment is advanced beyond the proximal segment), this technique can not be utilized for Class II patients at the same time as the advancement Surgery to correct the preexisting malocclusion. The two procedures must be staged with the modified condylotomy typically occurring first. Two critical components to the successful condylotomy patient include a stable occlusion and patient compliance. Patients with an un- stable occlusion or an occlusion with minimal or uneven contact will be difficult to fit together intra-operatively. If the patient’s occlusion does not allow a reasonable and stable fit, intermaxillary fixation may intro- duce a shift or may place the patient in an iatrogenic position. As healing between the proximal and distal segment occurs, the iatrogenic shift may be maintained. The second component for success is patient compliance. Pa- tients must be notified that depending on the surgeon’s protocol, they Will be placed in intermaxillary wire fixation for as little as ten days to as long as six to eight weeks. Following that time, they will require training elastics to retain and refine the bite. In addition, the patient must main- tain a soft diet. Failure to follow the surgeon’s recommendations can lead 10 displacement of the surgical segments, non-union, fibrous union, pain 207 Modified Condylotomy and increased dysfunction rather than functional improvement that the patient desires. With all surgical procedures, the tendency for post-surgical re- lapse also must be investigated. The modified condylotomy follows a similar relapse pattern as the intraoral vertical ramus osteotomy. Patients, (particularly non-compliant patients), tend toward a Class II open bite pattern due to the direction of muscle pull on the proximal and distal seg- ments. The gonial angle will increase, the distal segment will rotate downward and backward, and the proximal segment will rotate anteriorly and superiorly. It is unclear in TMD patients, however, whether the Class II open bite truly is a post-surgical change or a continuation of the con- dylar degeneration. Further prospective long-term investigations must be performed to address this question adequately. Because multiple surgical interventions are possible, the Ameri- can Association of Oral and Maxillofacial Surgeons (AAOMS, 1984) established practice parameters and criteria to define surgical success. Objective criteria for successful surgical outcomes include maximum opening is greater than or equal to 35 mm and lateral excursive move- ments greater than or equal to 4 mm. Additional criteria include a reduc- tion in a patient’s reported pain to less than 4 on a visual analog scale. Resumption of a more normal diet also is critical; this is indicated by a score greater than or equal to 8. To put this in perspective, an all-liquid diet is listed as a 1 and no dietary restriction is listed as a 10. Someone with an 8 is able to eat most foods, but must on occasion avoid harder, chewier foods. Because of the potential for facial change with some sur- gical procedures, additional criteria regarding acceptable facial appear- ance were included. CASE REPORTS Patient #1 The first patient presented to both an oral surgeon and the ortho- dontist (Fig. 6). The patient complained of unilateral right joint click with severe joint pain. She had a history of orthodontic treatment and Subsequently had undergone conservative management with an occlusal splint and non-steroidal anti-inflammatory medication prior to seeking care now. Upon presentation to the surgeon, she complained of pain, re- duced range of movement, and a negative change in diet. Decreased 208 Conley Figure 6. This patient presented with unilateral right severe joint pain, joint clicking, and decreased range of motion. She underwent successful modified condylotomy to relieve these symptoms. joint space was observed on a transcranial radiograph. The patient re- ported no improvement from her conservative therapy with the bite splint and medication. Additional attempts at conservative therapy were made, but the patient again failed to respond to this type of treatment. At the same time, the patient also expressed an interest in orthodontics. She had a mild Class II malocclusion with a dual bite into a well interdigitated Class I position. During the time of insurance authorization, orthodontic appliances were placed to align the teeth initially. Once insurance authorization was obtained, heavy surgical wires were placed in lieu of arch bars. The patient underwent condylotomy with intermaxillary fixa- tion for approximately three to four weeks. Following the surgery, the Patient wore training elastics for approximately six to eight weeks. The training elastics were discontinued and the orthodontic therapy was com- pleted. Following the surgery, increased joint space was observed radio- graphically, and the pain was markedly reduced (Fig. 7). The patient was Satisfied with the procedure and the postoperative result. 209 Modified Condylotomy ". . Figure 7. Representative pre- and post-surgery transcranial radiographs demonstrating the decreased joint space before modified condylotomy and the increased joint space obtained from the procedure. Patient #2 As previously stated, because of the similarity between the modi- fied condylotomy procedure and the IVRO, patients who are Class III skeletally with TMJ pain and dysfunction may undergo the modified condylotomy to address both complaints. At presentation, her chief com- plaint was “my under bite.” The patient had a concave facial profile, with a prominent mandible and minimal incisal display upon smile (Fig. 8). Intraorally, she had a half cusp Class III skeletal and dental malocclusion with reverse overjet and 15% overbite. Mild mandibular crowding and mild to moderate maxillary crowding were present. Mild condylar changes were observed in her panoramic radiograph. A TMJ examination revealed pain and clicking in both joints. The full range of orthodontic and surgical options was discussed. Due to the skeletal malocclusion and the TMJ discomfort she elected to pursue a combined orthodontic and surgical treatment. Because of esthetic reasons, she was not a candidate for LeFort I osteotomy to advance the maxilla. Because of the promi- nence of the mandible, the choice was between a BSSO setback or an 210 Conley Figure 8. This patient presented with both a skeletal Class III malocclusion and bilateral TMJ pain and clicking. After presentation of the treatment options, she elected to have an IVRO/modified condylotomy setback. IVRO/modified condylotomy setback. The second treatment approach Was deemed superior as it would address both the prominence of the mandible and be more likely to improve the underlying joint discomfort. The patient underwent pre-surgical orthodontics to prepare the dental arches (Fig. 9). The surgery consisted of IVRO/modified condy- lotomy. No proximal to distal segment fixation was used in the mandible. The amount of inferior positioning of the proximal segment (to increase joint space) is evident in the postoperative panoramic radiograph by ex- amining the height difference either at the sigmoid notch or the inferior border of the mandible. Intra-operatively, the patient was placed in a Sur- gical splint with intermaxillary fixation. The IMF continued for three to four weeks. Following the IMF, post-surgical elastic traction was used for approximately six weeks. The patient continued with post-surgical Orthodontic treatment. At appliance removal, the patient had improved joint function and joint comfort. In addition, she had a favorable facial change (Fig. 10). The comparison between the pre-surgical and post- Surgical joint space is evident (Fig. 11). 2 || Modified Condylotomy Figure 9. Immediate postoperative panoramic radiograph demonstrating the osteotomy design. Note the absence of proximal to distal segment fixation. The patient was placed in an inter-occlusal splint with inter- maxillary fixation only. Figure 10. Post-surgical photographs. The facial profile has been im- proved and the joint symptoms have decreased. 212 Conley - Figure 11. Comparison of the pre- (top) and post-surgical (bottom) views of the Patient's joints. Note the increased joint space on the postoperative films. There *y be slightly less joint space change on the patient’s left side. Reports indi- * that sustained increase in joint space in bilateral condylotomy is less stable. 213 Modified Condylotomy CONCLUSIONS Though modified condylotomy is a surgical procedure, it can be a useful treatment approach to TMJD patients. It should be noted that this protocol is not a first line of treatment. For patients undergoing or- thodontic treatment, conservative approaches to manage the pain and dysfunction should be attempted first. This includes pausing active or- thodontic treatment, delivering a bite splint, prescribing non-steroidal anti-inflammatory medication and observing patient progress. In patients who fail to respond, modified condylotomy can be considered. Should the orthodontic patient require modified condylotomy, heavy orthodontic wires can be placed, avoiding the use of Surgical arch bars. In addition, orthodontic patients are already familiar with inter-arch elastics and the required dietary changes. REFERENCES AAOMS. 1984 Criteria for TMJ Meniscus Surgery. Chicago: American Association of Oral and Maxillofacial Surgeons 1984. Aaron LA, Turner JA, ManclDA, Sawchuk CN, Huggins KH, Truelove EL. Daily pain coping among patients with chronic temporoman- dibular disorder pain: An electronic diary study. J Orofac Pain 2006:20:125-137. Albury CD Jr. Modified condylotomy for chronic nonreducing disk dis- locations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997:84:234-240. Caldwell J, Gerhard R, Lowry R. Orthognathic Surgery. In: Kruger G, ed. Textbook of Oral and Maxillofacial Surgery. 6th ed. St Louis. Mosby 1984:530-531. Campbell W. Clinical radiological investigations of the mandibular joints. Br J Radiol 1965;38:401. de Bont LG, Dijkgraaf LC, Stegenga B. Epidemiology and natural pro- gression of articular temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:72–76. De Kanter RJ, Truin GJ, Burgersdijk RC, Van't Hof MA, Battistuzzi PG, Kalsbeek H, Kayser AF. Prevalence in the Dutch adult population and a meta-analysis of signs and symptoms of temporomandibular disorder. J Dent Res 1993;72:1509–1518. 214 Conley Dolwick MF, AW Wilson. Surgical treatment of TMJ internal derange- ment. In: Booth PW SS, Hausamen JE, eds. Maxillofacial Surgery. London: Churchill Livingstone 1999. Hall HD. A technique to improve predictability of condylar position with modified condylotomy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88: 127-128. Hall HD. In defense of condylotomy. J Oral Maxillofac Surg 1997:55:899. Hall HD. Modification of the modified condylotomy. J Oral Maxillofac Surg 1996:54:548–551. Hall HD. The condylotomy procedure. Atlas Oral Maxillofac Surg Clin North Am 1996;4:93-106. Hall HD, Indresano AT, Kirk WS, Dietrich MS. Prospective multicenter comparison of 4 temporomandibular joint operations. J Oral Maxillo- fac Surg 2005;63:1174-1179. Hall HD, McKenna S.J. Interpretation of disc-condyle relationships after modified condylotomy. J Oral Maxillofac Surg 1993;51:822. Hall HD, Navarro EZ, Gibbs S.J. One- and three-year prospective out- come study of modified condylotomy for treatment of reducing disc displacement. J Oral Maxillofac Surg 2000:58:7-17. Hall HD, Navarro EZ, Gibbs SJ. Prospective study of modified condy- lotomy for treatment of nonreducing disk displacement. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:147-158. Hall HD, Nickerson JW Jr, McKenna SJ. Modified condylotomy for treatment of the painful temporomandibular joint with a reducing disc. J Oral Maxillofac Surg 1993;51:133-142. Hall HD, Werther JR. Results of reoperation after failed modified condy- lotomy. J Oral Maxillofac Surg 1997:55:1250-1253. Katzberg RW, Tallents RH. Normal and abnormal temporomandibular joint disc and posterior attachment as depicted by magnetic reso- nance imaging in Symptomatic and asymptomatic subjects. J Oral Maxillofac Surg 2005;63:1155-1161. Katzberg RW, Westesson PL, Tallents RH, Drake CM. Anatomic disor- ders of the temporomandibular joint disc in asymptomatic subjects. J Oral Maxillofac Surg 1996;54:147-153. McKenna SJ. Modified mandibular condylotomy. Oral Maxillofac Surg Clin North Am 2006;18:369-381. 215 Modified Condylotomy McKenna SJ, Cornella F, Gibbs SJ. Long-term follow-up of modified condylotomy for internal derangement of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:509-515. McNeill C. Management of temporomandibular disorders: Concepts and controversies. J Prosthet Dent 1997;77:510-522. Okeson JP. Management of Temporomandibular Disorders and Occlu- sion. 4th ed. St Louis: Mosby 1998. Schellhas K. Internal derangement of the temporomandibular joint: Ra- diologic staging with clinical, surgical, and pathologic correlation. Magn Reson Imaging 1989;7:495. Ward T. Surgery of the mandibular joint. Ann R Coll Surg Engl 1961:28:139. Werther JR, Hall HD, Gibbs SJ. Disk position before and after modified condylotomy in 80 symptomatic temporomandibular joints. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:668-679. Wilkes C. Internal derangements of the temporomandibular joint. Arch Otolaryngol Head Neck Surg 1989; 115:469-477. Wolford LM, Cassano DS, Goncalves JR. Common TMJ disorders: Or- thodontic and surgical management. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Sepa- rating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. 216 TEMPOROMANDIBULAR JOINT ADAPTATIONS IN ADOLESCENTS AND ADULTS TREATED WITH THE HERBST APPLIANCE Hans Pancherz ABSTRACT The short- and long-term effects of Herbst treatment on the TMJ (condyle, gle- noid fossa and articular disc) are discussed in this chapter. The evidence-based research performed in Malmö, Sweden and Giessen, Germany over a period of 30 years is surveyed, and the relevant literature on TMJ adaptations verified by radiographic cephalometry, lateral tomography and magnetic resonance imaging (MRI) is reviewed. Herbst treatment has been found to result in the following TMJ adaptations: 1. Condylar and glenoid fossa modeling in both adolescents and adults on a regular basis; 2. The adaptive processes are seen especially at the posterior border of the condylar head and at the anterior border of the post-glenoid spine (distal fossa wall), thereby contributing to an increase in man- dibular prognathism and Class II correction; 3. Slight retrusion of the articular disc. This phenomena can be useful in the therapy of milder forms of anterior disc displacement (e.g., disc displacement with reduction); and 4. Neither in adolescents nor in young adults does Herbst treatment re- sult in any adverse short- or long-term effects on the different TMJ components (condyle, fossa and disc). In the treatment of Class II malocclusions, the effects of remov- able and fixed functional appliances on the temporomandibular joint (TMJ) and mandibular growth are a highly debated subject. Clinical studies in man give contradicting results. Removable Functional Appliances With respect to TMJ adaptations, some previous and recent ret- rospective studies in growing patients, using the Fränkel-FR 2, activator, bionator or the Twin-block, have shown that mandibular (TMJ) growth 217 TMJ Adaptations stimulation seems to be possible (Luder, 1981; Owen, 1981; Creekmore and Radney, 1983; Righellis, 1983; Birkebaeck et al., 1984; McNamara et al., 1985; Öztürk and Tankuter, 1994; Araujo et al., 2004; Türkkahra- man and Sayin, 2006; Marsan, 2007), while other investigations have not found any adaptive TMJ changes (Björk, 1951; Jakobsson, 1967; Har- vold and Vargervik, 1971; Wieslander and Lagerström, 1979; Calvert, 1982; Pancherz, 1984; Lux et al., 2001: Basciftci et al., 2003; Janson et al., 2003). The same is true when looking at recent prospective studies as well as randomized clinical trials (RCT). Mandibular growth stimulation was advocated to occur by some authors (Tulloch et al., 1997; Ghafari et al., 1998; Illing et al., 1998; Keeling et al., 1998; O'Brien et al., 2003) but denied by others (Jakobsson and Paulin, 1990; Nelsen et al., 1993). In adult Class II subjects treated with removable functional appliances (Fränkel–FR 2), no TMJ growth effects could be verified (McNamara, 1984). The disagreement between the above investigations may be ex- plained by several factors not being considered sufficiently: 1. Patient group – biased case selection and no clear definition of Class II; 2. Control group – mostly no matching untreated sub- jects; 3. Radiographic cephalometry – a method with mostly limited validity in the assessment of TMJ growth ef- fects; 4. Patient cooperation – difficult to control and to as- Sess; and 5. Presentation of results – mainly as mean value statis- tics. Fixed Functional Appliances Considering TMJ adaptations, many prospective studies using the Herbst appliance (Fig. 1) have demonstrated the occurrence of con- dylar and glenoid fossa adaptive processes in both adolescent and adult Class II patients. These adaptations have been verified by radiographic cephalometry (Pancherz, 1979, 1982; Wieslander, 1984, 1993; Pancherz and Hägg, 1985; Valant and Sinclair, 1989; McNamara et al., 1990; Ruf and Pancherz, 1999; de Almeida et al., 2005), TMJ tomography (Hansen et al., 1990) and magnetic resonance imaging (MRI; Ruf and Pancherz, 218 Pancherz Figure 1. The Herbst appliance. 1998a,b, 1999, 2004, 2006). Furthermore, the findings from human Herbst studies have been supported by those from experimental Herbst Studies in juvenile (Peterson and McNamara, 2003) and adult rhesus monkeys (McNamara et al., 2003). The aim of this chapter is to review the relevant literature on TMJ adaptations when using the Herbst appliance in adolescent and adult Class II subjects. As most of the evidence-based research has been per- formed in Malmö, Sweden and Giessen, Germany, the publications from these two universities will be scrutinized in particular. Using different methods of evaluation, the treatment and post-treatment adaptations in the mandibular condyle, glenoid fossa, articular disc and condyle-fossa relationship will be addressed. TMJ ADAPTATIONS VERIFIED BY RADIOGRAPHIC CEPHALOMETRY In Several Herbst studies comprising consecutively treated Class II, division 1 malocclusions, lateral headfilms in habitual occlusion and With the mouth wide open (for the identification of the condylar head) Were analyzed. Through this approach, condylar modeling (Pancherz and Hägg, 1985; Pancherz and Littmann, 1988, 1989) and condylar position changes (Pancherz and Stickel, 1989) were assessed indirectly. Habitual 9°clusion headfilms were superimposed on the anterior cranial base, While mandibular tracings of the mouth-open headfilms were superim- P9sed with the help of stable bone structures of the mandible (Björk and Skieller, 1983). 219 TMJ Adaptations Furthermore, the “effective” TMJ changes (Creekmore, 1967) were assessed on habitual occlusion headfilms (Pancherz et al., 1998; Ruf and Pancherz, 1998a, 1999; Pancherz and Fischer, 2003; Pancherz and Michaelidou, 2004). The “effective” TMJ changes are a summation of: 1. Condylar modeling; 2. Glenoid fossa modeling; and 3. Condylar position changes within the fossa. Condylar Adaptation Short-term In the publication of Pancherz and Littmann (1988), condylar growth changes in the Sagittal and vertical plane occurring during the active phase of Herbst treatment were analyzed considering the patients’ level of somatic maturation. A male sample of 71 consecutive Class II, division 1 malocclu- sions were screened. Sixty-five of the males were treated with Herbst appliance and assigned to the group of “Herbst subjects.” Herbst therapy was performed during an average period of six months, and all patients attained Class I or overcorrected Class I dental arch relationships after treatment. In the remaining six individuals and in an additional untreated 14 male Class II, division 1 subjects with the same dentoskeletal mor- phology as the Herbst patients, two lateral headfilms existed, covering an average time period of six months. These 20 untreated subjects were as- signed to the group of “control subjects.” Longitudinal growth records of standing height, collected over a time period of 5–10 years, were used for the assessment of somatic matu- ration of both the Herbst and control subjects (Pancherz and Hägg, 1985). From the growth records, individual velocity curves were con- structed, and three growth periods were established (Pancherz and Hägg, 1985) to which the patients were assigned: 1. Pre-peak – 30 Herbst subjects and all 20 control sub- jects; 2. Peak – 26 Herbst subjects; and 3. Post-peak – nine Herbst subjects. Mouth open lateral headfilms from before and after Herbst treatment as well as before and after the control period were analyzed. 220 Pancherz Comparison of Herbst and Control Subjects In order to assess the therapeutic influence of Herbst treatment on mandibular condylar growth, the Pre-peak Herbst and control subjects were compared. The posterior condylar growth was found to be larger in the Herbst than in the control subjects. No group differences were found for vertical condylar growth (Fig. 2). Comparison of Pre-peak and Peak Herbst Subjects The posterior as well as the superior condylar growth was larger in the Peak than in the Pre-peak subjects (Fig.2). Comparison of Pre-peak and Post-peak Herbst Subjects The vertical condylar growth was larger in the Post-peak than in the Pre-peak subjects (Fig. 2). Comparison of Peak and Post-peak Herbst Subjects Similar changes in vertical and sagittal condylar growth were registered in the two subject groups (Fig. 2). Herbst = Control Prepeak < Peak (ns) Prepeak < Postpeak (x) Peak = Postpeak Herbst > Control (xxx) Prepeak < Peak (x) Prepeak = Postpeak Peak > Postpeak (ns) Figure 2. Mandibular sagittal and vertical condylar growth adaptation during six months in 65 males treated with the Herbst appliance and in 20 male control Subjects, all with a Class II, division 1 malocclusion. In relation to the peak in pubertal growth, the Herbst subjects were treated during three growth periods: Pre-peak (n = 30), peak (n = 26) and Post-peak (n = 9). All 20 control subjects were in the Pre-peak period. xxx indicates significant at 0.1% level, xx at 1% level, x at 5% level and ns indicates no significance. 221 TMJ Adaptations Interpretation of the Results When interpreting the findings, it must be remembered that un- treated control subjects were available for only the Pre-peak period, but not for the peak and Post-peak periods. The most obvious finding was that Herbst treatment favored condylar growth in posterior direction only. As a result of this, mandibu- lar length was increased. Posterior condylar growth stimulation also has been verified with the aid of magnetic resonance imaging (Ruf and Pancherz, 1998a, b, 1999). Details will be presented later. When comparing Herbst subjects treated at different growth pe- riods, it became obvious that the somatic developmental stage of the pa- tients had an influence on condylar growth. Thus, the increase in the amount of posterior condylar growth was largest in the peak and smallest in the Pre-peak subjects. This pattern of condylar growth most probably was due to the differences in basic growth rate that, of course, was larg- est in the subjects treated during the peak period. On top of the basic growth rate, an equal amount of stimulated growth was added, irrespec- tive of the maturation of the subjects (Hägg et al., 1987). Long-term Condylar Adaptation. In the publication of Pancherz and Littmann (1989), the long-term effects of Herbst treatment on condy- lar growth are considered. The sample examined was based on the same 71 male Class II, division 1 subjects presented previously (Pancherz and Littmann, 1988). The first 12 of the 65 patients treated with the Herbst appliance were fol- lowed to the end of their growth, on average, seven years after treatment and were assigned to the group of “Herbst subjects.” From the previous group of 20 untreated male Class II, division 1 subjects (Pancherz and Littmann, 1988), 10 were re-examined at the end of growth. The total observation period of these 10 individuals was, on average, seven years. They were assigned to the group of “control subjects.” Mouth open lateral headfilms from before and after Herbst treatment as well as at the end of growth were evaluated. The headfilms of the control subjects were evaluated at comparable time intervals as those of the Herbst subjects. The analyzing method was the same as that used previously (Pancherz and Littmann, 1988). Treatment Period (T) Changes. Even if the number of subjects in the Herbst and Control groups was smaller than in the previous study (Pancherz and Littmann, 1988) the results (Fig. 3T) were comparable: 222 Pancherz posterior condylar growth was larger in the Herbst than in the control group. For vertical condylar growth, no group differences were seen. Post-treatment Period (P) Changes. The treatment changes re- Verted post-treatment. The amount of posterior condylar growth was less in the Herbst treated cases than in the control subjects (Fig. 3P). Total Observation Period (O) Changes. Vertical and sagittal condylar growth was comparable in the Herbst and control subjects (Fig. 3O). Interpretation of the Results The results revealed that the effect of Herbst treatment on poste- rior condylar growth is of a temporary nature. Adaptation in Condylar Position. When placing a Herbst appli- ance, the mandible (including the condyles) usually is advanced to an incisal edge-to-edge position. As a result of skeletal (mainly condylar) as well as dentoalveolar adaptive processes (Pancherz and Hansen, 1986), the condyles will return back to their original fossa position. The ques- tion is: will the condyles return completely to a centric position or not? In the publication of Pancherz and Stickel (1989) the short- and long-term changes in condylar position were assessed in 30 consecutive Class II, division 1 malocclusions (mean age 12.1 years) treated with the Herbst appliance during an average period of seven months. A compari- son was made with 12 untreated Class II, division 1 malocclusions (mean age 11.0 years). At the end of Herbst therapy, all patients had Class I or overcorrected Class I dental arch relationships. - Centric occlusion and mouth open (to visualize the condyle) pro- file roentgenograms were analyzed at five occasions: before treatment, start of treatment, after treatment, one year after treatment and three years after treatment. For the assessment of condylar position changes, mandibular tracings with the condyles from the mouth open headfilms were Superimposed on the centric occlusion headfilms using the nasion- sella-line (NSL) for reference. NSL and its perpendicular (NSLP) through sella (S) were used as reference for linear measurements. The results revealed the following (Fig. 4A): when starting Herbst treatment, the condyles on average were displaced 6 mm anteri- orly and 6 mm inferiorly. After seven months of treatment, the condyles were 0.8 mm inferiorly to their original position. No difference existed, however, between the Herbst and the control group (Fig. 4B and C). Dur- 223 TMJ Adaptations Herbst = Control Herbst > Control P Herbst = Control Herbst & Control O Herbst = Control Herbst = Control Figure 3. Long-term sagittal and vertical mandibular condylar growth adaptation in 12 males treated with the Herbst appliance and in 10 male control subjects, all with a Class II, division 1 malocclusion. T = treatment period of six months. P = post-treatment period of seven years (to the end of growth). O = total observa- tion period of 7.5 years. 224 Pancherz HEREST - - Before “After --- One year -- Three years T25 B rtin-i- 125 |20 115 |19 É s i mm CONTROL - - Before I- -T “ After T20 k - + --- One year - -- Three years C mm. Figure 4. Changes of the condyle position in the glenoid fossa. A. Schematically *Presentation of average changes during the active phase of Herbst treatment. B. Long-term changes (Mean and SD) in 30 male Herbst subjects. C. Long-term changes (Mean and SD) in 12 male control subjects. Before: Before the treat- *nt and control period, respectively. Start: At start of Herbst treatment when the appliance was placed. After. After a six months treatment and control period, 25 225 TMJ Adaptations (Figure 4 Continued) respectively. One year: one year after the six months treatment and control period, respectively. Three years: three years after the six months treatment and control period, respectively. (B and C from Pancherz and Stickel, 1989.) ing the total observation period of 3.5 years, the condyles in both examination groups moved posteriorly and inferiorly (Fig. 4B and C). Interpretation of the Results The position changes of the condyle in posterior and inferior di- rection during and after Herbst therapy was thought to result from nor- mal growth changes of the cranial base and thus also of the glenoid fossa, which is attached to the cranial base (Björk, 1955). Therefore, Herbst treatment was not thought to change the position of the condyle in rela- tion to the fossa. These results are supported by those from studies using TMJ tomography (Hansen et al., 1990) and MRI (Ruf and Pancherz, 1998a,b, 1999). “Effective” TMJ Changes. In both removable and fixed func- tional appliance treatment the position of the chin is affected by the fol- lowing adaptive processes in the TMJ: 1. Condylar modeling; 2. Glenoid fossa modeling; and 3. Condylar position changes in the fossa. In several cephalometric Herbst studies (Pancherz, 1979, 1981; Pancherz and Hägg, 1985; Pancherz and Littmann, 1988, 1989), these processes processes have been analyzed as single factors. However, the method of radiographic cephalometry makes it difficult to perform measurements of condylar and fossa changes with any degree of accuracy. In using the procedure of Creekmore (1967), on the other hand, it is possible to over- come this problem. An arbitrary condylar point (CoA) is used as refer- ence point for the assessment of “effective” TMJ changes (the sum of condylar modeling, fossa modeling and condylar position changes). The CoA point is defined on the first headfilm (Fig. 5A) and transferred to the other headfilms in a series by superimposition of the films on the stable bone structures of the cranial base (Björk and Skieller, 1983). The treat- ment and post-treatment changes of CoA are assessed by Superimposi- tion of the mandibular headfilm tracings on the mandibular stable struc- tures (Björk and Skieller, 1983) and by relating the changes to a reference grid (OL/OLp; Fig. 5B) defined on the first cephalogram. The OL (X-axis 226 Pancherz of the grid) is defined by the incisal edge of the most prominent central mandibular incisor and the distobuccal cusp of the first permanent man- dibular molar. The OLp (y-axis of the grid) is a line perpendicular to OL through the mid point of Sella turcica. “Effective” TMJ Changes in Adolescents. Pancherz and co- workers (1998) assessed the “effective” TMJ changes in 98 adolescent Class II, division 1 malocclusion subjects (59 males and 39 females) treated with the Herbst appliance for an average period of 0.6 years. At the end of therapy, all patients had Class I or overcorrected Class I dental arch relationships. The patients were re-examined 0.6 years after treat- ment (when the occlusion had settled), and three years after treatment. The age-related “Bolton Standards” (Broadbent et al., 1975) were used as the control group. The results revealed the following (Figs. 6 and 7): During the treatment period, “effective” TMJ changes were relatively more posterior directed and about three times larger than those in the untreated subjects (“Bolton Standards”; Fig. 6). During the first post-treatment period of 0.6 years, the changes recovered with respect to both the direction and the amount. During the second post-treatment period of 2.5 years, the changes were “normal.” When comparing the male and female Herbst subjects (Fig. 7), no gender differences existed with respect to the direction of changes. However, the amount of changes was more extensive in the male sub- jects, especially in the second post-treatment period. Interpretation of the Results Treatment Changes. In interpreting the findings, it must be re- membered that a large individual variation in the “effective” TMJ changes existed (Fig. 8; Ruf and Pancherz, 1998a). When compared to the control group, the larger amount and the backward direction of the “effective” TMJ changes in the Herbst subjects could primarily be ex- plained by the stimulating effect of the appliance on condylar growth in posterior direction (Pancherz and Hägg, 1985; Pancherz and Littmann, 1988, 1989; Ruf and Pancherz 1998a). Glenoid fossa modeling (Pancherz, 1979; Woodside et al., 1987; Ruf and Pancherz, 1998a; Pancherz and Fischer, 2003), however, also would contribute to the “ef- fective” TMJ changes. Repositioning of the condyle within the fossa, on the other hand, seemed to be of minor importance for the “effective” TMJ 227 TMJ Adaptations CoA (1,2) Head film 1 - - - - - - Head film 2 A Figure 5. Procedure for the assessment of “effective” TMJ changes. A: Marking of an arbitrary condylar point (CoA) on headfilm 1 (before treat- ment). Transfer of point CoA to headfilm 2 (after treatment or follow-up) after superimposition of the radiographs on the stable bone structures of the cranial base. B: Analysis of the “effective” TMJ changes by superimposi- tion of the two headfilms on the stable structures of the mandible. Meas- urement of the positional CoA changes from before (CoA 1) to after (CoA 2), relative to an OL/OLp reference grid (defined on headfilm 1; revised from Pancherz et al., 1998.) mm CO }* e T4 T4 | - | — Herbst F (n=98) | T | }* - – Bolton \ T3 \ H. (n=32) T2 #13 - | }= $T2 \ l— M mm F-T—T-T— H Figure 6. “Effective” TMJ changes (Mean values in mm) in 98 Herbst paz tients. Registrations at before treatment (T1), after seven months of treat- ment when the appliance was removed (T2), seven months post-treatment (T3) and three years post-treatment (T4). The corresponding changes in the Bolton Standards are shown. (Revised from Pancherz et al., 1998.) 228 Pancherz Co T4 Herbst/Males (n=59) * T4 T3 \ * - T2 Herbstſ emales.; T3 (n=39) T2° S. N. ^ N mm H-T-T—H Figure 7. “Effective” TMJ changes (Mean values in mm) in 59 male and 39 female Herbst patients. Reg- istrations at before treatment (T1), after seven months of treatment when the appliance was removed (T2), seven months post-treatment (T3) and three years post-treatment (T4; revised from Pancherz et al., 1998.) m m changes (Pancherz and Stickel, 1989; Hansen et al., 1990; Ruf and Pancherz, 1998a). Post-treatment Changes. The recovery of the “effective” TMJ changes during the first 0.6 years post-treatment and the “normal” devel- opmental changes thereafter have been verified in several other Herbst studies using conventional radiographic cephalometry (Pancherz and Hansen, 1986; Pancherz and Fackel, 1989; Pancherz and Littmann, 1989; Pancherz, 1991). The results from all the studies mentioned indicate that the original growth pattern prevails long term. Gender Differences. During the treatment and first post- treatment periods the amount and direction of “effective” TMJ changes were comparable in males and female subjects. During the second post- treatment period, however, the males exhibited changes twice as large as the females. This certainly was due to gender differences in growth po- tential during later age, at which the males still grew, whereas the fe- males almost had finished their growth. “EFFECTIVE” TMJ CHANGES IN HYPER- AND HYPODIVERGENT SUBJECTS Pancherz and Michaelidou (2004) analyzed the “effective” TMJ changes in 38 normodivergent (ML/NSL=26.5°-36.5°), 13 hyperdiver- gent (ML/NSL-37°) and 17 hypodivergent (ML-26°) adolescent Herbst 229 TMJ Adaptations Case 1 * case 2 " Case 3 " Case 4 " Case 5 oup | \ ol- ol- ol. ol. ou. | -- r- - - Case 6 * case 7 Case 8 Case 9 " Case 10 oup Case 11 olp Case 14 "I case 15 oup Figure 8. “Effective” TMJ changes (individual values in mm) during treatment in 15 adolescent Herbst patients (Cases 1-15). The “effective” TMJ changes of the age and treatment-time-related Bolton Standards are shown. (Revised from Ruf and Pancherz, 1998a.) subjects. Lateral headfilms from before, after and five years after treat- ment were scrutinized. All patients attained Class I or overcorrected Class I dental arch relationships after treatment. The results revealed that during treatment the “effective” TMJ changes were directed posteriorly more in the hyperdivergent than in the normodivergent and hypodivergent group (Fig. 9). Post-treatment, the TMJ changes were directed more vertically compared with the treatment changes, although the changes in posterior direction were more pro- nounced in the hyperdivergent group than in the other two groups. Interpretation of the Results The main contribution to “effective” TMJ changes comes from condylar growth (Pancherz and Fischer, 2003). In untreated subjects, Björk and Skieller (1983) have demonstrated a sagittal condylar growth 230 Pancherz superior ris º | e 10 A ! '. | | —C– Normo '. | —ºn - Hypo º ! H 5 - -A - Hyper º i. l \ [I2]* Nº * * * * \ posterior v 10 5 0 (mm) Figure 9. “Effective” TMJ changes (Mean values in mm) in 38 normodivergent (Normo), 17 hypodiver- gent (Hypo) and 13 hyperdivergent (Hyper) Class II, division 1 malocclusions treated with the Herbst ap- pliance. Tl: Before treatment. T2: After treatment. T3: Five years after treatment. (Revised from Pancherz and Michaelidou, 2004.) pattern (predominantly posterior-directed condylar growth) in hyperdi- Vergent subjects and vertical condylar growth pattern (predominantly Superior-directed condylar growth) in hypodivergent subjects. These growth patterns correspond to those of the present hyperdivergent and hypodivergent Herbst patients. Herbst treatment stimulates condylar growth in posterior direction (Pancherz, 1979; Pancherz and Littmann, 1988, 1989; Pancherz et al., 1998) and this seems particularly to be the case in hyperdivergent subjects. Clinically, this implies that for the man- dibular growth contribution to Class II correction, the Herbst appliance is more efficient in hyperdivergent than in hypodivergent subjects (Ruf and Pancherz, 1997). A stimulation of condylar growth in especially the pos- terior direction, as a response to mandibular advancement with the Herbst appliance, also has been verified histologically in animals (Wood- side et al., 1983; Peterson and McNamara, 2003) and in patients by TMJ radiography (Paulsen et al., 1995; Paulsen, 1997) and MRI (Ruf and Pancherz, 1998a,b, 1999). When comparing the treatment and post-treatment changes, the “effective” TMJ changes became oriented more vertically post-treatment. This would be, as mentioned above (Pancherz et al., 1998), due to the 231 TMJ Adaptations recovery after Herbst therapy. Thus, the amount and direction of growth return to their original patterns. “Effective” TMJ Changes in Adults In the publication of Ruf and Pancherz (1999), the “effective” TMJ changes were assessed in 14 consecutive young adult Class II mal- occlusions (four males and 10 females) treated with the Herbst appliance for an average period of 8.5 months. Young adulthood was defined by almost complete or complete fusion of the radius epiphysis with its diaphysis (Hägg and Taranger, 1980). Two groups were used for compa- rison – 25 adolescents treated with the Herbst appliance before or at the peak of pubertal growth as well as untreated subjects from the “Bolton Standards” (Broadbent et al., 1975). The “standards” were age related to the individual Herbst patients. All patients were treated to Class I or overcorrected Class Idental arch relationships. The results revealed that in both the adult and adolescent Herbst subjects, the amount of “effective” TMJ changes was several times larger and the direction of changes was relatively more horizontally posterior directed when compared with the age related “Bolton standards” (Fig. 10). The comparison between the two Herbst groups revealed changes that were twice as large in the adolescent as in the adult group. Interpretation of the Results Similar to the adolescents (Fig. 8), a large inter-individual varia- tion in the “effective” TMJ changes existed in the adults (Fig. 11). The results are consistent with those of the two studies on “effective” TMJ changes scrutinized above (Pancherz et al., 1998; Pancherz and Micha- elidou, 2004). Due to sagittal condylar growth stimulation during Herbst therapy, the “effective” TMJ changes in young adults were larger and more horizontally (posterior) directed than in untreated subjects. How- ever, the amount of “effective” TMJ changes was larger in the adoles- cents than in the young adults. This most likely is due to the basically larger mandibular growth rate in the adolescents (Bhatia and Leighton, 1993). TMJ ADAPTATIONS VERIFIED BY LATERAL TOMOGRAPHY There exists only one Herbst study (Hansen et al., 1990) in which the long-term effects of therapy on the TMJs were evaluated with the aid of lateral tomography. Nineteen consecutive male subjects with a 232 Pancherz Imm -T-6 — Herbst |- (young adults) OLp — Herbst + 5 (adolescents) + 4 - - -- Bolton (young adults) + 3 . . . . Bolton (adolescents) + 2 *-i- 1 OL mm | — | | | 6 5 4 3 2 1 Figure 10. “Effective” TMJ changes (mean values) during the active phase of Herbst treatment in 25 adolescent and 14 young adult patients. The “effective” TMJ changes of the age and treatment time related to the Bolton Standards are given. (Revised from Ruf and Pancherz, 1999.) 5 5 5 - 5 Case 1 ', olpſ Case 2 OL Case 3 Oip | Case 4 OLp - 4 4. 4 - 4 |- 3 3 |- 3 3. \ - 2 2 % -2 N 2 N. - 1 H \}. \, H 1 OL \ Ol. N Ot. OL N I—T-T—r—t n I-I f w I I h H —I I I I ſ T I I I I I 7 6 5 4 3 2 1 7 6 5 4 3 2 1 7 6 5 4 3 2 1 7 6 5 4 3 2 1 5 5 < - 5 R. 5 Case 5 Olp Case 6 Olp Case 7 Oip Case 8 OLp 4 \ 4 *, - 4 4-H * ^ i * S. ~, 3. \ 3 \ - 3 s]] ^ \, ~ | ^ |- 2 \ 2 \ |- 2 2- ~ \ * | N - 1 \ 1 \ - 1 1 OL N Ol. QL ^ OL ; : ; TWT. Tº #TTT; ; ; # * * * * * * # , ; ; ; ; ; 5 5 Case 9 Olp Case 10 OLp 4. 4 3. 3. N 2 2 _ Herbst — Bolton 1 1 OL Ot. —T- J I I- I-T I- I I T —I- º I I 7 6 5 4 3 2 1 7 6 5 4 $ 2 1 Figure 11. Effective” TMJ changes (individual values in mm) during treatment in 10 young adult Herbst patients (Cases 1-10). The “effective” TMJ changes of the age and treatment time related to the Bolton Standards are shown. (Based on the findings from Ruf and Pancherz, 1999.) 233 TMJ Adaptations Class II, division 1 malocclusion treated with the Herbst appliance were reinvestigated at the end of growth (an average of 7.5 years after treat- ment). Lateral tomograms of the right and left TMJ were analyzed with respect to the appearance of structural bone changes and the location of the condyle in the fossa – using the subjective well as the narrowest joint space methods of Pullinger and Hollender (1986). The results revealed structural bone changes in one of the 19 subjects. In this subject (Case 7), the left condyle looked flattened and an osteophyte was seen anteriorly. The remaining 18 subjects exhibited normal bone structures of the TMJ. The evaluation of the location of the condyle in the fossa re- vealed a minor deviation from an “ideal” centered condyle position: 55% of the condyles were concentric, while 37% were slightly anteriorly and 8% slightly posteriorly positioned in the fossa. The tomograms of the first 10 of the 19 subjects (Cases 1-10) are presented in Figure 12. Interpretation of the Results The structural bone changes in the left condyle of Case 7 (7.5 years post-treatment) cannot be explained, as no pretreatment tomograms were available. Thus, the significance of the finding is difficult to inter- pret. However, it should be remembered that structural condylar bone changes are not uncommon in young individuals (Dibbets, 1977). The variation in condyle position was similar to that found in an asymptomatic population of young male subjects (Pullinger et al., 1985). The condyle position, therefore, seemed to be unaffected by treatment. TMJ ADAPTATIONS VERIFIED BY MAGNETIC RESONANCE IMAGING (MRI) Parasagittal MRIs in closed-mouth (proton density weighted MRI sequences) and mouth open (T2-weighted MRI sequences) position were screened: before treatment (TO); at start of treatment with the Herbst appliance in place (T1); after 6-12 weeks of Herbst treatment (T2); and at the end of treatment after removal of the Herbst appliance (T3). The MRIs were taken perpendicular to the long axis of the condyle. Slice thickness was 3 mm with no inter-slice gap. At start of Herbst treatment (T1), the condyles in the patients were advanced anteriorly to be positioned on the articular eminence. Af. ter six to 12 weeks of therapy (T2), the condyles were relocated partially 234 Pancherz Right Left Case 1 Case 2 Case 3 Case 4 Case 5 Figure 12. Central section of the TMJ in lateral tomograms from 10 (Cases 1-10) male subjects treated with the Herbst appliance 7.5 years previously. Note the left TMJ of Case 7, exhibiting a flattened condyle with signs of an osteophyte. (From Hansen et al., 1990.) in a posterior direction in the fossa, and after treatment (T3) the condyles Were back in their “original” position in the fossa. Closed mouth images before treatment (TO) and after treatment (T3) were taken with the teeth in habitual occlusion. At treatment start (Tl) and during treatment (T2), the closed mouth images were taken with the appliance in place. The MRIs were analyzed visually for possible Signs of TMJ modeling as well as metrically to document possible con- dylar position changes within the fossa. 235 TMJ Adaptations In order to assess condylar position changes induced by the ap- pliance, an analysis of the anterior and posterior joint spaces in the Sagit- tal plane was performed: the central MRI scans of both the left and right TMJ from before (TO) and after (T3) Herbst treatment were traced and analyzed according to the method described by Kamelchuk and col- leagues (1996) and a Joint Space Index was calculated (Fig. 13). An in- dex value of “0” indicates a centric condylar position, a negative index a posterior condylar position and a positive value an anterior condylar po- sition. = post- ant . Index post + ant 100 Figure 13. Method for the assessment of the condyle-fossa relationship by measuring the an- terior (ant) and posterior (post) joint spaces. Cal- culation of a Joint Space Index. - Condylar Adaptation Adolescents. In the publication of Ruf and Pancherz (1998a), the subject material comprised of 15 consecutive adolescent Class II maloc- clusions (11 males and four females) treated with the Herbst appliance for an average period of seven months. In relation to the pubertal peak of growth, the patients were in the Prepeak-peak period, assessed with hand-wrist radiographs (Hägg and Taranger, 1980). All patients Weſt treated to Class I or overcorrected Class I dental arch relationships. The results of the MRI analysis (Fig. 14) revealed visible condy- lar modeling processes already after six to 12 weeks of Herbst therapy (T2) in all 15 patients (29 of the 30 investigated TMJs). The posterO. superior region at the condyle showed a distinct area of increased signal intensity (bright area) immediately below the signal-poor Zone surround- ing the condyle (dark area). The size and visibility of this zone of in- creased signal intensity varied between individuals. For all the subjects 236 Pancherz With the Herbst appliance for seven months. Registrations from before treat- ment, after 11 weeks of treatment and after treatment. (Fig. 14), a decrease in signal intensity between T2 and T3 was charac- teristic. Thus, in most of the adolescents, a normal condylar MRI appear- ance without signs of modeling was seen at time of removal of the appli- ance (T3). Adults. In the publication of Ruf and Pancherz (1999) the subject material comprised of 14 consecutive young adult Class II malocclusions (four males and 10 females) treated with the Herbst appliance for an av- Crage period of 8.5 months. Young adulthood was defined by almost complete or complete fusion of the radius epiphysis with its diaphysis (Hägg and Taranger, 1980). All patients were treated to Class I or over- 80rrected Class I dental arch relationships. The results of the MRI analysis (Fig. 15) revealed visible condy- lar modeling processes already after six to 12 weeks of Herbst therapy (T2) in 13 patients (26 of the 28 investigated TMJs). In one subject, signs of condylar modeling first could be identified at the end of Herbst treat- ment (T3). The area of increased signal intensity visible at T2 was situ- ºted between two signal poor zones (dark areas). One signal-poor zone Surrounded the condyle, and the other one was situated just above the *Tea of intermediate signal intensity of the bone marrow. This bone mar- 19W demarcation line, which resembled a double contour, was missing in the adolescent subjects. Furthermore, in the young adults the bright area * the condyle could be seen also at the time of removal of the appliance at T3 and occasionally increased in brightness when compared with T2. 237 TMJ Adaptations Before 12 weeks - - - Figure 15. Parasagittal MRI of the right TMJ from a 20-year-old male treated with the Herbst appliance for 10 months. Registrations from before treatment, after 12 weeks of treatment and after treatment. Interpretation of the Results In interpreting the MRIs, the following has to be taken into ac- count. During condylar growth, a significant increase in cartilage matrix, which consists to 80-90% of water, takes place (Bosshardt-Luehrs and Luder, 1991). The hydrogen proton of the water molecule is highly SuS- ceptible to the effects of the magnetic fields due to the high electro nega- tivity of oxygen. In the proton density weighted MRIs used in the pre- sented studies, the contrast of the image reflects the differences in proton density (relative number of hydrogen protons per unit volume) between the tissues. Tissues with a high proton density have a high signal and therefore appear bright, while tissues with a low proton density have a low signal and appear dark on the MRI. An increase in the relative num- ber of hydrogen protons per unit volume thus is reflected as an area of high signal (bright area). Therefore, the increase in MRI signal intensity (bright area) On the postero-superior aspect of the condyle found in the MRIs of adoles: cent and young adult Herbst subjects, most probably corresponds to the histologically proven hyperplasia of the prechondroblastic-chondro" blastic area demonstrated in juvenile (Peterson and McNamara, 2003) and adult (McNamara et al., 2003) animal Herbst studies. While in ado- lescent Herbst patients, this change would be the result of a stimulation of the active cells in the prechondroblastic zone; in the young adult Herbst patients it would be a reactivation of the inactive (“sleeping") cells in this zone. The stimulation or reactivation of cartilage growth rº 238 Pancherz Sults in bony apposition at the posterior surface of the condyle and lengthening of the mandible. In adult Herbst patients, in contrast to adolescent subjects, the bright MR signal in the posterior area of the condyle seen at T2 still per- sisted at T3. Also in the aforementioned histological animal studies (Pe- terson and McNamara, 2003; McNamara et al., 2003), the quantitative analysis of the thickness of the condylar cartilage revealed that in adult monkeys, condylar cartilage thickness only changed slightly between treatment weeks 12 and 24, while in adolescent monkeys the thickness decreased. Furthermore, as mentioned earlier, in the young adult Herbst patients the area of condylar modeling was located between two signal poor (dark) zones. The inner dark zone most probably corresponded to the continuous bony plate at the cartilage-bone interface that is charac- teristic of the adult condylar morphology (McNamara et al., 1982; Luder and Schroeder, 1992; McNamara et al., 2003). This cartilage- bone interface becomes invaded by blood vessels in young adult mon- keys, responding to protrusive function with cartilage hypertrophy (McNamara et al., 1982). As this bony plate at the cartilage-bone inter- face is missing in growing animals (McNamara et al., 1982; Luder and Schroeder, 1992; Peterson and McNamara, 2003), no inner dark zone was detectable in the MRIs of adolescent Herbst patients. Glenoid Fossa Adaptation in: 1. Adolescents. The same 15 adolescent Herbst subjects as those presented above (Ruf and Pancherz, 1998a) were investigated. The results of the MRI analysis re- Vealed signs of glenoid fossa modeling in 11 patients (22 of the 30 investigated TMJs). In contrast to con- dylar modeling, glenoid fossa changes seemed to de- velop later in the course of treatment (between T2 and T3). The adaptive processes were located on the anterior aspect of the post-glenoid spine in all cases. Most of the modeling took place at the inferior part of the spine and decreased towards the top of the fossa. The amount of glenoid fossa adaptation was smaller than that of the condyle. The MRI appearance of the glenoid fossa modeling varied between individuals. 2. Adults. The same 14 young adult Herbst subjects as those presented above (Ruf and Pancherz, 1999) were investigated. The results of the MRI analysis (Fig. 15) 239 TMJ Adaptations revealed signs of glenoid fossa modeling in 11 pa- tients (22 of the 28 investigated TMJs). In compari- son to condylar modeling, glenoid fossa changes seemed to develop later in the course of treatment (between T2 and T3). Similar to the adolescent sub- jects, the adaptive processes were located on the ante- rior aspect of the post-glenoid spine and the modeling was most intensive at the inferior part of the spine and decreased towards the top of the fossa. In most subjects, the amount of glenoid fossa modeling was smaller than the amount of condylar modeling. The MRI appearance of glenoid fossa modeling seemed, however, to be more pronounced in the adults than in the adolescents. Interpretation of the Results Histological animal studies have shown that the temporal bone of the glenoid fossa adapts to Herbst treatment both in juvenile monkeys (Peterson and McNamara, 2003) and adult monkeys (McNamara et al., 2003), with bone formation along the anterior border and bone resorp- tion on the posterior border of the post-glenoid spine. Thereby, the nor- mal posterior directed fossa displacement is reverted in anterior direc- tion. This also has been verified cephalometrically by Pancherz and Fischer (2003). - Fossa modeling, as visualized by MRI in 36 of the 50 investi- gated TMJs of the adolescent and in 22 of the 28 TMJs of the young adult Herbst subjects, occurred at a later treatment stage than condylar modeling. A similar delay in temporal bone response was shown his- tologically in Herbst-treated young adult monkeys (McNamara et al., 2003) but not in juvenile Herbst-treated monkeys (Peterson and McNa- mara, 2003). An explanation for the delayed MRI visualization of glenoid fossa modeling in comparison with the histological findings in adoles- cent animals might be the difference in the adaptive processes of the temporal bone (periosteal ossification) and the condyle (endochondral ossification). The periosteal ossification is not associated with large in- creases in water content of the tissue and does not seem to result in a marked change in MRI signal intensity. Thus, the bone apposition along the post-glenoid spine is visualized later in the MRI, at the time when the newly formed bone consolidates. Furthermore, fossa adaptation in 240 Pancherz the Herbst patients was less extensive than in the animals, which may be due to the fact that the size of the post-glenoid spine in humans is re- duced compared to that of monkeys (Hinton and McNamara, 1984). Adaptation in Articular Disc Position. Pancherz and coworkers’ study goal (1999) was to assess any possible changes in the relative posi- tion of the articular disc to the condyle during different phases of Herbst therapy. Fifteen consecutively treated adolescent Class II Herbst patients (10 males and five females) were screened longitudinally at five occa- sions: before treatment (T1); start of treatment (T2); after six weeks of treatment (T3); after 13 weeks of treatment (T4); and after seven months of treatment when the appliance was removed (T5). The average treat- ment time with the Herbst appliance was seven months. Herbst treatment resulted in Class I or overcorrected Class I dental arch relationships in all patients. Using a disc position index (Vargas Pereira 1997), parasagittal MRIs (central, medial and lateral slices) of the right and left TMJ were analyzed. In the analysis of the closed mouth position MRIs, the results re- Vealed the following (Fig. 16): 1. Before treatment (T1) the disc was in a slight protru- sive position relative to the condyle. 2. At start of treatment (T2) the mandible was advanced to an incisal edge to edge position and the disc at- tained a pronounced retrusive position. 3. After treatment (T5), the disc almost had returned to its original position, however, a slight retrusive disc position prevailed. Interpretation of the Results Before Herbst treatment, a slight tendency to an anterior disc displacement was noted: a frequent finding in Class II malocclusions (Fernandez Sanroman et al., 1997). When placing the Herbst appliance, the mandible with its condyles was advanced and the concomitant physiologic change in the relative position of the articular disc to the condyle resulted in a disc retrusion. After Herbst treatment the condyles were back in their original fossa position but a minor disc retrusion prevailed. Thus, Herbst treatment did not result in any pathological changes in disc position (anterior disc displacement). On the contrary, 241 TMJ Adaptations : T ! A | | {\ } l | | | protrusive | | | \ } ! . ! \ . l i ! O l ! l ! \ . . | : : : retrusive | : closed . l t mouth ; \; ! ! l i I i | \; ! | i | \! | | ! l ! . open | ! mouth i i : ! T1 T2 T3 T4 T5 Figure 16. Disc position (index) changes (mean values) in 15 Class II, division 1 malocclusions treated with the Herbst ap- pliance. Analysis of parasagittal MRIs (central slide) from the right TMJ in closed and open mouth position. TI: Before treatment. T2: At start of treatment when the appliance was placed. T3: After six weeks of treatment. T4: After 13 weeks of treatment. T5: After removal of the Herbst appliance at the end of treatment. (Revised from Pancherz et al., 1999.) the frequent observation of a disc retrusion occurring during treatment possibly could be used as a therapeutic measure in cases with milder forms of anterior disc displacement (anterior disc displacement with re- duction; Fig. 17). Adaptation in Condylar Position in: 1. Adolescents. The same 15 adolescent Herbst subjects as those presented above (Ruf and Pancherz, 1998a) were investigated. The results from the MRI analysis (Fig. 18) revealed that none of the condyles were cen- tered ideally in the fossa (Index = 0). In most subjects both before (TO) and after (T3) treatment a tendency for an anterior positioning of the condyles could be seen. The changes during treatment were insignificant statistically. 242 Pancherz Before Figure 17, Parasagittal MRIs of the right TMJ of a 12-year-old male Class II, division 1 subject treated with the Herbst appliance. Before: prior to treatment. Note the partial disc displacement with reduction. Start: initiation of Herbst treatment. The disc is recaptured. After and 1 Year: the recaptured disc is in a physiologic disc-condyle relationship. (Revised from Ruf, 2003.) 243 TMJ Adaptations Posterior Anterior Index Figure 18. Average left and right Joint Space In- dex in 15 adolescent Herbst patients before and after treatment (mean and SD). A positive index value implies an anterior condylar position in the glenoid fossa, while a negative value indicates a posterior condylar position. (Revised from Ruf and Pancherz, 1998a.) 2. Adults. Ten consecutively treated adult Class II Herbst subjects were screened (Ruf and Pancherz, 1998b). Herbst treatment resulted in Class I or over- corrected Class I dental arch relationships in all sub- jects. The results from the MRI analysis (Fig. 19) re- vealed a tendency of an anterior positioning of the condyle in most subjects. This was the case both be- fore (TO) and after (T3) treatment. On average, how- ever, the deviation from an ideally centered position was less in the adults (Fig. 19) when compared to the adolescents (Fig. 18). Interpretation of the Results Prior to Herbst treatment, the condyles in both the adolescent and adult Herbst patients were placed, on average, somewhat anteriorly. This deviation from ideal concentricity in Class II, division 1 patients also has been described by Pullinger and colleagues (1987). After treat- ment, the average condylar position was insignificantly more anterior than before treatment – an observation which also was made when and lysing lateral headfilms (Pancherz and Stickel, 1989). Furthermore, these findings coincide with those of Woodside and coworkers (1987) who, in 244 Pancherz Posterior Anterior Before After – | | | | | | -10 +20 +30 +40 Index Figure 19. Average left and right Joint Space In- dex in 10 young adult Herbst patients before and after treatment (mean and SD). A positive index value implies an anterior condylar position in the glenoid fossa, while a negative value indicates a posterior condylar position. (Revised from Ruf and Pancherz, 1998b.) mandibular protrusion experiments in monkeys found a proliferation of the posterior part of the articular disc that appeared to fill the gap created by condylar displacement, thus leading to an anterior eccentric condyle position at the end of treatment. SUMMARY AND CONCLUSIONS Functional appliance therapy of Class II malocclusions with the Herbst appliance results in the following TMJ adaptations: Condylar Adaptation 1. Increase (stimulation) of condylar modeling in poste- rior direction. 2. The modeling processes are most extensive in pa- tients treated around the pubertal peak of growth. 3. Hyperdivergent subjects exhibit more posteriorly di- rected condylar modeling than hypodivergent Sub- jects. 4. The modeling processes are visible (MRI) already af- ter six to 12 weeks of treatment. To the end of treat- ment they tend to fade away in adolescents but re- main in adults. 5. The modeling processes revert post-treatment. 245 TMJ Adaptations Glenoid Fossa Adaptation 1. Increase (stimulation) of glenoid fossa modeling at the anterior surface of the post-glenoid spine. 2. In comparison to condylar modeling, the modeling processes (MRI) in the fossa seem: • to be less extensive; • to vary more between individuals; • to develop later in the course of treatment; and • to be more pronounced in adults than in ado- lescents. Articular Disc Adaptation At the end of Herbst treatment, a normal relative position of the disc to the condyle exists. However, in comparison to before treatment, a tendency toward slight disc retrusion is noted. Adaptation in Condyle Position Neither in adolescents nor adults, Herbst treatment results in an abnormal eccentric position of the condyle in the fossa. Pathologic Adaptations Herbst treatment has no adverse short- or long-term effects on the different components (condyle, fossa, disc) of the TMJ. CLINICAL IMPLICATIONS 1. The TMJ adaptations (condyle and fossa) during Herbst therapy result in an increase in mandibular length and in an advancement of the mandible, which is most advantageous in the treatment of skeletal Class II malocclusions. 2. Even if Herbst treatment seems not to have any deci- sive long-term influence on condylar growth, the in- crease in mandibular length at the time of treatment is most important for the correction of the existing Class II malocclusion. Post-treatment, a solid Class I cuspal interdigitation of the teeth then will help to maintain 246 Pancherz the result, in spite of recovering mandibular (condy- lar) growth changes. 3. As TMJ adaptive processes occur even in young adults (at least up to the age of 25 years), many of these older patients can be treated successfully with the Herbst appliance, thus avoiding surgical interven- tion. 4. Herbst treatment does not result in any pathologic ad- aptations of the TMJ. On the contrary, in patients with milder forms of anterior disc displacement, the Herbst appliance may help to recapture a displaced disc. REFERENCES Araujo AM, Buschang PH, Melo AC. Adaptive condylar growth and mandibular remodelling changes with bionator therapy: An implant study. Eur J Orthod 2004:26:515-522. Basciftci FA, Uysal T, Büyükermen A, Sari Z. The effects of activator treatment on the craniofacial structures of Class II division 1 pa- tients. Eur J Orthod 2003:25:87–93. Bhatia SN, Leighton BC. A manual of facial growth: A computer analy- sis of longitudinal cephalometric growth data. Oxford: Oxford Uni- versity Press 1993. Birkebaek L, Melsen B, Terp S. A laminagraphic study of the alterations in the temporomandibular joint following activator treatment. Eur J Orthod 1984;6:257–266. Björk A. Facial growth in man, studied with the aid of metallic implants. Acta Odont Scand 1955; 13:9–34. Björk A. The principle of the Andresen method of orthodontic treatment: A discussion based on cephalometric X-ray analysis of treated cases. Am J Orthod 1951:37:437–458. Björk A, Skieller V. Normal and abnormal growth of the mandible: A Synthesis of longitudinal cephalometric implant studies over a period of 25 years. Eur J Orthod 1983;5:1–46. Bosshardtluehrs CPB, Luder HU. Cartilage matrix production and chon- drocyte enlargement as contributors to mandibular condylar growth in monkeys (Macaca fascicularis). Am J Orthod Dentofac Orthop 1991; 100:362-369. 247 TMJ Adaptations Broadbent BH Sr, Broadbent BH Jr, Golden WH. Bolton Standards of Dentofacial Development. St Louis: CV Mosby 1975. Calvert F.J. An assessment of Andresen therapy on class II division 1 malocclusion. Br J Orthod 1982;9:149-153. Creekmore TD. Inhibition or stimulation of the vertical growth of the facial complex: Its significance to treatment. Angle Orthod 1967:37:285-297. Creekmore TD, Radney LJ. Fränkel appliance therapy: Orthopedic or orthodontic? Am J Orthod 1983;83:89-108. de Almeida MR, Henriques JFC, de Almeida RR, Ursi W, McNamara JA Jr. Short-term effects produced by the Herbst appliance in the mixed dentition. Angle Orthod 2005;75:540-547. Dibbets JMH. Juvenile Temporomandibular Joint Dysfunction and Cra- niofacial Growth: A Statistical Analysis/door. BV Leiden: Stafleu & Tholen 1977. Fernández Sanromàn J, Gómez Gonzáles JM, Alonso del Hoya J. Rela- tionship between condylar position, dentofacial deformity and tem- poromandibular joint dysfunction: An MRI and CT prospective study. J Cranio Maxillofac Surg 1998:26:35-42. Ghafari J, Shofer FS, Jacobsson-Hunt U, Markowitz DL, Laster LL. Headgear versus functional regulator in the early treatment of Class II, division 1 malocclusion: A randomized clinical trial. Am J Orthod Dentofac Orthop 1998; 113:51-61. Hägg U, Pancherz H, Taranger J. Pubertal growth and orthodontic treat- ment. In: Carlson DS, Ribbens KA, eds. Craniofacial Growth Dur- ing Adolescence. Monograph 20, Craniofacial Growth Series. Center for Human Growth and Development. The University of Michigan, Ann Arbor 1987:87–115. Hägg U, Taranger J. Skeletal stages of the hand and wrist as indicators of the pubertal growth spurt. Acta Odont Scand 1980:38:187-200. Hansen K, Pancherz H, Petersson A. Long-term effects of the Herbst appliance on the craniomandibular system with special reference to the TMJ. Eur J Orthod 1990;12:244-253. Harvold EP, Vargervi K. Morphogenetic response to activator treatment. Am J Orthod 1971;60:478-490. Hinton RJ, McNamara JA Jr. Temporal bone adaptations in response to protrusive function in juvenile and young adult rhesus monkeys (Macaca mulatta). Eur J Orthod 1984;6:155-174. 248 Pancherz Illing HM, Morris DO, Lee RT. A prospective evaluation of bass, biona- tor and twin block appliances. Part I: The hard tissues. Eur J Orthod 1998:20:501-516. Jakobsson SO. Cephalometric evaluation of treatment effect on Class II, Division 1 malocclusions. Am J Orthod 1967:53:446-457. Jakobsson SO, Paulin G. The influence of activator treatment on skeletal growth in Angle Class II: 1 cases. A roentgenographic study. Eur J Orthod 1990; 12:174–184. Janson GRP, Toruno JLA, Martins DR, Henriques JFC, de Freitas MR. Class II treatment effects of the Fränkel appliance. Eur J Orthod 2003:25:301-309. Keeling SD, Wheeler TT, King GJ, Garvan CW, Cohen DA, Cabassa S, McGorray SP, Taylor MG. Anteroposterior skeletal and dental changes after early Class II treatment with bionators and headgear. Am J Orthod Dentofac Orthop 1998; 113:40-50. Luder HU. Effects of activator treatment: Evidence of the occurrence of two different types of reaction. Eur J Orthod 1981;3:205-222. Luder HU, Schroeder HE. Light and electron microscopic morphology of the temporomandibular joint in growing and mature crab-eating monkeys (Macaca fascicularis): The condylar calcified cartilage. Anat Embryol 1992;185:189-199. Lux CJ, Rübel J, Starke J, Conradt C, Stellzig A, Komposch G. Effects of early activator treatment in patients with Class II malocclusion evaluated by thin-plate spline analysis. Angle Orthod 2001;71:120- 126. Marsan G. Effects of activator and high-pull headgear combination ther- apy: Skeletal, dentoalveolar, and soft tissue profile changes. Eur J Orthod 2007:29:140-148. McNamara JA Jr. Dentofacial adaptations in adult patients following functional regulator therapy. Am J Orthod 1984;85:57-71. McNamara JA Jr, Bookstein FL, Shaughnessy TG. Skeletal and dental changes following functional regulator therapy on Class II patients. Am J Orthod 1985;88:91-110. McNamara JA Jr, How RP, Dischinger TG. A comparison of the Herbst and Fränkel appliances in the treatment of Class II malocclusion. Am J Orthod Dentofac Orthop 1990;98:134-144. 249 TMJ Adaptations McNamara JA Jr, Peterson JE Jr, Pancherz H. Histologic changes associ- ated with the Herbst appliance in adult rhesus monkeys (Macaca Mulatta). Sem Orthod 2003;9:26-40. Nelson C, Harkness M, Herbison P. Mandibular changes during func- tional appliance treatment. Am J Orthod Dentofac Orthop 1993; 104:153-161. O'Brian K, Wright J, Conboy F, Sanjie YW, Mandall N, Chadwick S, Connolly I, Cook P, Birnie D, Hammond M, Harradine N, Lewis D, McDade C, Mitchell L, Murray A, O’Neill J, Read M, Robinson S, Roberts-Harry D, Sandler J, Shaw I. Effectiveness of treatment for Class II malocclusion with the Herbst or Twin-block appliances: A randomized, controlled trial. Am J Orthod Dentofac Orthop 2003; 124:128–137. wº Owen AH. Morphologic changes in the sagittal dimension using the Fränkel appliance. Am J Orthod 1981;80:573–603. Öztürk Y, Tankuter N. Class II: A comparison of activator and activator headgear combination appliances. Eur J Orthod 1994; 16:149-157. Pancherz H. A cephalometric analysis of skeletal and dental changes contributing to Class II correction in activator treatment. Am J Or- thod 1984:85:125-134. Pancherz H. The effect of continuous bite jumping on the dentofacial complex: A follow-up study after Herbst appliance treatment of Class II malocclusions. Eur J Orthod 1981:3:49–60. Pancherz H. The mechanism of Class II correction in Herbst appliance treatment: A cephalometric investigation. Am J Orthod 1982;82:104- 113. Pancherz H. The nature of Class II relapse after Herbst appliance treat- ment: A cephalometric long-term investigation. Am J Orthod Dento- facial Orthop 1991;100:220-233. Pancherz H. Treatment of Class II malocclusions by jumping the bite with the Herbst appliance: A cephalometric investigation. Am J Or- thod 1979;76:423–442. Pancherz H, Fischer S. Amount and direction of temporomandibular joint growth changes in Herbst treatment: A cephalometric long-term investigation. Angle Orthod 2003;73:493-501. 250 Pancherz Pancherz H, Hägg U. Dentofacial orthopedics in relation to somatic maturation: An analysis of 70 consecutive cases treated with the Herbst appliance. Am J Orthod 1985;88:273-287. Pancherz H, Hansen K. Occlusal changes during and after Herbst treat- ment: A cephalometric investigation. Eur J Orthod 1986;8:215-228. Pancherz H, Littmann C. Morphologie und Lage des Unterkiefers bei der Herbst-Behandlung: Eine kephalometrische Analyse der Verände- rungen bis zum Wachstumsabschluss. Inf Orthod Kieferorthop 1989:21:493-5 13. Pancherz H, Littmann C. Somatische Reife und morphologische Verān- derungen des Unterkiefers bei der Herbst-Behandlung. Inf Orthod Kieferorthop 1988:20:455-470. Pancherz H, Michailidou C. Temporomandibular joint growth changes in hyperdivergent and hypodivergent Herbst subjects: A long-term roentgenographic cephalometric study. Am J Orthod Dentofac Or- thop 2004;126:153-161. Pancherz H, Ruf S, Kohlhas P. “Effective condylar growth” and chin position changes in Herbst treatment: A cephalometric roent- genographic long-term study. Am J Orthod Dentofac Orthop 1998; 114:437-446. Pancherz H, Ruf S, Thomalske-Faubert C. Mandibular articular disk po- sition changes during Herbst treatment: A prospective longitudinal MRI study. Am J Orthod Dentofacial Orthop 1999; 116:207-214. Pancherz H, Stickel A. Lageveranderungen des Condylus mandibulae bei der Herbst-Behandlung: Eine röntgenkephalometrische Untersu- chung. Inf Orthod Kieferorthop 1989;21:515–527. Paulsen HU. Morphological changes of the TMJ condyles of 100 patients treated with the Herbst appliance in the period of puberty to adult- hood: A long-term radiographic study. Eur J Orthod 1997;19:657- 668. Paulsen HU, Karle A, Bakke M, Herskind A. CT-scanning and radio- graphic analysis of temporomandibular joints and cephalometric analysis in a case of Herbst treatment in late puberty. Eur J Orthod 1995;17:165-175. Peterson JE Jr, McNamara JA Jr. Temporomandibular joint adaptations associated with Herbst appliance treatment in juvenile rhesus mon- keys (Macaca mulatta). Sem Orthod 2003;9:12-25. 251 TMJ Adaptations Pullinger AG, Hollender L. Variation in condyle-fossa relationships ac- cording to different methods of evaluation in tomograms. Oral Surg Oral Med Oral Pathol Oral Rad Endo 1986;62:719–727. Pullinger AG, Hollender L., Solberg WK, Petersson A. A tomographic study of mandibular condyle position in an asymptomatic population. J Prosth Dent 1985:53:706-713. Pullinger AG, Solberg WK, Hollender L, Petersson A. Relationship of mandibular condyle position to dental occlusion factors in an asymp- tomatic population. Am J Orthod Dentofac Orthop 1987;91:200-206. Righellis EG. Treatment effects of Fränkel, Activator and extraoral trac- tion appliances. Angle Orthod 1983:53:107-121. Ruf S. Short- and long-term effects of the Herbst appliance on temporo- mandibular joint function. Semin Orthod 2003;9:74-86. Ruf S, Pancherz H. Herbst/multibracket appliance treatment of Class II division 1 malocclusions in early and late adulthood: A prospective cephalometric study of consecutively treated subjects. Eur J Orthod 2006:28:352–360. Ruf S, Pancherz H. Kiefergelenkwachstumsadaptation bei jungen Er- wachsenen während Behandlung mit der Herbst-Apparatur. Eine prospektive magnetresonanztomographische und kephalometrische Studie. Inf Orthod Kieferorthop 1998b;30:735-750. Ruf S, Pancherz H. Orthognathic surgery and dentofacial orthopedics in adult Class II Division 1 treatment: Mandibular sagittal split osteot- omy versus Herbst appliance. Am J Orthod Dentofacial Orthop 2004;126:140-152. Ruf S, Pancherz H. Temporomandibular joint growth adaptation in Herbst treatment: A prospective magnetic resonance imaging and cephalometric roentgenographic study. Eur J Orthod 1998a;20:375- 388. Ruf S, Pancherz H. Temporomandibular joint remodeling in adolescents and young adults during Herbst treatment: A prospective longitudi- nal magnetic resonance imaging and cephalometric radiographic in- vestigation. Am J Orthod Dentofac Orthop 1999; 115:607-618. Ruf S, Pancherz H. The mechanism of Class II correction during Herbst therapy in relation to the vertical jaw base relationship: A cephalo- metric roentgenographic study. Angle Orthod 1997;67:271-276. 252 Pancherz Tulloch JFC, Phillips C, Koch G, Proffit WR. The effect of early inter- vention on skeletal pattern in Class II malocclusion: A randomized clinical trial. Am J Orthod Dentofac Orthop 1997;1 11:391-400. Türkkahraman H, Sayin MC). Effects of activator and activator headgear treatment: Comparison with untreated Class II subjects. Eur J Orthod 2006:28:27–34. Valant JR, Sinclair PM. Treatment effects of the Herbst appliance. Am J Orthod Dentofac Orthop 1989;95:138-147. Vargas Pereira MR. Quantitative Auswertungen bildgebender Verfahren und Entwicklung einer neuen metrischen Analyse für Kiefergelenk- strukturen im Magnetresonanztomogramm. Med Diss, Kiel 1997. Wieslander L. Intensive treatment of severe Class II malocclusions with a headgear-Herbst appliance in the mixed dentition. Am J Orthod 1984;86:1–13. Wieslander L. Long-term effect of treatment with the headgear-Herbst appliance in the early mixed dentition: Stability or relapse? Am J Or- thod Dentofacial Orthop 1993;104:319-329. Wieslander L, Lagerström L. The effect of activator treatment on Class II malocclusions. Am J Orthod 1979;75:20–26. Woodside DG, Altuna G, Harvold E, Herbert M, Metaxas A. Primate experiments in malocclusion and bone induction. Am J Orthod 1983;83:460–468. Woodside DG, Metaxas A, Altuna G. The influence of functional appli- ance therapy on glenoid fossa remodeling. Am J Orthod Dentofac Orthop 1987;92:181-198. 253 AN APPRAISAL OF TEMPOROMANDIBULAR DISORDERS IN CLASS III PATIENTS TREATED WITH MANDIBULAR CERVICAL HEADGEAR AND FIXED APPLIANCES Diego Rey, Giovanni Oberti, Tiziano Baccetti ABSTRACT The purpose of this study was to evaluate the incidence of TMD after treatment with the Mandibular Cervical Headgear (MCH) and fixed appliances in Class III patients. The records of 75 young adult patients (32 female, 43 male) were obtained from two private practices. They comprised three groups: 1. A control group of 25 untreated subjects; 2. 25 Class I patients who had undergone orthodontic non- extraction treatment with fixed appliances; and 3. 25 patients with dentoskeletal Class III disharmonies treated with MCH and fixed appliances. The duration of MCH and fixed appliance treatment ranged from two to three years. The prevalence rates for the values of the Helkimo index in the three groups, as well as in the two genders, were compared by means of z-score statis- tical comparisons. Values of the Helkimo index of zero represent absence of TMD, values of 1 to 4 refer to minimal TMJ dysfunction, and values of 5 to 9 indicate moderate dysfunction. No statistically significant differences for the Helkimo index in the three groups were found (P = .367). Most MCH patients (50, or 67%) had no signs and symptoms of TMD, whereas 3.1% had a mild Helkimo index score, and only 3% a moderate score. There were no statistically significant differences in the Helkimo values with sex as the discriminant vari- able. Class III subjects treated with MCH do not present with a greater preva- lence of TMD signs and symptoms when compared with subjects with Class I malocclusions treated with fixed appliances and orthodontically untreated sub- Jects. Temporomandibular disorders (TMD) are functional or patho- logical conditions that affect the temporomandibular joint (TMJ), the masticatory muscles and the tissues surrounding them. The physiopa- 255 Class III TMD Evaluations thology is not known totally, however, and it remains controversial be- cause many signs and symptoms can be self-limiting and they may recur or fluctuate with time (McNamara et al., 1995). TMDs have been related to several types of malocclusions, e.g. increased overjet, posterior crossbite, anterior deep bite, skeletal open bite and mandibular asymmetries (Keeling et al., 1994; McNamara et al., 1995). On the other hand, the literature suggests that orthodontic appli- ances rarely are involved in the etiology of TMD and that orthodontic treatment in general does not increase or decrease the risk of developing TMD throughout life (McNamara et al., 1995; Kim et al., 2002; Conti et al., 2003; Egermark et al., 2003, 2005; Mohlin et al., 2004). Several studies have indicated that the role of orthodontic treatment in the devel- opment of TMD is not known thoroughly and that it should be studied further in the long term (Wisth, 1984, Gavakos et al., 1991). A common finding in TMD is the displacement of the articular disc. Such a disc displacement can suggest that treatment modalities such as chincups or the mandibular cervical headgear (MCH) that position the condyle to a more posterior position could be associated with increased risk of joint dysfunction. Wyatt (1987) states that mechanotherapy that may cause upward and backward pressures on the condyle is not recom- mended, but other authors disagree with this statement. Rinchuse (1987), for instance, recommends that “the orthodontist must constantly keep in mind that the presumed causes of TMJ internal derangements are often no more than untested hypotheses. The claim that most patients with ac- quired TMJ disorder have had some distal pressure exerted on their man- dibular condyles is a limited hypothesis and reflects an inadequate under- standing and appreciation for the multi-factorial etiology of TMJ disor- ders.” It also appears that the condylar growth pattern can be altered by chincup therapy, and that the craniofacial structures adapt to the condylar changes and vice versa (Gokalp et al., 2005). In a study by Ueki and colleagues (2005), 88 joints of 44 skeletal Class III patients were examined; the authors concluded that TMJ stress was associated with TMJ morphology in Class III patients. Adaptive TMJ changes in absence of TMJ derangements were demonstrated. Tanne and coworkers (1996) evaluated by the finite element method the stress distribution in the TMJ produced by chincup therapy and they found that the stress distribution may depend on the direction of chincup forces. A directional angle of 30–40° generates an optimal level of com- pressive stress during the application of the orthopedic chincup force in order to yield a biomechanically balanced stress distribution. 256 Rey et al. As for experimental studies on animals, Janzen and Bluher (1965) reported that continuous retraction forces applied to the mandible in Macaca mulatta monkeys did not produce degenerative inflammatory changes in the TMJ of the animals. Treatment-induced modifications in the TMJ had to be interpreted as remodeling changes, similar to those described by Joho (1973), who applied a distal force to the lower first molars of four Macaca mulatta monkeys. After the treatment and relapse periods, the animals were suppressed and evaluated histologically. The TMJs were removed and cut sagittally into two parts. Extensive remodel- ing of the TMJ and the presence of reversal lines were found in several areas, indicating that the joints were relocated in an anterior direction during relapse, while they had been displaced posteriorly during active treatment. In terms of clinical trials, Deguchi and colleagues (1998) and Gavakos and Witt (1991) concluded that the relationship between chin- cup treatment and TMD is weak. Arat and coworkers (2003) published a clinical study that compared 32 Class III patients who were treated with chincup therapy to two control groups. One consisted of 39 untreated skeletal Class III individuals and the other one of 55 dental students with normal occlusions. These subjects underwent functional examinations testing for signs and symptoms of TMJ. The distribution of symptomatic individuals was 25% in the treatment group, 23% in the untreated Class III group and 42% in the normal group. The authors concluded that chin- cup therapy is not a risk factor for TMD and that the chincup patients did better than the untreated subjects in terms of comfort and absence of pain. To date, there are no studies concerning the influence on the TMJ by treatment of Class III malocclusion with a mandibular cervical headgear. The purpose of this study is to evaluate the incidence of TMD after orthodontic treatment with MCH combined with fixed appliances in Class III patients compared with untreated patients and Class I patients treated with orthodontics and without extractions. SUBJECTS AND METHODS For this study, the records of 75 adolescent and young adult pa- tients (32 female, 43 male) were obtained from two private orthodontic practices. They comprised three groups: 1. A control group of 25 patients with no previous ortho- dontic treatment who came for their first consultation; 257 Class III TMD Evaluations 2. 25 Class I patients who had undergone orthodontic non-extraction treatment by fixed appliances, with normal molar relation, overjet and overbite at the end of treatment; and 3. 25 patients who presented with dentoskeletal Class III disharmonies (pretreatment dentoskeletal characteris- tics included Wits appraisal - -2, ANB angle < 0°, Class III molar relationships, and negative overjet) treated with MCH and fixed appliances. The MCH had been worn approximately 14 hours per day with a force of 300g per side. The duration of MCH treatment followed by fixed appli- ances ranged from two to three years (Baccetti et al., 2007). The patients who had been treated with MCH and fixed appliances or with fixed ap- pliances alone had been in the retention phase for at least six months af. ter treatment. The Helkimo Index (Helkimo, 1974) was used for the analysis of the TMJ in all subjects. Signs and symptoms evaluated in- cluded mandibular mobility range, clicking or deviations in mandibular movement, pain at palpation of the TMJ or masticatory muscles and pain during opening and closing movements. The prevalence rates for the Val- ues of the Helkimo Index in the three groups were compared by means of z-score statistical comparisons on proportions. Differences regarding the Helkimo value in relation to sex in each group were tested statistically with the same test. RESULTS Sex distribution and the prevalence rates for the Helkimo Index in the three groups are given in Table 1. The patients’ age was similar in the three groups. Values of the Helkimo Index of zero points represent the absence of TMD, values of 1 to 4 points refer to minimal or slight dysfunction of the TMJ, and values of 5 to 9 points indicate moderate dysfunction. No statistically significant differences for the Helkimo Index in the three groups were found (P = .367). Most MCH patients (50, or 67%) had no signs and symptoms of TMD, whereas 3.1% had a mild Helkimo Index score and only 3% a moderate score. Of the 25 patients with some sign or symptom of TMD (33%), the most prevailing sign was clicking; that was found in 23 patients (92%). There were no statistically significant differences in the Helkimo values with sex as the discriminant variable. 258 Rey et al. Table 1. Distribution by gender, group of patients and total Helkimo Index. W/o treatment Class | w/ treatment Class || W/ MCH Sex Femal | Mal || Tota | Femal | Mal || Tota | Femal | Mal || Tota Values € e | € € | € € | 0 10 6 16 9 8 17 11 6 17 1 4 4 8 4 4 8 5 2 7 5 O 1 1 O O O O 1 1 Total 14 11 25 13 12 25 16 9 25 DISCUSSION A sample of 75 patients between 12 and 24 years of age was di- vided into three groups to compare the presence or absence of TMD in Class III patients treated with orthodontics and MCH, Class I patients treated orthodontically without extractions and subjects who had not been treated previously. Epidemiological studies have shown that the signs and symp- toms of TMJ can be found in patients between the ages of 15 and 25 (Egermark et al., 1983; Magnusson et al., 2000). Carlsson (1999) found that prevalence levels for TMD tend to increase at 35 years of age, whereas at earlier ages TMD might be less frequent (Dibbets et al., 1987). The Helkimo Index was used in this study because it is a com- monly used tool to evaluate signs and symptoms of TMJ (Van der Weele et al., 1987). Our results demonstrated that Class III patients treated with MCH and fixed appliances with an overall treatment duration of two to three years did not present with a greater prevalence of TMD signs and symptoms than Class I patients treated with fixed appliances only or or- thodontically untreated controls (Fig. 1). In a previous study, Gavakos and Witt (1991) found that treated Class III patients exhibited a better functional state compared with untreated prognathic patients (Wisth, 1984), but not better than the general population. Deguchi and colleagues (1998) studied the prevalence of TMD in Class III patients during and after active treatment with a chincup. Eighty-six out of 160 patients responded to a questionnaire and were checked for pain, clicking, and mouth opening. Twenty-eight subjects (32%) showed at least one symptom of TMD. These results are similar to those of our study in which mild TMJ dysfunction was found in 28% of the patients and moderate dysfunction in only 4%. In contrast to previous studies that showed more TMD in female subjects during the growing stages (Kim et al., 2002; Thilander et al., 2002), we found no statistically significant differences between the sexes in any tested group. 259 Class III TMD Evaluations 80 Group a º | W/o treatment 60 64 Class | w/treatment Class || W/ MCH E () 9 40 (I) ſl. 32 32 20 - | 0 1,00 Helkino Index Figure 1. Results of the Helkimo Index in three groups of subjects examined. CONCLUSIONS Subjects with Class III malocclusions treated with a mandibular cervical headgear and fixed appliances do not present with a greater prevalence of TMD signs and symptoms when compared with subjects with Class I malocclusions treated with fixed appliances and orthodonti- cally untreated subjects. ACKNOWLEDGEMENT We thank Gonzalo Alvarez for his assistance in the statistical analysis of the data considered in this study. REFERENCES Arat ZM, Akcam MO, Gokalp H. Long-term effects of chincup therapy on the temporomandibular joints. Eur J Orthod 2003:25:471-475. 260 Rey et al. Baccetti T, Rey D, Angel D, Oberti G, McNamara JA Jr. Mandibular cervical headgear Vs rapid maxillary expander and facemask for or- thopedic treatment of Class III malocclusion. Angle Orthod 2007;77:619–624. Carlsson GE. Epidemiology and treatment need for temporomandibular disorders. J Orofac Pain 1999; 13:232-237. Conti A, Freitas M, Conti P, Henriques J, Janson G. Relationship be- tween signs and symptoms of temporomandibular disorders and or- thodontic treatment: A cross-sectional study. Angle Orthod 2003;73:411–417. Deguchi T, Uematsu S, Kawahara Y, Mimura H. Clinical evaluation of temporomandibular joint disorders (TMD) in patients treated with chin cup. Angle Orthod 1998;68:91-94. Dibbets JMH, Van der Weele LT. Orthodontic treatment in relation to symptoms attributed to dysfunction of the temporomandibular joint: A 10-year report of the University of Groningen study. Am J Orthod Dentofacial Orthop 1987;91: 193-199. Egermark I, Carlsson GE, Magnusson T. A prospective long-term study of signs and symptoms of temporomandibular disorder in patients who received orthodontic treatment in childhood. Angle Orthod 2005;75:645-650. Egermark I, Magnusson T, Carlsson GE. A 20-year follow-up of signs and symptoms of temporomandibular disorders and malocclusions in subjects with and without orthodontic treatment in childhood. Angle Orthod 2003;73:109-115. Egermark-Eriksson I, Ingervall B, Carlsson GE. The dependence of mandibular dysfunction in children on functional and morphologic malocclusion. Am J Orthod 1983;83:187-194. Gavakos K, Witt E. The functional status of orthodontically treated prog- nathic patients. Eur J Orthod 1991;13:124-128. Gokalp H, Kurt G. Magnetic Resonance Imaging of the condylar growth pattern and disk position after chincup therapy: A preliminary study. Angle Orthod 2005;75:568-575. Helkimo M. Studies on function and dysfunction of the masticatory sys- tem: Index for anamnesis and clinical dysfunction and occlusal state. Swed Dent J 1974;67:101-121. Janzen EK, Bluher JA. The cephalometric, anatomic, and histologic changes in Macaca mulatta after application of a continuous-acting re- traction force on the mandible. Am J Orthod 1965;51:823–855. 261 Class III TMD Evaluations Joho JP. The effects of extraoral low-pull traction to the mandibular den- tition of Macaca mulatta. Am J Orthod 1973;64:555-577. Keeling SD, McGorray S, Wheeler TT, King GJ. Risk factors associated with temporomandibular joint sounds in children 6 to 12 years of age. Am J Orthod Dentofacial Orthop 1994;105:279-287. Kim MR, Graber TM, Viana MA. Orthodontics and temporomandibular disorder: A meta-analysis. Am J Orthod Dentofacial Orthop 2002:121:438–446. Magnusson T, Egermark I, Carlsson GE. A longitudinal epidemiologic study of signs and symptoms of temporomandibular disorders from 15 to 35 years of age. J Orofac Pain 2000; 14:310-319. McNamara JA Jr, Seligman DA, Okeson JP. Occlusion, orthodontic treatment and temporomandibular disorders: A review. J Orofac Pain 1995;9:73-90. Mohlin B, Derweduwen K, Pilley R, Kingdon A, Shaw WC, Kenealy P. Malocclusion and temporomandibular disorders: A comparison of adolescents with moderate to severe dysfunction with those without signs and symptoms of temporomandibular disorder and their further development to 30 years of age. Angle Orthod 2004;74:319-327. Rinchuse DJ. Counterpoint: Preventing adverse effects on the temporo- mandibular joint through orthodontic treatment. Am J Orthod Dento- fac Orthop 1987;91:500-506. Tanne K, Tanaka E, Sakuda M. Stress distribution in the temporoman- dibular joint produced by orthopedic chincup forces applied in vary- ing directions: A three-dimensional analytic approach with the finite element method. Am J Orthod Dentofacial Orthop 1996;110:502-507. Thilander B, Rubio G, Peña L, Mayorga C. Prevalence of temporoman- dibular dysfunction and its association with malocclusion in children and adolescents: An epidemiologic study related to specified stages of dental development. Angle Orthod 2002;72:146-154. Ueki K, Nakagawa K, Marukawa K, Takatsuka S, Yamamoto E. The relationship between temporomandibular joint disc morphology and stress angulation in skeletal Class lll patients. Eur J Orthod 2005:27:501-506. Van der Weele LT, Dibbets JMH. Helkimo index: A scale or just a set of symptoms? J Oral Rehabil 1987; 14:229–237. Wisth P.J. Mandibular function and dysfunction in patients with man- dibular prognathism. Am J Orthod 1984;85:193-198. 262 Rey et al. Wyatt WE. Preventing adverse effects on the temporomandibular joint through orthodontic treatment. Am J Orthod Dentofacial Orthop 1987;91:493-499. 263 TEMPOROMANDIBULAR MUSCLE AND JOINT DISORDERS: PROGRESS IN RESEARCH WITH NIDCR’S TMJ IMPLANT REGISTRY AND REPOSITORY Ana M. Velly, John Look, Sandra Myers, Ching-Chang Ko, Shanti Kaimal, João Ferreira, Jennifer Springsteen, Eric Schiffman, Nelson Rhodus, James Fricton ABSTRACT The National Institute of Dental and Craniofacial Research's TMJ Implant Reg- istry and Repository (NIDCR's TIRR) is a national research registry-repository established to collect clinical information and biological specimens on tem- poromandibular muscle and joint disorders (TMJD) patients (with and without temporomandibular joint implants) and controls. NIDCR's TIRR has two divi- Sions: The Registry and the Repository, responsible for recruiting and archiving the clinical and the biological data. One thousand and nine subjects (TMJD pa- tients and controls) are registered in the NIDCR's TIRR. They were invited to complete a self-report questionnaire and a calibrated examination following re- Search diagnostic criteria for temporomandibular disorders (RDC/TMD) proto- cols. Six hundred fifty-five samples of blood and saliva were collected. The overall purpose of the NIDCR’s efforts in this regard is the development of a sufficiently extensive TMJD registry and repository to conduct intramural re- search and facilitate extramural research on TMJD. The ultimate goal is to en- hance the understanding of clinical and biological factors related to TMJD. In- ternal and external validity are considered major concerns in NIDCR's TIRR. In this chapter, various types of selection bias and manners on how to prevent and control them are discussed. Interpretation of the data and concept of causality also has been considered. Determining appropriately which biological and clini- cal risk factors predispose a person to develop TMJD, or to develop a more se- were and dysfunctional chronic TMJD pain, is essential for providing insight into TMJD prevention and treatment. Temporomandibular muscle and joint disorders (TMJD) embrace an array of heterogeneous group of musculoskeletal diagnoses, from muscle contracture and myofascial pain syndrome to TMJ degenerative joint disease and disc displacement (Fricton, 1991; Okeson, 1996). 265 Progress in Research TMJD are a major cause of chronic orofacial pain. It has been estimated that approximately 5-10% of the US population will seek professional dental care for TMJD symptoms in their lifetime, and more than five mil- lion people sought care in a six to twelve-month time period at an esti- mated direct cost of $2 billion dollars (American Pain Society, 1995; Drangsholt and LeResche, 1999; Gatchel et al., 2006). A variety of contributing factors have been investigated for the occurrence and persistence of TMJD such as somatization, depression, anxiety, hormones, widespread pain and trauma (Marbach et al., 1988; Dworkin et al., 1990; Carlson et al., 1993; Von Korff et al., 1993; Vas- send et al., 1995; Ohrbach and Dworkin, 1998; Epker and Gatchel, 2000, Epker et al., 2000; Huang et al., 2002; John et al., 2003; Velly et al., 2003; Keefe et al., 2006; Balasubramaniam et al., 2007; LeResche et al., 2007). In addition, genetic variations in catechol-O-methyltransferase (COMT) – an enzyme that metabolizes catecholamines and catechol sub- stances, such as catecholestrogen – influence the risk of developing TMJD (Diatchenko et al., 2005). Women who processed COMT haplo- types that code for low levels of COMT activity show an increased risk to develop TMJD when compared to women who have COMT haplo- types coding for high levels of COMT activity, independent of the psy- chological factors (Slade et al., 2007). The studies cited previously indicated that there are several dis- tinct pathophysiological mechanisms associated with the occurrence and persistence of TMJD. The identification of the biological and clinical risk factors related to the development of TMJD, or to the development of a more severe and dysfunctional chronic TMJD pain in a larger and valid population using a standardized methodology, is essential for the understanding of TMJD. PROGRESS IN RESEARCH WITH NIDCR’S TMJ IMPLANT REGISTRY AND REPOSITORY In 2002, the NIH’s National Institute of Dental and Craniofacial Research (NIDCR) supported and funded the development of a National TMJ Implant Registry and Repository (NIDCR's TIRR, http://tmjregistry.org) at the School of Dentistry, University of Minne- sota. The aim is to collect comprehensive clinical data and biological specimens from patients with TMJD, with and without implants, as well as from control subjects without TMJD. The goal is to disseminate this valid database to conduct intramural research and facilitate extramural TMJD research, and to enhance the understanding of clinical and bio- 266 Velly et al. logical factors related to TMJD. To accomplish this aim, NIDCR's TIRR is organized into two divisions: 1. The Registry is responsible for the recruitment of the study population (TMJD and controls) and for the clinical data collection; and 2. The Repository is responsible to collect and archive high quality biological data and retrieved implants for dissemination. Data about NIDCR's TIRR have been published elsewhere (Myers et al., 2007). p Study Population and Data Collection The NIDCR's TIRR had two aims when recruiting the study population: 1. Recruit a valid sample that represents the target popu- lation; 2. Recruit enough subjects to meet the sample size re- quirements; and 3. Recruit a valid sample of controls (non-TMJD sub- jects). To attain these aims, the study population (TMJD cases and controls) is collected from three sources: web-based computer programs for patients; health professionals (e.g., clinicians and surgeons) who treat TMJD pa- tients; and TMJD clinical research studies at the University of Minne- Sota, following standardized methodology in which subjects are invited to receive a clinical examination performed by a trained dental hygienist. The examination specifications are based on those of the RDC/TMD. If present, the TMJD diagnoses are derived from the research diagnostic criteria for temporomandibular disorders (RDC/TMD) diagnostic algo- rithm (Dworkin and LeResche, 1992). Collection of comprehensive data on these patients is ongoing. The clinic data include: . Patient demographics; . Primary diagnosis; . Pain and dysfunctional measures; . Medical history; . Co-morbidities including rheumatic diseases; . Behavioral and psychosocial characteristics; 267 Progress in Research 7. If implants were used, the surgeon and specific im- plant data are registered; 8. Clinical, functional and imaging data before and after explantation; and 9. Circumstances of explanation implant failure. The Craniomandibular Index (Fricton and Schiffman, 1986, 1987) was used to assess muscle and joint tenderness and dysfunction, and IM- PATH (Fricton, 1990) that includes the Symptom Severity Index (SSI) and other items to assess behavioral and psychosocial characteristics. More specifically, TMJD pain intensity, frequency and pain duration were measured using the SSI. The SSI is a self-reported pain measure consisting of five reliable, valid subscales measuring sensory and affec- tive intensity, frequency, duration and tolerability of pain, and a non- specific symptom checklist (Fricton et al., 1987a, b, 2002). One thousand and nine subjects (TMJD and controls) registered in this NIDCR's TIRR. They were invited to complete a questionnaire and a calibrated examina- tion following RDC/TMD protocols. Six hundred fifty-five samples of blood and saliva were collected. Biological specimens including TMJ joint tissues, retrieved implants and imaging also were collected (Myers et al., 2007). NIDCR’s TIRR DATA DISSEMINATION To accomplish the overall purpose of the NIDCR’s TIRR devel- oping a sufficiently extensive TMJD registry and repository to conduct intramural research and facilitate extramural research on TMJD, the NIDCR’s TIRR developed a dissemination protocol for the purpose of providing the data to investigators for basic and clinical research. This Dissemination Plan is consistent with federal policy on “Sharing Bio- medical Research Resources: Principles and Guideline for Recipients of NIH Research Grants and Contracts” (http://www.ott.nih.gov/policyl rt guide final.html). The recipient of resources from NIDCR's TIRR may include a clinical researcher, a basic researcher or a student with appropriate mentorship. All investigators and their staff must be qualified professionally to conduct the proposed research. In addition, the investi- gator needs to complete an application form on NIDCR's TIRR website or the paper version as well as a proposal. A proposal needs to be prepared according to the guidelines pro- vided by the NIDCR’s TIRR statement of work. It should include a re- search question and/or study hypotheses, a background of significance, 268 Velly et al. the Study design, study population, the variables that will be used in the project and statistical analyses. The NIDCR's TIRR initial review board includes the current Executive Committee of NIDCR's TIRR, including the Principal Investigator, Director of the TMJ Implant Registry, Direc- tor of the TMJ Implant Repository, Director of Recruitment, Director of Neuroscience and Director of Biomaterials. METHODOLOGICAL ISSUES IN TMJD STUDIES Study Designs Cohort, case-control and cross-sectional studies may be per- formed using the NIDCR’s TIRR database. In the following section we describe each study design. Cohort Studies. Cohort study involves comparing disease inci- dence between groups exposed and not exposed to a risk factor over a period of time (Koepsell and Weiss, 2003). Cohort studies can be pro- spective and retrospective. Both start by identifying and enrolling sub- jects based upon the exposure without knowing the outcome. The type of cohort is determined by the difference when the outcomes of interest oc- cur relative to when the study is initiated. In the retrospective design, the cohort, the baseline measurements, the outcomes all have happened in the past. In the prospective, the study is initiated before any of the out- comes are known (Hennekens and Buring, 1987; Hulley et al., 2007). Figure 1 shows one example of a prospective study (LeResche et al., 2007) in which 1,996 children, all 11 years old, were followed for three years to determine the risk factor for onset of clinically significant TMJD pain during early adolescence. Every three months during the fol- low-up, the children received a questionnaire to identify the presence of TMJD pain. It was found that baseline predictors of clinically significant pain included female gender [Odds Ratio (OR)=2.0, 95% Confidence Interval (CI)=1.2–3.3] and negative somatic and psychological symptoms including somatization (OR=1.8, CI=1.1-2.8), number of other pain complaints (OR=3.2, CI-1.7-6.1) and life dissatisfaction (OR=4. 1, CI=1.9-9.0). Another example of a prospective study using NIDCR's TIRR was the investigation performed by Velly and coworkers (2008) to determine fibromyalgia and widespread pain as contributing factors for TMJD pain disability. This study, which included 272 subjects without TMJD pain disability at baseline (Grade 0 or I Global Chronic Pain Scale; GCPS), fibromyalgia (OR: 4.59, p=0.01), widespread pain (WP; 269 Progress in Research OR: 2.87, p=0.008) and depression (OR: 2.81, p=0.04) were associated with the onset of dysfunctional TMJD at the 18-month follow-up. One of the strengths of the cohort study is its potential to investi- gate the cause of the disease, because the exposure status is determined and recorded before the disease has been identified in any subjects. For example, in the previous studies, it is clear that negative somatic and psychological symptoms number of other pain complaints, and the fi- bromyalgia and widespread pain preceded the occurrence of the outcome (i.e., TMJD pain). This feature provides unambiguous information about whether or not exposure preceded the disease as required for a causal inference (Koepsell and Weiss, 2003). This methodology prevents the exposure measurements to be influenced by knowledge of the outcome (Hulley et al., 2007). The cohort study design, however, is expensive and inefficient for studying outcomes that happen so infrequently in any given year. Due to this infrequency, a large number of people need to be followed for long period of time to observe enough outcomes to make meaningful and powerful results. The strengths of a cohort study also can be undermined by incomplete follow-up of subjects (Hennekens and Buring, 1987; Hulley et al., 2007). - TMJD pain - *Negative somatic and psychological symptoms *Number of other pain - complaints Ys, - Non-TMJD pain - Study population - Absence of negative somatic and TMJD pain psychological symptoms number - of other pain complaints Non-TMJD pain Study start Follow-up of 18 months Figure 1. Cohort study. Case Control Studies. Case-control studies assess the frequenº) of past exposure between cases that developed the disease (or other Out- 270 Velly et al. come) and controls selected to represent the frequency of exposure in the underlying population at risk from which the cases arose (Koepsell and Weiss, 2003). The aim is to identify the predictor variables that may ex- plain why the cases developed the disease and the controls did not. Be- cause the case-control study looks backward to define the exposed group, it may be difficult to be sure if the predictor preceded the occurrence of the disease (Hennekens and Buring, 1987; Hulley et al., 2007). This study design is used frequently in TMJD studies, probably because it is an efficient design for rare outcomes and it is less expensive (Hennekens and Buring, 1987; Hulley et al., 2007). A drawback of this study design, however, is its susceptibility to bias. In addition, one of the greatest limi- tations related to case-control studies is the difficulty in verifying Whether or not the exposure preceded the occurrence of the disease (Hennekens and Buring, 1987). Figure 2 shows a case-control study that investigates risk factors for three diagnostic subgroups of painful TMJD, among 97 subjects with myofascial pain only, 20 with arthralgia only, 157 with both myofascial pain and arthralgia and 195 controls without TMD pain met criteria for study eligibility (Huang et al., 2002). In this study, myofascial pain with arthralgia was associated significantly with trauma (OR = 2.1), clenching (OR =3.3), third molar removal (OR = 4.0), somatization (OR = 5.1) and female gender (OR = 4.7). - Clenching *- TMJD - CaSCS Non-Clenching *- - - opulation Clenching pop *- Non TMJD - Non-Clenching controls - * V Figure 2. Study Case-Control. The occurrence of risk factors is investigated at the moment of the recruitment. The objective is to look for exposure that preceded the disease. 271 Progress in Research Cross-Sectional Studies. Cross-sectional studies measure the fre- quency of outcome(s) (e.g., TMJD pain, fibromyalgia, migraine) at a point time or over a short period. The difference with cross-sectional study is that exposure and outcome are ascertained at same point in time. Associations noted in cross-sectional study tended to rely more on the chronicity than the occurrence of a condition because most frequently, the cases with a condition for long duration are over-represented more frequently. Ambiguity about the direction of causality is a common limitation (Koepsell and Weiss, 2003). An example of cross-sectional studies using NIDCR's TIRR is the study conducted by Moana and colleagues (2008) that evaluated the relationship between prevalent comorbidities (self-reported) and TMJD. This study, which included 814 subjects with TMJD, found that migraine and muscle pain/rheumatism were associated positively with frequency, duration and intensity of TMJD pain (p<0.05). Internal and External Validity Internal and external validity were considered the two major concerns in NIDCR’s TIRR. Internal validity represents the degree to which the investigator draws the correct conclusions about what actually happened in the study (Hennekens and Buring, 1987; Hulley et al., 2007). Is it possible that the significant association between clenching and TMJD noted in few studies was biased by how subjects were se- lected for the study? External validity represents the degree to which these conclusions can be applied appropriately to people and events out- side the study. To increase the internal validity, the idea is to design and execute a study with sufficient control over the three main threats to in- ferences: bias (systematic error), confounding and chance (random er- ror). Bias. Bias is a process at any stage of inference that tends to pro- duce results or conclusions that differ systematically from the truth. In other words, bias is a systematic error in an epidemiologic study that re- sults in an incorrect estimate of the association between exposure and risk of disease (Sackett, 1979). This systematic error may occur when selecting the study population and/or collecting the information for the study. Examples of information bias are recall bias, interview and report- ing bias. Information bias will not be discussed in this chapter; the reader is therefore referred to Kleinbaum (1982), Hennekens (1987), Rothman (1998), Koepsell (2003), and Hulley (2007) for review. 272 Velly et al. Selection bias results when cases/controls and exposed/un- exposed are included or excluded from a study, because some character- istics they exhibit are related to exposure and disease under evaluation (Breslow and Day, 1980). Controls should come from the same cohort where diseased subjects become cases during the study time (Wacholder et al., 1992a). Controls should have the same chance as the cases to de- velop the disease. The selection of the study population in a clinic or hospital (clinical or hospital-based case-control studies) generally is an adequate design for case selection. This approach usually is less expen- sive and achieves better subject participation than population-based stud- ies (Hennekens and Buring, 1987). In these case-control studies, how- ever, it is more difficult to define the underlying cohort from which the cases originate (Wacholder et al., 1992a). Using a population-based study, obtaining data from all affected individuals or a random sample from a defined population (Hennekens and Buring, 1987) provides an excellent design for choosing controls since the data will be derived from the same base as the cases. On the other hand, it is difficult to attain the complete TMJD case identification in the base, particularly if the prob- ability of disease diagnosis depends on access to medical care and the probability of case identification depends on exposure (Breslow and Day, 1980; Wacholder et al., 1992a). In the following section we will describe important selection bi- ases that can be related to TMJD studies. Referral Bias When cases are referred for study, the reason for the referrals may be associated with a risk factor in the study (Wacholder et al., 1992a). Suppose dentists referred TMJD patients with generalized tooth- wear to a specific dental clinic because this clinic offers a particular treatment (e.g., occlusal appliances) at reduced fees. Consequently, TMJD patients selected in this clinic will have a greater chance of having tooth-wear than the controls, and a positive bias may be observed. Diagnostic Suspicion Bias This bias occurs when the disease diagnosis is influenced by the knowledge of the exposure, which may result when the investigator is advised of the subjects’ exposure status before the disease diagnosis and may influence the subsequent diagnosis process (Wacholder et al., 1992a). This bias may occur when the possible risk factor has received widespread publicity (Wacholder et al., 1992a,b). Suppose that subjects 273 Progress in Research with malocclusion are monitored more closely for TMJD diagnosis than those without malocclusion because this factor is assumed to be a risk factor for TMJD. Consequently, an association between TMJD and mal- occlusion, for example, may be observed due to a higher probability of diagnosing TMJD in subjects with malocclusion as compared to those without it. Prevalence-incidence Bias It generally is preferable to use incident cases rather than preva- lent cases in case-control studies involving disease etiology, in that prevalent cases may have changed their behavior (Hennekens and Buring, 1987). Furthermore, incident cases are preferred to maximize the chance that the exposure preceded the occurrence of the disease. For ex- ample, in a case-control study, including prevalent TMJD pain cases (e.g., TMJD pain for more than one year), it is difficult to determine if depression preceded the TMJD pain or if it is a consequence of the TMJD pain. Membership Bias, Friends and Neighbors Bias and Volunteer Bias Controls also may be selected among a specific group of activi- ties such as joggers, students or teachers. Depending on the study, this method may cause bias if the control group differs systematically from the base of the cases (Sackett, 1979). For example, in evaluating the as- sociation between TMJD and a risk factor such as malocclusion, and Se- lecting dental students as controls, we are more likely to observe that malocclusion is associated positively with TMJD. The explanation for this positive effect may be that the dental students might have a higher income level than the TMJD patients and higher access to orthodontic treatment and, therefore, they would be less likely to have malocclusion than TMJD patients. Selection of neighbors as controls years after the cases have been diagnosed may cause bias if the distribution of exposure is associated with socio-economic and ethnic characteristics in a neighborhood that has changed (Breslow and Day, 1980; Wacholder et al., 1992). Also, friends and neighbors may be more social and for this reason they agree to participate in the study. If the risk factor studied is associated with socio-demographic factors, bias may occur because the reason the con- trols have agreed to participate in a study is associated with the risk fac- tor. An additional problem associated with this type of control group is overmatching (Cole, 1980; Day et al., 1980), in which the study’s effi- 274 Velly et al. ciency is reduced by the restricted variability of the exposure factor. This may occur when the matched factors are correlated with the exposure of interest but not with the disease. Furthermore, subjects who agree to participate in a study may exhibit a different exposure distribution from those who do not agree, causing volunteer bias (Sackett, 1979). Non-respondents are more likely to have disease or to be exposed (e.g., to be smokers) than respondents (Criqui et al., 1979). Confounding Variables. A confounder is one variable that is: 1. A risk factor for the disease; 2. Associated with the exposure under the study in the Source population; and 3. Not an intermediate step in the path between expo- sure and the disease (Rothman, 1998). For example, in the study assessing if depression is a risk factor for TMJD pain, it is important to adjust the analyses by “gender” because the proportion of severe depression may be more frequent among fe- males independent of TMJD pain, and TMJD is more frequently noted among females, independent of depression. Consequently, if confound- ing is not controlled in the design or analyses, the results will be biased because the effect estimate will take into account the effect of the con- founder (Fig. 3). Depression TMJD pain Female gender Figure 3. Confounding diagram. Association Due to Chance. It is possible that a significant asso- ciation represents only a spurious association due to a random error, es- pecially in studies with small sample size (Hennekens and Buring, 1987; Hulley et al., 2007). For example, suppose that one study recruited 20 Subjects to assess the relationship between TMJD and coffee drinking. Suppose that the percentage of coffee drinking in the general population 275 Progress in Research is 12% and that there is no association between TMJD and coffee drink- ing. Due to the chance alone, however, in this study it was observed that the prevalence of coffee drinking among the TMJD cases was higher in this sample: eight of the 20 TMJD subjects (40%). Consequently, there is a possibility to observe a positive association between TMJD pain and coffee that is due only to chance. Preventing and Controlling Bias The better option is to prevent bias in the study design. The pre- vention of selection bias must be accomplished through careful study design, including the more appropriate choice of a study population (Kleinbaum and Kupper, 1982) and a standardized methodology ap- plied to both cases and controls or exposed and non-exposed (Sackett, 1979). In order to prevent bias, NIDCR's TIRR was vigilant in the selec- tion of the study population. The study population was not selected based on a specific aim; consequently, the probability of a subject being Se- lected should not be influenced by exposure history or disease status. Selecting TMJD and controls, both from the dental clinic at the Univer- sity of Minnesota, for example, suggest that controls may be more simi- lar than other controls because they are closer to the cases in relation to the subjective factors that influenced the subject’s choice of a particular hospital, the awareness of previous exposures, and the reason for reluc- tance to participate in the study. NIDCR's TIRR has standardized proto- col to prevent subject non-response at recruitment stage and the loss of follow-up at each time-point until the end of the study. After the data are collected, it may be necessary to adjust the es- timate of disease-exposure association in the risk factor and disease rela- tionship, because the exposure distribution of the risk factor may differ from the level of a confounder. The problem with the adjustment is the impossibility of collecting information on every possible confounder. Then, the adjustment depends on the degree to which the investigator is aware of possible bias (Criqui et al., 1979) and the quality of the data collected (Kleinbaum and Kupper, 1982). Interpretation of Data: Associations and Causality It is essential to understand the difference between mere associa- tion and causality. For example, Velly and coworkers’ case-control study (2003) noted that anxiety (OR=5.12; 95% CI: 1.36; 19.41) and depres- sion (OR=3.51; 95% CI: 1.07; 11.54) were associated with a myofascial pain diagnosis. Could we then interpret these associations as causes of 276 Velly et al. TMJD? Steps are recommended when evaluating if an association pro- vides a positive evidence for causality: 1. Temporality: The observation that an exposure pre- cedes the disease is essential to establish causality. Temporality is better assessed by the use of cohort studies. 2. Consistency with other studies of different designs, because it is less likely that random and systematic errors are responsible for the significant association noted in all those studies (Hennekens and Buring, 1987; Koepsell and Weiss, 2003; Hulley et al., 2007). 3. The strength of the association between putative risk factor and the disease. 4. A dose-response relation provides a positive evidence for causality. In John and coworkers’ study (2003), a dose-response relationship was noted between the number of baseline pain sites and the onset of dys- functional TMD pain, with the odds of dysfunctional TMJD pain. 5. Biologic plausibility is an important consideration for drawing causal inference. The problem with biologi- cal plausibility is that it depends on the current under- standing of the disease process, which might not be clear at that point in time and might get modified with further advances in the field. CONCLUSION The NIDCR's TIRR is a nationally recognized research registry and repository with the overall purpose to develop a sufficiently exten- sive TMJD registry and repository to conduct intramural research and facilitate extramural research on TMJD. The development of appropriate cross-sectional, case-control and retrospective and prospective cohort studies using NIDCR's TIRR data certainly will progress TMJD research by determining which biological and clinical risk factors predispose a person to develop TMJD or to de- velop a more severe and dysfunctional chronic TMJD pain. This type of research is essential for the understanding of clinical and biological fac- tors related to TMJD, which can provide insight into what interventions can contribute to prevention of this disorder. 277 Progress in Research ACKNOWLEDGEMENTS The authors gratefully acknowledge the cooperation of Dr. Patricia Fernandes of the Division of TMD and Orofacial Pain at the University of Minnesota, and Dr. Pawan Hari of the Department of An- esthesiology at the University of Minnesota in the preparation of this chapter. This study was funded by NIDCR/N01-DE-22635. REFERENCES American Pain Society Quality of Care Committee. Quality improve- ment guidelines for the treatment of acute pain and cancer pain. J Am Med Assoc 1995:274: 1874-1880. Balasubramaniam R, de Leeuw R, Zhu H, Nickerson RB, Okeson JP, Carlson CR. Prevalence of temporomandibular disorders in fibromy- algia and failed back syndrome patients: A blinded prospective com- parison study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 104:204-216. Breslow NE, Day NE, eds. Statistical Methods in Cancer Research. Wol 1. The analysis of case-control studies. Lyon: International Agency of Research on Cancer 1980. Carlson CR, Okeson JP, Falace DA, Nitz AJ, Curran SL, Anderson D. Comparison of psychologic and physiologic functioning between pa- tients with masticatory muscle pain and matched controls. J Orofac Pain 1993;7:15-22. Cole P. Introduction. In: Breslow NE, Day NE, eds. Statistical Methods in Cancer Research. Vol 1. The analysis of case-control studies. Lyon: International Agency for Research on Cancer 1980. Criqui MH, Austin M, Barrett-Connor E. The effect of non-response on risk ratios in a cardiovascular disease study. J Chron Dis 1979:32:633-638. Day NE, Byar DP, Green SB. Overadjustment in case-control studies. Am J Epidemiol 1980:112:696–706. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005;14:135-143. Drangsholt M, LeResche L. Temporomandibular disorder pain In: Crombie IK, Croft PR, Linton SJ, LeResche L, Von Korff M, eds. 278 Velly et al. Epidemiology of Pain: A Report of the Task Force on Epidemiology of the International Association for the Study of Pain. Seattle: IASP Press 1999:203-233. Dworkin SF, Huggins KH, LeResche L, Von Korff M, Howard J, True- love E, Sommers E. Epidemiology of signs and symptoms in tem- poromandibular disorders: Clinical signs in cases and controls. J Am Dent Assoc 1990; 120:273-281. Dworkin SF, LeResche L. Research diagnostic criteria for temporoman- dibular disorders: Review, criteria, examinations and specifications, critique. J Craniomandib Disord 1992;6:301-355. Epker J, Gatchel R.J. Coping profile differences in the biopsychosocial functioning of patients with temporomandibular disorder. Psychosom Med 2000;62:69–75. Epker J, Gatchel RJ, Ellis E III. A model for predicting chronic TMD: Practical application in clinical settings. J Am Dent Assoc 1999;130:1470–1475. Fricton JR. Musculoskeletal measures of orofacial pain. Anesth Prog 1990:37:136-143. Fricton JR. Recent advances in temporomandibular disorders and orofa- cial pain. JAm Dent Assoc 1991;122:24-32. Fricton JR, Hathaway KM, Bromaghim C. Interdisciplinary management of patients with TMJ and craniofacial pain: Characteristics and out- come. J Craniomandib Disord 1987a;1:115-122. Fricton JR, Look JO, Schiffman E, Swift J. Long-term study of tem- poromandibular joint surgery with alloplastic implants compared with nonimplant surgery and nonsurgical rehabilitation for painful temporomandibular joint disc displacement. J Oral Maxillofac Surg 2002;60:1400–1411. Fricton JR, Nelson A, Monsein M. IMPATH; Microcomputer assessment of behavioral and psychosocial factors in craniomandibular disor- ders. Cranio 1987b;5:372-381. Fricton JR, Schiffman EL. Reliability of a craniomandibular index. J Dent Res 1986;65:1359–1364. Fricton JR, Schiffman EL. The craniomandibular index: Validity. J Pros- thet Dent 1987:58:222-228. Gatchel RJ, Stowell AW, Wildenstein L, Riggs R, Ellis E III. Efficacy of an early intervention for patients with acute temporomandibular dis- 279 Progress in Research order-related pain: A one-year outcome study. J Am Dent ASSOC 2006; 137:339–347. Hennekens CH, Buring JE. Epidemiology in Medicine. Boston: Little, Brown & Co 1987. Huang GJ, LeResche L, Critchlow CW, Martin MD, Drangsholt MT. Risk factors for diagnostic subgroups of painful temporomandibular disorders (TMD). J Dent Res 2002;81:284-288. Hulley SB, Cummings SR, Browner WS, Grady D, Newman TB, eds. Designing Clinical Research. 3rd ed. Philadelphia: Lippincott Wil- liams & Wilkins 2007. John MT, Miglioretti DL, LeResche L, Von Korff M, Critchlow CW. Widespread pain as a risk factor for dysfunctional temporomandibu- lar disorder pain. Pain 2003;102:257-263. Keefe FJ, Dolan E. Pain behavior and pain coping strategies in low back pain and myofascial pain dysfunction syndrome patients. Pain 1986:24:49-56. Kleinbaum DG, Kupper LL. Epidemiologic Research: Principles and Quantitative Methods. New York: Vam Nostrand Reinhold 1982. Koepsell TD, Weiss NS. Epidemiologic Methods Studying the Occur- rence of Illness. New York: Oxford University Press 2003. LeResche L, MancllA, Drangsholt MT, Huang G, Von Korff M. Pre- dictors of onset of facial pain and temporomandibular disorders in early adolescence. Pain 2007;129:269-278. Marbach JJ, Lennon MC, Dohrenwend BP. Candidate risk factors for temporomandibular pain and dysfunction syndrome: Psychological, health behaviour, physical illness and injury. Pain 1988:34:139-151. Moana Filho AM, Velly J, Fricton JR. Comorbidities associated with temporomandibular disorders stratified by frequency, duration, in- tensity and number of tender points - NIDCR’s TIRR. E. American Association of Orofacial Pain, 37th Annual Meeting and Exhibition, 2008. Myers S, Kaimal S, Springsteen J, Ferreira J, Ko CC, Fricton J. Devel- opment of a National Implant Registry and Repository – NIDCR's TIRR. Northwest Dent 2007;86:13-18. Ohrbach R, Dworkin SF. Five-year outcomes in TMD: Relationship of changes in pain to changes in physical and psychological variables. Pain 1998;74:315-326. 280 Velly et al. Okeson J, ed. Orofacial Pain: Guidelines for Evaluation, Diagnosis, and Management. 3rd ed. Chicago: Quintessence 1996. Rothman KJ, Greenland SJ. Modern Epidemiology, 2nd ed. Philadelphia: Lippincott-Raven 1998. Sackett DL. Bias in Analytic Research. J Chronic Dis 1979:32:51-63. Slade GD, Diatchenko L, Bhalang K, Sigurdsson A, Finllingim BG, Belfer I, Max MB, Goldman D, Maixner W. Influence of psycho- logical factors on risk of temporomandibular disorders. J Dent Res 2007;86; 1120–1125. Vassend O, Krogstad BS, Dahl BL. Negative affectivity, somatic com- plaints, and symptoms of temporomandibular disorders. J Psychosom Res 1995:39:889-899. Welly AM, Gornitsky M, Philippe P. Contributing factors to chronic myofascial pain: A case-control study. Pain 2003; 104:491–499. Velly AM, Look JO, Kang W, Lenton, PA, Jackson AK, Carlson PL, Fricton JR. Fibromyalgia and widespread pain effect on TMD pain disability onset. J Pain 2008; submitted for publication. Von Korff M, Le Resche L, Dworkin SF. First onset of common pain symptoms: A prospective study of depression as a risk factor. Pain 1993:55:251-258. Wacholder S, McLaughlin JK, Silverman DT, Mandel JS. Selection of controls in case-control studies: I. Principles. Am J Epidemiol 199a2;135:1019–1028. Wacholder S, Silverman DT, McLaughlin JK, Mandel JS. Selection of controls in case-control studies: II. Types of controls. Am J Epide- miol 1992b;135:1029-1041. 281 CURRENT AND FUTURE INNOVATIONS IN DIAGNOSTICS AND THERAPEUTICS OF TMJ DISEASES Sunil D. Kapila ABSTRACT Because the etiologies and pathogenesis of temporomandibular disorders (TMDs) are poorly understood, currently the diagnoses for these disorders are based primarily on signs and symptoms and treatments remain largely palliative. Definitive diagnoses or rational treatments of TMDs can be achieved only through a comprehensive understanding of the etiologies, predisposing factors and pathogenesis of these disorders. Recent advances in biomedicine as well as in imaging and computer technologies and their application to TMDS hold Substantial promise for future developments in specific and sensitive diagnosis and appropriate treatments of these disorders. The goal of this review is to: 1. Summarize current approaches to the diagnosis and management of TMDs; 2. Discuss new and innovative findings on the pathogenesis of degenerative TMJ diseases; and 3. Describe the potential implications of this knowledge in the prevention, specific diagnosis, and rational therapeutic strategies for TMJ disorders. These advances include the identification of local or systemic biomarkers to diagnose disease or monitor improvements during therapy; the use of imaging technologies for earlier and more sensitive diagnostics; and the use of biomedicine, biomimetics, and imaging to design and manufacture bioengineered joints. Such advances are likely to help to customize and enhance the quality of care we provide to patients with TMJ disorders. Temporomandibular disorders (TMDs) refer collectively to a Spectrum of clinical conditions that involve the masticatory musculature, the temporomandibular joint (TMJ) and associated structures, with or Without an underlying psychological disorder (Fig. 1). These disorders often are accompanied by facial pain that involve the masticatory muscles and/or the TMJ, headaches, limitation or deviation in 283 Current and Future Innovations Psychological Pain Muscles Central & peripheral Hyper & parafunction components Fiber phenotypes TMJ Disc displacement, arthralgia Inflammatory and non-inflammatory joint degeneration Figure 1. The complex nature of TMDs that can involve one or more of the following: muscles of mastication; the TMJ and related structures; altered peripheral and central pain mechanisms; and an overarching psychological background. the mandibular range of motion, and TMJ sounds (Rieder et al., 1983; Dworkin et al., 1990; LeResche, 1997). Symptoms of TMD occur in approximately 6-12% of the adult population or approximately ten million individuals in the United States (Von Korff et al., 1988; Lipton et al., 1993). Of the patients with TMD, approximately 80% present with signs and symptoms of joint disease including disc displacement, arthralgia, osteoarthrosis, and osteoarthritis (Plesh et al., 2005; Manfredini et al., 2006), indicating that an understanding of the underlying pathobiology of diseases of the TMJ itself would be beneficial to a large proportion of patients with TMDs. These degenerative TMJ diseases are characterized by an imbalance in the synthesis and degradation of matrices, which are mediated by 284 Kapila chondrocytes and fibrochondrocytes in the cartilage and fibrocartilages of the TMJ, resulting in a progressive loss of extracellular matrix components of the disc and articular cartilage and/or subchondral bone. Due to a poor understanding of the etiology or pathogenesis of these diseases and the lack of definitive diagnostic or therapeutic approaches, patients often have to tolerate symptoms, including debilitating pain, that substantially impact their quality of life over extended periods of time. While little is known about the etiology or factors that predispose to TMDs, recent findings employing both biomedicine and new imaging and computer technologies specifically for the TMJ component of these disorders are beginning to provide important insights that may help in deriving rationale diagnostic and therapeutic strategies. The focus of this review is to: 1. Summarize current concepts in the management of TMDs; 2. Discuss new and innovative findings from studies utilizing advances in biomedicine and technology to discover novel aspects of the pathogenesis of degenerative TMJ diseases; and 3. Describe potential implications of this knowledge in the prevention, specific diagnosis, and rational therapeutic strategies for TMJ disorders. CURRENT APPROACHES TO DIAGNOSIS AND MANAGEMENT OF TMDS The currently accepted approaches to derive a diagnosis involve documentation of the history, clinical examination and supplementation of this information through radiographic imaging of the TMJ. These approaches, while often useful in defining appropriate palliative care, Categorize TMDS into diagnoses that are based primarily on signs and Symptoms rather than a rational understanding of etiology or pathogenesis of the diseases. Thus, for example, while radiographic imaging of the TMJ is helpful in defining gross anatomic changes in morphology and spatial relationships of joint tissues and can help in refining the diagnosis, most of the changes that are detected are relatively late in the disease process and do not help to decipher any pathogenic mechanisms. Fortunately, the imaging technologies have evolved from routine tomography and arthroScopy to magnetic resonance imaging (MRI) and computed tomography (CT), as discussed later in this chapter 285 Current and Future Innovations as well as in other chapters in this volume (Cevidanes et al., 2009, Hajati, 2009; Hatcher, 2009). Some of these technologies hold promise for being more sensitive and specific than radiographs in the detection of earlier changes in the joint. As a consequence of the poorly understood etiologies and pathogenesis of TMDS, current therapies primarily are aimed at addressing the symptoms and are largely palliative. Despite the limitations imposed by our current lack of comprehensive knowledge of TMDs, however, it is imperative that the clinician provides a diagnostic- specific management of musculoskeletal disorders affecting the jaw, as discussed in detail by McNeill and Rudd (2009). The appropriate and conservative management of the at-risk TMD patient includes: Patient education; Symptomatic care; Medications; Behavior modification; Relaxation strategies; and A comprehensive physical medicine approach. The goal of the multidisciplinary management program is to reduce pain, promote tissue repair and improve function with minimal risk for the patient. It also has been proposed that basic screening strategies for psychological distress be utilized by the practitioner to recognize any underlying psychosocial factors for management or referral (Carlson, 2009). The clinician also needs to understand and manage the challenges of the classic clinical triad of fatigue, pain and sleep dysfunction. Physical therapy both patient-performed and that provided by a trained person is considered to be an important adjunct for the management of pain and to improve function. Finally, patients in whom conservative therapy has failed and who have intractable TMJ diseases may require joint surgery as discussed in this volume by Conley (2009) and Wolford and coworkers (2009). CONTEMPORARY FINDINGS ON TMD Several key recent discoveries, including many presented in this monograph, offer contemporary and often novel findings that eventually may help us better understand TMJ-related diseases and ultimately lead to specific and sensitive diagnosis and rational therapies. Advances in pain research, for example, are demonstrating a genetic component to pain as well as the influence of sex hormones such as estrogen in 286 Kapila modulating pain (summarized by Castrillon et al., 2009 and Stohler, 2009). Additional evidence on the role of sex hormones in TMD pain are provided by epidemiologic studies that show an association of TMD with hormone replacement therapy, as well as by changes in clinical TMD pain across the menstrual cycle and during pregnancy (summarized by LeResche, 2009). Specifically, estrogen appears to modulate pain, with high pain occurring at times of lowest estrogen, whereas lower pain is reported when levels of estrogen are high. Taken together, these findings suggest that both genetic background and hormonal influences may act at the level of the central nervous system to impact on pain and its perception. In addition to human and animal studies on pain mechanisms, Substantial new findings on TMJ diseases are being generated due to advances in imaging technologies. Both standard radiographic imaging used in concert with assays on biologic mediators of joint degeneration as well as contemporary 3D imaging technologies may not only offer important insights into pathogenesis of degenerative TMJ changes, but also point to sensitive and specific markers for joint disease (Cevidanes et al., 2009; Hajati, 2009; Hatcher, 2009). Additional advances in imaging techniques and the ability to quantitate morphologic and compositional changes without (Cevidanes et al., 2009) or with the use of contrast agents (van Dijke et al., 1997; Owman et al., 2008) offer new possibilities in early detection of joint diseases. Finally, the use of such refined imaging methodologies also is leading to the development of better and more accurate computer models for the study of TMJ function in health and disease as discussed by Iwasaki and coworkers (2009) and Nickel and colleagues (2009). These studies offer insights into how the TMJ functions, magnitudes of joint loading and how the tissues may be adapted to optimally sustain these functions. These and similar studies are likely to provide important information on the loading thresholds for joint tissues, define what loads Would help sustain joint tissues and the loading regimens and patterns that could lead to degeneration, and also demonstrate if there are gender differences in tissue properties and joint function. Within the field of biomedical research, interesting new findings from animal models are identifying the genes that regulate development and differentiation of the TMJ and those whose levels are altered in disease states (summarized by Teixiera and coworkers, 2009 and 287 Current and Future Innovations Wadhwa and colleagues, 2009). Finally, as discussed in this chapter and in that of Wadhwa and coworkers (2009), systemic factors such as hormones (Kapila and Xie, 1998; Naqvi et al., 2005; Hashem et al., 2006) as well as genetic factors that may predispose to joint diseases and their mechanisms of action also are being investigated (Rintala et al., 1997; Xu et al., 2003; Wadhwa et al., 2005; Lam et al., 2007). The potential applications of these studies include the identification of biomarkers of disease, monitoring the changes in levels of specific genes during treatments to determine the efficacy of therapy and developing rational treatment approaches and strategies for the disorders. FUTURE DEVELOPMENTS IN DIAGNOSIS AND TREATMENTS OF TMJ DISEASES The recent progress in understanding the biomedical basis for TMJ disorders as well as in computer and imaging technologies are beginning to provide novel insights into the pathogenesis of degenerative TMJ diseases and point toward the possible use of this knowledge in devising rational diagnostic and therapeutic strategies. These advances, which will benefit our understanding and therefore enhance the treatments of TMDs, fall into three broad categories: 1. Biomedicine. This includes an understanding of the genetic and biologic basis for disease and disease mechanisms that will be critical to: a. The discovery of biomarkers for use in diagnosis, and for monitoring disease progression and responses to therapy; and b. Developing rational preventive strategies and therapies. 2. Technology. Innovations in imaging hardware and software as well as computer capabilities have contributed significantly to the increasing use of 3D imaging of craniofacial structures including the TMJ. The information derived from such images has become increasingly important for diagnosis, and in addition to continued improvements in the diagnostic capabilities offered by this technology, likely will have uses in monitoring disease progression or responses to therapy. 288 Kapila 3. Technology Plus Biomedicine. The combination of biomedicine with technology offers a rich interface for future developments and advances in health care. These range from the development of approaches for high throughput gene mapping to the bioengineering of tissues including joints. Biomedical Research in TMJ Diseases and Potential Clinical Implications Although the etiology or pathogenesis of TMJ diseases are not known, epidemiologic findings may provide clues on potential contributory factors, whose contributions to the disease processes can be further explored through biomedical research as we have done over the past several years (Kapila and Xie, 1998; Kapila, 2003; Naqvi et al., 2005; Hashem et al., 2006; Kapila et al., 2008; Wang et al., 2008). The epidemiologic predilection of TMDs in women is striking. In the general population, TMDs are two times more prevalent in women than in men, whereas in patient populations these diseases have a female-to-male preponderance as high as 10:1 (Solberg, 1982; Von Korff et al., 1988; Dworkin et al., 1990). Furthermore, unlike similar diseases of other joints, which also have a greater female predilection but occur postmenopausally (Felson and Nevitt, 1998), a large proportion of Women with TMDs are between 18-45 years of age (Carlsson and LeResche, 1995; Warren and Fried, 2001). The reasons for this marked Sexual dimorphism and age distribution remain unclear. Because of this gender and age distribution of TMJ disorders, it has been postulated that sex-based determinants (e.g., hormonal influences from estrogen, progesterone, and relaxin) may make an individual susceptible to degenerative TMJ diseases. Several lines of evidence support this hypothesis. Both estrogen and progesterone receptors have been localized in the TMJ of human and non-human primates (Aufdemorte et al., 1986; Milam et al., 1987; Abubaker et al., 1993), in male rats (Yamada et al., 2003), and in mice of both genders (Wang et al., 2008), with some findings suggesting a sexual dimorphism in the presence of estrogen receptors (Milam et al., 1987; Wang et al., 2008). Other evidence that estrogen is involved in TMD includes an association between facial pain and estrogen replacement therapy or the use of oral contraceptives (LeResche et al., 1997; Meisler, 1999), and elevated systemic levels of estrogen in women with TMJ disease vs. those in normal controls (Landi et al., 2005). In addition, polymorphisms 289 Current and Future Innovations in the estrogen receptor have been shown to be correlated to the intensity of pain (Kang et al., 2007), as well as facial axis angle and mandibular body length (Lee et al., 2006) in patients who suffer from TMJ osteoarthritis. Despite these studies, however, no direct evidence existed linking female reproductive hormones to TMJ degenerative diseases or defining the mechanisms by which these hormones may cause TMJ disease until recently. Degenerative diseases of the TMJ occur from the loss in equilibrium of anabolic and catabolic processes involving chondrocyte initiation, proliferation, differentiation, and matrix synthesis and degradation. In large part, these degenerative changes are characterized by increased degradation of the components of the extracellular matrix by the matrix metalloproteinase (MMP) family of enzymes in both rheumatoid arthritis and osteoarthritis (reviewed in Kapila, 1997; Milner et al., 2006). Between them, MMPs can degrade the major matrix macromolecules of cartilage, namely collagen and proteoglycans as well as most of the minor proteins in this tissue. During inflammatory arthritis, this upregulation of MMPs results due to cellular responses to proinflammatory cytokines, and has been strongly implicated in matrix degradation in these diseases (Kumkumian et al., 1989; Unemori et al., 1991). The direct modulation of MMPs by reproductive hormones such as relaxin and estrogen that may initiate or predispose to a subset of non- inflammatory joint diseases has only recently come under scrutiny (Kapila and Xie, 1998; Kapila, 2003; Naqvi et al., 2005; Hashem et al., 2006; Kapila et al., 2008; Wang et al., 2008). Recent findings by our group demonstrate that estrogen and relaxin may contribute to TMJ degeneration by enhancing the expression of MMPs from TMJ fibrocartilage (Fig. 2). More specifically, we have shown that relaxin increases the expression of the MMP-1 (collagenase- 1), MMP-3 (stromelysin-1), MMP-9 (92-kDa gelatinase) and MMP-13 (collagenase-3) in cell isolates and tissue explants from the rabbit and mice TMJ disc fibrocartilage (Kapila and Xie, 1998; Kapila et al., 2008). Progesterone attenuated the induction of MMPs and matrix loss by relaxin and estrogen. We have also shown that the modulation of MMPS by relaxin and estrogen are paralleled by changes in the predominant matrix molecules collagens and proteoglycans in TMJ disc fibrocartilage in vitro and in vivo (Naqvi et al., 2005; Hashem et al., 2006), suggesting a potential relationship between hormone-modulated MMPs and extracellular matrix homeostasis or degradation. 290 Kapila Hormones or other agents Degradation of matrix Increased MMPs molecules º TMJ Fibrocartilage º • Loss ºf matrix molecules = Collagen * º to sustain function * Degenerative joint disease º Proteoglycans Figure 2. A model for the contribution of systemic or local agents possibly including hormones in causing or predisposing to TMJ degeneration by increasing the expression of matrix degrading enzymes of the matrix metalloproteinase (MMP) family in tissues of the TMJ. In this model, the hormonal or other stimulation of the cells within the TMJ tissues, in this Case represented by the disc fibrocartilage, leads to increased expression of MMPs that in turn degrade most of the matrix molecules including collagen and proteoglycans within the tissue. The tissue is compromised and unable to Sustain normal functions, leading to progressive degeneration of the joint. The modulation of matrix composition in TMJ fibrocartilage by these hormones was similar to that observed in the pubic symphysis, and differed from that of the knee meniscus fibrocartilage, which did not show any changes in its matrix composition. We also found that the two target tissues showing the greatest modulation of MMPs and matrix loss, namely the TMJ disc and pubic symphysis, had similar expression profiles of the estrogen receptors (ER)-O and (ER)-É, relaxin-1 receptor (RXFP1 or LGR7), and INSL3 receptor (RXFP2 or LGR8) that differed Substantially from those in cells from the non-responsive knee meniscus (Wang et al., 2008: Fig. 3). Because matrix degradation by MMPs is considered to be a primary event in the initiation and progression of joint disease, this hormone mediated loss in matrices likely affects the ability of the joint to sustain normal function and can lead to progressive degenerative changes in the joint. These findings, together with the elevated levels of estrogen in women with TMJ disease (Landi et al., *005), suggest a potential role of specific sex hormones in causing or Predisposing to TMJ degeneration. Together, these observations suggest *"ºvel model for targeted tissue turnover of cartilages of specific joints 291 Current and Future Innovations TMJ Disc Knee Meniscus Pubic Symphysis -ve Control § ER-a - § - - pz - — 3. - #|ER-3 - º - - 5|LGR7 - - E. § - - º º - .E - 3. LGR8 - Figure 3. The expression profiles of estrogen and relaxin receptors in TMJ. knee meniscus and pubic symphysis fibrocartilaginous cells correlate with the matrix degradative responses of these tissues to the respective hormones. Both the TMJ disc and pubic symphysis cells show high levels of the estrogen receptors, ER-0 and ER-6, and relaxin receptor LGR7. which correlates with enhanced expression of MMPs in response to estrogen and relaxin. In contrast, the knee meniscus cells, which express low levels of ER-0 and ER-6, and LGR7 but high levels of LGR8 do not show such increased expression of MMPs on stimulation by the respective hormones (reproduced with permission from Wang et al., 2008). through hormone-mediated induction of select MMPs, and point to potential diagnostic makers or therapeutic targets as discussed in the next Section. Biomedical Approaches to Diagnose, Alleviate, or Prevent Joint Degeneration If the disease mechanisms demonstrated by studies such as thos: described above are found to be valid, they could offer clues to potential diagnostic markers or therapeutic targets. For example, specific and localized blocking of estrogen or relaxin receptor activation by the respective hormones could help diminish the induction of MMPS and therefore minimize hormone-mediated joint degeneration. Similarly, the specific and localized inhibition of MMP induction or activity could help in minimizing joint degeneration mediated by hormones of other 292 Kapila stimulants such as pro-inflammatory cytokines. Indeed, the repression of MMP activity has been used in the treatment of inflammatory or degenerative joint diseases in animal models with some level of success (Ishikawa et al., 2005; Oliver et al., 2007; Pelletier et al., 2005; Aikawa et al., 2008). Much biomedical research still remains to be conducted, however, in order to discover reliable and highly efficacious approaches to preventing or treating such joint disorders. Biomarkers of diseases are a highly sought-after approach for the early diagnosis of various conditions and for evaluating the efficacy of treatment modalities. Various sources of samples are used for the assaying of disease biomarkers. In the case of joint disorders, these Samples include synovial lavages or aspirates, tissue samples, serum or plasma, or urine. The most common sample used in studies performed to date is Synovial lavages to determine the changes in various local biological mediators of disease that may be used subsequently in predicting the Status of the disease. Findings from such studies have demonstrated increased levels of inflammatory mediators (Shafer et al., 1994; Kubota et al., 1997; Tominaga et al., 2004), MMPs (Kubota et al., 1997; Srinivas et al., 2001; Tanaka et al., 2001; Miyamoto et al., 2002; Yoshida et al., 2006) and aggrecanase (Yoshida et al., 2005; Yoshida et al., 2006) in patients with TMJ disorders vs. controls. While the synovial lavage or aspirate samples typically are obtainable from subjects under going arthrocentesis, their availability for routine diagnostics is question- able because of the invasive nature of the procedure. Also, the inherent limitations in the methodology including unknown dilution effects make it difficult to compare data between subjects and over time (Aghabeigi et al., 2002) and impact on the utility of this approach for diagnostic purposes. Synovial tissues from patients with TMJ disorders also are a Source for evaluating potential biomarkers. Investigators using these Samples have shown that there is increased expression of Il-8 (Sato et al., 2007) and microvessel density (Sato et al., 2003) in TMD patients. Similar to synovial fluid, however, the invasiveness of the procedure to obtain Samples makes the evaluation of synovial tissues less than ideal. A less invasive sampling involves assays on urine or serum. Assays on urine samples have shown elevated levels of pyridinoline (Pyr) and deoxypyridinoline (Dpyr) collagen cross-links, which are known markers of bone and cartilage turnover, in patients with osteoarthritis of the TMJ 293 Current and Future Innovations (Tanimoto et al., 2004). Additionally, elevated amino acid secretion products were found in the urine of patients with chronic muscle pain TMD (McGregor et al., 2003). Similarly, preliminary studies using serum have suggested increased estrogen levels (Landi et al., 2005) in TMD patients, and increased levels of interleukin-1/3 and C-reactive protein in arthritic TMJ diseases (Nordahl et al., 2001). No studies have been performed to assay for potential biomarkers of TMJ disorders using saliva, which would be a highly desirable source for assaying biomarkers for disease or therapeutic outcomes. Also, while the studies cited above provide insights into potential biomarkers of TMJ diseases, much work remains to be done to demonstrate the specificity and sensitivity of any given marker of the disease status. While a “gold standard” biomarker for TMJ disorders remains elusive, powerful new technologies such as microarrays on tissue, synovial fluid, or serum samples may enable the identification of specific and sensitive biomarkers of TMJ disease in the future. Microarrays permit the analysis of the expression of thousands of genes even with extremely small quantities of sample. Therefore, the use of microarrays on blood samples from patients with TMD disorders may be able to identify novel genes or combination of genes that are predictive of TMD. In a recent study (Marshall et al., 2005), microarray analysis of 3,543 genes in blood samples in patients with mild knee osteoarthritis and non-symptomatic controls revealed nine genes considered to be predictive of knee osteoarthritis. These nine genes then were used to evaluate blindly a new sample of 67 subjects and demonstrated 72% sensitivity and 66% specificity as a test for osteoarthritis. In the next few years, it is likely that tests based on findings from such studies will become commercially available as viable tools to aid the clinician in the early and specific diagnosis of various joint disorders, including those involving the TMJ. Studies such as these also are likely to help identify key pathways and bioactive molecules that contribute to the perpetuation of the disease that can be targeted for rational therapeutics. Computer and Imaging Technologies in TMJ Disease Diagnosis and Therapies Several methods are available for imaging the TMJ, including basic radiography (such as panorexes and corrected tomograms), ultrasonography, MRI, and spiral or cone-beam CTs (CBCTs). The latter technologies allow the joint to be visualized both as sections in different 294 Kapila planes and also can be rendered as 3D volumetric reconstructions to enhance diagnostic capabilities. MRI and ultrasonography have the added advantage over CT scans in that they enable soft tissues such as the disc, ligaments, and muscles to be visualized and may be more useful than CTs when the patient presents with internal derangement or joint dysfunction (Takaku et al., 1998; Greess and Anders, 2005). With currently available software, which is relatively user friendly, the raw DICOM files obtained from MRI or CT scans can be compiled, manipulated, and visualized by the clinician in the office. The introduction of the CBCT systems specifically designed for use in dentistry has opened up new opportunities for deriving additional diagnostic information (Fig. 4). Although CT scans and MRI have been available for many years now, several barriers have precluded their widespread use in evaluating TMJ disorders. These include their high cost, radiation exposure (in the case of CT scans), and, to a lesser extent, difficulty in accessing units, most of which are located in hospitals and medical imaging laboratories. The introduction of CBCT units that are now available in dental schools, dental X-ray laboratories, and even in private practices has diminished some of these barriers to the use of advanced imaging technology when indicated in specific cases. One key issue in CBCT imaging involves its reliability and diagnostic capabilities relative to the spiral CT and conventional tomography. This issue has been assessed by several investigators (Honda et al., 2006; Hintze et al., 2007; Meng et al., 2007). In studies comparing spiral CT and CBCT, no significant differences were observed between the two techniques in findings of osseous abnormalities (Honda et al., 2006). The specificity of condyle assessment was 1.0 with both CBCT and spiral CT, and the sensitivity was 0.8 and 0.7 for these two imaging modalities, respectively. The investigators concluded that 3D images rendered by CBCT are a dose-effective and cost-effective alternative to spiral CT for the diagnostic evaluation of Osseous mandibular condyle abnormalities. Additional studies on the accuracy of linear measurements in CBCT-derived, multiplanar-reformatted projections for the TMJ compared to anatomical measures of skulls and in cephalograms showed high accuracy of these measurements on the CBCT, but not on the lateral or PA cephalograms (Hilgers et al., 2005). Additionally, the intra- observer measurements on the CBCT reconstructions were highly reliable relative to the anatomic truth, and significantly more so than those from the cephalograms. These findings together provide support 295 Current and Future Innovations Figure 4. CBCT images can be manipulated to derive sections of desired thicknesses in any plane of interest. In this example, sagittal (panel A), axial (panel B) and coronal (panel C) views of the TMJ, and 3D volumetric images that can be viewed from any perspective with superimposing tissues dissected out to clearly visualize the region of interest (panel D). The lines and arrows in panel B represent the planes and direction in which the sagittal and coronal images shown in panels A and C, respectively, were derived. (Images provided by Dr. David Hatcher). for the utility of CBCT imaging both for diagnostic and research purposes in TMJ disorders. The possible use of CBCT imaging technology has been tested for various applications in TMJ disorders. This includes its use in imagº guided access to the superior joint space for arthroscopic examinatiº" and treatment of individuals with disc perforations or adhesions (Honda and Bjørnland, 2006). The use of CBCT with arthroscopy may imprº the safety of arthroscopic procedures by decreasing the probability of inadvertent puncturing of the glenoid fossa into the middle cranial foSSã. 296 Kapila Future modifications to 3D-imaging methodologies are likely to involve techniques that enhance the sensitivity and specificity of these techniques. In one such approach, we determined whether the histopathologic severity of TMJ inflammation in an animal model of arthritis correlated with quantitative changes over time in the MRI signal from a macromolecular contrast agent, GdDTPA30 (Van Dijke et al., 1997). The arthritic TMJs showed marked enhancement of the synovial and subsynovial tissues, which had strong positive relationships with all histologic parameters of arthritis, indicating its utility for assessing the severity of joint inflammation. This or similar techniques may be useful for increased sensitivity and specificity of diagnosis, and as an aid in the noninvasive monitoring of disease severity and treatment response in arthritis. Finally, as discussed later, 3D images derived from these technologies are likely to become an important and integral part of bioengineering custom TMJs for subjects in irreversible stages of joint disease. The Integration of Technology and Biomedicine for Engineering the TMJ For many people suffering from severe and painful degenerative diseases of the TMJ, surgical replacement of the mandibular condyle or even a large part of the entire joint remains the only option. Until recently, the primary methods employed to reconstruct the TMJ included autogenous tissue grafting (e.g., from the rib) or the use of alloplastic materials, with neither being ideally suited for the task and sometimes leading to extreme deleterious effects (Wolford, 1997; Ta et al., 2002). Fortunately, due to recent advances in the understanding of stem-cell biology and biomaterials, in the near future it may be possible to reconstruct successfully a bioengineered TMJ replacement that is compatible with a host, biologically viable, and capable of withstanding the physiologic loads required of this joint. Tissue engineering involves developing in vitro and/or in vivo a biological replacement that mimics the biological, morphological, and organizational characteristics of the tissue it is replacing. The most common method for deriving engineered tissues involves the implantation of cells, typically derived from the host, into a biomimetic Scaffold and then stimulating it in a bioreactor or in vivo with appropriate signals to derive a replacement tissue or organ (Fig. 5; Kapila and King, 2005; King and Kapila, 2005). Cells from various sources, including articular cartilage cells, fibroblasts, human umbilical cord matrix stem 297 Current and Future Innovations cells, and mesenchymal stem cells, have been used in efforts to reconstruct the TMJ (Schek et al., 2005; Bailey et al., 2007). Of these cells, stem cells have gained increasing prominence in the tissue engineering of joints and have been used by various investigators for developing prototype TMJ condyles. Unlike primary cells such as chondrocytes that have limited capacity to propagate, stem cells have the additional advantage of being stimulated by specific biological cues into differentiating into osteoblasts, chondrocytes, fibroblasts and myocytes. These cell types in turn generate cartilage, bone, ligaments and muscles, respectively, to derive all key components of the TMJ complex. Thus, in recent studies (Alhadlaq and Mao, 2003; Mao et al., 2006), rat bone marrow mesenchymal stem cells were grown separately in chondrogenic differentiation media or in osteoblastic differentiation media. Subsequent transfer of the two cell populations into a scaffold with two stratified and integrated layers, and then implantation into the backs of immunodeficient mice for 12 weeks, resulted in a structure containing both cartilage and bone tissue in a construct of the shape and dimensions of human mandibular condyle. Regardless of the source, cells require appropriate stimuli and materials or scaffold into which to be seeded in order to differentiate and express bone and cartilage matrices into suitable structural organization and anatomy of the TMJ. For this purpose, 3D imaging technologies can be used to design the scaffold of the same shape and size required at the defect site (Fig. 5). Indeed, this use of image-based design coupled with solid free-form fabrication has been used to generate biomimetic scaffolds that are both load bearing and match the defect site geometry (Schek et al., 2005; Smith et al., 2007). Further improvements in this approach have been used to generate Poly-l-lactic acid/hydroxyapatite composite biphasic composite scaffolds that, when seeded with chondrocytes as well as appropriately stimulated fibroblasts, respectively, resulted in the expression of cartilage and bone in discrete regions with a stable interface between cartilage and subchondral bone. Such approaches to TMJ tissue engineering provide site-specific anatomical configuration as well as autologous tissues that have the potential ability to adapt to the loading forces placed on it during function, and hold great promise for patients needing joint replacements. Another area in , which the integration of technology with biomedicine may provide substantial insights that may be useful in the prevention of TMJ disorders is genome sequencing. Recently, significant resources have been directed toward high-throughput genome sequenc- 298 Kapila Gº = MSCs • Cºs = other cells Retrieve cells from recipient's bone marrow or other source of stem cells Seed cells into anatomic scaffold constructed from 3D image of recipient's TMJ Expand MSCs Figure 5. Bioengineering the TMJ. In experimental models, a mixed cell population containing mesenchymal stem cells (MSCs) is retrieved from the tissue recipient’s bone marrow or other source rich in MSCs. The cells are expanded in culture, and the MSCs isolated from this mixed cell population are further expanded to attain the desired number of cells. The MSCs then can either be stimulated separately toward osteoblastic and chondrogenic lineage before being embedded into an anatomic scaffold or alternatively embedded in their native phenotype into the scaffold and stimulated in situ to become chondrocytes in the cartilaginous zone and osteoblasts in the sites where bone is desired. The anatomic scaffold can be constructed from appropriate materials using 3D images of the patient’s joint. The cell- Scaffold construct is then matured in vivo or in vitro in a bioreactor before being transplanted into the recipient. ing, and it seems highly likely that in the next 10–20 years, health Professionals will have their patient’s genomes available for analysis. This diagnostic tool, coupled with advances in understanding the $ºnes that contribute or predispose to TMJ disorders, may make it Possible to identify patients who are at risk for developing TMJ disorders *nd enable the implementation of strategies to prevent the disease. CONCLUSIONS - As with other areas of medicine and dentistry, advances in biomedicine and computer-based technologies offer great promise for helping patients predisposed to or suffering from TMJ diseases. These 299 Current and Future Innovations technologies will enhance diagnostic capabilities and rational therapeutics or preventive strategies. Genetic analysis, biomarkers, imaging, and tissue engineering will likely expand the repertoire and improve the specificity of diagnostic and therapeutic approaches for diseases of the TMJ. ACKNOWLEDGEMENTS This work was supported by grants ROl DE DE018455 and KO2 DE00458. REFERENCES Abubaker AO, Raslan WF, Sotereanos GC. Estrogen and progesterone receptors in temporomandibular joint discs of symptomatic and asymptomatic persons: A preliminary study. J Oral Maxillofac Surg 1993;51:1096-1 100. Aghabeigi B, Cintra N, Meghji S, Evans A, Crean SJ. Temporomandibular joint synovial fluid sampling: Estimation of dilution factor using calcium ion concentration. Int J Oral Maxillofac Surg 2002:31:646-649. Aikawa Y, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, Hirono S, Shiozawa S. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol 2008:26:817- 823. Alhadlaq A, Mao J.J. Tissue-engineered neogenesis of human-shaped mandibular condyle from rat mesenchymal stem cells. J Dent Res 2003;82:951–956. Angelo M, Thant LM, Palmer G, Attur M, Abramson S, Teixeira CC. F- Spondin: A new regulator of cartilage maturation in development and osteoarthritis. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Aufdemorte TB, Van Sickels JE, Dolwick MF, Sheridan PJ, Holt GR, Aragon SB, Gates GA. Estrogen receptors in the temporomandibular joint of the baboon (Papio cynocephalus): An autoradiographic study. Oral Surg Oral Med Oral Pathol 1986;61:307-314. 300 Kapila Bailey MM, Wang L, Bode CJ, Mitchell KE, Detamore MS. A comparison of human umbilical cord matrix stem cells and temporomandibular joint condylar chondrocytes for tissue engineering temporomandibular joint condylar cartilage. Tissue Eng 2007:13:2003-2010. Carlson C. Psychological factors in TMD and orofacial pain. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Carlsson GE, LeResche L. Epidemiology of temporomandibular disorders. In: Sessle BJ, Bryant PS, Dionne RA, eds. Temporomandibular Disorders and Related Pain Conditions. Progress in Pain Research and Management. Seattle: IASP Press 1995:211-226. Castrillon EE, Cairns BE, Ernberg M, Wang K, Sessle B, Arendt-Nielsen L., Svensson P. Peripheral NMDA receptors and TMD pain mechanisms. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Cevidanes LH, Walker DG, Styner M, Lim PF. Condylar resorption in patients with TMD. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Chen J, Trettel L., Kalajzic Z, Gupta T, Wadhwa S. Altered temporomandibular joint loading. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. 301 Current and Future Innovations Conley RS. The modified condylotomy for TMJD patients: A good solution or just another surgery? In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Dworkin SF, LeResche L, DeRouen T, Von Korff M. Assessing clinical signs of temporomandibular disorders: Reliability of clinical examiners. J Prosthet Dent 1990:63:574-579. Felson DT, Nevitt MC. The effects of estrogen on osteoarthritis. Curr Opin Rheumatol 1998; 10:269-272. Greess H, Anders K. Indications for validity of computed tomography and magnetic resonance imaging of the temporomandibular joint [in German]. Rontgenpraxis 2005:56:1-11. Hajati A. Early signs of bone tissue resorption in the TMJ of patients with recent diagnosis of rheumatoid arthritis. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Hashem G, Zhang Q, Hayami T, Chen J, Wang W, Kapila S. Relaxin and beta-estradiol modulate targeted matrix degradation in specific synovial joint fibrocartilages: Progesterone prevents matrix loss. Arthritis Res Ther 2006:8:R98-108. Hatcher D. CBCT (3D Imaging): Application for selected articular disorders and associated facial growth. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pedi- atric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Hilgers ML, Scarfe WC, Scheetz JP, Farman AG. Accuracy of linear temporomandibular joint measurements with cone beam computed tomography and digital cephalometric radiography. Am J Orthod Dentofacial Orthop 2005;128:803-811. 302 Kapila Hintze H, Wiese M, Wenzel A. Cone beam CT and conventional tomography for the detection of morphological temporomandibular joint changes. Dentomaxillofac Radiol 2007:36:192-197. Honda K, Bjørnland T. Image-guided puncture technique for the superior temporomandibular joint space: Value of cone beam computed tomography (CBCT). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102:281–286. Honda K, Larheim TA, Maruhashi K, Matsumoto K, Iwai K. Osseous abnormalities of the mandibular condyle: Diagnostic reliability of cone beam computed tomography compared with helical computed tomography based on an autopsy material. Dentomaxillofac Radiol 2006:35:152-157. Ishikawa T, Nishigaki F, Miyata S, Hirayama Y, Minoura K, Imanishi J, Neya M, Mizutani T, Imamura Y, Ohkubo Y, Mutoh S. Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840. Eur J Pharmacol 2005:508:239-247. Iwasaki LR, Uchida S, Marx DB, Yotsui Y, Maeda T, Inoue H, Nickel JC. Ipsilateral and contralateral human TMJ loads compared via validated numerical models. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Kang SC, Lee DG, Choi JH, Kim ST, Kim YK, Ahn H.J. Association between estrogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients. Int J Oral Maxillofac Surg 2007:36:391-394. Kapila S. Biology of TMJ degeneration: The role of matrix-degrading enzymes. In: McNeill C, ed. Science and Practice of Occlusion. Chicago: Quintessence Publishing Co., 1997:235-258. Kapila S. Does the relaxin, estrogen and matrix metalloproteinase axis contribute to degradation of TMJ fibrocartilage? J Musculoskelet Neuronal Interact 2003:3:401–405. 303 Current and Future Innovations Kapila S, King G, eds. Conference on Orthodontic Advances in Science and Technology (COAST) Foundation’s Second Biennial Symposium: Craniofacial Skeletal Bioengineering. Orthod Craniofac Res 2005;8(4). Kapila S, Wang W, Uston K. MMP induction by relaxin causes cartilage matrix degradation in target synovial joints: Receptor profiles correlate with matrix turnover. Annals New York Acad Sci: in press, 2008. Kapila S, Xie Y. Targeted induction of collagenase and stromelysin by relaxin in unprimed and beta-estradiol-primed diarthrodial joint fibrocartilaginous cells but not in synoviocytes. Lab Invest 1998;78:925-938. King G, Kapila S, eds. Conferences on Orthodontic Advances in Science and Technology (COAST) Foundation's Second Biennial Symposium: Craniofacial Skeletal Bioengineering. Orthod Craniofac Res 2005;8(3). Kubota E, Imamura H, Kubota T, Shibata T, Murakami K. Interleukin | beta and stromelysin (MMP3) activity of synovial fluid as possible markers of osteoarthritis in the temporomandibular joint. J Oral Maxillofac Surg 1997:55:20-27. Kumkumian GK, Lafyatis R, Remmers EF, Case JP, Kim SJ, Wilder RL, Platelet-derived growth factor and IL-1 interactions in rheumatoid arthritis: Regulation of synoviocyte proliferation, prostaglandin production and collagenase transcription. J Immunol 1989; 143:833- 837. Lam NP, Li Y., Waldman AB, Brussiau J, Lee PL, Olsen BR, Xu L. Age. dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice. Arch Oral Biol 2007:52:579-584. Landi N, Lombardi I, Manfredini D, Casarosa E, Biondi K, Gabbanini M, Bosco M. Sexual hormone serum levels and temporomandibular disorders: A preliminary study. Gynecol Endocrinol 2005:20:99-103. Lee DG, Kim TW, Kang SC, Kim ST. Estrogen receptor gene polymorphism and craniofacial morphology in female TMJ osteoarthritis patients. Int J Oral Maxillofac Surg 2006:35:165-169. 304 Kapila LeResche L. Epidemiology of temporomandibular disorders: Implications for the investigation of etiologic factors. Crit Rev Oral Biol Med 1997:8:29.1-305. LeResche L. Gender and hormonal effects on clinical TMJD pain. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. LeResche L, Saunders K, Von Korff MR, Barlow W, Dworkin SF. Use of exogenous hormones and risk of temporomandibular disorder pain. Pain 1997;69:153-160. Lipton JA, Ship JA, Larach-Robinson D. Estimated prevalence and distribution of reported orofacial pain in the United States. J Am Dent Assoc 1993;124; 115-121. Manfredini D, Chiappe G, Bosco M. Research diagnostic criteria for temporomandibular disorders (RDC/TMD) axis I diagnoses in an Italian patient population. J Oral Rehabil 2006:33:551-558. Mao JJ, Giannobile WV, Helms JA, Hollister SJ, Krebsbach PH, Longaker MT, Shi S. Craniofacial tissue engineering by stem cells. J Dent Res 2006:85:966-979. Marshall KW, Zhang H, Yager TD, Nossova N, Dempsey A, Zheng R, Han M, Tang H, Chao D, Liew CC. Blood-based biomarkers for detecting mild osteoarthritis in the human knee. Osteoarthritis Cartilage 2005;13:861-871. McGregor NR, Zerbes M, Niblett SH, Dunstan RH, Roberts TK, Butt HL, Klineberg J.J. Pain intensity, illness duration, and protein catabolism in temporomandibular disorder patients with chronic muscle pain. J Orofac Pain 2003; 17:112-124. McNeill C, Rudd P. Management of jaw disorders (TMJ). In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. 305 Current and Future Innovations Meisler JG. Chronic pain conditions in women. J Womens Health 1999;8:313-320. Meng JH, Zhang WL, Liu DG, Zhao YP, Ma XC. Diagnostic evaluation of the temporomandibular joint osteoarthritis using cone beam computed tomography compared with conventional radiographic technology [in Chinese]. Beijing Da Xue Xue Bao 2007:39:26-29. Milam SB, Aufdemorte TB, Sheridan PJ, Triplett RG, Van Sickels JE, Holt GR. Sexual dimorphism in the distribution of estrogen receptors in the temporomandibular joint complex of the baboon. Oral Surg Oral Med Oral Pathol 1987:64:527–532. Milner JM, Rowan AD, Cawston TE, Young DA. Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro- collagenase activation as a critical step for collagenolysis. Arthritis Res Ther 2006:8:R142. Miyamoto K, Ishimaru J, Kurita K, Goss AN. Synovial matrix metalloproteinase-2 in different stages of sheep temporomandibular joint osteoarthrosis. J Oral Maxillofac Surg 2002;60:66-72. Naqvi T, Duong TT, Hashem G, Shiga M, Zhang Q, Kapila S. Relaxin's induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in Synovial joint fibrocartilaginous explants. Arthritis Res Ther 2005;7:R1-11. Nickel JC, Iwasaki LR, Gallo LM, Palla S, Marx DB. Tractional forces, work and energy densities in the human TMJ. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Nordahl S, Alstergren P, Eliasson S, Kopp S. Radiographic signs of bone destruction in the arthritic temporomandibular joint with special reference to markers of disease activity: A longitudinal study. Rheumatology (Oxford) 2001;40:691-694. Oliver SJ, Firestein GS, Arsenault L, Cruz TF, Cheng TP, Banquerigo ML, Boyle DL, Brahn E. Vanadate, an inhibitor of stromelysin and collagenase expression, suppresses collagen induced arthritis. J Rheumatol 2007:34:1802-1809. 306 Kapila Owman H, Tiderius CJ, Neuman P, Nyquist F, Dahlberg LE. Association between findings on delayed Gadolinium-enhanced magnetic resonance imaging of cartilage and future knee osteoarthritis. Arthritis Rheum 2008:58: 1727-1730. Pelletier JP, Boileau C, Boily M, Brunet J, Mineau F, Geng C, Reboul P, Laufer S, Lajeunesse D, Martel-Pelletier J. The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major cartilage catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther 2005;7:R1091-1102. Plesh O, Sinisi SE, Crawford PB, Gansky SA. Diagnoses based on the research diagnostic criteria for temporomandibular disorders in a biracial population of young women. J Orofac Pain 2005; 19:65-75. Rieder CE, Martinoff JT. The prevalence of mandibular dysfunction. Part II: A multiphasic dysfunction profile. J Prosthet Dent 1983;50:237- 244. Rintala M, Metsäranta M, Säämänen AM, Vuorio E, Rönning O. Abnormal craniofacial growth and early mandibular osteoarthritis in mice harbouring a mutant type II collagen transgene. J Anat 1997;190:201-208. Sato J, Segami N, Nishimura M, Yoshitake Y, Kaneyama K, Kitagawa Y. Expression of interleukin 8 in synovial tissues in patients with internal derangement of the temporomandibular joint and its relationship with clinical variables. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:467-474. Sato J, Segami N, Nishimura M, Yoshimura H, Demura N, Yoshitake Y, Nishikawa K. Correlation between the arthroscopic diagnosis of synovitis and microVessel density in synovial tissues in patients with internal derangement of the temporomandibular joint. J Craniomaxillofac Surg 2003:31:101-106. Schek RM, Taboas JM, Hollister SJ, Krebsbach PH. Tissue engineering osteochondral implants for temporomandibular joint repair. Orthod Craniofac Res 2005;8:313–319. Shafer DM, Assael L. White LB, Rossomando EF. Tumor necrosis factor-alpha as a biochemical marker of pain and outcome in temporomandibular joints with internal derangements. J Oral Maxillofac Surg 1994;52:786–791. 307 Current and Future Innovations Smith MH, Flanagan CL, Kemppainen JM, Sack JA, Chung H, Das S, Hollister SJ, Feinberg SE. Computed tomography-based tissue- engineered scaffolds in craniomaxillofacial surgery. Int J Med Robot 2007;3:207-216. Solberg WK. Epidemiology, incidence, and prevalence of temporomandibular disorders: A review. In: The President's Conference on the Examination, Diagnosis, and Management of Temporomandibular Disorders. Chicago: American Dental Association 1983:30–39. Srinivas R, Sorsa T, Tjäderhane L, Niemi E, Raustia A, Pernu H, Teronen O, Salo T. Matrix metalloproteinases in mild and severe temporomandibular joint internal derangement synovial fluid. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:517-525. Stohler CS. Temporomandibular joint diseases and disorders: The future is now. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Ta LE, Phero JC, Pillemer SR, Hale-Donze H, McCartney-Francis N, Kingman A, Max MB, Gordon SM, Wahl SM, Dionne RA. Clinical evaluation of patients with temporomandibular joint implants. J Oral Maxillofac Surg 2002;60:1389–1399. Takaku S, Sano T, Yoshida M, Toyoda T. A comparison between magnetic resonance imaging and pathologic findings in patients with disc displacement. J Oral Maxillofac Surg 1998:56:171-176. Tanaka A, Kumagai S, Kawashiri S, Takatsuka S, Nakagawa K, Yamamoto E, Matsumoto N. Expression of matrix metallo- proteinase-2 and -9 in synovial fluid of the temporomandibular joint accompanied by anterior disc displacement. J Oral Pathol Med 2001:30:59-64. Tanimoto K, Ohno S, Imada M, Honda K, Ohno-Nakahara M, Kapila S, Tanne K. Utility of urinary pyridinoline and deoxypyridinoline ratio for diagnosis of osteoarthritis at temporomandibular joint. J Oral Pathol Med 2004:33:218–223. Tominaga K, Habu M, Sukedai M, Hirota Y, Takahashi T, Fukuda J. IL- 1 beta, IL-1 receptor antagonist and soluble type II IL-1 receptor in 308 Kapila synovial fluid of patients with temporomandibular disorders. Arch Oral Biol 2004:49:493-499. Unemori EN, Hibbs MS, Amento EP. Constitutive expression of 92-kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines. J Clin Invest 1991:88: 1656–1662. Van Dijke CF, Kirk BA, Peterfy CG, Genant HK, Brasch RC, Kapila S. Arthritic temporomandibular joint: Correlation of macromolecular contrast-enhanced MR imaging parameters and histopathologic findings. Radiology 1997:204:825–832. Von Korff M, Dworkin SF, Le Resche L, Kruger A. An epidemiologic comparison of pain complaints. Pain 1988:32:173-183. Wadhwa S, Embree MC, Kilts T, Young MF, Ameye LG. Accelerated osteoarthritis in the temporomandibular joint of biglycan/fibromodulin double-deficient mice. Osteoarthritis Cartilage 2005;13:817-827. Wang W, Hayami T, Kapila S. Female hormone receptors are differentially expressed in mouse fibrocartilages. Osteoarthritis Cartilage 2008;doi:10.1016/j.joca.2008.09.015. Warren MP, Fried JL. Temporomandibular disorders and hormones in women. Cells Tissues Organs 2001;169:187-192. Wolford LM. Temporomandibular joint devices: Treatment factors and outcomes. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:143-149. Wolford LM, Cassano DS, Goncalves JR. Common TMJ disorders: Orthodontic and surgical management. In: McNamara JA Jr, Kapila SD, eds. Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus. Monograph 46, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor, 2009. Xu L, Flahiff CM, Waldman BA, Wu D, Olsen BR, Setton LA, Li Y. Osteoarthritis-like changes and decreased mechanical function of articular cartilage in the joints of mice with the chondrodysplasia gene (cho). Arthritis Rheum 2003:48:2509-2518. Yamada K, Nozawa-Inoue K, Kawano Y, Kohno S, Amizuka N, Iwanaga T, Maeda T. Expression of estrogen receptor alpha (ER alpha) in the rat 309 Current and Future Innovations temporomandibular joint. Anat Rec A Discov Mol Cell Evol Biol 2003:274:934-941. Yoshida K, Takatsuka S, Hatada E, Nakamura H, Tanaka A, Ueki K, Nakagawa K, Okada Y, Yamamoto E, Fukuda R. Expression of matrix metalloproteinases and aggrecanase in the synovial fluids of patients with symptomatic temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102:22-27. Yoshida K, Takatsuka S, Tanaka A, Hatada E, Nakamura H, Nakagawa K, Okada Y. Aggrecanase analysis of synovial fluid of temporomandibular joint disorders. Oral Dis 2005; 11:299-302. 310 DEVELOPING FUTURE BIOCERAMICS FOR TEMPOROMANDIBULAR JOINT TISSUE ENGINEERING Ching-Chang Ko, João Ferreira, Sandra Myers ABSTRACT The development of a new bioceramic for temporomandibular joint (TMJ) tissue engineering is described. Metal prosthetic devices and petroleum polymers have been used in TMJ reconstruction for many years to improve jaw function, pain and quality of life. Metal-on-metal prostheses (MOM) often have resulted in allergic reactions associated with the metal wear debris produced in such a significant load bearing environment. Metal hypersensitivity has occurred mostly with cobalt-chromium alloys, but the underlying mechanism still is a Subject of controversy. Catastrophic failures associated with polymeric products include periprosthetic osteolysis and implant fractures. Unfortunately, none of the currently available commercial biomaterials appears to be ideal for TMJ tissue engineering scaffolds. Reviewing the pitfalls of previous TMJ implants and biomaterials provides valuable insight that can be used to develop new materials. The chemistry and processing of a new bioceramic that mimics the biosynthesis of natural bone and reflects suitable properties for bone tissue engineering is described. These properties include compressive strength (150 MPa – 250 MPa), Young’s modulus (22 GPa – 26 GPa.), formability, cytocompatibility, ability for resorption, osseoinductivity and osseoconductivity. This technology is highly significant in that it may provide a novel way to regenerate joints in situ through a durable, resorbable biomaterial scaffold. INTRODUCTION Total temporomandibular joint (TMJ) replacement, unlike total hip and total knee replacement, has a history of poor long-term success (> 5 years). Many difficulties with TMJ alloplastic implantation are due to anatomic constraints and inherent high joint forces associated with function and parafunction. Naturally growing bone to regenerate the joint has the capability to produce improved outcomes over other implants used currently in TMJ surgery. Recently, approaches to engineer tissues for the TMJ have been intiated in various laboratories. In combination 3.11 Future Bioceramics with bone morphogenetic proteins, gene therapy and stem cells, novel polymeric and ceramic matrices have been developed as new scaffolding materials to support tissue growth. Current results have shown that engineered growth of new bone can be bolstered effectively within non- unified bony defects. This is now a promising prediction that the engineered bone graft could be the first successful application in the field of tissue engineering (Service, 2000). It is well known that the physical properties of biodegradable polymeric and ceramic matrices are unsatisfactory for application in a load bearing joint such as the TMJ. Other composite mixtures of polymers and ceramic powders do not mimic real bone nanostructure and are not suitable for such an application. Serious barriers exist to the development of a nanostructural composite, conducive to the actual bony polymer-ceramic (collagen- hydroxyapatite) nano-bonding structures and providing adequate tissue engineering matrices. The goals of this chapter are to: • Review the history of TMJ surgery and outcomes of current TMJ implants; * Review the availability of biomaterials for bone tissue engineering; and • Introduce a new biomimetic material (as an osseous inductive material) that can serve as a load bearing scaffold to carry osteogenic cells and form bone. The content focuses on the biomaterials aspect, rather than cells and their growth factors. The chapter is organized in two sections: future trends in TMJ implant surgery and biomaterials. FUTURE TRENDS IN TMJ IMPLANT SURGERY: IS IT TIME FOR TMJ TISSUE ENGINEERING2 Management of TMJ Disorders: The Path from Conservative Modalities to Surgical Treatment Temporomandibular joint disorder (TMJD) is a clinical term that embraces a number of medical conditions that involve the masticatory musculature, the TMJ and associated structures, or both (AAOMS, 1993; de Leeuw, 2008). This condition affects over 10 million Americans according to the NIH (2006) and 3.6% to 7% of the population are estimated to be in need of treatment (Dworkin et al., 1991; de Leeuw, 2008). TMJ disc displacements (TMJ DD) and TMJ osteoarthritis (TMJ 312 Ko et al. OA) are the most common jaw joint disorders (de Leeuw et al., 1994; Mercuri, 2008). A variety of clinical strategies, such as pharmacological management, oral appliances, physical therapy and surgery have been advocated in the treatment of TMJ DD and TMJ OA to reduce inflammation and pain commonly associated with these conditions and to prevent further disc displacement and joint degeneration (Ash, 1986; Stegenga et al., 1989; Okeson, 1996; de Leeuw, 2008). Surgical treatment has been indicated mainly to improve moderate to severe TMJ pain and/or the disabling joint dysfunction by means of reducing inflammation and reversing the structural damage (AAOMS, 1992). According to the 1993 International Consensus Meeting of Oral and Maxillofacial Surgeons, three criteria must be met to render TMJ surgery: the failure of a previous six-month nonsurgical treatment; the absence of any medical or psychological contra- indications; and the existence of a patient’s request (Goss, 1993; Dimitroulis, 2005a,b). Prior to the 1993 consensus, the surgical approach usually was recommended initially to ameliorate a variety of TMJ symptoms (Laskin, 2007). Understanding the past is vital to contemplating the present and directions and trends of the future. This premise is definitely true for understanding the complexity of TMJDs. Scientific knowledge of the past not only is important in making researchers and clinicians aware of how we arrived at our current treatment of these disorders, but it also helps us to learn and progress from the therapeutical outcomes that have previously occurred. TMJ Surgery: Revisiting the Past The earliest written reports of TMJD management date back to the 5" century BC when Hippocrates interestingly described a method for manually reducing dislocations of the mandible (Laskin, 2007). Reports of TMJ surgical operations started appearing around the end of the 19th century, to treat jaw dislocations and to release joint ankylosis mainly (Annandale, 1887; Dimitroulis, 2005a). Prior to this, conditions referred to as “fixations” including trismus and ankylosis due to infection, trauma or arthritis were reported. Physicians managed these patients with medications and devices in use for other body joints (Dimitroulis, 2005a; Laskin, 2007). Forms of TMJ internal derangement, involving disc integrity and position were not recognized until 1887 when Annandale published a report describing two cases of discoplasty for the management of disc displacement (Annandale, 1887). 3.13 Future Bioceramics The first published case of discectomy for painful TMJ internal derangement was reported by Lanz (1909) in the German literature in very early 1900s. Until the 1960s, discectomy remained the surgical procedure of choice for painful TMJ dysfunction and surgery played only a minor role in the management of TMDs (Kiehn and Desprez, 1962; Silver and Simon, 1963). In the 1970s, the concepts of myofascial pain and dysfunction syndrome developed by Laskin (Laskin and Block, 1986) overshadowed developments in the intracapsular pathology of the TMJD recognized initially by Annandale (1887). The important role of the articular disc in TMJ pain and dysfunction started gaining acceptance in the 1970s when TMJ arthrography techniques became more highly developed (Farrar, 1968; Toller, 1974; Wilkes, 1978). TMJ disc displacement since then generally has been adopted as the mechanism that helps explain the pain, clicking and locking reported by patients diagnosed with TMJ internal derangement. TMJ Surgery consequently gathered momentum in US as various treatment procedures were advocated to reposition, repair or remove the diseased disc (Wilkes, 1991). These procedures included TMJ arthroscopy, arthrocentesis, discectomy, disc repair procedures and total joint replacement (Kent et al., 1983, 1993; Wilkes, 1991). Discectomy without replacement has enjoyed the longest record of long-term success – up to 30 years (Eriksson and Westesson, 1987; Takaku and Toyoda, 1994). This procedure was performed mainly in cases of disc perforation and to decrease symptoms associated with chronic non-reducing TMJ disc displacement (disc cannot be recaptured by the mandibular condyle). The uncertainty of long-term effects of degenerative joint disease progression, found without replacing the disc, however, opened the way to replacement with autogenous or homolo- gous grafts. Implant disc replacement was an attempt to restore “normal” structural relations in the TMJ after discectomy. Synthetic alloplastic TMJ interpositional implants (TMJ IP) frequently were employed up to 1993 whenever discectomy was indicated. The implant material was inserted between the articular surface of the condyle and the glenoid fossa to function as an artificial disc (Wolford, 1997; Mercuri, 2008). Other replacement procedures such as autologous grafting, using dermis, auricular cartilage, fat, costochondral graft or temporalis muscle, also have been developed to provide interposing tissue between the condyle and temporal bone (Witsenburg and Freihofer, 1984; Meyer, 1988; Feinberg and Larsen, 1989; Wolford et al., 1994; Milam, 1997). Additional surgical replacement procedures have utilized allogeneic 3.14 Ko et al. materials, including lyophilized dura, to reconstruct the TMJ after discectomy (Valentini et al., 2002). TMJ Implants: From Short-term Clinical Success to Failure Proplast/Teflon" (P/T) Interpositional TMJ Implants. Proplast/ Teflon" (P/T) is an artifical implant material that was introduced to correct various tissue defects (Wolford et al., 1995; Rubin and Yaremchuck, 1997). Proplast" is a porous form of polytetrafluoro- ethylene (PTFE) with an admixture of fibers of either vitreous carbon (Proplast I) or aluminum oxide (Proplast II or PTFE-Al2O3). Porous sheets of Proplast" were laminated to Teflon", a dense'smooth form of PTFE (Table 1). P/T implants were found to have a high melting point (above 250° C), insolubility in all common solvents, resistance to chemical attack, anti-frictional properties and a modulus of elasticity resembling that of bone or fibrous tissue (Table 1; Homsy, 1982; Ryan, 1989, 1994). Certain investigators considered that porous PTFE offered more stability than nonporous silicone implants (Gallagher and Wolford, 1982). Other highly desirable properties were identified such as freedom from adverse immune reactions, toxicological safety, capability for rapid tissue ingrowth and biocompatibility (Homsy, 1982, 1991). Early success rates for P/T and Silastic” disc implants were presented at scientific meetings and in the literature. A retrospective review by Estabrooks and colleagues (1990) of 301 TMJ discectomies with P/T replacement implants showed an overall success rate of 89% with these materials over 33 months average follow-up. Bee (1986), Gallagher and Wolford (1982) and Kiersch (1984) all reported successful outcomes with P/T implants. A review of these follow-up studies for discectomy with P/T disc replacement showed a mean satisfactory result of 92% supporting their continued use (Kiersch, 1984). In the early 1990s and beyond, P/T implants were observed to loosen, break down or undergo rejection because of the high biomechanical forces placed on them in the TMJ (Fig. 1; Spagnoli and Kent, 1992; Chuong et al., 1993; Trumpy and Lyberg, 1993; Wolford et al., 1995; Milam, 1997; Fricton et al., 2002; Mercuri and Giobbie- Hurder, 2004; Ferreira et al., 2008). The production of fragmented particles often resulted in an immune foreign body response (Fig. 2), leading to severe cutaneous inflammatory reactions in the pre-auricular and cheek areas (Kulber et al., 1995; Ferreira, 2005); severe degenerative joint disease with resorption, erosion of the TMJ bony structures (such as condyle and fossa) with perforation to the middle cranial fossa (Chuong 315 Future Bioceramics et al., 1993), chronic pain, increased noises in the TMJ, joint hypomobility and occlusal changes (malocclusion; Spagnoli and Kent, 1992; Milam, 1997). Dramatic catastrophic clinical failure of these implants was observed and documented (Spagnoli and Kent, 1992; Ferreira et al., 2008). In response, the US Food and Drug Administration (FDA) recommended immediate and appropriate clinical and radiographic examination of all previous TMJ P/T disc implant patients due to problems such as implant perforation, fragmentation, and/or foreign body response resulting in progressive bone degeneration (FDA, 1990; AAOMS, 1993). A consensus at the American Academy of Oral and Maxillofacial Surgery (AAOMS) 1992 workshop meeting stated that “Proplast/Teflon" interpositional implants should be discontinued because it is an inappropriate material” (AAOMS, 1993). Table 1. TMJ implant commercialized systems not currently on the market. permanently (Silastic") or temporarily (Silastic HP sheeting, Medical Grade Silastic Sheeting and Wilkes design) Implant Brand Implant System Description Manufacturer Silastic" disk Sheeting or block silicone placed between Dow Corning replacement condyle and fossa to act as a disk, either Proplast" I, II or Sheeting or block composite of Vitek, Inc. and weight polyethylene (UHMWP) HA sheeting or | Polytetrafluoroethylene (PTFE) Aluminum subsidiaries: blocks Oxide (II) or Hydroxylapetite (HA) from Novamed, Inc., which various devices were formed by and Oral surgeon. Used as an Interpositional implant Surgery placed between the condyle and fossa Marketing, Inc. permanently. Proplast/Teflon" | Proplast I or II with polyamide or polyester | Vitek, Inc. and IPI disk fiber and silicone or fluorinated ethylene its subsidiaries replacement propylene (Teflon") copolymer Kent/Vitek” Stock order with condyle made of Co-Cr- Vitek, Inc. and joint including Mo alloy with Proplast on the condyle. its subsidiaries V-I, VK-I Fossa: Polyamide fiber and Teflon.” Kent/Vitek” Stock order with condyle: Co-Cr-Mo alloy Vitek, Inc. and joint including with Proplast on the condyle. Fossa: its subsidiaries V-II, VK-II Proplast HA with ultra high molecular Misc. implant 1. Dacron” reinforced Silastic" (not Individually materials trademarked or copyrighted) constructed at 2. Self-curing silicone (DeChamplain) time of surgery 3. Methylmethacrylate as self-curing with raw implant for the glenoid fossa materials Morgan Implant No information is available No information 316 Ko et al. 10x * º 100x Figure 1. Features of explanted Proplast/Teflon” (P/T) implant fragments. Stereo zoom microscopy: A PT breakdown fragments with signs of perforation condylar surface; B. P/T breakdown fragments – temporal/porous surface with signs of perforation and attached soft tissue: C. P/T fragment with perforation; D. Top fragment: debris with extruded polytetrafluorethylene (PTFE) or Proplast” fibers. Bottom fragment: smooth fluorethylenepropylene (Teflon") fibers; E. Lateral view of implant thickness with tearing of the two PTFE layers; F. Histomorphometric analysis with polarized light. P/T implant with bone Ingrowth (small arrow) on PTFE (Proplast") layer. - º Figure 2, A.B. Polarized light images showing P/T implant fragments (large "OW) Surrounded by multinucleated giant cells (small arrows; H & E stain. Magnification – 200x). Silastic". Interpositional TMJ Implants. Silicone elastomers have been studied extensively and used clinically as implants for a wide range 317 Future Bioceramics of purposes in various anatomic locations, such as finger, wrist, elbow, shoulder, hip and metatarsal joints (Charnley, 1966; Ryan, 1989, 1994). Silastic" is a flexible and inert polydimethylsiloxane (silicone rubber) with resilient properties, high and low temperature stability, wide hardness range (10-80 Shore A), chemical resistance and compression set resistance (Table l; Moriconi and Popowich, 1986). In addition to the excellent properties above, silicone rubber is extremely easy to fabricate, particularly when compared to conventional organic elastomers. Silicone rubber flows easily, can be molded or extruded using relatively low amounts of energy, is easily carved and readily adaptable to the TMJ, and does not allow tissue ingrowth (Moriconi and Popowich, 1986). Silastic" implants range in thickness from 1 to 2 mm and may be reinforced with Dacron" (polyethylene terephthalate) fibers (Ryan, 1994). Studies advocating the use of Silastic" have mentioned its ability to form a fibrous connective tissue capsule that might act as a disc substitute (Mercuri and Giobbie-Hurder, 2004). Silastic" was introduced to the medical community in 1968 as an interpositional material for the reconstruction of arthritic or destroyed joints in the hand after experimental evidence showed its biocompati- bility. Experimental evaluation by researchers (Charnley, 1966; Hartman, 1988) showed that various types of Silastic" implants became surrounded by a fibrous capsule with occasional intracellular particles of silicone elastomer observed within macrophages. In spite of this, it was believed still that solid silicone fulfilled many of the requirements of an ideal implant material. Silicone implants also showed less mechanical stability but 50% less gross tearing than Proplast II implants. In early 1980s, silicone rubber replacement after TMJ discectomy became popular with negligible long term foreign body giant cell reaction to the material observed (Nalbandian et al., 1983). Later published reports documented the long-term instability of this material when used in the TMJ. Foreign-body giant-cell reaction around fragmented silicone elastomer particles was observed, along with silicone particulate matter within peri-implant lymph nodes, and a severe reactive synovitis occasionally resulting in condylar destructive arthritis (Westesson et al., 1986; Hartman et al., 1988; Mercuri and Giobbie- Hurder, 2004). Silastic” implants were removed from the market in January 1993 by the manufacturer. At the 1992 AAOMS workshop meeting, continued controversy existed on the use of temporary Silastic” material following discectomy. Consensus was reached, however, for the 3.18 Ko et al. use of Silastic" exclusively in preventing recurrence of ankylosis (AAOMS, 1993). TMJ Total Joint Implants. A number of joint replacement devices have been used in TMJ reconstruction over the years, condylar and/or fossa replacements and the total joint prosthesis for major structural rehabilitation (Henry and Wolford, 1993; Wolford, 1997; Wolford et al., 2000). Materials used in partial and total TMJ reconstruction included Proplast/Teflon" (P/T), polymethylmethacrylate (PMMA), dense ultra-high-molecular-weight polyethylene (UHMWPE), and various metal alloys (Tables 1 and 2; Milam, 1997; Wolford, 1997; Mercuri and Giobbie-Hurder, 2004). Wolford and coworkers (2003) emphasized the following material properties to ensure success for the total joint prosthesis: 1. Biocompatibility; 2. Functionality; 3. Low wear, flow, and fatigue coefficients when loaded under functional conditions; 4. Adaptability to anatomical structures; 5. Rigidly stabilized components; and 6. Corrosion resistant and non-toxic. Table 2. Current TMJ implant systems available in the market. fossa is made from commercially pure titanium mesh (ASTM F67 and F1341) with an articular surface of medical grade polyethylene known as UHMWPE (UHMWPE ASTM F648). Implant Brand Implant System Description Manufacturer TMJ concepts Custom made, patient specific, computer-aided | TMJ system” (formerly design and manufactured implant of medical CONCEPTS, Inc. Techmedica/ grade titanium alloy (ASTM F136) with a Anspach/TMJ condylar head of cobalt-chromium- Implant”) molybdenum alloy (ASTM F1537). The glenoid & (8) Christensen Stock off the shelf. Surgical quality Cr-Co-Mo TMJ Implants, (Dr. David Hoffman) alloy and coated with UltraCoat” to reduce wear and abrasion. systems Alloy (ASTM F75/ASTM F799) total joint and Inc. individual fossa. A custom made, patient specific, computer-aided designed and manufactured implant also is available. Lorenz TMJ joint Fossa component is made of Arcom.” W. Lorenz replacement UHMWPE. Mandibular condyle component is Surgical Inc./ system” made of Co-Cr alloy. Three stock sizes. BIOMET Inc. (Dr. Peter Quinn) Hoffman-Pappas” | CAD-CAM technology is used to fabricate a ENDOTECH, joint system custom metallic joint and fossa from titanium Inc. 3.19 Future Bioceramics In the following section, TMJ replacement systems with published follow-up clinical outcomes are discussed. Christensen" Implant System. The first total joint system for the TMJ (TMJ Implant Inc., Golden, CO) was an alloplastic device devel- oped in the 1960s by Christensen (Alexander, 1999; Christensen et al., 2004); highly polished cobalt-chromium alloy (chromium 28%, cobalt 64%, molybdenum 7% and nickel 1%) glenoid fossa-eminence prosthesis was fabricated for use, either by itself or in conjunction with a condylar prosthesis. The condylar prosthesis was composed of a Co-Cr framework with a molded polymethylmethacrylate (PMMA) condylar head (TMJ Implant, Inc., Golden, CO; Table 2: Chase et al., 1995; Alexander, 1999; Christensen et al., 2004). In the past, PMMA never had been used for articulating surfaces in any non-TMJ approved orthopedic devices due to poor wear properties and breakdown (Wolford, 1997). TMJ Implant, Inc., also developed a Christensen" implant system but without the PMMA condyle. Instead, the manufacturer used a TMJ condyle made of a cobalt-chromium alloy in the Co-Cr framework. This Christensen" metal device had a metal condylar head against a metal fossa (Alexander, 1999). Wolford and coworkers (2003a) maintained that the design of metal against metal would increase metal wear debris, create stress loading of the fossa component, result in metallosis and corrosion and increase exposure to these elements in hypersensitive individuals. More than 24,000 Christensen” implants had been placed as of 2003 (Christensen et al., 2004). The first retrospective study on 69 patients had successful outcomes (Chase et al., 1995), including decreased pain (95% to 100% of patients), improved eating ability (82% to 96%) and increased incisal opening (77% to 91%). Christensen” system of metal condyle and fossa joint prosthesis obtained an FDA pre-amendment approval in 1995. One prospective study relative to the use of this metal device was published by the manufacturer (Christensen et al., 2004). It was a ten-year retrospective study on all Christensen” device systems and reported them as a safe and effective biomechanical solution. The FDA’s voluntary Manufacturers And User Facility Device Experience Database (MAUDE) provides healthcare institutions, professionals, and consumers with data concerning reported “adverse events” related to the use of medical devices, including TMJ device systems. From 2002–2003, Mercuri (2004) reported that MAUDE had 39 reports of adverse events, 21 (53.8%) involved either the Christensen” 320 Ko et al. fossa/eminence or the Christensen" total joint replacement systems. From 2000-2001, 46 of 66 TMJ devices reported to MAUDE (69.7%) were adverse events associated with Christensen" prostheses (Mercuri, 2004). An important but often overlooked factor contributing to many implant failures is metal sensitivity. Hypersensitivity or immune reactions to various metals is relatively common in the general population. Metal hypersensitivity (type IV, delayed hypersensitivity) may be present before surgery or develop after implant placement and can lead to alterations in surgical outcome. The most common metal allergies are to nickel and chromium, which is a probable contraindication to the use of stainless steel or chromium-cobalt-based alloy in hypersensitive patients. The Christensen” prosthesis throughout the entire device contains 1% nickel and 28% chromium. In addition, cobalt and molybdenum, which also are contained throughout the Christensen" implant, evoke hypersensitivity in some patients (Wolford et al., 2000, 2003a). Lorenz" TMJ System. The Lorenz TMJ Joint Replacement system" (W. Lorenz Surgical Inc., subsidiary of Biomet Inc., Jackson- ville, FL) has been manufactured and clinically used since July 1995 under an approved investigational device exemption (IDE) from the FDA. According to the manufacturer, the mandibular component of this prosthesis has two different styles and three sizes (45 mm, 50 mm, and 55 mm). This device is made of Co-Cr (cobalt-chromium) alloy, and the undersurface of the prosthesis is coated with titanium plasma spray for increased bony integration into the mandibular prosthesis (Table 2). The fossa prosthesis was designed to replace the articulating surface of the TMJ, comprised of the glenoid fossa and the articular eminence of the temporal bone. The fossa prosthesis is made of Arcom” UHMWPE and is available in three sizes (small, medium, and large). The system screws are composed of titanium (Table 2). Since 1995, over 200 patients have received the prosthesis, with a 96% patient success rate according to clinical trial for systems approval (Quinn, 2000). In a three-year follow-up study, Quinn showed a significant improvement in pain reduction and jaw function outcome measures in 50 patients with 69 Lorenz TMJ Joint Replacement” prostheses. To date, one complication related to a staphylococcal scalp infection was reported with this prosthesis. However, reports of metal allergies to the chromium in this device and the production of UHMWPE wear debris are common in the literature (Li and Burstein, 1994; Quinn, 2000; Wolford et al., 2000). 321 Future Bioceramics TMJ Concepts" System. TMJ Concepts" prostheses were brought to the US market at the end of the 1990s. This prosthesis is custom-made and uses materials proven in orthopedics for joint replacement: titanium mandibular shaft and fossa liner, chromium-cobalt alloy for the condylar head and dense UHMWPE as the functional fossa surface (Wolford et al., 2003a). The fossa liner is composed of two parts: 1. A commercially pure titanium sheet conforming to the fossa anatomy including articular eminence, lateral aspect of the fossa and adjacent arch; and 2. Four layers of titanium mesh bonding both sides of the sheet by a special diffusion process (Wolford et al., 2003a). * The functional condyle of the mandibular component is made of wrought chromium-cobalt-molybdenum alloy with 2% trace elements including nickel, iron, carbon, silicone, manganese and nitrogen. The functional surfaces of the chromium-cobalt-molybdenum alloy and the UHMWPE represent the gold standard for orthopedic joint replacement in terms of wear and structural stability. A 3D plastic model of the TMJ and associated bony structures is fabricated from computed tomography data and the joint prosthesis then is constructed to each patient's specific anatomic features (Mercuri et al., 1995; Wolford et al., 2003a; Mercuri and Giobbie-Hurder, 2004). Preliminary results using the Techmedica System" were reported in a prospective multicenter study in 1995 (Mercuri et al., 1995). Clinical and technical data reported in that study formed the basis for the FDA's July 1999 approval of the TMJ Concepts System" for management of specific TMJ disorders (FDA, 1999). These devices have been followed for up to 6.5 years with very good results. Published data (Mercuri et al., 1995) on 100 consecutive TMJ Concepts” prostheses placed in 56 patients reported 86% success with 16- to 46-month follow-ups. In this study, 49% of the joints had a history of P/T implants. Patient outcomes were affected by the number of previous surgeries. Eight (19%) of the 42 patients with two or more previous surgeries had unfavorable outcomes, related to no significant decrease in pain severity. A five-year follow-up study (Wolford et al., 2003b) evaluated the five to eight year subjective and objective results of 42 consecutive patients who had TMJ reconstruction using the TMJ Concepts”. 322 Ko et al. Complications, such as the formation of heterotopic bone and loosening of the implant mandibular component, occurred in six patients. Another factor contributing to implant failure was metal sensitivity. TMJ Concepts" system has 1% nickel, 28% chromium, cobalt and molybdenum in the condylar head, which might produce sensitivity in Some individuals. Hypersensitivity to titanium (also present in TMJ Concepts") also has been documented but is rare (Wolford et al., 2003a,b). Foreign-body Response From TMJ Implant Breakdown. All alloplastic materials used in joint reconstruction have a specific wear rate with the production of a wide range of particle size and breakdown products (Ryan, 1994, 1995). The severity of the local and systemic inflammatory response of the host to implant materials is governed by a number of factors including the material utilized, the size, shape and topography of the particles, the chemical structure of the surface and the surface electrical charge (Goodman et al., 1990). Host specific factors Such as implantation duration, age, gender, hormonal status, biomechanical forces and systemic sensitivity to the implant material also may influence the cellular and neural response to the debris (Kao, 1990). Macrophage surface adhesion and giant cell formation are central to host response to local and systemic wear debris (Hernandez-Pando et al., 2000). Multinucleated giant cells are a common feature of a local foreign body response (Fig. 2), and their formation from mono- cytes/macrophages is controlled by various cytokines (Hernandez-Pando et al., 2000; Lind et al., 1999). Wear particles in joint tissues recruit and activate mono- cytes/macrophages to secrete pro-inflammatory mediators that interact With osteoblasts, osteoclasts and immune cells (Goodman et al., 1990; Lind et al., 1999). Multinucleated giant cells result from the fusion of two or more macrophages that have been recruited from the peripheral blood. Investigators have demonstrated that these giant cells are an active Source of cytokines such as interleukin-1beta (IL-1ſł), interleukin-6 (IL- 6) and tumor necrosis factor-alpha (TNFo) and contribute to granulomatous inflammatory response initiation, maintenance and down- regulation (Hernandez-Pando et al., 2000; Kaneyama et al., 2005). TNFo is the principal mediator released from macrophages that modulates the release of bone reabsorbing factors from other cells. Macrophage release of pro-inflammatory mediators is dependent on a number of factors including the size and concentration of the wear debris (Horowitz et al., 1994; Hernandez-Pando et al., 2000). 323 Future Bioceramics Small sized debris particles have been shown to increase the biologic signal to local cell populations and the magnitude of the local and systemic biologic response dramatically. Larger particles appear to result in a diminished, less vigorous biologic response (Shanbhag et al., 1994; Zardeneta et al., 1996). In a study by Zardeneta and coworkers (1996), a particle size of 50 pum or less typically appears to increase dramatically the biological signals to local cell populations and activate cellular cascades leading to inflammation. Other studies on the macrophage interaction with implant particulate wear debris from a loose joint prosthesis revealed a macrophage response dependent on the particle size, composition and dose (Ryan 1994, 1995; Shanbhag et al., 1994). They stated that many of the P/T particles in the range of 0.58 pm are smaller than the resolution of the light microscope and cannot be identified on histological evaluation. Further, Ryan identified a greater infiltration of histiocytes in the more severe reactions, indicating an increase of submicroscopic particles and possible release by histiocytes of various cytokines including IL-1ſ, IL-6, TNFO, collagenase, and prostaglandin PGE2. These function to induce bone loss through osteoclast regulation. This inflammatory reaction cascade also was reported by Green and coworkers (1998) in hip joints. The study suggests that high molecular polyethylene particles in the phagocytosable size range of 0.3-10 pum are the most biologically active in vitro. In addition, particles as large as 80 pum in diameter can be transported through the lymphatic vessels to the regional lymph nodes. The largest TMJ implant particle reportedly found in a lymph node was 42 pum (Ryan, 1994, 1995). Local and Systemic Effects of TMJ Implants. Baird and colleagues (1999) studied 14 patients with TMJ alloplastic implants and all exhibited chronic symptoms of chemical hypersensitivity that were not present before implant placement. The symptoms included memory loss, confusion, imbalance, dizziness, non-immune vasculitis, petechiae, spontaneous bruising, edema, Raynaud’s phenomenon pain and autoimmune dysfunction. Laboratory data were abnormal showing immunological abnormalities, including positive auto-antibodies and altered T and B lymphocyte function. Provocation skin testing revealed reaction to the patients respective implant material. In contrast, Raphael and coworkers (1998) published a study of 14 patients with Proplast" in 1998 and 64 patients with Proplast” in 1999, finding that P/T-exposed patients had higher levels of pain and dysfunction, but did not report more systemic conditions than similar patients unexposed to alloplastic 324 Ko et al. jaw implants. Milam (1997) confirmed that comorbid systemic diseases have been observed in patients with signs of a severe foreign body response to microparticulate alloplastic implant debris. In a study performed at the National Repository for Temporomandibular Joint Implants (NIDCR's TIRR), we found that 15 patients who had undergone TMJ implant surgery presented mainly with complaints of chronic Orofacial pain and jaw impairment (Fig. 3; Ferreira, 2008). Disastrous results with the majority of alloplastic materials led TMJ Surgeons to turn to the use of autogenous tissues as a disc replacement. The tissues included dermis, temporalis muscle, and auricular cartilage. Inconsistent results with these tissues, however, prompted many surgeons to perform discectomy without disc replacement (Witsenburg and Freihofer, 1984; Meyer, 1988; Feinberg and Larsen, 1989). Patient's Main Complaints Jaw fatigue Tooth pain 4% * Facial Pain o 4% Temple pain Jaw noises” 20% 4% Foreign body reaction 4% inability to open jaw Wideſ limited ROM 1.1% Ear pain - 4% Neck pain - None Jaw pain 1.1% 7% 10% TMJ pain 10% Figure 3. Main complaints presented by patients who had undergone TMJ Implant surgery (n = 15; unpublished data). The Alternative for Failed Alloplastic Implants. Tissue Engineering Approaches Surgery has been advocated to correct the structural problems in the TMJ that are associated with TMJ DD and TMJ OA. More than 30,000 alloplastic TMJ implants were placed between 1974-1993 (Spagnoli and Kent, 1992; Ryan, 1994; Milam, 1997; Fricton et al., 2002). Historically, TMJ implants have been composed of a variety of *terials such as gold plate, magnesium, tantalum foil, polyethylene, *rylic spacers, P/T", Silastic" and more recently, metallic Ti and Cr-Co total joint prostheses (Ryan, 1994; Milam, 1997; Mercuri and Giobbie- Hurder, 2004). Unfortunately, nearly all alloplastic TMJ implants have 325 Future Bioceramics been found to break down due to the high biomechanical forces placed on them. Local and systemic immune reactions to implant breakdown products have resulted in complications such as multiple surgeries, severe pain, dysfunction and disability in many patients (Milam, 1997; Fricton et al., 2002; Ta et al., 2002; Ferreira et al., 2008). No engineering products have been developed successfully that solve the historical major iatrogenic problems associated with TMJ implants and/or offer these patients appropriate functionality to chew, swallow and communicate (Wang and Detamore, 2007). Regeneration of the patient's own bone and cartilage tissues to treat TMJ deficiencies definitely will have an impact in improving quality of life for these patients. BIOMATERIALS Background s The use of autogenous costochondral rib grafts has been more Successful than alloplastic replacment materials for general bony tissue and TMJ reconstructions (Cook et al., 1994; Perrot et al., 1994; Raustia et al., 1996; Feinberg et al., 2001). Bone autografts have many appealing features that make them ideal as skeletal substitutes: • They retain their viability due to an intact intrinsic blood supply, demonstrate proportional growth when used in children; - • They do not degenerate with time, heal in an infected field; and • They exhibit normal rigidity and flexibility at joints. Many of these properties may be attributed partially to organic-inorganic binding and hierarchy ultra-structures. Disadvantages, however, include the source of autografts being extremely limited and the natural shape of donor bone (e.g., rib) not satisfying the anatomy of defects (Feinberg et al., 2001). Sándor and colleagues (2007) reported that severe overgrowth (in 10 years) of a costchondral rib graft caused facial asymmetry. Langer and Vacanti (1993) defined Tissue Engineering (TE) as “an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ.” The engineered biological substitutes need to possess advantages of natural tissues without the disadvantages of nonfitting shapes and unwanted tissue growth. There is a general consensus that biomaterials mimicing natural bone microstructure would provide the best scaffolding 326 Ko et al. environment for cell growth and generation of the biological substitute (Service, 2000). The following text provides background information about: 1. Natural bone as the target of ideal biomaterials; 2. Available scaffold biomaterials; 3. Current progress of biomimetic hydroxyapatite-gelatin nanocomposite; and 4. New GEMOSIL biomaterials. What is Natural Bone? The building unit of normal or natural bone is a collagen- hydroxyapatite complex in which entire collagen triple helices lie in parallel, staggered arrays (Alberts et al., 1994; Yamauchi, 2002). The gaps of 67 nm between the ends of the tropocollagen subunits serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component which is primarily hydroxyapatite, Caro(PO4)6(OH)2 (Deer et al., 1966; Kaplan et al., 1994; Curry, 2002). Studies using Fourier transform infrared spectroscopy (FTIR) have shown that there are direct bonds between hydroxyapatite and the carboxylic/amide functional groups that occupy the nanometer gaps (Evans et al., 1992; Paschalis et al., 1996). During bone formation, collagen synthesis precedes hydroxyapatite deposition as a continuous matrix. Recently, both theoretical and experimental mechanics suggest that hydroxyapatite should act as a continuous phase in addition to collagen (Wegner and Gibson, 2000; Oyen, 2005; Oyen and Ko, 2005). Such interpenetrating biphases furnish bone with high fracture resistance (attributed to cross- linked collagen) and high stiffness (due to hydroxyapatite crystal Structures). Current Scaffolding Biomaterials The current scaffolds for bone reparation can be classified into three types of materials: biodegradable polymers, ceramics, and hybrids of polymers and ceramics (Middleton and Tipton, 2000; Griffith, 2002). The biodegradable polymers include: 1. Natural origin – alginate, hyaluronate, collagen, laminins, chitin, glycosaminoglycans; and 2. Synthetic polymers – polyglycolic acid (PGA), polylactic acid (PLA), polycarbolactone (PCL), polyvinyl alcohol (PVA). 327 Future Bioceramics Ceramics include hydroxyapatite, tricalcium phosphates, and metallic oxides. All of the above scaffolds have biocompatible surfaces, contain no toxic contaminants that can leach out and produce no toxic by- products during degradation. The effectiveness (i.e., degradation rate, mechanical strength and abilities for cell and protein attachment) of the currently available matrices, however, is limited. The biodegradable polymers (e.g., PGA, PLA and collagen- delivery systems) have low mechanical strength and low bulk corrosion resistance (materials erode in body fluid at a fast rate with a massive volume loss). Recent studies also have indicated that matrices made of biodegradable polymers shrank during in vitro cell culture testing, and the materials showed mechanical degradation of the scaffold-cell construct over time (Allen and Athanasiou, 2008). Hydroxyapatite has been investigated extensively as the major component of synthetic bone graft materials due to its biocompatibility, Osteoconductivity, osteophilicity, non-toxicity and non-immunogenic behaviour (Jarcho, 1981; LeGeros, 1988; Parks and Lakes, 1992; Dubok, 2000; Sun et al., 2001; LeGeros, 2002). However, synthesis of hydroxyapatite often utilizes high temperature sintering (1300°C; Chu et al., 2002). Even with hydrothermal processing that converts tricalcium phosphate to hydroxyapatite, heating temperatures around 200-800°C are used. These processing steps, therefore, limit the incorporation of growth factors during material preparation. In addition, in dental and orthopedic implants, hydroxyapatite materials appeared to stay in the body with no resorption for a long time (>10 years). This low degradation rate is a severe disadvantage for the use of hydroxyapatite as a scaffolding material in tissue engineering applications. Amorphous tricalcium phosphate (TCP), which resorbs too quickly and bioglass (Na2O-CaO- P2O5-SiO2 system) both are non-porous, have low mechanical properties and low fracture toughness, making them poor candidates for TE (Sun et al., 2001). More recently, composite hybrids have been developed in an attempt to combine the properties of both polymer and ceramics; their current development, however, is unsatisfactory due to undesired microstructures. For example, the mixtures made by blending collagen fibrils with hydroxyapatite powders result in a dispersed particle phase with entangled fibers. The material lacks binding forces between the entangled fibers and the hydroxyapatite particles, which results in low physical strength for the mixture. Precipitation of calcium phosphate in polymer solution has been attempted to try to stiffen biodegradable 328 Ko et al. polymers (Hakimimehr et al., 2005). Development of PLGA-Cap composites, however, still is in its infancy. Bulk corrosion of PLGA leading to acidic inflammation may limit the use of this type material. Other petroleum based products such as Teflon" used in TMJ implants, polyester, and braided carbon/polyetheretherketone (PEEK) all have potential to cause foreign body reactions and thus are not applicable for tissue engineering (Horowitz et al., 1994; Ikeda et al., 1998; Lind et al., 1999; Hernandez-Pando et al., 2000). Hydroxyapatite-Gelatin Nanocomposites (HAP-GEL). In the past two decades, scientists have explored the kinetics of bone formation using solution process and double diffusion mechanisms (Mann et al., 1993; Mann and Ozin, 1996; Boskey, 1998). Theoretically, collagen molecules facilitate hydroxyapatite nucleation in a supersaturated calcium/phosphorus solution at 38° C with a pH around 8.0. The diffusion process was very slow, however, and the crystals formed were a few microns in size, suggesting that formation of the bone building blocks at low temperature (room to body temperature) was feasible in theory, but mass production in the same conditions was not possible currently. Since 2000, Ko and coworkers have worked on a scale-up Synthesis using a diluted gelatin and a diluted calcium hydroxide solution (Fig. 4). Ko and colleagues used mechanical agitation to speed up the biomimetic process: coprecipitation reaction of hydroxyapaptite (HAP) nanocrystals in soluble denatured collagen and phosphorylated gelatin (GEL; Chang et al., 2003; Ko et al., 2007). Using this bio-mimetic process, the production of an imitation bone was reported at the rate of 3 grams per hour. The HAP is nucleated in situ on the phosphorylated gelatin molecules by the calcium ions in the Ca(OH)2 solution. The artificial bone material, HAP-GEL nanocomposite, mimics the chemical bonds between hydroxyapatite and carboxyl and amide functional groups of gelatin that provide similar nano-scale micro-structures to natural bone. Because this material is prepared at body temperature (38° C), future incorporation of cells and soluble growth factors should be feasible. Our preliminary studies showed that HAP-GEL nanocomposite not only mimics the biochemistry or nanostructures of bone but also its mechanical properties. This is evidenced by the similarities of both Young's modulus and compressive strength of the HAP-GEL to those of natural bone. 329 Future Bioceramics Gelatin (10*M) Ca(OH)2 H.P.O. (0.03M) Figure 4. Schematic drawing shows the biomimetic reactor. Base (calcium hydroxide) and acid (phosphorylated gelatin) reaction performed under temperature (38°C) and pH (8.0) control results in precipitation of hydroxyapatite nanocrystals in gelatin molecules. The hydroxyapatite-gelatin nanocomposite particles are cross-linked by glutaraldehyde. Plane strain Young’s modulus of the nanocomposite was measured by the nanoindentation method (Ko et al., 1995; Rho et al., 1997; Zysset et al., 1999; Oyen and Ko, 2007). The overall stiffness is very close to that of natural bone (Table 3), reducing the stress discontinuity when the material is implanted into the body. Increased gelatin content at fixed glutarahdehyde content resulted in slightly increased plane strain modulus values for the largest nanoindentation loads. Based on the TEM observations along with previous examinations of mineralized nanocomposite structure-properties relationships via finite element modeling (Oyen and Ko, 2005), we hypothesize that the gelatin effect on elastic modulus is mediated through changing the ultrastructural arrangement of the nanocrystals (Ko et al., 2006) Decreased HA crystal size may be associated with better packing of the HA crystals, decreasing the interparticle distance for HA and allowing for more efficient strain transfer in the stiff phase. Compression strength was conducted using cylindrical rods (4 mm in diameter, 8 mm in height) machined from the solid nano- composite and tested using an Instron 4204 (Canton, MA, USA) at the speed of 0.5 mm/min. At a constant gelatin content (5 g), glutaraldehyde additions had no significant effects on compressive strength (p − 0.05) The stress-strain curve demonstrated a post-yield plastic deformat" regimen rather than brittle failure (Fig. 5A). Cross-linkage of the material makes the gelatin fibers longer and the composite stronger. Interestingly. although it altered the toughness, the amount of cross-linkaº (glutaraldehyde concentration) did not affect the compressive strength of HAP-GELs. The average compressive strength was 130.7+13.0 MPa. 330 Ko et al. Table 3. Indentation Plane Strain Modulus, E' (GPa, presented as mean + standard deviation), for HAP-GEL materials with varied gelatin content and fixed glutaraldehyde content. Composite Pmax F Pmax = Pmax F Pmax - (). I m/N I m/N 10 mN 100 mN GEL2.5GAL_|_E (GPa.) | 29.5 + 6. 1 || 33.5 + 7.8 || 31.7 H 8.3_|_22.1 + 1.8 GEL.GA E (GPa.) | 29.9 + 7.9 29.7 + 7.9 || 25.8 + 2.6 25.2 + 2.3 GEL: 3GA | E (GPa.) | 30.0 + 11.3 28.8 + 5.0 | 28.7 ± 3.3 || 26.2 + 2.3 This value is comparable to those for compact bone: human, 170+4 Mpa; pig, 100+1 Mpa; cattle, 147+1 Mpa, Fung, 1984) and the material may be suited for functional loading. Note that the elastic modulus calculated from the macro- compression curve (1-2 GPa) was much lower than that of nano- indentation modulus (20–30 GPa). This is due to the method of compression test in which the cross-head position was used to estimate strains. The crushing at the contact areas between the samples (Fig. 5B) and the machine amplified the strain levels and, thus, decreased Young's modulus compared to that obtained from nanoindentation test. The nano- indentation using the elastic rebounded curve in conjunction with the theory of elasticity provides better estimates of intrinsic Young's modulus (Ko et al., 1995; Rho et al., 1997). The HAP-GEL proved to be biocompatible both in vitro and in vivo tests. Osteoblasts appeared to adhere to and grow well on the HAP- GEL material (Ko et al., 2006). In addition, the material also can host Osteoclasts as the TRAP stain showed that resorption area in relation to Osteoclast cultivated samples (Fig. 6A). Unlike the pure hydroxyapatite, resorption of the HAP-GEL also was observed in vivo (Fig. 6B,C). This preliminary data proves that HAP-GEL could be a good candidate for tissue engineering scaffold, partly because of its resorbable nature. Preparing porous scaffolding, however, has been challenging for this system. Previous attempts using water soluble cross-linking agents Such as glutaraldehyde, N-(3-dimethylaminopropyl)-N'-ethylcarbo- diimide (EDC), and N-hydroxysuccinimide (NHS) focus on gelatin- gelatin bonding during scaffolding (Ko et al., 2004; Kim et al., 2005). The process results in a weak structure and prohibits itself from using common scaffolding techniques such salt leaching. This experience leads us to develop sol-gel processing for the HAP-GEL System. 331 Future Bioceramics 1 4. o 1 2 o 1 o o so so i 40 20 º o o-1 0.2 0.3 0.4 o.5 d.6 o.7. A strain B Figure 5. A. Stress-strain curves of compression tests. Data were collected from solid HAP-GELs, showing plastic deformation after yielding. Variations exist between samples. B. Image of multiple damaged fragments at crushing. Some fracture lines seem to stop from propagation indicating potential toughening mechanisms due to cross-linkage of gelatin, which require further SEM inspection. Arrows indicate the compressed surfaces during test. Figure 6. A. Con-focal microscopic image shows TRAP stain (dark areasº bracketed) on the HAP-GEL matrix (grey background) cultivated with Osteoclasts. B. The scallop pattern (arrow) along the border between HAP-GEL and new bone formation (dark gray) indicates in vivo resorption after eight weeks of implantation in rat femurs. Note the cracks (black lines) were due tº grinding and cutting process (magnification = 200x). C. TRAP strain (bracket) confirms in vivo Osteoclast activity (magnification = 400x). Development of Hydroxyapatite/GEMOSIL. Sol-gel based biomaterials have attracted much attention because they can be synthesized from solution processes at room temperature. This |OW processing temperature makes sol-gel based biomaterials suitable for the 332 Ko et al. incorporation of biomolecules (Jin and Brennan, 2002) and living cells (Carturan et al., 2004) for biomedical applications. The sol-gel process is a wet chemical technique for the fabrication of materials (typically a metal oxide), starting from a chemical solution that reacts to produce colloidal particles (sol; Luo et al., 2005; Choi et al., 2007). Typical precursors are metal alkoxides and metal chlorides that undergo hydrolysis and polycondensation reactions to form a colloid, a system composed of solid particles (size ranging from 1 nm to 1 pum) dispersed in a solvent. The sol then evolves toward the formation of an inorganic network containing a liquid phase (gel). Formation of a metal oxide involves connecting the metal centers with oxo (M-O-M) or hydroxo (M- OH-M) bridges, therefore generating metal-oxo or metal-hydroxo polymers in solution. The drying process removes the liquid phase from the gel, thus forming a porous material. A thermal treatment (firing) may be used to promote polycondensation further and enhance mechanical properties. Silicon with a silica precursor is the most common sol-gel chemicals. Studies on sol-gel-derived biomaterials have proved to be Osteoblast compatible (Anderson et al., 1998) and have shown little toxicity in animal tests (Kortesuo et al., 1999). One reason for the biocompatibility is that the hydroxyl groups on the surface of sol-gel- derived materials promote hydroxyapatite formation and, therefore, promote tissue attachment (Li et al., 1994). In a most recent initiative, Ko and colleagues (2008) studied the interaction between HAP-GEL and enTMOS. The mixture of these two materials underwent a more rapid Solidification and dehydration than either material alone. New biomaterials made of organically modified animosilane (e.g., bis[3-(trimethoxysilyl)-propyl]ethylenediamine, enTMOS) and HAP-GEL exhibit a 70% increase in compressive strength (Fig. 7), Superb formability for scaffolding (Fig. 8), and upregulated cell differentiation (Fig. 9). Because gelatin appeared to participate in the sol- gel processing, we have named this new biomaterial as GEMOSIL, the gelatin modified silane (Luo et al., 2007). For porous scaffolds, porosity and surface density were calculated using Imageſ” software (Table 4). The porosity measures per- centage of void within the scaffold. The surface areas calculate the amount of surface areas, both inner and outer surface areas of the Scaffold. It is expected that increasing surface areas require more seeding cells for the culture study. 333 Future Bioceramics 250 ** ºf } 2 200 º: | gº' _ºr º 150 º º º º E. tº 100 gº º … # 50 f - r O 0 0.1 0.2 0.3 0.4 0.5 Strain 334 Ko et al. <- Figure 7. Compression curves of HAP-GEL (e) and the new mixture (O) composites. The peak strength of these curve are within or superior to the range of normal strength of mammalian cortical bone (100-170 MPa). <- Figure 8. Various scaffolds with pore size, ranging from 425-1000 pum, were generated. Photos and micro-CT data (SkyScan 1074, Micro Photonics, Allentown, PA) show connected pores and channels. A: Photograph of the porous cylinder with 600 pum pore. B: Micro-CT images of the 425 pum pore-size sample show three cross-sections (left) and the volume rendering. The cross-section images were used to calculate 2D Euler numbers, which describe holes and loops. The superimposition of the adjacent 2D images was used to calculate 3D Euler numbers for quantifying pore connectivity. C: Micro-CT image of the 600 pum pore-size sample shows the volume rendering. D: Micro- CT image of the 1000 pum pore-size sample shows the volume rendering. 0.4 0.4 DControl 0.3 * Material -T- T I 0.3 HI 0.2 0.2 0.1 - 0.1 - 0.0 I T | day 0 day 3 day 7 day 10 Figure 9. ALP (alkaline phosphotase) activities of control and HAP/GEMOSIL Osteoblasts did not reveal considerable differences. Table 4. The connectivity index (x3) estimated using Euler-Poincare Characteristics method. Increasing positive values indicate decreasing connectivity of the structure, and decreasing negative values indicate increasing connectivity. The high x3 in the small pore-size sample indicates there are more channels in the scaffold. Pore size | Connectivity Index e3 | Porosity Surface areas (mm”) 425 um –20.319 71.1% 9765 600 um –4.093 69.1% 6097 1000 um –2.425 53.2% 4629 335 Future Bioceramics Signs of cell adhesion, growth (proliferation), and function (differentiation) have been routine techniques used to assess biomaterials/scaffolds for tissue engineering applicability. Our pilot data showed that bone cells (MC3T3-El) adhered and grew normally on the surfaces of the new HAP-GEL-enTMOS matrix. The cells reached confluence four days following the seeding, which was equivalent to the time course for growing the same cell in a normal Petri dish without involving any biomaterials (control). Results also showed that there were no differences in alkaline phosphatase activity (synthesis function) between cells on the material and the control (data not shown). Alizarin red stain further confirmed mineralization both for the experiment and the control. The total mineralization area was similar between two groups. Some material dishes revealed the mineralization pattern resembling a trabecular network, while the pattern on the control revealed homogeneous, dispersed spots without connectivity between the minerals. On the patterned material dishes, cells seemed to conflate themselves into the trabecular network structures (Fig. 10). This left no cells between the trabecular spaces. In contrast, the control dishes had cells covered all over the entire surface. The patterned structure is favored in tissue engineering for load transfer. We stipulated that the HAP-GEL-enTMOS mixture must facilitate cell self-organization by cell-matrix interaction and cell migration. Gene expression was used to investigate sub silentio action between cells and materials. Preliminary real-time PCR results showed that Cbfal (osteoblastic differentiation gene) on material coated plates were higher significantly relative to control plates on Day 0, similar values on Day 3 and lower values on Day 7 (Fig. 11). There were no differences in the expression pattern of COL102 and BSP. This suggests that the material itself may promote cell differentiation. It remains to be tested if the accelerated cell differentiation is related to the trabecular mineralization pattern. A 3D culture was tested using a porous scaffold made by the CaCl2 salt leaching process. Preliminary results showed live cells attached onto and penetrated into the insides of the pores and channels after 24 hours of cultivation (Fig. 12). This result shows promise for longer time culture studies. 336 Ko et al. - - - - - - - º º -- - | | | | | - º - - - - . * - º - ". º º - º º º º - º, º 'º. º ºſº, º Figure 10. A. Alizarin red staining showing mineralized nodules forming a network pattern on material dish taken Day 15 with four days of preculture (Photo 1:1). B: Alizarin red stain of mineralized nodules on control dish taken Day 15 with four days of preculture (Photo 1:1). 8 I I I I I -º-Cbfat -M -3- Cbfat -C --Osterix – M --> --Osterix – C — — — OPN - M -El- OPN - C -A-Col 1a2 - M — -º- Colfaz - C —4–BSP - M -4 - BSP – C 12 Day Figure 11. Real-time PCR results (Cbfa1) demonstrate an earlier expression on HAP/GEMOSIL material coated plates when compared to control plates without "laterial coating. The other genes (COL1a2, Osterix, OPN, and BSP) hold the ºne patterns between the control and HAP/GEMOSIL (no statistical difference). 337 Future Bioceramics Figure 12. 3D cell culture shows live cells (green) attach to the wall of porous scaffold at 24 hours of cultivation. The microscopy focused on a single plain; the pore structure reveals blur due to its 3D topological nature. Block represents hole areas. Figure 13 shows the preliminary data of compression strengths for four different porous scaffolds. The compression rate 0.5 mm/min was the same as used previously for solid matrix. All samples were prepared in cylindrical shape (7 mm in diameter and 14 mm in height). Increasing pore size decreased strength. The porosity data (limited to 425 um, 600 um and 1000 um) seemed correlated inversely with the strength. This finding might be attributed to the internal truss-structure of the scaffold. At this point, however, there were not enough data (due to small sample size, n=3) to establish such a relationship. The preliminary data combining 600 um and 1000 um pore samples addressed the "wet" conditions, simulating in vivo environment. The wet condition Was controlled by immersing the dry scaffolds into the fixed amount (50 ml) of distilled water for 48 hours prior to the test. The compression strengths of the scaffolds were 0.354+0.182 MPa and 0.222+0.146 MPa for the dry and wet samples, respectively. It seemed there Was aſ approximately 30% decrease in strength in the wet state. Again, the difference was not statistically significant (n=6). Power analysis showed that a minimum sample size (n=10) may be required to detect “ difference 0.066 MPa at a level of 0.05. A degradation study Was parallelized to investigate the wet condition. It found that there was "" approximately 3.5% weight loss when the samples were immersed in water for four days. This may explain why strength decreased in Wº condition. The effect of degradation on mechanical properties, howevº may depend on porosity and total surface areas of the scaffold. In conclusion, the preliminary study demonstrated SO" promising biomaterial technologies that can be used in TMJ tiss" 338 Ko et al. 2. 5 }* 2 pºss 5 }* 1 – 0.5 – I T | O 1 il 1–1–1–1–1–1–h-i-m-i- | li 300 425 600 1000 pm Pore Size Figure 13. Compressive strength of various scaffold. The smaller the pore size, the higher the strength. engineering. Compression strength of the porous scaffolds with pore size greater than 425 um appeared very weak and fragile. The 300 um pore- Sample had an average strength 2.2 MPa, which is relatively closer to that of trabecular bone (5-10 Mpa; http://www.lib.umich.edu/dentlib/ Dental tables/Ultcompstr.html). It is expected that the small pore-size Scaffold (<300 um) should have strength greater than 2 MPa. SUMMARY The preliminary data suggest that developing this GEMOSIL biomaterial may lead to a downstream benefit that potentially can resolve challenges in the tissue engineering of the TMJ. These challenges include: * Promoting extra-cellular matrix synthesis and tissue maturation of stem cell-derived chondrogenic and osteogenic cells encapsulated in biocompatible and bioactive scaffolds. 339 Future Bioceramics Because this material is prepared at body temperature (38°C), future incorporation of cells and soluble growth factors should be feasible. • Enhancing the mechanical properties of a tissue engineered mandibular condyle for ultimate in situ implantation into the human TMJ. Having similar compressive strength and elastic modulus to natural bone, the HAP/GEMOSIL likely to sustain an in situ force. Future development will focus on wear resistance and fracture toughness to facilitate clinical trials. • Facilitating the remodeling potential of a tissue-engineered mandibular condyle (Mao et al., 2006). HAP/GEMOSIL is recognized by osteoclasts and starts resorption two months after implantation. This remodeling ability will yield a seamless interface between the implant and the host tissues. ACKNOWLEDGMENTS This work is supported, in part, by NIDCR K08DE018695, NIDCR R21DE015410, NIDCR NO1-DE-22635, NC Biotech Center Grant;2008-MRG-1 108, 3M ESPE Dental, American Association of Orthodontists Foundation, Portuguese Foundation for Science and Technology (FCT)/Government of the Portuguese Republic grant SFRH/BD/36841/2007, and School of Dentistry at University of North Carolina-Chapel Hill. Special thanks to Dr. James Fricton for his support and advisory comments. REFERENCES Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular Biology of the Cell. 3rd ed. New York: Garland Publishing 1994. Alexander R. Total temporomandibular joint replacement: Who? What? When? Where? NY State Dent J 1999;65:28-32. Allen KD, Athanasiou KA. Scaffold and growth factor selection in temporomandibular joint disc engineering. J Dent Res 2008;87:180- 185. American Association of Oral and Maxillofacial Surgeons. Parameters of care for oral and maxillofacial surgery: A guide for practice, monitoring and evaluation. J Oral Maxillofac Surg 1992;S2,50:1- 174. 340 Ko et al. American Association of Oral and Maxillofacial Surgery. Recommen- dations for management of patients with temporomandibular joint implants. J Oral Maxillofac Surg 1993;51:1164-1172. Anderson SI, Downes S, Perry CC, Caballero AM. Evaluation of the osteoblast response to a silica gel in vitro. J Mater Sci Mater Med 1998;9:731-735. Annandale T. On displacement of the inter-articular cartilage of the lower jaw and its treatment by operation. Lancet 1887; 129:411. Ash MM. Current concepts in the aetiology, diagnosis and treatment of TMJ and muscle dysfunction. J Oral Rehab 1986; 13:1-20. Baird DN, Rea WJ. The temporomandibular joint implant controversy: Part II. Its clinical implications. J Nutrit Environ Med 1999;9:209- 222. Bee DE. The Proplast-Teflon" implant in TMJ reconstruction following meniscectomy. New Orleans, LA; Annual meeting of the AAOMS, Sept 24-28, 1986. Boskey AL. Will biomimetics provide new answers for old problems of calcified tissues? Calcif Tissue Int 1998;63:179-182. Carturan G, Toso RD, Boninsegna S, Monte RD. Encapsulation of functional cells by sol-gel silica: Actual progress and perspectives for cell therapy. J Mater Chem 2004;14:2087-2098. Chang MC, Ko CC, Douglas WH. Preparation of hydroxyapatite-gelatin nanocomposite. Biomaterials 2003:24:2853–2862. Charnley J. An artificial bearing in the hip joint: Implications in biological lubrication. Fed Proc 1966:25:1079–1081. Chase DC, Hudson JW, Gerard DA, Russell R, Chambers K, Curry JR, Latta JE. Christensen RW. The Christensen prosthesis: A retrospective clinical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80:273-278. Choi Y, Huh U, Luo TJM. A microfluidic device for optoelectro- chemical sensing. NSTI-Nanotech 2007;3:363-366. Christensen RW, Alexander R, Curry JT, Christensen MS, Dollar JV. Hemi and total TMJ reconstruction using the Christensen prostheses: A retrospective and prospective evaluation. Surg Technol Int 2004;12:292–303. 341 Future Bioceramics Chu TMG, Hollister SJ, Halloran JW, Feinberg SE, Orton DG. Manufacturing and characterization of 3D hydroxyapatite bone tissue engineering scaffolds. Ann NY Acad Sci 2002;961:114-117. Chuong R, Piper MA, Boland T.J. Recurrent giant cell reaction to residual Proplast in the temporomandibular joint. Oral Surg Oral Med Oral Pathol 1993;76:16-19. Cook SD, Baffes GC, Wolfe MW, Sampath TK, Rueger DC, Whitecloud TS III. The effect of recombinant human osteogenic protein-1 on healing of large segmental bone defects. J Bone Joint Surg Am 1994; 76:827-838. Currey JD. Bone: Structure and Mechanics. New Jersey: Princeton University Press 2002. de Leeuw R. Temporomandibular disorders. In: de Leeuw R, ed. Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management. The American Academy of Orofacial Pain. Chicago: Quintessence Publishing Co. Inc., 2008;129-204. de Leeuw R, Boering G, Stegenga B, de Bont LG. Clinical signs of TMJ osteoarthrosis and internal derangement 30 years after nonsurgical treatment. J Orofac Pain 1994;8:18-24. Deer WA, Howie RA, Zussman J. An Introduction to the Rock-forming Minerals. New York: Wiley 1966. Dimitroulis G. The role of surgery in the management of disorders of the temporomandibular joint: A critical review of the literature. Part 1. Int J Oral Maxillofac Surg 2005a:34:107-113. Dimitroulis G. The role of surgery in the management of disorders of the temporomandibular joint: A critical review of the literature. Part 2. Int J Oral Maxillofac Surg 2005b:34:231-237. Dubok VA. Bioceramics: Yesterday, today, tomorrow. Powd Metall Metal Ceram 2000:39:381-394. Dworkin SF, LeResche L, Von Korff MR. Studying the natural history of TMD: Epidemiologic perspectives on physical and psychological findings. In: Vig KD, Vig PS, eds. Clinical Research as the Basis of Clinical Practice. Craniofacial Growth Series, Center for Human Growth and Development, Vol 25, The University of Michigan, Ann Arbor 1991:39–60. Eriksson L, Westesson PL. Results of temporomandibular joint diskectomies in Sweden 1965-85. Swedish Dental J 1987; 11:1-9. 342 Ko et al. Estabrooks LN, Fairbanks CE, Collett RJ, Miller L. A retrospective evaluation of 301 TMJ Proplast-Teflon implants. Oral Surg Oral Med Oral Pathol 1990:70:381-386. Evans LA, Macey DJ, Webb J. Calcium biomineralization in the radular teeth of the chiton, Acanthopleura hirtosa. Calcif Tissue Int 1992:51:78-82. Farrar WB. Diagnosis and treatment of painful temporomandibular joints. J Prosthetic Dent 1968:20:345-351. Federal Drug Administration. FDA safety alert: Serious problems with Proplast coated TMJ implant. 1990. p Federal Drug Administration. TMJ concepts: Patient-fitted TMJ reconstruction prosthesis system (P980052). Rockville, MD: Office of Device Evaluation, Center for Devices and Radiological Health, July 2, 1999. Feinberg SE, Hollister SJ, Halloran JW, Chu TM, Krebsbach PH. Image- based biomimetic approach to reconstruction of the temporo- mandibular joint. Cells Tissues Organs 2001;169:309-321. Feinberg SE, Larsen PE. The use of a pedicled temporalis muscle- pericranial flap for replacement of the TMJ disc: Preliminary report. J Oral Maxillofac Surg 1989;47: 142-146. Ferreira JN, Ko CC, Myers S, Swift J, Fricton JR. Evaluation of surgically retrieved temporomandibular joint alloplastic implants: Pilot study. J Oral Maxillofac Surg 2008;66:1112-1124. Ferreira JN, Ko CC, Myers S, Swift J, Fricton JR. Preliminary evaluation of surgically retrieved temporomandibular joint Proplast/Teflon interpositional implants. Phoenix, AZ: AAOP and AAOM joint meeting, April 2005. Fricton JR, Look JO, Schiffman E, Swift J. Long-term study of temporomandibular joint surgery with alloplastic implants compared with nonimplant surgery and nonsurgical rehabilitation for painful temporomandibular joint disc displacement. J Oral Maxillofac Surg 2002;60:1400–1411. Fung YC. Biomechanics: Mechanical Properties of Living Tissues. New York: Springer-Verlag 1984. Gallagher DM, Wolford LM. Comparison of Silastic and Proplast implants in the temporomandibular joint after condylectomy for osteoarthritis. J Oral Maxillofac Surg 1982;40:627-630. 343 Future Bioceramics Goodman SB, Fornasier VL, Lee J, Kei J. The histologic effects of the implantation of different sizes of polyethylene particles in the rabbit tibia. J Biomed Mater Res 1990:24:517-524. Goss AN. Toward an international consensus on temporomandibular joint surgery. Report of the Second International Consensus Meeting, April 1992, Buenos Aires, Argentina. Int J Oral Maxillofac Surg 1993:22:78-81. Green TR, Fisher J, Stone M, Wroblewski BM, Ingham E. Polyethylene particles of a ‘critical size’ are necessary for the induction of cytokines by macrophages in vitro. Biomaterials 1998; 19:2297-2302. Griffith LG. Emerging design principles in biomaterials and scaffolds for tissue engineering. Ann NY Acad Sci 2002;961:83-95. Hakimimehr D, Liu D-M, Troczynski T. In-situ preparation of poly(pro- pylene fumarate)-hydroxyapatite composite. Biomaterials 2005:26: 7297-7303. Hartman LC, Bessette RW, Baier RE, Meyer AE, Wirth J. Silicone rubber temporomandibular joint (TMJ) meniscal replacements: Postimplant histopathologic and material evaluation. J Biomed Mater Res 1988:22:475-484. Henry CH, Wolford LM. Treatment outcomes for temporomandibular joint reconstruction after Proplast-Teflon implant failure. J Oral Maxillofac Surg 1993;51:352-358. Hernandez-Pando R, Bornstein OL, Aguilar LD, Orozco EH, Madrigal VK, Martinez CE. Inflammatory cytokine production by immunological and foreign body multinucleated giant cells. Immunology 2000;100:352-358. Homsy CF. Biocompatibility of clinical implant materials: Vol. 2. Boca Raton: CRC Press Inc., 1982. Homsy CA. Reasons for failure of Proplast/Teflon disc replacements. J Oral Maxillofac Surg 1991;49:778–779. Horowitz SM, Rapuano BP, Lane JM, Burstein AH. The interaction of the macrophage and the osteoblast in the pathophysiology of aseptic loosening of the joint repacements. CalcifTissue Int 1994:54:320-324. Ikeda T, Ikeda K, Sasaki K, Kawakami K, Hatake K, Kaji Yea. IL-13 as well as IL-4 induces monocytes/macrophages and a monoblastic cell line (UG3) to differentiate into multinucleated giant cells in the presence of M-CSF. Biochem Biophys Res Commun 1998:253:265-272. 344 Ko et al. Jarcho M. Calcium phosphate ceramics as hard tissue prosthetics. Clin Orthop Relat Res 1981;157:259-278. Jin W, Brennan JD. Properties and applications of proteins encapsulated within sol-gel derived materials. Analytica Chimica Acta 2002; 461 : 1-36. Kaneyama K, Segami N, Sun W, Sato J, Fujimura K. Analysis of tumor necrosis factor-alpha, interleukin-6, interleukin-1beta, soluble tumor necrosis factor receptors I and II, interleukin-6 soluble receptor, interleukin-1 soluble receptor type II, interleukin-1 receptor antagonist, and protein in the synovial fluid of patients with temporomandibular joint disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:276-284. Kao WJ. Evaluation of protein-modulated macrophage behavior on biomaterials: Designing biomimetic materials for cellular engineering. Biomaterials 1990:20:2213-2221. Kaplan FS, Hayes WC, Keaveny TM, Boskey A, Einhorn TA, Iannotti JP. Form and function of bone. In: Simon Sr, ed. Orthopedic Basic Science. Rosemont IL: AAOS 1994. Kent JN, Block MS, Halpern J, Fontenot MG. Update on the vitek partial and total temporomandibular joint systems. J Oral Maxillofac Surg 1993;51:408-415. Kent JN, Misiek DJ, Akin RK, Hinds EC, Homsy CA. Temporomandibular joint condylar prosthesis: A ten-year report. J Oral Maxillofac Surg 1983;41:245-254. Kiehn CL, Desprez JD. Meniscectomy for internal derangements of the temporomandibular joint. Br J Plast Surg 1962;15:199-204. Kiersch TA. The use of Proplast-Teflon implants for meniscectomy and disk repair in the temporomandibular joint [Abstract]. Presented at AAOMS Clinical Congress on Reconstructive Biomaterials: Current Assessment and Temporomandibular Joint: Surgical Update. San Diego, CA 1984. Kim H-W, Kim H-E, Salih V. Stimulation of osteoblast responses to biomimetic nanocomposites of gelatin-hydroxyapatite for tissue engineering scaffolds. Biomaterials 2005:26:5221-5230. Ko CC, Chang MC, Douglas WH, Hu W-S. Biomimetic Nanocomposite. 2007;US Patent USOP#11-305663. 345 Future Bioceramics Ko CC, Douglas WH, Cheng Y-S. Intrinsic mechanical competence of cortical and trabecular bone measured by nanoindentation and microindentation probes. ASME 1995;BED-29:415-416. Ko CC, Douglas WH, Chu T-M, Chang MC, Narayanan RA, Hu W-S. Forming 3D scaffolds of hydroxyapatite-gelatin nano-composites using mechanical method and selective solid etching method. Sydney: Proceeding World Biomaterials Conference 2004. Ko CC, Luo TJM, Chi L, Ma A. Hydroxyapatite/gemosil nano- composite. Proceeding of 32nd International Conference and Exposition on Advanced Ceramics and Composites, January 2008. Ko CC, Oyen M, Fallgatter AM, Hu W-S. Mechanical properties and cytocompatibility of biomimetic hydroxyapatite-gelatin nanocom- posites. J Mater Res 2006:21:3090-3098. Kortesuo P, Ahola M, Karlsson S, Kangasniemi I, Kiesvaara J., Yli-Urpo A. Sol-gel processed sintered silica xerogel as a carrier in controlled drug delivery. J Biomed Mater Res 1999;44:162-167. Kulber DA, Davos I, Aronowitz J. Severe cutaneous foreign body giant cell reaction after temporomandibular joint reconstruction with Proplast-Teflon. J Oral Maxillofac Surg 1995:53:719–722. Langer R, Vacanti JP. Tissue engineering. Science 1993:260:920–926. Lanz W. Discitis mandibularis. Zentralbl Chir 1909;9:289-291. Laskin DM. Temporomandibular disorders: The past, present, and future. Odontology 2007;95:10-15. Laskin DM, Block S. Diagnosis and treatment of myofacial pain- dysfunction (MPD) syndrome. J Prosthetic Dent 1986:56:75-84. LeGeros RZ. Calcium phosphate materials in restorative dentistry: A review. Adv Dent Res 1988:2:164-180. LeGeros RZ. Properties of osteoconductive biomaterials: Calcium phosphates. Clin Orthop Rel Res 2002;395:81-98. Li PJ, Ohtsuki C, Kokubo T, Nakanishi K, Soga N, de Groot K. The role of hydrated silica, titania, and alumina in inducing apatite on implants. J Biomed Mater Res 1994:28:7-15. Li S, Burstein AH. Ultra-high molecular weight polyethylene. The material and its use in total joint implants. J Bone Joint Surg Am 1994;76:1080-1090. Lind M, Trindade MC, Nakashima Y, Schurman DJ, Goodman SB, Smith RL. Chemotaxis and activation of particle-challenged human 346 Ko et al. monocytes in response to monocyte migration inhibitory factor and C-C chemokines. J Biomed Mater Res 1999:48:2246-2250. Luo TJM, KO CC, Tulloch JFC. Formable bioceramics. US Patent No. 60/949,281.2007. Luo TJM, Soong R, Lan E, Dunn B, Montemagno C. Photo-induced proton gradients and ATP biosynthesis produced by vesicles encap- sulated in a silica matrix. Nature Materials 2005;4:220–224. Mann S, Archibald DD, Didymus JM, Douglas T, Heywood BR, Meldrum FC, Nicholas JR. Crystallization at inorganic-organic interfaces: Biomaterials and biomimetic synthesis. Nature 1993; 382:313–318. Mann S, Ozin GA. Synthesis of inorganic materials with complex form. Nature 1996:382:313–318. Mao JJ, Giannobile WV, Helms JA, Hollister SJ, Krebsbach PH, Longaker MT, Shi S. Craniofacial tissue engineering by stem cells. J Dent Res 2006:85:966-979. Mercuri LG. Osteoarthritis, osteoarthrosis, and idiopathic condylar resorption. Oral Maxillofac Surg Clin North Am 2008:20:169-183. Mercuri LG. Ultra-high molecular weight polyethylene fossa wear and incidence of adverse effects. J Oral Maxillofac Surg 2004;62:906- 907. Mercuri LG, Giobbie-Hurder A. Long-term outcomes after total alloplastic temporomandibular joint reconstruction following exposure to failed materials. J Oral Maxillofac Surg 2004;62:1088– 1096. Mercuri LG, Wolford LM, Sanders B, White RD, Hurder A, Henderson W. Custom CAD/CAM total temporomandibular joint reconstruction system: Preliminary multicenter report. J Oral Maxillofac Surg 1995:53:106-115. Meyer RA. The autogenous dermal graft in temporomandibular joint disc surgery. J Oral Maxillofac Surg 1988:46:948-954. Middleton JC, Tipton AJ. Synthetic biodegradable polymers as orthopedic devices. Biomaterials 2000:21:2335-2346. Milam S. Failed implants and multiple operations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:156-162. Moriconi E, Popowich L. Alloplastic reconstruction of the temporo- mandibular joint. Dent Clin North Am 1986:30:307-325. 347 Future Bioceramics Nalbandian R, Swanson A, Maupin B. Long-term silicone implant arthroplasty: Implications of animal and human autopsy findings. JAMA 1983:250: 1195–1198. Okeson JP, ed. Orofacial Pain: Guidelines for Assessment, Diagnosis, and Management. Chicago: Quintessence Publishing Co. Inc., 1996. Oyen ML. Ultrastructural characterization of time-dependent, inhomogeneous materials and tissues. PhD Thesis. University of Minnesota 2005. Oyen ML, Ko CC. Examination of local variations in Viscous, elastic, and plastic indentation responses in healing bone. J Mater Sci Mater Med 2007;18:623–628. Oyen M, Ko CC. Finite element modeling of bone ultrastructure as a two-phase composite. In: MRS Proceedings Vol. 844. Mechanical Properties of Bioinspired and Biological Materials 2005;Y8.7. Parks JB, Lakes RS. Biomaterials: An Introduction. New York: Plenum Press 1992; 123-125. Paschalis EP, DiCarlo E, Betts E, Sherman P, Mendelsohn R, Boskey AL. FTIR microspectroscopy analysis of human osteonal bone. Calcif Tissue Int 1996:59:480–487. Perrott DH, Umeda H, Kaban LB. Costochondral graft reconstruction/ reconstruction of the ramus/condyle unit: Long term follow-up. Int J Oral Maxillofac Surg 1994:23:321-328. Quinn PD. Lorenz prosthesis. Oral Maxillofac Surg Clin North Am 2000;12:93-104. Raphael KG, Marbach JJ, Keller SE, Bartlett JA. Systemic health consequences of alloplastic implants of the TMJ: A pilot study. J Orofac Pain 1998; 12:293–299. Raustia A, Pernu H, Pyhtinen J, Oikarinen K. Clinical and computed tomographic findings in costochondral grafts replacing the mandibular condyle. J Oral Maxillofac Surg 1996;54:1393-1400. Rho JY, Tsui TY, Pharr GM. Elastic properties of human cortical and trabecular lamellar bone measured by nanoindentation. Biomaterials 1997;18:1325-1330. Rubin JP, Yaremchuck MJ. Complications and toxicities of implantable biomaterials used in facial reconstructive and aesthetic surgery: A comprehensive review of the literature. Plast Reconstr Surg 1997;102:1766–1768. 348 Ko et al. Ryan D. Alloplastic disc replacement. Oral Maxillofac Surg Clin North Am 1994;6:307-321. Ryan D. Alloplastic implants in the temporomandibular joint. Oral Maxillofac Surg Clin North Am 1989; 1:427–441. Ryan DE. Severe cutaneous foreign body giant cell reaction after temporomandibular joint reconstruction with Proplast-Teflon. J Oral Maxillofac Surg 1995:53:722-723. Sándor GKB, McGuire TP., Ylikontiola LP, Serlo WS, Pirttiniemi PM. Management of facial asymmetry. Oral Maxillofacial Surg Clin N Am 2007; 19:395-422. Service RF. Tissue engineers build new bone. Science 2000:289:1498– 1500. Shanbhag AS, Jacobs JJ, Black J, Galante JO, Glant TT. Macrophage/particle interactions: Effect of size, composition and surface area. J Biomed Mater Res 1994:28:81–90. Silver CM, Simon SD. Meniscus injuries of the temporomandibular joint: Further experiences. J Bone Joint Surg 1963;45:113-124. Spagnoli D, Kent JN. Multicenter evaluation of temporomandibular joint Proplast-Teflon disk implant. Oral Surg Oral Med Oral Path 1992; 74:411–421. Stegenga B, de Bont LG, Boering G. Osteoarthrosis as the cause of craniomandibular pain and dysfunction: A unifying concept. J Oral Maxillofac Surg 1989;47:249-256. Sun L, Berndt CC, Gross KA, Kucuk A. Material fundamentals and clinical performance of plasma-sprayed hydroxyapatite coatings: A review. J Biomed Mater Res 2001:58:570–592. Ta LE, Phero JC, Pillemer SR, Hale-Donze H, McCartney-Francis N, Kingman A, Max MB, Gordon SM, Wahl SM, Dionne RA. Clinical evaluation of patients with temporomandibular joint implants. J Oral Maxillofac Surg 2002;60:1389–1399. Takaku S, Toyoda T. Long-term evaluation of discectomy of the temporomandibular joint. J Oral Maxillofac Surg 1994;52:722-726. Toller PA. Opaque arthrography of the temporomandibular joint. Int J Oral Surg 1974;3:17-28. Trumpy IG, Lyberg T. In vivo deterioration of proplast-teflon temporomandibular joint interpositional implants: A scanning electron microscopic and energy-dispersive X-ray analysis. J Oral Maxillofac Surg 1993;51:624–629. 349 Future Bioceramics Valentine JD Jr., Reiman BE, Beuttenmuller EA, Donovan MG. Light and electron microscopic evaluation of Proplast II TMJ disc implants. J Oral Maxillofac Surg 1989;47:689-696. Valentini V, Vetrano S, Agrillo A, Torroni A, Fabiani F, Iannetti G. Surgical treatment of TMJ ankylosis: Our experience (60 cases). J Craniofac Surg 2002; 13:59-67. Wang L, Detamore MS. Tissue engineering the mandibular condyle. Tissue Eng 2007:13:1955-1971. Wegner LD, Gibson LJ. The mechanical behavior of interpenetrating phase composites: I. Modeling. Internat J Mech Funct Relat 2000:42:925-942. Westesson PL, Eriksson L, Lindstrom C. Destructive lesions of the mandibular condyle following diskectomy with temporary silicone implant. Oral Surg Oral Med Oral Path 1986;63:143-150. Wilkes CH. Arthrography of the temporomandibular joint in patients with the TMJ pain-dysfunction syndrome. Minnesota Medicine 1978;61:645-652. Wilkes CH. Surgical treatment of internal derangements of the temporomandibular joint. A long-term study. Arch Otolaryngol Head Neck Surg 1991;1 17:64-72. Witsenburg B, Freihofer HP. Replacement of the pathological temporomandibular articular disc using autogenous cartilage of the external ear. Int J Oral Surg 1984;13:401–405. Wolford LM. Temporomandibular joint devices: Treatment factors and outcomes. Oral Surg Oral Med Oral Path Oral Radiol Endod 1997;83:143-149. Wolford LM, Cottrell DA, Henry C. Sternoclavicular grafts for temporomandibular joint reconstruction. J Oral Maxillofac Surg 1994:52:119-128. Wolford LM, Dingwerth DJ, Talwar RM, Pitta MC. Comparison of 2 temporomandibular joint total joint prosthesis systems. J Oral Maxillofac Surg 2003;61:685–690. Wolford LM, Henry CH, Nikaein A, Newman JT, Namey TC. The temporomandibular joint alloplastic implant problem. In: Sessle BJ, Bryant P, Dionne R, eds. Temporomandibular Disorders and Related Pain Conditions, Progress in Pain Research and Management. Seattle: IASP PreSS 1995. 350 Ko et al. Wolford LM, Mehra P, Rea W. Metal hypersensitivity in patients with total joint prosthesis. J Oral Maxillofac Surg 2000:58:S1:29. Wolford LM, Pitta MC, Reiche-Fischel O, Franco PF. TMJ Concepts/Techmedica custom-made TMJ total joint prosthesis: 5- year follow-up study. Int J Oral Maxillofac Surg 2003:32:268-274. Yamauchi M. Collagen biochemistry: An overview. Advances in Tissue Banking 2002;6:445-500. Zardeneta G, Mukai H, Marker V. Milam SB. Protein interactions with particulate Teflon: Implications for foreign body response. J Oral Maxillofac Surg 1996:54:873-878. jº Zysset PK, Guo XE, Hoffler CE, Moore KE, Goldstein SA. Elastic modulus and hardness of cortical and trabecular bone lamellae measured by nanoindentation in the human femur. J Biomech 1999:32:1005-1012. 351 F-SPONDIN: A NEW REGULATOR OF CARTILAGE MATURATION IN DEVELOPMENT AND OSTEOARTHRITIS Marina D'Angelo, Lwin Mon Thant, Glyn Palmer, Mukundan Attur, Steve Abramson, Cristina C. Teixeira ABSTRACT Cartilage health and function requires a delicate interplay between proteins produced by chondrocytes and signaling to these chondrocytes from the extracellular matrix. Alterations in these interactions result in osteoarthritis, a degenerative disease of permanent cartilage, and chondrodysplasias or dwarfism, diseases of transient cartilage of the long bones. One such molecule, F-spondin, a heparin-binding extracellular matrix glycoprotein, is highly expressed in growth plate and osteoarthritic cartilage. We report here that F- spondin alters endochondral bone formation in cultured embryonic tibiae by inhibiting growth, as measured by length and simultaneously increasing maturation as measured by mineralization. These results support the role of F- spondin in endochondral bone formation. Cartilage is an avascular tissue characterized by an abundant extracellular matrix rich in type II collagen and high molecular weight proteoglycan. There are two types of cartilage, a permanent and a transient cartilage that, while having the same embryonic origin follow divergent differentiation pathways, fulfill different functions and ultimately as their name suggests, have different fates. Articular, tracheal, and other cartilage structures are classified as permanent cartilage. The chondrocytes in these structures maintain a stable phenotype and persist throughout life. In contrast, most of the embryonic cartilaginous skeleton, the epiphyseal growth plates of long bones, the cartilaginous callus formed at fracture sites, and the tissue created during distraction osteogenesis consist of transient cartilage (Ferguson et al., 1999; Iwamoto et al., 2001). Through a series of maturational changes this transient cartilage gradually is replaced by bone. The developing limb has been the subject of numerous studies of molecules that characterize and regulate the differentiation pathway in 353 Regulator of Cartilage Maturation both permanent and transient cartilage. Initially in a limb bud, the mesenchyme condenses in the area of the future bone, and after cell differentiation into chondrocytes and proliferation, a cartilage model of the bone is created. Eventually the chondrocytes in the center of this model undergo maturation, becoming hypertrophic. During hypertrophy cells exhibit increased plasma membrane alkaline phosphatase activity (O’Keefe et al., 1990), elevated synthesis of type X collagen (Schmid and Linsenmayer, 1985; Hoyland et al., 1991), down regulation of type II collagen production (Hillarby et al., 1996), and raised secretion of osteonectin (Metsaranta et al., 1989) and osteocalcin (Mark et al., 1988). The hypertrophic chondrocytes release matrix vesicles that serve as sites of nucleation for mineral formation (Anderson, 1969). Vascular invasion of this calcified cartilage in the diaphysis brings osteoprogenitor cells that remodel the cartilage and replace it with bone. As the marrow cavity expands toward the epiphysis, more cartilage is replaced by bone slowly, with the residual cartilage forming a growth plate and an articular surface at the end of the long bones. In the growth plate, located between the epiphysis and the diaphysis, these maturation events are recapitulated and chondrocytes are arranged in distinct zones that correlate to specific stages of maturation: resting, proliferating, hypertrophic and calcified zone (Karaplis, 2002; Malemud, 2006). In Figure 1, hematoxylin staining of embryonic tibial growth plates identifies chondrocytes at these various stages of maturation. The resting zone of endochondral ossification represents the earliest stage of differentiation where chondrocytes are least mature, and they produce collagen type II, Indian hedgehog and Osteocalcin, among other cartilage markers. As maturation continues, chondrocytes proliferate, align in columns, and express collagen type II (Schmid and Linsenmayer 1985; O’Keefe et al., 1990; Hillarby et al., 1996). As seen in Figure 1B, the onset of hypertrophy is characterized by the expression of collagen type X, as well as collagenase 3 (MMP-13), and a decrease in collagen type II expression followed by an increase in alkaline phosphatase production (Leboy et al., 1988; Alini et al., 1992; D’Angelo et al., 2000; Karaplis, 2002; Tchetina et al., 2006). In later stages of hypertrophy, increased matrix metalloproteinase (MMP) production results in remodeling of the matrix in preparation for and promotion of matrix calcification (Alini et al., 1992, 1996). The zone of calcification represents the most mature zone in endochondral ossification, where chondrocytes die by apoptosis (Hatori et al., 1995; Mansfield et al., 2001; Teixeira et al., 2001) leaving behind lacuna in the calcified cartilage where invading osteoblasts begin laying down bony trabeculae. 354 D'Angelo et al. Resting Proliferating Hypertrophic Calcified º- º- - - º:-5. ºF º º - - - -- Figure 1. Immunolocalization of maturation markers in growth plate Cartilage. Longitudinal sections through the tibial growth plate of 20- day-old chicken embryos were immunostained using antibodies against type X collagen, and counterstained with hematoxylin. A. Control Section was incubated with pre-immune serum. The different regions of the growth plate are identified on the left side of the image. B: Staining for Type X collagen. Brown color indicates positive staining. A Vascular channel invading the calcified region can be observed in the Sections (VC). Magnification 200X. Contrasting with this transient structure, articular cartilage exhibits a more stable phenotype. Articular chondrocytes under normal physiological conditions do not progress through the maturational stages described earlier. However, during osteoarthritis articular chondrocytes Synthesize type X collagen (von der Mark et al., 1992; Walker et al. 355 Regulator of Cartilage Maturation 1995; Eerola et al., 1998), MMP-13, transglutaminase (Johnson and Terkeltaub, 2005), osteopontin (Pullig et al., 2000a) and osteocalcin (Pullig et al., 2000b), markers of the hypertrophic chondrocytes. In addition, osteoarthritic chondrocytes exhibit high alkaline phosphatase activity (Pullig et al., 2000a) mineralize the extracellular matrix (von der Mark et al., 1992; Walker et al., 1995; Hashimoto et al., 1998, 2002), and die by apoptosis (Blanco et al., 1995; Aigner et al., 2002). This evidence suggests that during osteoarthritis, chondrocytes may behave similar to the cells in the growth plate and express the hypertrophic phenotype. While the osteoarthritic process has been described as a cartilage degeneration or degradation event, formation of newly synthesized connective tissue, osteophytes, has been observed in human and experimentally induced osteoarthritis (van der Kraan and van den Berg, 2007). These structures are composed of proliferating, differentiating and hypertrophic chondrocytes. Furthermore, the pattern of gene expression in osteophytes resembles the epiphyseal growth plate. Type II and type X collagen are found in osteophyte cells and after vascularization, these areas undergo endochondral ossification (Aigner et al., 1995; Eerola et al., 1998; Hashimoto et al., 2002). Evidence from all these studies strongly supports the hypothesis that during osteoarthritis the articular chondrocyte switches its developmental program from a permanent cartilage cell to a transient cartilage one. Hence, pathways involved in growth plate chondrocyte maturation, hypertrophy and apoptosis are extremely important not only as targets for growth therapies but also as targets for new therapies to osteoarthritis. In addition, factors regulating osteoarthritis also may have a role in endochondral ossification and bone growth. With the overall aim of identifying novel pathways associated with osteoarthritis pathogenesis, Bauer and coworkers (2006) previously have discovered enhanced expression of the extracellular matrix glycoprotein, F-spondin, in Osteoarthritic cartilage and F-spondin expression also increased in rat OA model. F-spondin (“Floor plate” and “thrombospondin” homology; also Spondin-1 and VSGP) is a 110 kDa, secreted, heparin-binding extracellular matrix glycoprotein. F-spondin first was identified as a novel protein secreted by neuronal cells that caused a rat hippocampal progenitor cell line and primary cortical neural cells to differentiate into cells with the morphological and biochemical features of neurons (Klar et al., 1992). It is a member of a family of proteins that collectively belong to a subgroup of TSR (thrombospondin) 356 D'Angelo et al. type I class molecules, which include COMP, CTGF, ADAMTS-7& 12 and CILP (Feinstein and Klar, 2004; Tucker, 2004). Current work in our laboratory shows that the expression of F- spondin protein also is upregulated during hypertrophy of chicken growth plate chondrocytes (data not shown). Recently, Yamane and colleagues (2007) have shown that F-spondin also is highly expressed in mouse growth plate chondrocytes relative to normal articular chondrocytes. However, there are no studies characterizing the role of F- spondin in cartilage or endochondral bone formation. In this investigation, we report that modulating F-spondin levels affects endochondral bone formation and growth of cultured embryonic tibiae. MATERIALS AND METHODS Organ Culture CD1 timed-pregnant mice (Charles River Laboratories, Wil- mington, MA) were euthanized, and tibiae were isolated from E15.5 embryos using a stereomicroscope (Nikon Instruments, Melville, NY). Dissection day was considered day 0, and tibiae were allowed to recover from dissection overnight in serum-free 0-MEM media containing 0.2% bovine serum albumin (BSA), 0.5m M L-glutamine, 40 U/mL penicillin, and 40 pg/ml streptomycin as described by Serra and coworkers (1999). The following morning, tibiae were placed in 24-well Falcon plates and initial longitudinal length was measured using a stereomicroscope. Tibiae then were treated with either 0.5 pig/ml F-spondin recombinant protein (R&D Systems, Minneapolis, MN) or 1 pigſml of F-spondin neutralizing antibody (a generous gift from Dr. A. Klar). Media was changed every 24 hours beginning on day one, and tibial length was measured again at the end of one week. The results were expressed as percentage changes in length relative from day one. Statistical analyses were performed using SPSS 13.0 (Chicago, IL). The mean differences in the length among the three experimental groups were evaluated by using the nonparametric Mann-Whitney test. All p values presented were two- tailed and considered statistically significant at p < 0.05. Alizarin Red and Alcian Blue Staining For alizarin red/alcian blue staining (staining for mineral and proteoglycan respectively), tibiae were fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS) overnight. Subsequently, tibiae were 357 Regulator of Cartilage Maturation placed in staining solution (0.05% Alizarin red, 0.015% Alcian blue, 5% acetic acid in 70% ethanol) for 45-60 minutes. Digital images of stained tibia were collected using a stereomicroscope (Nikon Instruments, Melville, NY) and a digital camera. RESULTS We previously have identified expression of F-spondin in the hypertrophic and calcified zones of the embryonic growth plate, but its effects in cartilage and bone have not been described (Teixeira et al., 2007). To determine whether F-spondin regulates endochondral bone formation, in this investigation we used a mouse tibiae organ culture approach. Embryonic mouse tibiae treated with 0.5 pig/ml F-spondin for seven days in culture exhibited growth impairment when compared to control tibiae. These tibiae were on average 8% smaller than control (Fig. 2). In contrast, tibiae treated with blocking antibody to F-spondin, for the same length of time, showed a 6% increase in length when compared to control (Fig. 2). While the difference between control and experimental limbs approached statistical significance, only the difference between F-spondin and antibody treated limbs were statistically significant. The cultured embryonic tibiae also were stained with alizarin red to evaluate the extent of mineralization, and alcian blue to visualize the cartilage regions. Interestingly, F-spondin-treated limbs showed evidence of increased mineralization extending into the epiphyseal region, as shown in Figure 3 by augmented alizarin red staining (compare Fig. 3C with Fig. 3D). DISCUSSION The thrombospondin-related protein, F-spondin, is expressed in embryonic growth plate cartilage and can enhance the expression of chondrocyte maturation markers, suggesting a regulatory role for this protein in chondrocyte terminal differentiation and endochondral bone formation (Teixeira et al., 2007). The organ culture experiments reported here indicate that F-spondin inhibits limb growth and increases mineralization of growing tibiae. Detailed histological studies of these developing bones currently underway in our laboratory will help determined how F-spondin affects chondrocyte function. Is the impairment of tibiae growth due to accelerated chondrocyte hypertrophy and premature mineralization in response to F-spondin? Does this protein affect the number of proliferating or dying chondrocytes in the growing tibia? 358 D'Angelo et al. 45 40 35 30 25 - 15 10 - 2 O - Control F-spondin Antibody Figure 2. F-spondin affects growth rates of embryonic tibiae. Tibiae isolated from E15.5 mouse embryos were grown in culture for two weeks and exposed either to F-spondin recombinant protein (F-spondin), F- Spondin blocking antibodies (Antibody), or none of these agents (Control). The length of the tibia was measured at the beginning and end of the culture period. Growth of the tibia is expressed as % change in length relative to day one. * Statistically different from F-spondin treated tibiae. A B H [. | 1 mm C D H Figure 3. F-spondin affects growth and mineralization of embryonic tibiae. Tibiae solated from E15.5 mouse embryos were grown in culture for one week and 359 Regulator of Cartilage Maturation (Figure 3 Continued) exposed either to F-spondin blocking antibodies (B), F-spondin recombinant protein (D), or none of these agents (A and C). Figure shows results from two different experiments and respective controls. Tibiae were stained with alizarin red to visualize mineral, alcian blue to visualize cartilage, and photographed. Interestingly, other TSR (thrombospondin) type I class molecule family members have been shown to play a role in normal skeletal development and/or in cartilage pathology. Mutations in the cartilage oligomeric matrix protein (COMP) has been reported to cause pseudoachondroplasia, a well described form of dwarfism also associated with severe osteoarthritis requiring joint replacement (Adams and Horton, 1998). ADAMTS-7 and ADAMTS-12 are metallo-proteinases found to bind directly to and degrade COMP. The relevance of this interaction is exemplified by their significantly higher levels in the cartilage and synovium of patients with both osteoarthritis and rheumatoid arthritis than in normal cartilage and synovium (Liu et al., 2006). Indeed, several studies suggest that monitoring of COMP levels (in both joint fluid and serum) can be used to assess the presence and progression of arthritis (Lohmander et al., 1994; Morozzi et al., 2007). Connective tissue growth factor (CTGF) is another molecule of this family involved in skeletal development. Mice null for this factor show impaired endochondral ossification throughout the entire skeleton. According to histological analysis of the growth plates, chondrocyte hypertrophy was affected severely, the hypertrophic zones were enlarged, without proper vascular invasion (Ivkovic et al., 2003). And finally, cartilage intermediate layer protein (CILP), an extracellular matrix protein abundant in cartilaginous tissues, is implicated in osteoarthritis and lumbar disc disease (Seki et al., 2005). CILP expression also is up-regulated in articular cartilage from patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease and genetic polymorphism in CILP also is shown to be associated with knee OA susceptibility (Hirose et al., 2002; Valdes et al., 2006). While the phenotype of the F-spondin null mice has not yet been described, organ and cell culture data gathered in our laboratory strongly support a role for F-spondin in promoting transient cartilage maturation. Due to the similarities in growth plate chondrocyte and osteoarthritic chondrocyte behavior, we can infer a role for F-spondin also in the abnormal cellular phenotype of permanent cartilage during osteoarthritis. Our future studies will clarify the cellular pathways activated by this extracellular matrix protein. 360 D'Angelo et al. REFERENCES Adams CS, Horton WE Jr. Chondrocyte apoptosis increases with age in the articular cartilage of adult animals. Anat Rec 1998;250:418-425. Aigner T, Dietz U, Stöss H, von der Mark K. Differential expression of collagen types I, II, III, and X in human osteophytes. Lab Invest 1995;73:236-243. Aigner T, Kurz B, Fukui N, Sandell L. Roles of chondrocytes in the pathogenesis of osteoarthritis. Curr Opin Rheumatol 2002; 14:578- 584. Alini M, Kofsky Y, Wu W, Pidoux I, Poole AR. In serum-free culture thyroid hormones can induce full expression of chondrocyte hypertrophy leading to matrix calcification. J Bone Mineral Res 1996; 11:105-113. Alini M, Matsui Y, Dodge GR, Poole AR. The extracellular matrix of cartilage in the growth plate before and during calcification: Changes in composition and degradation of type II collagen. Calcif Tissue Int 1992:50:327-335. Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol 1969:41:59-72. Bauer DC, Hunter DJ, Abramson SB, Attur M, Corr M, Felson D, Heinegård D, Jordan JM, Kepler TB, Lane NE, Saxne T, Tyree B, Kraus VB; Osteoarthritis Biomarkers Network. Classification of osteoarthritis biomarkers: A proposed approach. Osteoarthritis Cartilage 2006;14:723–727. Blanco FJ, Ochs RL, Schwarz H, Lotz M. Chondrocyte apoptosis induced by nitric oxide. Am J Pathol 1995;146:75-85. D'Angelo M, Yan Z, Nooreyazdan M, Pacifici M, Sarment DS, Billings PC, Leboy P.S. MMP-13 is induced during chondrocyte hypertrophy. J Cell Biochem 2000;77:678-693. Eerola I, Salminen H, Lammi P, Lammi M., von der Mark K, Vuorio E, Säämänen AM. Type X collagen, a natural component of mouse articular cartilage: Association with growth, aging, and osteoarthritis. Arthritis Rheum 1998:41:1287-1295. Feinstein Y, Klar A. The neuronal class 2 TSR proteins F-spondin and Mindin: A small family with divergent biological activities. Int J Biochem Cell Biol 2004:36:975-980. 361 Regulator of Cartilage Maturation Ferguson C, Alpern E, Miclau T, Helms JA. Does adult fracture repair recapitulate embryonic skeletal formation? Mech Dev 1999;87:57- 66. Hashimoto S, Creighton-Achermann L, Takahashi K, Amiel D, Coutts RD, Lotz M. Development and regulation of osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage 2002:10:180-187. Hashimoto S, Ochs RL, Rosen F, Quach J, McCabe G, Solan J, Seegmiller JE, Terkeltaub R, Lotz M. Chondrocyte-derived apoptotic bodies and calcification of articular cartilage. Proc Natl Acad Sci USA 1998;95:3094-3.099. Hatori M., Klatte KJ, Teixeira CC, Shapiro IM. End labeling studies of fragmented DNA in the avian growth plate: Evidence of apoptosis in terminally differentiated chondrocytes. J Bone Miner Res 1995; 10:1960-1968. Hillarby MC, King KE, Brady G, Grant ME, Wallis GA, Boot-Handford RP. Localization of gene expression during endochondral Ossification. Ann NY Acad Sci 1996:785:263-266. Hirose J, Ryan LM, Masuda I. Up-regulated expression of cartilage intermediate-layer protein and ANK in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate crystal deposition disease. Arthritis Rheum 2002:46:3218-3229. Hoyland JA, Thomas JT, Donn R, Marriott A, Ayad S, Boot-Handford RP, Grant ME, Freemont AJ. Distribution of type X collagen mRNA in normal and osteoarthritic human cartilage. Bone Miner 1991;15:151-163. Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM. Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 2003;130:2779-2791. Iwamoto M, Higuchi Y, Enomoto-Iwamoto M, Kurisu K, Koyama E, Yeh H, Rosenbloom J, Pacifici M. The role of ERG (ets related gene) in cartilage development. Osteoarthritis Cartilage 2001;9:S41- 47. Johnson KA, Terkeltaub RA. External GTP-bound transglutaminase 2 is a molecular switch for chondrocyte hypertrophic differentiation and calcification. J Biol Chem 2005:280:15004-15012. 362 D'Angelo et al. Karaplis AC. Embryonic development of bone and the molecular- regulation of intramembranous and endochondral bone formation. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of Bone Biology. 2nd ed. San Diego: Academic Press 2002:33-58. Klar A, Baldassare M, Jessell TM. F-spondin: A gene expressed at high levels in the floor plate encodes a secreted protein that promotes neural cell adhesion and neurite extension. Cell 1992;69:95-110. Leboy PS, Shapiro IM, Uschmann BD, Oshima O, Lin D. Gene expression in mineralizing chick epiphyseal cartilage. J Biol Chem 1988:263:8515-8520. p Liu CJ, Kong W, Xu K, Luan Y, Ilalov K, Sehgal B, Yu S, Howell RD, Di Cesare PE. ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein. J Biol Chem 2006:281:15800-15808. Lohmander LS, Saxne T, Heinegård DK. Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis. Ann Rheum Dis 1994:53:8-13. Malemud C.J. Matrix metalloproteinases: Role in skeletal development and growth plate disorders. Front Biosci 2006; 11:1702-1715. Mansfield K, Teixeira CC, Adams CS, Shapiro IM. Phosphate ions mediate chondrocyte apoptosis through a plasma membrane transporter mechanism. Bone 2001:28:1-8. Mark MP, Butler WT, Prince CW, Finkelman RD, Ruch JV. Developmental expression of 44-kDa bone phosphoprotein (osteopontin) and bone gamma-carboxyglutamic acid (Gla)- containing protein (osteocalcin) in calcifying tissues of rat. Differentiation 1988:37: 123-136. Metsäranta M, Young MF, Sandberg M, Termine J, Vuorio E. Localization of osteonectin expression in human fetal skeletal tissues by in situ hybridization. Calcif Tissue Int 1989;45:146-152. Morozzi G, Fabbroni M., Bellisai F, Pucci G, Galeazzi M. Cartilage oligomeric matrix protein level in rheumatic diseases: Potential use as a marker for measuring articular cartilage damage and/or the therapeutic efficacy of treatments. Ann NY Acad Sci 2007;1108:398-407. O'Keefe RJ, Rosier RN, Puzas JE. Differential expression of biological effects in maturationally distinct subpopulations of growth plate chondrocytes. Connect Tissue Res 1990:24:53-66. 363 Regulator of Cartilage Maturation Pullig O, Weseloh G, Gauer S, Swoboda B. Osteopontin is expressed by adult human osteoarthritic chondrocytes: Protein and mRNA analysis of normal and osteoarthritic cartilage. Matrix Biol 2000a:19:245-255. Pullig O, Weseloh G, Ronneberger D, Käkönen S, Swoboda B. Chondrocyte differentiation in human osteoarthritis: Expression of osteocalcin in normal and osteoarthritic cartilage and bone. Calcif Tissue Int 2000b;67:230–240. Schmid TM, Linsenmayer TF. Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J Cell Biol 1985; 100:598–605. Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, Mio F, Mori M, Miyamoto Y, Masuda I, Tsunoda T, Kamata M, Kubo T, Toyama Y, Kimura T, Nakamura Y, Ikegawa S. A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet 2005:37:607- 612. Serra R, Karaplis A, Sohn P. Parathyroid hormone-related peptide (PTHrP)-dependent and -independent effects of transforming growth factor beta (TGF-beta) on endochondral bone formation. J Cell Biol 1999; 145:783–794. Tchetina EV, Antoniou J, Tanzer M, Zukor DJ, Poole AR. Transforming growth factor-beta2 suppresses collagen cleavage in cultured human osteoarthritic cartilage, reduces expression of genes associated with chondrocyte hypertrophy and degradation, and increases prostaglandin E(2) production. Am J Pathol 2006; 168: 131-140. Teixeira CC, Mansfield K, Hertkorn C, Ischiropoulos H, Shapiro IM. Phosphate-induced chondrocyte apoptosis is linked to nitric oxide generation. Am J Physiol Cell Physiol 2001:281:C833-839. Teixeira C, Palmer G, Attur M, Nemelivsky Y, Piton A, Al-Mussawir HE, Abramson SB. The thrombospondin-related protein, F-spondin, is expressed in embryonic growth plate cartilage and can enhance the expression of chondrocyte maturation markers. World Congress of Osteoarthritis, Osteoarthritis Research Society International. Fort Lauderdale, FL; December 9, 2007. Tucker RP. The thrombospondin type 1 repeat superfamily. Int J Biochem Cell Biol 2004:36:969–974. Valdes AM, Van Oene M, Hart DJ, Surdulescu GL, Loughlin J, Doherty M, Spector TD. Reproducible genetic associations between candidate 364 D'Angelo et al. genes and clinical knee osteoarthritis in men and women. Arthritis Rheum 2006:54:533–539. Van der Kraan PM, van den Berg WB. Osteophytes: Relevance and biology. Osteoarthritis Cartilage 2007; 15:237-244. Von der Mark K, Kirsch T, Nerlich A, Kuss A, Weseloh G, Glückert K, Stöss H. Type X collagen synthesis in human osteoarthritic cartilage: Indication of chondrocyte hypertrophy. Arthritis Rheum 1992:35:806-811. Walker GD, Fischer M, Gannon J, Thompson RC Jr, Oegema TR Jr. Expression of type-X collagen in osteoarthritis. J Orthop Res 1995; 13:4-12. Yamane S, Cheng E, You Z, Reddi AH. Gene expression profiling of mouse articular and growth plate cartilage. Tissue Eng 2007:13:2163-2173. 365 EARLY SIGNS OF BONE TISSUE RESORPTION IN THE TMJ OF PATIENTS WITH RECENT DIAGNOSIS OF RHEUMATOID ARTHRITIS Anna-Kari Hajati ABSTRACT Damage of the temporomandibular joint (TMJ) is common in patients with rheumatoid arthritis. The damage often is irreversible and associated with pain, functional disability and adverse facial changes that taken together reduce the quality of life. Radiographic erosions are considered to be the first sign of bone tissue resorption and may be non-symptomatic in early RA. Early detection of Such changes may be accomplished by including the TMJ in the first radio- graphic screening that may identify patients at risk for bone tissue destruction and thus be of benefit for patients with RA. A major concern, however, is the lack of knowledge regarding the early pathophysiology of RA in the TMJ limits the diagnostic possibilities and its local and specific treatment. This chapter focuses on early detection of structural changes in the TMJ with rheumatoid arthritis and their pathophysiology. The role of the cyto- kines TNF, IL-13 and IL-6 as well as the RANKL-RANK-OPG system, the amino acid glutamate and estradiol in bone resorption will be described. This chapter also provides an overview of possible future perspectives to study the pathophysiology in RA TMJ. Permanent damage of the temporomandibular joint (TMJ) is common in patients with general inflammatory disorders like rheumatoid arthritis (RA; Koh et al., 1999; Lin et al., 2007). The structural damage may cause disabling functional and aesthetic changes. The clinical pic- ture in these conditions often is dominated by pain, especially during movement and functional limitations that reduce the quality of life (Voog et al., 2003; Helenius et al., 2005). At the same time there is some evi- dence that early TMJ bone resorption, as expressed by radiographic ero- Sions and pain, partly are independent processes, although both probably are associated with an inflammatory process in the joint. Early bone tis- Sue resorption may thus be non-symptomatic in RA patients (Hajati et al., 2008, unpublished observations). 367 Early Signs of Resorption Early and aggressive treatment is important for successful treat- ment outcome in RA (Allaart et al., 2006). Early detection of structural changes in the TMJ or even better, early identification of patients at risk for such changes, therefore, would be of great benefit. There is, however, still limited knowledge regarding the early pathophysiology behind the structural changes of RA in the TMJ and its local and specific treatment. This chapter focuses on the current knowledge about detection of early structural changes of the TMJ in RA in relation to some putative molecular mechanisms behind these changes. It also provides an over- view of possible future perspectives to study the pathophysiology in inflammatory joint diseases. PREDICTORS OF RADIOGRAPHIC JOINT PROGRESSION Progression of structural changes in joints, as determined by ra- diographic methods, is associated to loss of physical function over time (Ødegård et al., 2006). Although in the earliest phases of RA, radio- graphic damage and HAQ scores (derived from a 20-item questionnaire that asks about functioning within eight domains of routine human activ- ity) are not related (Scott et al., 2000). RA prognosis might be a more useful predictor, therefore, than clinical status regarding radiographic progression (Morel and Combe, 2005). So far the most prominent predic- tors of progression of structural changes in RA are female gender, the shared epitope of HLA-DRB1/4, and presence of antibodies to cyclic citrullinated peptides are the most significant predictors of radiographic progression (Sanmarti et al., 2007). Other predictive factors include presence of the rheumatoid fac- tor, high systemic inflammatory activity as estimated by C-reactive pro- tein, and erythrocyte sedimentation rate (Syversen et al., 2008). Post- menopausal estrogen deficiency might be one possible predictor in the future. As estrogen deficiency leads to increased osteoclast formation partly as a result of the deficiency itself and partly driven by cytokines (Pfeilschifter et al., 2002). A majority of patients with early RA and pain-free TMJs, however, showed radiographic signs of bone tissue de- struction in the TMJ (Fig. 1; Hajati et al., 2008, unpublished observa- tions). 368 Hajati Figure 1. A cone-beam computer tomography (CBCT) image of the left TMJ condyle from a patient with early rheumatoid arthritis (RA). The TMJ is pain-free and the condyle shows clear erosion, the first radiographic sign of bone tissue resorp- tion. The image is from the 12-month follow-up after RA di- agnosis. The erosion was absent at the first CBCT examination 12 months earlier. MECHANISMS OF BONE RESORPTION Bone tissue, including the TMJ bone structure, is a dynamic tis- Sue With continuous remodelling to adapt to the dual role as a supporting tissue as well as a regulator of mineral homeostasis. Remodeling of bone tissue is dependent on coordinated activities of osteoblasts and osteo- clasts. These activities are induced mainly by mechanical loading and 90ntrolled by cytokines, hormones and neuroregulators (Lerner, 2006a). In addition, the pathogenic mechanism causing loss of bone tissue might 369 Early Signs of Resorption share several features with physiologic mechanisms in the cellular and molecular mechanisms involved (Lerner, 2006b). Cytokines Cytokines are small and pleiotropic extracellular peptides Syn- thesized and produced by all nucleated cells; most cell types respond to them. They are involved in most physiological processes including tissue repair and remodulation. Mostly, the cytokines are important mediators in inflammatory and immune processes in diseases like RA (Duff, 1994). There is a dramatic increase in cytokine production in inflamma- tory disorders like RA; at the same time the balance between the produc- tions of pro- and anti-inflammatory cytokines is disturbed which seems at least as important as absolute levels of individual cytokines (Jouvenne et al., 1998). Immune cells are an important source of a variety of cyto- kines with the capacity to stimulate the differentiation and activity of bone tissue resorbing osteoclasts as well as the synthesis of bone matrix proteins and calcification of bone tissue by the osteoblasts (Tanaka et al., 2005). Tumor necrosis factor (TNF), interleukin-1beta (IL-13) and in- terleukin-6 (IL-6) are expressed highly in inflamed synovium and present in synovial fluid from patients with RA. They all have been found to be involved in the pathogenic mechahisms that lead to bone resorption in this disease (Duff, 1994; Walsh and Gravallese, 2004). Many cytokines influence osteoclast differentiation and bone resorption indirectly via the Receptor Activator for Nuclear Factor k B Ligand (RANKL) / Receptor Activator of Nuclear Factor k B (RANK) – osteoprotegrin (OPG) system (Lacey et al., 1998). RANKL modulates osteoclast differentiation and function via the RANK receptor on the osteoclasts, whereas OPG acts as a decoy receptor for RANKL, thereby inhibiting osteoclast differentia- tion and function (Simoney et al., 1997). In physiologic conditions there is a balance between RANKL and OPG. In RA, activated T-cells and synovial fibroblasts provide additional potential sources of RANKL that may increase osteoclastic activity (Gravallese et al., 2000; Kotake et al., 2001). TNF has a prominent role in driving inflammation and primarily is activated by T-cells and macrophages (Danning et al., 2000). TNFO, has the capacity to regulate osteoclast differentiation and function directly 370 Hajati and indirectly, independent of its role in inflammation (Kobayashi et al., 2000; Komine et al., 2001). TNFo and IL-13 have overlapping effects to a great extent, but not entirely. IL-13 is produced at high levels by acti- wated macrophages and synovial fibroblasts (Danning et al., 2000). Simi- lar to TNF, IL-13 can indirectly regulate osteoclastogenesis by upregulat- ing RANKL expression in osteoblasts (Hofbauer et al., 1999). IL-13 can promote the survival and function of mature osteoclasts (Jimi et al., 1999; Kobayashi et al., 2000). TNF levels are increased in the synovial fluid and the synovial membrane of patients with RA (Buchan et al., 1988; Saxne et al., 1988). The TNFO levels in plasma (Voog et al., 2003) as well as in the TMJ synovial fluid (Nordahl et al., 2000) are related to local TMJ bone tissue destruction. Presence of IL-13 in plasma (Nordahl et al., 1998) and in the TMJ synovial fluid (Alstergren et al., 1998) also is related to TMJ de- Struction expressed as anterior open bite in patients with chronic inflam- matory disorders. High levels of IL-1 sRII in plasma and TMJ synovial fluid (Alstergren et al., 2003) and the soluble TNFO receptor II (Alster- gren et al., 2006) in plasma have been associated with no or only small degree of TMJ destruction in RA, indicating an influence of these recep- tors on the disease progression. Furthermore, high TMJ synovial fluid levels of the IL-1 receptor antagonist IL-1 ra and low plasma levels of IL- 13 are associated with a more rapid resolution of arthritis (Nordahl et al., 2001), which illustrates the importance of the local balance between pro- and anti-inflammatory cytokines for the progression of the inflammatory process (Jouvenne et al., 1996). Neutralization of TNFo and IL-1 by soluble IL-1 and TNFO re- ceptors decreases the osteoclast formation and bone loss in experimen- tally induced arthritis (Walsh and Gravallese, 2004). Treatment of RA with TNFO antagonist results in retardation of radiographic progression (Walsh and Gravallese, 2004) and inhibition of IL-1 by IL-antagonists leads to decreased progression of radiographically assessed bone loss. IL-1, TNFO and IL-6 enhance RANKL expression (Kwan et al., 2004). IL-6 has a prominent role in inflammation-induced bone resorp- tion and primarily is produced by osteoblasts, which also express recep- tors for IL-6 (Bellido et al., 1996). IL-6 synthesis in osteoblasts also is upregulated by decreased estrogen levels (Girasole et al., 1992; Poli et al., 1994). 371 Early Signs of Resorption Estradiol Estradiol is a sex steroid hormone and the major estrogen. Estro- gen influences bone resorption by several mechanisms and can regulate the immune responsiveness in humans (Bouman et al., 2005). The estro- gen receptor ol (ERO) is distributed widely and expressed in both os- teoblasts and osteoclasts. Activation of ERO in osteoclast progenitor cells decreases osteoclast formation; in terminally differentiated osteoclasts, activation of the ERO receptor inhibits their resorbing activity (Oursler et al., 1991; Taranta et al., 2002) and enhances osteoclastic apoptosis (Hughes et al., 1996; Chen et al., 2005) in murine osteoporosis and in vitro. Experimental models have shown that estrogen can modulate the course and severity of rheumatoid arthritis (Grossman and Brahn, 1997). Because osteoblasts are crucial for osteoclast formation due to the ex- pression of RANKL and the osteoclast-inhibiting factor OPG, activation of estrogen receptors in osteoblasts may play a role in the regulation of osteoclastogenesis. That is consistent with earlier findings that estrogen increases OPG mRNA and protein expression in human osteoblasts (Hofbauer et al., 1999). The effect of estrogen on bone resorption also may be due to the inhibition of RANKL-stimulating cytokines as estro- gen inhibits production of TNFo and IL-13 (Pacifici, 1999) and IL-6 in osteoblasts (Girasole et al., 1992). It is interesting which role the osteo- clast-stimulating cytokines may have in bone tissue affected by estrogen deficiency. There is evidence for increased expression and secretion of TNF, Il-1 and IL-6 after natural or surgical menopause (Pacifici et al., 1989, 1991; Pfeilschifter et al., 2002). Our findings regarding patients with recently diagnosed RA Sug- gest that radiographic signs of TMJ bone tissue resorption are associated with elevated glutamate levels in plasma. This relationship is stronger in patients with postmenopausal levels of estrogen (Hajati et al., 2008, unpublished observations) indicating that glutamate may influence the bone tissue homeostasis in RA. Glutamate Glutamate is an excitatory amino acid involved in inflammation and bone remodeling. Elevated plasma levels have been reported in RA (Trang et al., 1985). Potential sources of glutamate in RA are excess release in inflamed tissues from thrombocytes, lymphocytes, macro- phages, neutrophils, fibroblasts and from nerve terminals (Lawand et al., 2000) as well as osteoclasts (Genever and Skerry, 2001). The mature resorbing osteoclast is a target for glutamate by the N-methyl-D-aspartic 372 Hajati acid (NMDA) receptor (Spencer et al., 2006), which is one of the recep- tors for glutamate resulting in bone resorption in healthy individuals (Chenu, 2002). Endogenous glutamate seems to be involved in early TMJ bone tissue destruction in RA (Hajati et al., 2008, unpublished observations). The association between plasma levels of glutamate and extension of erosions seems to be particularly strong in females with low estradiol level and low systemic inflammatory activity, suggesting a particular role for circulating glutamate in local bone tissue resorption in individuals without or with low systemic inflammatory activity (Hajati et al., 2008, unpublished observations). y FUTURE PERSPECTIVES A biologic approach combined with the use of novel techniques and procedures may facilitate our quest for increased knowledge regard- ing the local pathophysiology in RA and to identify patients at risk of TMJ damage. Determination of TMJ bone loss over time, for example, combined with the levels of relevant biomarkers from the joint should improve our diagnostic and predictive capabilities. Three-dimensional Imaging -- The use of a low-radiation dose cone-beam computerized tomo- graphy (CBCT; Mah et al., 2003) in dentistry has opened for 3D model- ing and 3D superimpositioning of hard tissues including the TMJ region. The volumetric changes can be visualized or calculated. The current Visualization provides a summation of displacement of the condyle rela- tive to the skull base as well as condyle destruction (Fig. 2). The 3D techniques have been developed and validated by Cevidanes and col- leagues (2005). It seems possible in the near future, therefore, to perform Visualization and volumetric calculations of the extent of bone tissue loss over time. It was suggested recently that 3D virtual surface models can be used to detect even small bone changes in arthritic TMJ conditions (Cevidanes et al., 2007, unpublished observations). Synovial Fluid Sampling and Analysis Analysis of the content in synovial fluid is still underused as a diagnostic tool despite its clinical value in assessment of disease activity in TMJ conditions (Hamada et al., 2008). Synovial fluid analysis (Fig. 3) enables identification and quantification of disease markers and media- 373 Early Signs of Resorption tors taking part in the local disease process. Sampling of TMJ synovial fluid, however, requires a special technique in that the amount of syno- vial fluid present in the TMJ is generally small (Alstergren et al., 1999; Kopp and Sommer, 2007). The technique developed in our clinic and laboratory enables calculation of the true concentration of mediators in the synovial fluid, which is not possible by other synovial fluid sampling techniques (Alstergren et al., 1999). Figure 2. The first superimposed 3D models of TMJ condyles from two COnº beam computer tomography (CBCT) examinations 12 months apart in a patient with early rheumatoid arthritis and without pain. The panel shows frontal and axial superimpositioned views of the right and left condyle separately. The first 3D models (mesh model) were created at the time of diagnosis and the second (solid color model) at the 12-month follow-up. The blue color denotes condylar morphologic changes and displacement in a posterior-inferior direction; the red color marks changes and displacement in an anterior-superior direction; the green color indicates no volumetric change. The right TMJ condyle shows ºf tensive changes between the examinations whereas the left condyle shows only minor or no changes. 374 - - 4 Figure 3. Synovial fluid sampling from the right TMJ of a patient with rheuma- toid arthritis. The TMJ first is punctured, under anesthesia, with a standard dis- posable needle inserted into the posterior part of the upper joint compartment (l). Synovial fluid samples are obtained by washing the joint cavity with saline, using a push-and-pull technique performed with two syringes connected to the arthrocentesis needle by a three-way stopcock: one for the washing solution to be injected and one for aspiration (2). The injection solution that consists of 78% Saline and 22% Behepan (vitamin B12: red color) is injected slowly into the joint cavity 1 mL at a time, and then aspirated (3, 4). The synovial fluid volume in the aspirate is calculated by the difference in light absorbance between the Washing solution and the aspirate as measured in a spectrophotometer. This technique enables calculation of the true synovial fluid concentration of the Investigated mediators (Alstergren et al., 1999). CONCLUSIONS It is well known that patients with inflammatory disorders like RA have an increased risk of TMJ bone tissue destruction and reduced function that could be disabling and reduce the quality of life. Determi- nation of bone loss, especially over time by 3D imaging in combination With analysis of inflammatory mediators and markers from the joint and the blood may enhance greatly the understanding of the processes behind articular bone tissue destruction in RA. The new techniques may permit *Curate monitoring of the longitudinal development of these changes. Increased knowledge about the molecular mechanisms may enable accu- 375 Early Signs of Resorption rate diagnosis and risk prediction on an individual basis, even before the first signs of erosions occur. In the future, permanent TMJ destruction in inflammatory conditions like RA may be prevented or minimized by local blocking of important mediators. ACKNOWLEDGEMENTS I wish to thank my supervisors, Professor Sigvard Kopp and As- sociate Professor Per Alstergren, for their excellent scientific guidance and support in my doctoral project. I am very grateful to Dr. Lucia Ce- vidanes from the Orthodontic Department at University of North Caro- lina Dental School for her enthusiasm and support in developing the 3D imaging and superimposition technique for our application. Thanks also to Karin Trollsas for her skilful laboratory work and Marie-Louise Bjerdahl for her assistance at the clinic of the Department of Clinical Physiology. We thank the personnel in the Departments of Rheumatology and Oral Radiology at our university for their assistance with patients. REFERENCES Allaart CF, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Breedveld FC, Dijkmans BA; FARR study group. Aiming at low disease activ- ity in rheumatoid arthritis with initial combination therapy or initial monotherapy strategies: The BeSt study. Clin Exp Rheumatol 2006:24:S77-82. Alstergren P, Benavente C, Kopp S. Interleukin-1beta, interleukin-1 receptor antagonist, and interleukin-1 soluble receptor II in tem- poromandibular joint synovial fluid from patients with chronic pol- yarthritides. J Oral Maxillofac Surg 2003;61:1171–1178. Alstergren P, Ernberg M, Kopp S, Lundeberg T, Theodorsson E. TMJ pain in relation to circulating neuropeptide Y, serotonin, and interle- ukin-1 beta in rheumatoid arthritis. J Orofac Pain 1999; 13:49-55. Alstergren P, Ernberg M, Kvarnström M, Kopp S. Interleukin-1beta in synovial fluid from the arthritic temporomandibular joint and its rela- tion to pain, mobility, and anterior open bite. J Oral Maxillofac Surg 1998:56:1059-1065. 376 Hajati Alstergren P, Kopp S. Insufficient endogenous control of tumor necrosis factor-alpha contributes to temporomandibular joint pain and tissue destruction in rheumatoid arthritis. J Rheumatol 2006:33:1734–1739. Bellido T, Stahl N, Farruggella TJ, Borba V, Yancopoulos GD, Manola- gas SC. Detection of receptors for interleukin-6, interleukin-11, leu- kemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow Stromal/Osteoblastic cells. J Clin Invest 1996;97:431– 437. Bouman A, Heineman M.J., Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update 2005; 11:411-423. Buchan G, Barrett K, Turner M, Chantry D, Maini RN, Feldmann M. Interleukin-1 and tumour necrosis factor mRNA expression in rheu- matoid arthritis: Prolonged production of IL-1 alpha. Clin Exp Im- munol 1988;73:449-455. Cevidanes LH, Bailey LJ, Tucker GR Jr, Styner MA, Mol A, Phillips C, Proffit WR, Turvey T. Superimposition of 3D cone-beam CT models of orthognathic surgery patients. Dentomaxillofac Radiol 2005:34:369-375. Chen JR, Plotkin LI, Aguirre JI, Han L, Jilka RL, Kousteni S, Bellido T, Manolagas SC. Transient versus sustained phosphorylation and nu- clear accumulation of ERKs underlie anti-versus pro-apoptotic ef- fects of estrogens. J Biol Chem 2005:280:4632–4638. Chenu C. Glutamatergic regulation of bone resorption. J Musculoskelet Neuronal Interact 2002:2:423-431. Danning CL, Illei GG, Hitchon C, Greer MR, Boumpas DT, McInnes IB. Macrophage-derived cytokine and nuclear factor kappaB p55 expres- sion in synovial membrane and skin of patients with psoriatic arthri- tis. Arthritis Rheum 2000:43:1244-1256. Duff GW. Cytokines and acute phase proteins in rheumatoid arthritis. Scand J Rheumatol 1994; 100:S9-19. Genever PG, Skerry TM. Regulation of spontaneous glutamate release activity in osteoblastic cells and its role in differentiation and sur- vival: Evidence for intrinsic glutamatergic signaling in bone. FASEB J 2001; 15:1586–1588. Girasole G, Jilka RL, Passeri G, Boswell S, Boder G, Williams DC, Ma- nolagas SC. 17 beta-estradiol inhibits interleukin-6 production by 377 Early Signs of Resorption bone marrow-derived stromal cells and osteoblasts in vitro: A poten- tial mechanism for the antiosteoporotic effect of estrogens. J Clin In- vest 1992;89:883-891. Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Gold- ring SR. Synovial tissue in rheumatoid arthritis is a source of osteo- clast differentiation factor. Arthritis Rheum 2000:43:250–258. Grossman JM, Brahn E. Rheumatoid arthritis: Current clinical and re- Search directions. J Womens Health 1997;6:627-638. Hamada Y, Kondoh T, Holmlund AB, Sakota K, Nomura Y, Seto K. Cytokine and clinical predictors for treatment outcome of visually guided temporomandibular joint irrigation in patients with chronic closed lock. J Oral Maxillofac Surg 2008;66:29-34. Helenius LM, Hallikainen D. Helenius I, Meurman JH, Kononen M, Leirisalo-Repo M, Lindqvist C. Clinical and radiographic findings of the temporomandibular joint in patients with various rheumatic dis- eases: A case-control study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:455-463. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999; 140:4367–4370. Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 1996:2:1132-1136. Jimi E, Akiyama S, Tsurukai T, Okahashi N, Kobayashi K, Udagawa N, Nishihara T, Takahashi N, Suda T. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol 1999; 163:434–442. Jouvenne P, Fossiez F, Garrone P, Djossou O, Banchereau J, Miossec P. Increased incidence of neutralizing autoantibodies against interleu- kin-1 alpha (IL-1 alpha) in nondestructive chronic polyarthritis. J Clin Immunol 1996; 16:283-290. Jouvenne P, Vannier E, Dinarello CA, Miossec P. Elevated levels of soluble interleukin-1 receptor type II and interleukin-1 receptor an- tagonist in patients with chronic arthritis: Correlations with markers of inflammation and joint destruction. Arthritis Rheum 1998:41:1083- 1089. 378 Hajati Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M., Kotake S, Nakagawa N, Kinosaki M., Yamaguchi K, Shima N, Yasuda H, Mo- rinaga T, Higashio K, Martin TJ, Suda T. Tumor necrosis factor al- pha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 2000;191:275- 286. Koh ET, Yap AU, Koh CK, Chee TS, Chan SP, Boudville IC. Tem- poromandibular disorders in rheumatoid arthritis. J Rheumatol 1999:26:1918-1922. Komine M, Kukita A, Kukita T, Ogata Y, Hotokebuchi T, Kohashi O. Tumor necrosis factor-alpha cooperates with receptor activator of nu- clear factor kappaB ligand in generation of osteoclasts in stromal cell-depleted rat bone marrow cell culture. Bone 2001:28:474-483. Kopp S, Sommer C. Inflammatory mediators in temporomandibular joint pain. In: Türp JC, Sommer C, Hugger A, eds. The Puzzle of Orofa- cial Pain: Integrating Research into Clinical Management. Basel: Karger 2007:28–43. Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takaha- shi K, Furuya T, Ishiyama S, Kim KJ, Saito S, Nishikawa T, Takaha- shi N, Togari A, Tomatsu T, Suda T, Kamatani N. Activated human T cells directly induce osteoclastogenesis from human monocytes: Possible role of T cells in bone destruction in rheumatoid arthritis pa- tients. Arthritis Rheum 2001;44:1003-1012. Kwan Tat S, Padrines M, Théoleyre S, Heymann D, Fortun Y. IL-6, RANKL, TNF-alpha/IL-1: Interrelations in bone resorption patho- physiology. Cytokine Growth Factor Rev 2004; 15:49-60. Lacey DL, Timms E, Tan HL, Kelley M.J, Dunstan CR, Burgess T, Elli- ott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle W.J. Osteoprote- gerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-176. Lawand NB, McNearney T, Westlund KN. Amino acid release into the knee joint: Key role in nociception and inflammation. Pain 2000;86:69–74. Lerner UH. Bone remodeling in post-menopausal osteoporosis. J Dent Res 2006a;85:584-595. 379 Early Signs of Resorption Lerner UH. Inflammation-induced bone remodeling in periodontal dis- ease and the influence of post-menopausal osteoporosis. J Dent Res 2006b;85:596–607. Lin Y, Hsu M, Yang J, Liang T, Chou S, Lin H. Temporomandibular joint disorders in patients with rheumatoid arthritis. J Chin Med AS- Soc 2007;70:527–534. Mah JK, Danforth RA, Bumann A, Hatcher D. Radiation absorbed in maxillofacial imaging with a new dental computed tomography de- vice. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96:508–513. Morel J, Combe B. How to predict prognosis in early rheumatoid arthri- tis. Best Pract Res Clin Rheumatol 2005; 19:137-146. Nordahl S, Alstergren P, Eliasson S, Kopp S. Interleukin-1beta in plasma and synovial fluid in relation to radiographic changes in arthritic temporomandibular joints. Eur J Oral Sci 1998; 106:559-563. Nordahl S, Alstergren P, Eliasson S, Kopp S. Radiographic signs of bone destruction in the arthritic temporomandibular joint with special ref- erence to markers of disease activity: A longitudinal study. Rheuma- tology 2001;40:691-694. Nordahl S, Alstergren P, Kopp S. Tumor necrosis factor-alpha in syno- vial fluid and plasma from patients with chronic connective tissue disease and its relation to temporomandibular joint pain. J Oral Max- illofac Surg 2000:58:525-530. Ødegård S, Landewe R, van der Heijde D, Kvien TK, Mowinckel P. Uhlig T. Association of early radiographic damage with impaired physical function in rheumatoid arthritis: A ten-year, longitudinal ob- servational study in 238 patients. Arthritis Rheum 2006:54:68-75. Oursler MJ, Osdoby P, Pyfferoen J, Riggs BL, Spelsberg TC. Avian osteoclasts as estrogen target cells. Proc Natl Acad Sci 1991;88: 6613-6617. Pacifici R. Aging and cytokine production. Calcif Tissue Int 1999;65: 345-351. Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci 1991;88:5134-5138. Pacifici R, Rifas L, McCracken R, Vered I, McMurtry C, Avioli LV, Peck WA. Ovarian steroid treatment blocks a postmenopausal in- 380 Hajati crease in blood monocyte interleukin 1 release. Proc Natl Acad Sci 1989;86:2398-2402. Pfeilschifter J, Köditz R, Pfohl M, Schatz H. Changes in proinflamma- tory cytokine activity after menopause. Endocr Rev 2002:23:90-119. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Cili- berto G, Rodan GA, Costantini F. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 1994; 13:1189-1196. Sanmarti R, Gómez-Centeno A, Ercilla G, Larrosa M, Viñas O, Vazquez I, Gómez-Puerta JA, Gratacós J, Salvador G, Cañete JD. Prognostic factors of radiographic progression in early rheumatoid arthritis: A two-year prospective study after a structured therapeutic strategy us- ing DMARDs and very low doses of glucocorticoids. Clin Rheumatol 2007:26:1111–1118. Saxne T, Palladino MA Jr, Heinegård D, Talal N, Wollheim F.A. Detec- tion of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 1988:31:1041-1045. Scott DL, Pugner K, Kaarela K, Doyle DV, Woolf A, Holmes J, Hieke K. The links between joint damage and disability in rheumatoid ar- thritis. Rheumatology 2000:39:122-132. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bu- cay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle W.J. Osteopro- tegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-319. Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG. Wnt sig- nalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 2006; 119:1283-1296. Syversen SW, Gaarder PI, Goll GL, 0degård S, Haavardsholm EA, Mowinckel P, van der Heijde D, Landewe R, Kvien TK. High anti- cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: Results from a 10-year longitudinal study. Ann Rheum Dis 2008;67:212-217. 381 Early Signs of Resorption Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy 2005;4:325–328. Taranta A, Brama M, Teti A, De luca V, Scandurra R, Spera G, Agnus- dei D, Termine JD, Migliaccio S. The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 2002:30:368-376. Trang LE, Fürst P, Odebäck AC, Lövgren O. Plasma amino acids in rheumatoid arthritis. Scand J Rheumatol 1985; 14:393-402. Voog U, Alstergren P, Eliasson S, Leibur E, Kallikorm R, Kopp S. In- flammatory mediators and radiographic changes in temporomandibu- lar joints of patients with rheumatoid arthritis. Acta Odontol Scand 2003;61:57-64. Voog U, Alstergren P, Leibur E, Kallikorm R, Kopp S. Impact of tem- poromandibular joint pain on activities of daily living in patients with rheumatoid arthritis. Acta Odontol Scand 2003;61:278-282. Walsh NC, Gravallese EM. Bone loss in inflammatory arthritis: Mecha- nisms and treatment strategies. Curr Opin Rheumatol 2004;16:419- 427. O. 382 PERIPHERAL NMDA RECEPTORS AND TMD PAIN MECHANISMS Eduardo E. Castrillon, Brian E. Cairns, Malin Ernberg, Kelun Wang, Barry J. Sessle, Lars Arendt-Nielsen, Peter Svensson ABSTRACT The etiology and pathogenesis of ongoing pain in the muscles of mastication and the temporomandibular joint (TMJ), known as temporomandibular disorders (TMDs), still are not understood completely. There are a considerable number of animal and human studies suggesting that an increased concentration of the excitatory amino acid glutamate in the masticatory muscles and TMJ may be one of the factors responsible for the development and maintenance of chronic myofascial TMD pain. Glutamate injection into the masseter muscle has proven to be a safe reliable transient myofascial TMD pain model. N-methyl-d-aspartate (NMDA) receptor antagonists such as ketamine can attenuate glutamate-evoked pain that suggests that glutamate acts, at least in part, on peripheral NMDA receptors to evoke muscle and joint pain. Moreover, it has been suggested that there may be some sex-related differences in these mechanisms that may be influenced by sex hormones. Even though there has been a great effort to clarify peripheral mechanisms of underlying muscle pain in conditions such as TMD, there still are a number of questions to be answered. In this chapter, it is our aim to review the current scientific literature on this topic, including the results of our own Studies, in order to make a critical evaluation of the possible role of the glutamate and peripheral NMDA receptors in certain musculoskeletal chronic pain conditions, such as TMD. The role of peripheral mechanisms in the etiology and patho- genesis of myofascial temporomandibular disorders (TMD), which have a female predominance and are characterized by symptoms of localized ongoing and activity-provoked masticatory muscle pain, remains unclear (Carlsson and LeResche, 1995; Stohler, 1999; Lam et al., 2005). These TMD conditions are characterized by ongoing pain and pain in the muscles of mastication, the temporomandibular joint (TMJ), or both. Additionally, pain on palpation and pain on function commonly are reported to be present in these conditions (LeResche, 1997). 383 Peripheral NMDA Receptors The most common subtypes of TMD in clinic populations appear to be myofascial pain and arthralgia, followed by disc displacements with reduction (Truelove et al., 1992). Pain in the temporomandibular region appears to be relatively common, occurring in approximately 10% of the population over 18 years of age. It primarily is a condition of young and middle-aged adults, rather than of children or the elderly, and it is approximately twice as common in women as in men (LeResche, 1997). Some lines of evidence support the concept that a peripheral mechanism involving the elevation of muscle tissue levels of peripherally active neurotransmitters, such as serotonin and glutamate, may contribute to the development and maintenance of pain and sensitization in these disorders (Ernberg et al., 1999; Castrillon et al., 2008c). A recent review suggests that increased tissue concentrations of the excitatory amino acid (EAA) glutamate, which acts on EAA receptors, including N-methyl-D-aspartate (NMDA) receptors, may play a role in certain musculoskeletal pain conditions and that this itself may involve a peripheral interaction with vanilloid type 1 receptor (TRPV1; Lam et al., 2005). Studies showing that elevated glutamate concen- trations in depp tissues, such as in the synovial fluid of arthritis sufferers and in the tendon tissues of patients suffering from “Jumpers knee” and tennis elbow, are associated with ongoing pain and sensitization (McNearney et al., 2000; Alfredson et al., 2001; Alfredson and Lorentzon, 2002). This evidence is consistent with our recent findings that demonstrated elevated concentrations of glutamate are found in the masseter muscle of myofascial TMD patients (Castrillon et al., 2008c). Moreover, the fact that pain and mechanical sensitization pro- duced by experimentally elevated levels of glutamate in the masseter muscle can be attenuated by local co-administration of the NMDA receptor (Fig. 1) antagonist ketamine, suggests that activation of peripheral NMDA receptors mediates these effects (Cairns et al., 2003a, 2006). These findings were not replicated in a similar experimental Setting on healthy young women, however, suggesting potential sex differences (Castrillon et al., 2007). The intensity of pain evoked by injection of glutamate into the masseter muscle is greater in healthy young women than in healthy young men (Fig. 1; Cairns et al., 2001; Svensson et al., 2003). These observations are consistent with the findings in animal studies in which masseter nociceptive afferent excitability and jaw electromyographic 384 Castrillon et al. Figure 1. Use of the technique to appy the injections in the masseter muscle. activity reflexively evoked by glutamate application to the masseter muscle are significantly greater in female rats than male rats (Cairns et al., 2001). All these results together have led to speculation that sex- related differences (Greenspan et al., 2007) in the intensity of glutamate- evoked masseter muscle pain could be mediated through alterations in the activity or number of peripheral NMDA receptors in women (Castrillon et al., 2007). It also has been suggested that estrogens may play a role in TMD (LeResche et al., 1997; Dao et al., 1998), but our results have not shown any differences in glutamate-evoked pain and ketamine effect between women taking oral contra-ceptives (W-FOC) and not taking them (W-OC; Castrillon et al., 2007). Furthermore, our unpublished results show that salivary estradiol levels of W-OC did not have strong correlations with the pain responses to glutamate-evoked pain in healthy young volunteers. In this chapter, we will discuss the possible underlying physiology of the NMDA receptors as well as its implications in the thronic myofascial TMD pain mechanisms, based on the available literature and on our own studies. 385 Peripheral NMDA Receptors Figure 2. An example of the intensity of the pain evoked by an injection of glutamate in the masseter muscle is illustrated. The pain intensity is assessed on a Visual Analogue Scale. GLUTAMATE-EVOKED PAIN Although central nervous system reactions, including sensiº tization of second order neurons and endogenous pain modulatory mechanisms, undoubtedly also play important roles in the patho- physiology of TMD pain, there is evidence supporting the concept that * peripheral mechanism involving the elevation of muscle tissue levels ºf peripherally active neurotransmitters (Sessle, 2005) like Seroton!" (Ernberg et al., 1999) and glutamate (Lam et al., 2005; Castrillon et al. 2008c) also may contribute to the development and maintenance of pain 386 Castrillon et al. and sensitization in these disorders. The findings that support this concept are: 1. Peripheral NMDA receptors are localized in human Achilles tendons in patients with chronic painful tendinosis (Alfredson et al., 2001); and 2. Suggestions that increased tissue concentrations of the EAA glutamate, which can be synthesized by primary afferent cell bodies and some afferent endings in peripheral tissue receptors, are able to excite EAA receptors, including NMDA receptors (Sessle, 2005). Moreover, taking into account that experimentally induced increase in glutamate concentration in the human masseter muscle has shown to evoke pain consistently (Figs. 1 and 2), decrease the pressure pain threshold (PPT), and enhance the amplitude of the jaw-stretch reflex (Cairns et al., 2001, 2003b,c, Svensson et al., 2003; Wang et al., 2004; Castrillon et al., 2007), local administration of an NMDA receptor antagonist like ketamine should attenuate this pain. This approach may have some advantages over approaches that target pain-related processes in the central nervous system. For example, it is possible that localized peripheral pain control in orofacial pain conditions may avoid systemic drug levels, which can cause adverse effects. Lowered systemic drug levels afforded by local drug administration also would have the advantage of minimizing the possibility for drug interactions in patients who also are taking drugs which act in the central nervous systems (e.g., tricyclic antidepressants) for pain relief (Sawynok, 2003). Testing the effects of local application of peripheral NMDA receptor antagonists like ketamine, therefore, may have some advantages as a new approach to treatment. The hypothesis that a NMDA receptor antagonist will decrease or block the effects of the glutamate injections have been supported in Orofacial pain experiments. In these studies, it has been shown that in healthy young men, pain and mechanical sensitization produced by elevated levels of glutamate in the masseter muscle can be attenuated by local co-administration of the NMDA receptor antagonist ketamine (10 mM). These findings suggest that activation of peripheral NMDA recep- tors mediates these effects (Cairns et al., 2003a, 2006). Our later studies, however, have not been able to show the same effects of the same concentration of ketamine in healthy young females (Castrillon et al., 387 Peripheral NMDA Receptors 2007) or in TMD patients, although some individual patients showed clinical pain relief (Castrillon et al., 2008). This sex-related difference in response to ketamine may be explained by an increased expression of NMDA receptors by masseter muscle afferent fibers in females (Dong et al., 2007). This finding may indicate that higher concentrations of ketamine are needed more in women than in men to attenuate pain and sensitization produced by elevated masseter muscle glutamate concentrations. Our findings, therefore, suggest that activation of peripheral NMDA receptors is only one of several factors that could be involved in the maintenance of myofascial pain in TMD patients (Castrillon et al., 2008a). Limitations to this interpretation related to other glutamatergic- initiated effects, the concentration, volume and disposition of intra- muscularly injected ketamine, need to be considered carefully before entirely ruling out a more important role for peripheral NMDA receptor activation in chronic myofascial pain. As discussed above, it is possible that our failure to show significant effects of ketamine on muscle pain in women (Castrillon et al., 2007, 2008c) resulted from a too low concentration of ketamine being employed and that a higher concen- tration "of ketamine may have shown more remarkable results. The problem with this approach is that while we have demonstrated that 10 mM ketamine does not exert non-selective, local anesthetic-like actions (Cairns et al., 2003b), there is a concern that higher concentrations of ketamine could exert local anesthetic effects in addition to NMDA receptor blockade, which would make positive results with higher concentrations in female difficult to interpret (Brau et al., 1997). In clinical studies of female TMD patients, an additional concern is that the relatively small volume of ketamine may not have permitted distribution of the drug to a sufficient number of painful sites within the muscle to cause a significant decrease in the overall pain ratings. Indeed, injection of a similar volume of local anesthetics into the masseter muscle of TMD sufferers has been found previously to be no more effective than isotonic saline in reducing pain and mechanical sensitivity in myofascial TMD sufferers (McMillan and Blasberg, 1994; Tschopp and Gysin, 1996). Another factor related to this may be the rapid clearance of ketamine from the masseter muscle. The blood flow in the masseter muscle is three times higher than in limb muscles, and the clearance of other injected chemicals like glutamate (t1/2 -100s) is rapid, suggesting that ketamine may be cleared from the masseter muscle at a rapid rate, 388 Castrillon et al. limiting its ability to interact with peripheral NMDA receptors within the muscle (Palmer et al., 2002; Cairns et al., 2003b; Gambarota et al., 2005). Finally, although the activation of peripheral NMDA receptors alone may be sufficient to induce mechanical sensitization upon injection of glutamate into the masseter muscle (Fig. 1), this does not exclude the possibility of a contribution by other receptor mechanisms. There is evidence that non-NMDA receptors as well as metabotropic glutamate (mGlu) receptors also may contribute to glutamate-induced mechanical sensitization of the masseter muscle (Cairns et al., 2002; Ro et al., 2007) and that elevated interstitial levels of glutamate in the masseter muscle could result in the release of neuropeptides (Hargreaves et al., 1994). These are mechanisms that could affect mechanical sensitivity without ongoing NMDA receptor activation and, thus, may not be amenable to NMDA receptor blockade. TISSUE GLUTAMATE LEVELS There is good evidence indicating that small-volume (0.2 ml) injections of high concentrations (500-1000 mM) of glutamate into the human masseter muscle reliably evoke localized muscle pain (Figs. 1 and 2) and induce localized mechanical sensitization; these symptoms are similar to those reported by myofascial TMD patients (Cairns et al., 2001, 2003b,c, Svensson et al., 2003; Wang et al., 2004; Castrillon et al., 2007). Moreover, it has been suggested that only a brief elevation of intramuscular glutamate concentration is sufficient to trigger a cascade of events within the muscle tissue and alter the response properties of muscle afferent fibers (Cairns et al., 2007). Along the same line of research findings, human experiments have shown that muscle pain and mechanical sensitivity associated with artificial elevation of masseter muscle glutamate concentration (Fig. 2) appear to be mediated by activation of peripheral NMDA receptors, although other receptor mechanisms probably contribute to these effects of glutamate as well (Cairns et al., 2003a, 2006). Furthermore, animal studies have provided evidence that NMDA excites slowly-conducting, putative nociceptive masseter afferent fibers and that almost half of the trigeminal ganglion neurons that innervate the masseter muscle express NMDA receptors (Dong et al., 2007). These animal studies also have demonstrated that a two- to three- fold increase in glutamate concentration in the masseter muscle is 389 Peripheral NMDA Receptors sufficient to excite and mechanically sensitize masseter afferent fibers through activation of peripheral NMDA receptors (Cairns et al., 2007). These findings imply that relatively small increases in masseter muscle glutamate levels may be sufficient to alter pain perception and suggest that elevated concentrations of glutamate in the masseter muscle of myofascial TMD patients could be part of the pathophysiological mechanisms related to ongoing pain and mechanical sensitivity, which are characteristic features of this condition. The localized nature of muscle pain in some myofascial TMD suggests that a peripheral mechanistic component may contribute to these disorders, although it has been difficult to demonstrate significant localized changes in the muscle tissue associated with this pain. It has been suggested, however, that concentrations of the EAA glutamate also may be elevated in chronic myalgia of the trapezius muscle and that there is an association between glutamate tissue concentrations and pain as well as mechanical sensitivity in this condition (Alfredson et al., 2001, 2002, 2003; Rosendal et al., 2004; Flodgren et al., 2005). Q It should be mentioned that another study (Ashina et al., 2003) could not detect differences in glutamate levels in trapezius tender points in patients with chronic tension-type headache compared with healthy controls. Nonetheless, we have been able to demonstrate that there are significantly elevated concentrations of interstitial glutamate in the masseter muscle of myofascial TMD patients compared with healthy individuals (Castrillon et al., 2008c). This novel finding identifies for the first time a specific change in the interstitial environment of the masseter muscle associated with chronic myofascial TMD and supports the view that local release of algogenic substances in the masseter muscle may be involved in the pathophysiology of persistent myofascial TMD pain in this condition. There were no significant correlations between pain rating scores and interstitial or plasma glutamate concentrations in the myofascial TMD patients (Castrillon et al., 2008c). This finding, however, is consistent with a previous study that reported a decrease in pain intensity scores but not in glutamate concentration after treatment of Achilles tendons (Alfredson and Lorentzon, 2003). Therefore, it is possible that elevated concentrations of interstitial glutamate found in the masseter muscle of myofascial TMD patients reflect a more global metabolic change in the masseter muscle tissue and, thus, are not directly responsible for masseter muscle pain (Castrillon et al., 2008c). 390 Castrillon et al. Our findings of elevated glutamate levels in the masseter muscle of myofascial TMD patients also are consistent with other studies that have shown elevated tissue concentrations of glutamate in chronic, non- inflammatory deep tissue pain conditions of muscles and tendons in other anatomic parts of the body (Alfredson et al., 2001; Alfredson and Lorentzon, 2002, 2003; Rosendal et al., 2004; Flodgren et al., 2005). Finally, consistent with other human studies of non-inflammatory deep tissue pain, interstitial glutamate concentrations in the masseter muscle were found to be one and a half to four times greater in TMD patients than in pain-free controls. Together, these findings suggest that elevated levels of interstitial glutamate in craniofacial muscles and that glutamate itself, or through its interactions with other algesic substances, may play a role in the development and/or maintenance of chronic myofascial TMD pain conditions. SEX AND HORMONES IN OROFACIAL PAIN A literature review of gender and clinical pain indicates that a significant number of women receive treatment for pain conditions and Suggests that women report more severe pain, more frequent pain, and pain of longer duration than do men (Dao and LeResche, 2000). Moreover, chronic pain conditions such as fibromyalgia and myofascial TMD have been shown to be diagnosed more often in women than in men (Berkley, 1997); evidence suggests that these differences may be due to hormonal influences (LeResche et al., 2003). In experimental conditions, women have been shown to be more Sensitive to certain forms of stimulation, to be affected by many situational variables, to have lower thresholds and greater ability to discriminate higher pain ratings and less tolerance to noxious stimuli; however, there is some inconsistency in the scientific literature on this point (Berkley, 1997; Greenspan et al., 2007). Orofacial pain research studies have shown that healthy female Subjects report significantly greater masseter muscle pain after glutamate injection than do healthy male subjects (Cairns et al., 2001, 2003c; Svensson et al., 2003). These features of glutamate injection into the masseter muscle are reminiscent of certain of the characteristics of myofascial TMD patients; in fact, pain intensity produced in healthy Subjects after glutamate injection is similar to that reported by myofascial 391 Peripheral NMDA Receptors TMD patients (Castrillon et al., 2008). It is tempting, therefore, to speculate, based on these similarities, that elevated interstitial glutamate levels in the masseter muscle of TMD could be a contributing factor in this disorder (Castrillon et al., 2008). Moreover, the contrasting findings that locally administered ketamine had no detectable effects on glutamate-evoked masseter muscle pain or sensitization in healthy young women but it had over young healthy men (Cairns et al., 2006; Castrillon et al., 2007), suggesting that different mechanisms may underlie the development of muscle pain in women than in men. As mentioned in the previous section, there appears to be a sex- related difference in the effectiveness of the NMDA receptor antagonist ketamine to block glutamate-evoked muscle pain in healthy young women (Castrillon et al., 2007). This finding differs from results in healthy young men (Cairns et al., 2006), in whom co-injection of the same concentration of ketamine under analogous experimental conditions attenuated the glutamate-evoked peak pain, duration of pain and overall pain by ~50%. It is unlikely that methodological issues such as sample size or ketamine dose could be the main reason for the lack of ketamine-induced effects in our study (Cairns et al., 2006). Even though we employed a similar methodology in our previous study in men (Cairns et al., 2006) and used a paired design in which the female subjects acted as their own controls, we cannot rule out that a higher dose of ketamine would have been effective. Moreover, we anticipated women to be more sensitive and not less sensitive to administration of ketamine and therefore, it could be speculated that different mechanisms may underlie the development of mechanical sensitization in women than in men. One possible biological explanation for this apparent sex-related difference in the effect of ketamine on glutamate-evoked muscle pain could be that other peripheral glutamate-receptor subtypes, such as amino-5-methyl-4-isoxazolone-propionic acid (AMPA), kainate or metabotropic receptors (Cairns et al., 1998; Carlton, 2001), may play a more significant role than NMDA receptors in glutamate-evoked muscle pain in women compared with men. Additionally, it is possible that the active participation of other peripheral receptor processes, such as those involving the TRPV1 (Lam et al., 2005; Sessle, 2005), neuropeptides or serotonin (Ernberg et al., 1999), may play a greater role in the development of glutamate-induced masseter muscle mechanical sensitization in women. 392 Castrillon et al. This apparent sex-related difference in the ability of ketamine to antagonize glutamate-evoked masseter muscle pain also raises questions about the possible differences in the mechanisms responsible for the effect of ketamine in blocking NMDA receptors. Future studies of NMDA and non-NMDA receptor mechanisms in glutamate-evoked pain will need to take into account the findings that sex-related differences in analgesia may be influenced by multiple factors. Among these possible factors we could mention the anatomical location of the pain, types of receptors involved, pain model, type of drug, dose, mechanisms of action of the drug, psychological factors (Fillingim and Gear, 2004; Christidis et al., 2005; Fillingim et al., 2005a,b), as well as age and health status of the subjects studied. Another factor to consider regarding the effects of ketamine is that there may be sex-related differences in pain perception mediated through activation of peripheral NMDA receptors. As mentioned previously, glutamate-evoked acute masseter muscle pain is attenuated significantly by co-injection of ketamine in healthy young men (Cairns et al., 2006), but not in healthy young women (Castrillon et al., 2007). In female but not male rats, the magnitude of masseter nociceptor discharge acutely evoked by activation of peripheral NMDA receptors is correlated positively with serum estrogen levels, a phenomenon that appears to be due to an estrogen-mediated increase in the number of masseter nociceptors that express NMDA receptors (Dong et al., 2007). If this effect also occurs in women, it may explain not only why women report a greater intensity of pain than do men after injection of glutamate into the masseter muscle, but also why higher doses of ketamine may be required in women to adequately attenuate pain related to increased interstitial concentrations of glutamate. A further complication of pain studies is that in women who take oral contraceptives (OC), which change the natural fluctuation of sex hormones (e.g., progesterone and estrogens) have the potential for decreased sensitivity to painful stimuli (LeResche et al., 2005). Nevertheless, the results of our study (Castrillon et al., 2007) indicate that there are no major differences between the two groups of women (W-OC and W+OC) in terms of their PPTs and PPTOLs as well as their response to glutamate-evoked pain. This finding suggests that estrogen has limited if any influence on the glutamate-related pain parameters in Women. Furthermore, our unpublished analyses of the salivary concentration of estradiol levels did not correlate significantly with the 393 Peripheral NMDA Receptors correspondent VAS peak scores obtained during the same experimental session (Fig. 3). As a consequence of all these finding, it could be suggested that, at least for experimental pain research purposes, significantly larger groups will be needed to detect any possible differences in glutamate-evoked masseter pain between women using and not using OC. 10. * . ( . ( ) 8 ( . C. © © º º Ç ( . ) ( . < 6 Ç. G. ( ) § Q & Cº. C- * e ( . . % * * @ > 4 *s C. ( ) gº º Q *e eº 2 Ç ©º O'O 2 '4 '6 '8 |10 Estradiol salivary concentrations (pg/mL) Figure 3. The scatter plot shows the correlation of the salivary estradiol concentration with the VAS peak of W-OC in response to an injection of 0.2 ml glutamate into the masseter muscle (n = 19, 3 sessions registered per subject; data from seven measurements missing). There were no significant correlations (Pearson, R = 0.104, P = 0.474). PSYCHOLOGICAL VARIABLES Although human experimental models of pain applied to the orofacial area are valuable and can provide clinically relevant information, TMD myofascial patients and the characteristics of their persistent pain experience are more complex than acute experimental pain (Castrillon et al., 2008b). It has been suggested that the differences between experimental pain conditions and chronic myofascial pain conditions could be due to the fluctuation of pain, the chronicity of the 394 Castrillon et al. pain, psychosocial distress, functional disabilities, and concomitant pain conditions that may influence their pain perception (Svensson, 2007). Such factors limit the direct comparison of the results obtained from clinical experiments on TMD myofascial chronic pain patients vs. experimental pain in healthy human subjects (Svensson, 2007). Moreover, pain is influenced by a multitude of factors, including psychological factors that have been shown to be important determinants of pain experience (Melzack, 1975; Rollman and Gillespie, 2000). Thus, it has been reported that patients suffering from myo- fascial pain dysfunction or atypical facial pain are more likely to show elevations in psychometric scales for hypochondriasis and depression (Rollman and Gillespie, 2000). It also has been shown that psychosocial Variables such as coping strategies may have implications for the underlying physiology of pain, (e.g., predicting important clinical Outcomes), including pain severity and disability (Turk and Okifuji, 2002). There is plenty of evidence showing that psychosocial variables (e.g., catastrophizing and stress) play an important role in the perception, control and chronification of pain in clinical conditions (Rollman and Gillespie, 2000; Grossi et al., 2001; Turk and Okifuji, 2002) and should be taken into account. Our studies have shown that glutamate-evoked jaw muscle pain in healthy subjects shares many of the characteristics of persistent pain in the TMD patients, but that the psychosocial scores differ between the two groups in particular (Castrillon et al., 2008b). Moreover, it has been shown that there are significant associations between measures of pain intensity and psychosocial scores predominately in the TMD pain patients (Castrillon et al., 2008b). According to the literature, TMD pain patients have more psychosocial/psychometric distress than matched control subjects (Epker and Gatchel, 2000; Auerbach et al., 2001; Jerjes et al., 2007). In accordance with this notion, our study showed that some psychological characteristics of the myofascial TMD pain patients differed from those in the healthy subjects (Castrillon et al., 2008b). These discrepancies between the groups were especially in their ability to cope with pain and their control of pain, their ability to decrease the pain, the ability to divert their attention, and the ability to increase behavioral activities (Castrillon et al., 2008b). The characteristics of Coping Strategies Questionnaire (CSQ) did not let us establish whether these psychosocial variables were 395 Peripheral NMDA Receptors consequences of a chronic pain condition or were pre-existing conditions to the establishment of persistent myofascial TMD pain and it worked as one of the etiological factors. The possibility that coping strategies may have implications for the underlying physiology of pain (e.g., to predict important clinical outcomes, including pain severity and disability) can not be ruled out (Turk and Okifuji, 2002) because our experimental design was not a longitudinal prospective study that followed the healthy volunteers to see whether they developed persistent TMD pain and its associated characteristics. Another option may be that the inadequacies of some coping strategies could work as facilitators to establish chronic pain. This latter rationale is based on evidence that during mild pain there is a relation between catastrophizing and activity in cortical regions associated with affective, attention and motor aspects of pain (Seminowicz and Davis, 2006). This evidence indicates a possible physiological explanation for how psychological factors may interfere with pain responses and facilitate their establishment. One of the greatest differences between TMD patients and healthy controls in our study was the finding of a considerable correlation between PPT and PPTOL values and coping scores in TMD patients, but no evidence of similar correlations in healthy subjects injected with glutamate (Castrillon et al., 2008b). Moreover, injection of glutamate into the masseter muscle of healthy subjects did not achieve the same degree of mechanical sensitization observed in TMD patients. In addition, individual healthy subjects may have experienced significant challenges when responding to the questions about pain coping strategies. These factors likely explain the absence of correlations between mechanical pain and coping scores in healthy subjects (Castrillon et al., 2008b). Although TMD patients and healthy subjects used similar words from the McGill Pain Questionnaire (MPQ) to describe their pain experience, the frequency of use of some words differed significantly between them (Castrillon et al., 2008b). The increased frequency of the use of the term “tender” by TMD patients seems likely to be related to their increased mechanical pain sensitivity, which was clearly greater than that which could be produced in healthy subjects after intramuscular injection of glutamate. The increased use of the term “spreading” by the healthy controls shows the anatomical area of influence of the peripheral glutamate evoked pain condition. On the other hand, the increased frequency of the term “tiring” by TMD patients and “boring” by healthy 396 Castrillon et al. Volunteers suggests that the ongoing pain experienced by patients has a different emotional component than the acute muscle pain experienced by healthy controls receiving intramuscular injections of glutamate (Castrillon et al., 2008). These findings serve to illustrate further that while single intramuscular injections of glutamate can produce, for a short time, a similar magnitude of muscle pain in healthy controls, this type of acute pain is not able to recruit the same degree of emotional response with which chronic muscle pain in TMD patients appears to be associated (Castrillon et al., 2008b). CONCLUSIONS All the literature reviewed in this chapter and our own results Support the concept that experimentally-induced increases in glutamate concentration in the human masseter muscle evoke pain, decrease pressure pain threshold (PPT), and enhance the amplitude of the jaw- stretch reflex (Cairns et al., 2001, 2003b,c, Svensson et al., 2003; Wang et al., 2004; Castrillon et al., 2007) and that increased tissue concentrations of the EAA glutamate may act on EAA receptors, including NMDA receptors. Scientific evidence suggests that elevated glutamate concen- trations in deep tissues of non-inflammatory chronic pain conditions are associated with ongoing pain and sensitization (McNearney et al., 2000; Alfredson et al., 2001; Alfredson and Lorentzon, 2002). This concept is Supported by our findings that demonstrate, for the first time, that elevated concentrations of interstitial glutamate can be found in the masseter muscle of myofascial TMD patients and that these concen- trations are higher than in healthy controls (Castrillon et al., 2008c). All together, this evidence suggests that peripherally released glutamate could be involved in pathophysiology of TMD either by direct activation of peripheral NMDA and/or other peripheral glutamate receptor Subtypes, or indirectly through the release of other neuro-active agents. Even though it has been demonstrated that local administration of an NMDA receptor antagonist, like ketamine, attenuates experimental glutamate-evoked pain conditions (Cairns et al., 2006); it has been shown that women do not react in a similar way (Castrillon et al., 2007). Moreover, ketamine had no significant effect on female chronic myofascial TMD pain patients (Castrillon et al., 2008). Some evidence Suggests that sex differences on pain, related to sensitivity, could be due 397 Peripheral NMDA Receptors to hormonal influences (LeResche et al., 2003), but our studies were not able to show any difference between W-OC and W+OC, and suggest that at least for experimental settings, bigger samples may be needed in order to show if hormonal levels are able to influence pain experience (Castrillon et al., 2007). Further, we were not able to show strong correlations of hormonal levels of W+OC with experimental pain responses. We can conclude that the available evidence suggests that glutamate-evoked pain can model certain characteristics of persistent myofascial pain conditions (Castrillon et al., 2008) and that there may exist possible sex differences in the physiology of those conditions (Castrillon et al., 2007). Additionally, the evidence suggests that different mechanisms may underlie the development of mechanical sensitization in women than in men and that OC status does not seem to influence pain responses in experimental pain models. Therefore, taking into account that myofascial TMD pain patients are similar in several characteristics with healthy subjects exposed to glutamate-evoked pain, it is tempting to speculate that elevated interstitial glutamate levels in the masseter muscle of TMD could be a contributing factor in this disorder (Castrillon et al., 2008). Nevertheless, caution must be taken to interpret all this findings because it still remains uncertain what role peripheral glutamate plays in persistent myofascial TMD and further studies will be needed to reveal the physiological basis for the pain in these conditions. REFERENCES Alfredson H, Forsgren S, Thorsen K, Lorentzon R. In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper's knee. J Orthop Res 2001;19:881-886. Alfredson H, Lorentzon R. Chronic tendon pain: No signs of chemical inflammation but high concentrations of the neurotransmitter glutamate. Implications for treatment? Curr Drug Targets 2002;3:43- 54. Alfredson H, Lorentzon R. Intratendinous glutamate levels and eccentric training in chronic Achilles tendinosis: A prospective study using microdialysis technique. Knee Surg Sports Traumatol Arthrosc 2003; 11:196-199. 398 Castrillon et al. Ashina M, Stallknecht B, Bendtsen L, Pedersen JF, Schifter S, Galbo H, Olesen J. Tender points are not sites of ongoing inflammation: In vivo evidence in patients with chronic tension-type headache. Cephalalgia 2003:23:109-116. Auerbach SM, Laskin DM, Frantsve LM, Orr T. Depression, pain, exposure to stressful life events, and long-term outcomes in temporomandibular disorder patients. J Oral Maxillofac Surg 2001:59:628–633. Berkley K.J. Sex differences in pain. Behav Brain Sci 1997:20:371-380. Brău ME, Sander F, Vogel W., Hempelmann G. Blocking mechanisms of ketamine and its enantiomers in enzymatically demyelinated peripheral nerve as revealed by single-channel experiments. Anesthesiology 1997;86:394-404. Cairns BE, Dong X, Mann MK, Svensson P, Sessle BJ, Arendt-Nielsen L, McErlane KM. Systemic administration of monosodium glutamate elevates intramuscular glutamate levels and sensitizes rat masseter muscle afferent fibers. Pain 2007;132:33-41. Cairns BE, Gambarota G, Dunning PS, Mulkern RV, Berde CB. Activation of peripheral excitatory amino acid receptors decreases the duration of local anesthesia. Anesthesiology 2003a;98:521-529. Cairns BE, Gambarota G, Svensson P, Arendt-Nielsen L, Berde CB. Glutamate-induced sensitization of rat masseter muscle fibers. Neuroscience 2002; 109:389-399. Cairns BE, Hu JW, Arendt-Nielsen L, Sessle BJ, Svensson P. Sex-related differences in human pain and rat afferent discharge evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2001;86:782–791. Cairns BE, Sessle BJ, Hu JW. Evidence that excitatory amino acid receptors within the temporomandibular joint region are involved in the reflex activation of the jaw muscles. J Neurosci 1998;18:8056– 8064. Cairns BE, Svensson P, Wang K, Hupfeld S, Graven-Nielsen T, Sessle BJ, Berde CB, Arendt-Nielsen L. Activation of peripheral NMDA receptors contributes to human pain and rat afferent discharges evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2003b;90:2098-2105. 399 Peripheral NMDA Receptors Cairns BE, Svensson P, Wang K, Castrillon E, Hupfeld S, Sessle BJ, Arendt-Nielsen L. Ketamine attenuates glutamate-induced mech- anical sensitization of the masseter muscle in human males. Exp Brain Res 2006; 169:467-472. Cairns BE, Wang K, Hu JW, Sessle BJ, Arendt-Nielsen L, Svensson P. The effect of glutamate-evoked masseter muscle pain on the human jaw-stretch reflex differs in men and women. J Orofac Pain 2003c, 17:317-325. Carlsson GE, LeResche L. Epidemiology of temporomandibular disorders. In: Sessle BJ, Bryan PS, Dionne RA, eds. Temporo- mandibular Disorders and Related Pain Conditions. Seattle: IASP PreSS 1995. Carlton SM. Peripheral excitatory amino acids. Curr Opin Pharmacol 2001:1:52-56. Castrillon EE, Cairns BE, Ernberg M, Wang K, Sessle BJ, Arendt- Nielsen L, Svensson P. Effect of a peripheral NMDA receptor antagonist on glutamate-evoked masseter muscle pain and mechanical sensitization in women. J Orofac Pain 2007:21:216-224. Castrillon EE, Cairns BE, Ernberg M, Wang K, Sessle BJ, Arendt- Nielsen L, Svensson P. Effect of peripheral NMDA receptor blockade with ketamine on chronic myofascial pain in temporomandibular disorder patients: A randomized, double-blinded, placebo-controlled trial. J Orofac Pain 2008a;22:122-130. Castrillon EE, Cairns BE, Ernberg M, Wang K, Sessle B, Arendt-Nielsen L., Svensson P. Glutamate-evoked jaw muscle pain as a model of persistent myofascial TMD pain? Arch Oral Biol 2008b;53:666-676. Castrillon EE, Ernberg M, Cairns BE, Sessle BJ, Arendt-Nielsen L, Svensson P. Interstitial glutamate concentration is elevated in the masseter muscle of myofascial temporomandibular disorder patients. 2008c; submitted for publication. Christidis N, Kopp S, Ernberg M. The effect on mechanical pain threshold over human muscles by oral administration of granisetron and diclofenac-sodium. Pain 2005; 113:265-270. Dao TT, Knight K, Ton-That V. Modulation of myofascial pain by the reproductive hormones: A preliminary report. J Prosthet Dent 1998;79:663-670. Dao TT, LeResche L. Gender differences in pain. J Orofac Pain 2000;14:169-184. 400 Castrillon et al. Dong XD, Mann MK, Kumar U, Svensson P, Arendt-Nielsen L, Hu JW, Sessle BJ, Cairns BE. Sex-related differences in NMDA-evoked rat masseter muscle afferent discharge result from estrogen-mediated modulation of peripheral NMDA receptor activity. Neuroscience 2007; 146:822–832. Ernberg M, Hedenberg-Magnusson B, Alstergren P, Kopp S. The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia. Life Sci 1999;65:313-325. Ernberg M, Hedenberg-Magnusson B, Alstergren P, Lundeberg T, Kopp S. Pain, allodynia, and serum serotonin level in orofacial pain of muscular origin. J Orofac Pain 1999; 13:56-62. Epker J, Gatchel R.J. Coping profile differences in the biopsychosocial functioning of patients with temporomandibular disorder. Psychosom Med 2000;62:69–75. Fillingim RB, Gear RW. Sex differences in opioid analgesia: Clinical and experimental findings. Eur J Pain 2004;8:413-425. Fillingim RB, Hastie BA, Ness TJ, Glover TL, Campbell CM, Staud R. Sex-related psychological predictors of baseline pain perception and analgesic responses to pentazocine. Biol Psychol 2005a;69:97-112. Fillingim RB, Ness TJ, Glover TL, Campbell CM, Hastie BA, Price DD, Staud R. Morphine responses and experimental pain: Sex differences in side effects and cardiovascular responses but not analgesia. J Pain 2005b;6:116-124. Flodgren GM, Crenshaw AG, Alfredson H, Fahlström M, Hellström FB, Bronemo L, Djupsjöbacka M. Glutamate and prostaglandin E2 in the trapezius muscle of female subjects with chronic muscle pain and controls determined by microdialysis. Eur J Pain 2005;9:511–515. Gambarota G, Philippens M, Cairns BE, Dong XD, Renema WK, Heerschap A. MRS assessment of glutamate clearance in a novel masticatory muscle pain model. NMR Biomed 2005;18:345-351. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ; Consensus Working Group of the Sex, Gender, and Pain SIG of the IASP. Studying sex and gender differences in pain and analgesia: A consensus report. Pain 2007;132:S26-45. Grossi ML, Goldberg MB, Locker D, Tenenbaum HC. Reduced neuropsychologic measures as predictors of treatment outcome in 401 Peripheral NMDA Receptors patients with temporomandibular disorders. J Orofac Pain 2001; 15:329-339. Hargreaves KM, Swift JQ, Roszkowski MT, Bowles W, Garry MG, Jackson DL. Pharmacology of peripheral neuropeptide and inflammatory mediator release. Oral Surg Oral Med Oral Pathol 1994;78:503–510. Jerjes W, Madland G, Feinmann C, Hopper C, Kumar M, Upile T, Kudari M, Newman S. A psychological comparison of temporo- mandibular disorder and chronic daily headache: Are there targets for therapeutic interventions? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103:367-373. Lam DK, Sessle BJ, Cairns BE, Hu JW. Neural mechanisms of temporomandibular joint and masticatory muscle pain: A possible role for peripheral glutamate receptor mechanisms. Pain Res Manag 2005; 10:145-152. LeResche L. Epidemiology of temporomandibular disorders: Implications for the investigation of etiologic factors. Crit Rev Oral Biol Med 1997:8:29.1-305. LeResche L, Mancll, Sherman JJ, Gandara B, Dworkin SF. Changes in temporomandibular pain and other symptoms across the menstrual cycle. Pain 2003;106:253-261. LeResche L, Saunders K, Von Korff MR, Barlow W, Dworkin SF. Use of exogenous hormones and risk of temporomandibular disorder pain. Pain 1997;69:153-160. LeResche L, Sherman JJ, Huggins K, Saunders K, Mancll A, Lentz G, Dworkin SF. Musculoskeletal orofacial pain and other signs and symptoms of temporomandibular disorders during pregnancy: A prospective study. J Orofac Pain 2005; 19:193-201. McMillan AS, Blasberg B. Pain-pressure threshold in painful jaw muscles following trigger point injection. J Orofac Pain 1994;8:384- 390. McNearney T, Speegle D, Lawand N, Lisse J, Westlund KN. Excitatory amino acid profiles of synovial fluid from patients with arthritis. J Rheumatol 2000:27:739–745. Melzack R. The McGill Pain Questionnaire: Major properties and scoring methods. Pain 1975; 1:277–299. Palmer GM, Cairns BE, Berkes SL, Dunning PS, Taylor GA, Berde CB. The effects of lidocaine and adrenergic agonists on rat sciatic nerve 402 Castrillon et al. and skeletal muscle blood flow in vivo. Anesth Analg 2002;95:1080– 1086. Ro JY, Capra NF, Lee JS, Masri R, Chun YH. Hypertonic saline-induced muscle nociception and c-fos activation are partially mediated by peripheral NMDA receptors. Eur J Pain 2007; 11:398-405. Rollman GB, Gillespie JM. The role of psychosocial factors in temporomandibular disorders. Curr Rev Pain 2000;4:71-81. Rosendal L, Larsson B, Kristiansen J. Peolsson M, Søgaard K, Kjaer M, Sørensen J., Gerdle B. Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: m=Microdialysis in rest and during exercise. Pain 2004;112:324–334. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev 2003:55:1-20. Seminowicz DA, Davis KD. Cortical responses to pain in healthy individuals depends on pain catastrophizing. Pain 2006;120:297-306. Sessle B.J. Peripheral and central mechanisms of orofacial pain and their clinical correlates. Minerva Anestesiol 2005;71:117-136. Stohler CS. Muscle-related temporomandibular disorders. J Orofac Pain 1999; 13:273-284. Svensson P. What can human experimental pain models teach us about clinical TMD'? Arch Oral Biol 2007:52:391-394. Svensson P, Cairns BE, Wang K, Hu JW, Graven-Nielsen T, Arendt- Nielsen L, Sessle B.J. Glutamate-evoked pain and mechanical allodynia in the human masseter muscle. Pain 2003; 101:221-227. Truelove EL, Sommers EE, LeResche L, Dworkin SF, Von Korff M. Clinical diagnostic criteria for TMD: New classification permits multiple diagnoses. J Am Dent Assoc 1992;123:47-54. Tschopp KP, Gysin C. Local injection therapy in 107 patients with myofascial pain syndrome of the head and neck. ORL J Otorhinolaryngol Relat Spec 1996:58:306–310. Turk DC, Okifuji A. Psychological factors in chronic pain: Evolution and revolution. J Consult Clin Psychol 2002;70:678-690. Wang K, Sessle BJ, Svensson P, Arendt-Nielsen L. Glutamate evoked neck and jaw muscle pain facilitate the human jaw stretch reflex. Clin Neurophysiol 2004;115:1288–1295. 403 IPSILATERAL AND CONTRALATERAL HUMAN TMJ LOADS COMPARED VIA VALIDATED NUMERICAL MODELS Laura R. Iwasaki, Shinji Uchida, David B. Marx, Yoritaka Yotsui, Teruta Maeda, Hiroshi Inoue, Jeffrey C. Nickel ABSTRACT How the central nervous system (CNS) organizes the masticatory muscles de- termines the magnitudes of loads imposed on the temporomandibular joints (TMJs). The objectives were first to validate numerical models in two ways by determining if: 1. A model based on minimization of joint loads (MJL) accu- rately predicted effective sagittal TMJ eminence morphol- ogy; and 2. Models based on MJL or minimization of muscle effort (MME) accurately predicted masseter, temporalis, and lat- eral pterygoid muscle activities for static unilateral molar biting. If validated, then, these computer models were used to test the hypothesis that the contralateral TMJ was loaded more heavily than the ipsilateral TMJ during Static unilateral molar biting. Seven healthy male volunteers produced unilateral static bites on first molars while force and EMG data were recorded. ANOVA and linear regressions were used to test for significant differences and accuracy. Modeling then was conducted for each subject, where ipsilateral and contralat- eral TMJ loads were calculated for a survey of bite-force angles imposed on the right mandibular first molar. Pooled data showed significant differences (p<0.05) between MJL model-predicted and in vivo data for the lateral pterygoid muscle, but no significant differences between MME model-predicted and in vivo data. Overall, predictions from the MME model were more accurate, rang- ing from within -10% to +6% of in vivo data (0.81sR*=0.94). Validated model calculations showed that for specific directions of biting, ipsilateral TMJ loads were 20% to 70% greater (p<0.05) than contralateral TMJ loads. During static unilateral molar biting, minimization of muscle effort may be a common organi- Zational goal governing masticatory muscle activities and ipsilateral or contra- lateral TMJ loads are higher depending on biting angle. 405 Human TMJ Loads Compared Contact mechanics in the temporomandibular joint (TMJ) reflect the combined effects of magnitudes of TMJ loads and morphologies of the articulating surfaces (Gallo et al., 2000, 2006; Iwasaki et al., 2004; Nickel et al., 2004, 2006). Forces generally are considered to be higher on the contralateral condyle than on the ipsilateral condyle during static loading of the dentition (Hannam et al., 1997). Efforts to measure human TMJ forces are compromised because available methods are too invasive to be used in living subjects. Compressive TMJ loads in animals have been recorded with indwelling instrumentation but without characteriza- tion of magnitudes and directions of forces applied to the jaw or resulting in the TMJ (Highlander, 1979; Brehan et al., 1981; Hohl and Tucek, 1982; Marks et al., 1997; Liu and Herring, 2000; Langenbach et al., 2002). Moreover, the peculiarities of hominid musculoskeletal and dental morphology are linked to local biomechanics in ways that cannot be ex- trapolated readily from experiments on other species (Herring, 2007). For these reasons, computer-assisted modeling of the muscle and joint forces in the human craniomandibular apparatus has become an attractive method to study control of mandibular loading. Synovial joint systems, including the craniomandibular appara- tus, are mechanically indeterminate because the number of muscles in- volved is more than the minimum needed to produce static equilibrium. Consequently, there are an infinite number of combinations of muscle and joint forces that are capable of producing static equilibrium. One approach, used in computer-assisted mathematical modeling, is to make specific assumptions so that a unique solution for static equilibrium can be rendered. Such assumptions have included constraining the direction of condylar loading (Koolstra et al., 1988; van Eijden, 1990, 1991; Kool- stra and van Eijden, 1995, 1997, 2005; Peck et al., 2000; Koolstra, 2002, 2003) and assigning forces based on cross-sectional areas of muscles, inferred contractile properties of muscles, and averaged electromyog- raphic (EMG) data (Osborn and Baragar, 1985; Korioth, 1990; Throck- morton et al., 1990; Osborn, 1995; Koolstra, 2002, 2003; Schindler et al., 2007). These assumptions, based on pooled data, produce results that are correct mathematically but may not accurately predict muscle or joint forces for an individual (Trainor et al., 1995; Koolstra, 2002). Neverthe- less, the results of these mathematical models often are used with finite element methods to calculate the distribution of stresses and strains in the mandible and TMJ during function (Beck et al., 2000; Koolstra, 2003; Koolstra and van Eijden, 2005). Historically, there has been a paucity of studies conducted to validate the accuracy of the assumed muscle and 406 Iwasaki et al. joint forces employed. Therefore, the application of data produced from mathematical and finite element modeling to the craniomandibular appa- ratus in living humans remains uncertain. Fidelity of a model to the prototype can be checked if the model uniquely predicts parameters that are measurable in vivo and thus are testable. One approach that accomplishes this uses a three-dimensional (3D) numerical method to render solutions based on an objective that is likely to be of biological importance, and, hence, represents a theory of underlying neuromuscular control (Smith et al., 1986; Trainor and McLachlan, 1992; Trainor et al., 1995; Koolstra, 2003). Objectives such as maximization of biting force, minimization of joint loads, joint loads- Squared, muscle force, muscle effort, or muscle force-cubed, have been investigated. Numerical models based on minimization of joint loads (MJL) and muscle effort (MME) have predicted accurately, to within 15%, the sagittal shape of the TMJ eminence and the outputs of mastica- tory muscles during static jaw-loading tasks for living subjects. The ac- curacy of these predictions were validated by experimental results from the same subjects and differences in muscle and TMJ forces in healthy individuals and subjects with temporomandibular disorders were demon- strated (Iwasaki et al., 2003a, b, 2004; Nickel et al., 2002, 2003; Nickel and Iwasaki, 2004). To date, the validation of numerical models used to predict load- ing of the mandibular condyle has been based on comparing model- predicted and measured data such as ipsilateral/contralateral ratios of muscle activities during static unilateral biting. These validation tests were limited because subject- and muscle-specific changes in activity (mV) per unit (N) of biting force (BF) were not investigated. The objec- tives of the current project were first to validate numerical models in two Ways by determining if: 1. A model based on minimization of joint loads (MJL) accurately predicted effective sagittal TMJ eminence morphology; and 2. Models based on MJL or minimization of muscle ef- fort (MME) accurately predicted masseter, anterior temporalis, and lateral pterygoid muscle activities for conditions of static unilateral molar biting. If Validated, then, these computer models were used to test the hypothe- sis that that the contralateral TMJ was more heavily loaded than the ipsi- lateral TMJ during static unilateral molar biting. 407 Human TMJ Loads Compared MATERIALS & METHODS Seven adult male subjects gave informed consent to participate. The study was approved by the Institutional Review Boards affiliated with the investigators. Using previously described methods (Iwasaki et al., 2003a,b; Nickel et al., 2002, 2003) the relative positions of the con- dyles, teeth, and five pairs of masticatory muscles (masseter, anterior temporalis, medial pterygoid, lateral pterygoid, anterior digastric) were determined from standardized lateral and posteroanterior cephalometric radiographs, according to a 3D coordinate system (Fig. 1). Maximum errors in repeated measures were + 3.5 mm. Anatomical data for a given subject, in the form of 3D coordi- nates defining the relative positions of the mandibular condyles, the tooth row (mandibular first molars, canines, and incisors), and five pairs of masticatory muscles (masseter, anterior temporalis, lateral pterygoid, medial pterygoid, and anterior digastric), were called a geometry file. This geometry file was first used in the numerical models (Trainor et al., 1995) to predict the effective TMJ eminence morphology. These predic- tions then were compared to the effective TMJ eminence morphology measured in the same subject. The effective eminence morphology is the sagittal plane projection of the stress-field trajectory during symmetrical protrusion and retrusion of the mandible (Gallo et al., 2000, 2006) as described in previous studies (Iwasaki et al., 2003a,b; Nickel et al., 2002, 2003). Each subject performed a set of 10 protrusive-retrusive move- ments, where a custom-made mandibular removable appliance and at- tached face bow delineated the instantaneous positions of the mandibular condyles through bilateral video recording. The recordings were viewed frame-by-frame, and positions of each condyle were traced. The condylar path was quantified using a custom-made computer program that re- corded horizontal and vertical coordinates, corrected for scale, and calcu- lated a best-fit cubic polynomial that represented the experimentally measured effective eminence shape. A numerical modeling program us- ing optimization based on unconstrained MJL and the subject’s geometry file were employed to predict the unique effective sagittal TMJ eminence morphology (Trainor et al., 1995). To do this, joint forces were calcu- lated for a series of symmetrical bilateral vertical bite forces applied from first molars to central incisors in 20 steps. At each step, the mandi- ble was repositioned anteriorly by the modeling program to be consistent with the biting position and the muscle orientations changed accordingly, before the direction of TMJ force was calculated. 408 Iwasaki et al. fy finan. L finº. R Figure 1. Force vectors involved in numerical models of isometric biting in hu- mans. Forces on the mandible (external load), at the joints (Foondyle), and repre- Senting five muscle pairs (m. 2 = masseter, m3, 4 = anterior temporalis, ms, 6 = lateral pterygoid, m1, 8 = medial pterygoid, mo, 10 = anterior digastric muscles) are illustrated. The axis system used to characterize the relative positions of the condyles, the teeth, and the muscle vectors, based on an individual’s anatomy, also is shown. Force magnitude was expressed as a percentage of external load. (Modified from previous publications: Smith et al., 1986; Iwasaki et al., 2003). 0,, (Azimuth Angle,”) is parallel to the occlusal plane and varies between 0° and 359°, 9, (Angle from Vertical, *) describes the angle of the biting force relative to normal to the occlusal plane (0, = 0°). For equilibrium, each TMJ force was expected to be directed perpendicular to the effective eminence. Hence, the predicted effective Sagittal eminence shape was determined by a series of 20 short lines rep- resenting surfaces perpendicular to the predicted joint force direction for the series of 20 bilateral vertical bite forces, whereby the condyles were in retruded through protruded positions. The predicted shape was stored as a cubic polynomial and compared metrically, using linear regression analysis, to the measured effective eminence morphology. Percent error was calculated as the difference between the slope of the model- predicted vs. measured linear regression relation for each individual, and a theoretically perfect-match slope of 1.00. 409 Human TMJ Loads Compared To test whether or not computer models could predict individual- Specific in vivo muscle forces during biting tasks, bilateral bipolar sur- face and indwelling EMG electrodes and a BF-transducer device were used to measure muscle activity per N of BF. The center of the muscle bulk was located by palpation for masseter and anterior temporalis mus- cles, and surface EMG data were recorded according to previously de- scribed methods (Iwasaki et al., 2003a,b; Nickel et al., 2002, 2003). An intraoral approach was used to gain access to the inferior heads of the lateral pterygoid muscles bilaterally, and EMG data were recorded using bipolar fine-wire electrodes as per previous methods (Uchida et al., 2001, 2002). Correct electrode placement was confirmed by isolated ac- tivation of the lateral pterygoid muscles relative to adjacent musculature and computed tomography (Fig. 2). Figure 2. Verification of electrode placement within the inferior heads of the right and left lateral pterygoid muscles by computed tomographic imaging. Horizontal slice showing fine-wire electrode tips (circled) within the muscles in one participant. 410 Iwasaki et al. Static biting tasks occurred on a small steel ball, 5 mm in diame- ter, between custom acrylic crowns cemented to maxillary and mandibu- lar right and left first molars. A precalibrated electrically resistant film (Flexforce", Tekscan Inc., South Boston MA), positioned between the Steel ball and the flat occlusal surface of the maxillary crown, measured the magnitude of the BF. The bolus position relative to the center of re- Sistance of the mandibular molar was known through the use of five Small depressions, 5 mm apart, on each mandibular crown (Fig. 3). The depressions were parallel to the z-axis and numbered 1 through 5 from buccal to lingual, representing extreme and medium buccal tipping mo- ments, Vertical biting, and extreme and medium lingual tipping moments, respectively. Each subject was asked to produce a comfortable BF for five seconds, five times at each of five positions on each mandibular crown, with approximately 10 seconds between bites. Subjects were asked to produce a variety of BFs at each position with their jaws ap- proximately centered mediolaterally and in an anteroposterior position on the path to maximum intercuspation, without direct visual or auditory feedback. If an eccentric or protruded jaw position was used, this was recorded quantitatively by dental midline relations and overjet and these relations were modeled for that subject and biting task. In vivo Modeled Modeled In vivo BF, BF, BF, BF, : 6 : 9, -270° 0,, = 90° Extreme Buccal Moment Extreme Lingual Moment Figure 3. Biting positions and tipping moments. Applied bite forces for molar biting tasks. Line diagrams of the mesial views of the mandibular right first molar with acrylic crowns in place. CR is the centre of resistance of the tooth, M is the moment about the axis. , indicates the moment arm vector of the +Mx, buccal tipping, and -MX lingual tipping moments. (Modified from previous work: Nickel et al., 2003). 411 Human TMJ Loads Compared Muscle activities were amplified, viewed in real-time and stored on tape. EMG data were replayed and analyzed using commercial soft- ware (Fig. 4). For a given subject and side of biting (right, left), muscle activities over a two second period, where the BF was relatively steady, were sampled at 600 samples/s/channel and expressed as root-mean- square (RMS) values (mV). BF (N) was averaged for the same two- second period. A peak RMS value was identified for each subject, side of biting, and muscle, and a peak BF was identified for each subject and side of biting. Then, for each subject, side of biting, muscle and biting position, EMG RMS normalized to peak EMG RMS values vs. BF nor- malized to peak BF were plotted for the series of five bites (Fig. 5). The slope and linear regression relation were calculated for each plot. Two 3D numerical models, each using a different objective to produce a unique Solution for static equilibrium, predicted muscle and TMJ forces per unit of BF using the geometry file and validated effective eminence for each subject. The objectives were: 1. Minimization and equalization of right and left TMJ loads (MJL); and 2. Minimization of the sum of muscle forces-squared (MME). MME and MJL models calculated muscle and joint forces for the range of BF angles on the mandibular first molars that mimicked the in vivo tipping moments produced at the five different biting positions on each mandibular molar (Fig. 3). Modeled BF angles that simulated vertical BF/no tipping moment at biting position 3 had 6, of 0° (Fig. 1). Modeled BF angles that simulated buccal tipping moments at biting positions 1 and 2 and lingual tipping moments at biting positions 4 and 5 had 0, up to 30° and 0,z (Azimuth Angles in the occlusal plane) of 270° E 20° and 90° + 20°, respectively (Fig. 1). Each predicted muscle force for a given BF angle was expressed as a percentage of the applied BF, and normal- ized to peak predicted force for the muscle, subject and side of biting. Normalized model-predicted and measured data were compared using analysis of repeated measures for differences in least squares means (ANOVA). As well, subject-specific slopes and linear regression relations were calculated for plots of normalized model-predicted vs. measured muscle outputs to determine the accuracy of model predictions. Accuracy was determined by comparison of slopes with a theoretically perfect slope of 1.00. 412 Iwasaki et al. 0.1 mV 0.1 mV 0.1 mV 0.1 mV 4.0 mV 4.0 mV 286 N Figure 4. Example of raw EMG and biting force signals for Subject 5, left molar biting, position 2. Shown in order from top to bottom are outputs from: 1) left masseter (LMass); 2) left temporalis (LTemp); 3) right masseter (RMass); 4) right temporalis (RTemp); 5) left lateral pterygoid (LLatPt); 6) right lateral pterygoid (RLatPt) muscles; and 7) BF transducer (BFG). Calibration bars indi- Cate mV or N as marked. A. Ipsilateral Right Masseter Muscle 1.0 - A D £– slope = 0.96 = # 0.8- slope = 1.14 R* = 0.85 3 # R* = 0.94 © q > 75 00 0.6- #: A == * A $ $ 0.4- B. 9. Tº % A Fº © É g: 0.2- slope = 0.32 2 R* = 0.99 0.2 0.4 0.6 0.8 10 Normalized Biting Force (BFIPeak BF) B. Contralateral Left Masseter Muscle 1.0 - [T] slope = 0.98 [] £- pe. X 2 : 0.8- R* = 0.90 tº E <ſ ºf AA Gº > § É 0.6- * slope = 0.85 > R* = 0.92 *: $ $ 0.4- .N 0- 3 & 0.2- slope = 0.64 R* = 0.92 O u u 0.2 0.4 0.6 0.8 1.0 Normalized Biting Force (BF|Peak BF) 413 Human TMJ Loads Compared C. Ipsilateral Right Temporalis Muscle slope = 0.95 0.8- R* = 0.94 0.6 - slope = 0.83 2 – 0.4- R* = 0.86 Ef D slope = 0.11 R* = 0.92 —ºf wrv 0.2- O D 0 O 0.2 0.4 0.6 0.8 1.0 Normalized Biting Force (BF|Peak BF) 1.0 D. Contralateral Left Temporalis muscle 0.8- slope = 0.76 0.6- • R* = 0.86 * A A slope = 0.18 A 0.2- R* = 0.94 slope = 0.08 0- R* = 0.73 O 0.2 0.4 0.6 0.8 1.0 Normalized Biting Force (BF|Peak BF) E. Ipsilateral Right Lateral Pterygoid Muscle A 0.8- slope = 1.05 R* = 0.99 0.6- 0.4- 0.2- O © slope = 0.13 O R* = 0.48 º n DI I © I- 0 0.2 0.4 0.6 0.8 1.0 Normalized Biting Force (BF|Peak BF) 0 F. Contralateral left lateral pterygoid muscle 1.0- slope = 1.68 0.8- R* = 0.94 0.6- 04: A slope = 0.21 A R* = 0.83 slope = 0.06 R* = 0.54 [T] 0 0.2 0.4 o's o's 1.0 Normalized Biting Force (BFIPeak BF) 0.2- 414 Iwasaki et al. Figure 5 (previous pages). Biting tasks on the right molar by Subject 3. Normal- ized muscle activity (RMS/Peak RMS values) vs. normalized biting force (BF/Peak BF) plotted for the ipsilateral and contralateral (A and B) masseter, (C and D) temporalis, and (E and F) lateral pterygoid muscles. Linear regression relations and slopes are shown for three of five biting positions: 1 (extreme buc- cal tipping moment, X), 3 (vertical biting force, 9), and 5 (extreme lingual tip- ping moment, O). Data points are shown for other biting positions: 2 (medium buccal tipping moment, D) and 4 (medium lingual tipping moment, /\). A numerical model was validated for a subject if its predicted muscle activities for the modeled biting tasks matched measured muscle activities for the in vivo biting tasks within +10%. The validated model then was used to calculate TMJ forces in response to a static BF of 100 units applied at a survey of BF angles. TMJ forces were expressed rela- tive to the applied BF. BF angles were varied for 0, from 0° to 40° and for 0, from 0° to 359° (Fig. 1). Difference in ipsilateral vs. contralateral TMJ forces, predicted by validated numerical models, was determined for each BF angle for each subject. Results from all subjects and BF an- gles were plotted and commercial software (SigmaPlot, Systat Software, Inc., San Jose, CA) was used to calculate the overall mean difference and Standard error and to fit a polynomial to the pooled data. Differences that were greater than twice the standard error value above or below the mean were identified and the hypothesis that the contralateral TMJ is more heavily loaded than the ipsilateral TMJ was tested. RESULTS Accuracy of Model-Predicted Effective Eminence Morphology The accuracy of model-predicted eminence morphology was tested for a maximum of 5 mm of condylar protrusion. An absolute aver- age error of 11% was shown for all subjects, with a range of under- and over-estimation of eminence slope of -1.4% (Subject 3) and +1.6% (Sub- ject 7; Table 1). Accuracy of Model-Predicted Muscle Forces During Static Biting Peak BFs for the subjects were on average 230 N and ranged from 63 N to 346 N. Relations between EMG and BF were linear for a given subject, muscle, and biting position (data not shown). Slopes of the linear regression relations for the masseter muscles in all subjects gener- ally varied less over the range of biting positions (e.g. Figs. 5A,B) than for the temporalis muscles (e.g. Figs. 5C,D) and for the lateral pterygoid 415 Human TMJ Loads Compared Table 1. Summary of results for model predictions based on minimization of joint loads (MJL) vs. measured effective TMJ eminence morphology. Subject || MJL-model predicted vs. measured effective TMJ eminence morphology - R2 Error (%) 1 0.98 - 9 2 0.79 - 10 3 0.98 - 14 4 0.99 + 7 5 0.99 + 7 6 0.99 - 1 1 7 0.98 + 16 Average of absolute error 1.1% muscles (e.g. Figs. 5E,F). In some cases (e.g. Fig. 5F), these slopes var- ied by more than 10:1 between biting positions 1 and 5. ANOVA of pooled data showed that there were no significant differences between MME and MJL model-predicted masseter and tem- poralis muscle forces and measured muscle activities during biting (p=0.05; Table 2). ANOVA of pooled data showed significant differ- ences between MJL model-predicted muscle forces and measured muscle activities during biting for ipsilateral (p<0.05) and contralateral (p<0.0001) lateral pterygoid muscles (Table 2). Linear regression rela- tions of normalized model-predicted muscle forces vs. normalized meas- ured EMG activities for all muscles showed that the accuracy of the MME model-predictions ranged from -10% to +6% (Fig. 6), with an av- erage absolute error of 5% (Table 3). By comparison, the accuracy of the MJL model-predictions ranged from -64% to +6%, with an average abso- lute error of 43%. In two subjects (6, 7; Table 3), however, MJL model- based calculations were in error by +6% (R*=0.89) and -8% (R*=0.81) respectively, and therefore, very similar to the MME model-based calcu- lations for these subjects. Differences in Ipsilateral vs. Contralateral TMJ Forces Ipsilateral and contralateral TMJ forces in response to 100 units of static BF, applied at a survey of 0, and 0, angles on the right man- dibular first molar, were calculated using a validated numerical model for each subject. Overall, mean ipsilateral TMJ force for the BF angles surveyed was 90% of the applied BF, while mean contralateral TMJ force for the BF angles surveyed was 120% of the applied BF. Ipsilateral TMJ forces for all subjects for a given BF angle (0,0,z) were averaged and plotted (Fig. 7A). Similarly contralateral TMJ forces for all subjects 416 Iwasaki et al. Table 2. Results of Bonferroni-adjusted ANOVA differences in least squares means (LSM) of model-predicted vs. measured (in vivo) muscle outputs for sample, where standard errors were 0.0624 and degrees of freedom were 55.8. (*l or C = ipsilateral or contralateral to the biting force.) Muscle I Or C* Method LSM | Method LSM | p value Masseter I MJL model || 0.798 } in vivo 0.788 0.88 Masseter I MME model || 0.821 | in vivo 0.788 0.63 Masseter C MJL model || 0.764 in vivo 0.820 0.42 Masseter C MME model || 0.834 in vivo 0.820 0.83 Temporalis I MJL model 0.668 in vivo 0.661 0.91 Temporalis I MME model || 0.638 in vivo || 0.661 0.38 Temporalis C MJL model | 0.486 || in vivo 0.578 0.18 Temporalis C MME model 0.529 in vivo 0.578 0.48 Lateral Pterygoid I MJL model | 0.345 | in vivo 0.482 | < 0.05 Lateral Pterygoid I MME model || 0.381 | in vivo 0.482 0.14 Lateral Pterygoid C MJL model | 0.666 in vivo || 0.371 | < 0.0001 Lateral Pterygoid C MME model || 0.478 in vivo || 0.371 0.12 for a given BF angle (0, 0,...) were averaged and plotted (Fig. 7B). Gen- erally, average ipsilateral TMJ forces were highest during non-vertical biting (34° 3 9, s 40°) where BFs were directed posteriorly (9, 305° – 360°) and directed medially (0, 20° – 140°, Fig. 7A). Average ipsilateral TMJ forces were lowest where BFs were directed laterally (0x, 225° – 310°; Fig. 7A). Average contralateral TMJ forces were highest during non-vertical biting (13° - 6, s 40°) where BFs were directed posteriorly (0, 0°- 45° and 310°–359°; Fig. 7B). Average contralateral TMJ forces were lowest during non-vertical biting (5° - 0, s 40°) where BFs were directed medially and anteromedially (0, 90°– 180°: Fig. 7B). Differences in ipsilateral vs. contralateral TMJ forces for all sub- jects for a given BF angle (0, 0,…) were averaged and plotted (Fig. 8). These data fit a fourth order polynomial. Average differences in ipsilat- eral vs. contralateral TMJ forces varied between +60% to -60% of the applied BF (Fig. 8), where a positive (+) value indicated that the ipsilat- eral TMJ force was relatively larger and a negative (-) value indicated the contralateral TMJ force was relatively larger. On average, the ipsilateral TMJ force was larger than the contralateral TMJ force during non- vertical biting (17° 30, s 40°) where BFs were directed medially and anteromedially (9,90°-180°: Fig. 8). The difference between ipsilateral and contralateral TMJ forces for a subject and BF angle was considered significant when this difference was greater than twice the standard error 4.17 Human TMJ Loads Compared 1.0-1 A. Subject 2 ~5 § .9 L1- *C. § º 0.8- d: E Top D TO ºr š & 0.6 - ## > P 0.4- Tº dº slope = 0.90 $ 3 0.2 R* = 0.90 * = U. Z." # = 5 2 0 T T I T O 0.2 0.4 0.6 0.8 1.0 Normalized Measured EMG Activity Per BF (N) 1.0-1. B. Subject 6 Ll- * 0.8- "E =) # 0.6— g slope = 1.06 tº 0.4- R* = 0.94 Q} "G (ſ) =5 E O 0.2 0.4 0.6 0.8 1.0 Normalized Measured EMG Activity Per BF (N) Figure 6. Tests of model predictions: worst-case results for predictions from MME model. Plots of normalized MME model-predicted muscle force per unit BF vs. normalized measured EMG activity per BF (N) are shown for (A) Subject 2 and (B) Subject 6. Slopes of linear regression relationships were compared to a theoretically perfect slope of 1.00. → Figure 7. A: Average ipsilateral forces. B: Contralateral TMJ forces. Forces are expressed as a percentage of a 100 unit bite-force (% of Biting Force). Úy (Angle from Vertical, *) is the direction of the BF relative to the vertical axis, perpendicular to the occlusal plane, and varies between 0° and 40°, 9, (Azimuth Angle, ") is the direction of the BF in the occlusal plane and varies between 0° and 359°, 4.18 Iwasaki et al. Table 3. Summary of results for MJL- and MME-model pre- dicted vs. measured muscle outputs. Subject MJL-model predicted vs. measured MME-model predicted vs. measured muscle outputs muscle outputs d Error (%) R* Error (%) 1 0.09 -64 0.89 - 4 2 0.22 - 59 0.90 - 10 3 0.22 – 48 0.84 - 2 4. 0.18 - 57 0.90 +5 5 0.19 - 56 0.81 - 9 6 0.89 + 6 0.94 + 6 7 0.81 – 8 0.91 - 5 Average of absolute error 43% 5% 120 110 100 § 90 § º 80 § 2 7° 3. º 60 A F 3 50 § 40 - 30 Average Ipsilateral 20 TMJ Force 10 % º ºº: º 3. 25 2 & *_ ſo Q- ºr 0 § 3. 10 º, 3 315 360 20 º, 5 so 225 °7° 30 ° o 45 ° 135 40 0 (Azimuth 50 x- es) | 60 Angie, degº L 70 D 80 [T] 90 120 [ ] 100 110 110 – 100 120 B Average Contralateral TMJ Force * 419 Human TMJ Loads Compared 525 º ** 1802; 1615 Noº rees) * 315 so º Figure 8. Difference in ipsilateral and contralateral TMJ forces averaged for all subjects for each BF angle (0, 0,). 0, (Angle from Vertical, *) is the direction of the BF relative to the vertical axis, perpendicular to the occlusal plane, and Var- ies between 0° and 40°, 9, (Azimuth Angle, *) is the direction of the BF in the occlusal plane and varies between 0° and 359°. Differences in TMJ forces are expressed as a percentage of a 100 unit bite-force (% of Biting Force). Positive values indicate that, on average, ipsilateral TMJ forces were larger than contra- lateral TMJ forces. of the mean difference for the sample at that BF angle. The majority of differences were negative where the contralateral TMJ force was signif cantly larger than the ipsilateral TMJ force for the survey of BF angles investigated (Fig. 9). For a range of medially and anteriomedially diº rected BFs, however, the ipsilateral TMJ force was larger significantly than the contralateral TMJ force (Fig. 9). DISCUSSION Evaluations of the accuracy of model-predicted TMJ joint mº" phology were limited to two of three rectilinear components for the join loading vector. Although the mediolateral component (Z-axis) of the joint load was predicted by the model, only the sagittal aspects (X-. y-axes) of 420 Iwasaki et al. 2 7 0 2 1 0 10 20 30 40 0, (Angle from Vertical, *) Figure 9. Plot of statistically significant average differences between ipsilateral and contralateral TMJ forces for subjects over a range of BF angles (0, 0,…). Difference in numerical model-predicted ipsilateral vs. contralateral TMJ forces Was determined for each subject at each BF angle. These results were averaged for each BF angle, plotted, and standard error values were calculated. Average differences that were greater than + 2 standard error values were defined as sta- tistically significant. Green regions indicate the BF angles that resulted in sig- nificantly larger ipsilateral TMJ forces. Black regions indicate the BF angles that resulted in significantly larger contralateral TMJ forces. Red regions indicate no significant differences between ipsilateral and contralateral TMJ forces. the joint loading direction could be inferred from the in vivojaw tracking data. Testing predictions in 3D requires dynamic stereometry, where 3D kinematic and anatomic information are integrated (Gallo et al., 2000, 2006). These tests remain for future study. The results shown are the first to demonstrate that objective- based numerical models can predict inter-individual differences in the EMG activity (mv) vs. BF (N) relationships for the ipsilateral and con- Talateral masseter, temporalis, and lateral pterygoid muscles during Static biting. MME, or MME and MJL in the case of Subjects 6 and 7. Were used to predict in vivo muscle activities to within 10%. This im- Proves on the accuracy of our previous studies (Iwasaki et al., 2003; Nickel et al. 2003) where, similarly, muscle forces during static biting Were consistent with objectives of MME or MJL, or both, depending on the individual. biting location and moment. Whether or not the activities 421 Human TMJ Loads Compared of the medial pterygoid and digastric muscles can be predicted by nu- merical modeling has yet to be determined. If the craniomandibular system was organized for MME and MJL, this would be potentially advantageous because fatigue of the mas- ticatory muscles and mechanical stress in the TMJ would be attenuated. In five of seven subjects, MME was the objective that best described the organization of muscle activation by the CNS during static biting. In these individuals, optimization of muscle effort may come at the expense of unequal and larger joint loads, and a consequent increase in the me- chanical stresses imposed on the articulating surfaces of the TMJ. The most extreme examples of the differences in ipsilateral-contralateral TMJ forces were seen in Subject 4, where ipsilateral TMJ forces exceeded 300% of the applied BF and were 250% higher than the contralateral TMJ forces. * For the subjects studied, the contralateral TMJ force was signifi- cantly larger than the ipsilateral TMJ force for the majority but not all of the BF angles in the survey. That is, for a specific range of directions of biting on the mandibular first molar, ipsilateral TMJ forces were signifi- cantly larger than contralateral TMJ forces. CONCLUSION MME, and in some cases, MJL, appear to be the biological ob- jectives governing the masticatory muscles during unilateral static molar biting. The specific direction of the BF affects which condyle is more heavily loaded during a static biting situation. ACKNOWLEDGMENTS We gratefully acknowledge Mr. Kim Theesen, Graphic Artist, UNMC College of Dentistry, for helping with the figures; and the sub- jects for participating. Funding, in part, was provided by the D.H. Rein- hardt Scholar Fund, UNMC College of Dentistry. REFERENCES Beek M, Koolstra JH, van Ruijven LJ, van Eijden TM. Three- dimensional finite element analysis of the human temporomandibular joint disc. J Biomech 2000:33:307-316. 422 Iwasaki et al. Brehman K, Boyd RL, Laskin J, Gibbs CH, Mahan P. Direct measure- ment of loads at the temporomandibular joint in Macaca arctoides. J Dent Res 1981;60: 1820–1824, Gallo LM, Chiaravalloti G, Iwasaki LR, Nickel JC, Palla S. Mechanical work during stress-field translation in the human TMJ. J. Dent Res 2006:85:1006–1010. Gallo LM, Nickel JC, Iwasaki LR, Palla S. Stress-field translation in the healthy human temporomandibular joint. J Dent Res 2000;79: 1740- 1746. Hannam AG, Langenbach GE, Peck CC. Computer Simulations of Jaw Biomechanics. In: McNeill C, ed. Science and Practice of Occlusion. Chicago: Quintessence Publishing Co., 1997: 187-194. Herring SW. Masticatory muscles and the skull: A comparative perspec- tive. Arch Oral Biol 2007:52:296–299. Hohl TH, Tucek WH. Measurement of condylar loading forces by in- strumented prosthesis in the baboon. J Maxillofac Surg 1982; 10:1-7. Hylander WL. Experimental analysis of temporomandibular joint reac- tion force in macaques. Am J Phys Anthropol 1979:51:433-456. Iwasaki LR, Baird BW, McCall WD Jr., Nickel JC. Muscle and tem- poromandibular joint forces associated with chincup loading pre- dicted by numerical modeling. Am J Orthod Dentofacial Orthop 2003a; 124:530-540. Iwasaki LR, Petsche PE, McCall WD Jr, Marx D, Nickel JC. Neuromus- cular objectives of the human masticatory apparatus during static bit- ing. Arch Oral Biol 2003b;48:767-777. Iwasaki LR, Thornton BR, McCall WD Jr, Nickel JC. Individual varia- tions in numerically modeled human muscle and temporomandibular joint forces during static biting. J Orofac Pain 2004;18:235–245. Koolstra JH. Dynamics of the human masticatory system. Crit Rev Oral Biol Med 2002:13:366-376. Koolstra JH. Number crunching with the human masticatory system. J Dent Res 2003;82:672-676. Koolstra JH, van Eijden TM. Biomechanical analysis of jaw-closing movements. J Dent Res 1995;74:1564–1570. 423 Human TMJ Loads Compared Koolstra JH, van Eijden TM. Combined finite-element and rigid-body analysis of human jaw joint dynamics. J Biomech 2005:38:2431- 2439. Koolstra JH, van Eijden TM. The jaw open-close movements predicted by biomechanical modelling. J Biomech 1997:30:943-950. Koolstra JH, van Eijden TM, Weijs WA, Naeije M. A three-dimensional mathematical model of the human masticatory system predicting maximum possible bite forces. J Biomech 1988:21:563-576. Korioth TW, Hannam AG. Effect of bilateral asymmetric tooth clenching on load distribution at the mandibular condyles. J Prosthet Dent 1990;64:62-73. Langenbach GE, Zhang F, Herring SW, Hannam AG. Modelling the masticatory biomechanics of a pig. J Anat 2002;201:383-393. Liu ZJ, Herring SW. Bone surface strains and internal bony pressures at the jaw joint of the miniature pig during masticatory muscle contrac- tion. Arch Oral Biol 2000;45:95-112. Marks L, Teng S, Artun J, Herring S. Reaction strains on the condylar neck during mastication and maximum muscle stimulation in differ- ent condylar positions: An experimental study in the miniature pig. J Dent Res 1997;76:1412-1420. Nickel JC, Iwasaki LR. In vivo tests of TMJ morphology and masticatory muscle forces predicted by computer-assisted models. In: Davido- vitch Z, Mah J, eds. Biological Mechanisms of Tooth Movement and Craniofacial Adaptation. Boston: Harvard Society for the Advance- ment of Orthodontic 2004:63-74. Nickel JC, Iwasaki LR, Beatty MW, Marx DB. Laboratory stresses and tractional forces on the TMJ disc surface. J Dent Res 2004;83:650- 654. Nickel JC, Iwasaki LR, Beatty MW, Moss MA, Marx DB. Static and dynamic loading effects on temporomandibular joint disc tractional forces. J Dent Res 2006:85:809–813. Nickel JC, Iwasaki LR, Walker RD, McLachlan KR, McCall WD, Jr. Human masticatory muscle forces during static biting. J Dent Res 2003;82:212-217. Nickel JC, Yao P, Spalding PM, Iwasaki LR. Validated numerical mod- eling of the effects of combined orthodontic and orthognathic surgi- 424 Iwasaki et al. cal treatment on TMJ loads and muscle forces. Am J Orthod Dento- facial Orthop 2002; 121:73-83. Osborn JW. Biomechanical implications of lateral pterygoid contribution to biting and jaw opening in humans. Arch Oral Biol 1995:40: 1099- | | 08. Osborn JW, Baragar FA. Predicted pattern of human muscle activity dur- ing clenching derived from a computer assisted model: Symmetric vertical bite forces. J Biomech 1985; 18:599–612. Peck CC, Langenbach GE, Hannam AG. Dynamic simulation of muscle and articular properties during human wide jaw opening. Arch Oral Biol 2000:45:963-982. Schindler HJ, Rues S, Türp JC, Schweizerhof K, Lenz J. Jaw clenching: Muscle and joint forces, optimization strategies. J Dent Res 2007;86:843–847. Smith DM, McLachlan KR, McCall WD Jr. A numerical model of tem- poromandibular joint loading. J Dent Res 1986;65:1046-1052. Throckmorton GS, Groshan GJ, Boyd SB. Muscle activity patterns and control of temporomandibular joint loads. J Prosthet Dent 1990;63:685-695. Trainor PG, McLachlan KR. A numerical model to predict the force out- put of the jaw musculature. Engineering Optimization 1992;18:317- 328. Trainor PG, McLachlan KR, McCall WD. Modelling of forces in the human masticatory system with optimization of the angulations of the joint loads. J Biomech 1995:28:829-843. Uchida S, Whittle T, Wanigaratne K, Murray GM. Activity in the infe- rior head of the human lateral pterygoid muscle with different direc- tions of isometric force. Arch Oral Biol 2002:47:771-778. Uchida S, Whittle T, Wanigaratne K, Murray GM. The role of the infe- rior head of the human lateral pterygoid muscle in the generation and control of horizontal mandibular force. Arch Oral Biol 2001:46:1127–1140. Van Eijden TM. Jaw muscle activity in relation to the direction and point of application of bite force. J Dent Res 1990;69:901-905. Van Eijden TM. Three-dimensional analyses of human bite-force magni- tude and moment. Arch Oral Biol 1991:36:535-539. 425 TRACTIONAL FORCES, WORK AND ENERGY DENSITIES IN THE HUMAN TMJ Jeffrey C. Nickel, Laura R. Iwasaki, Luigi M. Gallo, Sandro Palla, David B. Marx ABSTRACT The role of mechanics in degenerative joint disease of the temporomandibular joint (TMJ) is largely unknown. Objectives were to: 1) develop an empirical model to relate variables of cartilage mechanics and tractional forces; and 2) use the empirical model to estimate tractional forces for calculations of work done (m) and energy densities (m)/mm’) in living human TMJs. Sixty-four porcine discs were statically, then dynamically loaded. Aspect ratios and Velocities of stress-fields, compressive strains, and tractional forces were recorded and fit to a quadratic equation to derive the empirical model. Aspect ratios and Velocities of stress-fields and cartilage thicknesses then were measured via dynamic stereo- metry in 15 humans with healthy TMJs and 11 with TMJ disc displacement. These data were used in the empirical model to estimate tractional forces for each TMJ, and then mechanical work done and energy densities were calculated. Mechanical work (m.J) was on average 20 times greater in TMJs with disc dis- placement than in healthy TMJs (P<0.02). TMJs with disc displacement showed 350% more mechanical work (m.J) and 180% higher energy densities in women compared to men (P<0.02). A power analysis (0–0.05, B=0.90) indicated that 40 women and 40 men would be required to detect a 50% difference in TMJ energy densities between genders. Mechanical work was significantly higher (P<0.05) in TMJs with disc displacement compared to healthy TMJs, and mechanical work done and energy densities were significantly higher (P<0.05) in TMJs with disc displacement in women compare to men. Degenerative joint disease (DJD) of the temporomandibular joint (TMJ) is evident in 3-29% of the population age 19-40 years (Pullinger et al., 1988) and shows an age-dependent increase in the severity of tis- Sue degeneration to about age 60 years (Luder, 2002). Persistent pain associated with the TMJ is estimated to affect 10% of the adult popula- tion at any one time (Stohler, 1995). Notably, women are 2-3 times more likely than men to be afflicted (Warren and Fried, 2001; Velly et al., 2003). DJD of the TMJ can lead to a major disruption in daily activities 427 Tractional Forces and can impair social and personal functioning (Storey, 1995; Dworkin, 1997). To date, therapeutic interventions to address DJD and to improve the quality of life for those afflicted have not been predictably successful. Aggressive therapies such as surgical reconstruction of the TMJ have resulted in severe disabilities (Fontenot, 1995). Insufficient knowledge of the contact mechanics within the TMJ and the mechanisms involved in tissue breakdown are, at least in part, to blame. The mean age of onset of DJD in the TMJ is between 25 and 35 years (Heloe and Heloe, 1975; Solberg et al., 1979; Nilner, 1981; Pullin- ger et al., 1988), which is a decade earlier than DJD in the hip (Lawrence et al., 1989; Felson et al., 1997; Vingard et al., 1997). Although consid- erable efforts are being made to uncover the molecular biology and ge- netics of chronic pain associated with disorders of the temporomandibu- lar apparatus (Flores et al., 2003; Neugebauer et al., 2003; Zubieta et al., 2003; Diatchenko et al., 2005), the variables associated with mechanical failure of articulating tissues in young synovial joints have been investi- gated rarely (Gallo et al., 2000, 2006). Energy density is the mechanical work imposed on a volume of TMJ disc cartilage (m.J/mm’) and is balanced by internal strain energy. Some studies have explored the effects of energy density on growth, ad- aptation and fatigue of living tissues (Carter et al., 1987; Krishnan et al., 2003; Fitzgerald, 2006). The biomechanical and biochemical integrity of tissues such as the TMJ disc is dependent on energy density transfer to the solid matrix of the cartilage. Biphasic modeling of the contact kinet- ics of the TMJ disc cartilage has demonstrated that stress-field translation and subsequent shear strain localization is greatest in the lateral portion of the disc (Donzelli, 2004). This also is where the greatest frequency of disc degeneration has been observed (Oberg, 1971). → Figure 1. Plowing as a source of surface tractional forces in articulating tis- sues (modified from previously published work; Mow et al., 1993). Loading of the articular surfaces causes pressurization of the fluid phase of the cartilage matrix. As a static load is maintained, compression of the cartilage occurs as fluid moves laterally along the hydraulic gradient. If lateral movement of the stress-field occurs, further pressurization of the fluid phase of the matrix occurs ahead of the encroaching stress-field because the porosity of the matrix limits the velocity of the fluid phase. The result is a “bow wave” and plowing forces produced by the pressurized fluid within the cartilage. 428 Nickel et al. Stress-field translation (Fig. 1) and resultant tractional forces may contribute to cartilage wear and fatigue (Dunbar et al., 2001; Nickel et al., 2004, 2006), in particular if the translation is mediolateral, because the disc is relatively weak in this aspect (Beatty et al., 2001, 2003). Given that the TMJ disc has the function of stress distribution and lubri- cation in the TMJ (Nickel et al., 1994a, b, 2001), the mechanical failure of the disc may be an important predisposing factor leading to the rela- tively early degenerative changes seen in the TMJ. Tractional forces are the result of frictional and plowing forces produced by the deformation of the cartilage matrix as a stress-field translates over the surface (Fig. 1; Linn, 1967; Mow et al., 1993: Ateshian et al., 1994; Gallo et al., 2000). For the TMJ disc, plowing forces are expected to be the dominant com- ponent of tractional forces. This is because laboratory studies have shown that static and especially dynamic frictional forces measured on the surface of the TMJ disc are low (Nickel et al., 1994b, 2001), and tractional forces associated with plowing on the surface of the TMJ disc are 10 times greater than static frictional forces (Nickel et al., 2004, 2006). Peak velocities of stress-field translation used in the laboratory experiments were like those demonstrated in vivo in humans (Gallo et al., 2000). Tractional forces increased with duration of static loading prior to the start of movement and with increasing velocity of stress-field translation. The tractional coefficients reported were consistent with the tractional forces measured in whole TMJ experiments (Kawai et al., 2004; Tanaka et al., 2004). Load J. Motion * = _º_ D. 429 Tractional Forces Recently, it was reported that during movement of a load over the surface of the TMJ disc, compressive strains and tractional forces were correlated in a non-linear manner (Nickel et al., 2006). These re- sults demonstrated that tractional forces were strain-related at the start of movement and velocity-dependent during movement and should be con- sidered in analyses of mechanical work and energy densities imposed on the articulating surfaces during normal function. For the current project, ex vivo tests of 64 porcine TMJ discs were used to develop an empirical model to relate the variables of stress- field geometry and dynamics and tractional forces on the surface of the disc. This empirical model then was used with data measured in humans 430 Nickel et al. by means of dynamic stereometry of the TMJs to determine: 1) if there were differences in the work done to discs in healthy TMJs and those with disc displacement; and 2) if there were gender differences in work done and energy densities in TMJs with disc displacement. MATERIALS AND METHODS Ex vivo Tests for Development of the Empirical Model Tests were conducted on 64 TMJ discs from 32 pigs which were obtained from a local abattoir in a manner consistent with institutional regulations. This empirical approach was necessary at present, due to the paucity of data from human TMJs in vivo and the difficulty in obtaining pristine, unpreserved human TMJ discs for testing. Right and left discs were identified and stored separately in 0.1 M phosphate buffered physiological saline solution (PBS, pH = 7.3) for approximately 45 minutes while in transport. Tests were either per- formed on the same day or discs were frozen in PBS at -15°C, and then thawed within two weeks for use. During the tests the TMJ discs were maintained at 39°C in PBS. <- Figure 2. Equipment (modified from previously published work; Nickel et al., 2004). A. Loading beam: a hinged beam facilitated placement of a static load at one end of the beam, which caused the acrylic indenter to load the TMJ disc at the other end of the beam. During experiments, the disc was supported by a curved acrylic base and tray. B: Indenter: the acrylic indenter had a major radius of 125 mm and a minor radius of 31 mm, polished loading surfaces, and milled holes to reduce the effect of mass on tractional forces measurements. The inden- ter was connected to a pendulum by an instrumented steel strut. Strain gauges attached to the surfaces of the strut (see B) measured bending of the strut during movement of the indenter over the surface of the cartilage. Tractional forces were measured in real time via calibration of output voltages from gauges for given loads. C. Electromagnetic force generator: a computer and custom-built software controlled the position and velocity of force generator displacement. D: Linear voltage differential transformer used to measure cartilage thickness during translation of the indenter over the surface of the disc. E. Linear voltage differen- tial transformer used to measure real-time horizontal position of the indenter relative to the disc. F. Accelerometer: output of the accelerometer was used to identify the start of movement of the indenter across the mediolateral axis of the disc. G. Pressure sensitive array: an array of transducers lined the inside of the loading tray and measured pressure along the mediolateral axis of the disc. The most medial portion of the disc was positioned over pressure transducer #1 or #9. 431 Tractional Forces Each disc was tested once using equipment and methods de- scribed previously (Fig. 2A and B; Nickel et al., 2004, 2006). A static 10 N load was applied to the condyle-facing surface for 1, 5, 10, 30, or 60 s, and then moved along the mediolateral axis of the disc. This normal (perpendicular) load was imposed using a hinged beam via an acrylic indenter shaped to produce a mediolateral radius of contact similar to that measured in humans (Gallo et al., 2000), and reflected the minimum condylar load expected during a light bite force. Stress-field translation following static loading was confirmed by fluctuating compressive stresses with respect to time measured by a linear array of nine pressure transducers, 3 mm apart, under the disc. Transducer sensitivities were +10 kPa. Instantaneous disc thickness and compressive strain measure- ments were recorded continuously to within 0.05 mm using a calibrated linear voltage differential transformer (LVDT). Aspect ratio (a/h) was determined by dividing the radius of the stress-field (a) by the instantaneous thickness of the TMJ disc (h). The radius of the stress-field for each disc was established by identifying which pressure gauges recorded stress during the time period between the point when the acrylic indenter began to translate following static loading and the point at which maximum or minimum thickness was measured immediately following the start of movement. The gauges that registered at least 10% of the peak stress during this period were in- cluded and the 3 mm distance between each of the included pressure gauges were added together to calculate the radius. Following the static loading period, electrical output from a cali- brated accelerometer indicated the start of movement of the indenter. Position and velocity of the indenter were determined by calibrated elec- trical output from a second LVDT and controlled through a hinged pen- dulum connected to an electromagnetic force generator and a computer (Fig. 2B). Instantaneous velocity was the distance traveled by the inden- ter divided by time. The sampling frequency allowed instantaneous ve- locities to be calculated every 0.003 s using custom software. Total trans- lation of the center of the stress-field during dynamic loading was ap- proximately + 4 mm and occurred at velocities between 5 and 120 mm/s, a range that was consistent with in vivo conditions where stress-field translation was recorded during symmetrical human jaw movement (Gallo et al., 2000). . Tractional forces were measured every 0.003 seconds from the start of movement. Calibration of the instrumented strut permitted meas- urement of tractional forces to an accuracy of + 0.05 N. Data were re- 432 Nickel et al. corded at 300 Hz and stored on magnetic tape using commercial com- puter hardware and software. Data describing instantaneous geometry and Velocity of the stress-field and tractional coefficient (f= tractional force/normal force) for each disc were fit to a quadratic regression, the empirical model, which was of the following form: f = g-05(x-x)/b); (v-yo)/c) )) where a, b, c were constants and the variables of interest were tractional coefficient (f), Velocity of movement (y), and the product of aspect-ratio and the cube of the compressive strain (x). Work and Energy Densities in the Human TMJ Disc Fifteen subjects with healthy TMJs and 11 subjects with TMJ disc displacement consented to participate in the study in accordance with the appropriate Institutional Review Board. Mean ages (+ standard deviations [SD]) of subjects in the two groups were 29 (+4) years and 25 (+ 7) years, respectively. Status of the TMJ disc was determined by his- tory, clinical examination, and magnetic resonance imaging (MRI). In addition to MRI, all subjects performed jaw opening and closing tasks for jaw tracking recordings. MRI and jaw tracking data were integrated through dynamic stereometry (see below) and used to measure variables applied to the empirical model and thus to estimate in vivo tractional forces for subjects’ TMJs. These tractional forces then were used in cal- culations of mechanical work done and energy densities. An initial analysis determined if there were group differences in mechanical work done (m.J) in the TMJ. In a secondary analysis, eight Subjects (four women and four men) from the group with TMJ disc dis- placement provided data to test for gender differences in work done (m.J) and energy densities (m)/mm’). In vivo Dynamic Stereometry Dynamic stereometry of the TMJ consisted of the 3D reconstruc- tion of real anatomical structures, captured from MRI (Fig. 3A), and the animation of these structures by application of corresponding real motion data tracked with six degrees of freedom (Fig. 3B; Krebs et al., 1995). MR images of each subject were made from serial oblique sagittal slices perpendicular to the main condylar axis of each TMJ using a 1.5 T 433 Tractional Forces 434 Nickel et al. MRI tomographic apparatus (Gyroscan ASC-II) with TMJ surface coils of 12 cm radius. During the process of scanning, each subject bit into a custom occlusal registration appliance that carried a head reference sys- tem (three contrast spheres) to enable integration of MR images with re- cordings from jaw tracking. Static recordings of the subject biting into the occlusal appliance carrying the head reference system and motion recordings of the jaws (jaw tracking) of each subject, performing 10 symmetrical opening and closing movements, were made by means of the opto-electronic system (Fig. 4; Mesqui et al., 1985; Krebs et al., 1995; Gossi et al., 2004). Two triangular target frames, carrying three non-collinear light emitting di- odes (LEDs) each, defined maxillary and mandibular coordinate systems. The target frames were fixed temporarily to vestibular surfaces of maxil- lary and mandibular canines and first premolars on one side by means of custom splints. The LEDs determined head- and mandible-related coor- dinate systems. The time-varying maxillary and mandibular LED posi- tions were recorded by three linear cameras (Fig. 4) with fixed geometry and resolution of better than 10 pum at a sampling frequency of 200 Hz. Motion of the lower jaw was calculated relative to the head, thus, head motion was eliminated. Reconstruction and animation of the TMJ were performed on a graphics workstation by means of custom software (Krebs et al., 1995; Gossi et al., 2004). MR scans segmented for extraction and vectorial de- scription of anatomical structures as well as for determination of the cen- ters of the reference spheres. Segmentation of the anatomy was obtained first by tracing on each MR slice object contours defined by driving points of spline functions. To reconstruct the MR image in 3D (Fig. 3A), the contour sets were triangulated and the resulting surfaces were repre- sented realistically by means of shading algorithms. Resolution was im- <- Figure 3. Healthy TMJ (disc not shown), right. A: Frontal view, where the condyle is at the end of the jaw-opening phase and the 3D reconstruction of the stress-field reveals the congruence of the surfaces of the condyle relative to the crest of the TMJ eminence. B: Superior view, with the center of the stress-field (minimum condyle-fossa/eminence distance) during jaw opening and closing identified by the red dots. The center of the stress-field depended on the con- gruence of condyle-fossa/eminence surfaces at a given jaw position. In this case, it tracked along the mediolateral axis of the condyle during the move- ments associated with jaw opening and closing, starting in the lateral aspect of the joint when the teeth were in maximum intercuspation. 435 Tractional Forces Figure 4. Opto-electronic tracking and capture of movement of the mandible in real-time. Three triangular target frames, carrying three non-collinear light emitting diodes (LEDs) each (A) are shown for the left side. The most posterior target frame is attached to the head refer- ence system and occlusal registration appliance. The two anterior target frames defined maxillary and mandibular coordinate systems and were fixed temporarily to the vestibular surfaces of maxillary and mandibu- lar canines and first premolars on one side by means of custom splints. The LEDs determined head- and mandible-related coordinate systems (B). The time-varying maxillary and mandibular LED positions were recorded by three linear cameras (C) with fixed geometry and resolu- tion of better than 10 um at a sampling frequency of 200 Hz. Motion of the lower jaw was calculated relative to the head, thus, head motion was eliminated. Motion was viewed in real time during the experiments (B). 436 Nickel et al. proved by calculating inter-slice surface points and applying a smoothing algorithm (Fig. 3A). Animation of the TMJ (Fig. 3B) was achieved by means of mathematical transformations, using the computer to calculate continuously the spatial positions of all vertices of polygons describing the recorded surfaces. Tests of the system showed maximum errors of 0.9%. Magnitudes of the variables of interest (a/h, Ah /h, AD, V, Q) for each subject were determined from the reconstructed and animated MR images for each subject over 5 ms time intervals. The stress-field in the TMJ was located by finding the area of minimum condyle- fossa/eminence distance (Nickel and McLachlan, 1994; Gallo et al., 2000, 2006). For each sampling time of mandibular motion, the 30 small- est adjacent condyle-fossa/eminence distances, measured between polygon vertices, were identified. These distances were averaged to de- termine the minimum condyle-fossa/eminence distance or disc thickness, h. The centroid of the area defined by these 30 minimum distances was calculated and defined the mediolateral position of the stress-field, D. The standard deviation of the positions of the 30 minimum distances about the centroid also was calculated to determine the radius of the stress-field, a. The path of D was displayed graphically in a planar coor- dinate system representing the condylar surface (Fig. 3B). The medio- lateral axis corresponded to the direction of the condylar long axis. The coordinates of the mediolateral position of D were smoothed over 30 ms, and velocity of the stress-field translation (V, mm/s) calculated. Volume of cartilage (Q, mm') under the leading edge of the translating stress- field also was measured. The magnitudes of these variables were used in the empirical model and the results employed to determine instantaneous mechanical work and energy densities in the right and left TMJs of each Subject during jaw movement. Mechanical Work Done and Energy Density Equations Data collected from individual subjects were input to the empiri- cal model describing the relationship between tractional coefficient (f= tractional force/normal force) and stress-field geometry and dynamics. Tractional force (Fraction) estimates were determined assuming a normal force of 10 N, and then employed in work and energy density calcula- tions using two equations. Instantaneous mechanical work done (W, m.J) was calculated continuously over 5 ms intervals during cyclic movement of the mandible by the equation: 437 Tractional Forces W s: Facton O AD Instantaneous energy density calculations over 5 ms time inter- vals during cyclic movement of the mandible were accomplished using the equation: \P = (F, AD)/Q Analysis of Variance compared average cumulative work done per open-close cycle of the jaws for subjects with healthy TMJs and those with TMJ disc displacement. Average instantaneous work done and energy density per cycle were tested for significant gender differences within the disc displacement subjects. raction Results The ex vivo experiments produced surface tractional forces and mediolateral movements of the stress-field like those reported for the human TMJ (Gallo et al., 2000, 2006), as confirmed by variation in the outputs from pressure transducers under the TMJ disc (Fig. 5A). In addi- tion, instantaneous measurements of tractional forces and cartilage thick- nesses varied with position and velocity of the stress-field (Fig. 5B). Data collected from 64 porcine discs were fit to a quadratic equation (Fig. 6; R* = 0.83), defined as the empirical model, which showed non-linear increases in tractional forces with increasing Velocity of stress-field translation and aspect ratio X compressive strain’. Data recorded from subjects with healthy TMJs (n = 15) and with TMJ disc displacement (n = 11) during jaw opening-closing were used in the empirical model (Fig. 6) to estimate in vivo tractional forces based on stress-field geometry and dynamics. The tractional forces were used in the calculation of average cumulative work done per cycle for each TMJ. Average cumulative work done (+ SD) per cycle was signifi- cantly higher (P = 0.014-0.015) in TMJs with disc displacement (4445 + 1008 m.J at 1.0 Hz) compared to healthy TMJs (191 + 1.65 m.J at 0.5 Hz, 251 + 210 m.J at 1.0 Hz) by 18-23 times (Fig. 7). 438 Nickel et al. Media. t 0 0.05 0.10 0.15 0.20 0.25 0.30 0.35 Time (s) Figure 5. Data measured during ex vivo tests on the surfaces of porcine discs. A. Data shown are for time during Cycle 1 of indenter transla- tion on disc pair 22 (R = right, L = left). Discs 22R and 22L were ori- ented with medial aspect over pressure transducer #1. Compressive stresses (MPa) are plotted on vertical axes and color-coded according to the key. B: Instantaneous tractional force and thickness data re- corded for disc pair 22. Indenter position (x) and velocity (Pk) were the same for all discs. Instantaneous tractional forces (Discs 22, R = º, L = []) and disc thickness (Discs 22, R = • , L = <>) were recorded during movement. 439 Tractional Forces 0.25 | Figure 6. An empirical model of the relationship between velocity of stress-field translation, aspect ratio of the stress-field, compressive strain’ and tractional forces. Data collected from 64 porcine discs were fit to a quadratic equation (R* = 0.83). The tractional forces were expressed as a coefficient, where the Fnormal - 10 N. The non-linear increases seen in tractional coefficient reflect the effects of stress-field velocity, geometry and compressive strain on the pressurization of the fluid within the TMJ disc. 6000 - p = 0.015 5000 - 4 0 O O 23 OO OO OO 1000 - i i — Disc Displaced Healthy 0.5 Hz Healthy 1.0 Hz Category and Opening-Closing Frequency 440 Nickel et al. In a secondary analysis of gender differences in TMJs with disc displacement, the average instantaneous work values per jaw opening- closing cycle were over 350% higher (P<0.01; Fig. 8) in women (71 + 85 m.J) compared to men (20 + 14 m.J), whereas, average instantaneous energy density per cycle was about 180% higher (P º 0.02; Fig. 8) in women (24 + 1.9 m.J/mm) compared to men (1.3 + 1.5 m.J/mm’). The regional distribution of instantaneous energy density varied for TMJs with disc displacement (Fig. 9). TMJs with disc displacement in women, however, had higher average energy densities, with peak energy densities located primarily in the lateral aspect of the joint (e.g. Fig. 9). In contrast, TMJs with disc displacement in men had lower average energy densities and energy densities were distributed more evenly (e.g. Fig. 9). [] Men Women Norm. Work Norm. Energy Density Figure 8. Gender differences in work done and energy densi- ties in TMJs with disc displacement. Average instantaneous values per cycle were normalized to the peak value for all subjects for work done and for energy density to illustrate these results in the same figure. - Figure 7. Average cumulative work done per cycle in healthy TMJs and TMJs With disc displacement. Data were calculated over 10 symmetrical opening- closing movements of the mandible at 0.5 and 1.0 Hz in healthy subjects, and 1.0 Hz frequency in subjects with disc displacement. 441 Tractional Forces 100 l Female || -8.0 –6.0 –4.0 -2.0 0.0 2.0 4.0 6.0 8.0 Mediolateral Position (mm) 10.0 i Male 9.0 - cº 8.0 - 5 g 7.0 | # P 6.0 - 7 ſº © 5.0 - © à © ſº T KXX 6–6–3 ºf & 3& & I ſ & §§ & NYº I i I -8.0 -6.0 –4.0 –2.0 0.0 2.0 4.0 6.0 8.0 Mediolateral Position (mm) Figure 9. Magnitudes and distributions of instantaneous energy den- sities in TMJs of one female (top) and one male (bottom) subject with disc displacement. Mediolateral position (mm) along the man- dibular condylar axis is plotted horizontally, where + values are me- dial and – values are lateral. Instantaneous energy density is plotted vertically (m)/mm’). 442 Nickel et al. DISCUSSION AND CONCLUSIONS It was possible that the large gender differences seen in the sec- ondary analysis were due to the small number of women and men pro- viding data. A power analysis was performed to determine the numbers of subjects expected to discriminate clinically significant gender differ- ences in work and energy densities. In order to detect a more modest dif- ference of 50% (o = 0.05, B = 0.90), 40 men and 40 women would be required. It remains to be determined whether the effects of loading on tractional forces and compressive stresses in laboratory tests are like those produced in vivo. The applied static loads of 10 N were lower than loads in the human TMJ during mastication and bruxism but not unlike the loads typical of symmetrical opening and closing (Nickel et al., 1997; Iwasaki et al., 2004). In addition, stress-relaxation behavior of cartilage is affected by the radius of the contact area relative to the thickness of the cartilage (Suh and Spilker, 1994). The standardized indenter used in the current study did not reproduce exactly the area of loading that occurs in vivo and possibly had a smaller radius of contact area. Overall, these data represent a “best-case scenario,” where it is evident that tractional forces occur during light loading on the surface of the TMJ disc. Plowing forces acting on cartilage cause dynamic compressive and shear strains within the collagen-proteoglycan matrix, leading to hy- draulic pressures and fluid movement through this porous matrix (Donzelli et al., 2004). The current results appear to be consistent with those previously reported (Nickel et al., 2004; Tanaka et al., 2004). In a study of whole TMJs, 5 seconds of static loading with 50 and 80 N pro- duced tractional coefficients of 0.0145 and 0.0191, respectively (Tanaka et al., 2004). These measurements were reported as “friction,” but were an order of magnitude greater than previously reported values for coeffi- cient of static friction (Nickel et al., 1994b, 2001), and comparable to the Values for tractional coefficients at the start of movement in the ex vivo tests of the current study. It has been noted that whole joint measure- ments of friction cannot eliminate the plowing forces produced by stress- field translation (Linn, 1967; Mow et al., 1993). Therefore, rather than classical frictional forces, plowing forces were likely the most significant element of tractional forces produced during the aforementioned whole- TMJ experiments (Kawai et al., 2004; Tanaka et al., 2004). 443 Tractional Forces The consequent strain energy imposed on the matrix is likely to be influenced by magnitude and frequency of the forces applied to the surface of the cartilage, properties of the TMJ disc such as the anisot- ropic nature of its yield strength (Beatty et al., 2001) and propensities for crack propagation and fatigue failure (Beatty et al., 2003, 2008). Specific mechanisms, by which static and dynamic strains in the matrix affect the fibrochondrocytes of the TMJ disc to promote either repair or failure of the matrix, remain unknown. However, the importance of cyclic matrix strain in chondrocyte mechanotransduction has been emphasized by ex- periments involving dynamic shear strain of hyaline cartilage (Fitzgerald et al., 2006). These experiments have demonstrated that, in the absence of fluid flow or hydrostatic pressure gradients which are normally asso- ciated with dynamic compression, there was an increase in synthesis of cartilage matrix components such as glycosaminoglycans and collagen, but also in production of the enzymes which break down the matrix, such as metalloproteinases (Fitzgerald et al., 2006). The balance between anabolic and catabolic activities of carti- lage cells may be influenced by factors that affect the internal strain con- ditions. For example, the hormone relaxin is of interest because of gen- der differences in its expression and its potential to affect strain energy concentrations in cartilage. This 6-kDa polypeptide hormone is related structurally to the insulin family of hormones and has been shown to have a particular affinity for the fibrous connective tissues of the sym- physis pubis and TMJ. The effects of matrix remodeling on tissue me- chanics were proposed in early work when it was unknown what mole- cules initiated the changes seen in the symphysis pubis during pregnancy (Aspden, 1988). Recent work (Hashem et al., 2006) suggests that concentrations of relaxin in the blood stream are correlated with matrix remodeling of the symphysis pubis and the TMJ disc. It is yet to be determined, but re- laxin may induce matrix reorganization of the TMJ disc to an extent that there is a reduction in yield strength of the matrix and increased suscep- tibility to fatigue. That is, the effect of relaxin could be the chemical equivalent of blunt trauma, where impulse magnitude is correlated posi- tively with area of surface microfractures (Nickel et al., 2001). Surface cracking increases the local strain energies necessary for fatigue-related crack propagation of the matrix (Beatty et al., 2008). Thus, a previous history of exposure to relaxin or physical trauma, or both, could lead to a 444 Nickel et al. mechanically compromised TMJ disc. Whether or not the disc fails may depend ultimately on individual-specific differences in the magnitude and frequency of energy densities imposed on the disc during function. In conclusion, amounts of work done (m.J) were significantly higher in TMJs with disc displacement compared to healthy TMJs. A pilot analysis of TMJs with disc displacement found that women im- posed greater work on their TMJ discs and the energies input were con- centrated compared to men. The current study suggests that future inves- tigations should confirm the gender differences and whether or not en- ergy density-related strain results in changes in cell metabolism within the TMJ disc in a dose-dependent manner. y ACKNOWLEDGEMENTS The authors thank the subjects for their participation and Farm- land Foods Corporation, Crete, Nebraska for their support. The contribu- tions of Kim Theesen, Bobby Simetich, Aaron Jacobsen, Krista Evans, Adam Shaver, Laura Rothe, Tien Nguyen, Matthew Moss and Paul Robinson to the work are gratefully acknowledged. Funds for technical assistance and equipment were provided in part by the University of Ne- braska Medical Center (previous institution of J. Nickel and L. Iwasaki) through the College of Dentistry Research Committee, the Office of the Dean, and the Departments of Adult Restorative Dentistry and Growth and Development. REFERENCES Aspden RM. The theory of fibre-reinforced composite materials applied to changes in the mechanical properties of the cervix during preg- nancy. J Theor Biol 1988;130:213-221. Ateshian GA, Lai WM, Zhu WB, Mow VC. An asymptotic solution for the contact of two biphasic cartilage layers. J Biomech 1994:27:1347- 1360. Beatty MW, Bruno MJ, Iwasaki LR, Nickel JC. Strain rate dependent orthotropic properties of pristine and impulsively loaded porcine tem- poromandibular joint disk. J Biomed Mater Res 2001;57:25-34. Beatty MW, Hohl RH, Nickel JC, Iwasaki LR, Pidaparti RMV. Mode I and mode III fracture in intermediate zone of full-thickness porcine temporomandibular joint discs. Ann Biomed Eng 2008:36:801-812. 445 Tractional Forces Beatty MW, Nickel JC, Iwasaki LR, Leiker M. Mechanical response of the porcine temporomandibular joint disc to an impact event and re- peated tensile loading. J Orofac Pain 2003; 17:160-166. Carter DR, Fyhrie DP, Whalen RT. Trabecular bone density and loading history: Regulation of connective tissue biology by mechanical en- ergy. J Biomech 1987:20:785-794. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain per- ception and the development of a chronic pain condition. Hum Mol Genet 2005; 14:135-143. Donzelli PS, Gallo LM, Spilker RL, Palla S. Biphasic finite element simulation of the TMJ disc from in vivo kinematic and geometric measurements. J Biomech 2004:37: 1787–1791. Dunbar WL Jr, Un K, Donzelli PS, Spilker RL. An evaluation of three- dimensional diarthrodial joint contact using penetration data and the finite element method. J Biomech Eng 2001;123:333-340. Dworkin SF. Behavioral and educational modalities. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83: 128-133. Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman B, Aliabadi P, Levy D. Risk factors for incident radiographic knee osteoarthritis in the elderly: The Framingham Study. Arthritis Rheum 1997:40:728- 733. Fitzgerald JB, Jin M, Grodzinsky AJ. Shear and compression differen- tially regulate clusters of functionally related temporal transcription patterns in cartilage tissue. J Biol Chem 2006:281:24095-24103. Flores CA, Shughrue P, Petersen SL, Mokha SS. Sex-related differences in the distribution of opioid receptor-like 1 receptor mRNA and colo- calization with estrogen receptor mRNA in neurons of the spinal tri- geminal nucleus caudalis in the rat. Neuroscience 2003; 118:769-778. Fontenot MG. Temporomandibular joint devices: Past, present, and fu- ture. In: Sessle BJ, Bryant PS, Dionne RA, eds. Temporomandibular Disorders and Related Pain Conditions, Progress in Pain and Re- search and Management. Seattle: IASP Press 1995:309-322. Gallo LM, Chiaravalloti G, Iwasaki LR, Nickel JC, Palla S. Mechanical work during stress-field translation in the human TMJ. J. Dent Res 2006:85:1006–1010. 446 Nickel et al. Gallo LM, Nickel JC, Iwasaki LR, Palla S. Stress-field translation in the healthy human temporomandibular joint. J Dent Res 2000;79:1740- 1746. Gossi DB, Gallo LM, Bahr E, Palla S. Dynamic intra-articular space variation in clicking TMJs. J Dent Res 2004;83:480–484. Hashem G, Zhang Q, Hayami T, Chen J, Wang W, Kapila S. Relaxin and beta-estradiol modulate targeted matrix degradation in specific syno- vial joint fibrocartilages: Progesterone prevents matrix loss. Arthritis Res Ther 2006:8:R98. Heloe B, Heloe L.A. Characteristics of a group of patients with temporo- mandibular joint disorders. Community Dent Oral Epidemiol 1975;3:72-79. Iwasaki LR, Thornton BR, McCall WD Jr., Nickel JC. Individual varia- tions in numerically modeled human muscle and temporomandibular joint forces during static biting. J Orofac Pain 2004;18:235–245. Kawai N, Tanaka E, Takata T, Miyauchi M, Tanaka M, Todoh M, van Eijden T, Tanne K. Influence of additive hyaluronic acid on the lubri- cating ability in the temporomandibular joint. J Biomed Mater Res A 2004;70:149-153. Krebs M, Gallo LM, Airoldi RL, Palla S. A new method for three- dimensional reconstruction and animation of the temporomandibular joint. Ann Acad Med Singapore 1995:24:11-16. Krishnan R, Park S, Eckstein F, Ateshian GA. Inhomogeneous cartilage properties enhance superficial interstitial fluid support and frictional properties, but do not provide a homogeneous state of stress. J Biomech Eng 2003;125:569-577. Lawrence RC, Hochberg MC, Kelsey JL, McDuffie FC, Medsger TA Jr, Felts WR, Shulman LE. Estimates of the prevalence of selected ar- thritic and musculoskeletal diseases in the United States. J Rheumatol 1989; 16:427–441. Linn FC. Lubrication of animal joints. I: The arthrotripsometer. J Bone Joint Surg Am 1967:49:1079–1098. Luder HU. Factors affecting degeneration in human temporomandibular joints as assessed histologically. Eur J Oral Sci 2002;110:106-113. Mesqui F, Kaeser F, Fisher P. Real-time, non-invasive recording and three-dimensional display of the functional movements of an arbitrary mandible point. Proc SPIE 1985;602:77-84. 447 Tractional Forces Mow VC, Ateshian GA, Spilker RL. Biomechanics of diarthrodial joints: A review of twenty years of progress. J Biomech Eng 1993; 115:460- 467. Neugebauer V, Li W, Bird GC, Bhave G, Gereau RW. Synaptic plastic- ity in the amygdala in a model of arthritic pain: Differential roles of metabotropic glutamate receptors 1 and 5. J Neuroscience 2003:23:52–63. Nickel JC, Iwasaki LR, Beatty MW, Marx DB. Laboratory stresses and tractional forces on the TMJ disc surface. J Dent Res 2004;83:650- 654. Nickel JC, Iwasaki LR, Beatty MW, Moss MA, Marx DB. Static and dynamic loading effects on temporomandibular joint disc tractional forces. J Dent Res 2006:85:809–813. Nickel JC, Iwasaki LR, Feely DE, Stormberg KD, Beatty MW. The ef- fect of disc thickness and trauma on disc surface friction in the por- cine temporomandibular joint. Arch Oral Biol 2001:46:155-162. Nickel JC, Iwasaki LR, McLachlan KR. Effect of the physical environ- ment on growth of the temporomandibular joint. In: McNeill C, ed. Science and Practice of Occlusion. Chicago: Quintessence 1997:115- 124. Nickel JC, McLachlan KR. An analysis of surface congruity in the grow- ing human temporomandibular joint. Arch Oral Biol 1994:39:315- 321. Nickel JC, McLachlan KR. In vitro measurement of the stress- distribution properties of the pig temporomandibular joint disc. Arch Oral Biol 1994a:39:439-448. Nickel JC, McLachlan KR. In vitro measurement of the frictional proper- ties of the temporomandibular joint disc. Arch Oral Biol 1994b;39:323-331. Nilner M. Prevalence of functional disturbances and diseases of the sto- matognathic system in 15–18 year olds. Swed Dent J 1981;5:189-197. Oberg T, Carlsson GE, Fajers CM. The temporomandibular joint: A mor- phologic study on a human autopsy material. Acta Odontol Scand 1971:29:349-384. Pullinger AG, Seligman DA, Solberg WK. Temporomandibular disorders. Part I: Functional status, dentomorphologic features, and sex differ- ences in a nonpatient population. J Prosthet Dent 1988:59:228-235. 448 Nickel et al. Solberg WK, Woo MW, Houston JB. Prevalence of mandibular dysfunc- tion in young adults. J Am Dent Assoc 1979;98:25-34. Stohler CS. Clinical perspectives on masticatory and related muscle dis- orders. In: Sessle BJ, Bryant PS, Dionne RA, eds. Temporomandibu- lar Disorders and Related Pain Conditions, Progress in Pain and Re- search and Management. Seattle: IASP Press 1995:3-30. Storey A.T. Biomechanical and anatomical aspects of the temporoman- dibular joint. In: Sessle BJ, Bryant PS, Dionne RA, eds. Temporo- mandibular Disorders and Related Pain Conditions, Progress in Pain and Research and Management. Seattle: IASP Press 1995:257-272. Suh JK, Spilker RL. Indentation analysis of biphasic articular cartilage: Nonlinear phenomena under finite deformation. J Biomech Eng 1994; 116:1-9. Tanaka E, Kawai N, Tanaka M, Todoh M, van Eijden T, Hanaoka K, Dalla-Bona DA, Takata T, Tanne K. The frictional coefficient of the temporomandibular joint and its dependency on the magnitude and duration of joint loading. J Dent Res 2004;83:404–407. Velly AM, Gornitsky M, Philippe P. Contributing factors to chronic myofascial pain: A case-control study. Pain 2003; 104:491–499. Vingard E, Alfredsson L, Malchau H. Osteoarthrosis of the hip in women and its relation to physical load at work and in the home. Ann Rheum Dis 1997:56:293–298. Warren MP, Fried JL. Temporomandibular disorders and hormones in women. Cells Tissues Organs 2001;169:187-192. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects mu- opioid neurotransmitter responses to a pain stressor. Science 2003:299:1240–1243. 449 ALTERED TEMPOROMANDIBULAR JOINT LOADING Jing Chen, Lorin Trettel, Zana Kalajzic, Tina Gupta, Sunil Wadhwa ABSTRACT Approximately one percent of the U.S. population has osteoarthritis of the tem- poromandibular joint (TMJ-OA). In other joints, mechanical loading is an im- portant etiological factor in the development of osteoarthritis; however, the role of mechanical loading in the development of TMJ-OA is less clear. The tem- poromandibular joint (TMJ) is different from other joints in several ways. For example, while the articular surfaces of most diarthrodial joints are covered by pure hyaline cartilage, the articulating surfaces of the TMJ are composed of fi- brocartilage. In this chapter, we will review the role of mechanical loading in the de- velopment of TMJ-OA and a model of altered functional TMJ loading in a mouse. The development of an altered functional loading TMJ mouse model is important because it will elucidate the molecular and structural changes that occur during altered functional loading. In addition, the use of transgenic mouse technology will allow for the delineation of the role of specific genes involved in altered loading of the TMJ. Approximately ten percent of the population over age 18 experi- ences pain in the temporomandibular joint (TMJ) region (LeResche, 1997). Temporomandibular disorders can be divided into three groups: 1. Muscle disorders; 2. Disc disorders; and 3. Joint disorders (arthralgia, osteoarthritis or osteoar- throsis; Truelove et al., 1992). Approximately 12-55% of the people who have TMJ pain have joint dis- orders (Yap et al., 2003; Plesh et al., 2005; Manfredini et al., 2006). De- generative diseases of the TMJ (TMJ-DD) are a subset of the joint disor- ders group. TMJ-DD includes both mandibular condylar resorption and TMJ-osteoarthritis (TMJ-OA). Both are similar in that they involve de- 451 Altered TMJ Loading struction of the condylar cartilage but are different in respect to the sub- chondral bone. In condylar resorption, there is destruction of the sub- chondral bone while in TMJ-OA there is a remodeling response charac- terized by sclerosis and osteophyte formation (Buckwalter and Martin, 2006). In humans, it is postulated that TMJ-OA follows three stages. In the first stage, there is clicking of the joint and periodic locking, which also are common signs in other TMJ disorders. In the second stage, the TMJ becomes painful both at rest and during function. In the third stage, there is a reduction of clinical symptoms and normalization of function; radiographically, however, there is an increase in TMJ deformation (Zarb and Carlsson, 1999). The TMJ is thought to be a unique joint in the body. In most synovial joints, the articular surfaces are covered by hyaline cartilage. The TMJ is composed of fibrocartilage (Benjamin and Ralphs, 2004) displaying multiple layers of cells at various stages of differentiation. Fibrocartilage contains both types I and II collagens compared to articu- lar cartilage, which contains only type II collagen (Mizoguchi et al., 1992). Another unique property of the TMJ is the formation cartilage of the mandibular condyle via secondary cartilage, while the articular carti- lage in other joints is formed from primary cartilage (Symons, 1965). Secondary cartilage in the mandibular condyle develops following bone formation through intramembranous ossification. In contrast, primary cartilage develops by endochondral ossification, which precedes bone formation. Finally, unlike other joints, when the mandibular condyle is transplanted into a non-functional environment, select progenitor cells of the mandibular condylar cartilage differentiate into osteoblasts rather than chondroblasts, leading researchers to conclude that the mandibular condylar cartilage is derived from periosteum (Meikle, 2007). MECHANICAL LOADING AND TMJ-OA There is a well-established correlation between heavy physical activity and osteoarthritis of the knee joint (McAlindon et al., 1999). In addition, obesity and abnormal joint loading has been associated with osteoarthritis of the knee, hip, and hand (Felson et al., 1997; Oliveria et al., 1999). The relationship between mechanical loading and TMJ os- teoarthritis, however, is not as well established. Mechanical loading of the TMJ is essential for maintaining its mass and integrity. Conceptually, the mandibular condylar cartilage adapts to natural (muscle pull) and 452 Chen et al. therapeutic (orthodontic) mechanical strains to achieve a better balance between mechanical stress and the load bearing capacity of the fibrocarti- lage tissue. For example, loss of loading can decrease fibrocartilage pro- liferation and maturation (Meikle, 2007), while forward positioning of the mandible by the use of orthodontic functional appliances leads to an increase in proliferation and chondrocyte maturation in the mandibular condylar cartilage (Rabie and Hägg, 2002a, b, 2003; Tang et al., 2004; Shen et al., 2006). Evidence that mechanical loading may play a role in the etiology of TMJ-OA comes from the fact that overuse of the joint has been shown to be associated with TMJ-OA; resting the joint can be an effective treatment for patients who suffer from TMJDs. In the TMJ, the correlate of heavy physical activity is considered to be clenching and grinding, also known as parafunctional activity. Analogous to physical activity in other joints, parafunctional activity in the TMJ has been described as an etiologic factor in progression of TMJ osteoarthritis (Tanaka et al., 2008). Inducing parafunctional habits in a subset of otherwise asympto- matic individuals, by increasing the masseter muscle activity leads to pain in the TMJ and a subsequent diagnosis of TMJD (Glaros et al., 1998; Glaros and Burton, 2004). Parafunctional habits also are associated with condylar degeneration (Guler et al., 2003). Israel and colleagues (1999) examined patients with severe TMJ symptoms who were unre- Sponsive to palliative, non-surgical treatment. Here, parafunctional activ- ity was correlated with both clinically and arthroscopically diagnosed TMJ osteoarthritis. Because parafunctional behaviors correlate with TMJ-OA, con- Versely one may expect that reducing the load at the TMJ would alleviate symptoms. Resting the TMJ by avoiding hard foods and preventing the teeth from occluding during non-eating periods by splints or patient edu- cation has been shown to be effective in relieving the symptoms associ- ated with TMJ-OA. In a short-term study, resting the joint was just as effective as arthroscopic surgery in relieving the clinical symptoms asso- ciated with TMJ-OA (Stegenga et al., 1993). In long-term studies of pa- tients who were diagnosed with TMJ-OA thirty years ago and received non-surgical treatment involving resting the joint, they did not have any more clinical signs (de Leeuw et al., 1994) and symptoms of TMJ-OA (de Leeuw et al., 1995) than those of age-matched controls. Interestingly, resting the joint by patient education seems to be just as effective as Splint therapy (Truelove et al., 2006). 453 Altered TMJ Loading RODENT MODELS OF ALTERED TMJ FUNCTIONAL LOADING Due to the difficulty in obtaining human TMJ samples, research- ers have used rodent TMJ models to examine the effects of mechanical loading on TMJ remodeling. The masticatory sequence in rodents can be classified into two stages: incision and chewing (Thomas and Peyton, 1983). Changing the dietary consistency from a hard pellet diet to a soft diet has been shown to cause significant decrease in the duration of inci- sion stage, in the number of masticatory cycles in the incision stage, the amount of molar force required during the chewing stage and in the mas- seteric integrated electromyograms of the incision stage, suggesting a decrease in masticatory function (Hinton and Carlson, 1986; Hinton, 1988; Kobayashi et al., 2002). Besides eating, rodents also use their masticatory incisor appara- tus for biting their cages and gnawing on wood chips, which could com- pensate for the decrease of masticatory incisal function caused by the administration of the soft diet (Shibata et al., 2006a). Trimming the inci- sors out of occlusion may decrease these non-feeding incisor masticatory behaviors in rodents and as well as causing alterations in the masticatory sequence (more difficult for the rodent to obtain a bolus of food; Hinton and Carlson, 1986; Hinton, 1988). Altering masticatory loading by the administration of a soft diet and/or incisor clipping in rats causes structural changes within the man- dibular condylar cartilage and subchondral bone. In rats, the administra- tion of a soft diet has been shown to change the mineralization of the mandibular condyle (Tanaka et al., 2007), decrease the bone mineral density of the mandibular condyle (Mavropoulos et al., 2005), decrease the condylar growth (Kiliardis et al., 1999), reduce the number of chon- drocytes in the mandibular condylar cartilage (Pirttiniemi et al., 1996) and reduce the thickness of the condylar cartilage (Bouvier and Hy- lander, 1984). In addition, incisor clipping in rats has been shown to cause a reduction in the size and density of bony trabeculae underlying the condylar cartilage, diminished staining for alcian blue, and decreased thickness of the prechondroblastic layer of the condylar cartilage in the superior aspects and posterior parts of the condylar cartilage (Hinton and Carlson, 1986). The combination of incisor trimming and soft diet ad- ministration in rats has been shown to cause a decrease in the thickness of the mandibular condylar cartilage (Bouvier, 1988; Kiliardis et al., 1999; Ravosa et al., 2007) and a reduction of chondrocyte proliferation 454 Chen et al. (Hinton, 1988; Pirttiniemi et al., 2004; Sato et al., 2006). Taken together, these studies highlight the importance of normal masticatory function in the growth and differentiation of the mandibular condyle and mandibular condylar cartilage in rats. In contrast to rats, little is known about the effects of incisor trimming and soft diet administration in mice. Shibata and coworkers (2006a) found that that the administration of a soft diet for seven weeks did not produce any significant morphological or histological differences in the mandibular condyle compared to mice, which are fed a normal hard diet. Sasguri and colleagues (1995) found that soft diet and incisor trimming for two weeks caused a decrease in the mRNA expression of bone sialoprotein (Bsp), osteopontin (Opn), osteocalcin (Oc) and colla- gen type I (Col I) from the mandibular condyle. Due to lack of informa- tion on mechanical loading induced TMJ remodeling in mice, we devel- oped an altered loading TMJ mouse model. MATERIALS AND METHODS Mice All experiments were performed under an institutionally ap- proved protocol for the use of animals in research (University of Con- necticut Health Center #2005-195). Twenty-one-day-old CD-1 female mice (Charles River, Wilmington, MA) were used for this study. The eruption of molars and occlusion was complete at this age (Shibata et al., 1995). The mice were divided into two groups. One group was fed a normal pellet diet (normal loading) while the second group was fed a soft dough diet with the same nutritional composition (Transgenic Dough Diet BioServ, Frenchtown, NJ) and had their mandibular incisors trimmed out of occlusion (approximately 1 mm of tooth structure was removed every other day) with an orthodontic light wire clipper (Altered Functional Loading). The mice were sacrificed when they were 35, 49, and 63 days old (Fig. 1). Histology and Immunohistochemistry The TMJs were dissected and fixed in 10% formalin for three days at room temperature. The samples were washed with tap water for five minutes, decalcified in 14% EDTA for one week and then processed for standard paraffin embedding. Serial sections of the TMJ were per- formed with every fifth section stained with H&E staining. 455 Altered TMJ Loading Euthanasia Pºº- Normal | | | | | ſº Loading O 1 2 3 4 weeks 21-Day f g Female —Normal pellet diet CD 1 wº Euthanasia Mice Altered ! ºx Functional O 1 2 3 4 Weeks Loading t —Soft dough diet —Incisor trimming (1mm every other day) Figure 1. Schematic of mouse grouping. Twenty-one-day-old female CD1 mice were divided into two groups: normal loading group, which was fed with normal pellet diet; and altered functional loading group, which was fed with soft dough diet and treated with mandibular incisor trimming every other day. Immunohistochemistry Tissue sections were deparaffinized with xylene and rehydrated with decreasing concentrations of ethanol. Following rehydration, the sections were treated with 3% peroxide to block endogenous peroxidase activity and digested for 60 minutes with pepsin for unmasking (Lab Wi- sion, Fremont, CA; Cat #AP-9007-006). Immunohistochemistry staining was performed using the VECTASTAIN ABC-AP Kit (Vector Labs, Cat #AK-5001, Burlingame, CA) following the procedure recommended by the manufacturer. The antibody Sox9 was obtained from Abcam (Cam- bridge, MA; Cat #59265, 1:75 in TBS buffer). To evaluate for non- specific binding, substitution of the primary antibody with rabbit IgG (Upstate, Charlottesville, VA; Cat #12-370) was performed. RESULTS As mice age, there is gradual decrease in the thickness of the condylar cartilage due to the decrease in number of hypertrophic chon- drocytes as they pass their peak growth period. The thickness of the con- dylar cartilage also appears to be influenced by masticatory loading. Al- tered functional loading (incisor trimming and soft diet administration) for four weeks decreased the thickness the condylar cartilage compared to the normal group (Fig. 2). 456 Chen et al. - | º Figure 2. Representatives of the Hematoxylin and Eosin staining of the TMJ. A. TMJ of 21-day-old mouse when the experiment was initiated. B: Four-week normal loading. C. Four-week of altered functional loading. Scale bars = 200 um. Four weeks of altered functional loading led to pronounced changes in the micro-architecture of the subchondral bone, including larger marrow spaces and less trabecular bone compared to the normal loading group (Fig. 2). The Sox9 gene normally is expressed in the second layer (poly- morphic or proliferative zone) and the third layer (flattened or chondro- blastic zone) of the condylar cartilage. In the altered functional loading model, Sox9 protein expression pattern was highly restricted to a very narrow area in the thinning condylar cartilage (Fig. 3). 457 Altered TMJ Loading DISCUSSION In general, decreased loading results in cartilage atrophy. For ex- ample, in articular cartilages decreased loading of the knee in humans with either a spinal cord injury (Vanwanseele et al., 2003) or an ankle fracture (Hinterwimmer et al., 2004) resulted in a significant decrease in the thickness the articular cartilage. In addition, loss of loading by hindlimb suspension has been shown to reduce the height of the growth plate cartilage in rats (Basso and Heersche, 2006). In this study, we show that incisor trimming and soft dough diet causes a decrease in the size of the condylar cartilage, which is consistent with other studies in the TMJ from mice (Sasaguri et al., 1998) and from rats (Hinton and Carlson, 1986; Hinton, 1988). Surprisingly, under-loading of the mandibular con- dylar cartilage in mini-pigs has been associated with an increase in con- dylar cartilage thickness (Rafferty et al., 2007). The mini-pig may re- spond differently than other animals to reduced loading conditions. - - - º T T - º º Tº Figure 3. Immunohistochemistry of Sox9. A. Normal loading. B. Altered funct tional loading. C. Negative control performed on sagittal sections of the TM area from female CD-1 49-day-old mice. The cellular nuclei of Sox9 positive cells were stained pink with the AEC substrate. Scale bars = 100 um. Even though it would appear that incisor trimming and soft ad- ministration would be an under-loading model of the mandibular condy- lar cartilage, direct strain measurements have not been performed. Fu- ture experiments will include strain measurements of the mandibular condyle during soft diet administration and incisor trimming to confirm these findings. The Sox9 protein is thought to be an important regulator of chondrogenesis because it controls the expression of genes, which en- 458 Chen et al. code important cartilage extracellular matrix (ECM) proteins such as col- lagen type II, aggrecan and cartilage link protein (Hardingham et al., 2006). In the mandibular condylar cartilage, Sox9 expression is critical for its initial formation (Shibata et al., 2006b). In addition, the applica- tion of functional appliances has been shown to increase Sox9 expression (Ng et al., 2006). In this study, we found that Sox9 expression was de- creased in the altered functional loading group compared to the normal loading group. This result suggests that Sox9 is a mechanoresponsive gene in the mandibular condylar cartilage, and chondrogenesis of the mandibular condyle is affected by altered masticatory loading. Because the exact etiology for TMJ-OA is unknown, most den- tists and physicians have been inclined to believe that the single most important etiological factor is altered mechanical loading, which sur- passes the adaptive capacity of the joint (Zarb and Carlsson, 1999; Mi- lam, 2005). Thinning of the cartilage in the mandibular condyle due to altered functional loading may cause changes in the stress distribution throughout the TMJ, which may render the joint vulnerable to os- teoarthritic degeneration. Due to the highly adaptive capacity of the mandibular condylar cartilage in most individuals (Shen and Darendeli- ler, 2005), the condylar cartilage probably regains its thickness once normal masticatory loading conditions returns. There maybe a genetic predisposition or gender differences, however, that influence the adaptive capacity of the mandibular condylar cartilage, making certain individuals or populations more prone to degenerative diseases of the TMJ. CONCLUSION We have developed an altered functional loading mouse model and shown that incisor trimming and soft diet administration for four weeks lead to changes in the mandibular condylar head, including the cartilage and the subchondral bone. Our data suggested that altered func- tional loading decreased the chondroblastic differentiation rate. Coupled With transgenic mouse technology, this model will enable further investi- gation of the molecular and structural changes as well as elucidate the role of specific genes in mediating the mechanical loading response of the TMJ. This model also will unveil the role of mechanical loading in TMJ degenerative diseases. These finding will eventually aid in the de- velopment of novel therapies for patients who suffer from degenerative disease of the TMJ. 459 Altered TMJ Loading REFERENCES Basso N, Heersche JN. Effects of hind limb unloading and reloading on nitric oxide synthase expression and apoptosis of osteocytes and chondrocytes. Bone 2006:39:807-814. Benjamin M, Ralphs JR. Biology of fibrocartilage cells. Int Rev Cytol 2004:233: 1-45. Bouvier M. Effects of age on the ability of the rat temporomandibular joint to respond to changing functional demands. J Dent Res 1988;67:1206-1212. Bouvier M, Hylander WL. The effect of dietary consistency on gross and histologic morphology in the craniofacial region of young rats. Am J Anat 1984; 170: 117-126. Buckwalter JA, Martin JA. Osteoarthritis. Adv Drug Deliv Rev 2006:58:150-167. de Leeuw R, Boering G, Stegenga B, de Bont LG. Clinical signs of TMJ osteoarthrosis and internal derangement 30 years after nonsurgical treatment. J Orofac Pain 1994;8:18-24. de Leeuw R, Boering G, Stegenga B, de Bont LG. Symptoms of tem- poromandibular joint osteoarthrosis and internal derangement 30 years after non-surgical treatment. Cranio 1995; 13:81–88. Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman B, Aliabadi P, Levy D. Risk factors for incident radiographic knee osteoarthritis in the elderly: The Framingham Study. Arthritis Rheum 1997:40:728- 733. Glaros AG, Burton E. Parafunctional clenching, pain, and effort in tem- poromandibular disorders. J Behav Med 2004:27:91-100. Glaros AG, Tabacchi KN, Glass EG. Effect of parafunctional clenching on TMD pain. J Orofac Pain 1998;12:145-152. Güler N, Yatmaz PI, Ataoglu H, Emlik D, Uckan S. Temporomandibular internal derangement: Correlation of MRI findings with clinical symptoms of pain and joint sounds in patients with bruxing behav- iour. Dentomaxillofac Radiol 2003:32:304-310. Hardingham TE, Oldershaw RA, Tew SR. Cartilage, SOX9 and Notch signals in chondrogenesis. J Anat 2006;209:469-480. 460 Chen et al. Hinterwimmer S, Krammer M, Krötz M, Glaser C, Baumgart R, Reiser M, Eckstein F. Cartilage atrophy in the knees of patients after seven weeks of partial load bearing. Arthritis Rheum 2004:50:2516–2520. Hinton RJ. Effect of altered masticatory function on [3H]-thymidine and [35S]-sulfate incorporation in the condylar cartilage of the rat. Acta Anat (Basel) 1988; 131: 136-139. Hinton RJ, Carlson DS. Response of the mandibular joint to loss of in- cisal function in the rat. Acta Anat (Basel) 1986; 125: 145-151. Israel HA, Diamond B, Saed-Nejad F, Ratcliffe A. The relationship be- tween parafunctional masticatory activity and arthroscopically diag- nosed temporomandibular joint pathology. J Oral Maxillofac Surg 1999:57:1034–1039. Kiliaridis S, Thilander B, Kjellberg H, Topouzelis N, Zafiriadis A. Effect of low masticatory function on condylar growth: A morphometric study in the rat. Am J Orthod Dentofacial Orthop 1999; 116:121-125. Kobayashi M, Masuda Y, Fujimoto Y, Matsuya T, Yamamura K, Ya- mada Y, Maeda N, Morimoto T. Electrophysiological analysis of rhythmic jaw movements in the freely moving mouse. Physiol Behav 2002:75:377-385. LeResche L. Epidemiology of temporomandibular disorders: Implica- tions for the investigation of etiologic factors. Crit Rev Oral Biol Med 1997:8:29.1-305. Manfredini D, Chiappe G, Bosco M. Research diagnostic criteria for temporomandibular disorders (RDC/TMD) axis I diagnoses in an Italian patient population. J Oral Rehabil 2006:33:551-558. Mavropoulos A, Ammann P, Bresin A, Kiliaridis S. Masticatory de- mands induce region-specific changes in mandibular bone density in growing rats. Angle Orthod 2005;75:625-630. McAlindon TE, Wilson PW, Aliabadi P, Weissman B, Felson DT. Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in the elderly: The Framingham study. Am J Med 1999; 106:151-157. Meikle MC. Remodeling the dentofacial skeleton: The biological basis of orthodontics and dentofacial orthopedics. J Dent Res 2007;86:12–24. Milam SB. Pathogenesis of degenerative temporomandibular joint arthri- tides. Odontology 2005;93:7-15. 461 Altered TMJ Loading Mizoguchi I, Nakamura M, Takahashi I, Kagayama M, Mitani H. A comparison of the immunohistochemical localization of type I and type II collagens in craniofacial cartilages of the rat. Acta Anat (Basel) 1992;144:59-64. Ng AF, Yang YQ, Wong RW, Hägg EU, Rabie AB. Factors regulating condylar cartilage growth under repeated load application. Front Bi- osci 2006; 11:949-954. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee. Epidemiology 1999; 10:161-166. Pirttiniemi P, Kantomaa T., Salo L, Tuominen M. Effect of reduced ar- ticular function on deposition of type I and type II collagens in the mandibular condylar cartilage of the rat. Arch Oral Biol 1996:41:127-131. * Pirttiniemi P, Kantomaa T., Sorsa T. Effect of decreased loading on the metabolic activity of the mandibular condylar cartilage in the rat. Eur J Orthod 2004:26:1-5. Plesh O, Sinisi SE, Crawford PB, Gansky SA. Diagnoses based on the Research Diagnostic Criteria for Temporomandibular Disorders in a biracial population of young women. J Orofac Pain 2005; 19:65-75. Rabie AB, Hägg U. Factors regulating mandibular condylar growth. Am J Orthod Dentofacial Orthop 2002a: 122:401–409. Rabie AB, Leung FY, Chayanupatkul A, Hägg U. The correlation be- tween neovascularization and bone formation in the condyle during forward mandibular positioning. Angle Orthod 2002b;72:431-438. Rabie AB, Tang GH, Xiong H, Hägg U. PTHrP regulates chondrocyte maturation in condylar cartilage. J Dent Res 2003;82:627-631. Rafferty KL, Sun Z, Egbert M, Bakko DW, Herring SW. Changes in growth and morphology of the condyle following mandibular dis- traction in minipigs: Overloading or underloading? Arch Oral Biol 2007:52:967–976. Ravosa MJ, Kunwar R, Stock SR, Stack MS. Pushing the limit: Mastica- tory stress and adaptive plasticity in mammalian craniomandibular joints. J Exp Biol 2007:210:628-641. Sasaguri K, Jiang H, Chen J. The effect of altered functional forces on the expression of bone-matrix proteins in developing mouse man- dibular condyle. Arch Oral Biol 1998;43:83-92. 462 Chen et al. Sato I, Uneno R, Miwa Y, Sunohara M. Distribution of tenascin-C and tenascin-X, apoptotic and proliferating cells in postnatal soft-diet rat temporomandibular joint (TMJ). Ann Anat 2006; 188: 127-136. Shen G, Darendeliler MA. The adaptive remodeling of condylar carti- lage: A transition from chondrogenesis to osteogenesis. J Dent Res 2005;84:691-699. Shen G, Rabie AB, Zhao ZH, Kaluarachchi K. Forward deviation of the mandibular condyle enhances endochondral ossification of condylar cartilage indicated by increased expression of type X collagen. Arch Oral Biol 2006:51:315-324. Shibata S, Oda T, Abe T, Yamashita Y, Takano Y. Structural features of incremental line-like striations in mandibular condylar cartilage of c- src-deficient mice. Arch Oral Biol 2006a;51:951-959. Shibata S, Suda N, Suzuki S, Fukuoka H, Yamashita Y. An in situ hy- bridization study of Runx2, Osterix, and Sox9 at the onset of condy- lar cartilage formation in fetal mouse mandible. J Anat 2006b;208:169-177. Shibata S, Suzuki S, Tengan T, Yamashita Y. A histochemical study of apoptosis in the reduced ameloblasts of erupting mouse molars. Arch Oral Biol 1995:40:677-680. Stegenga B, de Bont LG, Dijkstra PU, Boering G. Short-term outcome of arthroscopic surgery of temporomandibular joint osteoarthrosis and internal derangement: A randomized controlled clinical trial. Br J Oral Maxillofac Surg 1993:31:3-14. Symons NB. A histochemical study of the secondary cartilage of the mandibular condyle in the rat. Arch Oral Biol 1965;10:579-584. Tanaka E, Detamore MS, Mercuri LG. Degenerative disorders of the temporomandibular joint: Etiology, diagnosis, and treatment. J Dent Res 2008;87:296-307. Tanaka E, Sano R, Kawai N, Langenbach GE, Brugman P, Tanne K, van Eijden TM. Effect of food consistency on the degree of mineraliza- tion in the rat mandible. Ann Biomed Eng 2007:35;1617-1621. Tang GH, Rabie AB, Hägg U. Indian hedgehog: A mechanotransduction mediator in condylar cartilage. J Dent Res 2004;83:434–438. Thomas NR, Peyton SC. An electromyographic study of mastication in the freely-moving rat. Arch Oral Biol 1983:28:939–945. 463 Altered TMJ Loading Truelove EL, Huggins KH, Mancll, Dworkin SF. The efficacy of tradi- tional, low-cost and nonsplint therapies for temporomandibular dis- order: A randomized controlled trial. J Am Dent Assoc 2006; 137: 1099-1 107. Truelove EL, Sommers EE, LeResche L, Dworkin SF, Von Korff M. Clinical diagnostic criteria for TMD. New classification permits mul- tiple diagnoses. JAm Dent Assoc 1992; 123:47-54. Vanwanseele B, Eckstein F, Knecht H, Spaepen A, Stussi E. Longitudi- nal analysis of cartilage atrophy in the knees of patients with spinal cord injury. Arthritis Rheum 2003:48:3377–3381. Yap AU, Dworkin SF, Chua EK, List T, Tan KB, Tan HH. Prevalence of temporomandibular disorder subtypes, psychologic distress, and psy- chosocial dysfunction in Asian patients. J Orofac Pain 2003; 17:21- 28. * Zarb GA, Carlsson GE. Temporomandibular disorders: Osteoarthritis. J Orofac Pain 1999; 13:295-306. 464 A MOVEMENT SYSTEM IMPAIRMENT TREATMENT OF TMD Debra F. Fink, Mary Kate McDonnell, Michelle Kinney, Shirley Sahrmann, Linda Van Dillen ABSTRACT For patients who seek orthodontic treatment for alleviation of temporomandibular dysfunction (TMD), there is a low cost, non-invasive physi-cal therapy approach that can reduce pain and signs of joint disturbance (clicking/popping). The approach is based on a specific movement analysis of the temporomandibular joint (TMJ) and importantly a postural assessment of the patient’s jaw, head, neck, shoulder girdle, and trunk alignment. Patients are instructed in an exercise regimen that addresses postural and movement impairments with particular attention to precise movement of the mandible and neck. A retrospective chart review was conducted of patients with TMJ pain and signs of joint disturbances (clicking/popping) who were treated with this physical therapy approach. Twenty- six patients with TMD (25 females, 1 male; age 32+18 years) were seen between April 2002 and July 2007. Patients received 4+2.5 physical therapy sessions over the course of 1.5 months on average. The emphasis of these sessions was to monitor and modify the patient’s home program of specific exercises aimed at restoring correct movement patterns of the TMJ and proper alignment of the jaw, head, neck, shoulder girdle and trunk. Data indicate that patients showed significant improvement in active TMJ opening range of motion from 39.0+8.7 mm before treatment to 42.0+6.2 mm on follow-up (O. = 0.01, mean difference 3.0 mm. 95% C.I. 1.5 to 4.6). Comparing this outcome to the normative range of 45–55 mm active opening range of motion norm, these patients were approaching a normal range of motion. Patients also showed a significant improvement in active TMJ opening range of motion before the onset of clicking/popping. A subset of 16 patients with signs of joint disturbances initially only achieved 29+11 mm of active TMJ opening before the onset of clicking/popping. At follow up, they showed significant improvement with 39.946.6 mm before the onset of clicking/popping (0. = 0.001, mean difference 10.8 mm. 95% C.I. 8.9 to 12.7). While all patients reported a reduction in pain and signs of joint disturbance, 42% of patients with complaints of pain were pain-free at follow-up and 50% of patients with signs of joint disturbance reported no clicking/popping upon follow-up. These data provide evidence that a patient-performed exercise program of precise jaw movements without the help of modalities or manual mobilization/manipulation may provide a low cost effective option for TMD management. 465 Movement System Impairment Treatment Forward head position and/or cervical extension are the results of a movement impairment syndrome whose origins can begin numerous places in the trunk of the body. Once the forward head position and its origins are corrected through exercises, TMD is eliminated or reduced. This is a matter of ongoing research. The Movement System Impairment approach (MSI; Sahrmann, 2002) in the diagnosis of pain takes a complete view of the individual’s body and his or her daily routine, rather than focus on a disc or a muscle or even one joint. The first cause of pain may be far from the pathoanatomic source of the pain. A goal of treatment is to eliminate pain by following the trail to the first cause of the pain that is associated with movement. The primary causes of mechanical pain are movements that deviate from the normal kinesiological standard (Sahrmann, 2002). Pain is associated with loss of precise movement because non-ideal move- ment mechanically irritates the tissues leading to microtrauma and eventually to macrotrauma (Sahrmann, 2002). MSI diagnosis focuses on the movement impairment that produces pain because correction of the movement impairment will redistribute forces and allow the affected tissues to heal, alleviating the pain associated with movement. Movement impairments occur over time. These faulty movement patterns are associated most often with daily work habits, recreational activities or exercise. Impairment can be caused by repeated movements (e.g., an avid golfer’s Swing) or by Sustained postures (e.g., slouching when sitting in a chair). The human body is marvelously adaptive to such repeated or sustained incorrect postures. Movement impairments will affect the length, strength and stiffness of muscles that, in turn, affects the movement patterns of the joint, neighboring muscles and interacting joints (McDonnell, 2002). This MSI approach seeks first to correct the movement causing the pain by teaching proper posture, proper movement patterns, and corrective exercises. Only then are the appropriate muscles strengthened with exercise. Modalities such as ultrasound, spray and stretch, electrogalvanic stimulation, acupuncture, trigger point injections, TENS and cold laser are not used (Sahrmann, 2002). These modalities merely disguise the pain; it is the pain that provides a diagnostic indicator of the incorrect movement for both the physical therapist and the patient. Orthodontic treatment, dental restorative treatment or the use of splints does not interfere with the MSI approach. The goal is to establish correct 466 Fink et al. movement which is pain free and which the patient can maintain without reliance on the health care system. There is an array of benefits to the patient that have been demonstrated by the MSI approach: • It eliminates or reduces pain within the first month; • It restores function, that is, ability for increased mouth opening and chewing: • It is non-invasive; • It is cost effective, that is, patient is responsible for co-pay only; p • It empowers the patient with personal management skills that make him independent of the health care system; and • The MSI physical therapist routinely trains the patient to posture and move their backs, shoulders, arms, neck and TMJ more optimally. The MSI approach in treating TMD is an extension of Dr. Shirley Sahrmann’s movement impairment system of diagnosis, classification and treatment of backs, hips, legs, arms, shoulders and necks that she developed at Washington University School of Medicine. The MSI approach to treatment views the movement mechanics of the human body in its entirety, taking into account neurological, medical, and psychological as well as biomechanical factors that contribute to dysfunction and pain. In the literature, there is evidence of successful outcomes from therapeutic exercises and posture training in the treatment of TMD. Research has shown the efficacy of therapeutic exercise and postural training in treating TMD of muscle origin (Komiyama et al., 1999), disc displacement without reduction (Yoda et al., 2003), disc displacement with reduction (Yuasa and Kenichi, 2001) and TMD due to inflammatory responses (Tegelberg and Kopp, 1988). There is not yet proof for the hypothesis of a causal relationship between forward head position and TMD (Olivo et al., 2006; Kraus, 2007). Yet there is evidence that 71% of patients with TMD also have neck, back and/or shoulder pain (Turp et al., 1997) and that a co- morbidity exists between long-term back pain and TMD (Weisinger et al., 2007). In this pilot study, forward head position can be a predisposing factor for TMD. Forward head position typically is a 467 Movement System Impairment Treatment product of a muscle impairment syndrome, but the cause of the impairment may be located away from the neck and TMJ. The length and strength of the cervical spine muscles responsible for forward head position are influenced by the alignment of the thoracic spine, which is influenced by the alignment of the lumbar spine. For example, it is the lumbar spine and associated muscles that are affected first by slouching in a chair. That incorrect posture affects the thoracic and cervical spine and associated muscles, leading to a forward head position. The MSI-trained physical therapist analyzes the entire spine, shoulder girdle, neck and lastly the TMJ. This method identifies and eliminates the underlying mechanical problems that influence, directly or indirectly, the muscles associated with movement of the TMJ. Correct posture is established first, in case the underlying mechanical problem is in the abdomen or thorax. Once the proper posture is achieved, then exercises for the TMJ can begin. This system educates the patient to correct the primary cause of the mechanically induced TMD and gives the patient the tools to manage or prevent recurrences of TMD. Impairments can be isolated to the TMJ and not part of a syndrome. The MSI exercises provide benefits to patients exhibiting bruxism and/or poor posturing of the mandible. MATERIALS AND METHODS Twenty-six patients with TMD (25 females, 1 male; mean age 31.9+17.5 years) were seen in a university-based outpatient physical therapy practice between April 2002 and July 2007. The median level of disability for patients on intake was 22.5 on a 62-point TMJ disability questionnaire. A retrospective chart review was conducted of patients with TMJ pain and signs of joint disturbances (clicking/popping) who were treated with the Movement Systems physical therapy approach. This study received university IRB-approval. All patients were treated by the same orthopedic board certified physical therapist with 25 years of outpatient orthopedic clinical experience. Patients were referred for TMJ pain and signs of joint disturbances (clicking/popping) by a mix of local physicians and dentists. The emphasis of these treatment sessions was to monitor and modify the patient’s home program of specific exercises aimed at restoring correct movement patterns of the TMJ and proper 468 Fink et al. alignment of the jaw, head, neck, shoulder girdle and trunk. Patients received 4+2.46 physical therapy treatment sessions over the course of 1.5 months on average. Charts reviewed contained basic demographic information. A completed TMJ disability questionnaire outcome measure was provided by the patient on intake. Subjective pain complaints (pain/no pain) and a numeric pain rating score (0-10) were recorded on the initial and final Visits as well. Objective measures analyzed included gross jaw opening range of motion and jaw opening range of motion prior to the onset of joint disturbance (pain and/or clicking). Both measures were taken by the same physical therapist from the incisal edge of the maxillary incisors to the incisal edge of the mandibular incisors, using the cervical range of motion instrument (CROM Deluxe, Performance Attainment Associates, St. Paul, MN). Descriptive statistics were used to relay demographic information and level of disability of the patient sample. Paired t-tests were used for gross changes in total jaw opening range of motion as well as changes in range of motion prior to onset of joint pain/clicking. Simple percentages were used to show changes in subjective report of pain and signs of joint disturbances. RESULTS An analysis of the data revealed a statistically significant increase in active TMJ opening range of motion from 39.0+8.7 mm before treatment to 42.0+6.2 on follow-up (O. = 0.01, mean difference 3.0 mm. 95% C.I. 1.47 to 4.55). These measurements were compared to the normative range of 45–55 mm active opening range of motion. Of the 26 charts reviewed, 16 patients had reported signs of joint disturbances (clicking/popping). Those 16 patients with signs of joint disturbances initially only achieved 29.1+10.70 mm of active TMJ opening before the onset of clicking/popping. At follow up, they showed significant improvement with 39.94-6.7 mm before the onset of clicking/popping (0. = 0.001, mean difference 10.8 mm. 95% C.I. 8.90 to 12.74). While all patients reported a reduction in pain and signs of joint disturbance, 42% of patients with complaints of pain were pain-free at follow-up and 50% of patients with signs of joint disturbance reported no clicking/popping upon follow-up. The mean difference on numeric pain rating score from initial to final visit was 0.3 (not statistically significant at 0 = 0.01). 469 Movement System Impairment Treatment DISCUSSION Primary Findings / Hypothesis Currently, the specific factors contributing to TMD are not understood fully. The data presented suggest that impairments not only in the TMJ region but also in the adjacent regions may be important to consider in the treatment of TMD. The MSI approach to treatment of the TMD provides patients a specific exercise program that emphasizes correction of patient’s postural and movement impairments of the entire upper quarter region, with particular attention to the alignment of cervical spine and precise movement of the mandible. The treatment approach focuses on: • Improving alignment in each region; • Improving strength of cervical, scapulothoracic and trunk muscles; • Eliminating compensatory movements of the adjacent regions especially the cervical spine during movement of the TMJ, and • Precise movement of the mandible during opening. Proposed Mechanism of Movement Impairment in the TMJ Ideal arthrokinematic movement during TMJ opening should include simultaneous rotation and translation (Oatis, 2004). The primary muscles responsible for the rotation movement are the muscles that depress the mandible, which include the suprahyoid and infrahyoid muscles. The primary muscle responsible for the anterior translation movement is the inferior head of the lateral pterygoid The common movement impairment that we observe with opening of the TMJ is greater anterior translation than rotation of the condyle. We propose that the common muscle imbalance that occurs with this movement impairment is greater recruitment of the lateral pterygoid and reduced recruitment of mandible depressors. Thus, the focus of treatment is to perform precise movement of the mandible with emphasis on recruitment of the mandible depressors while in ideal alignment of the cervical, thoracic and lumbar region. Instructing the patient to retract the mandible when opening usually results in diminished anterior translation and improved rotation of the condyle during opening. We have observed that attention to this precise motion and alignment of the cervical spine, scapulothoracic region, and lumbar 470 Fink et al. spine often increases the amount the patient can open the mouth without complaint of clicking or pain within the first treatment session. Examination Resulting in a Patient Specific Exercise Program Other authors have described the importance of posture as it relates to TMD (Komiyama et al., 1999; Wright et al., 2000; Cleland and Palmer, 2004). They have described general posture exercises that are helpful in the management of TMD. The MSI approach of diagnosis and treatment requires a specific examination of the patient’s alignment and muscle impairments. Assessment of the alignment, strength and length of muscles in these regions results in a patient specific exercise program to address the patient’s impairments. Assessing the patient’s specific alignment and muscle impairments of the cervical, Scapulothoracic, thoracic and lumbar region are critical. The most common impairment that we observed in the cervical region is a forward head posture and/or increase extension of the upper cervical region. Addressing head and neck position before the initiation of precise movement of the mandible is critical. The correction of the patient’s thoracic and lumbar alignment faults also needs to be addressed. The most common thoracic alignment impairment is a varying degree of thoracic kyphosis. When the kyphosis alignment impairment is present, the patient’s specific exercise prescription will include the best correction of the kyphosis alignment before initiation of arm, cervical and TMJ movement is required. We also observe non-ideal scapular alignment. Frequently, the scapulae are positioned in excessive abduction and/or depression. The patient’s scapula thoracic muscles usually test weak and require prescription of specific exercises to address the alignment of the scapulae and strengthening of the scapulothoracic muscles. Patient Education In addition, the MSI treatment will educate the patients concerning their specific impairments and how they can modify daily habits and postures that could contribute to their pain problem. The more common habits that we have addressed include facial posturing and non- ideal cervical alignment. For example, the patient may have the habit of biting of the lower lip that could include repetitive protrusion and lateral deviation of the mandible. They may use bifocals that require repetitive posturing of upper cervical extension. These daily habits and positions could increase stress on the tissues in the TMJ region. The patient may 471 Movement System Impairment Treatment not be aware of this habitual and repetitive activity that could contribute to their problem. Educating the patient concerning their habits and reducing the frequency of the postures are strategies to decreasing the stress on pain producing structures. Assessment of the patient’s specific alignment and movement impairments is critical when treating patients with TMD. The MSI approach to examination, diagnosis and treatment provides a systematic method to produce a patient specific treatment to address the contributing factors to the patients with complaint of TMJ pain and joint disturbances. We have communicated informally with some of our patients up to a year after treatment was completed. They have reported continued relief of symptoms. A long-term systematic assessment of the effect of this treatment strategy on patient outcomes is needed. FINAL REMARKS MSI-trained physical therapists are concerned with aligning the body while providing good function. In this pilot study, we conclude that the MSI approach to treatment of the entire body is extended successfully to the treatment of TMD movement syndrome. The MSI approach offers a unique array of benefits to the TMD patient: eliminate or reduce pain; restore function in the TMJ and trunk of body; and non- invasive, efficient, cost effective and eliminate recurrences of TMD. REFERENCES Cleland J, Palmer J. Effectiveness of manual physical therapy, therapeutic exercise, and patient education on bilateral disc displacement without reduction of the temporomandibular joint: A single-case design. J Orthop Sports Phus Ther 2004:34:535-548. Komiyama O, Kawara M, Arai M., Asano T, Kobayachi K. Posture correction as part of behavioural therapy in treatment of myofascial pain with limited opening. J Oral Rehabil 1999:26:428-435. Kraus S. Temporomandibular disorders, head and orofacial pain: Cervical spine consideration. Dent Clin North Am 2007;51:161-183. McDonnell MK. Physical Therapy of the Cervical Spine and Thoracic Spine. Grant R, ed. New York: Churchill Livingstone 2002. Oatis, CA. Kinesiology: The Mechanics and Pathomechanics of Human Movement. Philadelphia: Lippincott Williams & Wilkins 2004. 472 Fink et al. Olivo SA, Bravo J, Magee DJ, Thie NM, Major PW, Flores-Mir C. The association between head and cervical posture and temporomandibular disorders: A systematic review. J Orofac Pain 2006:20:9–23. Tegelberg A, Kopp S. Short-term effect of physical training on temporomandibular joint disorder in individuals with rheumatoid arthritis and ankylosing spondylitis. Acta Odontol Scand 1988:46:49–56. Türp JC, Kowalski CJ, Stohler CS. Temporomandibular disorders: Pain outside the head and face is rarely acknowledged in the chief complaint. J Prosthet Dent 1997;78:592–595. Sahrmann S. Diagnosis and Treatment of Movement Impairment Syndromes. St. Louis: Mosby 2001. Yoda T, Sakamoto I, Imai H, Honma Y, Shinjo Y, Takano A, Tsukahara H, Morita S, Miyamura J, Yoda Y, Sasaki Y, Tomizuka K, Takato T. A randomized controlled trial of therapeutic exercise for clicking due to disk anterior displacement with reduction in the temporomandibular joint. Cranio 2003:21:10–16. Yuasa H, Kurita K; Treatment group on temporomandibular disorders. Randomized clinical trial of primary treatment for temporo- mandibular joint disk displacement without reduction and without Osseous changes: A combination of NSAIDs and mouth-opening exercise versus no treatment. Oral Sug Oral Med Oral Pathol Oral Radiol Endod 2001;91:671-675. Weisinger B, Malker H, Englund E, Wänman A. Back pain in relation to musculoskeletal disorders in jaw-face: A matched case control study. Pain 2007:131:311-319. Wright EF, Domenech MA, Fischer JR Jr. Usefulness of posture training for patients with temporomandibular disorders. J Am Dent Assoc 2000;131:202-210. 473 TOWARD A BETTER UNDERSTANDING OF BISPHOSPHONATES AND THEIR POTENTIAL FOR IMPACTING ORTHODONTIC THERAPY Chad M. Novince and Laurie K. McCauley ABSTRACT Bisphosphonates, therapeutic agents that inhibit bone resorption, commonly are utilized to treat metabolic bone diseases and cancers that metastasize to the skeleton. The impact of bisphosphonates on orthodontic therapy and the associated risk of osteonecrosis of the jaw (ONJ) have been investigated infrequently. ONJ has been identified as an idiosyncratic oral complication of bisphosphonate therapy. While the American Dental Association (ADA), the American Association of Oral and Maxillofacial Surgeons (AAOMS), and the American Society for Bone and Mineral Research (ASBMR) have established treatment recommendations for bisphosphonate patients, these recommendations fail to address orthodontic therapy specifically. Bisphosphonate related ONJ of the jaw frequently is associated with manipulation of the osseous structures of the jaw. Orthodontic tooth movement and the placement of microimplants for anchorage during orthodontic therapy involve the alveolar bones of the jaws directly. Animal studies and case reports suggest bisphosphonate therapy may inhibit orthodontic tooth movement without increasing the incidence of ONJ. Clinical studies and case reports suggest that oral bisphosphonate therapy does not influence implant outcomes or alter the risk of ONJ. Practitioners should disclose to patients that bisphosphonate therapy may affect orthodontic treatment outcomes and the risk of osteonecrosis of the jaw. Bisphosphonates are a class of drugs developed originally as Synthetic analogues of inorganic pyrophosphate (PPi; Coxon et al., 2006). There are two main classes of bisphosphonates: the simple PPi resembling bisphosphonates and the more potent nitrogen containing bisphosphonates. The primary use of these medications is to treat metabolic bone diseases (e.g., osteoporosis, Paget’s disease) as well as cancers that metastasize or localize in the skeleton (e.g., breast, prostate, myeloma). In that they act by inhibiting bone resorption, their use has been considered for the treatment of periodontal disease (Tenenbaum et al., 2002). More recently, an unusual presentation of osteonecrosis of the 475 Better Understanding of Bisphosphonates jaw (ONJ) has been discussed widely in the literature in patients taking bisphosphonates. There is a paucity of information regarding the etiology of Such lesions. Treatment decisions for dental patients taking bisphosphonates and requiring procedures that impact the osseous structures have become more complex by widespread concerns of ad- Verse outcomes and the lack of information supporting the epidemiology and etiology. BISOPHOSPHONATES: MECHANISMS OF ACTION Bisphosphonates possess a pyrophosphate-like P-C-P structure with a strong affinity for calcium and, hence, have the ability to bind to mineralized matrix. Their affinity for bone is due largely to their ability to chelate calcium, but recent evidence suggests that the side chains of the nitrogen-containing bisphosphonates also can influence affinity (Coxon et al., 2006). The bone targeting properties of bisphosphonates, coupled with their selective effects on osteoclasts, support their use for diseases and disorders that compromise skeletal integrity. The nitrogen-containing bisphosphonates (e.g., alendronate, ibandronate, risedronate and zolendronate) have bulkier side chains than the simple bisphosphonates and contain a nitrogen moiety. These newer generation bisphosphonates act by inhibiting an enzyme, farnesyl diphosphonate (FPP) synthase in the mevalonate pathway (Fig. 1). FPP synthase is responsible for catalyzing the reaction that leads to FPP and geranylgeranyl diphosphate (GGPP) that are required for the prenylation of proteins necessary for osteoclast activity and survival. FPP and GGPP are critical for a post-translational modification called isoprenylation of small GTPases. These prenylated GTPases are signaling proteins that are important for various aspects of osteoclast morphology. Membrane ruffling is an osteoclast cellular modification that provides a greater area for the exchange of protons via the osteoclast proton pump and facilitates the acidification of the subcellular compartment (Teitelbaum, 2000). This unique morphology allows the osteoclast to create a microenvironment where bone resorption can occur via mineral removal followed by lysis of collagen. Inhibition of FPP thus restricts the process of resorption. There also is evidence that FPP may play a role in regulating the differentiation of mononuclear cells into tartrate resistant acid phosphatase (TRAP) positive cells of the osteoclast lineage and in regulating apoptosis (Kimmel, 2007). These three actions have been reported to be dose dependent (Kimmel, 2007). At high doses, biS- phosphonates stimulate apoptosis of osteoclasts while at moderate doses 476 Novince and McCauley osteoclast differentiation is inhibited. At low doses, alterations of the membrane ruffling restrict resorption. Such considerations may be relevant in the development of ONJ that has been reported to occur with higher dose and potency bisphosphonates (Hoffet al., 2008). Bisphosphonate: Mechanism of Action HMG-CoA Mevalonate ! Isopentenyl diphosphate 3. FPP Synthase Farnesyl diphosphate (FPP) º Prenylated proteins Geranylgeranyl diphosphate (GGPP) Osteoclastic cell Loss of actin rings Loss of survival signals Bone Resorption Figure 1. Mechanism of action of nitrogen-containing bisphosphonates. Nitrogen-containing bisphosphonates act by inhibiting an enzyme, farnesyl diphosphonate (FPP) synthase in the mevalonate pathway. FPP synthase is responsible for catalyzing the reaction that leads to FPP and geranylgeranyl diphosphate (GGPP) that are required for the prenylation of proteins necessary for osteoclast activity and survival. FPP and GGPP are critical for isoprenylation of small GTPases. These prenylated GTPases are signaling proteins that are important for various aspects of osteoclast morphology that are essential for bone resorption. One of the frequently cited cautions regarding bisphosphonates relates to their pharmacokinetics and duration of exposure. As bisphosphonates are sequestered in the mineralized matrix, in particular at sites of active resorption, questions arise as to whether a patient taking a bisphosphonate for two years will differ in their osseous wound healing response vs. a patient taking a bisphosphonate for ten years. To date, this question has not been addressed adequately with epidemiologic or clinical studies, and pharmacokinetic studies are challenging due to the mechanism of action of the bisphosphonates and the short duration of 477 Better Understanding of Bisphosphonates most of the studies. Once administered, bisphosphonates are found within hours in the kidney and skeleton and are cleared rapidly from circulation (Cremers et al., 2005). Those destined for the kidney are excreted in the urine and those destined for the skeleton are localized in a manner dependent on the cellular activity at individual bone surfaces. Surfaces with active turnover have a greater uptake of bisphosphonate. This observation has several important implications. First, a patient on chronic bisphosphonate therapy would have reduced turnover (estimates are 70% lower turnover) and, hence, less incorporation of bisphosphonate. Consequently, the accumulation of bisphosphonate in the skeleton is not linear over time. Furthermore, it could be speculated that in situations where bone turnover is promoted locally (e.g., during orthodontic treatment, local infection, post-extraction) there may be a greater accumulation of bisphosphonates. This relationship has not been validated experimentally. Kimmel (2007) provided valuable insight into the uptake of bisphosphonates in the skeleton. He described differences of bis- phosphonate incorporation into resting, resorbing, and forming surfaces in a bone from the vertebrae, a highly trabecular skeletal site. The resting, or inactive surfaces comprise approximately 85% of surfaces and have the lowest affinity for bisphosphonates. The forming surfaces comprise 10-12% of the surfaces and have about four times higher affinity for bisphosphonates than do the resting surfaces. The highest affinity for bisphosphonates are the resorbing surfaces that comprise approximately 2% of all surfaces and have approximately eight-fold higher affinity for bisphosphonates than the inactive surfaces. Once incorporated in the bone, the bisphosphonate remains inert biologically until Osteoclastic activity resorbs the matrix and releases it. Upon release, it can be recycled for osteoclast uptake, redistributed in the skeleton or excreted in the urine. Hence, the complexity of the pharmacokinetics of bisphosphonates relative to skeletal metabolism along with unique features of the bones of the craniofacial region render it difficult to elucidate aspects of timing and dosage relative to potential side effects of bisphosphonates. BISPHOSPHONATES AND ORTHODONTIC TOOTH MOVEMENT While animal studies have demonstrated that local and systemic bisphosphonate administration inhibits orthodontic tooth movement, no clinical studies have been performed to evaluate how bisphosphonate 478 Novince and McCauley therapy influences the outcomes of orthodontic treatment. Several case reports describe limited orthodontic tooth movement in patients undergoing concomitant bisphosphonate and orthodontic therapy. Schwartz (2005) described restricted orthodontic tooth movement in a 53-year-old woman who was prescribed zoledronic acid once monthly intravenously for the treatment of metastatic breast cancer. Several months after the patient began receiving zoledronic acid, orthodontic treatment was initiated, and bisphosphonate therapy continued throughout orthodontic treatment. The patient was placed in fixed orthodontic appliances, and the maxillary premolars were extracted to correct Class II division 1 malocclusion with mild bimaxillary crowding. During the initial months of orthodontic therapy, alignment of the maxillary anterior and initiation of canine retraction progressed normally. When the premolar spaces were one-third closed, orthodontic movement ceased. The application of varying levels of force, both continuous and intermittent, failed to induce tooth movement. A more recent case described limited orthodontic tooth movement in a 35-year-old female afflicted with Addison’s disease (primary adrenal insufficiency) who was prescribed alendronate orally one time weekly to enhance bone density (Rinchuse, 2007). The patient underwent bisphosphonate therapy for 16 months prior to orthodontic therapy and continued bisphosphonate therapy during her 30-month orthodontic treatment. Maxillary and mandibular right first premolars were extracted followed by full banded/bonded orthodontic therapy to correct a Class II division 1 subdivision right malocclusion. Initially Orthodontic tooth movement was uneventful, but as therapy progressed, closing the extraction spaces and paralleling the roots became very difficult. Orthodontic treatment was discontinued with less than ideal results. Another case described by Rinchuse and colleagues (2007) reported restricted orthodontic tooth movement and the incidence of ONJ in a 77-year-old man who was taking once monthly Zoledronic acid intravenously to inhibit the metastasis of Sacral plasmacytoma. The patient also had radiation and chemotherapy prior to the initiation of orthodontic therapy. He was on zoledronic acid for 11 months prior to and during the 13 months of orthodontic therapy. Additional medications taken throughout the course of orthodontic treatment included: Alkeran (anti-neoplastic), Prednisone (corticosteroid), Percocet (narcotic analgesic), furosemide (Diuretic) and Theragen (artificial tears). During orthodontic therapy, the patient was diagnosed with multiple myeloma 479 Better Understanding of Bisphosphonates and his oral condition presented with periodontal disease. His ortho- dontic treatment included canine-to-canine ceramic brackets in the mandible to close several millimeters of space that was secondary to the extraction of an ectopically positioned incisor. Tooth movement was restricted, and space closure was obtained via tipping rather than bodily tooth movement. Thirteen months into orthodontic therapy, a bleeding ulceration was identified at the buccal mucosa of the mandibular right premolar-molar area. The lesion was diagnosed as a small area of osteonecrosis and orthodontic therapy was ceased. The single reported case of ONJ incidence during concomitant orthodontic and bisphosphonate therapy was inconclusive because the 77-year-old patient had multiple risk factors for ONJ. The patient was older than 65 years, was afflicted by metastatic cancer, was taking a potent intravenous bisphosphonate and was undergoing chemotherapy and corticosteroid therapy concurrently. He also had an extensive history of radiation therapy. Locally, the patient was afflicted by periodontal disease, subjected to alveolar trauma via tooth extraction (in a separate but nearby site) and underwent orthodontic therapy in the mandible vs. the maxilla. The previously mentioned three case reports of limited orthodontic tooth movement in patients concurrently undergoing bisphosphonate therapy suggest that concomitant orthodontic and bisphosphonate therapy should be considered judiciously, but clearly highlight a paucity of evidence to make treatment recommendations. The mechanisms by which bisphosphonates disrupt osteoclastogenesis may inhibit orthodontic tooth movement in that osteoclast mediated bone resorption is essential for tooth movement. BISPHOSPHONATES AND ORTHODONTIC USE OF IMPLANTS The orthodontic microimplant, placed to provide anchorage, is being used more frequently in orthodontic therapy. The risks of micro- implant placement and loading during concomitant bisphosphonate therapy should be evaluated thoroughly by the practitioner and disclosed to the patient prior to microimplant placement. There is no literature on microimplants and the potential risks in bisphosphonate users. The literature on endosseous dental implants and bisphosphonate use also is weak, but may provide more insight for application to microimplant uSage. 480 Novince and McCauley The American Dental Association (ADA), the American Association of Oral and Maxillofacial Surgeons (AAOMS) and the American Society of Bone and Mineral Research (ASBMR) have established recommendations for implant placement during bisphosphonate therapy (Migliorati et al., 2005; American Dental Association, 2006; Advisory Task Force, 2007; Khosla et al., 2007). The ADA generally does not recommend modification of treatment for oral bisphosphonate patients. Documented informed consent disclosing the risks, benefits, and treatment alternatives associated with implant placement should be obtained from the patient. If implants are to be placed in multiple areas, the ADA advocates a trial sextant approach. The ASBMR does not suggest contraindications to placing implants in oral bisphosphonate patients with osteoporosis or other nonmalignant bone diseases. Documented informed consent should be obtained from patients who have been taking oral bisphosphonates for more than three years. At this time, the ASBMR does not recommend a drug holiday before or after implant placement. The AAOMS affirms that there is no contraindication to implant placement in patients who have taken an oral bisphosphonate for less than three years with no clinical risk factors. Informed consent should be provided to patients concerning possible future implant failure and Osteonecrosis if the patient continues to take an oral bisphosphonate. | Such patients should be placed on regular recall, and the prescribing physician should be contacted to consider alternate dosing, a drug holiday or an alternative to the bisphosphonate therapy. The AAOMS recommends for patients who have taken oral bisphosphonates for more than three years and/or taken corticosteroids concomitantly that the prescribing physician be contacted to consider discontinuing the oral bisphosphonate for at least three months prior to implant placement, if systemic conditions permit. Bisphosphonate therapy should not be restarted until Osseous healing has occurred. The ASBMR and AAOMS do not recommend the placement of dental implants in oncology patients receiving intravenous bisphos- phonate therapy. While the ASBMR and AAOMS have not established a recommendation for implant placement in Osteoporosis patients receiving intravenous bisphosphonate therapy, there is no evidence to date that there is a difference in the risk of ONJ associated with oral vs. intravenous bisphosphonate therapy for osteoporosis patients. 481 Better Understanding of Bisphosphonates Clinical studies investigating bisphosphonates and implant outcomes do not support bisphosphonate therapy influencing implant success or the incidence of ONJ. Several case reports, however, have described the occurrence of compromised implant healing, implant failure, and/or ONJ in bisphosphonate patients who have undergone implant placement. Jeffcoat (2006) carried out a longitudinal single-blind controlled study comparing implant success in patients taking oral bisphosphonates vs. age-matched controls. The subjects were 50 postmenopausal women diagnosed with osteoporosis. The 25 experimental patients had been taking alendronate or risedronate for a mean period of 3 + 0.1 years (range: 1-4 years) while the 25 age-matched control patients had not taken bisphosphonates. A total of 210 two-stage osseointegrated implants were placed. Fixed screw-retained prostheses were placed and removed to assess mobility. The patients were followed for at least three years via clinical examinations, radiographs, and routine maintenance. Mobility was assessed at least one time per year, and implant success rate was based on Kaplan-Meier analysis in which success was defined as less than 2 mm of alveolar bone loss, lack of mobility, lack of infection and absence of pain and ONJ. No cases of ONJ were observed in either group. One-hundred percent of the implants placed in the experimental bisphosphonate group and 99.2% of the implants placed in the control group were successful, with no significant differences noted between the study groups. This study suggests there is no reason for concern in placing implants in patients on bisphosphonate therapy. However, caution must be taken because the duration of bisphosphonate use generally was three years or less. Fugazzotto and coworkers (2007) performed a retrospective case record analysis of 61 female patients, ages ranging from 51-83 years, who underwent routine implant treatment in two private practices. The study assessed post-operative healing, osseointegration, and 12–24 month survival patterns of implants in patients taking oral bisphosphonates, with or without concomitant tooth extraction and regenerative therapy. The patients had been taking alendronate or risedronate for a mean period of 3.3 years (range: one to five years). A total of 169 implants were placed: 126 implants without and 43 implants with concomitant tooth extraction and regenerative therapy. Six weeks postoperatively, radiographs were taken and the implants were assessed clinically for immobility prior to implant restoration. Final data collection was obtained one to two years post-implant placement, and implant success 482 Novince and McCauley was determined using the criteria defined by Albrektsson and colleagues (1986). No osteonecrosis was noted post-operatively or during the follow-up period, and all implants were functioning successfully. A recent retrospective case record analysis of female patients over 40 years of age who had implant surgery included 1,319 patients who were surveyed for oral bisphosphonate use (Grant et al., 2008). Twenty-five percent of respondents reported taking oral bisphosphonates before or after implant surgery. Eighty-nine patients started oral bisphosphonate therapy before implant placement, while 26 patients began therapy after implant placement and healing. The mean age was 67 years and mean duration of bisphosphonate therapy was 38 months. A total of 458 implants were placed. There were no identified or reported cases of ONJ, and 99% of the implants were successful according to criteria defined by Albrektsson and colleagues (1986). Two incidences of implant failure occurred in patients who had taken oral bisphosphonates for more than three years prior to implant placement. Both patients had multiple implants placed successfully with only one single implant failure. One patient chose to not replace the failed implant, reporting uneventful healing at the failure site. The other patient underwent implant replacement, resulting in successful integration and definitive restoration. A case report by Wang and coworkers (2007) described compromised implant healing in a 65-year-old female, afflicted by Osteoporosis and osteoarthritis, along with a ten-year history of alendronate use. Implant surgery proceeded uneventfully. Six weeks post-surgery, the patient presented with fluctuant Swelling at the buccal mucosa near implants placed in the mandible. The site was incised and drained, and the patient was prescribed antibiotics. Radiographs revealed radiolucencies at the apices of implants. Surgical exposure revealed bony defects at the apex of one implant and adjacent to another. The areas were degranulated, detoxified and repaired with mineralized human cancellous bone, and the patient was prescribed post-operative antibiotics and an antimicrobial rinse. Post-operative clinical exams and radiographs revealed healing of the periapical lesions at all implants. At 15 months, with temporary prosthesis in function, radiographic examination demonstrated bone fill and resolution of the periapical radiolucencies. Brooks and colleagues (2007) reported a case of implant failure and ONJ in a 62-year-old osteopenic female who had an 11-month history of risedronate therapy (prior to extractions). The patient was treatment-planned for the placement of ten maxillary implants. Five 483 Better Understanding of Bisphosphonates remaining maxillary teeth were extracted, and extraction sites were grafted with freeze-dried bone allograft. Nine months later, autogenous hip marrow was grafted to the maxillary sinuses. Four months later, a noted bony sequestrum in the maxillary left posterior region was removed. Four months later, a bony spicule causing a mucosal fenestration and associated infection in the upper left vestibule was removed, and the patient was prescribed a course of antibiotics. Three months later, the fenestration was not resolved and was closed via a pedicle flap following debridement of the adjacent bone. Three months later, ten dental implants were placed in the maxillary arch. Two months later, two small spicules of necrotic bone were removed from the posterior left maxillary area, and the patient was prescribed two courses of antibiotics. A repeat CT scan revealed a bony defect of the left maxillary sinus floor with a moderately severe sinusitis. One month later, the left sinus was explored and four fragments of necrotic bone were removed along with the inflamed sinus mucosa. A final diagnosis of osteomyelitis with acute and chronically inflamed sinus mucosa was made. One month later, the sinus wound subsequently dehisced resulting in an oroantral fistula, and one implant was removed and nearby bone debrided. The patient was prescribed methylprednisolone, levofloxacin, budesonide nasal spray and oxymetazoline nasal spray by an ear, nose, and throat physician. The fistula underwent successful spontaneous closure. One of the first reports in the literature that suggested concern regarding implants in bisphosphonate-treated patients reported the failure of multiple implants in a 75-year-old female who initiated diphosphonate therapy for the treatment of osteoporosis post-implant placement (Starck and Epker, 1995). The patient had been edentulous for over 50 years and presented with severe atrophy of the maxilla and mandible with virtually no residual alveolar ridges. Five endosseous implants were placed in the anterior mandible and the maxillary residual alveolar ridge was augmented with non-resorbable particulate hydroxyapatite. Healing was uneventful. Four months post-implant placement and ridge augmentation, a new complete maxillary denture and fixed hybrid mandibular denture were delivered. Over the course of the next 18 months, panoramic radiographs taken at five recall appointments revealed normal healing. Nine months later, the patient presented complaining of pain in the mandible. A panoramic radiograph revealed extensive uniform osteolysis around all five mandibular implants. The patient reported that she began taking etidronate disodium, a non- 484 Novince and McCauley nitrogen containing bisphosphonate, three months prior. One month later the implants were removed. Considering the numbers of patients taking bisphosphonates along with the number of dental implants placed per year, the few reports of adverse events should not be surprising. These clinical reports indicate that implant placement is not contraindicated in patients undergoing oral bisphosphonate therapy but caution should be taken considering the duration of bisphosphonate use and co-morbid conditions when treating these patients. The studies do not provide evidence that oral bisphosphonate administration decreases implant success or increases the risk of ONJ. Nevertheless, the above case reports, documenting the incidence of compromised implant healing, implant failure and/or ONJ in oral bisphosphonate patients suggests that practitioners must be cautious When placing implants in patients undergoing oral bisphosphonate therapy. As recommended by the ADA, AAOMS and the ASBMR, practitioners should obtain informed consent disclosing the risks, benefits and treatment alternatives associated with implant placement When treating oral bisphosphonate patients. CONCLUSIONS, FUTURE DIRECTIONS, AND UNANSWERED QUESTIONS The use of bisphosphonates for the treatment of skeletal metastasis and metabolic bone diseases is well established for its therapeutic efficacy, and these agents are used widely in the medical community with well-accepted benefits to thousands of patients. The dental community recently has recognized that bisphosphonates may have the potential to modify the course of dental treatments. There are few studies in the literature elucidating the mechanisms of action of bisphosphonates that impact the maxillofacial skeleton selectively. Case reports suggest that orthodontic therapy may be inhibited in patients taking bisphosphonates. Many unanswered questions persist, including: • Is there a greater concentration of bisphosphonates locally in craniofacial sites where bone turnover has been induced by mechanical means (e.g., orthodontic tooth movement)? • Do various regions of the oral cavity respond differently to bisphosphonates? • What are the precise risk factors for developing osteonecrosis of the jaw? 485 Better Understanding of Bisphosphonates * How does the duration and dose of bisphosphonates specifically impact craniofacial Osseous wound healing? In the meantime, the medical and dental community should be prudent and preventive in their approach to the care of patients on bisphosphonates, with special caution in patients on intravenous bisphosphonates for the treatment of malignancy. Recommendations have been published by the ADA, AAOMS and ASBMR and should be followed for updates as new information is obtained. REFERENCES Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369-376. Albrektsson T, Zarb G, Worthington P, Eriksson AR. The long-term efficacy of currently used dental implant: A review and proposed criteria of success. Int J Oral Maxillofac Implants 1986; 1:11-25. American Dental Association Council on Scientific Affairs. Dental management of patients receiving oral bisphosphonate therapy: Expert panel recommendations. J Am Dent Assoc 2006; 137:1144- 1150. Brooks JK, Gilson AJ, Sindler AJ, Ashman SG, Schwartz KG, Nikitakis NG. Osteonecrosis of the jaws associated with use of risedronate: Report of 2 new cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:780-786. Coxon FP, Thompson K, Rogers MJ. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006;6:307-312. Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmaco- dynamics of bisphosphonates: Use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 2005:44:551-570. Fugazzotto PA, Lightfoot WS, Jaffin R, Kumar AJ. Implant placement with or without simultaneous tooth extraction in patients taking oral bisphosphonates: Postoperative healing, early follow-up, and the incidence of complications in two private practices. J Periodontol 2007;78:1664–1669. 486 Novince and McCauley Grant BT, Amenedo C, Freeman K, Kraut RA. Outcomes of placing dental implants in patients taking oral bisphosphonates: A review of 115 cases. J Oral Maxillofac Surg 2008;66:223–230. Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN. The frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res:2008:23:826-836. Jeffcoat MK. Safety of oral bisphosphonates: Controlled studies on alveolar bone. Int J Oral Maxillofac Implants 2006:21:349-353. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L., Silverman SL, Van Poznak CH, Watts N, Woo SB, Shane E; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007:22:1479–1491. Kimmel DB. Mechanism of action, pharmacokinetic and pharmaco- dynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res 2007;86:1022-1033. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis. An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658–1668. Rinchuse DJ, Sosovicka MF, Robison JM, Pendleton R. Orthodontic treatment of patients using bisphosphonates: A report of 2 cases. Am J Orthod Dentofacial Orthop 2007;131:321-326. Schwartz JE. Ask us: Some drugs affect tooth movement. Am J Orthod Dentofacial Orthop 2005;127:644. Starck WJ, Epker BN. Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: A case report. Int J Oral Maxillofac Implants 1995; 10:74–78. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000:289:1504– 1508. Tenenbaum HC, Shelemay A, Girard B, Zohar R, Fritz PC. Bisphos- phonates and periodontics: Potential applications for regulation of 487 Better Understanding of Bisphosphonates bone mass in the periodontium and other therapeutic/diagnostic uses. J Periodontol 2002;73:813–822. Wang HL, Weber D, McCauley LK. Effect of long-term oral bisphosphonates on implant wound healing: Literature review and a case report. J Periodontol 2007;78:584–594. 488 º ------------ ; ; ; ; ; ; , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iſſ T . . . . . . . . . . . . . . 3 9015 10064 18 88 º º º º º º º º º º º º º º º º º º º º º º # º º #. # º º º: # º i. º i. º º º º - º - i ºfflº º º i. - . # º º º º º º º º º º º | º - º º º º º º: º º º º º º º º º º º º º º º º - º º i - #. - º º º º º º º - º . º - # # # º ºfflº º ºffl # º #: º º #. # # # º - |- º º # º º º º º º º º º i. i. º º #. i º: . º - º º i º º º # （ # （ | | º -|| | --- º º | | º º º º º º º : º i. º º º º | | | º º º º º : º º i # # º º º º - # i. º º º º | | º - || ||i || |º # º - º - --- º º º i. º º º º i i i. º i. i. i. i. º º º º - º º -º-º-º-º: ºfflº º ºffli º º º --- {{# º º i. º º # # # º --- º º --- - - - º º º º º º º # º º: º º º # º º º º i. º º º º - º º º º º: # （ º H º i. i. º # # H # # i. º º º º | | º º º º º # º i. º i. º º º º º º º #. º - º | º ###########. º - º |- --- | - º - | º - ########. º . º º º : º º º: |- |- - # º ######## º º º º - - º- |- |ºº º º - - ----- # º: - i. # º #. º i. i - -- ºffl （ º i º º ºº º º º º | | |: | º - - # º #. º º º º º º # （ º º i. i. º #. - - º i º i. i #i. º # | - i. º - º º - （ - # # º . º # # º H --- | | | º | | |- | º º - - - º - - - º º - º - º - - º º º º . º º --- - - - - #. - º #. - - - º - - - --- --- - - - - - --- º º º - - º - | --- º º - º - （ º º º （ - º - - - --- - --- - -- - - º . --- º º º --- - - º º º º - º - - º H # º --- º º º ºn. º º º º: - º º （ º #. i. º º º --- - - - - . - - - T - º º - º - º: - - º º i # º -------- | º º - -- º * * * （ º - º iii. - - - - º … - - ºiri. - º º º º: º º º - - º º --~~~ -------- º º º º º （ º ºffl º - º º º º |- º - º - º º º