ºr re- - . . . . . . . . . . . ºrt- - ºr -º- - ******* ºw ºverwri-tº-wºve-wv- --~~~~ * | | THE 40th MOYERS SYMPOSIUM: LOOKING BACK ... LOOKING FORWARD This volume includes the proceedings of the Fortieth Annual Moyers Symposium March 8–10, 2013 Ann Arbor, Michigan Editor James A. McNamara Jr. Associate Editor Kristin Y. De Koster Volume 50 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 ©2014 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 The 40th Moyers Symposium: Looking Back ... Looking Forward Volume 50 ISSN 0162 7279 ISBN 0-929921-00-3 ISBN 0-929921–46–1 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. DEDICATION Dr. Vincent G. Kokich during his keynote address at the 40th Moyers Symposium on Friday morning, March 8, 2013. Photograph: Per Kjeldsen. Our Symposium family lost one of its most outstanding members on July 24, 2013 with the sudden death of Dr. Vincent G. Kokich from an apparent heart attack. Vince was one of three keynote speakers at the 40th Moyers Symposium; in fact, he was the first speaker to be contacted by the organizing committee because of his worldwide reputation as a lecturer, educator and clinician. At the time of his death, Vince was Editor-in-Chief of the Ameri- can Journal of Orthodontics and Dentofacial Orthopedics, having served previously as president of the American Board of Orthodontics and presi- dent of the American Academy of Esthetic Dentistry. Vince was a respect- ed leader and advocate of interdisciplinary treatment. He was a prolific researcher and author, and he gave over 850 lectures and courses nation- ally and internationally. Vince appeared on the Moyers Symposium program on three occasions, the first time over 20 years ago when he spoke at the 1991 meeting that considered the topic of Bone Biodynamics in Orthodontic and Orthopedic Treatment. His contribution was Sutural Responses to Orthodontic Forces, in which he discussed the human and non-human primate studies conducted at The University of Washington. He also prognosticated about the use of implants as anchorage in orthodontics long before this therapeutic approach became a clinical reality. Vince also presented the Fifth Moyers Memorial Lecture in 2000, which was based, in part, on the classic research conducted by his son, Vince Jr., and himself on the perception of orthodontists, dentists and the lay public concerning anterior dental esthetics. Vince's contribution to the 40th Moyers Symposium was on the first day as keynote speaker. He presented an eloquent talk on The Evolution of Adult Orthodontics: The Importance of a Realistic Approach. As one would expect, Vince had his book chapter to us in a timely manner and had the opportunity to approve the page proofs of his chapter only a few days before he died. The reader will find his chapter in this volume “Classic Kokich,” in that he outlined a clinical roadmap to deal with the adult patient that should be read and understood by all dental specialists and generalists. | personally have many fond memories of Vince over the years. last talked with him on July 22, having a friendly and warm conversation, briefly about his Moyers chapter and then for an extended time about projects planned for the future. Vince not only helped us select speakers for many Moyers Symposia, but also he was a wonderful resource for organizing AAO annual sessions and midwinter meetings. Given his perspective as editor of the AJO-DO, he always had his finger on the pulse of orthodontics, dentofacial orthopedics and interdisciplinary treatment worldwide. We recognize the significant contributions of Dr. Vincent G. Kokich to our specialty, honoring his memory by dedicating this volume to him. James A. McNamara Jr. Ann Arbor, Michigan December, 2013 DEDICATION annual Moyers Symposium, now in its 40th year. Photo provided by the Primack family. Shortly after the 40th Moyers Symposium concluded, we lost the person who started it all. Dr. Verne M. Primack died on March 19, 2013 in Denver, where he had resided since 2007. He and his wife Naomi were the inspiration behind establishing the Moyers Symposium in 1974. Verne was a graduate of The University of Michigan School of Dentistry in 1956. Naomi graduated the same year from The University of Michigan Dental Hygiene Program. They were married for 56 years. It was during a critical time in Verne's dental education that Verne and Bob Moyers met. Bob's advice to Verne encouraged him to stay the course in dental school and finish his education. Bob not only was a teacher for Verne and his classmates, he also was interested in their lives as individuals in a special way and gave several of them helpful guidance during difficult times. After graduation, Verne entered the United States Army Dental Corps, in which he served as captain. In 1959, the Primacks moved to Saginaw, Michigan, where Verne practiced general dentistry for 40 years; Naomi also practice hygiene two years longer than Verne did in addition to raising three sons. Verne served as president of the Saginaw Dental Society, was appointed to the State of Michigan Board of Dentistry and was a regent of the Alpha Omega Dental Fraternity. A truly unique individual who never stopped thinking of others, Verne was a member of the Saginaw Township School Board and also was a sponsor of the Can-American games. After he retired from private practice, he was a volunteer for CASA, a Court-appointed special advocate assisting foster children. After he moved to Denver, he helped Russian immigrants prepare for their citizenship examinations. Naomi also has had a long history of serving others, having been recognized by the State of Michigan for her efforts in human services, community welfare and faith-based activities. She also has been ac- knowledged for her efforts in improving racial harmony. Verne was a frequent attendee at the Moyers Symposium during its long existence. He was charming, outspoken and never was afraid to speak his mind. He and Naomi wanted to establish something meaningful to honor Bob Moyers—they succeeded far beyond their wildest expecta- tions. Thanks, Verne and Naomi, for making the Symposium a reality through your vision, enthusiasm and financial support. James A. McNamara Jr. Ann Arbor, Michigan December, 2013 Vi CONTRIBUTORS ROLF G. BEHRENTS, Lysle Johnston Professor of Orthodontics, Program Director of Orthodontics, The Center for Advanced Dental Education, Saint Louis University, St. Louis, MO. DAVID S. CARLSON, Regents Professor and Vice President for Research and Graduate Programs, Texas A&M Health Science Center, Texas A&M University, College Station, TX. LUCA CONTARDO, Assistant Professor and Head of the Orthodontic Pro- gram, Department of Medical, Surgical and Health Sciences, School of Dentistry, University of Trieste, Trieste, Italy. p HUGO DE CLERCK, Adjunct Professor, Department of Orthodontics, Uni- versity of North Carolina; private practice of orthodontics, Brussels, Bel- gium. LORENZO FRANCHI, Assistant Professor, Department of Orthodontics, University of Florence, Florence, Italy; Thomas M. Graber Visiting Scholar, Department of Orthodontics and Pediatric Dentistry, School of Dentistry, The University of Michigan, Ann Arbor, MI. WILLIAM V. GIANNOBILE, Chair and Professor, Department of Periodon- tics and Oral Medicine, School of Dentistry, The University of Michigan, Ann Arbor, MI; Professor, Department of Biomedical Engineering, College of Engineering, The University of Michigan, Ann Arbor, MI. LEE GRABER, Past President, American Association of Orthodontists; private practice of orthodontics, Vernon Hills, IL. NAN HATCH, Assistant Professor, Department of Orthodontics and Pedi- atric Dentistry, School of Dentistry, The University of Michigan, Ann Ar- bor, MI. LYSLE E. JOHNSTONJR., Professor Emeritus, Department of Orthodontics and Pediatric Dentistry, The University of Michigan and Department of Orthodontics, Saint Louis University, St. Louis, MO. VINCENT G. KOKICH (deceased), Editor-in-Chief, American Journal of Or- thodontics and Dentofacial Orthopedics; Professor, Department of Ortho- dontics, University of Washington, Seattle, WA. G. GIBSON McCALL, Adjunct Assistant Professor, Department of Ortho- dontics, School of Dentistry, University of North Carolina, Chapel Hill, NC; private practice of orthodontics, Greenville, NC. Vii JAMES A. McNAMARA JR., Thomas M. and Doris Graber Endowed Pro- fessor, Department of Orthodontics and Pediatric Dentistry, School of Dentistry; Professor, Cell and Developmental Biology, School of Medicine; Research Scientist, Center for Human Growth and Development, The Uni- versity of Michigan, Ann Arbor, MI; private practice of orthodontics, Ann Arbor, MI. ANA M. MERCADO, Clinical Assistant Professor, Member of Medical Staff, Nationwide Children's Hospital, The Ohio State University, College of Dentistry, Columbus, OH. MIN OH, Department of Periodontics and Oral Medicine, School of Dentistry, The University of Michigan, Ann Arbor, MI. HANS PANCHERZ, Professor Emeritus, Department of Orthodontics, University of Giessen, Giessen, Germany. • GIUSEPPE PERINETTI, Research Fellow, Department of Medical, Surgical and Health Sciences, School of Dentistry, University of Trieste, Trieste, Italy. JASMINA PRIMOZIC, Assistant Professor, Department of Orthodontics and Jaw Orthopedics, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia. WILLIAM R. PROFFIT, Kenan Distinguished Professor, Department of Orthodontics, School of Dentistry, University of North Carolina School of Dentistry, Chapel Hill, NC. LISA RANDAZZO, Marketing Manager, Dolphin Imaging & Management Solutions, Chatsworth, CA. DAVID L. SACKETT, Ottawa, London, Edinburgh, Trout Research & Educa- tion Centre, Irish Lake, Ontario, Canada. DAVID M. SARVER, private practice of orthodontics, Vestavia Hills, AL. RILEY A. SCHIFF, Department of Periodontics and Oral Medicine, School of Dentistry, The University of Michigan, Ann Arbor, MI. NICOLE R. SCHEFFLER, former Assistant Professor, Department of Ortho- dontics, School of Dentistry, University of North Carolina, Chapel Hill, NC; private practice of orthodontics, Boone, NC. ANDREl D. TAUT, Department of Periodontics and Oral Medicine, School of Dentistry, The University of Michigan, Ann Arbor, MI. viii HILDE TIMMERMAN, private practice of orthodontics, Hulst, The Neth- erlands. FRANS P.G.M. VAN DER LINDEN, Emeritus Professor, Department of Orthodontics, Radboud University, Nijmegen, The Netherlands. KATHERINE W.L. VIG, Professor Emeritus and former Chair of Orthodon- tics, The Ohio State University, College of Dentistry, Columbus, OH. CHESTER H. WANG, Director, Dolphin Imaging and Management Solu- tions, Chatsworth, CA. PREFACE The 40th annual Moyers Symposium was held in Ann Arbor during the second weekend of March 2013. We celebrated this special 40th anniversary meeting with a three-day event featuring 19 outstanding Speakers from past Symposia. The attendance was the highest ever for a Moyers Symposium, with over 800 participants. The Symposium, which began in 1974, honors Robert E. Moyers, the former Chair of the Department of Orthodontics and the Founding Director of the Center for Human Growth and Development at The University of Michigan. Forty years is a long time. Where have we been and where are we going as a specialty? What questions have been answered; what questions have eluded answers; what innovations are on the horizon? These and other issues were discussed during this unique event and are addressed in this volume. Three keynote lectures were presented, one each day. The first was given Friday morning by Vincent Kokich, editor of the American Journal of Orthodontics and Dentofacial Orthopedics. The second was presented on Saturday morning by David Sackett MD, the “father” of evidence-based practice in medicine. Lysle Johnston delivered the final keynote lecture on Sunday morning. The 17th annual Robert E. Moyers Memorial Lecture was presented as a retrospective by James McNamara. Two novel social events highlighted the meeting. A reception and poster session was held on the 4th floor of the Horace H. Rackham School of Graduate Studies building immediately following the meeting on Friday, a session organized by Nan Hatch and Sunil Kapila. Faculty and residents were encouraged to present posters at this Session and travel awards of $1000 were awarded to the best scientific work in the junior faculty and resident categories. The junior faculty award was presented to Lorri Morford of The University of Kentucky; the resident category was won by Megan LeCornu of The University of North Carolina. Of special interest was the reception at Michigan Stadium on Saturday evening. The reception was held in the Skyboxes that have been added to the stadium as part of the recent renovation project. Attendees were able to access the field and the Michigan football locker room. The evening was a wonderful time to reunite with old friends and make new acquaintances in an informal Setting. Many individuals have worked on the 40th Moyers Symposium who need to be recognized formally. We acknowledge Sunil Kapila, the Chair of the Department of Orthodontics and Pediatric Dentistry, for providing the financial resources to underwrite partially the publication of this volume. We also thank Brenda Volling, the Director of the Center for Human Growth and Development, for the continued financial and moral support of the Moyers Symposium provided by the Center. We are fortunate to work with the same staff from the Office of Continuing Dental Education in their organizing and running the Sympo- sium. We thank Michelle Jones and Karel Barton for managing the meet- ing in a smooth and efficient fashion. We also thank Mike Leto, Jared Little, Spencer Crouch and Nicole Pentis for their efforts in updating our international email list. We note with great sadness the death of our good friend Debbie Montague of the Office of Continuing Dental Education following a long battle with cancer. Debbie was a major player in organizing the Symposium for a decade; her presence is missed by all of us. Several people must be recognized for their efforts in preparing this book, the 50th volume of the Craniofacial Growth Series, published by The University of Michigan and distributed by Needham Press of Ann Arbor. Most importantly, we recognize the continuing major contribution of Kris De Koster, the Associate Editor of the Craniofacial Growth Series. For the past six years, she has facilitated the publication of this annual volume by communicating with the authors, editing, manipulating many figure formats, checking references and formatting the layout of the book. It is always a challenge for us to produce Such a high-quality volume in the time frame prior to the next Symposium, but she makes it happen. We welcome back Kathy Ribbens, who helped with the publica- tion of Volume 3 from the inaugural Moyers Symposium in 1974 and was a named editor on seven previous Symposium volumes. This year, she assisted Kris by generating the final typeset of the text, due to recent Xi changes with the printer. Her continued support and assistance with these volumes is appreciated. We also thank the contributors for sending us their excellent material in a timely fashion—but with the all-star cast of presenters we assembled, that is no surprise. This volume easily could be the best of all of the books emanating from the 40 years of the Moyers Symposium. James A. McNamara Jr. Ann Arbor, Michigan December, 2013 xii FOREWORD Having attended the first Moyers Symposium as a student, the 40th anniversary Moyers Symposium as a mature academic and the Sym- posia in between, it is clear that there must be reasons why I am such a fan of the event. I will mention two. Of the greatest significance to me were the people involved; this includes the leadership, speakers and attendees–basically everyone involved. Robert E. Moyers and James A. McNamara have been the driving force behind the conduct and continuation of the Symposium; they deftly chose the topics and speakers who were the best speakers that could be found throughout the world for each theme and during each Symposium. They were arranged so that the science of the topic came first and the clinical application came last, with a blend in the middle. The attendees were a rich mix of people young to old, students, teachers, researchers, practitioners, from the U.S. and abroad. Most importantly, personal and professional relationships were established among the speakers and attendees during the Symposium itself and through informal discussions in the foyer of Rackham Auditorium; at formal lunches, dinners and receptions; and sometimes late into the night at local restaurants and bars. Of equal significance was the information that was shared at each Symposium. The Speakers shared their ideas, knowledge and experience with all. If you missed something, the monographs always were there to inform in great detail. The monographs stand as a record of the proliferating knowledge and evolution of concepts that form the biological basis of craniofacial biology and its related clinical disciplines, especially Orthodontics. They also provide testimony that our understanding and clinical performance has improved. On this basis, it is clear that the Moyers Symposium has been Crafted well, but more important has been timely, relevant and fun. One hopes that it will be continued and continuously successful in those ways in the future. So, as the next Moyers Symposium comes near, remember the encouragement of Dr. Moyers: xiii So much important research is yet to be done, so much challenge lies ahead if we are to do all our patients, our colleagues and society expect of us. I wish I were just starting anew. (Robert E. Moyers, 1990) Rolf G. Behrents Chair, Department of Orthodontics Saint Louis University Editor Designate, American Journal of Orthodontics and Dentofacial Orthopedics xiv TABLE OF CONTENTS Vincent G. Kokich Dedication Verne and Naomi Primack Dedication Contributors Preface Foreword 17th Annual Robert E. Moyers Memorial Lecture: Reflections on the Moyers Symposium: A Living History of Contemporary Orthodontics and Craniofacial Biology James A. McNamara Jr., The University of Michigan Heynote Lecture Evolution of Adult Orthodontics: The Importance of a Realistic Approach Vincent G. Kokich, The University of Washington and Editor, American Journal of Orthodontics and Dentofacial Orthopedics Orthodontic Diagnosis and Treatment from the Outside In David M. Sarver, Vestavia Hills, Alabama Longitudinal Growth Studies: Comments on the Benefits and Risks Rolf G. Behrents, Saint Louis University Skeletal Anchorage: Its Possible Impact on Orthognathic Surgery William R. Proffit, Nicole R. Scheffler, G. Gibson McCall, The University of North Carolina Periodontal Screening: Practical Protocols for the Orthodontist Lee W. Graber, Vernon Hills, IL |Keynote Lecture On the Vanishing Need for M.D. Randomized Trialists at Moyers Symposia David L. Sackett, McMasters University, Hamilton, Ontario Vii xiii 29 59 83 113 127 145 XV Development of the Human Dentition: A Life's Work Frans P.G.M. van der Linden, Radboud University, Nijmegen, The Netherlands Toward a Modern Synthesis for Craniofacial Biology: A Genom- ic-Epigenomic Basis for Dentofacial Orthopedic Treatment David S. Carlson, Texas A&M University Orthopedic Changes by Bone-anchored Intermaxillary Elastic Traction in Class III Growing Patients Hugo De Clerck and Hilde Timmerman, The University of North Carolina, Brussels, Belgium and Hulst, The Netherlands Clinical Alteration of Mandibular Growth: What We Know After 40 Years Lorenzo Franchi, Luca Contardo, Jasmina Primožič, Giuseppe Perinetti, The University of Florence, Italy, The University of Trieste, Italy and The University of Ljubljana, Slovenia Treatment Timing of Herbst Appliance Therapy Hans Pancherz, The University of Giessen, Germany Contemporary Management of Craniofacial Anomalies: Will Past Experiences Influence and Predict the Future? Katherine W.L. Vig and Ana M. Mercado, The Ohio State University FGF Signaling in Craniofacial Skeletal Development and the Pathogenesis of Craniosynostosis Nan Hatch, The University of Michigan |Keynote Lecture Envoi: The Moyers Symposium, A Miner's Canary for 21st Century Orthodontics Lysle E. Johnston Jr., The University of Michigan; Saint Louis University Anti-resorptive and Bone Anabolic Agents for Periodontal Therapy Andrei D. Taut, Riley A. Schaff, Min Oh, William V. Giannobile, The University of Michigan The Future of Technology in the Orthodontic Practice: Looking Back ... Looking Forward Chester H. Wang and Lisa Randazzo, Dolphin Imaging, Chatsworth, CA 167 193 249 263 287 319 355 383 391 427 Xvi REFLECTIONS ON THE MOYERS SYMPOSIUM: A LIVING HISTORY OF CONTEMPORARY ORTHODONTICS AND CRANIOFACIAL BIOLOGY James A. McNamara Jr. ABSTRACT The Moyers Symposium series began in 1974 as a way to honor Robert E. Moyers, Professor of Dentistry and Founding Director of the Center for Human Growth and Development on the Ann Arbor campus of The University of Michigan. This annual meeting has become recognized as the most prestigious meeting of its kind worldwide, drawing an international group of people chosen annually for their expertise in the specific topic being discussed. Themes were identified carefully to reflect contemporary issues or controversies facing the Specialty at a particular time. There have been more than 320 formal presentations during the 40 years, each of which was followed by stimulating discussions either after each talk or included in panel discussions. A unique feature of the annual Moyers Symposium is the Presymposium, which now is known more formally as the Annual International Conference on Craniofacial Research. It became obvious after the first Symposium that those attending, both academics and clinicians, generally were of such high quality that many could have been speakers on the Symposium program. The Presymposium has allowed additional investigators, both seasoned experts and junior researchers, to present their material in a more informal setting preceding the Moyers Symposium. Active participation by the attendees always has resulted in lively discussions at the Symposium and particularly at the Presymposium. The transactions of the Moyers Symposia as well as selected papers from the Presymposium have been published annually as a monograph in the Craniofacial Growth Series (CGS). This ongoing living history of the 40 Symposia is a unique resource in orthodontics and craniofacial biology. The Symposia and the publication of the monograph series allow the reader to revisit themes that have encompassed a wide range of topics. KEY WORDS: Robert Moyers, Moyers Symposium, Craniofacial Growth Series, Presymposium, growth symposium Reflections on the Moyers Symposium This initial chapter provides an overview of the 40 years of the Moyers Symposium. Forty years in anyone's life is a long time, a professional lifetime for most of us. Forty years of a high-caliber academic endeavor such as the Moyers Symposium invites celebration and reflection. I have been part of the Moyers Symposium family from the beginning; as a fledging researcher and clinician, I was one of the inaugural speakers in 1974. Since then, I have been involved in every Symposium from planning both the content and local arrangements to moderating most of the meetings. I also have edited or co-edited 30 of the 40 volumes of the Craniofacial Growth Series (CGS) monographs associated with the Symposium. Thus, I have a unique insider's perspective of the organization and execution of each annual event. Writing this chapter has been both great fun and an intellectual challenge. Remember that the Moyers Symposium was started decades before the advent of personal computers, Word documents and Excel spreadsheets, all of which we now take for granted. Therefore, it was necessary to rely heavily on my own paper files as well as old brochures from the meetings (Fig. 1). Without the CGS publications used for this review, the history of the Symposium would, in part, be lost. So how do you begin to summarize 40 Symposia that covered a wide array of topics in orthodontics, dentistry, medicine and craniofacial biology as well as psychology, art and esthetics, information technology, radiology, clinical epidemiology and ethics? Obviously I am not going to focus on each of the symposia in the same depth. Rather, I have chosen to discuss in detail some of the Symposia that have been truly interdisciplinary in nature, a hallmark of the meetings. The reader is provided with a list of the speakers and topics covered at all of the 40 symposia at the end of this book (pages 443- 471). Simply glancing over the list of speakers and topics will provide the reader with an understanding of why the Moyers Symposium has earned the respect of the thousands of academics, clinicians, residents and students who have attended over the years. * In this chapter I have noted specific disciplines for those participants who were not orthodontists. If no discipline is listed, the assumption can be made that the speaker was from the specialty of orthodontics. McNamard - - | M. Nºwºsº. OF MICHGAN º ºciololo Divisiºn a sponsored s ----------- | The Effe developmenta Surgical Inte OF TEMPOROMA Clinical Research | Joint psor as the on Basis of Clinical P - Craniofacial - February 27- | -bruary 2-7 - - M OY - R S. – || | | | | | SYMPCSUM º º º - LOOKING BACK. | | |OOKING FORWARD º º A Symposium of Interest to - - - All Dental Professional: º - is tº is tº - - - - - - e- - – --~~~~~~~ --~~~~~~~ - - - - - -- ~~~~ -º-º-º-º: Cranio- *. - º -------- facial * | - ** L Biology wº MARCH 8-0 Figure 1. Many sources were used to reconstruct the programs that occurred during the pre-computer years of the Symposium, including the original bro- chures advertising the meetings. WHO WAS BOB MOYERSP Any discussion of the Moyers Symposium begins with the person who has been honored at this meeting since its inception in 1974, Robert Edison Moyers (Fig. 2). Several summaries of Dr. Moyers' life have been published both in journals and in previous Moyers Symposia volumes. This part of the chapter will rely heavily on material from Dunaway and McNamara (1992) with additional material obtained from chapters by Behrents (2003) and Vig (2006). Robert E. Moyers was born on November 12, 1919, in Sydney, Iowa, where he spent his childhood and most of his adolescence. Shortly after graduating from high school in 1937, Bob went to lowa City where he worked to earn enough money to begin his university education that fall. At age 17, he attended the State University of Iowa, entering the College of Liberal Arts where he was enrolled in the honors English program. Bob also was a member of the University Players (he always had a flair for the theatrical). During his undergraduate years, Bob served as student pastor at a small church outside of Iowa City earning the nickname “Deacon.” Because of his success as a preacher, he continued to serve as pastor Reflections on the Moyers Symposium Figure 2. Robert Edison Moyers, DDS, MS, PhD. These photos were taken at the occasion of his retirement in 1990. until he finished dental school at lowa, graduating in December 1942 at which time he began his military career. Bob was assigned to the Office of Strategic Services (OSS; Clemente, 2010). In preparation for his OSS duties, he underwent intensive training in physical conditioning, cryptography, parachuting and survival techniques. As one of a group of five soldiers, Bob parachuted into Greece on the second anniversary of Pearl Harbor, the first Americans to do so. There Major Moyers (Fig. 3) served as the senior allied medical liaison officer to the Greek resistance movement. His wide-ranging exploits are described in detail by Dunaway and McNamara (1992). Major Moyers was discharged in early September 1945, leaving the Army with the Bronze Star, the Legion of Merit, the Purple Heart (he was wounded twice), the Order of the British Empire and the Order of Phoenix (Greek). Bob was the most highly decorated dental officer to serve in World War ||. In late September 1945, Bob returned to Iowa City to begin his graduate work in orthodontics. He received his Master's degree in 1947 and a PhD in neuromuscular physiology in 1949. While at Iowa, Bob be- came a pioneer in electromyography; he was one of the first individuals McNarnard Figure 3. Major Robert Moyers in a photo taken during World War II. to monitor electrical activity in the masticatory and facial muscles. His doctoral thesis earned him what is now known as the Milo Hellmann Research Award, the highest research award given by the American Association of Orthodontists. After completing his PhD research, Bob was appointed chair of the Orthodontic Department at The University of Toronto in 1949. While at Toronto, he established two research centers: the Burlington Orthodontic Research Centre and the Craniofacial Anomalies Clinic at the Hospital for Sick Children in Toronto. Both of these research centers still are active today. After the sudden death of Dr. George Moore at The University of Michigan, Bob was asked to assume the chairmanship of the Orthodontic Reflections on the Moyers Symposium Department at The University of Michigan, a position he accepted in 1952. Early in his career in Ann Arbor, Bob became involved with The University of Michigan Elementary and Secondary School Growth Study, adding cephalometric and hand-wrist film data to the data gathered annually from the students in the University’s “laboratory school” located within the School of Education. This extensive database has served as a research source for many scholars at Michigan and for those who have come from around the world to study and conduct research at The University of Michigan. In 1963,The University of Michigan began an initiative to establish an interdisciplinary research unit in human development on campus. Because Bob had taken his training at the lowa Growth Center, the dean of the Dental School asked him to represent the School of Dentistry on this committee. Bob ultimately became the Founding Director of the Center for Human Growth and Development (CHGD) that was established in 1964. When I came to Ann Arbor in 1968 to start my doctoral work in anatomy, the Center was located at 611 Church Street. It was a time of intense intellectual excitement at the Center, especially for a young doctoral student like me. During Bob's long tenure as Director of the CHGD, he convinced many visiting scholars to take their sabbaticals at The University of Michigan, usually for a period of a year or more. Visiting scholars at the CHGD during the late 1960s and early 1970s included Leif Linge from Norway, Frans van der Linden and Herman Duterloo from the Netherlands, José Carlos Elgoyhen from Argentina, Kalevi Koski from Finland and Takayuki Kuroda from Japan. Dental students (and future orthodontists) Mike Riolo, Bill Northway and Lee Graber also were in the mix. Other international scholars who became part of CHGD in the mid-to-later part of the 1970s included Alexandre Petrovic from France, Jos Dibbets from the Netherlands and Daryl Bowden from Australia. Each of these individuals enhanced the intellectual atmosphere of the CHGD greatly and many participated as Speakers at subsequent Moyers Symposia. Bob served as director of the CHGD until 1980 and continued to head the Craniofacial Biology Group at the CHGD for another decade. In 1990, he retired and became Fellow Emeritus of the CHGD and Professor Emeritus of Dentistry. He also retired from his private orthodontic prac- McNamard tice, but he continued to be a productive researcher until his untimely and unanticipated death in 1996 at age 75. Bob Moyers was one of the University's most creative and inno- vative faculty members. His horizons were far broader than dentistry and orthodontics, as is indicated by his vision that led to the founding of the CHGD and his leadership and coordination of the disparate research foci of the biologists and psychologists comprising the CHGD faculty. Through his pioneering efforts, the CHGD gained international prominence for its interdisciplinary research in craniofacial biology, developmental psychol- ogy, developmental biology, nutrition and public health, morphometrics, anthropology and pediatrics. Bob's first love, however, was orthodontics and his contributions to the specialty were immense. His doctoral investigations and subse- quent clinical research provided a better understanding of the role of the neuromusculature both in normal facial growth and during clinical treat- ment. His leadership of an NIH-funded program project in craniofacial growth and development led to a broader understanding of the form- function relationship in the craniofacial region. Bob also wrote an orth- odontic textbook that was used throughout the world for many decades. ESTABLISHING THE MOYERS SYMPOSIUM The first Moyers Symposium was held in April 1974 (Fig. 4). The original idea for the Symposium came from Dr. Verne Primack (Fig. 5), a 1956 graduate of The University of Michigan School of Dentistry. Dr. Primack and his wife Naomi wanted to provide a living honor for Dr. Moyers in appreciation of his encouragement at a crucial time in Verne's dental education, his advice and his mentoring that led Dr. Primack to continue his education in dentistry. It was the wish of the Primack family to provide a broad forum for new ideas in craniofacial growth and development that would be open to practitioners in dentistry, medicine and allied health fields. The inaugural Symposium, held in Kellogg Auditorium in the School of Dentistry, was entitled Control Mechanisms in Craniofacial Growth and was attended by approximately 200 individuals. This first Symposium was traditional in format (the format would change in Subsequent years) in that there were eight speakers, each dealing with a specific topic related to the overall theme of the meeting. Reflections on the Moyers Symposium A SPONSORED SYMPOSIUM Mechanisms | ºniºia. º APRIL 26, and 27, 1974 4– Figure 4. Original brochure from the inaugural Symposium in 1974. The first Symposium was the only meeting held in the auditorium in the Kellogg Dental Building. Almost all subsequent meetings were held in the auditorium of the Horace H. Rackham School of Graduate Studies. J. Figure 5. The initiator of the Moyers Symposium was Dr. Verne Primack (right) of Saginaw, Michigan. Dr. Primack is shown in a photo taken in 1976 at the third Moyers Symposium. He and his wife Naomi jointly supported the Symposium for many years. McNamard The speakers in order were: • James Bosma, physiology, NIDR: Form and Function of the Mouth and Pharynx • Melvin Moss, anatomy, Columbia University: Neuro- trophic Regulation of Craniofacial Growth • James McNamara, anatomy and CHGD, The University of Michigan: Muscle and Bone Interaction in Craniofa- cial Growth • T.M. Graber, orthodontics, The University of Chicago: Extrinsic Factors Influencing Craniofacial Growth • Frans van der Linden, orthodontics, The University of Nijmegen, The Netherlands: Mechanisms Controlling the Development of the Dentition • Judson Van Wyk, pediatrics, University of North Caro- lina: Somatomedins: A New Class of Growth Regulat- ing Hormones • Donald Woodside, orthodontics, The University of Toronto: Growth Guidance Appliances The evening of the first day featured a banquet held at the Ann Arbor Inn. For more than a decade, it became a Symposium tradition for an esteemed member of the university faculty to give an after-dinner talk on a non-orthodontic topic. The first such presenter was Frank H.T. Rhodes,” Professor of Geology and Vice-President of Academic Affairs at Michigan. His talk (Rhodes, 1975), which was entitled, Of Craniofacial Sutures and The Rest Of The Universe, actually was a discussion of Thomas Aquinas and how his ideas have continued to be relevant to current day issues. These “out of the box” discussions were typical of Bob Moyers and his influence was seen throughout the many years of the Symposium. Over the years, the Symposium has taken on a life and style of its own, with several evolutionary changes occurring as it matured. Today the meeting is held in Rackham Auditorium in the Graduate School on the Ann Arbor campus (Fig. 6). The auditorium in Rackham is elegant and * Frank Rhodes went on to become the President of Cornell University and was the longest-serving Ivy League president. Rhodes became a national leader as an advocate for education and research. He played a significant role in the development of national science policy under several presidents. Reflections on the Moyers Symposium Figure 6. Contemporary photos of the exterior and interior of the Horace H. Rackham School of Graduate Studies where the Moyers Symposium has been held beginning in 1975. Both the lobby and the auditorium were used. In later years, the Presymposium was held in the 4th floor amphitheater of the same building. spacious (with a capacity of 1,200), a venue that is appropriate given the unique nature of the Symposium and the large number of individuals who attend each year. THE CRANIOFACIAL GROWTH MONOGRAPH SERIES The Craniofacial Growth Series (CGS) published by the CHGD actually was started in 1972 with the publication of my doctoral thesis in monograph form (Monograph 1, CGS; McNamara, 1972). The second book to be published was the blue cephalometric atlas (Riolo et al., 1974) containing the data from lateral headfilms from the Michigan Growth Study that had been traced, digitized and presented in atlas form. The green dental cast atlas (Moyers et al., 1976) was published two years later. 10 McNarndra Figure 7. Thirty-nine volumes of the Craniofacial Growth Series (CGS). The series includes chapters by over 1,000 authors and involves over 12,000 pages of text. For size comparison are two-and-a-half-year-old Kendall McNamara and three- year-old Alex McClatchey. The CGS is available through Needham Press, Inc., of Ann Arbor, MI (www.needhampress.com). It was a subvention from the NewConn Orthodontic Study Group in 1974 that allowed the publication of the transactions of the proceed- ings of the first Moyers Symposium. In March 1974, our research team, including Bob, Don Enlow, me and several others, presented the program at the 5th Biennial NewConn Growth Seminar in New York City. With the help of Dr. Richard Sands, a major force behind the NewConn Group, this led to the NewConn group's monetary gift that was used to underwrite the publication of Volume 3 of the CGS, Control Mechanisms in Craniofa- Cial Growth (McNamara, 1975). This modest subvention set the wheels in motion for 40 years of Continuous publication of the proceedings of the Moyers Symposium (Fig. 7). The continuity of publication is one of the reasons that this event has 11 Reflections on the Moyers Symposium had such a major influence on orthodontics and craniofacial biology. The 40 volumes of the CGS associated with the Moyers Symposium contain chapters written by a total of 1,006 authors with more than 12,500 pages of text. I edited the majority of the volumes; David Carlson took over that role for about a decade before he left the university for Baylor College of Dentistry in 1993. Others have served in an editorial capacity when the topic was appropriate, including Katherine Ribbens, Carroll-Ann Trotman, Katherine Kelly, Katherine Vig, Christian Stohler, Sunil Kapila and Nan Hatch. A complete listing of the Moyers Symposium volumes that are part of the CGS can be found at the end of this volume. THE PRESYMPOSIUM We all were pleased with the outcome of the first Symposium, both in the number of attendees and in the quality of the presentations. It became obvious that because of the high quality of the program, there were many attendees who could have presented their own research material. Thus, the Presymposium was initiated the following year (Fig. 8). The intent of the Presymposium (now called the Annual Interna- tional Conference on Craniofacial Research) was to provide an opportu- nity for other investigators (particularly junior investigators) to present their material in an informal venue. Each speaker's presentation was fol- lowed by challenging and often animated discussions. Over the years, the Presymposium has taken on a life of its own with many memorable discussions of (and arguments over) topics in orthodontics and craniofacial growth. The papers presented at the Presymposium were not always related directly to the theme of that year's Symposium; the best of the papers that were relevant to the overall theme of a Symposium were included in the related volume of the CGS. THE SECOND MOYERS syMPOSIUM The second Moyers Symposium is noteworthy for several changes in format. First, due to the increasing interest in the Symposium, the attendance blossomed and we had to find a new venue for the meeting. The capacity of Kellogg Auditorium was approximately 250 people. We 12 McNamard Figure 8. The more informal setting of the Presymposium, held the day before the Moyers Symposium. The Presymposium has been held at various venues, including the ballroom of the Michigan League shown here. In the opinion of many attendees, the Presymposium meeting often was "more fun than the Symposium" because of the spirited discussions that occurred not only after the presentations, but also in the hallways afterward. decided to hold the meeting in the first floor auditorium of the Rackham Graduate School, which had a much greater capacity. It was fortuitous that we made the change in that the typical attendance at the Moyers Symposium historically had been 350-500 individuals, with many reaching Well above 500; the 40th Moyers Symposium was attended by more than 800. The grandeur of Rackham Auditorium and its large atrium used for breaks has made it a pleasant and convenient venue for the Symposium each year. - The second format change was the inclusion of discussants in the program—individuals who provided a commentary on the remarks made by of one of the presenters. The speakers at the 1975 meeting, Determinants of Mandibular Form and Growth, were: 13 Reflections on the Moyers Symposium • Milford Wolpoff, anthropology, The University of Michigan: Mandibular Evolution • Donald Enlow, anatomy, University of West Virginia: Rotations of the Mandible During Growth • Robert Ricketts, private practice of orthdontics, Pacific Palisades, CA: A Series of Inquiries on the Growth of the Mandible • Alexander Petrovic, medicine and bone biology, Stras- burg, France: Control Mechanisms in the Condylar Cartilage • Egil Harvold, Center for Craniofacial Anomalies, The University of California, San Francisco: Experiments on Mandibular Morphogenesis The discussants usually were given a copy of the presentation in advance and prepared a 5-10 minute summary of the talk. Some discussants also presented their own original material. The discussants occasionally would contribute written versions of their remarks to the Symposium volume from that year. In 1975, the discussants were: • Melvin Baer, craniofacial biology, The University of Michigan • Richard Christiansen, Orthodontics, National Institutes of Dental Research, Bethesda, MD - • Arthur Craven, private practice of orthodontics, East Lansing, MI • Stanley Garn, CHGD, genetics and nutrition, The Uni- versity of Michigan • Richard Litt, orthodontics, University of Detroit The third major change in the 1975 Symposium was the introduc- tion of what has come to be known as the “Edison,” based on Bob Moy- ers' middle name. The speakers at the first Symposium each were given a mounted piece of Steuben glass as a memento of the meeting. Bob, how- ever, wanted to provide each speaker with something more special, so he commissioned The University of Michigan artist Tom McClure to create a piece of bronze sculpture (Fig. 9) that has been given to the speakers each year beginning with the second Symposium. 14 McNamard º Figure 9. The "Edison,” a bronze statue created by The University of Michigan faculty member Thomas F. Mc- Clure. This piece of art has been given to each speaker at the Symposium, beginning in 1975. SELECTION OF SPEAKERS Before beginning a detailed overview of some of the symposia, a few comments about the speaker selection process is in order. Each year a planning committee was selected from faculty and post-doctoral scholars from the CHGD. After the first decade, members of the orthodontic department also participated in the planning process. The members of the initial planning committees were Bob Moyers, Don Enlow and me and our three post-docs, Rolf Behrents, David Carlson and Lee Graber, all of whom have remained integral to the Symposium planning process over the years. Additionally, several of our international scholars have participated, particularly Frans van der Linden and Alexandre Petrovic. Beginning in the early 1980s, the chair of orthodontics as well as some of 15 Reflections on the Moyers Symposium the orthodontic faculty participated, including Peter Vig, Lysle Johnston, Sunil Kapila, Kate Vig, Nan Hatch, Scott Conley and Lucia Cevidanes. Prosthodontist Christian Stohler also was a frequent contributor, especially to the TMD/orofacial pain Symposia. A total of 322 individuals have made formal presentations at the Moyers Symposium. Which speakers have appeared most often on the Symposium program? The answer to that question is not surprising—the most frequent speakers have been Lysle Johnston (8), Jim McNamara (7), Rolf Behrents (6), Bill Proffit (6) and Christian Stohler (5); Lee Graber, Katherine Vig, David Sarver, Birte Melsen and David Hatcher have appeared as speakers four times. Many others have appeared three times, including Bob Moyers, Frans van der Linden, Tom Graber, Lorenzo Franchi, Tiziano Baccetti, Sunil Kapila, Vince Kokich, Bob Scholz, Chester Wang, Hans Pancherz, Harold Slavkin and David Sackett. Numerous other experts have either appeared as speakers or discussants over the years— Shelly Baumrind, Jos Dibbets, Mike Riolo, Charles Burstone, Bob Isaacson, Pat Turley, Gene Roberts, Peter Vig and Ravi Nanda to name a few. THE FIRST DECADE OF MOYERS SYMPOSIA When the Moyers Symposium began, the first few meetings focused on the mechanisms of craniofacial growth and adaptation: 1974: Control Mechanisms in Craniofacial Growth 1975: Determinants of Mandibular Form and Growth 1976: Factors Affecting the Growth of the Midface 1977: Biology of Occlusal Development 1978: Muscle Adaptation in the Craniofacial Region 1982: Clinical Alteration of Craniofacial Growth The early symposia featured luminaries who became legends in orthodontics such as Alexandre Petrovic and Arne Björk (Fig. 10), Tom Graber and Coenraad Moorrees (Fig. 11), as well as Robert Ricketts, Egil Harvold, Don Enlow, Melvin Moss, William Bell, Bruce Epker, Frans van der Linden and Bill Proffit. It should be noted that during this period, functional jaw ortho- pedics (particularly the Fränkel appliance, the bionator and the Herbst appliance) were making their way into the orthodontic scene. In addi- tion, orthognathic surgery was becoming much more sophisticated 16 McNamard Figure 10. Polaroid photo of Alexandre Petrovic (left) and Arne Björk, two of the featured speakers at the third Moyers Symposium concerning Factors Influencing the Growth of the Midface. - º Figure 11, Polaroid photo of (left to right) Tom Graber, Bob Moyers and Coenraad Moorrees taken at the fourth Moyers Symposium on the Biology of Occlusal Development. 17 Reflections on the Moyers Symposium with the emergence of the LeFort | osteotomy and the bilateral sagittal split osteotomy; two-jaw surgery also was becoming a viable treatment option. During the same period, the topics considered at the symposia broadened to include presentations by experts from related disciplines. 1979: Naso-respiratory Function and Craniofacial Growth 1980: Psychological Implications of Facial Form 1981: Effects of Surgical Intervention on Craniofacial Growth 1983: Malocclusion and the Periodontium Of particular interest was the 1979 Symposium that considered the relationship of nasal obstruction, large tonsils and allergies to the growth of the face. The form-function relationship was becoming topi- cal, with much discussion in the medical and dental communities as to whether altered respiratory function was a subject relevant to the practi- tioner. Featured speakers included ENT physician Charles Bluestone and allergist William Solomon, as well as orthodontist Sten Linder-Aronson from Sweden, physiologist Donald Warren from North Carolina and or- thodontist Egil Harvold and physiologist Arthur Miller from UCSF. Col- laborations established at this meeting led to joint studies between the Children's Hospital of Pittsburgh and our group at Michigan. THE SECOND DECADE OF MOYERS SYMPOSIA 1984: Developmental Aspects of Temporomandibular Disorders One of the most highly attended Moyers Symposia was held in 1984, when the topic of Developmental Aspects of Temporomandibular Disorders was considered. It should be noted that this meeting was held three years before the “infamous” malpractice case that resulted in a judgment of one million dollars against a Michigan orthodontist. This meeting marked the beginning of an increased interest in the temporomandibular joint (TMJ) region. Speakers included Alfred Crompton, a comparative zoologist from Harvard, prosthodontist William Solberg from UCLA, Birgit Thilander from Sweden, Jos Dibbets from the Netherlands, Arthur Storey from Toronto and Bob Moyers. 1985: Science and Clinical Judgment in Orthodontics 1990: Clinical Research as the Basis of Clinical Practice 18 McNamara In retrospect, another pivotal meeting was the 1985 Symposium entitled Science and Clinical Judgment in Orthodontics. For the first time, the topic of evidence-based practice was discussed at the Symposium and for all practical purposes in mainstream orthodontics. Bob Moyers receives full credit for this meeting, as is described in the chapter in this volume written by David Sackett (2014). Sackett is a Canadian physician and a pioneer in evidence-based medicine. He founded the first department of clinical epidemiology in Canada at McMaster University and the Oxford Centre for Evidence-Based Medicine. He and fellow physicians Alvan Feinstein and David Ransohoff appeared on the 1985 program, with Sackett chiding the orthodontic specialty for its lack of understanding of evidence-based medicine (Sackett, 1985). Also appearing on the program were Coenraad Moorrees from Forsythe, Lysle Johnston from St. Louis and Peter Vigfrom Michigan. Much interesting discussion occurred during and after this meeting. Sackett would return nine years later to evaluate the progress of our specialty in this regard. The topic of evidence-based practice was addressed again at the 1990 Symposium. The meeting was headlined by June Osborn, Dean of the School of Public Health at Michigan, who spoke on the clinical application of knowledge, especially as it affected the AIDS epidemic (then, a very hot topic). Other speakers included Ronald Marks from Florida on clinical epidemiology from a statistical standpoint, orthodontist Peter Vig from Michigan, dentist and clinical psychologist Sam Dworkin from Washington, orthodontist Bill Shaw from Manchester, England and craniofacial biologist Harold Slavkin from The University of Southern California who spoke on moral and ethical issues in craniofacial biology. 1986: Craniofacial Growth During Adolescence 1987: Craniofacial Morphogenesis and Dysmorphogenesis 1988: Orthodontics in an Aging Society 1989: Craniofacial Growth and Orthodontic Treatment 1991: Bone Biodynamics in Orthodontic and Orthopedic Treatment & 1993: Biological and Psychological Aspects of Orofacial Pain Much of the first decade of the Symposium focused on the broad question of what makes the face grow, especially at the mechanistic level. The later part of the 1980s dealt in part with growth and treatment of the adolescent as well as of the then presumably “non-growing” 19 Reflections on the Moyers Symposium adult. The landmark work by Rolf Behrents was presented at the 1988 Symposium on Orthodontics in an Aging Society. It was about this time that dentistry in general was experiencing a dramatic increase in the treatment of the dentally and medically compromised patients. Behrents' work demonstrated clearly that the face never stops changing, only remodeling at a much slower rate than observed during the pubertal growth spurt. 1992: Esthetics and the Treatment of Facial Form The general topic of facial esthetics was considered from an expansive perspective, perhaps the broadest interdisciplinary approach ever taken at the Moyers Symposium. The first speaker was Rudolph Arnheim from the Department of the Psychology of Art at Harvard. He was followed by art historian Clifton Olds from Bowdoin College in Maine, who talked about the evolution of the concepts of facial beauty overthree millennia. Sheldon Peck and Bob Moyers spoke about facial esthetics from an orthodontic perspective and philosopher William Taschek from Ohio State talked about the notion of the grotesque. The final four speakers (surgeons Stephen Cohen, Bruce Epker, Douglas Ousterhaut and Henry Kawamoto) addressed treatment of facial deformities from a surgical perspective. 1992 marked the first time that a registration fee was charged to attend the Moyers Symposium, which is amazing in that the Symposium was in its 19th year of existence. Until that year, the cost of the Symposium was underwritten by the financial support of the Primack family, by sales of the CGS and by a modest annual contribution from the CHGD. For many years, additional contributions that were used to support the meeting were generated by donations to the “Friends of the Symposium” fund. THE THIRD DECADE OF MOYERS SYMPOSIA 1994: Orthodontic Treatment: Outcome and Effectiveness The first Symposium of the third decade saw a return to the general topic originally considered in 1985—the evidence-based prac- tice. The keynote speaker was David Sackett (1994a,b) who reviewed 20 McNamard the progress made by our specialty with regard to randomized controlled trials (RCTs) in orthodontics. He provided a commentary on the salutary methodological evaluation that had occurred since his last visit to Ann Arbor. Sackett was encouraged by the progress made in orthodontic clinical research and noted specifically the highly sophisticated methods employed in RCTs. Lysle Johnston then discussed alternative experimental designs that were of use in answering questions not appropriate for RCTs. Other orthodontic speakers (Sheldon Baumrind, Stephen Keeling, Camilla Tulloch and Joseph Ghafari) reported on the outcomes of the first RCTs in orthodontics. David Kinser reported the findings of the lowa study of temporomandibular dysfunction and Katherine Vig discussed the development of appropriate orthodontic outcomes. The discussions at this Symposium were important in helping focus future research efforts in orthodontics. 1995: Orthodontic Treatment: The Management of Unfavorable Sequelae 1996: Creating the Compliant Patient 1998: Growth Modification: What Works, What Doesn’t and Why 1999: The Enigma of the Vertical Dimension 2001: Treatment Timing: Orthodontics in Four Dimensions 2003: Growth and Treatment: A Meeting of the Minds The six Symposia listed above generally considered the topic of orthodontic treatment. Most of the speakers were the leading orthodon- tic experts on the particular topic being considered. Speakers from other disciplines, however, always were included. For example, for the 1995 Symposium on unfavorable sequelae, psychologist Peter Frensch from the Max Planck Institute in Berlin was the featured speaker; he spoke on why people make mistakes. Attorney Richard Small discussed the medico-legal implications of such occurrences. The 1996 meeting on patient compli- ance featured psychologist Ann Peterson from Minnesota (who gave the first Robert E. Moyers Memorial Lecture), psychologist Lynn Cooper from Missouri, pediatrician Susan Jay from Loyola in Chicago and pediatrician David Rosen from Michigan, all of whom addressed various aspects of the adolescent patient/provider relationship. 21 Reflections on the Moyers Symposium 1997: Advances in Craniofacial Orthopedics: Tissue Engineering, Regeneration and Distraction Osteogenesis This highly interdisciplinary Symposium dealt with advances in tissue engineering and distraction osteogenesis (DO). Featured speakers included Joseph Vacante, a surgeon-scientist in the field of pediatric Surgery and transplantation surgery from Harvard who gave a broad overview concerning tissue engineering. Mikhail Samchukov from Dallas, Fernando Molina from Mexico and Suzanne McCormick and Barry Grayson from New York presented their work on DO. Anatomist Bruce Carlson, biologist David Mooney and periodontist Martha Somerman from Michigan and physician Steven Cohen also gave presentations on advances in tissue engineering, opening the way for fruitful areas of research that would be discussed at future Symposia and Presymposia. 2000: Frontiers of Dental and Facial Esthetics Another pivotal Symposium was the 2000 Symposium that con- sidered dental and facial esthetics from an interdisciplinary perspective. The 5th Moyers Memorial Lecture was delivered by Vincent Kokich Sr., from Washington. He presented an approach to understanding and cre- ating anterior dental esthetics. He was followed by periodontists Pres- ton Miller from Cincinnati and prosthodontist Jörg Strub from Freiburg, Germany. They were succeeded by Eugene Roberts from Indiana who discussed dental implants as anchorage in orthodontics. The program concluded with presentations in the treatment of dentally complex pa- tients by prosthodontists Frank Spear from Seattle and Maurice Salama from Atlanta. This meeting reinforced the importance of interdisciplin- ary treatment for the adult patient with wide-ranging dental and medical conditions. 2002: Clinical Orthodontics and Information Technology The first Symposium to address advances in technology occurred in 2002, the 29th Moyers Symposium. A technology overview was deliv- ered by Richard Walker, an early innovator in developing diagnostic and treatment planning programs for the orthodontist and the surgeon. Oth- er papers included presentations on using technology in the orthodontic practice, three-dimensional (3D) digital models, the recent introduction of cone-beam computed tomography (CBCT), motion animation of den- tofacial structures and the virtual patient. This meeting recognized the 22 McNamard paradigm shift about to take place in the everyday orthodontic practice, one that certainly has been realized a decade later. THE FOURTH DECADE OF MOYERS SYMPOSIA 2004: Implants, Microimplants, Onplants and Transplants 2007: Microimplants as Temporary Anchorage in Orthodontics There were several overriding themes during the fourth decade of the Moyers Symposium, one of which was the use of implants and temporary anchorage devices (TADs) in orthodontic treatment. The 2004 Symposium was the first meeting that was devoted to this general topic. The Moyers Memorial Lecture was given by Eugene Roberts from Indiana who addressed the biology of osseointegration and tissue engineering. He was followed by Birte Melsen from Denmark, Hee-Moon Kyung from Korea and Frank Celenza from New York. William Hohlt then described the use of onplants in orthodontic treatment. The final two speakers, Hans- Ulrik Paulsen and William Northway, spoke about autotransplantation of teeth, a technique used infrequently in North America. Three years later, the Moyers Symposium focused on the use of TADs in orthodontic treatment. Several of the 2004 speakers were invited back (Melsen, Kyung and Roberts). Others included Axel Bumann from Germany, Hyo-Sang Park from Korea and Shou-Hsin Kuang from Taiwan. Jason Cope from Dallas and Sarandeep Huja from Ohio also spoke. The most innovative presentation was that of Hugo De Clerck from Belgium who described the use of skeletal bone anchors (plates) and elastics in the treatment of Class Ill malocclusion. 2005: Digital Radiography and Three-dimensional Imaging 2012: CBCT in Orthodontics: Indications, Insights & Innovations The topics of digital radiography and 3D imaging were revisited twice during the fourth decade. The two CBCT Symposia brought to- gether a wide range of experts on digital imaging. In 2005, radiologist David Hatcher discussed State-of-the-art digital imaging in his Moyers Memorial Lecture; he then gave a second presentation the following morning on CBCT in orthodontic practice. Also presenting was radiolo- gist Sharon Brooks from Michigan who spoke about radiation dosage. Other speakers included Robert Scholz, IT guru Chester Wang, Joseph 23 Reflections on the Moyers Symposium Caruso, James Mah from California and radiologist Jacques Friel from France. The keynote speaker for the 2012 meeting was Sunil Kapila who addressed the controversy surrounding the use of CBCT in routine orthodontic practice. A number of radiologists also were on the program, including Alan Farman and William Scarfe from Louisville, Christos Angelopoulos from New York, Bernard Friedland from Harvard, Michael Vannier from Illinois and David Hatcher from California. Featured orthodontic speakers were Birte Melsen from Denmark, Aaron Molen from California and Lucia Cevidanes from Michigan. 2011: Taking Advantage of Emerging Technologies in Clinical Practice A further discussion of the digital revolution occurred at the 2011 Symposium entitled, Taking Advantage of Emerging Technologies in Clinical Practice. A wide-ranging discussion of this topic that is relevant to the practitioner in private practice ensued and included presentations on cyber infrastructure, the future of healthcare delivery technology (by a senior strategist from Microsoft), the electronic patient record, search engine optimization, social and business networking, mobile computing, VolP and cloud computing. 2006: Early Orthodontic Treatment: Is the Benefit Worth the Burden? 2008: Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus 2009: Surgical Enhancement of Orthodontic Treatment 2010: Effective and Efficient Tooth Movement The topics considered in the remaining five Symposia again addressed areas of focus in the early 21 century, including many reoccurring topics such as one- vs. two-phase treatment, TMD and orofacial pain, corrective jaw surgery and other surgical esthetic enhancements, as well as consideration of new orthodontic appliance systems. The discussions emanating from these meetings included many of the new approaches and technologies that have been of interest to researchers and clinicians in orthodontics, dentofacial orthopedics and craniofacial biology for many years. 24 McNamara At the 2006 Symposium, Katherine Vig delivered the Eleventh Annual Robert E. Moyers Memorial Lecture following her return from Oxford University where she collaborated with the Cochrane Oral Health Group. She discussed the methodology of systematic reviews and critical appraisal of the literature in the hierarchy of an evidence-based approach to clinical practice ten years after the results from the Class || RCTs. A review of early treatment interventions continues to remain controversial in spite of an evidence-based approach. 2013: The 40th Moyers Symposium: Looking Back ... Looking Forward The 40th Moyers Symposium, the transactions of which can be found in this volume, was an appropriate celebration of the long history of this landmark event. Extending the Symposium to three days, we invited nineteen previous speakers to return to Ann Arbor to bring us up to date with the latest advances in their respective areas of interest. This year marked the introduction of the poster presentation and the junior investigator travel awards competition that will become an annual part of future Symposia. We also held a special Saturday night reception in the skyboxes of the newly renovated Michigan Stadium, a fitting celebration of the longevity of the Moyers Symposium. FINAL REMARKS It has been my privilege to be a part of the Moyers Symposium for the last 40 years. We have witnessed the growth of our specialty and the birth of the field of craniofacial biology firsthand. We at Michigan have been able to meet in a friendly venue, enjoy a stimulating scientific program and reunite with friends and colleagues from throughout the world. Typically, hundreds of residents from across North America attend the Symposium each year as an introduction to their future in orthodontics. Attending the Moyers Symposium has been an incredibly Special experience for all. One of the fortunate aspects of the Symposium is the networking that naturally has occurred over the last four decades. We have been able to identify critical issues of broad interest and then seek out those individuals worldwide who could provide answers to the questions being raised. The professional and personal relationships that have been forged 25 Reflections on the Moyers Symposium have lasted a lifetime. Listening to leading clinicians and scientists present their data and perspectives and then reading their written material have allowed each Symposium to live on through the years. The Moyers Symposium is a unique event. We celebrate its long history by looking back to determine how orthodontics and craniofacial biology have evolved over the last four decades. We look forward in an attempt to prognosticate where we will be as clinicians and researchers after 40 more years of Moyers Symposia. It has been a fun and productive ride thus far. REFERENCES Behrents RG. The past as present: What have we learned about facial growth? In: McNamara JA Jr, ed. Growth and Treatment: A Meeting of the Minds. Monograph 41, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor 2003;1-10. Clemente JD. Robert E. Moyers: OSS dentist with the Greek resistance. OSS J 2010;34–36. Dunaway J, McNamara JA Jr. Robert E. Moyers: A perspective. In: Hunter WS, Carlson DS, eds. Essays Honoring Robert E. Moyers. Monograph 24, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1992;1-26. McNamara JA Jr. Neuromuscular and Skeletal Adaptations to Altered Orofacial Function. Monograph 1, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1972;180 pages. McNamara JA Jr, ed. Control Mechanisms in Craniofacial Growth. Monograph 3, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1975. McNamara JA Jr. Robert Edison Moyers DDS PhD 1919–1996. McNamara JA Jr, Trotman CA, eds. Orthodontic Treatment: Management of Unfa- vorable Sequelae. Monograph 31, Craniofacial Growth Series, Center 26 McNamara for Human Growth and Development, The University of Michigan, Ann Arbor 1996;iii-V. Moyers RE, van der Linden FPGM, Riolo ML, McNamara JA Jr. Standards of Human Occlusal Development. Monograph 5, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1976;379 pages. Rhodes FHT. Of Craniofacial sutures and the rest of the universe: Remarks at a banquet honoring Dr. Robert E Moyers. In: McNamara JA Jr, ed. Control Mechanisms in Craniofacial Growth. Monograph 3, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1975;1-8. Riolo ML, Moyers RE, McNamara JA Jr, Hunter WS. An Atlas of Craniofacial Growth: Cephalometric Standards from The University School Growth Study, The University of Michigan. Monograph 2, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1974;371 pages. Sacket DL. The science of the art of clinical management. In: Vig PS, Ribbens KA, eds. Science and Clinical Judgment in Orthodontics. Monograph 19, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1985;237- 251. Sackett DL. Nine years later: A commentary on revisiting the Moyers Symposium. In: Trotman CA, McNamara JA Jr, eds. Orthodontic Treatment: Outcome and Effectiveness. Monograph 30, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1994a;1-5. Sackett DL. On identifying the best therapy. In: Trotman CA, McNamara JA Jr, eds. Orthodontic Treatment: Outcome and Effectiveness. Monograph 30, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1994b;7-19. Sackett DL. On the vanishing need for MD randomized trialists at Moyers symposia. In: McNamara JAJr, ed. The 40th Fortieth Moyers Symposium: Looking Back ... Looking Forward. Monograph 50, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center 27 Reflections on the Moyers Symposium for Human Growth and Development, The University of Michigan, Ann Arbor 2014;145-166. Vig KD. Early orthodontic and orthopedic treatment: The search for evidence: Will itinfluence clinical practice? In: McNamara JAJr, ed. Early Orthodontic Treatment: Is the Benefit Worth the Burden? Monograph 44, Craniofacial Growth Series, Department of Orthodontics and Pediatric Dentistry and Center for Human Growth and Development, The University of Michigan, Ann Arbor 2006;13–38. 28 EVOLUTION OF ADULT ORTHODONTICS: THE IMPORTANCE OF A REALISTIC APPROACH Vincent G. Kokich ABSTRACT Although some orthodontists use the same goals and objectives for their adolescent and adult patients, there are distinct differences between these two patient populations. Adolescent orthodontics typically involves occlusally driven, standardized treatment protocols in order to achieve an Angle Class I occlusion. Adult orthodontics typically involves restoratively driven, prescription treatment protocols in order to achieve improved tooth position for the restorative dentist. When the first Moyers Symposium was held in 1974, the percentage of adults in orthodontic treatment was small; therefore, the percentage of time that was devoted to teaching residents and dental students about adult orthodontic treatment was commensurately low as well. With the advent of bonded brackets, flexible wires, orthognathic surgery and the emphasis on esthetic dentistry that prevailed during the late 20th century, however, adults began to seek orthodontic treatment. Over the past 40 years, since the initiation of the annual Moyers Symposium, the numbers of adults being treated by orthodontists in the U.S. has increased substantially. However, the education of pre-doctoral dental students regarding the value of interdisciplinary orthodontic-restorative treatment is lacking. As an orthodontic specialty, we should recognize this deficiency in pre-doctoral dental education and make a concerted effort to upgrade the information that we provide to our future restorative dental colleagues. This chapter will delineate the differences between adult and adolescent orthodontic treatment and to illustrate several problems with adult tooth position that present themselves to the general dentist and can be ameliorated with adjunctive orthodontic treatment. KEY words: adult orthodontics, pre-doctoral orthodontic education, pre- prosthetic orthodontics, restoratively driven treatment, prescription treatment protocols 29 Evolution of Adult Orthodontics INTRODUCTION I was among a select group of individuals who had appeared on one or more of the previous Moyers Symposia and was invited to provide a retrospective assessment on a specific area of orthodontics and how it had changed during the 40 years since the first Moyers Symposium in 1974. I chose the topic of adult orthodontics. When I graduated from my orthodontic residency in the mid- 1970s, the percentage of adults in orthodontic treatment was small. Therefore, the percentage of time that was devoted to teaching residents and dental students about adult orthodontic treatment was commensu- rately low as well. However, with the advent of bonded brackets, flexible wires, orthognathic surgery and the emphasis on esthetic dentistry that prevailed during the late 20th century, adults began to seek orthodontic treatment. Today, we are well into the second decade of the 21st century and the percentage of adults in orthodontic treatment has exceeded 25%; in some orthodontic practices, over 40% of the patients are adults. But one aspect that has not changed is how orthodontic departments teach pre-doctoral dental students about the benefits of orthodontic treatment. Most of the information that is transmitted to undergraduate dental students is about children and adolescents. The majority of pre- doctoral dental students are unaware of the benefits of pre-restorative orthodontics. Therefore, I would like to use this chapter to delineate the differences between adult and adolescent orthodontic treatment and to illustrate several problems with adult tooth position that present them- selves to the general dentist and can be ameliorated with adjunctive Orthodontic treatment. ADOLESCENT VERSUS ADULT ORTHODONTICS Adolescents comprise the majority of patients treated by most orthodontists. When an adolescent presents for orthodontic therapy, s/he typically has problems that could include dental crowding, excess overjet, excess overbite, posterior crossbite and an Angle Class II or Class Ill malocclusion. However, most of these adolescents also have few restorations, little or no tooth wear, no periodontal disease, no missing teeth and a limited dental history. As a result, orthodontists 30 Kokich usually prescribe a standard treatment protocol with the primary goal of providing an Angle Class I occlusion with well-aligned teeth. Therefore, the diagnosis and subsequent treatment of adolescent orthodontic patients typically is driven occlusally. When adults present for orthodontic therapy, they may have the same underlying problems of dental crowding, excess overjet, excess overbite, posterior crossbite and Class Il or Ill malocclusion, but they are much different dentally than adolescents. Adults often have multiple restorations, significant tooth wear, periodontal disease, missing teeth and an extensive dental history; therefore, it is inappropriate to propose standard treatment protocols for adults. Adult orthodontic patients require prescription treatment with the goal of improving tooth position, not necessarily achieving an Angle Class I occlusion. As a result, adult orthodontic treatment plans are driven restoratively, not occlusally. Attempting to treat an adult with an occlusally driven standardized treatment protocol could result in an inappropriate outcome that could hamper rather than help the restorative dentist. In order to illustrate how to choreograph restoratively driven treatment protocols, the remainder of this chapter will illustrate ten common dental problems that exist in adult patients requiring restorative dentistry. For each of these problems, I will explain and document how adjunctive orthodontics, managed in an interdisciplinary manner, can help the general dentist to produce exceptional restorative outcomes for their adult patients. EXTENSIVE ANTERIOR TOOTH WEAR Many adult restorative patients have maxillary and/or mandibular anterior tooth wear that has been caused by aberrant occlusal habits Such as protrusive bruxing (Fig. 1A-C). As teeth wear, they tend to erupt in order to maintain occlusal contact with the opposing arch. As a result, when a restorative dentist is faced with treating an adult patient with extensive anterior tooth wear and compensatory eruption, the crowns of the teeth are short and appear unesthetic. How does a restorative dentist rehabilitate the patient and provide normal tooth proportions? One option is crown lengthening (Sonic, 1997; Nemcovsky et al., 2001; Fletcher, 2011). However, crown 31 Evolution of Adult Orthodontics lengthening typically requires periodontal flap surgery, removal of bone and apically positioning the flap to expose the root of the tooth in order to create adequate crown length. Once the root is exposed, the restoration of this tooth becomes more complicated and typically requires a full crown rather than a veneer. A full-crown restoration of an abraded anterior tooth would require 2 mm of incisal reduction to create adequate thickness of porcelain at the incisal edge for strength of the restoration. This additional 2 mm of tooth reduction could result in infringement on the pulp of a significantly abraded tooth and, in some cases, could require root canal therapy in order to restore the tooth adequately. The other option for treating the patient with extensive anterior tooth wear is to reverse the compensatory eruption by intruding these teeth orthodontically (Kokich, 1993, 2003; Spear et al., 2006). This movement is accomplished by estimating the eventual desired tooth length prior to treatment. A good landmark to use when intruding maxillary incisors is to assess the gingival margin levels of the incisors relative to the canines. If the canines are not worn or abraded, then their gingival margin level can be used as a guide to positioning the maxillary central incisors and lateral incisors. In an unworn dentition, the central incisor and canine gingival margins typically are located at the same level. So, the clinician easily can estimate the amount of tooth intrusion necessary prior to beginning orthodontic therapy. Once this knowledge has been ascertained, the orthodontist should place the brackets on the worn teeth nearer the incisal edge in order to facilitate intrusion of the incisors during the early stages of the orthodontic treatment (Fig. 1D). As the teeth intrude gradually, the gingival margin levels are used as the guide for how much to intrude the abraded incisors (Fig. 1E). Once the incisors have been intruded sufficiently, their abraded edges can be restored to appropriate length temporarily with a bonded restorative composite restoration (Fig. 1F-G), in order to establish the final orthodontic tooth position adequately. However, this newly established tooth position is unstable ini- tially. As these teeth are intruded, the principal fibers of the periodon- tal ligament become oriented obliquely due to the intrusion. Re- searchers have shown that this change in principal fiber orientation is 32 Kokich G H. - | Figure 1. This adult male had significant maxillary incisal wear resulting in short teeth, due to his protrusive bruxing habit (A-C). As a result, orthodontics was necessary to intrude the maxillary incisors (D-E), so the dentist could restore the tooth length temporarily with composite (F-G) and eventually with porcelain Veneers (H-1). temporary and eventually will become reoriented with time (Reitan, 1967). Although we do not know how long this accommodation process takes in humans, it is estimated that it could take six to twelve months. Therefore, these intruded incisors must be held in position either with the orthodontic brackets and wires or some sort of retainer to prevent re-eruption of these teeth during the time that the periodontal fibers are undergoing reorientation. It is wise to accomplish this type of intrusion at the start of Orthodontic therapy, during the leveling and aligning process. This early movement allows for stabilization to occur during the finishing stages of the orthodontics, while the brackets and wires still are in place. This type of tooth movement also can be accomplished with removable plastic aligners that are not as versatile as brackets and wires, but do have the capability to intrude teeth efficiently. 33 Evolution of Adult Orthodontics Forty years ago, when adult orthodontic treatment was not common, this type of interdisciplinary management of extensive anterior tooth wear was not possible; now, however, it is. The problem is that most pre-doctoral dental students are not shown examples of this type of treatment during their dental education. Therefore, many general dentists in private practice are unaware of the benefits of orthodontics for treating patients with extensive anterior tooth wear. This type of interdisciplinary dental care should be an integral part of pre-doctoral dental education. POSTERIOR TOOTH EROSION Some adults suffer from gastroesophageal reflux and, as a result, the pH of their saliva becomes acidic. If this problem is not detected at an early stage, the integrity of the enamel crowns will be jeopardized and these individuals eventually will have varying degrees of erosion of the occlusal surfaces of their posterior teeth (Donovan, 2009; Curtis et al., 2011; Ranjitkar et al., 2012). As these occlusal surfaces become eroded, the teeth gradually erupt in order to maintain contact with the opposing dental arch. With time and significant erosion, an individual could lose 2 mm or more of the occlusal surface of posterior teeth, often exposing the underlying dentin. Eventually, if the problem is recognized and the restorative den- tist plans to restore the occlusal surfaces with porcelain or gold onlays or crowns, the dentist must prepare these posterior teeth for the res- torations by reducing an additional 2 mm to create adequate strength for the restorative materials. If a tooth already has eroded 2 mm and an additional 2 mm of tooth reduction is necessary, the tooth preparation may become too short to provide adequate retention for the restoration. In these cases, it is possible to perform periodontal crown lengthening by elevating a flap, removing alveolar crestal bone and apically positioning the flap. However, when the eroded teeth are molars, the crown length- ening is complicated by the location and position of the root furcation of the molar. Another option for dealing with this difficult situation is to consider intrusion of the eroded and over-erupted molar (Kokich and Spear, 1997) in order to provide restorative space for the dentist and to 34 Kokich eliminate the need to remove additional enamel and dentin during tooth preparation (Fig. 2). Typically, the teeth that have super-erupted can be identified easily by evaluating a bitewing radiograph of the posterior teeth (Fig. 2C,D). If the patient has a healthy periodontium, there will be a crestal bone level discrepancy between the super-erupted tooth and the adjacent non-eroded teeth. Therefore, as the tooth is intruded orthodontically, the bone level on the intruded tooth/teeth will become level relative to the adjacent teeth (Fig. 2E-H). This type of change will improve the probing sulcus depths between adjacent teeth and make these areas more accessible for the patient to maintain a plaque- free environment. In addition, the dentist will not have to reduce the occlusal surface of the tooth further, thereby reducing the possibility of encroaching on the pulp of the tooth (Fig. 2H, I). This type of interdisciplinary treatment can result in a much better restorative situation for the general dentist and a less destructive repair for the patient. Is this type of treatment possibility being taught to pre-doctoral dental students? The management and restoration of posterior tooth erosion is extremely challenging to a restorative dentist. However, collaborative treatment with orthodontic intrusion of eroded posterior teeth produces a much easier situation for the restorative dentist to resolve. Pre-doctoral dental students should be exposed to this treatment possibility during their training. REDUCED VERTICAL DIMENSION Many adults present to the general dentist with significant man- dibular anterior tooth wear due to abnormal parafunctional habits (Fig. 3). As the mandibular incisors become abraded, they tend to continue to erupt to maintain occlusal contact. Eventually, if the abrasion is sig- nificant, the restorative dentist may suggest restoration of these abraded teeth (Fig. 3B). But how does the restorative dentist obtain inter-occlusal Space to restore severely abraded mandibular incisors? One option is to restore all of the posterior teeth and open the patient's vertical dimension of occlusion. Although restoring the pos- terior teeth is a common treatment for this type of situation, there are some problems that could be encountered with this approach. First of all, the posterior teeth may not be restored nor need restoration. Is it 35 Evolution of Adult Orthodontics Figure 2. This adult female had an Angle Class III malocclusion (A-B) that required maxillary surgical advancement. However, she had significant enamel erosion (C- D) due to gastroesophageal reflux. In order to provide restorative space for her eroded mandibular molars, these teeth were intruded during the pre-operative orthodontic phase (E-F) so that they could be restored following the completion of orthodontic treatment (G-1). judicious and/or appropriate to restore non-restored teeth simply to provide inter-occlusal space to restore abraded mandibular incisors? Another problem with opening the vertical dimension with pos- terior restorations is that the outcome may be unstable. Previous re- search has shown that orthognathic surgery to increase posterior vertical dimension is relatively unstable (de Mol van Otterloo et al., 1996; Major et al., 1996). With time, the vertical facial height tends to return to its original dimension. Although the reason for the relapse in these situa- tions is not understood clearly, it likely is due to the incapability of the masticatory muscle fibers to accommodate to increased length in adults easily. An additional possibility for increasing anterior vertical dimen- sion to facilitate restoration of abraded mandibular incisors is to con- sider mandibular surgery. This type of surgery is accomplished with a 36 Kokich Figure 3. This adult male had an extremely deep anterior overbite (A) and vertical bruxing habit that produced significant labial wear of his mandibular incisors (B). His upper lip was well related to the maxillary incisal edges (C), so the overbite was due to mandibular incisor over-eruption. The mandibular incisors were restored temporarily with composite (D), bracketed (E) and intruded (F-H) in Order to correct the impinging overbite and permit restoration of the teeth (l). Sagittal split ramus osteotomy and a downward rotation of the distal fragment of the mandible during the surgical procedure (Kokich, 2008). If the surgery is accomplished in this manner, the posterior teeth remain in contact, but the downward rotation of the distal fragment of the mandible creates an opening of the anterior vertical dimension and Space to restore the abraded mandibular incisors. This type of surgery typically requires that an exaggerated curve of Spee is produced before the Surgery. The curve of Spee is leveled by extruding the premolars after the surgery. This type of increase in anterior vertical dimension does not increase posterior vertical dimension and, therefore, does not affect the masticatory muscle fibers and results in a stable correction. Another approach to opening the anterior vertical dimension is to intrude the maxillary incisors, the mandibular incisors or both in order 37 Evolution of Adult Orthodontics to create restorative space. How does one determine if tooth intrusion is a viable alternative? This type of diagnostic evaluation (Kokich, 2008) should be taught to all pre-doctoral dental students in order to help them understand how to manage vertical dimension problems in their patients. The first step in assessing vertical dimension problems is to es- tablish the functional esthetic occlusal plane for the patient. This occlusal plane can be assessed either on a cephalometric headfilm or by using dental casts mounted on an articulator. A mark is placed on the occlusal cusp of the distal-most mandibular molar on the cephalometric radio- graph. Why on this molar? Because this position is difficult to change vertically, due to the factors mentioned previously regarding muscle fiber length. A second mark is placed on the patient's upper lip. Why the upper lip? Because this landmark is unable to be changed and, at the end of treatment, we would like to produce a change in vertical dimension that still will keep the maxillary incisor in an esthetically acceptable position relative to the upper lip. Once these two marks have been established, then a line is drawn to connect these two marks. I define this as the functional-esthetic occlusal plane. - The next step is to determine the relationship of the maxillary incisor to the functional esthetic occlusal plane. Is it above, below or at its appropriate level commensurate with the age of the patient? In the example shown in Figure 3, the patient is 55 years of age. Most individuals at this age would show 1 mm of the maxillary incisal edge at rest. In this patient, the maxillary incisal edge is at the level of the lip. Therefore, for this patient, intrusion of the maxillary incisors to open the anterior vertical dimension would be inappropriate because it would affect the maxillary incisal display negatively at rest. Next evaluate the position of the mandibular incisal edge relative to the occlusal plane. Ideally, the mandibular incisal edge should be touching either the occlusal plane or perhaps be 1 mm above that line. In this example, the mandibular incisal edge is 5 mm above the occlusal plane (Fig. 3C); therefore, the problem is the over-eruption of the mandibular incisor. The solutions either are to intrude the mandibular incisor orthodontically or to perform mandibular jaw surgery to rotate the 38 Kokich mandible downward to increase anterior vertical dimension, followed by eruption of the premolars. How does one select the appropriate solution? If a surgical approach is chosen, the end result will lengthen the patient's anterior facial height and, therefore, change the balance between upper and lower facial proportions. In order to determine if Surgery is appropriate, one must measure and calculate the current upper and lower facial proportions. In Figure 3, the facial balance for this patient currently is satisfactory or within a normal range. Therefore, surgery to lengthen the anterior facial height would be inappropriate. So, in this patient, mandibular incisor tooth intrusion was chosen as the Solution. To facilitate the attachment of brackets to the teeth and intrude the mandibular incisors, these teeth first required provisional restoration with composite (Fig. 3D). Temporary composite build-ups were placed on the posterior teeth to create sufficient space to restore the mandibular incisors and facilitate bracket placement. In this example, it took nearly a year to intrude the mandibular incisors 5 mm (Fig. 3E-1). However, this movement was the appropriate solution for this patient because it did not affect the esthetic relationship between the maxillary incisors and the upper lip negatively during and after the treatment. These types of reduced vertical dimension situations are common among adult restorative patients. Do pre-doctoral dental students receive the appropriate knowledge during their training to accomplish the proper diagnosis of these cases in order to choreograph the interdisciplinary solution to this problem? This type of knowledge should be a requirement in pre-doctoral dental education. FRACTURED TEETH Occasionally, adults will injure an anterior tooth accidentally due to trauma. If the injury is minor and results in a small fracture of enamel, the fracture can be restored with light-cured composite or porcelain veneers. However, in some situations, the fracture may extend beneath the level of the gingival margin and terminate at the level of the alveolar ridge. In these situations, restoration of the fractured crown is impossible because the tooth preparation would extend to the level of the bone. This over-extension could result in an invasion of the biologic width of the tooth and cause persistent inflammation of the marginal gingiva. In these 39 Evolution of Adult Orthodontics situations, it may be beneficial to erupt the fractured root out of the bone and move the fracture margin coronally so that it can be restored without creating gingival inflammation (Kokich, 2002). In some situations, however, if the fracture is too severe, it may be better to extract the tooth and replace it with an implant or bridge. The orthodontist, restorative dentist and periodontist should evaluate six criteria to determine if the tooth should be erupted or extracted forcibly (Kokich, 2002). The first criterion is root length. Is the root long enough so that a 1:1 crown-root ratio will be preserved after the root has been erupted? In order to determine the answer to this question, the clinician must know how far to erupt the root. If a tooth fracture extends to the level of the bone, it must be erupted 4 mm. The first 2.5 mm will move the fracture margin far enough away from the bone to prevent a biologic width problem. The other 1.5 mm will provide the proper amount of ferrule for adequate resistance form of the crown preparation. Therefore, if the root were fractured to the bone level and must be erupted 4 mm, the clinician must evaluate a periapical radiograph and subtract 4 mm from the end of the fractured tooth root. Then the length of the residual root should be compared with the length of the eventual crown on this tooth. The root- to-crown ratio should be about 1:1; it is less than this amount, too little root may remain in the bone for stability. In the latter situation, it may be more prudent to extract the root and place a bridge or implant. Root form is the second criterion that determines whether forced eruption is feasible. The shape of the root should be broad and non-tapering rather than thin and tapered, which will provide a narrower cervical region after the tooth has been erupted 4 mm and could compromise the esthetic appearance of the final restoration. The internal root form also is important. If the root canal is wide, the distance between the external root surface and root canal filling will be narrow. In these situations, the walls of the crown preparation will be thin, which could result in early fracture of the restored root. The root canal should not be more than a third of the overall width of the root. In this way, the root still could provide adequate strength for the final restoration. 40 Kokich A third criterion that determines whether a fractured root should be erupted is the level of the fracture. If the entire crown is fractured 2-3 mm apical to the level of the alveolar bone, it is difficult, if not impossible, to attach to the root in order to facilitate eruption. The fourth criterion is the relative importance of the tooth. If the patient was 70 years of age and both adjacent teeth had prosthetic crowns, then it could be more prudent simply to construct a bridge attaching to the crowned teeth. However, if the patient was 15 years of age and the adjacent teeth were unrestored, then forced eruption would be much more conservative and appropriate. The fifth criterion to evaluate prior to beginning forced eruption of a fractured root is esthetics. If the patient has a high lip line and shows 2-3 mm of gingiva when smiling, then any type of restoration in this area will be more obvious. In this situation, keeping the patient's own tooth would be much more esthetic than any type of implant or prosthetic replacement. The sixth and final Criterion to determine whether or not a tooth should be erupted is the endo/perio prognosis. If the tooth has a significant periodontal defect, it may not be possible to salvage the root. In addition, if the tooth root has a vertical fracture, then it is hopeless and must be extracted. If all of these factors are favorable, then forced eruption of the fractured root is indicated (Fig. 4). The orthodontic mechanics necessary to erupt the tooth could vary from elastic traction to orthodontic banding and bracketing. If a large portion of the tooth still is present, then orthodontic bracketing will be necessary. If the entire crown has fractured leaving only the root, then elastic traction from a bonded bar may be possible. The tooth root may be erupted rapidly or slowly. If the movement is performed rapidly, the alveolar bone will be left behind temporarily and a circumferential fiberotomy may be performed to prevent bone from following the erupted root. However, if the root is erupted slowly, the bone will follow the tooth. In this situation, the erupted root will require crown lengthening and an apically positioned flap to expose the correct amount of tooth to create the proper ferrule, resistance form and retention for the final restoration. 41 Evolution of Adult Orthodontics G H I - - Figure 4. This adult female fractured her maxillary right central incisor just below the level of the gingiva (A-B) and there was insufficient tooth remaining to support a crown. Root canal therapy was performed (C), the tooth was erupted (D) and the crown was equilibrated (E). Crown lengthening (F) provided an esthetic gingival margin relationship (G) and the tooth was restored with a porcelain crown (H-1). After the tooth root has been erupted, it must be stabilized to prevent it from intruding back into the alveolus. The reason for re- intrusion is the orientation of the principal fibers of the periodontium. During forced eruption, the periodontal fibers become oriented obliquely and stretched as the tooth root moves coronally (Reitan, 1967). These fibers eventually will reorient themselves after about six to twelve months. Before this time, the tooth root can re-intrude significantly. Therefore, if this type of treatment is performed, an adequate period of stabilization is necessary to avoid significant relapse and re-intrusion of the root. As the root erupts, the gingiva will move coronally with the tooth. As a result, the clinical crown length will become shorter after extrusion. In addition, the gingival margin may be positioned more incisally than adjacent teeth. In these situations, gingival surgery is necessary to cre- ate ideal gingival margin heights (Fig. 4E-G). The type of surgery varies 42 Kokich depending upon whether or not bone removal will be necessary. If bone has followed the root during eruption, the surgeon will elevate a flap and remove the appropriate amount of bone to match the bone height of the adjacent teeth. If the bone level is flat between adjacent teeth, a simple excisional gingivectomy will correct the gingival margin discrepancy. After gingival Surgery, an open gingival embrasure may exist between the erupted root and adjacent teeth (Fig. 4G). This space occurs because the narrower root portion of the erupted tooth has been moved into the oral cavity. This space may be closed in two different ways. One method involves over-contouring of the replacement restoration. The other method involves reshaping of the crown of the tooth and movement of the root to close the space. This latter method often helps to improve the overall shape of the final crown on the restored tooth (Fig. 4H). Are pre-doctoral dental students taught about the interdisciplin- ary management of a traumatized and fractured anterior tooth? This information should be an integral part of the pre-doctoral education of every dental student. LACK OF INTEROCCLUSAL SPACE Occasionally an adult restorative patient may have lost a posterior tooth either due to decay, trauma or periodontal disease. If the tooth were not replaced with an implant or bridge pontic, the teeth in the opposing arch eventually would erupt beyond the adjacent teeth and into the inter-occlusal space between the maxillary and mandibular arches (Fig. 5A-B). This dental migration creates a difficult situation for the restorative dentist who needs the inter-occlusal space to replace the missing tooth. There are two options for creating inter-occlusal space in these types of situations. One option is to equilibrate the super- erupted tooth. The other option is to intrude the super-erupted tooth orthodontically. How does the general dentist decide which option is the best for the patient? The first step is to assess the alveolar crestal bone level between the super-erupted tooth and the adjacent teeth. In a patient with a healthy periodontium, the bone level will move coronally as the tooth super erupts (Fig. 5C). Therefore, the appropriate solution is to intrude 43 Evolution of Adult Orthodontics Figure 5. This adult female had lost her mandibular second molar in an accident and the maxillary molar had over-erupted (A-B) causing a bone level discrepancy (C) between first and second molars. The maxillary second molar was intruded orthodontically (D–G), the hemiseptal defect was eliminated (H) and an implant and crown were placed to restore the missing molar (1). the tooth orthodontically, which would accomplish two objectives (i.e., to increase the inter-occlusal space and to level the alveolar crestal bone). However, if the patient has had periodontal bone loss on the affected and super-erupted tooth, then the bone level will appear flat. In this situation, tooth intrusion is inappropriate because it could create a hemi-septal defect that could compromise the patient's ability to clean inter-proximally in this area adequately. The appropriate solution in this situation is to equilibrate the super-erupted tooth to increase the inter- occlusal space. Examples of both of these potential solutions are shown in Figures 5 and 6. When the decision is made to intrude a posterior tooth, the orthodontic treatment will require sufficient anchorage to accomplish the tooth desired tooth movement. If only one posterior tooth was over- erupted, it is possible to use the adjacent teeth to intrude the affect tooth (Fig. 5D-E). The opposing teeth and the patient's occlusion typically 44 Kokich G - - H Figure 6. This adult female was missing mandibular first and second molars Causing over-eruption of the maxillary first molar (A). However, the bone level between the first molar and second premolar was flat (B). So, the crown of the first molar was equilibrated (C-E) to increase the inter-occlusal space. During the Orthodontic treatment (F-G), the flat interproximal bone level was maintained (H) So that after orthodontics, the increased interocclusal space was maintained (I). Will provide sufficient resistance to facilitate the intrusion and avoid extrusion of the adjacent teeth. If more than one tooth has over-erupted, however, it is beneficial to use temporary anchorage devices (TADs) Such as mini-screws or mini-plates to accomplish the tooth movement. In either situation, it is important to retain the intruded position of the tooth until the restoration is placed in the opposing arch, because tooth intrusion temporarily alters the orientation of the principal fibers of the periodontium, which have a tendency to cause tooth re-eruption. The other option for increasing the posterior inter-occlusal Space is to equilibrate the over-erupted tooth (Fig. 6). Equilibration is the appropriate solution if the bone levels are flat between adjacent Posterior teeth (Fig. 6B). The problem with equilibration is that it could expose the dentin on the affected tooth and, thereby, make the affected 45 Evolution of Adult Orthodontics tooth sensitive to cold stimuli or be susceptible to caries. Therefore, some equilibrated teeth could require restoration. Are pre-doctoral dental students taught how to diagnose and manage problems with inadequate posterior inter-occlusal space? These types of situations and their solution should be a part of the pre-doctoral educational training of all dental students. LACK OF BONE FOR IMPLANTS Some adult restorative patients may be missing mandibular second premolars congenitally. If the primary second molar has remained in the dental arch for several years, it could have become ankylosed and submerged. When the adjacent teeth are unrestored, the common method of replacing missing teeth is with a single-tooth implant. However, when a submerged primary molar is extracted, a vertical ridge defect will be likely and with time, the mandibular edentulous ridge will become narrower buccolingually. Although bone grafting will improve the buccolingual dimension of the edentulous ridge prior to implant placement, it often is difficult for the surgeon to ameliorate a vertical ridge defect predictably. Is there another approach for resolving this type of ridge deficiency prior to implant placement? One way of improving an alveolar ridge defect due to a missing mandibular second premolar is to consider orthodontic movement of the adjacent first premolar into the site of the missing second premolar, thereby creating adequate ridge thickness to place an implant in the first premolar site (Kokich and Kokich, 2006). When faced with this decision, clinicians often are fearful that there is insufficient alveolar ridge width in which to move the permanent first premolar. However, previous stud- ies have shown that a wider tooth root can be pushed through a narrow alveolar ridge without compromising the eventual bone support around the repositioned tooth root. Figure 7 shows a typical situation where a primary molar became ankylosed and submerged in this adult patient. The restorative dentist suggested an implant and crown, but when the primary molar was extracted, the ridge quickly narrowed buccolingually and was deficient 46 Kokich Figure 7. This adolescent male was missing his mandibular left second premolar Congenitally (A) and the primary molar was ankylosed and submerged (B), Causing a vertical bone defect after extraction (C-D). The narrow alveolar ridge (E) was enhanced by moving the first premolar distally (F-1), which created a better ridge for future implant placement. Vertically. Orthodontics was initiated to move the first premolar distally to ameliorate the ridge deficiencies. The post-treatment result shows how the buccolingual and vertical bony deficiencies were improved. During this type of movement, the pace or rate of tooth movement should be slow and no more than 0.5 mm/month to ensure that the alveolus Can remodel adequately through periosteal apposition on the labial and lingual surfaces as the tooth is moved through the edentulous ridge. In these Cases, the ridge created on the trailing side of the tooth movement typically is adequate to place an implant without bone grafting. Do pre-doctoral dental students receive information about the Orthodontic possibilities for improving alveolar ridge defects prior to implant placement? This type of treatment should be part of the pre- doctoral education of all dental students. 47 Evolution of Adult Orthodontics PERIODONTAL BONE LOSS Adult restorative patients occasionally may have underlying periodontal defects that could compromise their future dental prognosis. Although periodontists can improve and/or eliminate most of these defects surgically, some periodontal defects are more amenable to improvement by correcting tooth position orthodontically. One of these types of defects is the hemiseptal defect. Hemiseptal defects are one- or two-wall osseous defects and often are found around mesially tipped teeth or teeth that have super- erupted. These defects usually can be eliminated with the appropriate orthodontic treatment. In the case of the tipped tooth, uprighting and eruption of the tooth will level the bony defect (Kokich, 2002). In the case of the super-erupted tooth, intrusion and leveling of the adjacent cemento-enamel junctions can help to level the osseous defect. It is imperative that periodontal inflammation be controlled before orthodontic treatment. The control of inflammation usually can be achieved with initial debridement and rarely requires any pre-orthodontic surgery. After completion of orthodontic treatment, these teeth should be stabilized for at least six months and reassessed periodontally. The pocket often has been reduced or eliminated and no further periodontal treatment is needed. It would be injudicious to do pre-orthodontic osseous corrective surgery in lesions such as these, if orthodontics is a part of the overall treatment plan. In the periodontally healthy patient, orthodontic brackets are positioned on the posterior teeth relative to the marginal ridges and cusps. However, some adult patients may have marginal ridge discrepancies caused by uneven tooth eruption during orthodontic treatment. When the orthodontist encounters marginal ridge discrepancies, the decision as to where to place the bracket or band is not determined by the anatomy of the tooth. In these situations, it is important for the orthodontist to assess bitewing or periapical radiographs of these teeth in order to determine the interproximal bone level. If the bone level is oriented in the same direction as the marginal ridge discrepancy, then leveling the marginal ridges will level the bone. If the bone level is flat between adjacent teeth and the marginal ridges are at significantly different levels, however, correction of the marginal ridge discrepancy orthodontically will produce a hemiseptal defect in the 48 Kokich bone. This defect could lead to a periodontal pocket between the two teeth. In some patients, a discrepancy may exist between both the marginal ridges and the bony levels between two teeth (Fig. 8), though these discrepancies may not be of equal magnitude. In these patients, orthodontic leveling of the bone still may leave a discrepancy in the marginal ridges (Fig. 5C-E). In these situations, the clinician should not use the crowns of the teeth as a guide for completing orthodontic therapy. The clinician should level the bone orthodontically and equilibrate any remaining discrepancies between the marginal ridges. This method will produce the best occlusal result and improve the periodontal health. During orthodontic treatment, when teeth are being extruded to level hemiseptal defects, the patient should be monitored regularly by the dentist or periodontist. Initially, the hemiseptal defect will have a greater sulcular depth and be more difficult for the patient to clean. As - - Figure 8. This adult female had a hemiseptal periodontal defect between the mandibular left first premolar and the tipped first molar (A-B). In order to reduce the restorative expense, the first molar root was tipped mesially (C-D), the molar Was erupted (E) and equilibrated (F), in order to level the bone (G) and enhance the restorability of the teeth (H-1). 49 Evolution of Adult Orthodontics the defect is ameliorated through tooth extrusion, interproximal cleaning becomes easier. The dentist or periodontist should recall the patient every two to three months during the leveling process to control inflammation in the interproximal region. Are pre-doctoral dental students taught how to manage the interdisciplinary care of patients with one-wall hemiseptal defects? This type of treatment should be a part of the pre-doctoral education of all dental students. SPACE CONSOLIDATION Some adult restorative patients may be missing several posterior teeth on one side of the dental arch. In these cases, the space that exists may be too small or too large to facilitate the proper number and size of replacement teeth, in the form of implants or pontics. How would the restorative dentist resolve this situation? One option is to utilize implant supported orthodontic anchorage to close part of the existing edentulous space in order to obtain the appropriate-sized space for restoration (Kokich, 2000). In the example in Figure 9, the patient is missing the mandibular first and second molars on one side. The third molar has tipped mesially, the resulting edentulous space is too large for replacement of two teeth and too small for three teeth. In these situations, it could be advantageous to place a single-tooth implant in the appropriate position prior to the orthodontic treatment (Fig. 9F). These implants can be restored and used as anchors to close any excess and remaining space, using the implant as an anchor to avoid unwanted occlusal changes in the remaining dentition (Fig. 9G-1). The advantage to the patient is a reduction in the number of restorations required to fill the edentulous space. The advantage to the orthodontist is having an immobile anchor in the bone to protract or retract the adjacent teeth to close the space. The advantage to the restorative dentist is a simplification of the restorative procedures with a more predictable treatment result. This type of interdisciplinary therapy requires proper planning, the construction of a diagnostic wax-up and precise positioning of the implant to satisfy the orthodontic, surgical and restorative objectives. 50 Kokich - Figure 9. This adult female was missing her mandibular left first and second molars (A–B) and the third molar had tipped mesially (C-D). The restorative dentist wanted to keep the mandibular third molar, but upright it and tip the root mesially (E). Two traditional implants were placed in the alveolar ridge (F), restored (G) and used as anchorage to protract the third molar mesially (H-1). If an implant is used to move adjacent teeth and close an edentulous space, the timing of implant loading is an important factor. In the past, implant loading traditionally has been delayed until the implant had integrated fully with the surrounding bone. However, recent studies have shown that early or immediate loading is possible, especially in the orthodontic patient (Jung et al., 2011). The difference is that an Orthodontic load is continuous and in one direction, whereas an occlusal load is intermittent and in different directions. Researchers have shown that a continuous load in the same direction actually stimulates bone formation, which further enhances the osseo-integration of the implant. So, in most orthodontic situations, implants may be loaded early, soon after the restorative dentist has placed the temporary restoration. Are pre-doctoral dental students exposed to this type of Interdisciplinary treatment during their training? This type of therapy should be a part of the pre-doctoral education of every dental student. 51 Evolution of Adult Orthodontics LACK OF RESTORATIVE SPACE Occasionally, an adult restorative patient may have insufficient space to place an implant and an appropriate-sized restoration for a missing tooth. What are the options for the restorative dentist? One option simply is to avoid the implant and place a three-unit bridge with a small pontic. The other option is to utilize orthodontic intervention to push the adjacent teeth apart in order to create the appropriate amount of restorative space (Kokich, 2004; Kokich and Kokich, 2006). In the example in Figure 10, the patient was missing both mandibular right and left second premolars congenitally. The space had closed on the left side due to adjacent tooth drift and the mandibular dental midline had shifted toward that side. The space on the opposite side still remained, but the teeth had tipped. The restorative dentist wanted to have implants placed on both right and left sides, with appropriate-sized crowns on the implants. Therefore, orthodontic space opening mechanics were employed on both sides to push the first premolars and first molars apart. This type of tooth movement produced sufficient ridge width to avoid bone grafting during the implant placement. The restorative dentist had sufficient space to produce an occlusally and esthetically acceptable result for the patient (Fig. 10G-1). Are pre-doctoral dental students exposed to this type of interdisciplinary treatment during their training? This type of therapy should be a part of the pre-doctoral education of every dental student. VERTICAL ALVEOLAR DEFECTS Occasionally, the general dentist will be faced with re-restoring maxillary anterior teeth that previously had been restored, but are compromised structurally and periodontally. In some of these situations, the dentist may decide that implants are more appropriate than restoring the existing teeth. However, extraction of periodontally compromised teeth could produce a substantial vertical alveolar defect that could be difficult to overcome. One option for resolving this problem is to have a surgeon place a bone graft to compensate for the vertical bone defect. However, this approach could require more than one graft to achieve a reasonably esthetic result. 52 Kokich Figure 10. This adult female was congenitally missing both mandibular second premolars (A-C). However, the space on the left side had closed. Orthodontics was used to create implant space on the left side (D-F) and permit ideal restoration of the posterior and anterior occlusion (G-1). Another option would be to extrude the periodontally hopeless teeth orthodontically to the point of extraction in order to generate Vertical bone for the implants (Kokich and Kokich, 2011). Figure 11 shows a patient for whom this interdisciplinary strategy was used to overcome an extremely challenging situation for the restorative dentist. However, orthodontic extraction is not appropriate for all situa- tions. There are specific criteria that should be evaluated to determine Whether this treatment is indicated. Controlled extraction is a useful tool in implant site development. There are four criteria that should be evaluated to determine whether the patient would be a good candidate for controlled extraction. The first is to evaluate the position of the gingival margins of the maxillary anterior teeth. Do they need to be moved coronally? The maxillary left central and left canine in Figure 11 definitely needed to be moved incisally in order to make them appear esthetically commensurate with the contralateral 53 Evolution of Adult Orthodontics Figure 11. This adult female was missing her maxillary left lateral incisor congenitally (A). The patient was unhappy with the previously restored maxillary incisors. These roots of these teeth were short and deemed non-restorable (B). Implants were planned, so the incisors gradually were extracted orthodontically (C) in order to enhance the vertical bone (D-E) for implant placement (F). After healing (G), the implants were restored and the right lateral was replaced with a cantilevered pontic (H–1). - G teeth. The second criterion to evaluate is the bone levels. Does the crestal bone need to be moved incisally? The periapical radiograph (Fig. 11B) clearly shows the vertical bone discrepancy that could be improved with tooth eruption. The third criterion often is overlooked, but perhaps is the most important criterion for predictable success. One must assess the vertical angulation of the teeth to be erupted. When the central incisors are per- pendicular to the maxillary occlusal plane, then the eruptive movement of the teeth will be oriented vertically and the alveolar crestal bone will follow the teeth. However, if the crowns were proclined labially, the teeth would erupt labially and away from the alveolus. In this situation, the alveolar bone labial to the root would tend to dehisce and not follow the teeth. 54 Kokich The fourth and final criterion to evaluate when contemplating controlled extraction for implant site development is the periapical health of the teeth. Are there any periapical radiolucencies indicating an active infection in the area? When an inflammatory process is occurring, the bone will not follow the teeth as they are erupting because the periodontal ligament is interrupted by the intervening inflammatory process and prevented from stretching and stimulating bone formation. In the patient illustrated in Figure 11, the maxillary right lateral incisor had a periapical inflammatory lesion. Therefore, a favorable bony response was not anticipated in this area. As a result, the dentist and surgeon decided to place two central incisor implants and a cantilevered right lateral incisor pontic (Fig. 11F-1) rather than implants in the right lateral and left central incisor region with a three-unit implant supported bridge. Another key to successful implant site development when erupting hopeless teeth is the speed of eruption. I always prefer slow eruption to fast eruption. Why? First of all, when teeth are erupted rapidly, the gingival Sulcus will evert and a red margin appears around the tooth that is being erupted. The color red signals the eversion of the non-keratinized sulcular epithelium. The lack of keratinization is not the problem—the problem is the loss of the sulcus. When the sulcus is eliminated, the stretching of the periodontal ligament at the alveolar crest is proceeding at such a rapid pace that the deposition of crestal bone becomes jeopardized. As a result, the labial plate of bone, which is so critical in an anterior implant case, is difficult to maintain. This will result in a less-than-ideal esthetic gingival margin position in the final restoration. It is best to erupt the teeth slowly at around 0.5 mm/month. The patient in Figure 11 took ten months to erupt the incisors 5 mm. However, this rate of eruption gave the alveolar crestal bone an opportunity to keep up with the erupting teeth. In order to determine whether the tooth is being erupted too rapidly, the orthodontist simply should probe the sulcus at every appointment. As long as a probeable Sulcus is maintained, then the tooth probably is being erupted at an appropriate rate. Are pre-doctoral dental students exposed to this type of interdisciplinary treatment during their training? This type of therapy should be a part of the pre-doctoral education of every dental student. 55 Evolution of Adult Orthodontics SUMMARY AND CONCLUSIONS The purpose of this chapteristo delineate the difference between adult and adolescent orthodontic treatment. Adolescent orthodontics typically involve occlusally driven, standardized treatment protocols in order to achieve an Angle Class I occlusion. Adult orthodontics typically involves restoratively driven, prescription treatment protocols in order to achieve improved tooth position for the restorative dentist. Over the past 40 years since the initiation of the annual Moyers Symposium, the numbers of adults being treated by orthodontists in the U.S. has increased substantially. However, the education of pre-doctoral dental students regarding the value of interdisciplinary orthodontic- restorative treatment is lacking. As an orthodontic specialty, we should recognize this deficiency in pre-doctoral dental education and make a concerted effort to upgrade the information that we provide to our future restorative dental colleagues. REFERENCES Curtis DA, Jayanett J, Chu R, Staninec M. Decision-making in the management of the patient with dental erosion. J Calif Dent Assoc 2011;39(4):259-265. de Mol van Otterloo JJ, Tuinzing DB, Kostense P. Inferior positioning of the maxilla by a Le Fort osteotomy: A review of 25 patients with vertical maxillary deficiency. J Craniomaxillofacial Surg 1996;24(2):69-77. Donovan T. Dental erosion. J Esthet Restor Dent 2009;21(6):359-364. Fletcher P. Biologic rationale of esthetic crown lengthening using in- novative proportional gauges. Int J Periodontics Restorative Dent 2011;31(5):523-532. Jung BA, Harzer W, Wehrbein H, Gedrange T, Hopfennnüller W, Lüdicke G, Moergel M, Diedrich P, Kunkel M. Immediate versus conventional loading of palatal implants in humans: A first report of a multicenter RCT. Clin Oral Investig 2011;15(4):495-502. 56 Kokich Kokich VG. Altering vertical dimension in the perio-restorative patient: The orthodontic possibilities. In: Cohen M, ed. Advanced Treatment Planning and Total Case Management. Coal Stream, IL: Ouintessence Publishing, 2008;49-80. Kokich V. Anterior dental esthetics: An orthodontic perspective. I. Crown length. J Esthet Dent 1993;5(1):174-178. Kokich VG. Comprehensive management of implant anchorage in the multidisciplinary patient. In: Higuchi K, ed. Orthodontic Application of Osseointegrated Implants. Coral Stream, IL: Ouintessence Publishing, 2000;21-32. p Kokich VG. Excellence in finishing: Modifications for the perio-restorative patient. Semin Orthod 2003;9(3):184-203. Kokich VG. Maxillary lateral incisor implants: Planning with the aid of orthodontics. J Oral Maxillofac Surg 2004;62(9 Suppl 2):48–56. Kokich VG. The role of orthodontics as an adjunct to periodontal therapy. In: Carranza FA, Newman MG, Takei HH, eds. Clinical Periodontology. 9th ed. St. Louis: Mosby, 2002;704–718. Kokich VG, Kokich VO. Congenitally missing mandibular second premolars: Clinical options. Am J Orthod Dentofacial Orthop 2006; 130(4):437- 444. Kokich VG, Kokich VO. Managing treatment for the restorative patient with significant maxillary anterior bone loss. In: Cohen M, ed. Interdisciplinary Treatment Planning: Volume II. Comprehensive Case Studies. Coral Stream, IL: Ouintessence Publishing, 2011;2-17. Kokich VG, Spear F. Guidelines for managing the orthodontic-restorative patient. Semin Orthod 1997;3(1):3-20. Major PW, Phillippson GE, Glover KE, Grace MG. Stability of maxilla downgrafting after rigid or wire fixation. J Oral Maxillofac Surg 1996; 54(11):1287-1291. Nemcovsky CE, Artzi Z, Moses O. Preprosthetic clinical crown lengthen- ing procedures in the anterior maxilla. Pract Proced Aesthet Dent 2001;13(7):581–588. 57 Evolution of Adult Orthodontics Ranjitkar S, Smales RJ, Kaidonis JA. Oral manifestations of gastroesophageal reflux disease. J Gastroenterol Hepatol 2012;27(1): 21-27. Reitan K. Clinical and histologic observations of tooth movement during and after Orthodontic treatment. Am J Orthod 1967;53(1):721-745. Sonic M. Esthetic crown lengthening for maxillary anterior teeth. Com- pend Contin Educ Dent 1997;18(8):807-812. Spear F, Kokich VG, Mathews DP Interdisciplinary management of anterior dental esthetics. J Am Dent Assoc 2006;137(2):160-169. 58 ORTHODONTIC DIAGNOSIS AND TREATMENT FROM THE OUTSIDE IN David M. Sarver ABSTRACT Orthodontists now visualize cases in a vastly different way than they did two de- cades ago. Treatment plans are not determined by model relationships or cepha- lometric measurements, but are based on the soft-to-hard tissue interrelation- ships defined and quantified in the clinical examination. Rather than starting our evaluation with the determination of the Angle classification, contemporary as- sessment begins with the macro-esthetic (facial) evaluation. The quantification of attributes and the occlusal and esthetic goals follow, focused on all three esthetic components: macro-esthetics, mini-esthetics and micro-esthetics. This chapter proposes a simple alteration of the traditional “problem-oriented” treatment planning flow chart with a fundamental shift to the focus on “goal-centered” treatment. It covers the progression of thinking in orthodontic treatment plan- ning over the past two decades and illustrates the step-by-step decision-making process involved in macro-, mini- and micro-esthetics treatment planning. KEY WORDS: macro-esthetics, mini-esthetics, micro-esthetics, soft-tissue, smile a ſG Orthodontic diagnosis and treatment planning has been influ- enced greatly by our interdisciplinary experiences. With the surge of orthognathic surgery in the 1970s and our close cooperation with oral and maxillofacial surgeons, the resulting interdisciplinary collaboration became a normal part of practice. Then, in the 1990s, improvement of materials and dental techniques, such as implants and veneers, resulted in the subsequent growth of esthetic dentistry and further professional Cooperation. As a consequence, orthodontists now visualize cases in a vastly different way than they did two decades ago. For this manuscript, I deliberately have chosen the title Orth- odontic Diagnosis and Treatment: From the Outside In to reflect the shift in emphasis in orthodontic diagnosis. 59 From the Outside In The objectives of this chapter are to: 1. Demonstrate the expanding vision of diagnosis and treatment in the orthodontic specialty. 2. Reflect on how much orthodontists have merged their approaches to treatment to coincide more closely with the trends in dentistry. The relatively recent emphasis on treatment of the Smile reflects this interaction. 3. Facilitate your communication with other dentists and dental specialists, and the potential homogenization of interdisciplinary diagnostics. 4. Create a diagnostic environment that logically would result in better outcomes and patient care. These broad ideas are illustrated best with real case experiences, starting with an inside-out approach and its inherent limitations. The intraoral image in Figure 1 is that of a 19-year-old patient who had been followed by her family dentist and orthodontist since adolescence. The family had not elected to pursue any orthodontic treatment because she had an excellent occlusion and no functional problems; unless the spacing was an esthetic issue to them, treatment was not indicated. However, the patient finally decided that she wanted an improved smile and again sought the advice of her orthodontist who defined her problem list to that of anterior spacing—a problem readily treatable with clear aligner therapy, which was the recommended course of treatment. Figure 2 represents the patient's smile. The family dentist ex- panded the problem list (because of his cosmetic dental background) to include incomplete incisor display (only 50% of her maxillary incisor was displayed on smile) and a flat smile arc (Frush and Fisher, 1958; Hulsey, 1970; Ackerman and Ackerman, 1998; Sarver, 2001; Parekh et al., 2006). It is well documented that we exhibit less maxillary incisor both at rest and on smile over time (Vig and Brundo, 1978; Dickens et al., 2002; Sarver, 2010). In this instance, the patient was motivated by a desire for esthetic improvement. The dentist, understanding both the imme- diate and long-term issues with her Smile, suggested an option other 60 Sarver Figure 1. This 19-year-old patient had been followed by her family ortho- dontist since adolescence. No treatment had been recommended because She had an excellent occlusion. figure 2. The patient's smile was not pleasing to her Treatment was re- Cºmmended only because of the spacing issue. The orthodontist felt clear aligner therapy was adequate in her treatment. However, the family dentist *98mized her incomplete incisor display and flat smile arc. 61 From the Outside In than aligner therapy, namely cosmetic veneers to increase crown length and incisor display. Figure 3 is a computer mock-up of what veneers potentially could offer in terms of smile improvement. Our clinical examination reflected no incisor display at rest, 5 mm of incisor display on smile, with maxillary central incisor crown height of 10 mm. To reach the esthetic goals of full incisor display and consonant smile arc, 5 mm of incisor length would be required, which would necessitate veneers 15 mm in length to attain the desired outcome as shown in Figure 2. Knowing that other options were available, the dentist referred the patient to the orthodontist for an opinion. Our clinical assessment included all three major areas of esthetic classification: macro-esthetics (facial characteristics); mini-esthetics (smile characteristics); and micro- esthetics (dental characteristics). These three categories generally do not exist independently. In other words, the etiology of a macro-esthetic problem often has a mini-esthetic component and vice versa. A micro- esthetic issue may have a mini-esthetic component or may have an effect on the smile. Therefore, looking from the outside in, the etiology of the inadequate incisor display on smile was not a tooth problem, but instead reflected a counter-clockwise skeletal growth pattern, resulting in diminished incisor display. Her macro-esthetic presentation (Fig. 4) included a short lower facial height, diminished lip projection with thin vermilion display and a wide nasal base. Figure 5 represents a schematic conceptualization of another way to define skeletal relationships. Instead of defining skeletal relationships as Class I, II or Ill (which is the dental classification of Angle), skeletal interrelationships may be defined in terms of pitch, roll and yaw (Ackerman et al., 2007; Ghafari, 2012). On the oblique smile in Figure 6, we see that the maxillary palatal plane is parallel more with the horizontal plane, resulting in a flatter occlusal plane and a diminished mandibular plane angle, resulting in a short lowerfacial height. This counter-clockwise growth pattern is a result of inadequate vertical growth of the maxilla, leading to more mandibular prominence and less lip prominence. The nasal characteristics may or may not be connected closely to the skeletal pattern, but they do reflect the need for analysis of both hard and soft tissues at the same time. 62 Sarver Figure 3. A computer mock-up of what porcelain veneers could offer in terms of smile improvement. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Figure 4. The macro-esthetic presentation was char- acterized by a short lower facial height, poor lip pro- jection with thin vermilion display and a wide alar base. 63 From the Outside in Figure 5. Instead of defining skeletal relationships as Class I, II or III, many authors have recommended the concept of pitch, roll and yaw. After factoring in the frontal, oblique and profile facial charac- teristics, the problem list evolved from one of simple anterior spacing (micro) to a more global diagnosis of counter-clockwise skeletal pattern (macro) with incomplete incisor display on smile and flat smile arc (mini). The resulting treatment plan after preparatory orthodontics included: 1. Maxillary advancement with anterior downgraft, which results in increased upper lip support, increased incisor display and greater lower facial height. 2. Mandibular advancement with clockwise rotation in response to the clockwise palatal plane rota- tion, which adds to lip support, lengthening of the lower face and steepening the palatal, occlusal and 64 Sarver Figure 6. The oblique smile reveals a flat palatal plane, flat occlusion plane and diminished mandibu- lar plane angle compared to a more ideal divergence of the profile. mandibular planes through clockwise occlusal plane rotation (Reyneke and Evans, 1990; Sarver et al., 1993; Wolford et al., 1993, 1994; Chemello et al., 1994). The surgical movements were not based on cephalometric num- bers, but instead were based on our clinical exam that quantified the hard and soft tissue interrelationships: 1. The maxillary incisor display at rest was 0 mm; 2. 5 mm of incisor display on smile; and 3. The incisor height was 10 mm. The final surgical plan called for maxillary advancement of 5 ſºm, an anterior downgraft of 5 mm (10 mm crown height – 5 mm inci- $or display on smile = 5 mm needed for complete incisor display) and 65 From the Outside In mandibular surgery for advancement and clockwise rotation in concert with the maxillary movement (Fig. 7). To emphasize one of the major points of this paper, the surgical plan was not determined by model re- lationships or cephalometric measurements, but rather was based en- tirely on the soft-to-hard tissue interrelationships defined and quantified in the clinical examination, and on the occlusal and esthetic goals set in advance focused on all three esthetic components. FUNDAMENTAL SHIFT #1: TREATMENT PLANNING THAT FOCUSES ON GOAL SETTING Let us take a moment to look at a proposed shift in our treat- ment planning flow charts. Normally, we start with our problem list and look for solutions to fix the problem. Where this approach his- torically has led us astray has been in the treatment of a Class || mal- occlusion due to mandibular deficiency. For example, the girl in Figure 8 - orthosurgical Increase upper lip support Balance midface with lower face Increase lower facial height Increase incisor display Improve smile | arc. Figure 7. The final surgical plan called for maxillary advancement with anterior downgraft, mandibular Surgery for advancement and clockwise rotation. 66 Sarver Figure 8. Because of her Class || malocclusion, this pa- tient was treated with extraction of premolars to re- tract the maxillary incisors for overjet correction. The "problem" was a Class || dental relationship, when the true etiology was mandibular deficiency. Was treated with extraction of premolars for retraction of maxillary inci- SOFS to Correct overjet. While this protocol addressed the Class || maloc- clusion "problem,” it achieved occlusal correction at the expense of an ideal midface, resulting in an overly obtuse nasolabial angle and a convex profile. In this particular case, retreatment was implemented with surgi- cal bimaxillary advancement for recovery of her facial esthetics (Fig. 9). We propose a simple alteration of the treatment planning flow Chart, as depicted in Figure 10. The fundamental shift is articulated well by Brown and Phillips (personal communication), who have proposed a "protection Strategy” component of the flow chart, so that we recognize not only the problems that need to be solved, but also the positive attributes that need to be protected. Long and Christensen (personal 67 From the Outside in Figure 9. The patient was retreated with orthodontics, bimaxil- lary advancement, advancement genioplasty and rhinoplasty. communication) developed the notion of “goal-centered” treatment, ra- ther than “problem-oriented” treatment planning. FUNDAMENTAL SHIFT #2: THE SHIFT FROM STATIC-RECORDS BASED (CEPHALOGRAM, PHOTOGRAPHS AND MODELS) TO CLINICAL EXAMINATION EMPHASIS Macro-esthetic proportions often are general in nature, with the basic element consisting of vertical thirds (Fig. 11). The mini-esthetic examination is conducted directly on the patient with a ruler, caliper and periodontal probe, allowing quantification of esthetic characteristics that are not attainable any other way. – Figure 11. One of the basic elements of macro-esthetic analysis includes equal vertical thirds of the face. 68 Sarver TREATMENT PLANNING FLOWCHART Problem list Positive attributes | 1. solutions Protection Treatment optimization Figure 10. In addition to the time-honored problem-oriented treatment- planning flowchart, we recommended the additional consideration of what elements of a patient's esthetic makeup should be “protected.” 69 From the Outside In The order of the mini-esthetic examination is as follows: 10. 11. Philtrum length: measured in millimeters. Commissure height: measured in millimeters. . Vermilion display (Fig. 12): the amount of “wet lip” presented at repose. The ideal proportional relation- ship of the maxillary vermilion to mandibular vermil- ion in the female is 40% upper lip, 60% lower lip. Maxillary incisor at rest: measured in millimeters. This is a cue for the “current age” of smile since the incisor at rest measurement can be related to data that gives us a good idea “how old” the patient's smile may be. . Incisor display on smile: measured in millimeters, this measurement represents quantification not attain- able from a cephalogram or any other clinical meth- odology. Smile arc: Categorized as consonant (maxillary occlusal plane parallel to the lower curvature on smile) or non-consonant (maxillary occlusal plane parallel to the lower curvature on smile). These are guidelines, not absolute rules. . Buccal corridor: a relatively subjectively interpreta- tion. Three general classifications exist: inadequate, excessive and ideal. Smile mobility: measured as a percentage of lip eleva- tion (McEntire, 2013). Incisor width: measured in millimeters and with a cali- per for ideal accuracy. Incisor height: also measured with a caliper. Gingival depth of maxillary incisors: this requires peri- odontal probing and is an indicator of the ideal final crown display and height-width ratio. This is elemen- tal to the final position of the maxillary incisor. 70 Sarver Figure 12. Vermilion display represents the amount of “wet lip" visible in repose. The ideal proportion in the female is considered to be 40% upper lip and 60% lower lip. The micro-esthetic exam is featured visually in Figure 13, including Zeniths, connetors, contacts, incisal and gingival embrasure proportions. Connector - º º º Connector Long axis - - Connector ºple height (40%) — Gingival height zenith Width contact Height "Embrasure Figure 13. The recommended micro-esthetic examination and proportions. 71 From the Outside In FUNDAMENTAL SHIFT #3: TREATMENT PLANNING FEATURING MACRO-, MINI- AND MICRO-ESTHETIC PRINCIPLES AND GOAL-ORIENTED TREATMENT PLANNING The nine-year-old female patient seen in Figure 14 illustrates the global macro-mini-micro treatment approach. Born in Seoul, South Korea and adopted at age two by a Birmingham, Alabama family, she had a number of dental issues with severe dental malformations (Fig. 15). When the cephalogram is analyzed, often the first orthodontic question in the orthodontist's mind is, “What are the Korean cephalo- metric norms?” Herein lies the fundamental shift in treatment planning from problem-oriented to goal-oriented treatment planning: what is the goal of treatment? We can see the problems, but what is the goal of treat. ment—to maintain her Korean appearance as best we can or to acclimate her to U.S.—and specifically Birmingham, Alabama—esthetic goals? We decided to time her treatment to begin once she reached her adult denti- tion and approached her treatment from the outside in as follows: 1. Face at rest: The lower facial height was short and her upper-to-lower lip proportion was 25-75%. There were a number of ways of utilizing growth modi- fication and Orthodontic mechanics to increase her lower facial height to what would be considered more ideal facial proportion. We could erupt posterior teeth passively (biteplates, bite turbos, functional appliances) or with active force application (cervical headgear, reverse curve lower arch wires, vertical elastics) and, of Course, orthognathic surgery. 2. The mini-esthetic evaluation: There was no incisor display at rest and no incisor display on smile. Thera- peutically, anterior tooth display could be increased through differential bracket placement, growth modi- fication or orthognathic surgery. 3. Micro-esthetic evaluation: The incisor width mea- sured 8.8 mm between the contact point, but was tapered incisally, resulting in large incisal embrasures. 72 Sarver Figure 14. This nine-year-old female patient was an adopted child originally from South Korea. She had a short lower facial height with a verythin vermilion and deep labiomental sulcus. Figure 15. Her teeth presented the challenge of severe malformations. 4. This measurement was important because it indica- ted a “shape issue.” The teeth did not have an artistic shape that was regarded as even close to ideal. 73 From the Outside In Putting Macro-Mini-Micro into Practice After our three-part clinical examination, the treatment goals Were to: 1. Add length to the lower face (macro-esthetics). 2. Increase incisor display (mini-esthetics). 3. Improve incisor dimension and shape (micro- esthetics). In general, there are four methods of opening a deep bite: 1. Flare incisors. 2. Intrude maxillary incisors. 3. Intrude mandibular incisors. 4. Extrude posterior teeth. Looking at the patient's dental presentation and using the above list of treatment options: 1. Flaring of incisor: contraindicated because of the amount of spacing already present. 2. Intrude maxillary incisors: contraindicated because she had no incisor display at rest or on smile. 3. Intrude mandibular incisors: contraindicated because while this would open the deep bite, it would not improve lower facial height. 4. Extrude posterior teeth: this was the obviously correct choice in that this approach opens the bite and also increases lower facial height. The treatment plan was designed to be simple in its approach, SO treatment was delayed until she was in her full dentition and undergoing a growth spurt. We placed full-fixed appliances and used cervical headgear for growth modification. Maxillary incisor brackets were placed as apically as possible to erupt the anterior teeth in the growing dentoalveolus, while the cervical headgear was used to extrude posterior teeth. Once the deep bite was improved, it was appropriate to address the many other esthetic issues since there was excessive spacing between the anterior teeth and her incisor shape was poor. We referred her to her dentist for consultation to coordinate the next phase of treatment. 74 Sarver By intentionally creating more space than was present already, we made it possible for her dentist to restore the anatomical contours as ideally as possible. The recommendation was made to lengthen the periodontal crown as a valuable adjunctive procedure and referred the patient to the periodontist. Why crown lengthening? It permitted the brackets to be placed more superiorly (Fig. 16) for even more extrusion. Twelve months of orthodontic treatment changed the facial height dramatically (Fig. 17) as well as incisor display (Fig. 18). Now at age fourteen, her smile unquestionably was better than where she started, but still fell short of full incisor display and conso- nance of smile arc. For an ideal outcome, porcelain veneers were indi- cated because: 1. The original incisors were seriously malformed and were improved only temporarily with cosmetic bond- ing. More incisor display was a goal of treatment. The smile arc was flat and also could be improved. Improved shade of the teeth would be an added ben- efit. - Figure 16. After temporary bonding was placed to idealize tooth width, periodontal crown lengthening was performed in order to permit brackets to be placed even more superiorly. 75 From the Outside In Figure 17. After 12 months of orthodontic treatment to open her bite, the patient's facial height was in- creased dramatically. We delayed treatment until she had reached the appropriate age for veneers. At age seventeen, the dentist felt comfortable proceeding with veneers, and what followed was the incorporation of technology into our planning process and leads us to: FUNDAMENTAL SHIFT #4: VISUALIZATION AND OUANTIFICATION In the attainment of final mini-esthetic objectives, veneers were planned with the goal of obtaining full incisor display and consonant Smile arc. In the restorative process, the dentist often prepares the teeth, takes impressions and then sends the models to the laboratory for fabrication of the veneers, generally to ideal height-width ratio. If the dentist does not communicate the smile design goals with the laboratory, then the lab has no frame of reference to the soft tissue animation of the smile necessary for attainment of the goals of smile design. 76 Sarver Figure 18. At the end of orthodontic treatment, the smile relationship was improved markedly with increased incisor display. However, the patient still had a flat smile arc. This is where visualization becomes extremely important. Her close-up smile digital image was calibrated on computer software (calibration based on our measurement of the maxillary central incisor gathered in our clinical exam) so that we could measure anything in the field. After image calibration, we measured how far the incisal edges of the incisors were away from ideal placement as 2.2 mm away (Fig. 19). The dentist's first concern was that the veneers would be too long and the laboratory shared the same misgiving. The importance of visualization is described in the process that followed. After discussion with the patient, dentist and laboratory, we ſecognized that she did not show her gingival margins on smile, so that the ideal tooth proportionality was not as important in this case as the attainment of the smile esthetics. In orthodontics, we often use 77 From the Outside In Figure 19. After calibration of the digital computer image, the distance from the current incisal edge to the goal of ideal smile arc and incisor display. three-dimensional (3D) models to do indirect bracket setups, clear align- er appliance design; all of these approaches share the same shortcoming in that they do not relate to smile design and, thus, can fall short of our planned treatment goals. After the dentist, patient and laboratory all agreed that this was the target, the veneers were fabricated and her final outcome is shown (Figs. 20-21). CONCLUSION The title of this chapter, Orthodontic Diagnosis and Treatment from the Outside In, illustrates the importance for orthodontists to recognize that while the technological advancement in orthodontic wires and appliances has been an enormous boost to our productivity, ultimately it is the knowledge and visualization of the treatment goals by the orthodontist and the dental team that are the most important element in the treatment planning process. 78 Sarver Figure 21. The final close-up smile. 79 From the Outside in REFERENCES Ackerman JL, Ackerman MB, Brensinger CM, Landis JR. A morphometric analysis of the posed smile. Clin Orthod Res 1998;1 (1):2-11. Ackerman JL, Proffit WR, Sarver DM, Ackerman MB, Keane MR. Pitch, roll, and yaw: Describing the spatial orientation of dentofacial traits. Am J Orthod Dentofacial Orthop 2007;131(3):305-310. Brown D, Phillips T. Personal communication, 2009. Chemello PD, Wolford LM, Buschang PH. Occlusal plane alteration in orthognathic surgery: Part II. Long-term stability of results. Am J Orthod Dentofacial Orthop 1994;106(4):434–440. Dickens S, Sarver DM, Proffit WR. The dynamics of the maxillary incisor and the upper lip: A cross-sectional study of resting and smile hard tissue characteristics. World J Orthod 2002;3(3):313-320. Frush JO, Fisher RD. The dysesthetic interpretation of the dentogenic concept. J Prosth Dent 1958;8:558. Ghafari J. Vertical maxillary asymmetry: A prevalent lateral roll in spatial orientation. Orthodontics (Chic.) 2012;13(1):e127-e139. Hulsey CM. An esthetic evaluation of lip-teeth relationships present in the smile. Am J Orthod 1970;57(2):132-144. Long L, Christiansen J. Personal communication, 2009. McEntire C. Three-dimensional soft tissue changes upon smiling. VCU Digital Archives. www.https://digarchive.library.vcu.edu/handle/ 10156/4208, 2013. Parekh J, Fields H, Beck M, Rosenstiel S. The perception of selected as- pects of smile esthetics: Smile arcs and buccal corridors. Am J Orthod Dentofacial Orthoped 2006;129:711. Reyneke JP, Evans WG. Surgical manipulation of the occlusal plane. Int J Adult Orthod Orthog Surg 1990;5(2):99-110. Sarver DM. The aging face and how the dental team can affect esthetics for a lifetime. Compend Dent 2010;131(4):274–283. Sarver DM. The importance of incisor position in the esthetic smile: The smile arc. Am J Orthod Dentofacial Orthop 2001;120(2):98-111. Sarver DM, Weissman SM, Johnston MW. Diagnosis and treatment planning of hypodivergent skeletal pattern with clockwise occlusal plane rotation. Int J Adult Orthod Orthogn Surg 1993;8(2):113-121. 80 Sarver Vig RG, Brundo GC. The kinetics of anterior tooth display. J Prosth Dent 1978;39(5):502-504. Wolford LM, Chemello PD, Hilliard FW, Occlusal plane alteration in orthognathic surgery. J Oral Maxillofac Surg 1993;51(7):730–740. Wolford LM, Chemello PD, Hilliard F. Occlusal plane alteration in orthognathic surgery: Part I. Effects on function and esthetics. Am J Orthod Dentofacial Orthop 1994;106(3):304-316. 81 LONGITUDINAL GROWTH STUDIES: COMMENTS ON THE BENEFITS AND RISKS Rolf G. Behrents ABSTRACT The search for information on the growth and development of the craniofacial complex historically has been linked to assessment technologies and study designs that were available at the time of the inquiry. Over the last half century, one the most valued types of investigation has been the longitudinal assessment of the growth of the craniofacial complex using x-rays. The focus of this type of study has been to document and describe the morphological events that occur over time so that our treatments become better understood, more predictable and improved. Notably a new tool of research inquiry was developed, the roentgenographic cephalometer, which found widespread use in studies that were crucial to the examination of time-honored concepts in orthodontics as well as the opportunity for the development of new ideas and hypotheses. As the result of many studies, our knowledge of normal and abnormal growth has increased significantly. Over time, however, concern for the long-term effects of early radiation also has increased significantly. Fortunately, compelling evidence does not exist that early growth studies compromised the health of their participants in later life. In addition, because of improvements in x-ray technology and radiation hygiene practices, the employment of ionizing radiation in orthodontic diagnosis and treatment is considered beneficial to the patient. Given the concerns of the public, it is incumbent that practitioners educate and inform patients as to the benefit and risks involved and utilize radiation in the best interests of the patient. KEY WORDS: growth studies, longitudinal, cross-sectional, cephalometry, radiation INTRODUCTION As one contemplates the opportunity to participate in an anniversary event such as this, it is clear that the Moyers Symposium not only has meaning in the present, but also has a past that has served to 83 Longitudinal Growth Studies chronicle the issues and advancements important to orthodontic Science and practice over the past four decades. One of the areas that was of considerable interest 40 years ago involved longitudinal growth studies whose prime focus was to document, describe, predict and control the growth of the craniofacial complex. So that one can understand the evolution of research and discovery in this area, one must understand the types of study designs. GROWTH STUDY DESIGNS With regard to typical growth studies, there are two main designs (with many variations). In cross-sectional growth studies, information is gathered using different (independent) samples of individuals at each of several points on an age or some other time scale. Thus, each of the subjects is seen only on one occasion. Data produced often is averaged by age group and can provide general information about growth attained at a particular age. Cross-sectional studies have several advantages: they can be conducted in a relatively short period of time; they can cost less than other designs; and a large sample can be recruited and studied (Tanner, 1952, 1960, 1986). On the other hand, this design has significant disadvantages. Because different individuals are studied at different periods, the age groupings of the sample may not contain similar individuals and, thus, may not be representative of the population being studied. Cross-sectional data often are portrayed as though they represent a continuous process, but they do not; the data are static (i.e., no growth is occurring at all). For this reason, the rate of growth cannot be estimated accurately. While a cross-sectional study can provide useful information regarding the absolute value of a group, it does not provide valid information regarding the assessment of individual variation (Tanner, 1952, 1960, 1986). As a result, inferences drawn from cross-sectional studies may not be true for individuals. In a typical longitudinal growth study, a sample of subjects is seen early in life; then those same subjects are sampled again and again at appropriate intervals until the desired information is obtained. There 84 Behrents are obvious disadvantages associated with a longitudinal design. For ex- ample, such studies take a long time to conduct if the study period is long. As a result, this type of study usually is expensive to Conduct due to the need for permanent clinics, laboratories, research equipment and re- Search personnel; obtaining and maintaining financial support over time can be a parallel issue. Recruitment and attrition of the study sample also can be a significant problem as subjects move, tire of the study and die prematurely; attrition of the investigators also is consequential in main- taining a long study (Tanner, 1952, 1960, 1986). On the other hand, there are significant advantages of a longitu- dinal design. Outliers are easier to identify and correct for. Individual and group variation can be estimated accurately (Tanner, 1952, 1960, 1986). Data derived can provide information not only on the amount of growth attained, but also on the growth rate and changes in growth rate. Because the data derived are continuous, it is possible to compare individuals to themselves and to other individuals. In fact, the pattern of growth and de- velopment of a single child can be studied over a long period of time and produce useful serial comparisons with him/herself. As an example, the use of longitudinal data to plot incremental growth curves began when Scammon (1927) plotted semi-annual height data that Montbeillard had collected from his son's birth in 1759 to his eighteenth birthday (Fig. 1). |” The term “serial longitudinal” sometimes has been applied to Studies in which each child is seen at the same starting age, assessed on a regular “serial” basis over a long period of time and then again at the same specified final age. This type of longitudinal study carried on from birth to adulthood is considered the best design (Tanner, 1951, 1962; Nanda, 1955; Bambha, 1961; Sassouni, 1965). Besides these two basic designs, there are many variations. Semi-longitudinal and mixed-longitudinal studies try to make use of the advantages of both cross-sectional and longitudinal designs. In one form of a mixed-longitudinal study design, some children are seen at all time points, some at some of the time points and some only once. In another form of a mixed-longitudinal study, an overlapping series of short serial 85 Longitudinal Growth Studies * 20– 15- 10– 0 I I I H I I H I I lſ I l l 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Age (years) Figure 1. Growth in height of the son of the Count Montbeillard during the years 1759-1777 as plotted by Scammon (1927). data collection points occur; in this design, the beginning and end points differ (Harris, 1962; Singh and Savara, 1966). Using this design, a 15-year mixed-longitudinal study can be accomplished in three years of gathering data with each subsample including children for the same number of years (three), but starting at differing ages. Such designs can provide both cross-sectional and longitudinal data that can be useful in estimating growth attained and rate of growth. It has been noted that if the timing and velocity of growth changes needs to be studied in an accurate manner, a serial longitudinal analysis needs to be performed, but if only the amount of growth needs 86 Behrents to be analyzed, the mixed longitudinal design might be adequate (Tan- ner, 1962). Overlapping, limited-longitudinal and time-lag variations in study design also are described in the literature (Coben, 1955; Garn and Shamir, 1958; Van't Hof et al., 1976). Overall, there are clear advantages and disadvantages of both longitudinal and cross-sectional designs. A cross-sectional design might be good for determining a population growth trend, and a longitudinal design might be good for individual growth-trend analysis. A longitudinal design is in a better position to discern the impact of changes in growth (both large and small) over time than is the cross-sectional design that Studies the growth of age-differing groups of children at one time. Longitudinal designs are considered to have a higher productivity potential (i.e., the data can be grouped for one study and later regrouped to address a study with different objectives). Longitudinal studies also Can Suggest cause and later effect and serve as an important source of new hypotheses and studies. As a limitation, inferences drawn from Cross-sectional studies may not be true for individual subjects. Further, Some standards derived from cross-sectional studies are not suitable for clinical use. On the other hand, the cross-sectional design can be a good design when the objectives of the study are limited strictly. For example, a cross-sectional design can be employed successfully to study Cadavers, skeletons and archeological material, but it has its limitations when used to study living individuals. Thus, in the end, the problem being investigated and the available investigative technologies should dictate the approach. AN HISTORICAL PERSPECTIVE The quest for information on the growth and development of the face historically has been linked to the technologies and designs that were available at the time (Tanner, 1981, 2000). In the 18th, 19th and the first three decades of the 20th century, research was conducted that focused on tissue studies, animal experimentation and anthropometric inquiries (Newcomb, 1950; Brader, 1956). Studies conducted by Tomes, Wolff, Oppenheim, Benninghof, Belcher, Duhamel, Hunter, Brash, Camper, Welcher, Von Ihering, Angle, Hellman, Todd, Thompson, Case, Keith, Campion, Johnson, Lewis, Lündstrom, Rogers, Hrdlicka, Scammon, 87 Longitudinal Growth Studies Simon, Gregory, Krogman and many others were considered important contributions during that time. Of particular consequence to an understanding of facial growth were the anthropometric studies that were being conducted. Studies evolved during this time ranged from anthropometry to osteometry, to craniometry and then to cephalometry (i.e., measurement of the living head). Such studies were numerous and typically involved cross-sectional evaluations (Tanner, 1981, 2000). Measurements were made on dry skulls and cadavers, and casual observations or gross body measurements were made on living, growing individuals. Cephalometric measurements were difficultastheassessment of the hard tissues had to be estimated based on measurements taken through the soft tissues. Various samples (sex, race, ethnic origin) were evaluated and the subjects often were grouped into large age groupS. Group means were determined and compared as to younger and older groups or used for describing general size trends. However, there are difficulties in interpretation of such data as disease states, secular trends, timing of measurement effects, inaccurate age estimates and selective survival effects all served to confound as- sessments of individual ontogeny (Tanner, 1981, 2000). Thus, interpreta- tions of findings in these studies are limited in many ways. Their value lies primarily in the study of adaptation and in pointing out trends that can be confirmed or denied only by longitudinal assessment. Cross-sectional studies often can demonstrate what is not true, but can offer little in the way of clarifying or providing information as to what actually is occurring, However, cross-sectional studies do point out the features worth pursu- ing through subsequent longitudinal assessment. By 1930, a new tool of research inquiry had been developed that was crucial to the examination of time-honored concepts in orthodontics as well as the opportunity for the development of new ideas and hypotheses (McGonagle, 1956). This new tool was the roentgenographic cephalometer developed by Broadbent in 1926 and presented to the specialty formally in 1931 (Broadbent, 1931; Fig. 2). Importantly roentgenographic cephalometric X-rays were repro- ducible, magnification could be accounted for and distortions were com- parable; the technique was controlled and standardized. But, as pointed 88 Behrents - - º |- _ Figure 2. Dr. B. Holly Broadbent using the ro entgenographic cephalometer. * by McGonagle (1956), new research tools may not be embraced and ised to their greatest potential unless there is intellectual readiness for their proper use. Thus, beyond invention, the proper use of the ceph- alometer had to be demonstrated by individuals such as Björk (1947), Krogman and Sassouni (1957), Sassouni (1959) and others. Each used the 89 Longitudinal Growth Studies device for differing purposes, but they all demonstrated the value of the invention and its use. For example, Broadbent (1937a,b) focused on the accumulation of serial records on a large group of untreated individuals, while Brodie and associates (1938) used the cephalometer to study vari- ous aspects of clinical practice. Subsequent to 1930 and prior to the first Moyers Symposium, the documentation of normal facial growth, the effect of orthodontics on teeth and bones, and the pattern of facial growth were of considerable interest in orthodontic research endeavors. Work also continued during this period using vital staining and otherforms of animal experimentation, but there was a great deal of research initiated that employed the roentgenographic cephalometer and new study designs. This new focus was born via a confluence of opportunities in- cluding the widespread availability of x-ray equipment, the roentgeno- graphic cephalometer technique developed by Broadbent and longitudi- nal growth study designs. As a result, a number of growth studies were initiated across the country (Hunter et al., 1993; Table 1). BOLTON-BRUSH GROWTH STUDY The Bolton-Brush Growth Study is an excellent example of the value of the serial longitudinal design. The original Bolton-Brush Growth Studies were conducted at Case Western Reserve University in Cleveland, OH and consisted of longitudinal data gathered at regularly scheduled examinations, initiated at various young ages and terminating at various older ages. It is important to note that examinations were conducted four times during the first year of life, then twice per year to age five and then annually after that. The principal investigators were T. Wingate Todd, an anatomist and anthropologist, and Dr. B. Holly Broadbent, Sr. who was an orthodontist trained by Angle. Two studies were conducted simul- taneously: the Brush Inquiry focused on medical issues and the Bolton Study on dentofacial issues, but both shared the same intention—to study the growth and development of “normal and well” infants, children and adolescents from birth to adulthood. The Brush Inquiry began in 1928 and continued until WWII. This study was responsible for collecting various measurements of the body, radiographs of six skeletal areas (hand, elbow, shoulder, hip, knee and 90 Behrents Table 1. A listing of longitudinal growth studies (not inclusive and the names have changed over time). The Case Western Reserve University Bolton-Brush Growth Study The University of Toronto Burlington Growth Study The University of Oklahoma Denver Growth Study The Wright State University Fels Institute Longitudinal Study The Forsyth Research Center Twins Sample The University of Michigan Elementary School Study The University of lowa Child Welfare Study The University of Pacific Mathews Growth Study The Meharry Medical College Growth Study The University of Montreal Growth Study The Saint Louis University Bristol Growth Study foot), various psychological and behavioral tests, physician reports, hand- eye coordination exams, psychomotor development tests, food prefer- ence inquiries, muscle strength tests, foot and hand prints, and the col- lection of various questionnaires about education, health status, family illnesses, occupation and recreation. In all, some 22,000 examinations were conducted by the Brush Inquiry. The Bolton Study was conducted from 1928 until the 1960s, with intermittent records gathered to the present day. The Bolton Study collected photographs, height and weight recordings, conducted dental examinations, collected cephalograms and made dental impressions. Subsequent to discontinuation of the Brush Inquiry, the Bolton Study also collected hand-wrist x-rays. In all, the Bolton collection consists of 40,000- 50,000 dental casts and approximately 40,000 cephalograms. An average of 15 films were taken per participant, 600-2000 x-rays were available per age and three pure longitudinal cohorts exist. - The original Bolton Study population included almost 6,000 individuals who were generally of European ancestry and considered Clinically normal (both medically and dentally). The population is unique because of the size of the sample, duration of the record gathering and the completeness and precise standardization of the recordings made on each individual. - Once the Bolton Study was concluded in the 1960s, efforts were made to publish the results and were accomplished in 1975 (Broadbent, 91 Longitudinal Growth Studies 1975; Broadbent et al., 1975). The results of a similar investigation also were published that year based on a growth study at The University of Michigan (Riolo et al., 1975). This was an exciting and important time for those interested in facial growth. The finest serial collections of standardized cephalograms now were available. Using Bolton Study materials and similar collections, thousands of studies have been conducted, reported in the literature and thus have contributed to our understanding of normal and abnormal growth and development. The promise of the technology and strength of the longitudinal design had been fulfilled. A PERSONAL NOTE This was an important time for me in that I graduated from the orthodontic program at Case Western Reserve University (CWRU) in 1975 and accepted a position as a post-doctoral fellow at the Center for Growth and Development at The University of Michigan. During the next three years, I conducted research and began classes that eventually would lead to a PhD from The University of Michigan. In 1978, I returned to CWRU to begin an academic career. Early on, my colleague from Michigan, James McNamara, re- quested that I provide him with some cephalometric information on 18-year-olds from the Bolton Study collection for a project that he was working on at Michigan. This was fortuitous and pointed out one of the advantages of the longitudinal design mentioned above: Longitudinal de- signs also have a higher productivity potential; for example the data can be grouped for one study and later regrouped to address a study with different objectives. In collecting the information for Dr. McNamara, it was noted that additional cephalograms beyond 18 years of age were available in several Bolton subject folders. These cephalograms typically had been taken at 25-26 years of age by an investigator named C. Wesley Dupertuis. Dr. Dupertuis, an anthropologist at CWRU, had taken these films in the 1950s to investigate changes in the craniofacial complex in early adulthood over the span of 18-25 years. This study apparently was conducted to produce information for the military to aid in forensic identification (I can find no record of publication of these data). What was important was that it was clear that some of the individuals had 92 Behrents continued to grow into young adulthood. After investigating these Cephalograms, some preliminary findings were presented to my thesis advisor, Robert E. Moyers; he encouraged me to conduct a recall study at the Bolton Study and that was accomplished subsequently. ADULT GROWTH In the 1980s, a recall study was conducted at CWRU involving former participants in the Bolton Study (Behrents, 1984). The purpose of the study was to document and describe craniofacial alterations that occur during adulthood and aging. During the recall appointment, the following items were collected: health history, head and neck examination, temporomandibular joint examination, height and weight assessment, dental examination, dental impressions, lateral and posteroanterior Cephalograms, hand-wrist x-ray, and facial and intraoral photographs. In all, 113 individuals with existing records at least 17–35 years of age were Compared to recall films that were as old as 83 years of age (most of the recall participants were approximately 60 years of age). The results were unequivocal: craniofacial growth occurs in adulthood in a decreasing fashion from young adulthood, but even into the oldest ages studied. Both the size and shape of the bones of the craniofacial complex change with time; differential growth was evident (Figs. 3-4). In young adulthood, the directions of growth are specific to the individual, but in later adulthood, vertical dimensional changes are common. Males differed from females in terms of adult growth; females are smaller, grew less and grew in a more vertical direction than males. The maxillary incisors upright with age and the lower incisors flairforward, but only the females. Soft tissue change is more dramatic than that seen in the osseous Structures; there is an elongation of the nose, flattening of the lips and augmentation of the chin. Changes for some structures amounted to a 4-10% change. Overall, a few individuals showed no change of the Craniofacial complex, most showed some change albeit small, while a few other individuals demonstrated a large amount of change; variation in adult growth is obvious. Subsequent to the initial publications of this study (Behrents 1984, 1985, 1986, 1989, 1990, 1997), a number of similar studies have 93 Longitudinal Growth Studies B2537 Female 1 7–58 Figure 3. Superimposition involving a female from ages 17-58. been conducted; while there are details that differ, the overall findings generally are similar (Lewis and Roche, 1988; Love et al., 1990; Forsberg et al., 1991; Noverraz and van der Linden, 1991; Bishara et al., 1994, Formby et al., 1994; Cretot, 1997; West and McNamara, 1999; Dager et al., 2008). Based on the body of evidence, it is clear that much can be gleaned from longitudinal growth studies using roentgenographic cephalometry, but there are risks associated with such studies. One of the risks is considered so important that it often is stated that the growth studies that have been referenced in this paper would not be allowed to be repeated ever again. This most sensitive risk issue is radiation. 94 Behrents Male Figure 4. Superimposition of a male from ages 23-67. Note that this individual reported that he had a “nose job” during adulthood. RADIATION Recently, two publications have raised concerns about the use of radiation in a dental setting. The first was an article, “Radiation Worries for Children in Dentists' Chairs,” published in the New York Times by Bogdanich and McGinty (2010). The focus of the article was on a new imaging system called cone-beam computed tomography (CBCT). The expressed concern centered on the amount of radiation that the device produced. Given that the dissemination of the article was widespread across the Internet, many patients (or potential patients) were disturbed about the contents of the article and the seeming lack of controls associated with this new technology. Of course, such concerns incited professional organizations to respond with information and guidance. 95 Longitudinal Growth Studies As a second sensational volley, an article titled Dental X-rays and Risk of Meningioma was published in spring 2012 in the journal Cancer that again was distributed widely via the Internet and caused great concern. In the article, Claus and associates (2012) pointed out that ionizing radiation is an identified risk factor for meningioma, which is the most frequently reported brain tumor in the U.S. On that basis, the investigators wanted to determine whether or not there was an association between dental x-rays and the risk of meningioma. The method of study was described as a population-based case- control study that compared a group of individuals with meningioma (1433 patients, ages 20-79) to a group (1350) of control individuals matched on the basis of age, Sex and geography. Participants were asked to report from memory the types and frequency of dental x-rays they had had taken during their lifetime. This survey included self-reports of bitewings, full-mouth Series, panorex x-rays and cephalograms. In terms of findings, the authors indicated that individuals with meningioma were more than twice as likely to report ever having a bite- wing x-ray examination. They also indicated that individuals who report- ed receiving bitewing films on a yearly basis, or greater frequency, had an elevated risk. With panoramic X-rays, there was an increased risk of me- ningioma when the film was taken at a younger age or on a yearly basis or greater frequency. The study concluded that exposure to some dental x-rays appears to be associated with an increased risk of meningioma. There are some difficulties with this study. For example, recall bias is likely to occur in such studies when the subjects are asked to recall exposure to various risk factors (Lam and Yang, 2012). In addition, epidemiological studies like this only show associations and do not establish a cause-and-effect between exposures to risk factors and cancer. Perhaps most confusing, a full mouth x-rays series was not shown to be a risk factor even though bitewings were; this does not make any sense in that a bitewing examination is part of a full-mouth series. According to AAOMR, the study is invalid (Lam and Yang, 2012). Of additional concern are the potential risk factors that the participants in this study could have been exposed to over their lifetime that also might contribute to the risk for cancer; the study was conducted 96 Behrents from 2006-2011. As a result, the subjects were born sometime between the 1920s and 1990s. Given this range of time, one could ask as to what other risk factors were present during this time frame of some 70 years. RADIATION HISTORY Of course, the story of radiation begins with Wilhelm Conrad Roentgen who, on November 8, 1895, produced the first x-ray. Shortly thereafter, in 1898, Marie Curie discovered the radioactive properties of radium. These discoveries would have an immediate effect felt around the world (Wikipedia, 2013). The response by the medical and dental professionals was positive almost universally. For example, radioactive medicines and treatments touted to cure almost any ailment were developed quickly (Oak Ridge Associated Universities, 1998; Buchholz and Cervera, 2008; National Library of Medicine, 2013). In fact, the Kohler Antidote that was purported to Contain X-rays and cure headaches was advertised in 1896. In 1903, Thompson found that radioactivity could be found in well water. Early in the century, Yale professor Bertram Boltwood (1904, 1905) found that the healing waters of many spas contained radioactive water. On this basis, it was accepted that the reason that the many famous spas' waters had miraculous healing powers was because of the radiation. This effect was associated with hot springs at French Lick, IN; Hot Springs, AK; Mineral Wells, TX; Mount Clemens, MI; Saratoga Springs, NY; Steamboat Springs, CO; Warm Springs, GA; Warm Springs, VA; and many other spas across the country and around the world. Radioactivity was due to the presence of “radium emanation” which now is called radon gas produced by radium that is present in the ground through which the waters flow (Frame, 1989). Of course, not all could visit the spas, so bottled radioactive water became available to the public. This venture was short lived, however, as the U.S. government intervened because the half-life of radon gas is about 3.5 days and, therefore, bottled water often did not contain the radiation promised (Oak Ridge Associated Universities, 1998; National Library of Medicine, 2013). Thus, many alternate forms of radiating drinking water were developed. Most involved the inclusion of radium in 97 Longitudinal Growth Studies the construction of the water crock so that water could be added at night and the family could have radioactive water to drink by the next morning. The advertised result of drinking such water included curing just about any ailment including a promise that a third set of natural teeth would develop (Oak Ridge Associated Universities, 1998). Radium was added to common forms of candy, food, cooking utensils and dishes. Everyday items also contained radium, including jewelry, watches, automobile dials, clocks, cigarettes, cigarette holders, cigars, healing pads, comforters and pillows (Table 2). Radium was included in various beauty creams, soaps, bath salts and even toothpaste. To cure Sexual problems, radium-laced Suppositories, Condoms and devices designed to hold radium in a specific genital location were developed. Radium and/or uranium were available in some toys like chemistry sets and rings. Some golf balls even had a radioactive center (Oak Ridge Associated Universities, 1998; National Library of Medicine, 2013). Radioactivity also was found in the workplace. Portable x-ray devices were used by postal clerks to view the inside of packages; similar x-ray devices were used to look for nails in tires and radioluminescent rope was available because it glowed in the dark. Radiation was produced by electron tubes, sextants, smoke detectors and the electrodes of some Spark plugs were coated with radioactive polonium. Particularly common was the shoe-fitting fluoroscope. This device allowed a shoe salesman, parent and child to view a fluoroscopic image of the foot within the shoe simultaneously. Unfortunately, there was little shielding involved and after a period of time reports of dermatitis (a problem for shoe salesmen who put their hands into the device to check the size) and cancer (a problem for a shoe model requiring amputation of a leg) surfaced. In response, the U.S. Surgeon General issued a report on the matter and determined that these devices should expose the feet to no more than two Roentgens for no more than five seconds for each exposure and not more than twelve exposures per year (Oak Ridge Associated Universities, 1998). Medicinally, many pills, tablets, elixirs, salves and patent medi- cines were laced with radium and sold to the public. Medical treat- ments using radiation and radium were common. Treatments were available to remove body hair, treat respiratory problems and cure eye 98 Behrents problems, hearing problems, skin cancer, brain tumors, acne, eczema, birthmarks, ringworm and enlarged adenoids and tonsils (Mottram and Hill, 1949). With regard to tonsils and adenoids, treatment was performed in the 1920s until the 1970s in children and military personnel by placing long metal rods containing radium sulfate into the nostrils until they reached the back of the throat; they then were left in place for a designated time. This treatment was touted to reduce infection, shrink the tissues and prevent deafness. The technique also exposed the salivary, thyroid and pituitary glands and brain tissue during the process (National Cancer Institute, 2003). Similarly, tubes containing radium salts were placed internally via the mouth, esophagus, rectum, penis and vagina to treat Various maladies. While it might be thought that this listing of radiation uses is archaic and out of date, it is clear that the claims that radiation is useful in providing certain health benefits still are present. For example, since the 1980s, radioactive materials have been offered to the public in the form of bracelets, to add radiation to cigarettes, to deodorize refrigerators and to remove plaque from the teeth. Various forms of electromagnetic radiation also remain a concern with regard to television sets, computer monitors, cell phones and towers, microwave ovens, airline travel and airport security devices. Of course, there also are some people who believe in radiation hormesis (a belief that some radiation is good for you) who still can gather in spent uranium mines to take the cure (Luckey, 2006). ATTITUDE TOWARD RADIATION The history of radiation treatments is a curious one indeed, as attitudes at times have been both extremely positive and extremely negative. During the initial work by Roentgen, his discovery of x-rays was followed by an intense amount of testing by him as to the properties of X-rays. He conducted a series of experiments to determine the properties of radiation, before he made his announcement of the discovery. Other investigators were working to do the same thing, so he did this work in secret in his lab. Importantly, he discovered that radiation declined with distance from the x-ray source, and he found that x-rays did not go through lead, but did go through other things. In fact, he used lead 99 Table 2. Common radioactive products and treatments. These products and treatments can be found on the Internet by searching for them by name or category. When located on the Internet, it is not always clear which product images are copyright protected and which are not. For general information on these subjects, please consult Oak Ridge Associated Universities, 1998; Buchholz and Cervera, 2008; National Library of Medicine, 2013. WATCHES, COSMETICS, DRINKING FOOD, CANDY & CLOCKS, DIALS BEAUTY & . WATER COOKING & JEWELRY TOBACCO PADS & COMFORTERS HEALTH TOOTHPASTE * Emanators * Burkbraun * Vigor Health * Batscart * Degnens Radio-Active * Tho-Radia * Doramad (1930-35) Radium Pendant (1930) Radium Solar Pad (1915-30) Cream (1930s) Radiooktive * Radium Spa Schokolade * Radiolumine- Cigaretten * Ward’s Radium Ore * Revigorette Zahncreme * Revigator * Heidelberger scent watches * Virginia Healing Pad * Fitrite Radium (1945) (1912-38) Radium Pastillen * Automobile dials Radium Export | * Cosmos Radioactive Outfit Cream * Tho-Radia * Radium * Radium Brand * Clocks Cigars (1920s) Pad (1920s–30s) (hands) Dentifrice Emanator Cremery Butter * Gauges * Lifestone * Gra-Maze Uranium * Radisavon (1929) * Radiumyizes Cigarette Comforter (1960s) Radium Soap * Thomas Ketszersult Holders * Parapack * Radium Cone (bread) (1960s) * Radiowoll Pack Emanation (1930s) * Housekeepers X- * Radiogen Pack Bath (1925) * Zimmer radium cooking * Radio-active Body Pad Emanator utensils * Ray-Cura * Ionic *Uranium Colored * Standard Radium Charger Glass Compress (1960s) * Fiestaware * O-Ray Electro Radioactive Dry Compress * Radon Pillow § RECENT RADIATION X-RAY & PRODUCTS SEX/MALE TOYS & IN THE MISCEL- RADIUM & PROBLEMS SPORTS WORKPLACE LANEOUS MEDICINES TREATMENTS TREATMENTS *Vita Radium * Gilbert’s Atomic * Postal Clerks * Electron * Radithor * The California Radium | * Nico Clean Suppositories Energy Lab Portable X-ray Tubes * Arium Radium Milk & Rest Cure Tobacco Card * Nutex Radium (1940s-70s) Device (1938) * Sextants Tablets * Tricho System (1900s- (1990s) Condoms * Porter * Portable Tire X- * Smoke * RadionE Radium 20s; body hair * NAC Plate (1990) (1940s-50s) Chemcraft ray Device Detectors Lozenges removal) * Stryeris Wrist * Radiendoc- Atomic Energy * Radium House * Firestone * Radio X Tablets * Degnens Eye Band (2005) rinator Senior Outfit Heaters Spark (1920) Applicator (1915-30) * Medronics (1930) * Spinthariscopes * Radiolumine- Plugs with * Standard Radium * Radium Nose Cup Plutonium * Soothol (1940s-50s) scent Rope Radioactiv Solution for (respiratory Powered Radium * Kix Atomic Bomb (1930s-60s) e Drinking (1918- problems) Pacemakers Bougies Ring * Shoe Fitting Polonium 28) * Radium Respirator (1974) (1920s–30s) * Radioscope Fluoroscope Electrodes | * Kohlers Antidote (respiratory * Endless * Testone * Tom Mix Tiger- (1940s-60s) (1896; headache) problems) Refrigerator/ Radium eye Ring (1950) * X-rays (skin cancer) Freezer Appliance & * Radio Golf Balls * Liquid Sunshine (brain Deodorizer Suspensory (1910–30) tumors) (1983) (1920s–30s) * Acne & eczema X-rays | * Check-up Plaque (1900s-50s) Fighting Gum * Ultraviolet light (1980s) (1950s-80s) * Ringworm (1949) * Tonsils & adenoids (1926-60s) * Free Enterprise Radon Health Mine f £ Longitudinal Growth Studies Shielding so as to avoid exposing himself to x-rays. This finding, however, generally went unnoticed. After time, however, those investigating and using radiation came to understand that it did not cure everything and its use could be dangerous. Eventually it was noted that excessive x-rays produced erythema, skin lesions and cancer. For example, those who held films in position during the taking of X-ray films could develop dermatitis, necrosis and even cancer. Unfortunately, dentistry was slow to realize this danger. In the first half of the 20th century, concern about radiation began to increase in small ways, mainly via the media. When one of Thomas Edison's workers who was experimenting with radiation died in 1904, it became clear to some that repeated exposure could cause problems. Roentgen died in 1923 of intestinal cancer and it was believed widely that this resulted from exposure to X-rays (this probably is untrue; see above). In the 1920s and 1930s, a group of ladies, known as the Radium Girls, who painted watch faces using radium paint to make the numbers glow was described widely in the news. Their routine of dipping their brush in their mouth in order to “tip” the brush and then painting the numbers caused severe medical problems and death. In 1932, it was reported widely in the news that Eben Byers had developed a gruesome facial cancer and then died of radium poisoning (Wikipedia, 2013). This was news because he was a famous millionaire industrialist and champion golfer who began drinking a radium-laced elixir following an injury; after drinking three to four half-ounce bottles per day (and an overall estimated 1500 bottles total), he died. Shortly thereafter (1934), Marie Curie died of aplastic anemia directly relatable to exposure to radiation. While these events were singular in nature, their collective effect was to make a growing number of people aware that radiation could pose a danger and some manner of caution should be exercised in its use. Still, the public generally considered radiation in a positive light. The list of items in Table 3 presents a question whose answer might not be easy to discern: “What do all the items have in common?” The answer is “None have anything to do with radiation.” The apparent explanation is that the companies that manufactured and sold these items found it helpful to imply that these products were associated with radiation strictly for advertising purposes. 102 Behrents Table 3. Products advertised with reference to X-rays, radiation or radium. Radium Hair Clippers Radium Black Boot Polish Radium Leather Dye Radium Playing Cards Home Brand Radium Lump Gloss Patts X-ray Liniment Starch X-ray Dry Battery X-ray Renovator Cleaning Fluid X-ray Raisin Seeder X-ray Ointment X-ray Brand Lighting X-ray Oil X-ray Lemon Press X-ray Cream Furniture Polish X-ray Coffee Mill X-ray Soap X-ray Blue Razor Blades X-ray Stove Polish X-ray Brand Razor Hone X-ray Brand Golf Balls X-ray Brand Prophylactics X-ray Whiskey X-ray Waltzes Snitemanís X-ray Horse and Cattle Liniment Radium Dance Music Nestle Nuclear Chocolate Atomic Fireball Red Hots In the second half of the 20th century, opinions about radiation continued to change. The dropping of atomic bombs in Japan at the end of the WWII was celebrated as a great technological accomplishment and victory. However, the development of nuclear capabilities by other nations and the Cold War was viewed with great fear. Subsequently, nuclear bomb tests were conducted in the open air, causing great alarm and subsequent testing went underground. Similarly, the construction and use of nuclear power plants again was viewed as a great achievement, but the attitude toward them changed over time. This is understandable given that there have been approximately 100 nuclear accidents over the past 60 years, including those at Three Mile Island (1979), Chernobyl (1986) and Fukushima (2011). These changing attitudes were amplified by the popular media through the movies (e.g., Operation Uranium, The Atomic Kid, The Atomic Submarine and The China Syndrome), comic books (e.g., Atomic Mouse, the Atomic Superboy and even Superman himself became dangerous because of his x-ray vision). There was a growing fear that x-rays could produce genetic monsters. Since 1987, even the bumbling Homer Simpson has cast information about the dangers of radiation on a weekly basis via his job in a nuclear power plant and its potential effect on the environment (e.g., three-eyed fish). 103 Longitudinal Growth Studies A CONTEMPORARY VIEW OF RADIATION Before advancing some thoughts on present matters, perhaps it would be helpful to revisit the past, namely the Brush Inquiry and Bolton Study. When the recall studies were conducted in the 1980s, the effect of prior radiation was a significant concern. Many of the recall subjects had had many radiographic examinations during their youth and there was concern that this might have affected their health during adulthood. In the early years of the Bolton-Brush Studies, the radiographic examinations that they had undergone often were extensive (involving many views of the body as well as the head; Fig. 5), lengthy (i.e., some exposures were ten seconds in length), periodic (conducted regularly over many years) and customarily accomplished in such a way that secondary radiation was not considered (i.e., open tube-heads and no lead drape to shield). At the time (1930s-1940s), radiographic technology and radiation hygiene practices were extremely crude judging by today's Standards. Given this history of exposure, one might wonder then how the Bolton-Brush participants fared later in life. Because of this concern, a health history was included in the recall study in the 1980s. In addition, a retired radiologist went over the health history with the participant during the recall examination and a head and neck examination was performed. Approximately 160 health histories were available. In addition, mortality information on other participants (obviously these were not recalled) was provided by those recalled (e.g., other family members and childhood friends). Most of the recall participants were approximately 60 years old. Assessed in the 1980s, the health of the recall study partici- pants was considered good. Mortality rates generally were low for the group with regard to life expectancy. Most born in the 1930s had a life expectancy of about 62 years of age. Thus, the sample was “more alive" than expected. The largest cause of death was suicide and other forms of trauma (e.g., automobile accidents). Based on histories and mortality reports, low rates for cardiovascular disease and cancer were seen. The health histories suggest that ailments associated with aging were present (e.g., arthritis, hemorrhoids) and that there was no obvious relationship between radiation exposure and health conclusions 104 Behrents BO LTON – B RUSH RECALL STUDY RADIO GRAPH | C DATA O BTA|N E D AT EACH EXAM NATION CEPH A LO M ETR | C F | LMS NR- *** _/Č) | FRONTAL 2 * - LATE RA L A ) CHEST 2 SH O U LD ER S E LBOW — 2 WR IST — 2 H | P PE LV | S 2 & /** 2 T] B | A | FOOT 2 ANKLE ſº Q Figure 5. A diagram showing the radiographic image views collected at each examination during the original Bolton Brush Growth Studies. Compromising conditions often associated with radiation. In the end, the population who entered the original studies as normal, “well” children became normal “well” adults. In addition, it was clear that the children of the study participants were themselves normal and well. 105 Longitudinal Growth Studies Based on this assessment, it appears that several fair, practical conclusions might be drawn. It appears that people in good health can tolerate an occasional x-ray without health compromises. Also, given that it is unlikely that we would subject any of our patients to such extensive radiographic examinations as those seen with the Bolton-Brush Study participants, it is a reasoned opinion that our contemporary radiographic Surveys conducted with due care toward radiation hygiene are such that they should be of little consequence to our patients. It often is commented that serial longitudinal growth studies using X-rays would never be repeated for the purpose of documenting and describing normal growth and development and that surely is true; this sentiment is shared by many of the directors of the various growth studies (AACF Legacy Collection Project History, 2013). However, such a conclusion is based mainly on the present attitude about the dangers of radiation and, in spite of advancements that have been made, in radiation technology and hygiene practices. For example, the radiation equipment used in a contemporary setting is far less powerful than those used in the early part of the 20th century; the beam is focused, collimated and filtered; patient shielding is required; scout films can be generated (Panorex became available in the 1960s); dental film speed has progressed from D (Ultraspeed in 1940) to E (Ektraspeed in 1980) to digital sensors (1982); and screened film has progressed from slow, par and fast to ultraspeed with the introduction of rare earth screens and now to digital sensors. In addition, CBCT machines are becoming common in a dental setting, and the companies involved suggest that better (and more useful) images can be produced with less radiation than previously used. CONCLUSIONS On the basis of this discourse, it should be clear that the many longitudinal growth studies conducted during the previous century using x-rays are a valuable asset to those interested in the growth of the face. Knowledge of growth and development plays a fundamental role in orthodontic diagnosis, treatment planning, the evaluation of the outcome of care and the improvement of treatments. It is accepted that x-ray technology and hygiene practices have improved tremendously, Further, it also is clear that the value of x-ray images in orthodontics, for the most part, is not questioned. 106 Behrents What also is true is that the public generally is afraid of things that they do not understand and cannot sense. This is true particularly when new technology is introduced, and it is pointed out that the new technology can have both positive and negative consequences. Thus, in employing x-rays in practice, it is vital that practitioners appreciate the attitudes of the public they serve and educate them on the benefits and risks involved. 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A model for the study of developmental processes in dental research. J Dent Res 1976;55 (3):359-366. West KS, McNamara JA Jr. Changes in the craniofacial complex from adolescence to midadulthood: A cephalometric study. Am J Orthod Dentofacial Orthop 1999;115(5):521-532. Wikipedia. History of Radiation Therapy. March 24, 2013. Wikipedia.org/ wiki/History/History 111 SKELETAL ANCHORAGE: ITS POSSIBLE IMPACT ON ORTHOGNATHIC SURGERY William R. Proffit, Nicole R. Scheffler, G. Gibson McCall ABSTRACT Skeletal anchorage has the potential to change jaw relationships in two major ways: intrusion of maxillary posterior teeth to close anterior openbite by decreasing anterior face height and forward movement of the maxilla and mid- face to correct maxillary deficiency. Individual bone screws at the zygomatic Crest or in the palate can provide satisfactory anchorage for maxillary posterior intrusion; mini-plates rather than individual bone screws appear to be required for Class Ill growth modification. For posterior intrusion, using NiTi springs from the skeletal anchor to a bonded maxillary splint with occlusal coverage offers two major advantages: control of the faciolingual position of the teeth being intruded and an impediment to lower molar eruption that can limit the amount of favorable upward-forward mandibular rotation. A preliminary guideline is that up to 6 mm openbite closure with this method usually can be achieved; more severe problems likely will require Surgery. For protraction of the maxilla, current data from 25 consecutive early adolescent patients suggest that there is approximately an 80% chance of Successful forward displacement of the maxilla and a 30% chance of significant mid-face advancement. Significant retardation of mandibular growth was seen in about 33% of this group. The extent to which the initial treatment effects will be maintained during subsequent growth is not clear yet. It is likely that both of these applications of skeletal anchorage will decrease the number of patients needing surgery to reposition or advance the maxilla superiorly, but long-term follow-up is needed to establish how many patients can be treated non-surgically. Skeletal anchorage for camouflage of Skeletal problems is unlikely to have a significant impact on the amount of Surgical treatment. KEY words: orthognathic surgery, skeletal anchorage, bone plates, openbite, Class Ill malocclusion 113 Skeletal Anchorage Skeletal anchorage, based on individual bone screws or mini- plates attached with two or more screws, now makes it possible to accomplish types of tooth movement that previously were impossible. Such skeletal anchorage now might allow successful orthodontic treatment of patients who previously would have required orthognathic Surgery. This paper focuses on closure of anterior openbite by intrusion of maxillary posterior teeth as an alternative to orthognathic surgery. The other major use of skeletal anchorage that has the potential to alter the number of patients who need surgical correction of a skeletal Class III problem, growth modification in Class Ill children, is covered in Some detail in the companion paper in this volume by De Clerck and colleagues (2014). The impact of this method on orthognathic surgery and the possible use of more extensive tooth movement for camouflage of jaw discrepancies also will be discussed briefly in an attempt to put the skeletal anchorage/orthognathic surgery conflict in perspective. INTRUSION OF MAXILLARY POSTERIOR TEETH Technique The anchorage above the maxillary posterior teeth that is needed to intrude them can be obtained either from mini-plates at the base of the zygomatic arch, a bone screw that penetrates between the posterior teeth at the mucogingival junction into cortical bone or bone screws in the palate near the midpalatal suture. Experience suggests that mini- plates with three screws perform better in the maxilla than those with two screws, but four screws appear to offer no advantage over three (Fig. 1). Mini-plates have two advantages: they provide excellent resis- tance to being displaced when heavier forces are needed; and a wire can be attached to the attachment that comes through the tissue (ideally, at the mucogingival junction) so that the force vector can be adjusted as desired. They have a major disadvantage, however: to place them, a flap must be reflected to expose the bone surface and this must be repeated to remove them. While this procedure is not major surgery, it is significantly more than placement of a screw. Most orthodontists would feel comfortable with placing a screw, but would want a maxillo- 114 Proffit et al. Number 4. Figure 1. Data from this sequence of patients treated in Taiwan indicate that in the maxilla, three screws give a higher success rate than two screws, but four Screws are not better than three. Courtesy: Dr. Tony Wu. facial surgeon to place mini-plates—and outside major population cen- ters, it can be difficult to find a surgeon who is willing to do so. A successful technique for placing a mini-screw that will be used as anchorage for intrusion of maxillary posterior teeth has two steps (Scheffler and Proffit, in press). The first is diverging the roots of the teeth between which the screw will be placed. The second is placing the screw 50 that the screw head emerges into the mouth at the mucogingival junction above the teeth. There are two possible positions and the choice affects the hori- Zontal component of the force vector. Placing the screw between the sec- ond premolar and first molar provides a slight mesial component, which Would facilitate maintenance of a Class I molar relationship or mild com- pensation for a Class || tendency and is best if the patient has a reverse Smile arc and occludes on premolars and molars. Placing it between the first and second molars provides a slight distal component, which would Provide some compensation for a Class || tendency. This location is best for larger anterior openbites and for patients occluding only on second and/or first molars. Higher success rates have been reported for mini- *WS that were loaded immediately than when loading was delayed (Manni et al., 2011). 115 Skeletal Anchorage The force used to intrude the maxillary posterior segments, when applied from an anchor on the facial side, also causes these teeth to tip facially (Fig. 2) and thus must be controlled. One way to accomplish this is a second bone screw on the lingual. A lingual screw can be both difficult to connect so that continuous force is maintained and difficult for patients to tolerate. A second possibility is transpalatal lingual arches—usually two are required to control both first and second molars. With each of these approaches, it is difficult to control eruption of the mandibular posterior teeth as the maxillary teeth intrude. The best method at present is the use of a modified Erverdi appliance (Erverdi et al., 2006), a bonded splint over the posterior teeth that is connected to mini-screws by Niſi Coi springs hooked to attachments on the splint (Fig. 3). The splint provides excellent control of the transverse position of the teeth and its occlusal coverage impedes eruption of mandibular teeth. Retention after intrusion also is an important part of successful treatment. After intrusion is complete and the bonded splint is removed, the maxillary archwire (or brackets/molar tubes) should be tied to the screw head or mini-plate to control re-eruption (Fig. 4). When treatment is completed, immediate use of a suckdown retainer with a button embedded on the lingual side is recommended so that it can be tied to the skeletal anchor. As soon as feasible, this type of retainer should be replaced by a removable Hawley retainer with occlusal coverage and hooks for elastics to connect to the skeletal anchor. Changes in Treatment The best source of force for intrusion is superelastic Niſi springs (Fig. 3) because they require no cooperation and deliver a known force. As with intrusion of any type, light force is needed—two 150 gm springs per side to a splint over all the maxillary posterior teeth is adequate. A clinical observation is that the openbite closes on average about 1 mm — Figure 3. NiTi springs attached to hooks in the splint provide a known light force for intrusion. Typically, two springs that deliver 150 gm are arranged as shown here. With a screw between the first and second molars, there is a distal component of force that tends to retract slightly the teeth, which would decrease overjet. 116 Proffit et al. figure 2. Attaching posterior teeth to a screw on the facial side creates a moment to tip the teeth facially, which must be controlled during treatment. 117 Skeletal Anchorage Figure 4. After intrusion is complete and a fixed appliance has replaced the splint, it is important to tie the posterior segment to the anchor to prevent re-eruption. per month, but the first 2 mm of posterior intrusion occurs reasonably quickly and further intrusion is slower. In 28 intrusion patients evaluated recently at The University of North Carolina (UNC; further data displayed below), the average time for intrusion was 6.9 + 2.8 months and the openbite was completely closed in 26 of the 28 patients. It remained slightly open (< 1 mm) in the other two (McCall, 2012). Preventing the lower molars from erupting as the upper molaſs are intruded is an important component of successful reduction of anterior face height because if the lower molars erupt, the desired upward-forward rotation of the mandible would not occur. An advantagº 118 Proffit et al. of the bonded splint for intrusion is that it does impede eruption of the lower molars. The splint method was not used in early patients in the UNC sample and many of those are the patients who by now have follow- up data. The result was less decrease in anterior face height than was anticipated in many of the patients (Table 1). Note that the mandibular molars erupted almost as much as the maxillary molars were intruded and, as a result, both the vertical position of the chin and the mandibular plane Showed only small changes. Post-treatment Change On average, in intrusion patients with more than one year recall there was 0.8 mm re-eruption of the maxillary molar, with considerable variation (Table 1). The openbite remained closed, however, in 24 of the 26 patients in whom it was corrected. As Table 2 shows, none of the patients had major relapse (> 4 mm or 4°) and clinically significant changes (> 2 mm or 2°) were rare. Table 1. Intrusion of maxillary posterior teeth: outcome data. 28 patients with at least one year recall. Average time in active intrusion = 6.9 + 2.8 months. TREATMENT POST-TREATMENT DIMENSION CHANGE CHANGE Maxillary molar up 2.0 + 1.6 mm –0.8 + 0.7 mm Mandibular molar up 1.7+ 2.0 “ -0.2 + 1.4 “ Anterior face height –0.9 + 2.7 “ . 0.6+ 1.2 “ Mandibular plane angle -0.2 + 1.8° -0.2 + 1.5° Table 2. Intrusion of maxillary posterior teeth: number with clinically significant post-treatment change. n = 28 2-4 mm (°) >4 mm (°) up down Maxillary molar O 1 (3.6%) In One Mandibular molar O 2 (7.2%) In One Maxillary incisor O 2 (7.2%) In One Mandibular incisor 1 (3.6%) O nC)ne Mandibular plane angle || 5 (18%) 4 (14%) In One 119 Skeletal Anchorage Comparison with orthognathic surgery outcomes. The outcomes in 37 patients who had LeFort l osteotomy during the same time period as the intrusion patients are shown in Figure 5. Note that the patients Selected for surgery had significantly larger openbites prior to treatment (Fig. 5A). Correction of the openbite created an average of 1 mm overbite in both surgery and intrusion patients. There was some post- treatment decrease in overbite in both groups, but less than would have been expected from the amount of downward movement of the molars because of compensatory elongation of maxillary and/or mandibular incisors (which, however, never exceeded 2 mm; Table 2). 3-I-OVerbite– - - o Pre-tz 2–H - O End tx upper 1st molar O © Recall 1 -- +SD to palatal plane 0- - -L -- Mean ~ -1.--T - # -SD st -2 Ö -3- O –4–4– - –5–1. -6 | – - A Molars up Maxilla up Molarºp Maxilla up n = 28 n = 37 n = 28 n = 37 4 T-T- opre-tz 2 - - © End tx h © Recall 0 +SD 7 -2 - § -4 Mean ? T. § -6 O -SD -8 () -10 - 12- -14- 0 C Molars up Maxilla up D Molars up Maxilla up n = 28 n = 37 n = 28 n = 37 Figure 5. Graphs comparing the changes in patients treated with posterioſ intrusion versus those in patients who had a LeFort | osteotomy for superioſ repositioning of the maxilla. A: overbite; B: upper molar to palatal plane, 0. palatal plane to S-N; D: mandibular plane angle. 120 Proffit et al. As one would expect, the surgery patients had no change in the relationship between the upper first molar and the palatal plane, while the intrusion patients had a significant decrease (Fig. 5). In contrast, the intrusion patients showed no change in the inclination of the palatal plane to SN, while the surgery patients had an increase in this angle as the posterior maxilla was elevated. The mandibular plane angle had little change for the intrusion patients and an average 2.5° decrease for the Surgery patients. A summary of data from the UNC experience indicates that: • Intrusion of maxillary posterior teeth can give satisfac- tory correction of moderately severe openbite (up to 6 mm, perhaps more if incisor elongation is needed). • Part of the openbite correction in most molar intrusion patients is slight incisor elongation, which rarely is as much as 2 mm and never more than that. This occurs primarily during the finishing phase of treatment. • LeFort I surgery is more likely to produce a shortening of anterior face height. MODIFICATION OF CLASS III GROWTH De Clerck's use of relatively light Class III elastics to mini-plates in the maxilla and mandible has opened new possibilities for treatment of skeletal Class III problems. The presentation of this important data largely has been in terms of average changes and the best data set is 25 consecutive patients treated by De Clerck in Belgium who had 3D Superimposition analysis at UNC (Nguyen et al., 2011; De Clerck et al., 2012). The outcomes of this treatment are impressive, but variable, and mean changes become somewhat misleading. It is interesting to look at the percentage of that group who had significant maxillary and mandibular changes (Table 3; new data, not presented in the previous publications). Eight of the 25 patients had 4-5 mm forward growth of the midface and another 12 had 2-3 mm forward movement, while five had little or no maxillary change. So there was an 80% chance of a positive maxillary response. 121 Skeletal Anchorage Table 3. Class Ill elastics to miniplates: percentage of patients with skeletal change (Nguyen et al., 2011; De Clerck et al., 2012). 25 consecutive cases, change relative to cranial base. MIDFACE Forward 4-5 mm 8/25 = 32% Forward 2-3 mm 12/25 = 4.8% No response (0-1 mm) 5/25 = 20% MANDIBLE (CHIN) Back 4-5 mm 3/25 = 12% Back 2-3 mm 5/25 = 20% No response (0-1 mm) 17/25 = 68% Mandibular growth changes also were noted in most of the pa- tients, typically consisting of a decrease in the gonial angle, but Some- times there was a backward movement of the chin relative to the crania base—which previously has not been observed in humans, although it has been seen in primate experiments (Janzen and Bluher, 1965). How often does that occur? In this group, three of the 25 patients (12%) had the chin move backward 4-5 mm relative to the cranial base and another five (20%) had 2-3 mm backward movement of the chin. In the others, the chin stayed in the same place or grew forward. So there appears to be about one chance in three of major improvement in the mandibular growth pattern. That leaves multiple questions about the likely long-term outcomes of treatment. Two important ones: 1. This growth modification treatment has been carried out in early adolescence. What is likely to happen during the adolescent growth spurt and post-adoles- cent mandibular growth? No answer is possible until more long-term data are available; and 2. What are the characteristics of the patients who have a maxillary but not a mandibular response and vice versa? To date, that has not been established. 122 Proffit et al. When these questions have been answered, Class Ill growth modification certainly has the prospect of decreasing the number of Class Ill surgeries in the future. CAMOUFLAGE AS AN ALTERNATIVE TO SURGERY? Skeletal anchorage makes it possible to retract incisors further than previously was accomplished easily and to retract all the teeth in the maxillary or mandibular arch. This was not possible until mini-screws or temporary anchorage devices (TADs) became available. Tooth movement does not change jaw relationships, however, and it is important to keep in mind that tooth movement alone to correct a malocclusion may create or accentuate problems in both oral health and facial appearance. In a patient with a skeletal Class Il problem, excessive retraction of maxillary incisors risks apical root resorption as well as lack of lip support and related esthetic problems, while excessive proclination of lower incisors can lead to fenestration of alveolar bone and gingival recession without improving chin deficiency. In Class III patients, excessive proclination of upper incisors does not camouflage maxillary deficiency. Retraction of mandibular incisors for Class Ill camouflage esthetically is acceptable only in patients who have proclined incisors to start with. Class Ill patients of European descent usually have upright and lingually tipped mandibular incisors, so further retraction makes the chin more prominent. Those of Asian descent often have proclined lower incisors, as do some patients of African descent; this provides a greater opportunity for camouflage treatment—but the Soft tissue response is more favorable in Asians. The bottom line: the limitation of skeletal anchorage in camou- flage treatment is that it makes it possible to move teeth far enough to impair oral health and damage rather than improve the patient's facial appearance. CONCLUSIONS An estimate of the likely impact of enhanced incisor retraction, Class Ill growth modification and intrusion of maxillary posterior teeth is 123 Skeletal Anchorage shown in Figure 6. At this early stage in follow-up of skeletal anchorage patients, any estimate carries with it a large amount of uncertainty. New- ertheless, it seems likely that the greatest impact of skeletal anchorage on orthognathic surgery will be orthodontic-only treatment of patients with moderately severe anterior openbite, especially those in whom shortening anterior face height is not an important goal. Will skeletal anchorage for Class III elastics decrease the num- ber of patients who need maxillary advancement and/or mandibular setback? Although it seems reasonable that this should be the case, the extent to which catch-up growth will recreate the skeletal problem still is unknown. We already know that 66–75% of the pre-adolescent patients Surgical- Orthodontic Treatment. A Hierarchy of Stability ) Maxilla up H. Mandible forward Maxilla forward Mx up + Mn forward Mx forward + Mn back Mandible back Maxilla down _ Maxilla wider Figure 6. The likely impact of TADs on orthognathic jaw movements. The greates: effects will be on superior repositioning of the maxilla and advancement of the maxilla—the size of the arrows indicating the magnitude of the change is just guess at this point. Changes in the amount of surgery to advance the mandible or set it back would occur from more camouflage treatment. Minimal change in mandibular advancement would be expected and a decrease in setting the mandible back would be expected to be almost exclusively in patients of Asian descent because they are much more likely to have proclined lower incisors. Asia only 124 Proffit et al. with initially successful facemask treatment do not need surgery after adolescent growth—but 25-33% do. Will this be the eventual outcome for patients who achieve greater change with implant-supported elastics? Only long-term recall will answer that question. Excessive retraction of incisor teeth compromises dentofacial esthetics and this limits the number of patients for whom skeletal andhorage to increase the amount of maxillary or mandibular incisor retraction is a realistic alternative to repositioning the jaws. Class || Camouflage most likely is to be successful in patients of Asian descent. Even without TADs, it is possible to retract maxillary incisors too far in skeletal Class Il patients, so the impact of TAD-supported camouflage tooth movement on mandibular deficiency is likely to be small. ACKNOWLEDGEMENTS This project was supported in part by NIH grant DE-05215 from the National Institute of Dental and Craniofacial Research. We thank Ms. Debora Price for data base management and Dr. Ceib Phillips for statistical Consultation. REFERENCES De Clerck H, Nguyen T, de Paula L, Cevidanes L. Three-dimensional assess- ment of mandibular and glenoid fossa changes after bone-anchored Class Ill intermaxillary traction. Am J Orthod Dentofacial Orthop 2012; 142(1):25-31. - Erverdi N, Usumez S, Solak A. New generation open-bite treatment with zygomatic anchorage. Angle Orthod 2006(3);76:519–526. Janzen EK, Bluher JA. The cephalometric, anatomic and histologic changes in Macaca Mulatta after application of a continuous-acting retraction force on the mandible. Am J Orthod 1965;51(11):823-850. Manni A, Cozzani M, Tamborrino F, De Rinaldis S, Menini A. Factors influencing the stability of miniscrews: A retrospective study on 300 miniscrews. Eur J Orthod 2011;33(4):388-395. McCall G. The efficacy of temporary skeletal anchorage versus maxil- lary osteotomy in treatment of anterior open bite. Chapel Hill: Un- published Master's thesis, Department of Orthodontics, University of North Carolina 2012. 125 Skeletal Anchorage Nguyen T, Cevidanes L., Cornelis MA, Heymann G, de Paula LK, De Clerck H. Three-dimensional assessment of maxillary changes associated with bone-anchored maxillary protraction. Am J Orthod Dentofacial Orthop 2011;140(6):790-798. Scheffler NR, Proffit WR. Skeletal anchorage technique for intrusion of maxillary posterior teeth in treatment of anterior open bite. J Clin Orthod 2013; in press. 126 PERIODONTAL SCREENING: PRACTICAL PROTOCOLS FOR THE ORTHODONTIST Lee W. Graber ABSTRACT With the increasing number of adult patients being seen by orthodontists, it is important to identify those who might be at risk for adverse periodontal response during treatment. A recent Centers for Disease Control (CDC) study indicates that almost 50% of adults may have periodontitis, a much higher percentage than previously had been reported. Orthodontists need to be able to identify those patients who are at risk and properly refer them prior to initiating orthodontic treatment. This chapter outlines a periodontal screening protocol developed by a joint task force of the American Association of Orthodontists (AAO) and the American Academy of Periodontology (AAP). This protocol is a practical screening option for orthodontic clinicians and other members of the oral healthcare team. KEY WORDS: periodontal screening, periodontal disease and orthodontics, periodontal risk assessment, adult orthodontics, dental malpractice A PATIENT'S STORY It is 5:00 p.m. on what has been a very busy day in your orthodon- tic office. Like many of your colleagues, you have organized your time so as to Schedule a late afternoon examination, allowing some of your staff to leave as you work with your treatment coordinator on a new patient evaluation. The patient who presents today called the preceding Friday and informed your receptionist that she had a friend who was straight- ening her teeth with aligners. She went on to say that she was certain that She could wear aligners, but wanted to have a consultation. Unfor- tunately, as the call was taken at the end of the day, there was no time for your receptionist to follow up with the patient's dentist—and after all, the patient was “self-referred.” 127 Periodontal Screening The patient arrives at the office ten minutes late, but is excited about fixing her teeth. On your new patient questionnaire (combined with your office medical and dental history form), you ask for the patient’s “goals” from orthodontic treatment and she scribes, “Give me a new smile ©.” Initial examination notes are taken with the following summary notation: 34-year-old female with a normal medical history, Class I mal- occlusion with anterior openbite, tongue thrust, 3 mm of overjet with inflamed gingiva and fair oral hygiene. You proceed to recommend ful orthodontic diagnostic study records to complement the intraoral and facial photographs your new assistant has taken for the examination. In your office, diagnostic records include a panoramic radiographic survey, a cephalometric film and articulated study models. You also inform the patient that it is unlikely she will “qualify” for aligners due to the chal- lenge of her malocclusion. She remains positive, motivated by her vision of a beautiful smile. In line with the patient's excitement on starting her orthodontic treatment, records are scheduled for the following day with an “immediate consultation” later in the day after you have had a chance to look at the films. In your office, you develop both a treatment plan and treatment sequence after looking at the films and your clinical notes. For this patient, you write in your treatment plan: Braces Level upper anteriors Level lower anteriors Close openbite Space for restorative Retainers You write in your treatment sequence: Refer for Prophy: 1. Section bridge 2. Place braces 3. Complete alignment 128 Graber 4. Complete bite closure 5. Retain 6. Send back to dentist ... and you proceed accordingly. Of course, this is NOT your patient. These notes and procedures, however, demonstrate what is customary for orthodontic patient man- agement in many orthodontic practices. You simply have been asked to Step in to the shoes of a colleague like an armchair quarterback looking at somebody else's game. This patient is realthough and while the “facts” have been altered slightly to mask both the patient and treating ortho- dontist, they represent a patient protocol with which most experienced clinicians can identify. The patient's treatment outcome and relevance to adult Screening will be reviewed at the end of this chapter. A PERCEIVED NEED The number of adults in most orthodontic practices has continued to rise. The latest patient survey from the American Association of Orthodontists (AAO, 2013) indicates an almost 15% increase in the total number of adult patients from 2010-2012 being treated by AAO members. Over 1.25 million adults currently are under AAO-member care with the average orthodontist seeing 20% of the practice comprised of adults and some colleagues having limited their practice to adult treatment. Likely the percentage rise and total number of adults undergoing tooth alignment procedures is even higher than reflected in the AAO survey as non-specialists incorporate what they perceive to be “simple” orthodontic treatment into their own practices. Recognizing the importance of orthodontics for adults, the AAO has increased their focus on adult treatment within their Consumer Awareness Program. Informational videos, website banners and print placements have linked orthodontic treatment to daily life experiences, bringing the message that a healthy, good-looking smile is desirable and attainable through orthodontic treatment by orthodontic specialists. Initial Survey results indicate the message is striking a chord (AAC), 2013) and along with social pressures relating good esthetics to good health, appears to be an added motivating factor for adults in seeking orthodontic treatment. 129 Periodontal Screening This is good news for both patients and orthodontists as long as outcomes approach those that are expected. The problem arises for some clinicians who do not recognize that adult treatment is different from adolescent care; adult treatment often is fraught with multiple challenges not present in the adolescent or child patient. Adults have a medical, dental and psychological history that can be complicated with direct effects on treatment. For many clinicians whose education and initial specialty practice has been focused on children and adolescents, these differences may not be obvious (Boyd et al., 1989; Vanarsdall, 2004). One of the most silent aspects for the unsuspecting clinician charged with proper diagnosis, treatment planning and execution is the health of the periodontium (Vanarsdall and Secchi, 2011). For most orthodontists, patients come to their office by way of referral from a general dentist or another dental specialty colleague. These patients most likely are to present with a healthy periodontium. The concern is that with the increased number of adult patients, many of whom are self-referred, the traditional reliance on expected good dental and medical health may be inappropriate. What is the prevalence of periodontal disease in the adult popu- lation? Since 1960, there have been a series of government-supported surveys carried out at approximately ten-year intervals to assess the prevalence of periodontitis in the U.S. population (Papapanou, 2012). More recently, investigators have discovered that earlier health survey protocols severely underestimated the incidence of periodontal disease (Eke and Genco, 2007; Kingman et al., 2008; Eke et al., 2012a,b; Papapa- nou, 2012). The Centers for Disease Control (CDC) Periodontal Disease Surveillance Initiative developed improved surveillance procedures for assessment of periodontitis that include full-mouth periodontal probing protocols. The result is that the current 2009-2010 study of over 3,700 subjects (Table 1) reported that approximately 47% of U.S. dentate adults aged 30 years and older (representing approximately 65 million adults) have periodontitis, with 38% of the adult population 30 years and older and 64% of adults 65 year and older having either severe or moderate periodontitis (Eke et al., 2012a). The National Health and Nutrition Examination Survey (NHANES) survey also noted that there were variances in the prevalence of disease 130 Graber Table 1. Data from the National Health and Nutrition Examination Survey (NHANES) for adults 30 years of age or older that was obtained during 2009 and 2010. Mild periodontitis 8.7% Moderate periodontitis 30.0% Severe periodontitis 8.5% TOTAL PREVALENCE 47.2% based on a variety of factors. In terms of gender, age and ethnicity, males have a greater prevalence than females (56.5% versus 38.4%), older in- dividuals have greater incidence than younger (24.4% at age 30-34 ver- sus 70.1% 65 years and older) and Hispanics have the greatest incidence (Mexican Americans at 66.7% versus non-Hispanic blacks at 58.6% versus non-Hispanic whites at 42.6%; Eke et al., 2012a). As one might expect, Socio-economic factors also are related to the presence of periodontitis with lower education (less than high school diploma at 66.9% and those with more than a high school diploma at 39.3%). The use of tobacco smok- ing materials also was related to an increased incidence of periodontitis (smoker 64.2% versus non-smoker 39.8%) adding to the evidence that previously has been reported for increased incidence of periodontal dis- ease in smokers (Kinane and Chestnutt, 2000; Bergström, 2004). All of these, as well as some additional patient variables, are important to the orthodontist who is treating adults as they represent increased risks for the presence or development of periodontal disease in specific subsets of the adult patient population (Boyd et al., 1989; Al-Shammari et al., 2005; Sidiropoulou-Chatzigiannis et al., 2007; Bollen, 2008; Mukherjee and Al- mas, 2010; Gorman et al., 2012). With the percentage of periodontitis in adults reported to be ap- proaching 50%, does every adult patient that presents to an orthodontist need a referral to a periodontist “just to be sure?" Obviously not—but the question remains for the orthodontist as to how s/he will triage pa- tients to identify those with developing or existing periodontal problems. In reality, only those who have existing disease and those who are “at risk" (Kornman, 2001) need to be referred. As the number of adult pa- tients has increased over the past ten years, the question of how best to 131 Periodontal Screening evaluate patients has come to the fore for clinicians as well as the orth- odontic specialty organizations by which they are represented. DEVELOPING SCREENING PROTOCOLS In 2007, the American Board of Orthodontics (ABO) changed their case presentation examination requirements to better identify the presence or absence of periodontal factors in cases presented for AB0 certification examinations. Their initial paper suggested selecting from a series of different measurements, some clinical and some radiographic, as a means to identify periodontally compromised adults and adolescents (Grubb et al., 2008). This sparked significant discussion by educators and clinicians alike as to developing better.protocols to screen for patients who have or are at risk for periodontal problems prior to and during Orthodontic treatment. After much preliminary work, to address the increasing concerns regarding periodontal screening, a joint American Association of Ortho- dontists-American Academy of Periodontology (AAO-AAP) Task Force was commissioned jointly by the AAO and AAP Boards of Trustees in 2009. The Task Force was charged with jointly developing recommendations regarding the appropriate screening methods to identify potential peri- odontal concerns for prospective adult orthodontic patients. Specifically, the Task Force was asked to provide orthodontic specialists with: 1. A systematic method of identifying patients at risk for periodontitis, with discrete reporting options for inter-professional and patient communication, educa- tion and documentation. 2. A reliable evidence-based method to assist with diag- nosis and treatment planning. 3. A protocol that would be practical for screening of adults for potential risk of periodontal disease. Four Task Force members were selected by their respective organizations: Drs. Samuel B. Low and Paul Rosen from the AAP; and Drs. Lee W. Graber and Vincent G. Kokich from the AAO. With the help and 132 Graber review of the AAO and AAP councils, committees and respective governing boards, the Task Force developed a series of recommendations to assist clinicians in the evaluation of prospective adult orthodontic patients (Kokich, 2011; Kokich and Graber, 2011). The Task Force recognized that many clinicians have an excellent screening protocol in place and that any recommendations the Task Force made were provided as an alternative practical option for orthodontists and other dental professionals who desired either a new or additional screening protocol. The Task Force identified four critical areas in screening for patients who are at risk for periodontal problems during orthodontic treatment. These include: 1) medical/dental history; 2) dental radio- graphic evaluation; 3) periodontal charting; and 4) risk assessment. Medical and Dental History The medical and dental history is a key component of any orthodontists' initial patient evaluation. Within the history there are Several key questions that affect the risk for periodontitis in adults. 1. Frequency of dental care: How often a patient visits the dentist can influence the risk for periodontal disease. If the patient is seen regularly (i.e., once every six months), there is a reduction in the risk versus a patient who sees the general dentist irregularly or not at all (Sbaraglia et al., 2002; Giannobile et al., 2013). 2. History of periodontal treatment: For periodontal disease to develop and progress, the patient must have the presence of periodontal pathogens as well as an innate susceptibility to one or more of those bacterial pathogens (Socransky and Haffajee, 1992). Those who have exhibited disease in the past have a history that puts them at higher risk. In these patients, past history is a good predictor of future risk based on the biologic prerequisites for periodontitis. While these patients still can be treated, they more likely need more help and periodontal monitoring for removal of offensive bacterial flora. 133 Periodontal Screening 3. Diagnosis of diabetes: Patients with diabetes are more at risk for periodontal disease (Tsai et al., 2002). The presence or absence of diabetes and how well it is controlled as indicated by HbA1c (a blood glucose value used by most diabetics) will influence the risk of development of recurrence of periodontal disease. With the increased of diabetes in the general popula- tion (Wild et al., 2004), this is an important aspect to question for every adult patient. 4. Smoking: Smoking tobacco has been shown to increase the risk for development and progression of periodontal disease. Indeed, smoking tends to alter the tissue dynamics', and not only can affect susceptibility to periodontal pathogens, but also can have an effect on orthodontic tooth movement as well (Chamborne et al., 2009; Baboni et al., 2010). The 1) quantity of smoking, 2) how long the patient has been smoking or did smoke prior to quitting and 3) if s/he has quit and how long has it been since s/he smoked affect periodontitis risk. Radiographic Evaluation Characterizing the current tooth to bone relationships is done best with an evaluation of appropriate radiographs. The critical measures relate to the distance of the alveolar crestal bone margin to the cemen- toenamel junction (CEJ). A patient who has experienced a healthy peri- odontal history will demonstrate a crestal-CEJ distance of approximately 2 mm. If this distance is greater than 2 mm, then there is increased evi. dence of past loss of periodontal support that relates to increased risk for future compromise. The gold standard for determining the distance between the CE and alveolar crest radiographically is a combination of anterior tooth periapical films and posterior bitewing radiographs. These films provide a reliable and reproducible means by which these measurements may be made accurately. Unfortunately, most orthodontists do not take these films as a routine part of the screening process and, thus, they need to be secured from the patient's general dentist. While panoramic radiographs customarily are obtained for orthodontic patients, the distortion on 134 Graber these films makes them ill suited to evaluate the bone-to-CEJ relationship reliably. The increasing use of cone-beam computed tomographic (CBCT) images provides another alternative from which to assess the CEJ to alveolar crest relationship. These images escape the distortion of the Customary panoramic images. Their interpretation will be influenced by the resolution of the image, which is affected by voxel size, slice thickness and the field of view (FOV) used by the clinician. It is probable that further improvements in this technology and ongoing research will demonstrate that these three-dimensional (3D) images are even more reliable for measurement of the individual tooth-to-bone height associations. Periodontal Charting A current periodontal charting is important to define areas of potential disease in an adult patient. The charting provides critical infor- mation including, but not limited to, the depth of periodontal pockets, furcation defects, interproximal bone loss, loss of attachment and reces- Sion, bleeding on probing and often, tooth mobility. As was noted in the NHANES cited above, full-mouth periodontal probing evaluation is im- portant to discover adequately and document the presence or absence of periodontitis. This charting is done routinely in many general dental offices, with the information available to other dental professionals. The AAO-AAP Task Force directly addressed the issue of periodontal charting in the non-periodontal specialty practice. While the orthodontic specialist is trained in periodontal charting during his/her precursor dental school curriculum, his/her specialty education and skills are focused on use of the information developed via charting and not on developing that information clinically in their specialty office. Securing the appropriate charting notes from the general dentist and/or treating periodontist helps to draw the dental team into a more closely shared overall oral healthcare team relationship on behalf of the patient. This provides mutual understanding of needed pre-orthodontic periodontal treatment and any coincident periodontal management that may be required. It also should be noted that in those adversarial Situations where periodontal risk has not been addressed and progresses to an identified damaging level for a patient, a treating orthodontist likely 135 Periodontal Screening will share any patient's legal challenge with the general dentist (Grabeſ, 2004). Risk Assessment How does the orthodontist take the information gained through the evaluation process (medical and dental history, radiographic evalua- tion and periodontal charting) and come up with an estimate of "risk" for the patient? The information noted above will help to describe the cur. rent disease state and past history, but how does one practically put the material together to come up with a risk assessment that is of use to the orthodontist, the dental healthcare team and the patient? The classical means by which orthodontists assess periodontal risk is via referral to a periodontist or by way of consultation with the patient's general dentist. Many clinicians develop working relationships with their referring general dentists and periodontal specialists to review the pertinent periodontal factors of prospective orthodontic patients and prescribe appropriate care and caution. Interdisciplinary diagnosis and treatment can work well in this mutually supportive team approach. The AAO-AAP Task Force recognized that there are, however, orthodontists for whom these relationships have not been developed adequately Or where the orthodontist may seek alternate means to quantify, document and address risk of periodontitis coincident with orthodontic treatment. The Task Force worked to find a system that would aggregate the information and provide an objective report of disease state and patient risk. The requirements for the estimation of patient risk included that the calculations were evidence based, that procedures were practical for use by an Orthodontist in private practice and that reports developed were adequate and understandable for both the clinicians and the patient. The goal was to identify and quantify the current periodontal state and assist the orthodontist in prescribing any needed pre-orthodontic periodontal therapy, as well as a provide guide for needed periodontal treatment during orthodontics. After much research, the Task Force identified a computer-based system that was able to take the information developed from the medi. cal and dental history, radiographic and clinical evaluation and Compute a disease state and risk score for the orthodontist and patient. The Task 136 Graber Force and the AAO-AAP have no proprietary interests in, nor do they en- dorse any commercial product or protocol, but found the Previser system (www.PreWiser.com) to fit the requirements for a periodontal screening and reporting protocol that was systematic, reliable and practical. In addi- tion, the PreWiser protocol is evidence based (Page and Beck, 1997; Page et al., 2002, 2003, 2004; Persson et al., 2003; Martin et al., 2006, 2009, 2010; Page and Martin, 2007; Martin, 2010). Within the Previser online system, there are a series of informa- tional pages that must be completed. In addition to demographic infor- mation, the information from the three clinical areas of information dis- cussed above (history, radiographs and charting) are recorded. The result from the computed-risk assessment is a series of reports that are avail- able to the orthodontist, general dentist and/or patient depending on the format desired. These reports indicate two separate scores. The first is a risk score from 1 (low) to 5 (high) that indicates the relative chances of periodontal health worsening over time (if appropriate care is not provid- ed). The second number is the disease score that ranges from 1 (healthy) to 100 (severe periodontal disease). If the report is formatted for the pa- tient, the scores are described in lay terms, both numerically and graphi- cally, so the patient may understand better the clinical significance of the values listed on the report. With increased understanding comes higher motivation to follow through with recommended procedures. Periodontal Triage The computer-developed reports are helpful, but what do they mean regarding actual patient management? How can the orthodontist use the gathered information numbers from the disease state and risk assessments as a guide for appropriate management of patients? To assist in this goal, Previser completed a population analysis of data from 36 general dentist offices and 18,688 patient assessments and was able to establish a risk/disease distribution as per 1,000 adults. Using guidelines developed by the AAP, a decision matrix was developed that provides a general decision making guide for prospective adult orthodontic patients (Fig. 1). It is important to note that the matrix concept may be used with any method that quantifies risk and disease state. Based on the relative 137 Periodontal Screening Previser Periodontal Disease Score 1 to 3 4 to 10 11 to 36 37 to 100 Health, Periodontitis Gingivitis Mild Moderate Severe 1 or 2 Low A. B B Previser Periodontal 3 Moderate º B B Risk Score - 4 or 5 High º Figure 1. Guidelines to facilitate the prevention of an undesirable periodontal outcome during orthodontic treatment in the AAO-AAP periodontal referra matrix. Previser numbers are provided in the Task Force Matrix, but any System that quantifies risk and disease state can be used with this type of decision grid. position within the matrix, patients are divided into one of three groups. The Task Force report provides the following suggestions based on the AAP recommendations: Patients in Group A: It is safe to begin or continue orthodontic treatment. While a good prognosis exists and periodontal treatment is unlikely, periodic reassessment by the orthodontist would be beſ: eficial to identify any unexpected change in periodontal status during orthodontic treatment. Referral to a dentist or periodontist for periodon: tal care is not needed necessarily, but removal of plaque and calculus from supragingival and subgingival regions is required on regular inter vals during the entire period of orthodontictreatment. Patients in Group B: It may be hazardous to begin or continue orthodontic treatment. A good prognosis is possible if the treatment plan includes excellent management of the patient's periodontal risk factors during orthodontic treatment. While this may require periodon: tal treatment before beginning or continuing orthodontic treatment periodontal treatment may not be complex. An excellent outcome typi- cally requires referral to a dentist or periodontist who can provide the requisite level of periodontal care. Patients in Group C. It is likely to be hazardous to begin or continº orthodontic treatment. A good prognosis is possible if the treatment plan includes exceptional management of the patient's periodonta risk factors during orthodontic treatment. This may require complex 138 Graber periodontal treatment before beginning or continuing orthodontic treatment. An excellent outcome typically requires referral to a dentist or periodontist who can provide the requisite level of periodontal care. An instructional webinar video developed by the AAO-AAP Task Force is available that reviews the step-by-step process for the periodontal Screening. With the webinar, patient examples are shown and office management procedures are discussed (Kokich and Graber, 2011). In the Previser study from general dental offices, approximately 67% of patients fell into the safe to treat group (A) with approximately 16% in the potentially hazardous to treat group (B) and 17% in the likely hazardous to treat group (C) categories. This, of course, is only one study, but suggests that over 30% of presenting adult orthodontic patients may have a periodontal status that is at risk during orthodontic treatment. The new NAHANES study paints a potentially gloomier picture. The Task Force recommendations are intended to be general guidelines. The treating orthodontist, based on experience and unique patient factors and potentially in consultation with other dental and medical health professionals, must make the determination of when and where to refer a potentially compromised patient. Whether using the Classical referral approach, the alternate protocol suggested by the AAO- AAP Task Force or another set of procedures, it is important to use some means by which the periodontal status and potential for future problems may be assessed (Reichart, 2011), recorded and addressed within a patient's overall treatment plan. - A PATIENT'S STORY CONCLUSION At the start of this chapter, you were asked to step into the shoes of a colleague by way of the description of a series of appointments for a prospective adult orthodontic patient. The description in the text closely follows that of an actual patient who presented for orthodontic treatment. Indeed, she started her treatment based on the diagnosis and treatment plan/sequence initially outlined by her orthodontist. Unfortunately, treatment did not progress as planned. The female patient never followed up on the recommended initial “prophy” and the doctor had no follow-up notes on what he originally had noted as “puffy 139 Periodontal Screening gums.” In a post-treatment interview with the doctor, it was reported that hygiene had been “poor” and the patient had been referred to a periodontist, but the written record had multiple check marks for “good" hygiene. It was not until 18 months into treatment that the chart notes indicate a referral for recession and bone loss that had been noted earlier in treatment. When the patient finally saw a periodontist at 23 months, she was told she would lose some of her teeth and that the new Smile she wanted would include significant prosthodontic replacement and periodontal surgery. The patient lost teeth and the orthodontist both lost a patient and also suffered a significant loss in follow-up malpractice litigation. It often is said that hindsight is 20/20. Fellow clinicians can criticize the doctor for not following through on good office management of the patient, but the biggest flaw was the lack of recognition of the risk of starting treatment without adequate knowledge of this adult patient's periodontal status (Vanarsdall, 2004). If the patient had been referred for further screening and the orthodontist properly informed, the outcome likely would have been much different. The conclusion of this patient's story serves as an example to show the important added responsibility of periodontal screening as an ever-increasing adult patient population looks to Orthodontics. REFERENCES Al-Shammari KF, Al-Khabbaz AK, Al-Ansari JM, Neiva R, Wang HL. Risk indicators for tooth loss due to periodontal disease. J Periodonto 2005;76(11):1910-1918. American Association of Orthodontists. 2013 Economics of Orthodontics Study. St. Louis: May, 2013. Baboni FB, Guariza Filho O, Moreno AN, Rosa EA. 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Periodontal-orthodontic interrelationships. In: Graber LW, Vanarsdall RL, Vig KD. Orthodontics: Current Principles and Techniques. 5th ed. Philadelphia: Elsevier, 2011:807-808. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-1053. 143 ON THE VANISHING NEED FOR M.D. RANDOMIZED TRIALISTS AT MOYERS SYMPOSIA David L. Sackett ABSTRACT This chapter contains the personal reflections of a physician with expertise in internal medicine, epidemiology and biostatistics who now has participated in three Moyers Symposia spanning nearly thirty years. He comments on the changes that have occurred in clinical orthodontic research during this time period, including the increasing use of randomized clinical trials by the specialty. The second part of the chapter discusses the six prerequisites for a Successful clinical trial, six requirements that must be satisfied before a trial likely is to be funded, filled with patients, finished, productive of results that are Credible and valid, and regarded as a fruitful experience by its investigators. These prerequisites include: the trial needs to be done, the question posed is both appropriate and unambiguous, the trial architecture is valid, inclusion/ exclusion criteria strike a balance between efficiency and the need to extrapolate them beyond the trial, the trial protocol is feasible and the trial administration is effective. Further, the differences between explanatory trials and management trials are discussed in detail. KEY WORDS: randomized clinical trial, evidence-based treatment, explanatory trial, management trial INTRODUCTION I am an M.D. randomized trialist and my thesis here is that people like me are no longer needed at scientific meetings of orthodontists and Craniofacial biologists such as the annual Moyers Symposia. My prior contacts with orthodontics are meager, but intimate. In the 1940s, I was the resentful patient of Dr. Allan G. Brodie (a former Student of Edward Angle) for eight years, the first six of which appeared devoted to rearranging too many teeth around too small a playing field. Four premolar extractions in year seven and we soon were rid of each other. 145 Vanishing Need for Randomized Trialists After training in internal medicine, nephrology, epidemiology and biostatistics, I came to Canada in 1968 to help start the medical school at McMaster University and began performing and teaching about randomized clinical trials (RCTs) of drugs, operations, educational programs and new health professionals. I transferred to Oxford University in the mid-1990s to start their Centre for Evidence-Based Medicine and to launch an RCT Graduate Programme and the Steering Group for the Cochrane Collaboration. I met and was befriended by Bob Moyers when we served to- gether on the Alberta Heritage Foundation in the early 1980s, distrib- uting that province's newfound oil profits among its newfound health scientists. Our conversations soon turned to my experiences in random- ized trials and Bob revealed his keen interests in getting trials going in orthodontics. They culminated in his invitation to me to round up several other physician epidemiologists and present our ways of thinking to the 12th Moyers Symposium in 1985. | brought along David Ransohoff (1986) from Chapel Hill who spoke about evaluating and validating diagnostic tests and Alvan Feinstein (1986) from Yale who spoke about clinical measurement. I described the strategies and tactics of randomized trials of surgical interventions. We just had finished a 71-center, 13-country trial showing that extracranial. intracranial arterial anastomosis did more harm than good to stroke- prone patients and we were just embarking on a 50-center North American trial that was to show the benefits of endarterectomy among patients with high-grade symptomatic carotid Stenosis. A smart aleck at the best of times, I suggested that the state of trials in orthodontics was lagging behind “such treatment modalities as acupuncture, hypnosis, homeopathy and orthomolecular therapy, and on a par with scientology, dianetics and podiatry” (Sackett, 1986). This diagnosis resulted from my pre-meeting waltz with the National Library of Medicine’s ‘PubMed' software that unearthed no RCTs in Orthodontics before 1967 and about half a trial per year in the decade preceding my first appearance here in 1985. The state of orthodontics trials changed rapidly thereafter, with trial reports increasing 18-fold in the next decade (to about nine per year). Nonetheless, your organizers became convinced that further exhortation might benefit the field and invited me back for the 1994 Symposium (Sackett, 1995a,b). Following that meeting, reports around 146 Sackett and about randomized trials in orthodontics rose to more than one per week in the next decade (69 per year) and doubled again (to 129 per year) since 2005. Thus, randomized trials in orthodontics have increased rapidly since | first spoke here in 1985 and continue to accelerate. These data provide equal support to two competing hypotheses: Hypothesis #1. Sackett has had a positive, salutary effect on the frequency of randomized trials in orthodontics, the field is now flourishing and M.D. trialists like him are needed no longer at Moyers Symposia. p Hypothesis#2. Therapidly rising frequency of randomized trials in orthodontics was driven entirely from within the profession, the field flourished on its own and M.D. trialists like Sackett were not needed at these symposia in the first place. Regardless of which hypothesis is correct, the same conclusion applies: orthodontics is coming of age in the age of evidence-based health Care and does not need any help-if it ever did—from M.D. randomized trialists like me. Nonetheless, I have enjoyed my time with your group enormously and thank you for your many kindnesses. PREREQUISITES FOR A SUCCESSFUL CLINICAL TRIAL This contribution now will turn to discuss six prerequisites for a successful clinical trial. In other words, six requirements that must be Satisfied before a trial likely is to be funded, filled with patients, finished, productive of results that are credible and valid, and regarded as a fruitful experience by its investigators include: 1. The trial needs to be done. 2. The question posed is both appropriate and unam- biguous. 3. The trial architecture is valid. 4. The inclusion/exclusion criteria strike a balance be- tween efficiency and the need to extrapolate them beyond the trial. 5. The trial protocol is feasible. 6. The trial administration is effective. 147 Vanishing Need for Randomized Trialists The focus here is on what goes on before the entry of the first patient; accordingly, most issues in execution, analysis and interpretation are discussed elsewhere (Haynes et al., 2005). There are several elements to this prerequisite. First, the clinical disorder to be prevented or treated must produce sufficient misery to warrant an attack. That is, the disorder must have either a high enough incidence to affect a substantial proportion of the general population (e.g., malocclusion) or, if infrequent, a devastating course and prognosis (e.g., multiple Sclerosis), so that an attack upon it will promote the public good manifestly. Second, existing interventions must be of unknown, Or of known but insufficient usefulness in terms of efficacy, safety or cost. Prerequisite #1: The Trial Needs to be Done To warrant the effort required to evaluate it with rigor, the intervention to be tested must be judged to have a humanly important probability of doing more good than harm, regardless of whether this probability is described in terms of uncertainty (Sackett, 2000) or equipoise (Chard and Lilford, 1998). Thus, the intervention should be sensible biologically and consistent with our current understanding of human structure, function and response to stimuli. Moreover, there should be sufficiently favorable results from phase I and phase ll studies to suggest that the intervention might be valuable. The presence of additional evidence from phase Ill studies for related conditions also is helpful. Prerequisite #2: The Trial Ouestion is Both Appropriate and Unambiguous Gent and I have suggested elsewhere (Gent and Sackett, 1979, Sackett and Gent, 1979) that much of the controversy over the interpre- tation of the results of clinical trials arises from disagreements (often unrecognized) or ambiguities over the questions posed by these trial; that can be regarded usefully as lying between two poles (Schwartz and Lellouch, 1967; Sackett, 2013a,b). At the one extreme, a trial deals with explanations and asks such questions as: “Can drug A reduce tumor size under ideal conditions?” At the other extreme, a trial deals with man- agement and asks such questions as: “Does prescribing drug A to pa- tients with tumors do more good than harm under the usual conditions that apply in practice?” 148 Sackett These two types of trials have contrasting attributes (Sackett and Gent, 1979). The explanatory trial seeks to describe how a treatment produces its effects or to determine whether it can work, often under ideal or restricted circumstances. Conversely, the management trial Seeks to describe all the real-world consequences, both good and bad, of treating an illness in a certain way and to determine whether therapy does work, usually under as close to routine clinical circumstances as possible. Similarly and for sound scientific reasons, these two types of trials may recruit study patients in different fashions. The explanatory trial justifiably may restrict admission to patients most likely to take all of their medicine faithfully and to respond to it. The management trial also justifiably may accept all comers, including patients with poor compliance, to obtain a better estimate of the overall usefulness of starting down a particular therapeutic path. The experimental therapy may be applied differently in the two Sorts of trials, also with good reason. In a desire to monitor therapy closely and, thus, to optimize its benefit, the protocol for an explanatory trial may call for frequent examinations, elaborate dose-setting schemes and other procedures that violate contemporaneous practice. The management trial, on the other hand, usually strives to replicate current practice. Moreover, these two types of trials differ in the eligibility of the events used to determine the outcomes of therapy. The explanatory trial focuses on a restricted range of events and attempts to justify (often with little success) excluding from the analysis any events that occur before the experimental therapy has begun or takes hold. An example is the "seven-day rule” used in the Anturane Reinfarction Trial (ART Research Group, 1980) that ignored events in the first week of therapy or after experimental therapy has been abandoned or contaminated. In contrast, the management trial tends to encompass a wide range of events and usually includes all events that occur after ran- domization (such as mortality from any cause), so that the results of a decision to follow a given course of therapy can be assessed. The explanatory trial, in ruling certain events ineligible or “non-analyzable” (ART Research Group, 1980), runs the risk of sacrificing validity for efficiency (Sackett, 1980). Because of this risk, some methodologists and governments take a hard line and insist that the only valid approach is 149 Vanishing Need for Randomized Trialists to count all events from the instant of randomization and assign them to the allocated treatment. Debates over these alternative approaches frequently are enlightening and always are good theater. For a new treatment, which sort of question should be posed (and which sort of trial should be performed) first? Some trialists favor explanatory trials as the appropriate initial inquiry. First, because explanatory trials can exclude “background noise" by restricting admission to highly compliant, high-risk patients and by restricting events to those most likely to respond to the test therapy, they can obtain answers relatively quickly with a seemingly small numbers of study patients; that is, they can be efficient (Sackett, 1980). Thus, an early explanatory trial of antihypertensive drugs, al. though it involved only 143 men, pre-screened for high compliance and high risk and followed for only about a year and a half, was able to demonstrate a risk reduction of 92% (p<0.001) for a restricted set of events (Veterans Administration Cooperative Study Group on Antihypertensive Agents, 1967; Ontario Council of Health, 1977). By contrast, a more recent management trial of comprehensive antihypertensive care among all comers who were at relatively low risk had to follow 10,940 subjects for about five years to demonstrate a 17% (p < 0.01) risk reduction for total mortality (Hypertension Detection and Follow-up Program Cooperative Group, 1979). Moreover, if the results of an explanatory trial are powerfully negative (that is, if the confidence interval around the treatment effect excludes any clinically useful benefit), we can draw the unambiguous conclusion that the treatment deserves no further study for this condition. On the other hand, a positive result (whose confidence interval excludes zero or lies entirely above some minimally clinically important benefit is ambiguous, for it tells us only whether the treatment can work under ideal circumstances, not whether it will work under usual circumstances. Because management trials admit “all comers” regardless of their risk, responsiveness or compliance, they are bigger, usually longer and almost always are more costly than explanatory trials. The reward for this additional effort is the unambiguity of a positive result: it works in all comers in the real world. However, a negative result is ambiguous: is the treatment worthless or is its efficacy swamped by the noise generated by low-risk, low-response patients who do not take their medicine? 150 Sackett For example, a management trial found that post-myocardial infarction patients randomized to undergo high-intensity exercise had the same reinfarction and death rate as similar patients randomized to low- intensity exercise (Rechnitzer et al., 1978). Although all the study subjects were patients whose clinical status permitted exercise, only about half of them complied with their exercise prescription. Thus, was the failure to demonstrate a beneficial effect of exercise due to a lack of efficacy or to a lack of compliance? The recent confirmation that compliance is a marker for rosy prognosis (Coronary Drug Project Research Group, 1980; Sackett, 1980) means that this ambiguity cannot be resolved by comparing the outcomes between compliant and non-compliant patients. A group of us led by Sikhar Banerjee suggested a strategy for doing both trials at the same time (Banerjee et al., 1984). In it, the trialists put all eligible patients through some compliance task that simulates what they would have to do in the trial. Those who comply with this task are placed in one stratum, provided that their entry characteristics suggest that they are at high risk of the primary outcome and most likely to respond to the treatment under investigation. Thus, they are perfect subjects for an explanatory trial. However, those who fail the compliance test or are judged to be low risk or unlikely to respond to the study treatment are not discarded, but are placed in a second stratum. Randomization occurs from both strata. Since they were generated before randomization, they can be analyzed separately with no threat to validity. Results from the first stratum provide the explanatory answer and results for both strata Combined provide the management answer. - The perspective from which the trial question is posed also must be clear. When the question that forms the essence of the trial is posed from the investigator's perspective, the issue of primary interest either may be explanation or management. However, when the question is posed from the patient's perspective, the issue of primary interest is management. In the latter case, for example, the fact and mode of dying are far more important than the cause of death and all events are of interest. Finally, frank and open discussion and debate about the precise wording of the question should constitute a central component of any discussion with potential clinical collaborators. The understanding of and agreement on the question are essential to continued clinical efforts dur- ing the tough tasks of enrolling, treating and following up study patients. 151 Vanishing Need for Randomized Trialists Furthermore, it is in the process of agreement over the question that the clinical collaborators bond to the research team and the study becomes theirs to prosecute in the middle of the night and protect from its detrac. torS. Prerequisite #3: The Trial Architecture is Valid The chief device for achieving internal validity in a clinical trial is the execution of random allocation, so an explanation of the strength of this device is in order. Consider a hypothetical example: a microvascular Surgeon develops a technique for bypassing a Surgically inaccessible occluded carotid artery in experimental animals and wishes to evaluate this procedure for its potential benefit to humans. Because it is a lengthy procedure and not without risk, the surgeon carries out the first few bypasses on cerebrovascular patients who are, for the most part, free of hypertension or other extraneous disorders that increase their surgical risk. The results are encouraging: all survive the procedure and their cerebrovascular symptoms remain stable or even improve. In contrast, many of the poor-risk cerebrovascular patients who were rejected for surgery because of coexisting hypertension either died or experienced progression of their cerebrovascular symptoms. When the results are reported, a substantial segment of the profession concludes that the bypass procedure is of obvious efficacy and ought to be performed on all good-risk (and even some poor-risk) cerebrovascular patients. The canny reader will have identified three properties of hyper- tension in this hypothetical example: 1. It is extraneous to the question posed. At issue is the efficacy of bypass surgery, not the biology of hyper- tension. 2. It is a determinant of the outcomes of interest. Hy- pertensives are more likely to experience progressive cerebrovascular disease and to die than normoten- Sives. 3. It is distributed unequally among the treatment groups being compared. In this case, the inequality is marked; very few hypertensives were bypassed be- cause almost all were rejected for surgery. 152 Sackett In the technical jargon of causation, hypertension is a confounder and the presence of such confounders has complicated the evaluation of the efficacy of almost all preventive, therapeutic and rehabilitative maneuvers. Confounding leads to bias—the arrival at a conclusion that differs systematically from the truth—and examples abound in human research, both experimental (where allocation to the maneuvers under Comparison occurs by random allocation) and non-experimental (where allocation occurs by any other process; Sackett, 1979). If confounding hampers the valid demonstration of efficacy and effectiveness, how can it be avoided? Briefly, seven strategies, exist for preventing confounding; all of them attack its third property of unequal distribution among treatment groups and one of them clearly is superior to the rest. 1. One could prevent confounding by restricting the criteria for inclusion; one could simply exclude hyper- tensives from either the operated or non-operated patient groups. 2. One could match (in both the sampling and analysis ages) operated and non-operated patients individually for their hypertension status. 3. One could carry out stratified sampling, creating co- horts of operated and non-operated patients contain- ing identical proportions of hypertensives. 4. One could take all comers, but perform a stratified analysis, comparing outcomes among operated and non-operated hypertensives separate from the com- parison of outcomes among operated and non-oper- ated normotensives. 5. One could apply an adjustment or standardization procedure, analogous to age Standardization, in the analysis. 6. One could establish a model for the risk of the outcome of interest that would include a correction factor for hypertension and could be expanded to include other possible confounders, such as Symptomatic coronary heart disease and diabetes. 153 Vanishing Need for Randomized Trialists 7. Finally, one could allocate appropriate patients to un- dergo or not undergo the new microvascular surgical technology randomly. Any of the first three strategies can outperform randomization in generating comparable groups of patients for known confounders in randomized trials because they can be manipulated to generate perfect balance, whereas randomization will generate statistically significant imbalance for one in twenty confounders. Why then randomize? The reasons are two. First, if the random- ization list is concealed from the clinicians who are entering patients into the trial, it will make it impossible for them to tell which treatment the next patient will receive. A recent empiric investigation found that clini- cians who know the next treatment assignment tend to save it for pa- tients with better prognoses or greater responsiveness, so that random- ized trials with poor concealment tend to overestimate the efficacy of the test therapy (Schulz, 1995). Of course, other concealed allocations schemes could do this as well, but in many of them, once the code (e.g., allocation by odd or even date of birth) is broken for one patient, it is broken for all. Second, random allocation acts to prevent distortion by unknown as well as known confounders; thus, it acts to reduce bias both from known confounders and from potential confounders as yet undiscovered. It is this boon to validity that places the true experiment (where allocation to the maneuvers under comparison occurs by random allocation) above the non-experiment (where allocation occurs by any other process) as a means for determining the efficacy or effectiveness of new technology or of any other clinical maneuver. Accordingly, the randomized trial has become the “gold standard” approach for determining the efficacy and effectiveness of chemotherapeutic agents and most other drugs and is used increasingly in evaluating surgical technology as well. Finally, the foregoing strategies can be combined. For example, many of our trials involve randomization within prognostic strata, followed by adjustments for residual differences in the analysis. Is it ever appropriate to rely on non-experimental evidence for efficacy? I believe that two such circumstances exist. First, when a given health state has been shown to lead inevitably to death, any therapy followed by survival is efficacious and a randomized trial becomes not only superfluous but also, in many cultures, unethical. Examples are rare, but arguably include malignant hypertension, tuberculous meningitis 154 Sackett and choriocarcinoma. Second, and recalling that the working definition of efficacy often includes considerations of harm as well as good, some adverse effects of clinical maneuvers may be so rare or late as to preclude the feasibility of their experimental verification. For example, although her relative risk of myocardial infarction compared with non-users is 2.7 (Mann et al., 1975), the likelihood that a 30- to 39-year-old woman will Suffer a myocardial infarction while taking oral contraceptives is only about 1 per 18,000 per year. It readily can be shown (Sackett et al., 1980) that to be 95% sure of observing at least one such event in a one-year randomized trial, the number of treated women would have to be over 50,000. In summary, reliance upon non-experimental evidence in making judgments about efficacy or effectiveness constitutes a major pitfall in the evaluation of new therapeutic technology and the trigger for this trap is the confounding of risk with exposure. The true experiment, in which allocation to the technologies under comparison occurs by random assignment, acts to prevent distortion by both known and unknown confounders and, therefore, is the method of choice for determining the efficacy or effectiveness of new technology. However, random allocation does not prevent all sources of bias, nor does it ensure the validity and easy extrapolation of the results of an experiment. This section will close, therefore, with a brief discussion of four of these residual issues. First, the performance of additional therapeutic procedures (co-intervention) upon the experimental group should be avoided unless these same procedures are performed with equal vigor upon the comparison group (Sackett, 1979). For example, if experimental patients are seen more frequently than control patients, the additional opportunities for clinical evaluation and management either may inflate the estimate of the benefit of the test therapy spuriously or, by promoting the recognition of mild or transient side effects, may inflate the estimate of harm. A major strategy for preventing co-intervention is the blinding of study patients and their clinicians to the experimental therapy through the use of placebo drugs and maneuvers, and provisions for such blinding should influence study architecture at the outset. Second, knowledge of which the treatment a trial subject received may influence both the intensity and the results of the search for relevant outcomes. This situation is troublesome especially when the outcomes of interest are “soft” events such as changing neurologic 155 Vanishing Need for Randomized Trialists findings, self-reported exercise tolerance and the like. This pitfall repre- sents the second major reason for blinding both study patients and their clinicians. Other preventive strategies include explicit, objective outcome criteria and when blinding is impossible, the use of independent outcome adjudicators who review event data that have been purged of any treatment information. Third, the trial that is most efficient ensures that all experimental, but no control, subjects receive the test therapy. When members of the control group receive the test therapy inadvertently, the resulting contamination tends to reduce systematically any difference in outcomes between experimental and control subjects. The study architecture must recognize this danger and protect against it (Canadian Cooperative Study Group, 1978). • Finally, when a major event (such as death) precludes the Sub- sequent occurrence of a lesser event (such as stroke) in the same patho- genic sequence, the latter cannot be considered in isolation (Sackett and Gent, 1979). Otherwise, the therapy that kills patients before they have a chance to have a stroke could appear to be beneficial in the prevention of stroke. Such an interpretation, in fact, has been suggested by Some commentators following a randomized trial involving clofibrate (Report from the Committee of Principal Investigators, 1978). The risk reduction for non-fatal myocardial infarction was impressive. However, there was a corresponding risk increase for total mortality. This pitfall is avoided by the use of diagnostic hierarchies in which lesser events in a sequence are not considered in isolation. When such an analysis was carried out on the clofibrate trial data and rates for the hierarchy of myocardial infarction or death were compared, efficacy of the drug could not be demonstrated. Thus, the need for diagnostic hierarchies should be considered when developing the architecture for a trial. Prerequisite #4: The Inclusion/Exclusion Criteria Strike a Balance Between Efficiency and the Need to Extrapolate Them Beyond the Trial High statistical significance (that is, low p-values and narrow confidence intervals) is proportional directly to the arithmetic difference in event rates (absolute risk reductions). It follows that, for any given proportional (or relative) risk reduction achieved by the experimental treatment in a trial (as long as it is constant over different “baseline risks" 156 Sackett among untreated patients), sample size requirements are reduced when just high-risk patients are entered into a trial. Similarly, these absolute risk reductions are maximized among patients who are the most responsive to the experimental treatment (that is, their relative risk reductions are greater than those of less responsive patients). As a result, sample size requirements are lowest (the trial is least costly and most efficient) when a trial recruits only high-risk, highly responsive patients (Gent and Sackett, 1979). Conversely, trials are least efficient when they include low-risk, low-response patients. Paradoxically, it can be shown that the admission of a low-risk, low-response patient to a theoretical trial can increase, rather than decrease, the remaining Sample size requirement. On the other hand, clinicians and others want to extrapolate the results of trials to broad ranges of patients, including those who do not meet the strict risk-responsiveness criteria that were imposed in the trial (what social scientists call “external validity”). Concerns about "generalizability” have been voiced ever since trials became common and I made this problem worse in 1972 when I suggested that inpatient trials might not be “generalizable” to outpatients (Sackett, 1972). I now maintain that concerns about generalizability are unwar- ranted for two reasons. First, experiences on both my clinical service at the John Radcliffe Hospital in Oxford, UK and the -100 services I have vis- ited at other hospitals have documented that front-line clinicians do not want to “generalize” a trial's results to all patients, but only to “particular- ize” its results to their individual patient. They do this by making bedside adjustments to the trial results by using their clinical judgments about their patient's unique risk, responsiveness and values. For example, Sha- ron Straus has shown how to individualize rapidly a specific patient's risk, responsiveness, risk of side effects and preferences and tell him/her the likelihood that a given intervention will help rather than harm him/her (Sackett et al., 2000). Thus, “generalizability” to all patients is irrelevant to frontline clinicians. Second, cautionary pronouncements about generalizability should have credibility only if the failure to achieve it leads to qualitative differences (in kind) of responses in which experimental therapy on aver- age is helpful unambiguously inside the trial, but equally unambiguously harmful or powerfully useless, on average, to similar patients outside it. 157 Vanishing Need for Randomized Trialists Ouantitative differences (in the degree of help or harm) are to be expected, but are handled routinely by bedside adjustments using clinical judgment. | close this section by repeating a standing challenge to the readers of this book: a free dinner goes to the first person who provides me with six convincing examples of qualitative differences in the average responses of randomized patients (in RCTs with, say, at least 100 events) and eligible-but-not-randomized patients outside it. In that there have been approximately 280,000 RCTs in healthcare over the last half century, if generalizability really is so important, this dinner should be easy to win. Prerequisite #5: The Trial Protocol is Feasible The requirements here are three: 1) the protocol must be attrac- tive to the potential clinical collaborators; 2) appropriate types and num- bers of study patients must be available; and 3) minimal performance criteria for continuing or abandoning the trial must be set. Attractiveness to Potential Collaborators. Five elements influence the attractiveness of the protocol to potential clinical collaborators. First, there must be a convincing statement on the need for the trial. Such a statement will provide the basis from which these clinicians will justify to themselves, their colleagues and their patients the special conditions and additional efforts required to achieve success in the trial. Second, the experimental maneuver must be designed in a clinically sensible fashion that will permit application by study clinicians. Moreover, it must stand up to scrutiny so that these clinicians can defend it against its critics, should the need arise. Thus, for example, if the maneuver involves an operation, the expertise with which the maneuver is executed may vary sharply in time and space, and a biologically valuable maneuver may appear useless or even harmful when performed by the ham-handed. The credibility of the trial can be protected by invoking pre-set specifications on clinical competency (surgical mortality, graft patency) to be met prior to joining a trial, coupled with the pledge to monitor performance during the trial. If, despite these precautions, expertise is expected to shift with time, this shifting expertise should be taken into account by balancing treatment allocations at several points during the trial and by using calendar time as a co-variate in planning the analysis. The third element of feasibility that is important in the attractive- ness of the protocol to potential clinical collaborators is the specification 158 Sackett of the minimum appropriate requirements for the documentation and follow-up of study patients. Clinical trials often gather far more data than are required to answer the question at hand (especially in the United States) and investigators who feel burdened with the overly extensive documentation of overly frequent follow-up visits may flag in their entry of new study patients. Fourth, the principal investigators must present themselves to potential clinical collaborators as if they know what they are doing; they either must possess or quickly establish their credibility in the relevant areas of clinical medicine, human biology and research methods. Fifth and finally, each potential collaborator must be shown how participation inthetrial will bring personal rewards such as further education, additions to one's prestige and bibliography, and the recognition that one has made an essential contribution to the generation of useful new knowledge. Availability of Appropriate Patients. The second prerequisite for protocol feasibility is the availability of adequate numbers of patients who are appropriate for entry into the study. More important than these considerations, however, is the need to recognize that it simply is not enough to project estimates of the prevalence of the trial condition to the local population. Not only must the affected individuals be around; they and their referring clinicians also must be willing to participate, the experimental therapy and follow-up procedures must be acceptable to them and they must satisfy the specific inclusion/exclusion criteria. Even viewed through jaundiced eyes, the availability of suitable patients still may be overestimated; scarred investigators have suggested safety margins of 100-400%. When realistic estimates suggest that the required numbers of study patients may be hard to find, a number of strategies can be consid- ered. First, investigators can rethink the issues of risk and responsiveness raised earlier and strive to increase the trial's efficiency by restricting ad- mission to just the high-risk, high-response patients. Second, investiga- tors may wish to rethink the risks of type I and type II errors that they are Willing to take; when the restrictions are relaxed, the sample size require- ment falls. Third, attempts can be made to reduce the noise in the mea- Surement of events and outcomes by improving the precision of these measurements; the result will be higher values for the test statistic at any level of between-group differences. Where sensible, one also can benefit from the paired examina- tion of treatment effects within individual study patients by performing 159 Vanishing Need for Randomized Trialists crossover trials, although this solution should have been explored back when the basic architecture first was considered. Finally, the architects of the trial can solve the local sample-size problem by converting to a multi- center design, although at substantial costs in administrative complexity and investigator effort. The third prerequisite for protocol feasibility is the establishment and dissemination of minimal criteria for execution of the trial, coupled with a commitment to abandon the trial if these criteria cannot be met. Such criteria should specify minimum standards for the rate of patient entry, the quality with which the experimental maneuver is applied, the adequacy of the documentation of patients and events, and the extent of protocol adherence by both study patients and study staff. In multi-center trials these criteria also should specify the per- formance required for keeping in, or throwing out, a participating center. The Data Safety and Monitoring Board (see the sixth prerequisite) can help the Principal Investigator and Steering Group grapple with these is- SU 63S. In that the proof of the pudding is in the eating, a brief pilot run sometimes provides the ultimate test of a trial's feasibility in which a small number of patients are entered and put through the protocol. When considering whether to carry out a pilot study, investigators ought to bear in mind their advantages and disadvantages. Pilot studies certainly can help identify and solve problems in definitions, data forms and data flow, and they generally will debug the application of the study protocol. Moreover, when events are early and frequent, pilot studies can test (and, one hopes, confirm) earlier sample size estimates. Finally, pilot trials even on rare occasions can provide definitive answers to questions of efficacy when the test therapy is very, very good or very, very bad. Against these potential advantages must be considered the drawbacks and difficulties of such pilot studies. First, they consume patients who otherwise would be in the formal trial. Because pilot studies often are executed in an unblinded mode and because they often lead to substantive changes in the protocol, their subjects usually cannot be included in later analyses. Thus, if study patients are in short supply the pilot study can scuttle the trial. Moreover, if study events are rare or late, a pilot study cannot provide a helpful commentary on sample- size requirements. Furthermore, it may be difficult to interest potential clinical collaborators or funding agencies in committing themselves to a task with such meager short-term benefits. Finally, when pilot results 160 Sackett are not going to be included in later analyses for efficacy, the ethics of including human subjects in such enterprises takes on an additional dimension. Rather than adopting an all-or-none position on the need for a pilot study, investigators ought to define what they need to know prior to the formal execution of the protocol and then consider alternative Strategies for gaining this knowledge. For example, if the adequacy of forms, data flow and definitions is at issue, these issues can be tested on grab samples of consenting patients who, although they have the disorder of interest, otherwise are ineligible for the trial. Such patients also can be used to test the documentation and handling of events, thereby telescoping the long latent period that may occur in the trial proper. In this fashion, the investigators can have their pudding (by saving eligible patients for the later, definitive trial) and eat it too (by inviting ineligible patients to help with debugging the study protocol). Prerequisite #6: The Trial Administration is Effective When Smith (1979) corresponded with the investigators in twelve large hypertension trials over twenty years ago and asked them to identify their five worst problems, administrative problems led Scientific problems by more than 2:1. I believe that these problems are, if anything, greater now than before, given the size and scope of recent trials. Although some of these organizational problems are specific to multi-center trials, most are problems in the everyday management of the trial that, if mishandled, could destroy the credibility and validity of the trial. Accordingly, attention to administrative issues is the sixth and final prerequisite for a successful clinical trial. The trial protocol, when translated into the working document for the trial (hereafter referred to as the study manual) should include all the study forms and rules for their completion and submission. Moreover and vitally, the study manual should include unambiguous rules for following and reporting on study patients who refuse therapy, withdraw, fail to comply, suffer side effects, drop out or otherwise fail to adhere to the protocol, as well as precise and objective criteria for eligibility and events. Furthermore, the responsibilities for executing and documenting each step in the protocol need to be assigned, even to the point of job Specifications where necessary. Careful consideration should be given to the creation of an external advisory group of methodologists and clinicians who have no 161 Vanishing Need for Randomized Trialists direct participation in the trial, but are willing to review the protocol, recruitment, the timeliness and accuracy of study data and unblinded interim data analyses. Early in the trial, such a Data Safety and Monitoring Board (DSMB) can help the Principal Investigator and Steering Group firm up the protocol and procedures. During the trial, they can monitor unblinded adverse events carefully (and blow the whistle if necessary), accrual rates and data timeliness and accuracy, advising the Principal Investigator along the way. Finally, they can notify (and unblind) the Principal Investigator when the emerging trial results reduce uncertainty about efficacy to the point where serious consideration should be given to ending the trial. Some DSMBs are appointed by and report to the agency that funded the trial and are given the power to stop the trial on their own. After a few decades on both sides of such deliberations, I find it far preferable to serve on and work with DSMBs who, recognizing that the investigators know more than they do about the study question, act as advisors rather than watchdogs. Other key issues in the organization and administration of the trial may not appear in the study manual but are, nonetheless, key to its success. Chief among these is the specification of the authority and responsibility of the clinical and methodological investigators, who is to do what to whom and where the buck stops. Furthermore, publication policies (especially those related to authorship) should be stated at the outset, accompanied by the pledge to present the results first to the clinical collaborators (not to some scientific meeting, sponsor or the media). Finally, the financial support for the trial must be sufficient to support the staff, facilities and travel required for the assessment and follow-up of both the study patients and the study data, including circuit- riding by the Principal Investigator to maintain enthusiasm and patient accrual. A final requirement here is sufficient funds for thoughtful secondary data analyses that, in certain circumstances, can provide important clues to the presentation, course and prognosis of the disorder under study. 162 Sackett REFERENCES Antihypertensive Agents. Effects of treatment on morbidity in hyper- tension: I. Results in patients with diastolic pressures averaging 115 through 129 mm Hg. JAMA 1967;202:1028–1034. Anturane Reinfarction Trial Research Group. Sulfinpyrazone in the pre- vention of sudden death after myocardial infarction. N Engl J Med 1980;302:250–256. Canadian Cooperative Study Group. A randomized trial of aspirin and sul- finpyrazone in threatened stroke. 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J Chron Dis 1967;20:637-648. - Smith WM. Problems in long-term trials. In: Gross F, Strasser T, eds. Mild Hypertension: Natural History and Management. Pitman, London 1979;244-253. Veterans Administration Cooperative Study Group (Haynes RB, Sackett DL, Guyatt GH, Tugwell P). Clinical Epidemiology: How to Do Clinical Practice Research. 3rd ed. Philadelphia: Lippincott Williams & Wilkins 2005;chapters 4-6. 165 DEVELOPMENT OF THE HUMAN DENTITION: A LIFE'S WORK Frans PG.M. van der Linden ABSTRACT A report of the author's involvement in studies of the development of the dentition covering more than 50 years, resulting in the publication of a number of books and culminating in the publication of the e-book, Development of the Human Dentition, in 2013. KEY WORDS: development, dentition, sources, e-book, life's work In August 1960, I was offered the Professorship and Chair of Or- thodontics at the newly founded dental school at the Radboud University Nijmegen, to be started in September 1961. The medical school had be- gun ten years earlier. At that time, universities were autonomic in arrang- ing Curriculae, and these were put together by the professors only. On January 6, 1961, the professors of the medical school in Nijmegen, who were supposed to contribute to the teaching of dental Students and the already attracted professors of oral surgery and orthodontics, gathered with two professors from the dental school of The University of Groningen and two of The University of Utrecht dental School as advisors. In three hours' time, a six years curriculum was Outlined and forwarded to those who were assigned to take part in the teaching of dental students. However, the program was implemented Without adequate consultation and coordination among the teachers. Ten years later, doubts arose about the contents and quality of the program and a curriculum revision committee was appointed with Six Seconds-in-command of various dental departments. They started with evaluation Surveys among the alumni, academic staff and dental students. The outcomes made clear that the discomfort generally felt with the existing program was justified. It became obvious that superfluous 167 A Life's Work Subjects were taught, redundancies occurred and essential topics were missing. For example, a zoologist presented a one-year, two-hour course on the evolution of the skull and particularly the dentition from primitive fish until man. The biochemist was given too many hours and taught topics of no relevance for the rest of the program and for practicing dentists. On the other hand, essential parts were missing as how to deal with patients who are afraid or have pain and how to relate bad news to a patient. These deficiencies also applied to setting up a new dental office and buying/selling one, the management of an office, financial topics and dealing with staff, dental supply houses, insurance companies and the like. It was decided to divide the contents of the program in three lines differentiated around various skills: cognitive, motor and affective skills. Lines were organized in vertical tracts in a cyclical manner so that information provided in subsequent years was based on the contents provided in the preceding year. First, final objectives were defined that should have been realized at graduation. By working backward top down, the contents of the preceding years were shaped. Regarding orthodontics, it became obvious that the sequence from top to bottom should be orthodontic treatment methods, problems and procedures, diagnosis and treatment planning, facial growth and orthopedics, and development of the dentition. Consequently, the last subject had to be taught in the first year. When the new curriculum was implemented in 1974, it was reduced in duration from six years to five as it was better organized and more efficient than the former one. The curriculum was extended to six years again in 2009 to implement newly developed concepts and treatment procedures, and also because more medical aspects had to be included, as dentists are confronted nowadays with more elderly and very old people with complex and vulnerable health conditions. So, regarding orthodontics, I was confronted with the task of teaching the development of the dentition in the first year. I started lecturing extensively on this subject, although the textbooks of that time contained little information on dental development and particularly not on the development of malocclusions. In 1979, I composed a syllabus with many line drawings, but no photographs (van der Linden, 1979). Shortly thereafter, I found a publisher who was willing to produce the 168 van der Linden Syllabus as a book. With few changes and additions, it appeared in two Versions with the only difference being the color of the cover (Fig. 1A- B). One was for dental students and cost the equivalent of five dollars nowadays; the other one for dentists and others and was twice as expensive. It was cheaper for students to buy the book than to copy it, which was considerably more costly than today. In later years, I added an index and references, but the contents stayed essentially the same. New editions were more fancy looking and produced more nicely (Fig. 10). The book served well until 2010 when I had put together a new version, not So much regarding contents, but in way of presentation using modern techniques. For the composition of the new book, various projects in which | had been involved during my professional life served as resources. My Ph.D. dissertation (van der Linden, 1959) was based on the Groningen Growth Study that involved yearly-collected lateral cephalograms and dental casts of 72 children from seven to twelve years of age. My thesis dealt with the growth of the facial skeleton. In addition, I studied the dental casts series mainly to analyze the effect of premature loss of deciduous teeth. At that time, caries was common in the Dutch population. Many children had severe dental decay, particularly in the deciduous molars that rarely were restored (Fig.2). In 1969-70, served as ‘The Netherlands' Visiting Professor' at The University of Michigan and worked mainly in the Center for Human Growth and Development with Dr. Robert E. Moyers, the Founding Director of the Center. That turned out to be a most productive year for me. At the same time, Kalevi Koski, Takayuki Kuroda, Mike Riolo, Jose Carlos (Charlie) Elgoyhen and Stanley Garn were there. I spent most of the time with Jim McNamara in the laboratory of Don Enlow in the Department of Anatomy. Six months before coming over with my family, including five Children ages one to eight, I visited Ann Arbor not only to rent a house and find schools for the children, but also to discuss with Bob Moyers what my contribution to the Center could be in those twelve months. He informed me about the large growth study he had initiated in Ann Arbor called The University of Michigan Growth Study on 208 children from three to eighteen years of age. The data collection was completed in 1966 and Mike Riolo had already started to gather data from the lateral 169 A Life's Work g tandheelkundige scholing enº. andheelºndige sch. holing tandheelkundige scholin - Z is landhi - - nascholing tandhºekundige sºn mascholing 15 & indig noh eelkº lige Prº-ºr-º-º-º-º-º-º-º-º-Limºn - Iku indh g hol *…º.º. - indheelkundige scholing ºn mas g and heelkun ce biºrso Nºrwikkel. No en º GE BITS ON Twº I K K E LING - nº s dige scholing º and heelkund. noling ta gº scholºchºng a naschººl kundige slº massº ing ºn na º - scholing indige sº eelkundi ºn naschol andhee 1979 bling enºl Ang onderwijsuitgave scholº - - 94 ºf Figure 1. A-B: In 1979, an upgraded version of the syllabus appeared in two different covers: yellow for students; green for dentists and others (van deſ Linden, 1979). C. The Dutch version served well in the teaching of undergraduate and post-graduate courses until 2010 with the books upgraded technically and esthetically (van der Linden, 1994). Figure 2. At that time, children in the Neth- erlands frequently lost their deciduous mo- lars prematurely. 170 van der Linden Cephalograms. The cephalometric results were published as an atlas in 1974 (Riolo et al., 1974). With Bob Moyers, I discussed the option to quantify and analyze the dental cast collection, in digital three-dimensional (3D) data. To that purpose, a special machine was designed and constructed in Nijmegen that we called the Optocom (Fig. 3A). This device was packed in specially- made sturdy wooden cases and shipped to Ann Arbor. Indeed, the Optocom allowed 3D recording of dental casts' points and the occlusion of teeth. A maximum of 360 points could be measured on every set of casts. The points recorded allowed the construction of centers, of teeth that were used in the calculations of various values. Rugae points also were recorded (Fig. 3B-C). It was a tremendous task to collect the data from 3,328 sets of dental casts. I assembled a motivated team of six dental students who Worked continuously during six weeks around the clock in teams of two. The Success of this enterprise was realized largely by the competent Supervision of Bill Northway. At the time, computer facilities were rather primitive. The University of Michigan had only one mainframe computer in the Computing Center. Using a data converter, the raw data collected were punched in the paper tape of a Teletype that had to be delivered to the Computer center for processing and calculation. The resulting measurements had many errors. The corrections had to be undertaken by screening the complete printout by eye. This process took a long time and some persistence. That was one of the reasons that I continued as visiting scientist and came over four times per year for two weeks each for a few years. Finally, the data collection resulted in many tables with linear values and yearly changes, as well as longitudinal plots of dental arch dimensions and their changes over time (Fig. 3D). The results were published in an atlas by Moyers and colleagues (1976; see Fig. 5F later in the chapter). Herman Duterloo, who spent a year at the Center for Human Growth and Development two years before I did, had started to collect human skulls. I was able to extend the collection to about 100 skulls Covering all phases of the development of the occlusion and also malocclusions. The largest importer of skeletal material in the U.S., Kilgore International, was located in Coldwater, MI, a 1.5-hour drive 171 A Life's Work ------ ~ ----- - *::::- *::::- rº---- --- --~~~ -- it iſ tº: - - - - -- - - - - - º - º º - . * - --- - - ---- tº- & * * * * ºn tº º G- º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-ºrth- - opt--------------------------- :*:::- ------ ------ ------- * -> ----- -- - --- - --- - -- *. - - - - aſ lºs aGº ( ºr eCº- ------- ------- --- --- ---- n-vº ------- *** * * * *********** ** ºº --------th. -rm-teeth. - plus-------andibular by a mir-º-º-º- º: prºjectiºn-ºf-the-and-tº-ar-i-i-tat-in-th-fºur-tº- -º-tº- ----------the-rr- -------- --tº- -e-ºr-tº-a-º-º-º-o-º-ºu-tratº- are--sº-t-ºf-aired dental-ºf-si-lividual-ºbtained A " - ::::::::::::::-ºº-º-º-º: B -- 3. anch wrºte: marilliºt canºes --------- -vari-----180) -----~~~~ -------- - -- ----- - ------ ------ --- * *-* ---- - ---n ---. - ---. a mean s-p- - - ºn 1 - - - - --> --> * 24-T3 ...ºt --- - - - 35 2+--> --> 22 24-27 ---> * > -- -- - - - - - - --> ** 2-1 -55 - - - - - * 5, 27.53 +.53 - at 24.88 -t-. - - - - ; : # #; ; ; # #; ; ; : : ; # - fºll- ºf 3:4:: *.** Hº 25.5; 1:45 II - jº. -- :: * : *:::..: ; ; ; ; --- 2 ºz.º.º. 1.-- -- - ----> --> - 2a-2- .75 - - 3-1- 5 ºz. º.º. 12 tº 25-57 -º * 30-3- 1.42 : - --- 25 ji.52 1.8% -- - -27 ---- º t Iº irº -- 31 31.3- ºr - C - - * - - , ; ; ; ; ; -- # 1.3: 1-3: -5 G -- - - - as 32-37 -5° -- - ---- # : - : -- - - 32-25 º: ... : 3. º: - - - --- -º- - - tº - - --- º -: ; ; ; ; * }}:{{ }; º - 3° 33 32 *-e- Q 31 *~~~~ ſº 30 Ter 29 - ------- 28 27 25 ------ 25 *t → 2 u a 3 to 12 it 16 18 C 17 D º Figure 3. A: The Optocom machine that recorded 3D data from dental casts Wº built in Nijmegen, The Netherlands. B-C: Up to 360 points could be recorded including palatal rugae points. D. Many linear dimensions and changes Wºº calculated and presented as tables and graphs. The data on development of the dentition was obtained from Moyers and colleagues (1976). from Ann Arbor. Duterloo called me every time upon receiving me" material and offered me the first choice in order to facilitate arriving at an adequate collection. 172 van der Linden The skulls were taken to Nijmegen and subsequently stages of development were studied. The buccal and labial sides of the alveolar processes were removed and photographs taken (Fig. 4A-D). Silicone impressions with custom-made trays were made of the exposed dentitions. Subsequently, the teeth were removed from the jaws and placed in the correct positions in the silicone impressions. They were fixed with black wires and wax, first on the outside, then on the inside and photographed from various angles (Fig. 5A-D). In that way, a good 3D insight of occlusal development was gained. This study resulted in the publication of The Development of the Human Dentition: An Atlas (van der Linden and Duterloo, 1976). With a grant of The Netherlands Prevention Fund, I began to Collect data for the Nijmegen Growth Study, a multidisciplinary mixed- longitudinal investigation of 486 children with overlapping cohorts from 4-9, 7-12, 9–14 years and a recall at 22 years of age. Beside the Department of Orthodontics, Developmental Psychology, Pediatrics, Social Medicine and Human Biology (Utrecht, Germany) also participated in the study. It is the largest and most intensive growth study ever performed in Europe. Data were collected every six months, including lateral cephalograms and panoramic radiographs. During the first and second transitional period, extra dental casts were Collected in the middle of the six-month interval between the main recordings. The overall findings of this study were reported by Prahl- Anderson and associates (1979; Fig. 6). The finding based on the extra Collected dental casts, which showed varying pattern in the transition of the anterior and of the posterior teeth (Figs. 7 and 8), was reported by the author (van der Linden, 1982; Fig. 8). After my retirement, I was asked by the Ouintessence Company to serve as editor-in-chief and main author of Dynamics of Orthodontics,a multimedia and multilingual project covering the basic aspects of Orthodontics and related fields. The project resulted in a glossary and six DVDs (Fig. 8). One of the goals was to demonstrate the development of the normal dentition and that of the various malocclusions in virtual reality (Fig. 9A). 173 A Life's Work Figure 4-1 The skullofashidotabout six yearsotage represents the beginning stage of the first trans- tional period the average situation in the previous stagett tween the inferior rim-of-theorbits and the nasal floor has increased.--hasthesistance between the nasal floor and ºcclusal planeon oneside, and the occlusal plane and mandibular border on the other. The permanent first molars have emerged A tances. Note that the deciduousanterior teeth appear small compared to therest of the facial -tructures. --- - f, to six years of age the facial-eleton is relatively larger in all dimensions. The vertical distance-be- and further crupted but are not yet in tulivºlution The completedetiduous dentition is still present. Part of the diastemata now present between the front teethiºprobably-recent development associated with-limited increase in intercanine di- figure --> The specimen pre-nted here--how-protrusion of the upper and lower deciduousinº-A- rule the deciduous anterior teeth are more perpendicular to the occlusal planet-fºr-º-º: and -5). The contour of the buccalalveolar wall-reflect-the-position and length ºf the roots of the deciduous teeth. The anterior surface of the maxilla show-concavity just superior to the spice- of the deciduous centralinºisors. The bulging in the alveolar wall superior to the deciduous upper right first molar reflects the presence of the crown of its successor. B -- The first trººperiod Figure 4-6 The skull of achildof aboutsix years of age (see also figs, 4-1 and 4-3), seen after removal of the buccalalveolar wall. Thefarial skeleton-filled with developing permanent teeth, the positioning of which is related to their initial arrangement in early developmental stages. The spatial relationship between the permanent anterior crowns and the deciduous roots remain-ba- sically the same. The changes that took place vertically in this respectare associated with the lengthening of permanent teeth, the resorption of the roots of their predecessors and thein- crease in height of the facial skeleton. Figure 4-7 The spaceavailable in the anteroposterior direction for the developing permanentaminº and prºmosºmorelimited in the upperthan in the lowerjaw.the developingle” placedonia wider arch than the upper ones. Further, the difference in the sum of the mesodiºuſ width of the premolars and correspºnding deciduous molarºisser for the lower thanº" ſaw the lower sºng prºmºrºsºft, more deal in relatiºn to its predecessºr than" upper-one. the distal surface of the permanent uppercanine is generally inapproximation with “” avecervical region of the developing upper first premolar (see also fig. 4-10). C º-º-º-º-º-º-º-nitiºn º The first team-tº-ºried D Figure 4. A-D: A skull corresponding to five years of age before and after the buccal and labial alveolar bone was removed. 174 van der Linden figure 4-18A frontal view of the dentition.--cºnfrom above tº Dºrrºr--------ºr-tº- A B figure 4-zia ***Allow-theºnsulwen. Note the on and t ionship between deciduous insual view. Note the ord ide. clusion and the relationship-tº- draid C wº *hºnoratiºn D figure 4-1sb frontal view of the dentition, a--cenfrom below. --- 1-tº-------------- Q 2’s |-ic figure 4-21B 1. The roots of the four upper deciduous incisors are symmetrical, more or less parallel to each other and oriented perpendicular to the occlusal plane. - the uppet permanent lateral invisors are closer to the occlusal plane than the centrals. 3. The upper prºmolars are only partly visible as they archidden in this illustration behind the first and second permanent molars. They are placed directly above their deciduous prede- cessors, incontrast to the situation in the frontal region, where the permanent teeth are lingual to the deciduous ones The upper first permanent molars are distally inclined, an indication of their recent emergence. The mesiopalatal cusps of the upper ſirst permanent molars are close to the central fossae of the lowcrones. The upper second permanent molars are distobuccally inclined. . As in the upperhaw, the roots of the fourlower deciduous incisors are symmetrical parallel to each other and perpendicular to the occlusal plane. The lower permanent centralinºisers are closer to the occlusal plane than the laterals. Note the difference in this respect between upper and lower anterior tech tºre also figure:-ti). the roots of the lower laterals are shorter than those of the centrals; later they will belonger. The partly formed lowerptemolar crowns are placed directly below their deciduous predecessors . Note themesiolingual indination of the lower first and second permanent molars, compare this aspect also with the figures 4:34, 5-36, 7-14 and 8-10, ------ hip of ther first molars and --- +. . 7. : -------- -ul- the rigures mentioned under point or tº the Fire: Transitional Period º 5. A-B: Photograph of the ‘free’ dentition in frontal views in two directions. * As seen from the posterior with a drawing to indicate details. The results 9 the study on human skulls were published by van der Linden and Duterloo (1976). 175 A Life's Work A ºne ºne ºnal Sud º Bººlººse cºsºlsº ºul. Hºº. 1979 Figure 6. The results of The Nijmegen Growth Study (Prahl-Andersen et al., 1976). This project turned out to be a rather complex effort. First of all, the search for already available digital teeth did not lead to models of sufficient quality; therefore, they had to be made. We started Out with the set of permanent plaster teeth, twice the normal size, which obtained when I was a graduate student at The University of Washingto" in Seattle. Their anatomy was based on the work of Marseillier (1947). However, they did not include the apical halves of the roots. The root had to be extended. Furthermore, a set of deciduous teeth had to be carved in plaster that corresponded in size and shape and occlusion with the permanent teeth. Luckily, Marseillier's book also contained detailed drawings of deciduous teeth. I spent two months at The University of Freiburg in Germany and four weeks at the University in Düsseldorf where worked with Rutger Lauterjung from 8-18 hours, four days Pº" week (Fig. 9B). He was a university-trained architect, but could not find 176 van der Linden *-*-i-º-º-º-º: --- - tº--º-º-º-º-º-º-o-º-º-º-º-º-º-tº-per-nt-tº- -----------------tº-º-º-yºu- - ---------ºut-º-º-º-º-º-º-º-tº-acºn- - p-tº-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- A B 95. C ***********) rº---- -º-º-º-º-o-º-º-º-Pºst-roºt-tº-tº-nºtiºn Pattºn D. cº-º-º-º- -º-º-º-º-º-º-º-º-º- - - a -amºus--- - e: ºne-º-º-º-º-º-º-º-º-o-º-º-º-º-º-º-º-º-º-º-º: ----------- c. After ºn-º-º-o-º-º-º-º-º-º-º-ent--tº-ºtº-o-º-toº--ºn - - --- o: The ext-ºn---ºn------fºr-º-º-o-º-º-tº-dºº-º-o-º-º-º-tº- - 56 D near-cº-moºr-º-º-º-º-tºo-oº-eruption-of-the-to-pººr figure 7. A-B: Example of a transition pattern of the maxillary ante- "Of teeth, based on three-monthly data collection. C-D: Example of a transition pattern of mandibular posterior teeth. The results of the study of the transition were published by the author (1982). 177 A Life's Work - --------- John Daskalogiannakis, DDS, MSc ----------- Lehman applianc-S- -- --------º-º-º-º-º-º-º- - --on-ºr-molar ------ tº-woºt-º-º-º-º-º-º-º-º: -------------n -ptopro-ople --------- - --- ------pac- tº-º-º-º-º-º-º-º- ºn-tº- º --- --- - Glossary of ºº: ºº - -------- º Orthodontic Terms ºf --- - - Leveling wire any-------- ---ºr-------------- ---------------- Lºbº-nº- ------------cºp-oº-º-º-º- m-tº-º-º-º-º-º: Editorial Board: --to-a-di-tan- º: - - -------P- F. P. G. M. van der Linden R.-R. Miethke J. A. McNamara, Jr. Ligament fººt-ºn-o-º-º-º-º- compº-d--- -gament, Periodontal S-Pºo- -- -------, -and-tº-urgical procedure-- - -º-º-º-o-º-º-º: º orthodontics - -gament-to-th-tº-1 5-on- Dynamics, of] - -poºn- - B 157 ------------- - º º ºlossary of orthodontº º º-º-º-º- - --- º - Facial ºrowth --------------- ºn a Lº ------------tº- º Facial ºr nonetics *----------|-- - - - - - - | ------------------ - º Development of the Dentition | s -º-º-º-º-º-º- - -------------- º Orofacial Functions ºn-ºn-nu- º 2 ºn J. - Figure 8. A: English version of The Glossary of Orthodontic Terms. B: A page from The Glossary of Orthodontic Terms. C. The six DVDs from the Dynamics of Orthodontics Series. a job during the economically-challenged 1980s. As a student, he becam" interested in the development of artistic computer programs. He found a job as a designer of elaborate presentations for TV broadcasting companies and later became involved in a firm that made computº animations. He also worked as an instructor in that field. | explained to him the development of the dentition using Marseillier's atlas and my first book as main resources. Indeed, Wº realized the goal and created the development of the normal dentitioſ from the initial mineralization of the deciduous teeth until the completed permanent dentition, consisting of 4,200 frames. Also the eruption aſ transition of central incisors were shown together and in relation to 178 van der Linden the changes in the tongue, lips, nose and chin. Animations also were prepared for the various malocclusion types. This project was by no means simple and required working With several computers and views from various directions (Fig. 10A). After the central university computer had calculated the programmed information during the night (it required many calculating hours in those days), we had to spend about half of the next morning to correct the errors. However, the results we wanted were achieved (Fig. 10B). The new version was based on the first book in the van der Linden Series, Development of the Dentition (van der Linden, 1983). In addition, concepts and data from two additional volumes, Facial Growth and Facial Orthopedics (van der Linden, 1986) and Orthodontic Concepts and Strategies (van der Linden, 2004; Figs. 11-13), also were incorporated. A DVD was added to the Dutch version (van der Linden 2010) with 50 video scenes in virtual reality, demonstrating many aspects of the development of the dentition (Fig. 14). º 9. A. Set of natural teeth in virtual reality. B: The author working with . Lauterjung to realize the development of the dentition in virtual reality, "h the final stage in virtual reality. 179 A Life's Work Figure 10. A: To achieve the proper positions and occlusions, checking from various angles was required. B: Two examples out of the 4,200 frames from the beginning of the mineralization of the deciduous until the completed permanent dentition. Orthodontic Conce and Strategies Frans P.G.M. van der Linden Figure 11. The book Orthodontſ concepts and strategies (van * Linden, 2004) contained items aſ illustrations well suited for incorp" ration into the new book. van der Linden The Wander Linden Series Development of the Dentition Facial Growth and Facial Orthopedics Diagnosis and Treatment Planning in Maxillofacial Orthopedics Problems and Procedures in Maxillofacial Orthopedics Maxillofacial Orthopedics in General Practice Van der Linden Development of the Dentition Maxillofacial Orthopedics Treatment by an Orthodontist Van der Linden Van der Linden Van der Linden Van der Linden Boersma SBN 0-55-15-03-x Orthodontics with Fixed Appliances Practical Dentofacial Orthopedics Problems and Procedures in Dentofacial Orthopedics Diagnosis and Treatment Planning in Dentofacial Orthopedics van der linden Facial Growth and Facial Orthopedics Van der Linden Development of the Dentition Figure 12 A: The van der Linden Series was published in various languages. This designation was put on the back cover of the first book by the publisher Without Consulting the author. B: The six books of the van der Linden Series after completion. C. Development of the Dentition (1983) is the translation of the Dutch book with the same contents. 181 A Life's Work changes in the craniofacial skeleton During Postnatal Development solº staºnanos - Van der Linden Facial Growth and - Facial Orthopedics º soºn sannanos Figure 13. A: In Facial Growth and Facial Orthopedics (van der Linden, 1986), the biological aspects of skeletal growth and development of the face are elucidated. B-C: Illustration of the Bolton data in the book of Fig. 13A. In the first months of 2010, translated the new book into English and presented it to Quintessence together with all illustrations and the outline and layout to be published in other languages as a printed book. However, they were prepared to produce it only as an e-book, which is understandable considering the trend to move to digital teaching material It turned out to be the first e-book to be produced by Quintessence from scratch (Fig. 15). The e-books they made earlier were copies of sold-out printed versions. Preparing the e-book from scratch involved modifications of the manuscript and layout. This new format required frequent consultatio" between editor and author. However, it worked well. One of the advantages of an e-book is that video scenes can be incorporated. They 182 van der Linden Gebits- ontwikkeling bij de mens Prof. dr. F.P.G.M. van der Linden figure 14, A. The new Dutch book (2010) is updated and produced with modern sophisticated techniques. B-C. It contains a DVD with 50 videos taken from the Dynamics of Orthodontics Series. 183 A Life's Work produced only as e-book in which Figure 15. The English version is the videos are incorporated. ſza， <， > --> ---- CD {= （5 EēĒ， |C5Eſ-， CDza）， āſ ſēſtī, O （SOE) Figure 16. The e-book contains drawings of the syllabus (van der Linden, 1979). Frans P.G.M. van der Linden, DDs, PhD 184 van der Linden Fig 2-19 The teeth arranged as they were situated in the skull, ſa and b) The height difference between the incisal margins of the central and lateral permanent incisors is obvious in both the maxillary and mandibular teeth. The proximity of the distoincisal corners of the maxillary central Permanent incisors to the roots of the lateral deciduous incisors is clear. The mondibulor permo- ment incisors diverge occlurally. The crowns of the maxillory permanent incisotº. canines, and premolars are close together. That is not the case for the distally diverging maxiliary central inci- *otº. In both jaws, the permanent canines and premolars are located slightly more distally than their predecessors.In the maxilla, the permanent second molars are buccally inclined and distally *ngulated in the mandible, they are ſingually inclined and mesially angulated.The frontal viewis shown from above to and below(d) and the lateral view from above (e)and below (fl. Figure 17. Photographs from the skeletal material from the atlas by Van der Linden and Duterloo (1976). * Figure 16 legend as it originally appeared in the e-book. Fig 3-6 The most common mode of transition of incisors. (a) At 5 years of age, the eruption of the permanent incisors has not yet started. (band c) First the mandibular central deciduous inci- ** are lost, followed 1 year later by the maxillary central incisors. The distal displacement of the *illary lateral deciduous incisors is associated with the eruption of the central permanent inci- sº which starts a few months earlier. In the mandible, the eruption of the central permanent Incisors is not accompanied by migration of deciduous teeth. (d) Shortly before the mandibular lateral permanent incisorsemerge, the adjacent deciduouscanines move to the distal and buccal. º The initially more palatally positioned maxillary lateral permanent incisors erupt in a more la- bial direction than the central incisors. When their crowns come close to those of the central inci- *s, the central diastema reduces.” However, that reduction also occurs if this proximity is not eached, as often happens.” With the eruption of the lateral incisors, more room becomes avail- able for the roots, allowing those of the central incisors to move distally. Their mesiodistalangula- "on alters, and the crowns move toward each other, (f) The maxillary lateral permanent incisors *the last to reach the level of the occlusal plane. There are diastemata in the maxillary anterior *and quite often also in the mandibular region. The roots of the lateral incisors are near the *ns of the permanent canines. 185 A Life's Work Fig 3-5 transition of the centralinºintestion to the surrºunding-of-tºuetta The upper ºpcover: the mºnitºry deciduous indº, and the lower ºn cºvers the mandibulatinº as well-º-ºn-portion of the mºry incºors tº After emergence the mandibular permanent incºr-contact the lower ºn the nº margins of the mand buº permanent incºr-attan- non- han-hºº--------- tº-º-º-º: - er degree in the maxill-tº-Prº-to-nº following emergence the maxillºry permanent nº aremotel-bºy incºmed than themandibular incºot: The pressure exerted by the pºd-to- reduction ºf the ºbulin-ºn-ºn-ºn-tower lip support-th-maxillary nºw-tºº-y-to- gether with themandibularinº on the roots are competed after emergence in the cººlavity. tº the skeleton-well--the-of-tºu--and the non-continue to grow, resulting in-straighter * *ndfurther uprighting ºthernºon, more in thematº-thºninthemandible sº-chºp- A the Dº Printed from vand-unden et al-with perm-ºn- Fig.5-5 Transitioninsmall middlesections of the apical areas ta/themaxillary first premolar can emerge without hindrance, bºthemandibular canine, however, overlapºthelateralinºivorabi. ally after emergence-ſºlnthemaxilla, the second premolaremerges well.ſºhowever,thecanine ends up posit ide the dental arch.ſe) in the mandible, the at also emerges well-ſt) ºf the maxillary first premolar moves distally after premature loss of the second deciduous molar, the canine can erupt well, and the second premolar ends up palatally posi- tioned. It - --- - ti-º-º: is reduced severely, the second premolar emergestingually. It can even become impacted if the first permanent molar migrates excessively to themesial. If the maxillarylateral incisor emerge: palatally, it can end up in negative overjet. molari-loat The relative size of opposing sections of the apical areasquite often differs. For example, a small maxillary anterior section can be combined with a large mandibular anterior sec- tion. The same applies to middle sections. In addition, the relative size of the anterior and sections may vary within the same jaw. For example, a small maxillaryanteriorse:- C In becombined with a medium middle section and vice versa. - Fig 3-18 Eruption and position of first permanent molars (a) prior to emergence thereiº cient roomforthefirst permanent molars inboth jaws.ſb with eruption they become moteup right-ſcanddafter reaching occlusal contact they are guided by the cone-funnelmethanºmº with narrow mandibular second deciduous molars, they can immediately reach maximulinlet cuspation tº Their angulation does not alterprior to the emergence of the second permanen molars. The posterior extension of the tooth-beating parts of the jaws that precedes the * gence of molarsistelected in so-called molarfields behind the last toothin theº" region.” These molarfields are visible and palpable in the mouth, most clearly inthemaº illa where the morphology of the tuber seasy to assess it is more difficultospecify the posterior border of the alveolar process in the mandible. Molarfields develop priortothe emergence of deciduousand permanent molars. They can betoo smalfortheºdº emanent molarsifthe preceding posteriorjaw.extension has beeninsufficientº B discussed indetailinchapter 6. Fig 8-7 Eruption, emergence, and replacement of incisors ſayihe formation of a permanent" cºor starts before its predecessorbegins to erupt. (b) The formation of a deciduous and a . ment toothis accompanied by bone resorption.ſº) whena permanent incisor sº º as the root of its predecessor are resorbed (dande) Gradually, the permanent º * at- ther, and its predecessor resorbs more tº The emerging and erupting inciso: builds upitso" alveolar process. Deciduous inciscºsate smaller than their successors. The defectintheging” º. of the deciduous crown is repaired, and a new opening is created for thee D fthe successor (Fig.8-8). Figure 18. A: Illustration of the transition of the incisors that also shows the changes in nose, lip and chin until adulthood. A touch on the icon starts the Video showing the changes in continuity. B: Rotating sections from the development of the dentition. C. Normal transition of the posterior teeth. D. Eruption aſ transition of mandibular incisors. From the Dynamics of Orthodontics Series, Vol. 3A. Development of the Dentition. 186 van der Linden Fºº---------------- ------------------------------- ------------------- ------------------------- - - --- --- --tº-o-º-º-º-º: --------------------- Fig. 9-11. Th - ------------------- - - - - ---------------------- ºtestionshipoſtheantenorºtonwortheapical areas thendination of theinºvanese --- - -by toºthespices of the manuary cannes are located laterally and close to the pºiſomaperture. -------------------- … . --- º Tº ºut. - - ºn the nºn- ------- - --- A onoſtheannesadapts to the transverse relation of the apatareas. B ------ Figure 19. A: The 'dento-alveolar compensatory mechanism' for inci- Sors and canines. B: The contribution of the various growth sides to the Vertical and Sagittal growth of the facial skeleton. From the book Ortho- dontic Concepts and Strategies (van der Linden, 2004). Start with a touch on an icon. In addition, an e-book is cheaper than a printed book (Fig. 15). The e-book contains the normal development of the dentition with several variations and all malocclusions. Special attention is paid to that of openbites and non-occlusions. That also applies to the effects of premature loss of deciduous teeth. The last Chapter contains a large amount of statistical data. Figures 16–22 show examples from the various sources of ma- terial used in the e-book. Most textbooks and scientific publications are out of date after five years as new information and concepts arise. That is not the case for most anatomical textbooks and also not for the one on the development of the dentition described above. Fur- thermore, for more than 30 years, there has been a ban on commer- Cial export of human skeletal material. That happened to be a dubious activity in some very poor countries where the means are lacking for burying or Cremating those who pass away. The taking of radiographs 9 other procedures that have negative side effects for the exposed perSon also are extremely limited worldwide, unless they are indicated 187 A Life's Work Fig 12-6 ºn-cºntral permanent indºor-in-ºn-tº-º-º-º-º-ºn- mºnº-mandºuarnºon-tuptnomaly. The mºnºn-tºppedº tºyºto-ºn-ºthereafter they continuetoºl-tº-and-ºuptiºn contact is established the mandibular mºors also start to up ungually see ºpter ºoth- B Pºinted ºn vand-under-al-with permission. º Fig 11-5 rººm-tººth-nºnrelatiºn to theºn-in-cº-ºwºon malo- ºn-ºp-ºº-º-º-º-º-º-º-ou-denº-ºn-º-º-º-ºne-nº- ºn-ºn-ºn-ºn-on-ºn-ºn-uniºn proceed-nºmºyºnº anºthernandºu- -º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-ºn-tº- ºn-tº-pº-the-tº-perman-º-º-º-º-º-º-º-º-º-º- Tºº-º-º-º-º-º-º-º-º-º-º-º-º-ºuth-tº- ºppºng cº-º-º-º-º-º-º-º-º-nº-upported-tº-by-th-low-up --tº-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º: ºntº-ºn-º-º-º-º-º-º-º-o-tº-poºh-ºº-ºº-bºund-tº-mºn nºn-tº-nº-ºº-º-º-º-º-tºn ºf the tº the ºut-º-º-º- ºu-ºº-º-º-º-º-º-º-º-o-º-º-º-º-º-º-º-o-tº- Dºu Not-tº-º-º-º-º-º-º-º-ºwninth-ºo-º-tongue-poºl. ----------tº-mandºu-ºº-º-º-º-º-untº they reach the palate-the-tºngue tº on tºp ºf the mandibular nºn-verºcontact is not reached and non-ºn-º-º-º-º-region tPºinted ºnvand-unden--with permº- A tº Fig 16-8 ºn-tº-º-º-º-econd deciduous mºnºn-utº ºth- mºntemnºn-º-º-º-º-ºp manent moºn-ºn-dº" º ºt-mºnº-º-º-º-mºnth-ad-ºn-ºp-mºtº mº -º-º-º-ºne mºnadºu nº wºupº º D -º-tº- Fig 14-6 op-tº- ºn-º-º-º: - -º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-ºn-ºn- -º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-º-tºn tº-º-º-º-º-º-º-º-º-º-º-º-º-º-o-º-º-ºn-ºn-tº- ----------oº-º-º-º-º-º-º-º-º-º-º-º-º: ------------- Nºte ºn occurs quite ºften in Cº. ºn ºu. ºn tº ºne-ºn-the teeth are we alºned Cº. and the nº- ºn ºn tº do nºt knºw that then-ºany abnºrmat. In addition | º tº a tºº ºn in the ºntº regiºn ºn a sºurce ºf º ſ ºntº Fig 16-19 Pºnºration wandºn aneutrocºon whenamendº º, -------- - lary - - --- - º the mºnºgation ºf the mandibular first permanent molarſ and dº whenºmº ºptematurely themandibulºnd deciduous moº *" ºup-ºº-º-º-intervention a portion of the mºo-oº. ºf the tº ºn tº nº º -º-º-º-º-º-migration of the mºnary tºp-mºntº na º ºn-ºn-tº-ºncompºne ºbonded on theºdº surface - manºecºndevºting agittaloºns tº - º . ºpºnent ºn compºnemus becamed out ºntº-bºº" * nºn-the-ºn-º-º-º-edures will not º ºn-º-º-o-º-º-º-º-º-manent ºn wºuptuº º - other ºped tº eruption strategic use of this potential provideº the possibility” E ºundeº-ºration Cº-º-º-º-º-º-º-º-º-º-º-º-º-ºn-ºn the number ºf teethºd. The are ºn anaºan dental ºn and abº ºn tº party due to the abºe ºf the ºne-ºn-meº and the ºn ºf the ºn ºf ºppºng teeth ºthere mechanism dºes nºt functiºn ºn tºnguenºtiºn (Fig 14-7. An ºver, nºw mºlandental -º-º-º-º-º-º-ºn-tºp of each ºther transºye end-to-end cº- C ºn are cºed mºtº-interpoºn 188 van der Linden e- Figure 20. A: Transition of the incisors and subsequent development in a Severe Class Il division 1 malocclusion. B: The palatal tipping of maxillary incisors in a situation where they are covered excessively by the lower lip. C: Open bites and non-occlusions. D: Premature loss of a mandibular second deciduous molar and supereruption of its antagonist that blocks the mesial migration of the mandibular first permanent molar. E-F: Blocking the migration of the maxillary first permanent molar after loss of the maxillary second deciduous molar by Strategic grinding of the mandibular second deciduous molar, allowing over- eruption of its antagonist (E) or by bonding a blockade of resin composite on the OCClusal Surface of the mandibular second deciduous molar (F). From Dynamics of Orthodontics: Vol. 3B. Malocclusions and Interventions. - #. º: 2-10 1.81 61 25.65 1.87 88. - 135 -11 1.37 sº 2-79 1.93 83 º 1-0 : 188 º 2586 1.90 83. - 35 -- º ---> --> -> ** --~~~~ - : | Fig 17-15 superimposition of the dental arches of the permanent dentition, based on the cent- ers of the toothcrowns, arranged by chronologicage” | ? - A - * * * * * * *-ty. B Figure 21. A: Tables and graphs illustrating the dimension and increase of the *tance between the mandibular first permanent molars. B: Plots of arch form and changes in dimensions of subsequent years. Derived from the book *ºndards of Human occlusal Development (Moyers et al., 1976). 189 A Life's Work Develºpment of the HUMAN DENTITIO Frans P.G.M. van der Linden, pps, php º quintpub.com This book is available for download on your iPhone, iPad, or iPod touch with iBooks and on your computer with iTunes. Figure 22. The final product: the e-book, Development of the Human Dentition. for health reasons. So, longitudinal growth studies that include radiation effects cannot be carried out anymore. Indeed, the main resources that provided information for the development of the dentition barely will increase anymore. Finally, the processes involved in the development of the dentition are the Samº since mankind started to populate our planet. In addition, there are ſº essential differences in that respect between man and primates. Indeed, it is a comfortable feeling to be able to make information available that will not become outdated. have had the privilege to be part of investigations dealing With the subject that intrigued me from the beginning of my professional life, have sensed the moral duty to make the information I was so fortuned to gather accessible to others. I am grateful that my intellectual and physical condition allowed me to finish this task at a rather advanced age. 190 van der Linden Finally, this research has been made possible thanks to the inspiration, competence, support and help of many with whom I had the pleasure to work with over a period of more than half a century. REFERENCES Daskalogiannakis J. The Glossary of Orthodontic Terms. Dynamics of Or- thodontics Series. Chicago: Ouintessence Publ Co. Inc. 2000. Marseillier E. Les dents humaines: Morphologie. Paris: Gauthier-Villars 1947. Moyers RE, van der Linden FPGM, Riolo ML, McNamara JA Jr. Standards of Human Occlusal Development. Monograph 5, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1976. Prahl-Andersen B, Kowalski CJ, Heydendael PHJM, eds. A Mixed-longitu- dinal Interdisciplinary Study of Growth and Development. New York: Academic PreSS 1979. Riolo ML, Moyers RE, McNamara JA Jr, Hunter WS. An Atlas of Craniofacial Growth. Monograph 3, Craniofacial Growth Series. Center for Human Growth and Development, The University of Michigan, Ann Arbor 1974. Van der Linden FPGM. Development of the Dentition. Chicago: Ouintessence Publ Co. Inc. 1983. Van der Linden FPGM. Development of the Facial Skeleton of Children from 7 Until 11 Years of Age. Ph.D. Thesis. [In Dutch..] Groningen, Netherlands: Drukkerij Van Denderen 1959. Van der Linden FPGM. Development of the Human Dentition. [e-book] Chicago: Ouintessence Publ Co. Inc. 2013. Van der Linden FPGM. Facial Growth and Facial Orthopedics. Chicago: Ouintessence Publ Co. Inc. 1986. Van der Linden FPGM. Gebitsontwikkeling. [In Dutch..] 4th ed. Houten, Netherlands: Bohn Stafleu Van Loghum 1994. Van der Linden FPGM. Gebitsontwikkeling bij de mens. [In Dutch..] Houten, Netherlands: Bohn Stafleu Van Loghum 2010. Van der Linden FPGM. Orthodontic Concepts and Strategies. Chicago: Quintessence Publ Co. Inc. 2004. 191 A Life's Work van der Linden FPGM. The Development of the Dentition Syllabus. [In Dutch..] Alphen aan den Rijn, Netherlands: Stafleu & Tholen 1979. van der Linden FPGM, ed. Transition of the Human Dentition. Monograph 13. Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1982. van der Linden FPGM, Duterloo H. The Development of the Human Dentition: An Atlas. Hagerstown, Maryland: Harper & Row 1976. 192 TOWARD A MODERN SYNTHESIS FOR CRANIOFACIAL BIOLOGY: A GENOMIC-EPIGENOMIC BASIS FOR DENTOFACIAL ORTHOPEDIC TREATMENT David S. Carlson ABSTRACT Understanding of the role of the genome, which includes both the individual genes and properties intrinsic to the chromosomes that affect their expression, in normal development has evolved greatly in recent years. In particular, it now is clear in this new “epigenomic era” that the epigenome, which refers to all the non-DNA encoded factors of the genome as well as extrinsic factors that Control gene expression of regulatory proteins, plays a critical role in normal and abnormal development. As a result, understanding of both genomics and epigenomics is critical for understanding normal growth of the craniofacial Complex, as well as the efficacy of treatment to correct a developing dentofacial deformity. Five sequentially related axioms serve as starting points for the idea of a modern Synthesis of concepts from genomics-epigenomics and dentofacial Orthopedic treatment of malocclusion and more profound craniofacial deformities. This approach is built on the premise that concepts regarding the efficacy of dentofacial treatment always have been based on contemporary understanding of the mechanisms of craniofacial growth (Axiom 1). Because phenotype, including the rate and amount of growth possible, varies both normally during ontogeny and as a result of the activity of normal and abnormal gene variants (Axiom 2), the capability of patients to respond to orthopedic dentofacial treatment should be considered as part of the phenotype (Axiom 3) that should be taken into consideration when planning dentofacial orthopedic treatment (Axiom 4). Finally, the possibility of underlying variation of normal genetic polymorphisms for key regulatory factors may be a significant factor affecting the outcome of clinical orthodontic research on the effectiveness of dentofacial orthopedics (Axiom 5). KEY WORDS: genomics, epigenomics, dentofacial deformity, growth factors, Orthodontics, craniofacial biology 193 A Genomic-Epigenomic Basis With respect to clinical practice, is science useful merely because it is good science? The genome project, for ex- anple, may well revolutionize the treatment of schizo- phrenia or heart disease, but can the same be said of its potential impact on orthodontics? (Johnston, 2004) The first Symposium on Craniofacial Growth at The University of Michigan, also known as both the Michigan Growth Symposium and the Moyers Symposium, was held in 1974. As it was established in honor of Dr. Robert E. Moyers, former chair of the Department of Orthodontics and then director of the Center for Human Growth and Development, from the onset the Symposium reflected Bob's vision of a sustained intellectual environment in a major academic setting. The Symposium was designed to bring together experts in the fields of bio-medical/ dental Science and clinical orthodontics with scientists and scholars from a multitude other areas of academics, ranging from paleontology to psychology and sociology (Lucker et al., 1981) and even to the humanities, such as considerations of facial form and beauty as reflected through the history of art (McNamara, 1993). From its inception, the Moyers Symposium was more than a forum for scientific and clinical reports that typically would be found at the meetings of professional societies such as the annual meetings of the American Association of Orthodontists and the International Association for Dental Research. Rather, the Moyers Symposium provided a unique platform to present up-to-date Scientific and clinical information in the context of advancement of new and innovative concepts about the current status and future prospects for craniofacial research and orthodontics. There were few similar opportunities where scientists, scholars and clinicians actually were expected to put forward ideas of where the combined fields of craniofacial research and treatment of dento- facial deformities are, how they got there and where they are going in the future. In this respect, the Moyers Symposium was not just inter- disciplinary—it was transdisciplinary (Lee, 2005; Medicus, 2005) as 194 Carlson it promoted insights into the full spectrum of biological, psychosocial and humanistic issues related to the causes, progression and treatment of dentofacial disorders and to the advancement of orthodontics as a learned profession. The purpose of this chapter is to provide an overview of the development of modern concepts of genomics and epigenomics in the Context of advances in craniofacial research and orthodontic-orthopedic treatment of developing dentofacial deformities through a series of five related axioms as focal points for discussion (Fig. 1). The overarching goal is to promote a more apparent synthesis within craniofacial biology between the modern science of genomics and approaches to dentofacial Orthopedic treatment. 1. Dentofacial treatmentis based on contemporary concepts of craniofacial growth. 2. Phenotype changes normally throughout ontogeny. 5. Dentofacial research has been limited by inability to fully characterize genomic expression. 4. Dentofacial treatment should take into account genomic variation that affect the ability of the patient to respond. 3. The capability of patients to respond to treatment is part of the phenotype. figure 1. Axioms formulated as a basis for further discussion regarding the inter- relationship of Concepts and principles of genomics-epigenomics, craniofacial 50wth research and dentofacial orthopedic treatment. 195 A Genomic-Epigenomic Basis WHY SYNTHESISP During its early years, the Moyers Symposium included a dinner open to all those attending the two-day event. As entertainment for the evening, Bob would recruit a distinguished member of the faculty of The University of Michigan—someone not associated with dentistry or medicine—to present a brief after-dinner lecture on a subject that might be of broad interest. The dinner speaker for the first Moyers Symposium was Frank H.T. Rhodes, professor of geology and at the time Vice President for Academic Affairs", who spoke about the life and contributions of St. Thomas Aquinas (1225–1274). Aquinas was an Aristotelian who sought to “Christianize" Aristotle for the medieval world. Aquinas also was one of the most remarkable scholars of the Middle Ages who produced over 30 major works dealing with theology, science and philosophy. His monumental work, Summa Theologica, contains 60 volumes dealing with our perception of the universe through personal experience and science. Rhodes noted that, “the real originality of Aquinas lies not SO much in the discovery of the new but in the sheer boldness in tackling a synthesis of such monumental proportions” (1975, emphasis added). While acknowledging his “impudence of comparison,” Rhodes went onto observe that upon consideration of Bob Moyers' vision for the Symposium on Craniofacial Growth combined with his life experiences in Greece during World War II and during his distinguished academic career, it is "... easy to draw parallels between the great success of Thomas Aquinas as a synthesizer, a committed academic statesman, and an individual with a lifelong dedication to the wider service of humanity...” (1975, emphasis added). So, perhaps without realizing it, Professor Rhodes provided the perfect melding of Bob's passions—Aristotle and Greece in general, academic life, philosophy, science and, of course, orthodontics. Bob also was a great synthesizer who sought to apply scientific and scholarly principles from wherever he found them to address his overarching interest in orthodontics through craniofacial research. | Professor Rhodes later became president of Cornell University, where he re- tired as the longest serving president of any Ivy League university. 196 Carlson WHAT IS A SYNTHESISP A synthesis is simply a combination of two or more theses” that together create something novel. A true synthesis is a transdisciplinary melding of ideas and approaches from two relatively separate areas or fields to create new concepts and approaches that incorporate the principles of the previously distinct components. For the purposes of this chapter, synthesis is used to relate and combine modern concepts explicitly in the relatively new field of genomics and especially of its more recent offshoot, epigenomics, with concepts of craniofacial growth and Orthodontic research leading to insights about treatment of dentofacial deformities. Perhaps the easiest way to explain the concept of synthesis in Science is to use development of the “modern evolutionary synthesis” (Huxley, 1942) as an example. During the latter part of the 19th and first part of the 20th century, the study of evolution essentially became divided into three primary areas: 1) paleontology; 2) ecology, experimental biology and embryology; and 3) Mendelian genetics. The approach of paleontologists who worked in the field to discover fossil remains of extinct animals and then in the museum to assemble them characteristically inferred the process of evolution primarily through assembly of lineages representing progressive changes in morphology (phenotype) due to natural selection of morphological features and behavior/function. Embryologists, experimental biologists and ecologists focused on morphological variations in extant animals correlated with the environment to infer mechanisms for inheritance of gradual change over time (Morgan, 1926; Waddington, 1939, 1940, 1962). The emerging field of population genetics, on the other hand, accounted for evolution primarily through newer principles such as mutation and genetic Separation (drift and flow) leading to changes in genetic fitness (Haldane, 1932; Dobzhanski, 1937). The synthesis between these groups occurred in the late 1930s when it became clear that gene change provides a basis for change in phenotype that then is acted upon by the process of natural Selection. Thus, one group or idea was not supplanted by another; a Synthesis of all of them was essential to explain the process of evolution * Thesis: proposition maintained by argument; hypothetical proposition, espe- cially one that is put forward without proof. 197 A Genomic-Epigenomic Basis more fully” and, thus, they merged to become the neo-Darwinian field of evolutionary biology. CRANIOFACIAL BIOLOGY AND CLINICAL ORTHODONTICS Opinions regarding the etiology and natural history of malocclusion provide the fundamental rationale for the treatment "philosophies” that characterize the field of orthodontics. (Robert Moyers, personal communication) Craniofacial biology is defined as the study of the development, growth and function of the craniofacial skeleton, dentition and related tissues (Carlson, 1985). Basic research in craniofacial biology always has formed the foundation of orthodoñtic treatment and applied research in that area has been driven by clinical problems related to craniofacial deformities in general and orthodontic interest in dentofacial deformities in particular. From the time of Edward Angle (1907), orthodontists have based their treatment “philosophy” on prevailing concepts regarding the effects of (bio)mechanical forces on growth and remodeling of craniofacial skeletal structures. The efficacy of remodeling of alveolar bone in response to forces applied to the dentition was demonstrated Very early in the history of orthodontics. However, the ability to predictably modify skeletal growth at the sutures of the cranial vault and midface and through the cartilage of the mandibular condyle therapeutically has been debated for over a century. The earlier view that the pattern of craniofacial skeletal growth and remodeling other than that associated with alveolar bone cannot be altered obviously affirms emphasis on treatment focused around orthodontic mechanics to bring about tooth movement, typically after most or all of growth is completed (Brodie, 1946). On the other hand, belief that craniofacial skeletal growth can be altered by treatment is the basis for use of “growth-modifying appliances” in an effort to correct * It is interesting that even the modern evolutionary synthesis is, itself, “evolv- ing further with the advent of advances in developmental biology and genomics epigenomics into a new approach called evo-devo, which refers to the evolution- ary developmental biology (Carroll, 2005). 198 Carlson Skeletal malocclusions in younger, actively growing patients (Graber, 1983). CHANGING CONCEPTS OF GENETICS AND CRANIOFACIAL GROWTH For some time, attempts have been made to provide an overriding conceptual framework for all of craniofacial growth or, failing that, a neat synthesis of several “theo- ries.” These efforts generally have not been successful yet because of the varied aspects and complicated nature of craniofacial growth...It is very important to remember that old ideas persist in the literature...long after they have been abandoned by craniofacial research biolo- gists. (Moyers, 1988:48-50) The history of research in craniofacial biology and orthodontics is characterized by five sequentially arranged and relatively distinct hypotheses or theories,” to account for the mechanisms responsible for the growth of craniofacial skeletal structures and, concomitantly, the extent to which craniofacial growth might be influenced therapeutically With orthodontic treatment.” The first three of the principal theories of craniofacial growth, spanning the first six decades or more of the 20th century—the remod- eling theory, sutural theory and the nasal septum/cartilage theory—are Characterized by the view that development and growth of bone, sutures and all craniofacial cartilages, respectively, primarily are the result of intrinsic, inherited factors that essentially are immutable to any signifi- Cant degree. Together that group of theories and the corollary propo- sition that dentofacial orthopedic treatment cannot affect craniofacial * The terms “theory” and “hypothesis” are distinct formally, but often have been used as equivalent when characterizing the various concepts of craniofacial growth mechanisms. * Refer to Carlson (1985, 1999, 2005) for comprehensive discussions and refer- ences related to the historical development of theories and paradigms in craniofa- cial biology and orthodontics. 199 A Genomic-Epigenomic Basis growth to any significant degree can be described as components of a larger conceptual framework referred to as the genetic paradigm. Shortly after the mid-point of the 20th century, an alternative viewpoint was proposed that placed less emphasis on inherited "pre- determination” and immutability of craniofacial growth, but rather focused on the capacity for alteration of craniofacial skeletal growth in response to variations in biomechanical function, as well as in forces applied to craniofacial structures. The first and predominant theory of that era, the functional matrix hypothesis, provided a radical departure from the genomic paradigm as it focused on the role of muscle function as well as other soft tissues, organs and even spaces associated with the craniofacial region on the growth of the craniofacial skeleton. The subsequent general theory of craniofacial growth, the servosystem theory, also emphasized the role of muscle function with respect to altering craniofacial growth. However, the servosystem theory also focused on the role of hormonal factors affecting cell physiology as they relate to alteration of growth of the maxillomandibular skeleton. Because of the emphasis of these two theories on extrinsic “functional” factors, together they have been described as components of the functional paradigm of Craniofacial biology. Genetic Determinism and the Genetic Paradigm At its birth, genetics was a science of similarities, not—as it would become later—a science of the mechanisms that produce these similarities. (Morange, 2001:12) Considered in the light of current knowledge, the interpretation that all of ontogeny" and in particular development and growth of the craniofacial complex leading to certain immutable types or classifications of morphologies could be considered “pre-determined” is naïve at best. However, craniofacial biologists and orthodontists in the early part of the 20th century obviously did not have the benefit of current knowledge of molecular biology and genomics on which to base their views about craniofacial growth and treatment. Moreover, even full knowledge of concepts in genetics as they were understood at the time would have ° Ontogeny refers to the “life history of the individual.” The process of ontogeny includes the mechanisms of development (differentiation-maturity), cell growth and adaptation or plasticity during growth (Carlson, 2002). 200 Carlson provided little benefit because they were so incomplete and the field was in Such a fledgling State. Modern concepts of genetics were only at their very emergence when the remodeling theory was prominent in the 1920s and 1930s (Brash, 1924, 1934). Transmission genetics, which focused on mathemati- Cal principles of inheritance of discrete characteristics within a popula- tion, began in the early part of the 20th century after rediscovery of Men- del's experiments of heredity in plants. However, during the first half of the 20th century or more, there was no real knowledge of the nature of the gene and of the mechanisms of gene action. p The most widely held “pre-genetics” theory of inheritance in the early 20th century can be attributed to August Weismann (1834– 1914), who many consider as the father of modern genetics. It was Weismann who demonstrated that only the germ cells—sperm and egg-carried the units that were responsible for heredity. An alternative prior belief was based on the assumption that somatic cells, such as muscle and bone, contributed directly to inheritance. That latter view of inheritance through somatic cells formed the basis of Lamarck's principle of inheritance of acquired characteristics, which asserted that characteristics acquired during the parents' lifetime could be passed on to offspring. Weismann's central argument about the role of germ cells in inheritance obviously was correct and provided a basis for refuting La- marck's ideas effectively as it supported the theory of evolution by nat- ural Selection as proposed by Darwin. However, perhaps in his zeal to refute Lamarck's ideas about the inheritance of acquired characteristics, Weismann also made several corollary arguments that not only are in- Correct, but also unfortunately were detrimental to advancement of un- derstanding about the hereditary basis of development and growth for decades to come. Specifically, in rejecting the concept of inheritance of acquired characteristics Weismann (1892) also asserted that: 1) inheri- tance is based on a “pre-formative arrangement,” or blueprint, that is inherited through the germ plasm (cytoplasm) of the sperm and egg; and 2) the germ plasm contained “immutable determinants,” which later became known as “genes,” whose expression cannot be changed by the environment. 201 A Genomic-Epigenomic Basis Concepts relating to the role of the gene during development remained in their infancy as the sutural theory of craniofacial growth be- came accepted widely by the middle third of the 20th century. According to the sutural theory, general surface remodeling of bone has relatively little impact on craniofacial skeletal growth, as assumed according to the earlier remodeling theory. Rather, the primary immutable determinants of craniofacial growth are active at the sutures as well as all the cartilagi- nous joints of the craniofacial skeleton. It was assumed, therefore, that the inherited and immutable pattern for craniofacial growth is expressed by intrinsically regulated skeletal growth at Sutures, Synchondroses and condyles (Weinmann and Sicher, 1947). It was into this intellectual framework that the nasal Septum/ cartilage theory was reintroduced by James H. Scott (1953). According to the nasal septum/cartilage theory, intrinsically determined growth of the cartilages of the cranial base, including the nasal septal cartilage in particular, is responsible for downward and forward growth of the midface. Similarly, intrinsic growth of the mandibular condylar cartilage “pushes” the mandible downward and forward. Thus, according to the nasal-septum/cartilage theory, the cartilages of the craniofacial region are the primary tissues within which the genetically determined amount and pattern of skeletal growth leading to particular types of craniofacial form are expressed. Significant advances in understanding the structure of the gene, as well as how genes are duplicated and passed on, came about through discoveries regarding the structure of DNA as a double-helix. Shortly thereafter, Jacob and Monod (1963) proposed a preliminary concept, the operon theory, which asserted that the timing and rate of gene action may be regulated by special classes of regulator genes (“operons") that act as “switches,” much like a light switch, to activate or repress structural genes that actually code for a particular trait. However, translation and more widespread application of those concepts to understanding of gene expression during development of complex organisms would not be seen until the rise of molecular biology followed by development of animal models (typically mouse) several decades later. Thus, although each of the major early theories prior to the latter part of the mid-20th century emphasized inheritance of craniofacial development, growth and form, they all were formulated in an era when the nature and role of gene, 202 Carlson much less of the parameters and variability of gene expression, virtually Were unknown even by scientific experts in genetics of the time. Functional Paradigm as a Response to Genetic Determinism Just as the genetic determinists of the 1920s looked always for confirmation of their ideas and never for falsification, so the environmental determinists of the 1960s always looked for supporting evidence and averted their eyes from contrary evidence, when they should have been actively seeking it...It is the experts who have taken extreme and absurd positions at either end of the spectrum. (Ridley, 2000:79-80) Initial formulation of the functional matrix hypothesis by Melvin Moss occurred at approximately the same time that Scott advanced the nasal septum/cartilage theory. Both Scott and Moss focused initially on the role that sutures play in the growth of the craniofacial complex and Concluded correctly that sutures are secondary sites' of bone growth and, therefore, do not contribute in any deterministic fashion to cranial and midfacial growth (Scott, 1956; Moss, 1957). While the nasal septum/cartilage theory asserted that the cephalic Cartilages provided the intrinsic “motor” for growth, the functional matrix hypothesis proposed that the function of the soft tissues and growth of physiological spaces are the principal factors controlling growth of the craniofacial skeleton. According to Moss (1962, 1968), the soft tissues, organs and spaces comprising what he defined as the functional ' At approximately the time the functional matrix hypothesis initially was being articulated, Baume (1961) proposed that a clear distinction be made between skeletal growth centers and growth sites. The term growth centers was proposed to connote growth with “tissue separating capability,” which would include epiphyseal growth plates and the cartilages of the chondrocranium and nasal Septal cartilage. Because they resisted the influence of environmental factors Such as compressive load, skeletal growth centers were assumed to be regulated more intrinsically (i.e., genetic). Growth sites were locations of secondary and adaptive skeletal growth that were capable of being influenced greatly by their environment, including the intrinsic growth of adjacent growth centers. Examples of growth sites included periosteum and sutures, which were demonstrated to exhibit a specialized form of periosteal growth. 203 A Genomic-Epigenomic Basis matrix are the primary objects that grow in the craniofacial complex; the associated Sutures, Cartilages and bones of the individual skeletal units develop and grow secondarily in response to the functional matrix (MOSS and Salentijn, 1969). The position of the functional matrix hypothesis that primary car. tilage, especially the synchondroses of the cranial base and epiphyses of long bones, has no intrinsic growth potential was relatively extreme. The same is true for Moss' view that genetics plays just a minor role only in embryonic differentiation and virtually none with respect to subsequent skeletal growth. However, both these ideas also can be seen as logical reactions to the prevailing emphasis on genetic pre-determination and immutability of craniofacial growth and form that had characterized Cra- niofacial biology and orthodontics up to that time. As a result, the func. tional matrix hypothesis stimulated a whole new approach to craniofacial biology research and orthodontics by shifting emphasis on the causes of craniofacial disorders from a reliance solely on genetic pre-determination to consideration of the role of extrinsic, functional-behavioral and en- vironmental factors in the development and growth of the craniofacial complex. Thus, the functional matrix hypothesis provided the concep- tual framework for the shift from the genomic paradigm to the functional paradigm of craniofacial biology and provided a foundation for later ex- pansion of concepts regarding the combined role of intrinsic as well as extrinsic epigenetic factors in craniofacial growth. Historically, the last formal theory of craniofacial growth—the servosystem theory—developed almost serendipitously in the latter quarter of the 20th century” and marks the beginning of a trend toward synthesis between craniofacial biology and genetics. The servosystem * Legend has it that Petrovic's friend and colleague, J.P. Charlier, an orthodontist in Strasbourg and advocate for the use of functional appliances, introduced Petrovic to the apparently unique growth properties of the mandibular condyle as a secondary cartilage derived from membranous skeletogenic connective tissue. Petrovic then began to look at the cell physiology of the condyle in the rat as a model-system. Thereafter, following significant interest by the orthodontic community, he focused his research almost exclusively on experimental studies of modification of the growth of the condylar cartilage with a focus on dentofacial therapy using functional orthopedic appliances. 204 Carlson theory, also referred to as the cybernetic model of craniofacial growth, was developed by Alexandre Petrovic and his colleagues from the Louis Pasteur University in Strasbourg, France (Petrovic, 1974, 1983; Petrovic et al., 1990). Petrovic was an MD-physiologist with a specialty in endocrinol- ogy who was interested primarily in the effects of hormonal factors on the growth and adaptive properties of connective tissue; he was not con- Cerned about the growth of the craniofacial complex specifically. How- ever, because of his interest in the integrated role of hormones, mus- cle-biomechanical function and growth of a unique type of connective tissue—secondary cartilage such as comprises the cartilage of the man- dibular condyle—Petrovic's research was relevant to dentofacial ortho- pedics directly and especially to considerations of the modus operandi of growth-modifying functional appliances (Petrovic, 1985). Following considerable interest by orthodontists in his studies, Petrovic shifted his entire Scope of research to studies of craniofacial growth, especially of the mandible, with emphasis principally on the roles growth hormones (e.g., Somatomedin, Somatotrophic growth hormone) and sex hormones, as well as muscle function play in alteration of mandibular growth. Hormones are direct protein products of individual genes; there- fore, they are direct expressions of genetic inheritance. Because of his background in therapeutic endocrinology, Petrovic understood that these genetic factors may have differential effects on different tissues, depend- ing also on extrinsic influences, such as muscle function, at different stag- es of ontogeny. With its emphasis on muscle function, both directly and indirectly, the servosystem theory thus adopted many, but not all of the Concepts of the functional matrix hypothesis. The servosystem theory also extended these concepts into the more modern era with incorporation of endocrine factors as they affect normal growth and compensatory growth mechanisms in the craniofacial region. In this respect, the servosystem theory provided a bridge from traditional research on craniofacial growth as primarily a morphological Science to introduction of emerging research dealing with the expression of growth factors and signaling molecules influencing the growth and adaptability of cells and tissues comprising the craniofacial complex. 205 A Genomic-Epigenomic Basis CRANIOFACIAL BIOLOGY IN THE EPIGENOMIC ERA Instead of thinking of the genome as a book, imagine it as a piano keyboard. (Shreeve, 2005:15) lf the DNA sequence is like the musical score of a symphony, then the epigenome is like the key signatures ...that show how the notes of the melody should be played. (Oiu, 2006:146) Bateson introduced the term “genetics” in 1905 to refer to the study of genes, which would not be observed physically for another 50 years or more, as the theoretical units of heredity. The term “genome" was coined in 1920 by German botanist Hans Winkler (1877-1945) to refer to the integrated functions of an entire set of genes as opposed to the activity of single genes. Genomics as the study of the interaction of entire sets of genes and chromosomes was not appreciated more widely outside the field of genetics until the initiation of the Human Genome Project just prior to 1990. Completion of the Human Genome Project in 2003 also marks the beginning of the “post-genomic era” in modern biomedical Science, where the entire genetic makeup of an organism is being considered, especially insofar as individual genes and groups of genes, or haplotypes, are expressed and interact within a regulatory framework for gene expression. ° Omic is a Greek word that essentially means “in the nature of.” Within the past decade the “-omic” suffix has been used widely in a variety of scientific fields to refer to study of all the genetic components responsible for a given system function (Baker, 2013). For example, proteomics refers to the study all the proteins in a given system; metabolomics to all the small molecules in a system; and interactomics to refer to all the molecular interactions is a given system. There now is even the term incidentalomes that refers to the study of incidental findings that occur during genetic diagnostic testing for other possible conditions. 206 Carlson Epigenetics" also is a relatively old term, though its definition and nuances have changed considerably in recent years with improved understanding of the range of factors that control regulation of gene expression (Jablonka and Lamb, 2002; Ball, 2013). C.H. Waddington (1942) generally is credited with modern introduction of the term "epigenetics” to refer to all the factors, both inherited and non-inherited, that contributes to completion of the phenotype. By the end the 20th Century, epigenetics became focused more on the genome and generally Came to include all the factors, genetic and non-genetic, intrinsic and extrinsic to the chromosome, influencing expression of individuals genes and groups of genes during ontogeny (Holiday, 1990). Within the field of craniofacial biology, the term “epigenetics” has been used previously in a meaningful way by only a handful of researchers, most notably by van Limborgh (1970, 1972, 1983) in a Series of studies on craniofacial morphogenesis. While van Limborgh's understanding of epigenetics may have been accurate for the time, it Was extremely limited and does not reflect current understanding of the nature and scope of modern genomics and epigenomics fully. In van Limborgh's parlance, influences on growth by associated anatomically adjacent Structures are referred to as local epigenetic factors. General epigenetic factors include hormones that are produced at some distance from the target of growth and act systemically." Local environmental factors, which include muscle function, were considered to be distinct and apart from epigenetic factors. The conceptual model put forward by van Limborgh was a harbinger of current understanding of the distinction between specific Structures and traits, which he referred to as being the result of intrinsic genetic factors (i.e., genes) and the regulatory factors that influence the expression of the genes as part of the entire genome-epigenome. In this respect, van Limborgh's analysis appropriately should have expanded the scope of the functional matrix hypothesis to a more comprehensive "The prefix epicomes from the Greek to mean “around” and “in addition to.” The concept that development is not pre-determined goes all the way back to Aristotle’s On the Generation of Animals, which described the process of development as an “unfolding” of the individual in concert with internal and external influences. " The role of growth factors and cytokines as gene products in the form of regu- latory proteins was essentially unknown until the latter part of the 20th century. 207 A Genomic-Epigenomic Basis level where genetic, epigenetic and local environmental factors all played complementary roles in craniofacial development and growth. However, his synthesis had little direct impact on the field aside from occasional and perhaps naïve use of the term “epigenetic” as essentially a synonym for “functional” factors (cf. Moss, 1985). Defining the gene as the molecular unit of heredity comprised of DNA, current concepts posit that epigenetics refers to the action of “additions to the DNA and histones that are stably maintained [in the genome] and do not change the primary DNA sequence” (Feil and Fraga, 2012). In short, “the epigenome is the regulatory software for the ge- nome” (C. Walker, personal communication). Epigenomics extends the scope of genomics through consideration of the interaction of the genes encoded to express a particular systematic activity, to the intrinsic struc. ture of the chromosome, as well as to the non-genetic extrinsic factors that influence gene regulation and expression. In current usage, the Con- cept of epigenetics has been extended further with the proposition of the possibility of heritable transgenerational changes in gene function that cannot be explained by changes in DNA sequence (Riggs, 1996; Ball, 2013; Grossniklaus et al., 2013) and even the possibility of somatic cell reprogramming (Buganim et al., 2013). In the context of the present discussion, epigenomics refers broadly to the study of the entire scope of mechanisms, both intrinsicand extrinsic, by which the pattern of gene activity leading to development and growth is regulated and expressed. These mechanisms are based on the interaction of the genes comprising the genome as mediated by DNA methylation and chromatin structure as well as extrinsic, environmental factors that regulate gene expression in time, amount and duration (Smith and Meissner, 2013). Extrinsic, environmental factors would include, but not be limited to, mechanical forces and muscle function as typically might be associated with orthodontic treatment to correct a developing dentofacial deformity. Thus, emphasis on the approach of epigenomics with respect to understanding the entire span of ontogeny, including its prenatal development, peri- and postnatal growth and capacity for phenomic plasticity and compensatory growth, is critical for understanding growth of the of the craniofacial complex and the potential for therapeutic modification. 208 Carlson SPECTRUM OF DENTOFACIAL DEFORMITIES: A GENOMIC-EPIGENOMIC PERSPECTIVE Form is the visible expression of the formative process- es that have been instrumental in its shaping. The end result is but the residual record of its formative history. Clearly, then, changes in the standard pattern of forma- tive processes lead to deviations from the standard form: deformations end up as “deformities.” In this sense, “de- formities" become valuable clues to the inner workings of formative processes. (Weiss, 1960:23) The list of principal genes and protein products essential for regulation of normal as well as abnormal development and growth of the Craniofacial complex has expanded significantly over the past several years (Rice, 2005; Spears and Svoboda, 2005). However, the significance of variation with respect to normal gene variants, or polymorphisms,” in these and other key genes for ontogeny, including development, growth and adaptive capability of the craniofacial complex, has yet to be understood fully. For heuristic purposes, craniofacial disorders with a probable di- rect or indirect genetic basis can be organized along a spectrum from the most severe and debilitating craniofacial anomalies, many of which are well defined with respect to mutation of key developmental genes, to less severe acquired deformities that also may have a genomic basis, but one that might be attributable to a haplotype of essentially normal gene variants or polymorphisms (Hefer et al., 1998; Fig. 2). At one end of the deformities spectrum are such conditions as mandibulofacial dys- Ostosis, or Treacher Collins Syndrome, which is a major dysmorphogen- esis syndrome caused by a mutation of a specific gene (Treacle, TCOF1) resulting in significant reduction in migration of neural crest cells into the first and second branchial arches during the first weeks of embryonic * Genetic polymorphisms are “normal” gene variants. It now is believed that Virtually all human genes have single nucleotide polymorphisms (SNP) due to alternative splicing, alternative promotors and post-translational modification (e.g., microRNA). Such polymorphisms may produce normal variations in phenotypic expression ranging from negligible, to minor but observable, to significant. 209 A Genomic-Epigenomic Basis Abnormal Cell-Tissue Genetic Development Anomalies Gene Mutations Genome Intrauterine tº Genetic Environment Susceptibility Cºmmon D Polymorphisms Environment Acquired Deformities Secondary Effects from - Abnormal Forces Figure 2. Heuristic model illustrating the spectrum of craniofacial deformities from profound dysmorphogenesis syndromes associated with significant genetic anomalies to deformities with a heritable basis that may be acquired second arily. Adapted from Hefer et al., 1998. development. The lack of neural crest cells leads to a profound deficient) of mesenchymal tissues causing a significant hypoplasia of the mandible malar-orbital structures, muscles of mastication and external and internal Structures of the auditory system. Embryonic disruption events represent a midpoint of the Spe" trum of genomic influencing craniofacial development and form. As * example, it has been proposed that isolated craniofacial microSoml? which is the second most common major non-syndromal craniofacial de- formity after cleft palate, arises principally as a result of a hematoma that occurs during the transition in blood supply of the face from the stapedia artery to the maxillary artery at approximately five to six weeks' gest" tion (Poswillo, 1988). Depending on its size, the blood clot is thought tº disrupt formation and subsequent growth of the skeletal structures and muscle associated primarily with the ramus of the mandible and teſ" poromandibular joint (TMJ), as well as with the ear and auditory st" tures. - - - - - - O Craniofacial microsomia may be unilateral or bilateral and als has a significant genetic basis as it occurs with other syndromic conditions 210 Carlson However, there currently are no genes associated with isolated craniofacial microSomia (Luquetti et al., 2011). Therefore, even though the apparent immediate precipitating event leading to disruption of the development of the lateral facial structures may be disruption of precursor neural crest Cells or differentiated tissue development by the hematoma, it most likely is that isolated craniofacial microsomia has an epigenetically-modulated Component characterized by a genetic predisposition or susceptibility related to problems with the developing blood vessels, at least in the face at a specific point in time during development. At the other end of the spectrum in this heuristic model are Craniofacial deformities that have a probable heritable basis, but in which the genetic basis is found not as much with the affected individual as with the genomic background of the pregnant mother. Examples of these deformities are idiopathic plagiocephaly due to craniosynostosis Secondary to prenatal constraint of the calvarium and Pierre-Robin Sequence. Pierre-Robin Sequence is an acquired severe dentofacial defor- mity that exhibits perinatal phenotypic similarity with Treacher Collins Syndrome. Like Treacher Collins Syndrome, Pierre-Robin Sequence is Characterized by severe hypoplasia of the mandible as well as a complete Cleft palate. However, the causes of these two deformities are completely different, which has profound implications for treatment of dentofacial growth. While Treacher Collins Syndrome is a neurocristopathy caused by a mutation either de novo or through inheritance of the Treacle gene, Pierre-Robin Sequence occurs as a secondary effect on the offspring thought to be caused principally by fetal restriction in utero. Prior to six weeks' gestation, the cephalic region of the human embryo is flexed downward with the developing face and mandible in Close Contact with the cardiac Swelling and precociously developing heart. Soon thereafter, the embryo extends its neck, elevating the head and moving the face away from the cardiac swelling, thus freeing the mandible to move forward with anterior movement of the tongue. As the tongue thrusts forward, the palatal shelves are free to elevate as a first Step in the process of palatal closure and the unconstrained mandible is free to grow anteriorly. In cases where the pregnant mother produces insufficient amniotic fluid, the embryo and fetus may be constricted such 211 A Genomic-Epigenomic Basis that the head cannot be elevated and the face remains mechanically constrained against the cardiac swelling. As a result, the mandible is restricted severely in its early growth and the tongue remains between the palatal shelves causing complete cleft palate at birth. In this case, therefore, it is the epigenetic maternal uterine environment that leads to reduction in mandibular growth and resultant hypoplasia. Each of these disorders has some degree of underlying genetic basis that affects craniofacial development and subsequent growth as well as possibilities for treatment. The deformities used as examples range from a definitive mutation of a single gene critical for normal craniofacial development as in the dysmorphology that characterizes Treacher Collins Syndrome; to the possibility of genetic susceptibility or predisposition for occurrence of a vascular accident in the developing face in isolated craniofacial microsomia; to an epigenetic, mechanical modification of normal development and growth of the mandible and palate in Pierre- Robin Sequence. Thus, each deformity also presents a distinct biological rationale for different options for effective treatment based upon their underly- ing causes. For example, dentofacial orthopedic treatment designed to stimulate mandibular growth or even to correct the dentofacial defor- mity in a growing child with Treacher Collins Syndrome surgically and with distraction histogenesis are not successful primarily because of the profound deficiency in cells and tissues in the affected region, as well as the likelihood that the existing tissues are not capable of responding ad- equately to treatment fully (K. Salyer, personal communication; Gürsoyet al., 2007). Success of treatment options in isolated craniofacial microSO- mia depends in large part on the severity of the disruption event and the variable presence of normal cells and tissues (Harvold, 1983; Vig, 1988). Finally, the cells and tissues of the child affected with Pierre-Robin Se- quence should be considered essentially if not completely normal; the mandible simply is profoundly hypoplastic due to physical constraint. Therefore, in principle, dentofacial orthopedic treatment designed to en- hance growth of the mandible likely will lead to more favorable results in children with Pierre-Robin Sequence (Vig, 2002). 212 Carlson GENOMICS-EPIGENOMICS AND VARIATIONS IN CRANIOFACIAL DEVELOPMENT ...the epigenetic course of life, being decidedly not an automatic reeling off of a rigid chain of microprecisely concatenated events, offers man wide opportunity and the faculty for steering his course within that frame for better or worse...the general idea that “environment” enters the scene only when the bird hatches or the baby is born should be expunged. (Weiss, 1973:81) Craniofacial anomalies due to genetic mutations represent de- Velopment and growth gone awry and, thus, can be understood truly only as a complement to understanding of normal developmental and growth processes. Extrapolating from the previous examples of anoma- lous genetic and epigenetic influences on craniofacial deformities, it also is possible to gain insight into the potential roles that consideration of genomics-epigenomics might play in treatment to correct developing dentofacial deformities in patients who would not be characterized as "abnormal.” Prospective orthodontic patients typically are evaluated based on a number of clinical criteria, with particular emphasis on dental models and cephalometric radiographs as the bases for diagnosis and treatment planning to correct dentofacial misalignment and related deformities. Maturational indicators, such as the status of dental eruption and Ossification of the bones of the hand-wrist and cervical vertebrae, also may be used to assess maturational status and, thus, provide indirect evidence for the potential of further skeletal growth. There are many other factors whose expression as isoforms of regulatory proteins from closely related genes may affect the process of Skeletal growth and adaptation to dentofacial orthopedic treatment. In particular, there are many transcription factors, growth factors, cytokines and similar gene products that affect growth and remodeling of the cranio- facial Skeleton and related tissues that may be active to a variable degree throughout ontogeny (Fig. 3; see review by Spears and Svoboda, 2005). All of those factors, when expressed at variable time periods during ontogeny, also directly influence the capacity for adaptation through 213 A Genomic-Epigenomic Basis PHENOTYPE M-T....…". orphogenesis, Growth, Aging Cell/Tissue Interactions Cell Properties proliferation, synthesis Proteins Timing/rate of gene expression varies during ontogeny Regulation of gene expression of transcription factors * GENES Figure 3. General progression illustrating the relationship between genotype and phenotype. The arrows to/from morphogenesis, growth and aging were added to illustrate the fact that cell properties and capabilities for differentiation growth and adaptation change during ontogeny. Adapted from Thorogood, 1997. compensatory growth of craniofacial skeletal structures (Carlson, 2002). Normal variation in the degree of expression of these isoforms—from absence or insufficiency due to expression of only one allele as a result º haploinsufficiency and gene imprinting, to protein sufficiency, to proteſ overexpression—at critical time points during development and growth also are significant parts of the phenotype that will affect growth and responsiveness to treatment significantly. The principal product of epigenesis is not so much the phenotypº trait itself as it is the developmental process that results in that trait. Expression of genes responsible for the processes of development and 214 Carlson growth is turned on and off by factors both within the genome and in the epigenetic environment to produce specific traits as well as to influence Susceptibility to variations in the extrinsic environment. Development and growth of all cells and tissues are mediated within broad parameters by the activity of the genome of the individual. Therefore, normal individual genomic variation also may influence the rate, amount and timing of expression of gene variants for key molecular factors that regulate the normal growth process. Moreover, considering the linkage between growth processes and dentofacial orthopedic treatment, it is even more Critical to consider the possibility that such normal genomic variation is likely to affect the degree to which the non-genomic effectors of growth will produce a desired effect. It is within this conceptual framework that advances in the devel- opmental biology and genetics of the craniofacial complex potentially can be most beneficial to the field of clinical orthodontics. Recent research On the development and growth of sutures and of the condylar cartilage of the mandible provide examples of how genomics-epigenomics could play a role in the future of treatment to correct developing dentofacial deformities. Sutures An essential prerequisite [to dentofacial orthopedic treatment] is a careful and thorough diagnostic study of all the factors that might influence growth regulation. Therapy then becomes a biological solution, not a mechanical compromise. (Graber, 1983:325) There have been considerable advancements in understanding Of the biology of suture development and growth since early reliance On histological descriptions led to the erroneous conclusion that sutures Were intrinsic, genetically predetermined growth centers equivalent to epiphyseal growth plates in long bones. It subsequently was demonstrated that Sutures, which are unique to the craniofacial complex, are passive Sites of Compensatory bone growth associated with membrane bones of the Cranial vault and midface. The principal concern in suture biology then focused on the spe- cific extrinsic biomechanical factors that cause Sutures to form, grow and 215 A Genomic-Epigenomic Basis fuse. Initially, research studies principally addressed the effect of tensile forces brought about normally by expansion of organs such as the grow- ing brain and eyes as well as the more intrinsically-regulated growth of the cartilage of the cranial base and midface. As a result of integration of advances in genetics, research in suture biology during the past decade or more has shifted to a primary concern with the expression and com- plex interplay of molecular factors that regulate sutural growth, maintain suture patency and promote suture fusion, both normally and prema- turely as in craniosynostosis. Studies in experimental animals have identified the presence, lo- cation and function of a number of key transcription factors and growth factors that are responsible for suture development (Fig. 4; Rice et al., 2003; Opperman et al., 2005; Rice, 2005; Martinez-Abadias et al., 2011). With the discovery of the existence of isoforms of certain of these growth factors and how they interact during suture development, experimen- tal research began to address the potential for “rescue” of non-growing and even synostosed sutures by exogenous introduction of those fac tors that upregulate or repress expression of associated key isoforms BMP-4, BMP-7, TGF-31, TGF-32, FGFR3. Dura TGF-83, FGF-2, FGF-9, MSX1, MSX2. FGFR1, Osteogenic [] FGFR1c, FGFR2, FGFR3C, ...º - - -61, TGF-32, IGF- layers BMP-4, BMP-7, TGF-61, TGF-3 Osteogenic BMP-2, BMP-4, BMP-7, TGF-31, bone f FGFR1, FGFR3c. TGF-33, one fronts MSX2, AP, collagentype1&ll TGF-81, TGF-32, FGF-2, IGF-1, CBFA BSP-1, OC, Collagentypeſ - La. FGF-9 Presumptive BMP-4, BMP-7, FGF-2, FGF-4, FGF T, Colla entypell suture MSX1, MSX2, TWIS g FGF-9, MSX1, FGFR1, FGF-9, Suture | Collagentype III - TGF-81, TGF-32, MSX2, Collage" Fusing suture type, FGFR2, FGFR1, BSP-1.0° Bone FGF-2, Bsp.), esp-li, FGF-2.0M/AP Collagentype I Figure 4. Diagram illustrating expression of growth and transcription factº during development and maturation of a suture. A: Presumptive suture. B. Full formed suture. C. Mature suture undergoing fusion. The growth and transcriptioſ factors known to be active principally at each of these stages are listed for * location within the suture. Adapted from Opperman et al., 2000. 216 Carlson of regulating proteins (Opperman and Ogle, 2002; Moursi et al., 2003; Opperman et al., 2005; Rice, 2005; Shukla et al., 2007). Those studies clearly portend the possible longer-term goal of treatment approaches to correct and prevent syndromal and non-syn- dromal craniosynostosis, possibly as an adjunct to standard mechanical Orthodontic treatment to stimulate sutural growth in both the cranial Vault and midface. As a possibility for the short-term, assays of the pres- ence and concentration of growth factor isoforms could provide critical diagnostic information related to whether or not sutures are more or less likely to grow further, under what conditions of mechanical influence and during what time period. Mandibular Condylar Cartilage If...the mandible is really the material cause of the Class || malocclusion, then it would be appropriate to ask whether any treatments effectively target it. Specifically, are you going to employ 1 or more of the so-called functional appliances? To answer yes, you must first ask why. What do you hope to accomplish and is there any proof that what you hope for is possible? (Johnston, 2002:552-553) The condylar cartilage of the mandible is a secondary cartilage that is similar to a suture as both are derived from a skeletogenic membrane homologous to periosteum/perichondrium. As the condylar Cartilage has periosteum-like properties, its growth is highly adaptive and responsive to a variety of environmental factors, including in particular muscle function and mechanical load (Carlson, 1994; Hinton and Carlson, 2005; Hinton et al., 2009; Solem et al., 2011). Experimental research on the growth of the condylar cartilage in animal models has been prominent in craniofacial biology for many decades, principally due to its importance in overall mandibular growth and because of enthusiasm among clinicians for the possibility of altering growth of the mandible therapeutically. It should not be Surprising that studies on the growth of the condylar cartilage have focused on those putative principal mechanisms thought to regulate the amount, rate and direction of mandibular growth therapeutically, especially to stimulate condylar growth as part of correction of Class || malocclusion. 217 A Genomic-Epigenomic Basis Virtually all of the appliances designed to stimulate condylar growth have a number of overlapping characteristics in common, though with variable emphasis. These include: 1) increasing the neuromuscular activity and function of the muscles of mastication, generally by increasing bite opening; 2) repositioning of the mandible in a more forward, protrusive position, thus distracting the condyle from the glenoid fossa; and 3) relief of compressive forces on the condylar cartilage by mandibular protrusion as well as on the mandible as a whole by shielding of the perioral soft tissues. Alteration of muscle function, jaw position and mechanical load generally represent attempts to change those components of the environment thought to be the principal mechanisms, themselves, that control growth of the condylar cartilage. However, it is important to emphasize that as elements of the therapeutic environment, those elements are not themselves “control mechanisms” of growth—rather they are possible effectors" of condylar growth. Muscle function, jaw position and mechanical load are extrinsic, non-genomic epigenetic factors that potentially could influence regulation of genes responsible for expression of molecular factors that influence growth. Therefore, treatment approaches that alter these elements of the environment have the potential to alter such gene expression and, thus, alter condylar growth. However, the receptivity of the patient to alterations in these epigenetic effectors also is a function of their genome. Similar to advances in genetics and molecular biology in the study of suture development, significant progress has been made in recent years in the study of the growth of the cartilage of the mandibular condyle. For example, it has been shown that expression of isoforms of fibroblast growth factor (FGF) and insulin-like growth factor (IGF) regulatory proteins and their receptors, as well as transcription factors such as core bonding factor and Sox 9 within the condylar cartilage, are critical for normal growth of the mandibular condylar cartilage (Fuentes et al., 2002; Rabie and Hägg, 2002; Visnapau et al., 2002; Rabie et al., 2004; Hinton and Carlson, 2005; Hinton et al., 2009). * An effector is an agent that mediates a specific effect. In biology, effectors are substances or activities that regulate gene activity by increasing or decreasing enzyme activity, gene expression and cell signaling. 218 Carlson It also has been shown that distribution of each of these factors Varies within the several layers of the condylar cartilage during ontogeny (Hinton and Carlson, 2005; Shen et al., 2005; Fig. 5) and in response to experimental intervention that attempts to simulate therapy with a functional orthopedic appliance (Fuentes et al., 2002, 2003; Hajjar et al., 2003; Rabie et al., 2003; Delatte et al., 2004; Suzuki et al., 2004). In an experimental design using an intraoral appliance that created a crossbite and unilateral protrusivefunctional appliance, it was possible to determine significant differences in the expression of growth factors FGF-1, 2, 3 and IGF-1, as well as their receptors relative not only to control animals, but also to the different sides of the mandible within the same animal. For example, even within the experimental animals the protrusive and non- protrusive contralateral condyles showed altered gene expressions for FGF-2 and IGF-1 that essentially were in opposite directions (Fig. 6). The significance of the experimental studies of the mandibular Condylar cartilage cited above is not that key molecular factors related to growth of cartilage and bone are expressed in the condylar cartilage. The significance is, first, that their expression varies according to loca- tion and maturation in normal, genetically homogeneous strains of ex- perimental animals and second, that variations in the extrinsic environ- ment generally simulating dentofacial orthopedic treatment produce clear and discernible effects on that gene expression. Unfortunately, however, nothing is known about the presence and effects of normal Variants or polymorphisms of growth factors for condylar growth in hu- man Subjects. Understanding of the biology of suture development has been advanced considerably, principally because craniosynostosis is such a prominent characteristic in a large number of genetic anomalies for which tissue samples are available from surgery. Therefore, the mutations of key genes and expression of isoforms of key genes that affect sutural development and growth have been described relatively Well. Similar assays are not available—nor will they be for ethical reasons—to determine the presence and amount of expression of growth factors specifically in the mandibular condyles of patients with a Class || malocclusion due to mild-to-moderate mandibular deficiency. However, it is reasonable hypothesize that variants of normal genes known to have an impact on sutural growth that are co-expressed in the growing 219 A Genomic-Epigenomic Basis _Articular º Prechondroblastic Chondroblastic Hypertrophic Collagen Zone of bone formation Figure 5. Photomicrograph of a growth mandibular condylar cartilage illus trating primary areas of expression of receptors for fibroblast growth factoſ: (FGF1, FGF2, FGF3) and insulin-like growth factor (IGF-1). Adapted from Fueſ: tes et al., 2003. mandibular condyle could predispose to variations in the growth of the mandibular condyle and in the capacity for response to specific types of treatment and possible effectors. GENOMICS-EPIGENOMICS AND TREATMENT OF DENTOFACIAL DEFORMITIES All orthodontic appliance systems succeed in correcting malocclusion in some circumstances, but are less success- ful or outright failures in other circumstances. Selecting the right approach for any given patient remains the key to success. (Proffit, 1985:63) 220 Carlson Deviated Non-Deviated 150 100 - FGF-2 (% control) 50 - 13: - 0 - -73 -50 In 143 #| || -100 -150 Control Experimental f 250 200 - 150 - FGFR-2 [13d * (% control) 7d 14: -50 - - 100 – - 150 Figure 6. Gene expression for FGF-2 and its receptors as a percentage of ºntreated controls in the mandibular condyle of animals that wore a tooth- born unilateral appliance designed to create a unilateral crossbite. The crossbite Caused an asymmetric shift of the mandible resulting in a unilateral protrusion of the condyle on the deviated side of the mandible. These data indicate that gene %pression can be altered even in the same animal and at the same time with °ondylar protrusion. Adapted from Fuentes et al., 2003. One of the major questions that has confounded orthodontic treatment and resulted in considerable debate among clinicians is why treatment outcomes in patients who present with similar dentofacial deformities and who are treated essentially in the same manner often are Variable. Typically, such differences are ascribed to patient compliance." However, it also is likely that genomic differences related to the presence and regulation of individual gene variants and groups of variants are Important in accounting for individual variation in treatment response. T- * Lisa Tedesco (1997), a principal program discussant at the Moyers Symposium 9" management of the non-compliant patient, noted that, “In spite of major "provements in diagnosis and great advances in orthodontic technologies, *nt compliance remains the weak link in the chain between a good treatment Plan and a successful Outcome.” 221 A Genomic-Epigenomic Basis As reviewed previously, patients exhibiting profound dentofacial abnormalities with a heritable genetic basis can be considered accord- ing to a continuum from craniofacial anomalies characterized by major mutations of key developmental genes to deformities acquired indirectly within the uterine environment (refer to Fig. 2). A similar model may be instructive to account for the genomic-epigenomic basis for variable out- come of clinical treatment to correct developing dentofacial deformities in patients who appear to be “normal.” While earlier discussion focused on individuals who clearly are affected, directly and indirectly, by severe- to-moderate genetic abnormalities, this segment of the discussion will take those principles and apply them to a spectrum of the orthodontic patient population where the influence of genomic-epigenomic factors may be considerably less obvious. The dentofacial patient population can be divided conceptually into three overlapping groups; for lack of better terms these groups will be called Standard, Abnormal and Clinical (Fig. 7). Subjects in the Standard Group essentially provide the “norm” for how development and growth are Supposed to proceed—the way craniofacial growth generally is described in textbooks and taught during graduate training. Individuals in this group would be expected to have unaltered, normal genes and an array of genetic polymorphisms and haplotypes to guide expression of craniofacial developmental and growth leading to normal craniofacial form. Relatively minor variations in dentofacial form certainly exist within the Standard Group and naturally would lead to recommendations for orthodontic treatment. However, in the course of such treatment, dentofacial orthopedic patients in this group would tend to exhibit growth patterns and responses to growth effectors that are characteristic of the norm and, thus, would be expected in terms of the way the face and jaws are supposed to grow. Dentofacial orthopedic patients in the Standard Group also would be most capable of responding to treatment, perhaps even to a relatively wide range of different treatment approaches and appliances, in a more or less predictable and favorable fashion. 222 Carlson * Possible mutations and/or unfavorable polymorphisms * Unknown intrinsic epigenetic effects UNPREDICTABLE growth and treatment response CA3D º Clinical N Abnormal | Standard Z … * Mutation of key developmental genes - Favorable polymorphisms C Abnormal development/growth - Positive extrinsic epigenetic effects UNSATISFACTORY growth C SATISFACTORY growth and treatment response and treatment response Figure 7. Heuristic model illustrating the three major subgroups of orthodontic patients and the hypothetical relationship between genomic background and likelihood of favorable orthodontic treatment for treatment for a developing dentofacial deformity. Standard Group patients with mild-to-moderate dentofa- Cial malocclusion, such as a Class || malocclusion, have normal genomic structure and would be expected to respond favorably to treatment. Patients in the Ab- ſomal Group have genetic abnormalities that generally preclude normal growth and response to standard treatment. Patients in the clinical Group may be fully "ormal or may possess gene variants and haplotypes that could affect treatment ſeSponse. At the opposite end of the patient population spectrum is the Abnormal Group, representing subjects exhibiting profound craniofacial ºnomalies and deformities similar to those discussed previously. Patients In the Abnormal Group are characterized by genetic disorders ranging from Significant mutations of key developmental genes responsible for major dysmorphogenesis malformations (A1); genes that predispose for major disruptions of craniofacial development (A2); and deformation ºf *Sentially normal tissues (A3). Because of abnormalities in genom- * Structure and concomitant cell-tissue deficiencies, another principal haracteristic of these subjects especially in subgroup A1 and probably In A2 is a lack of Capacity for normal growth. As a result, subjects in the 223 A Genomic-Epigenomic Basis Abnormal Group likely are incapable of responding to dentofacial ortho- pedic treatment that was developed on the basis of understanding of standard craniofacial growth and normal response to its effectors. The most important group for the present discussion of the re- lationship between genomics-epigenomics, growth and treatment of dentofacial deformities according to this model is the Clinical Group, which lies intermediate to and overlaps with both the Standard and Ab- normal Groups. The Clinical Group is comprised of the largest number of patients with moderate-to-minor dentofacial deformities most likely to be seen in an orthodontic practice. It also is assumed that a large component of subjects within the Clinical Group have a standard or nor- mal intrinsic genomic background structure. Finally, this model proposes that a major component of the Clinical Group also may be characterized by unknown arrays of variants for individual genes and groups of genes that are normal, but may not be ideal for dentofacial growth; thus, they represent unfavorable, but not necessarily abnormal variants for dento- facial growth. This underlying genomic structure also would be expected to affect the response to treatment such that patients from the Clinical Group who fall in the normal range of gene variants respond favorably to treatment, while those outside the normal range would exhibit progreS- sively less favorable and more variable responses depending on their degree of departure from standard genomic structure. GENOMICS OF CRANIOFACIAL GROWTH TREATMENT AND CLINICAL RESEARCH [Clinical research on control of craniofacial growth) is a study of averages. There is no evidence that any case or group of cases behaves in any way differently from the average except as a result of growth. (Mills, 1983:37) The Median Isn’t the Message. (Gould, 1985; title of an article by Stephen J. Gould regarding the use of statistics in clinical research soon after he was diagnosed with cancer) 224 Carlson Discussion up to this point has emphasized the notion that great- er understanding of genomics-epigenomics and particularly of variants of key genes and their effectors is increasingly important in order to un- derstand craniofacial growth and, thus, to anticipate the likelihood of responsiveness to treatment of growth disorders related to dentofacial deformities more effectively. Understanding of the principles underlying a Synthesis between the genomics-epigenomics of craniofacial growth and treatment also is significant for shedding light on a major confounding factor related to clinical research in orthodontics. Discovery of genetic variations that underlie diseases and de- Velopmental deformities relies on DNA sequencing to determine the presence and location of individual genes and of whole groups of genes on the chromosomes (Fig. 8). That process begins with description and delineation of a well-characterized patient group that expresses a clear- ly defined disease, deformity or disorder with a strong likelihood of a definitive genetic basis. Biological samples taken from multiple mem- bers of the subject group then are screened with microarrays to look for shared variations in gene structure and loci. Once candidate genes are identified, cell-tissue studies and experiments on naturally occurring and genetically-engineered animal models are used to determine gene function related to the cascade of molecular interactions leading to the phenotypic features that characterize their expression (Hieter and Bo- guski, 1997). Consideration of a well-characterized craniofacial anomaly with a known genetic basis, Crouzon Syndrome, provides an example of the process of discovery of abnormal genes in a well-characterized patient population. Crouzon Syndrome is one of a related series of craniofacial dysmorphogenesis syndromes that exhibit a number of features related to abnormal growth of sutures and the cranial base. DNA sequencing of Crouzon patients revealed that the primary genetic defects include mu- tations of the genes for FGFR2 and FGFR3 (Jabs et al., 1994; Jabs, 2002; Rice, 2005). Once identified, in situ hybridization in a mouse model was used to determine localization and timing of gene activity. Finally, with an essentially complete understanding of the mutated gene variants, in- formation became available for use in diagnosis, prevention through ge- netic counseling and possible future treatment to prevent the deformity. 225 Deformity with Genetic Basis Diagnostics Polymorphisms, Haplotypes Understand Gene Function Well-Characterized Patient Groups Cell-Tissue Culture Animal Models - Prevention Gene arrays Proteomics Figure 8. General overview of the various steps required to discover genes for key traits related to disease, disorders and deformities. An essential starting point for this process is delineation of a well-characterized subject group for a trait that has a clear genetic basis. Adapted from D. DePaola, personal communication. § Carlson Sequence analysis to discover candidate genes for diseases and developmental deformities is most useful and efficient when the underlying genetic basis of the disorder is relatively profound. It is considerably more difficult to determine minor genetic differences between subjects who express normal genes, gene variants and haplotypes, not only because of the gene array technique itself, but also more critically because it is nearly impossible to define well-characterized and discrete samples of affected Subjects at the outset (Wilkie and Morris-Kay, 2001; Cheung et al., 2005; Justice et al., 2012).” It is well understood that malocclusion and minor dentofacial de- formities, such as mild-to-moderate maxillomandibular discrepancies in otherwise apparently normal subjects have no simple and straight-for- Ward genetic basis related to mutation of key developmental genes. Rath- er, it has been well established that such deformities represent “multifac- torial" expressions of continuous variation of normal dentofacial growth and form (Mossey, 1999a,b; Hartsfield, 2012). As a result, delineation of a subject pool of patients with a common dentofacial deformity, such as minor-moderate Class Il malocclusion, for example, that is well character- ized as being homogeneous for traits with a presumed genetic basis will prove to be difficult if not impossible. On the other hand, more profound malocclusions and certain classes of dentofacial deformities, such as skel- etal Class Ill malocclusion, may be more amenable to such analysis (Xue et al., 2010a,b). A typical clinical orthodontic research paradigm as a randomized clinical trial is to define subject study samples on the basis of morphological indicators of facial form, such as type or classification of malocclusion, as well as age and sex, and then examine response to * Genome-wide association analysis (GWA) attempts to analyze entire genomes in order to determine individual differences in common genetic variants such as single-nucleotide polymorphisms (Hinds et al., 2005). GWA generally is conducted to find associations and not causes of major diseases, not relatively minor phenotypic variations (Pearson and Manolio, 2008). GWA also is subject to the same concerns about selection of control and case populations for analysis. Therefore, GWA is not a likely solution for analysis of role of minor gene variants on craniofacial growth and dentofacial orthopedic treatment (Cheung et al., 2005). 227 A Genomic-Epigenomic Basis treatment with one or more types of orthodontic appliance and/or protocol (Koletsi et al., 2012). Missing in this approach is recognition of the possibility that the study population is likely to be heterogeneous for normal variants of regulatory proteins that affect craniofacial growth. Orthodontic patients that appear to be similar with respect to general phenotype and especially dentofacial form and classification of malocclusion not only might have considerable variability with respect to expression patterns for normal gene variants that affect growth, but these gene variants also could influence the manner and degree of responsiveness to treatment as an epigenetic effector of growth. While patients with favorable genomics may respond well for a given standard treatment, patients lacking favorable gene variants may respond less Well or even poorly. Thus, the combined.results of the standard analysis of treatment outcome study regress to the average or median response, which could compromise the validity and applicability of findings significantly as they pertain to subgroups of patients if they could be delineated appropriately. CONCLUSION: STARTING POINTS FOR A MODERN SYNTHESIS Altogether, the complexity of structural variant-pheno- type relationships calls for novel integrative and holis- tic approaches that involve the combined application of multiple models for well-phenotyped patients....This will form an essential prerequisite for improving predictions of disease onset and outcome, for developing therapeu- tic strategies and for facilitating translational molecular medicine research. (Weischenfeldt et al., 2013:136) We need to spend less time talking about the median and more time talking about the tail. (Kalein, 2013; remarks at the Aspen Cancer Conference) Five sequentially-arranged axioms were presented at the start of this review as starting points for consideration of a synthesis of concepts in orthodontics, dentofacial orthopedics and craniofacial research on the one hand and newly emerging advances in the field of genomicS- epigenomics (refer to Fig. 1). 228 Carlson Axiom 1 Approaches to orthodontic treatment of dentofacial deformities are based on contemporary concepts regarding the mechanisms of cra- niofacial growth. The foundation for advances in orthodontics always has been ac- Cepted scientific information and principles related to craniofacial biol- ogy, among other areas, that are available at the time. New Scientific dis- Coveries, often resulting from new technologies led to advances not only in this foundational information, but also to revision of the theories and paradigms used to organize and explain the relevance of that information for clinical treatment. From the beginning of modern orthodontics at turn of the 20th Century and for the subsequent 60 years, the prevailing scientific view Was that virtually all development and growth (and thus form) of the Craniofacial complex were a result of inherited genetic factors that were immutable. Thus, the growth of the face normally would not be subject to Change in pattern to any great extent and also could not be changed With extrinsic factors such as Orthodontic treatment. The theories of craniofacial growth that prevailed through the middle of the 20th century as components of the genetic paradigm did not question so much whether this interpretation was correct. Rather, they focused on where the intrinsic, genetic influence as the motor that drives Craniofacial skeletal growth was most active—was it in the periosteum and bone itself (remodeling theory), within sutures (sutural theory) or Within the cartilages of the cranial base and mandible (nasal septum/ Cartilage theory)? The functional matrix hypothesis abrogated the role of genetic factors in craniofacial growth altogether and instead emphasized the role of muscle function and growth of organs and physiologic spaces to account for the forces driving the process of craniofacial development and growth. The view that the functional matrix hypothesis caused a swing of Scientific approach entirely too far away from considerations of ge- netic factors can be explained by the fact that the field of genetics was so incomplete and knowledge about genetics among craniofacial biologists was especially rudimentary. Genetics of development and growth, espe- cially in higher organisms, essentially was a “black box” that would not 229 A Genomic-Epigenomic Basis begin to be understood reasonably in vertebrates until approximately the last two decades of the 20th century. Variations in growth and form that could not be explained by variations in “function” typically were said to be “genetic,” as if that explanation was sufficient. As a result, many researchers and clinicians alike looked primarily for a “functional” explanation for all variations in craniofacial growth and form, perhaps with the view that it is possible to influence extrinsic, “functional” factors while little or nothing could be done therapeutically short of surgery to affect “genetic” factors. The servosystem theory, however, did provide a transitional and moderating influence in craniofacial research because of its emphasis on growth hormones, which are direct gene products, as mediators of craniofacial growth and treatment response. Consideration of gene expression of regulatory protein growth factors advanced as research in developmental and molecular biology in general as well as elements of craniofacial biology entered the genomic era at the end of the 20th century with initiation of the Human Genome Project. The post-genomic era began following complete sequencing of the human genome, whereupon scientific attention turned to studies of the function of genes and their proteins important for development and disease. In craniofacial research, this was the time period when discovery was made of the many transcription factors and growth factors that We now recognize as critical for normal craniofacial development (Slavkin, 2004). We now are in the “epigenomic era,” where the greatest emphasis is concentrated on understanding molecular-developmental biology as this relates principally to the combined role of intrinsic and extrinsic effectors that regulate expression of the genes identified as comprising the genome that are most important for development of disease and of normal development and growth. Although of considerable value to understanding the history of craniofacial biology and orthodontics, in light of modern understanding of genomics in this “epigenomic era,” the differences between the genomic and functional paradigms now are blurring to the point where they no longer are exclusive mutually, but are complementary. The apparent dichotomy that was represented by earlier views that craniofacial growth was principally the result of intrinsic, unknown genetic factors on the one 230 Carlson hand versus non-genetic functional and environmental influences on the other no longer is useful except to explain the history of orthodontic Science and craniofacial biology. The modern synthesis in orthodontics and craniofacial biology in this “epigenomic era” is based on the melding of Current and emerging information, concepts and approaches from genomics-epigenomics with those of dentofacial orthopedic treatment. Axiom 2 The phenotype, which includes the total result of all gene ex- pression as well as the potential for producing or permitting morpho- logical and physiological variation in response to extrinsic variables, Changes normally throughout ontogeny in part as a result of expression of normal gene variants and regulatory proteins. Differences in morphological form of the face and jaws arise as a result of variations, perhaps even minor differences, in craniofacial growth at critical time periods of ontogeny. It is well known that growth Overall and also of the elements of the craniofacial complex varies significantly in rate and amount throughout prenatal and early post- natal life. What is less well appreciated is the fact that the presence of normal gene variants, especially those that affect the amount and timing of expression of proteins that regulate growth, provide an underlying basis for variations in growth and form that occur throughout ontogeny. The issues most relevant with respect to a synthesis of prin- ciples of genomics-epigenomics and dentofacial orthopedics include the impact of normal variations of key genes and haplotypes with re- Spect to susceptibility for dentofacial deformities early in development, predispositions toward certain patterns of craniofacial growth due to the presence of variations in key growth factors and the possibility of epigenetic modification of craniofacial growth in association with varia- tions in genomic background during ontogeny. Axiom 3 The capability of the orthodontic patient to respond to treat- ment to correct a developing dentofacial deformity is part of their phe- notype. 231 A Genomic-Epigenomic Basis To the orthodontist, phenotype most often exclusively refers to morphological appearance as assessed by facial appearance, as well as clinical assessment of radiographic cephalograms, dental models and maturational status. However, phenotypic traits include not only readily apparent morphological features, but also expression of growth mediators. The presence of variants of regulatory proteins that mediate craniofacial growth through their degree or amount of expression at specific times of development is critical to understand variability in craniofacial growth and form. Variations in the presence and differential expression of these same gene products at various stages of development and post-natal growth undoubtedly are critical with respect to the capability of patients to respond in a predictable fashion to certaintypes of dentofacial orthopedic treatment. Normal gene products do not regulate craniofacial development and growth in the sense that they determine variations in form. Rather, they affect the receptivity and responsiveness of growing structures to intrinsic and extrinsic stimuli. Axiom 4 Strategies to correct a dentofacial deformity should take into ac- count the underlying gene variants and intrinsic epigenetic factors that contributed to the disorder and that may affect the ability of the patient to respond to specific treatment approaches. In orthodontic parlance, some patients are considered to be “good growers,” while others might be considered “poor growers." For “good growers,” this likely is due to the presence and normal expression of variants of key growth factors that are favorable in terms of response to dentofacial orthopedic treatment. Similarly, "poor growers” may have individual gene variants and haplotypes that are normal, but unfavorable to the kinds of biomechanical effectors used in standard dentofacial treat- ment. Morphological description of dentofacial deformities and even modest success in prediction of facial growth within a relatively broad range based on individually appropriate population norms as averages are not difficult for normally growing subjects. However, in order to be most effective, dentofacial orthopedic treatment in the future will benefit not only from improved understanding of the underlying causes 232 Carlson of the deformity during growth at the level of variability in normal gene Variants, but also from awareness of how those same gene variants could affect treatment designed to modify future growth. The challenge to the field of craniofacial research is to advance understanding of the various gene variants alone and in combinations in Order to assess responsiveness to treatment to correct dentofacial defor- mities and to develop biomarkers that can be used to determine which gene variants are present in individual patients. With this information in hand, clinicians will be in a better position to discern where an individual patient falls within the continuum of growth responsiveness and, thus, to prescribe their treatment accordingly. The genomics of the individual patient will be used as a key diagnostic indicator to predict, at least on a broad level, “good growers” from “poor growers” and to modify treat- ment accordingly at the start. The underlying rationale for this approach is virtually the same as for the current emphasis in the medical community on pharmacogenomics and personalized medicine. Within the medical community, personalized medicine is focused appropriately at this time of its early development on diagnosis and treatment of major pathologies such as cancer, neurological disorders and cardiovascular disease; however, the same principles have been applied to treatment of dental disease and disorders such as oral Cancer, periodontitis, dental caries and dental anesthesia (Eng et al., 2012; Garcia et al., 2013) and can be applied to dentofacial deformities (Carlson, 1999). Simply stated, personalized medicine uses advances in molecular biology to target more precise clinical treatment based on the unique genomics of the patient in order to enhance the likelihood of successful treatment. This approach has two major goals. The first is to take into account individual gene variants as underlying causes of differential response to drugs in order to provide the right drug in the right dose With the minimum toxicity for each patient according to their genomic Structure (Kornman and Duff, 2012). The second major goal is to develop diagnostic biomarkers for molecular testing in order to predict disease Susceptibility, as well as patient response to treatment (Katsanis and Katsanis, 2013). In principle, these goals are exactly the same as those that clinicians should strive for in order to facilitate enhanced diagnosis and treatment of dentofacial deformities. 233 A Genomic-Epigenomic Basis Using microarray technology, protein biochips are able to iden- tify markers for certain diseases well before they are expressed more ob- viously in the phenotype. Similar technologies can be used to detect ex- pression of proteins from key genes in the patient that are responsible for regulating growth of craniofacial skeletal structures. Although microarray technology generally has been too highly technical and cost-prohibitive in the past, this approach already is becoming increasingly available and less costly, especially now with availability of next generation sequencers. As that trend continues, attention will turn from use of microar- ray analysis in just the most profound diseases in medicine to other areas, such as diagnosis and treatment to correct developmental and growth- related disorders, including dentofacial deformities (Nazmul-Hossain et al., 2008). When that occurs, the practicing orthodontist will have a technology suitable for determining whether or not individual patients in what has been described for the purposes of this discussion as the Clini- cal Group (refer to Fig. 7) have gene variants that likely are to be favorable or unfavorable with respect to treatment to modify growth and will be able to adjust the treatment approach accordingly. It would be of great value to know each patient's expression profile of key growth factors and cytokines that will influence growth of the face and jaws. With that infor. mation, it may be possible to prescribe a treatment approach that best fits the patient in order to predict the likely response to treatment, rather than find after a significant period of treatment that a patient was or Was not a “good grower.” Axiom 5 Clinical research in orthodontics has been limited by inability to characterize subject populations fully based on their complete phenotypic expression, which includes not only standard criteria for orthodontic diag- nosis, but also expression of normally occurring gene variants. A central point of this chapter is that normal variation in the indi- vidual's genome will influence not only growth, but also responsiveness to treatment. It follows, therefore, that delineation of subgroups of pa- tients that exhibit favorable and unfavorable variants is critical in clinical orthodontic research to improve understanding of efficacy of dentofa- cial orthopedic treatment. Unfortunately, use of microarrays to discover 234 Carlson gene Variants as described above has not been a practical approach in normal subjects (Wilkie and Morriss-Kay, 2001). Malocclusion is not a disease with a clear and simple genetic ba- sis. In addition, the standard classifications of malocclusion and dentofa- cial deformities are not precise sufficiently to define subject populations for the purpose of discovering normal gene variants that are responsible for their occurrence. A more practical approach to clinical research to determine the relationship between gene variants, growth and correc- tion of a developing dentofacial deformity is the opposite approach; first determination of genes responsible for craniofacial development and growth using animal models, and then looking for normal variations in those gene products in such parameters as rate, timing and amount of expression of regulatory proteins in subgroups of patients. In the absence of more detailed information about individual genomic background, den- tofacial patients and subjects in clinical trials become grouped together and critical information about the efficacy of various types of treatment to Correct dentofacial deformities by altering growth is lost. ENVOI I do not believe that knowing whether there are funda- mentally different underlying processes in morphogene- sis and dysmorphogenesis will alter our clinical manage- ment of patients whose distorted dentofacial structures impair them either physically or psychologically. (Acker- man, 1988:219–220) The comment above by Jim Ackerman was made as a final over- View and reaction to the proceedings of the 1988 Moyers Symposium entitled Craniofacial Morphogenesis and Dysmorphogenesis (Vig and Burdi, 1988) over 25 years ago. It illustrates well the prevailing under- Standing about genetics and its relevance to treatment of dentofacial deformities, even about severe craniofacial anomalies with a certain ge- netic basis, at that time. While the commentary may seem short-sighted today, it reflects the fact that even in the latter part of the last century, the field of genetics had not developed to the point where even many in- formed practitioners could see its current and future relevance. As noted 235 A Genomic-Epigenomic Basis previously as Axiom 1, dentofacial treatment is based on contemporary concepts of craniofacial growth. The rhetorical questions posed by Lysle Johnston 16 years later in the forward of the proceedings of the Moyers Symposium on Growth and Treatment: A Meeting of the Minds (Johnston, 2004) quoted at the beginning of this review suggest similar concerns about the relevance of advances in genomics for orthodontics. Expanding on those concerns, Johnston further noted that while treatment of “real diseases” may ben- efit from advances in modern biology, “what about treatment of Such non-diseases as Class Il malocclusion, unilateral crossbite, or protrusion and crowding?” Current understanding and future developments in the area of orthodontic-orthopedic treatment to correct developing dentofacial deformities have the potential for significant advancement in light of advances in genomics-epigenomics. The overall genomic structure, including both the genes themselves as well as the epigenome intrinsic to the chromosome, provides the foundation for the action of extrinsic epigenomic effectors, such as those that are part of clinical treatment. In the more distant future, orthodontists and other clinicians treating dentofacial deformities will be using biomarkers to identify key gene variants and to introduce or enhance specific growth factors that either are deficient in expression or absent altogether, almost certainly in conjunction with standard orthodontic mechanotherapy. That approach will come after significantly more advances in personalized molecular medicine. In the relatively near future, however, clinicians principally Will use molecular kits and biomarkers to determine the presence or absence of regulatory proteins in order to facilitate diagnosis of the molecular basis of the deformity and, more importantly, the likelihood of success of particular types of treatment approaches. As many have pointed out, malocclusion and even moderate dentofacial deformities are not mortal diseases. Patients do not succumb to dental crowding, crossbite and Class Il malocclusion, or even to relatively profound craniofacial deformities. Therefore, clinical treatment advances in personalized medicine initially have not been directed at orthodontic problems; they have focused on our most severe life- threatening diseases and disorders. There is no question that discoveries of critical biological processes, development of technologies to diagnose and treat diseases, and translation of these discoveries and technologies 236 Carlson into patient care will find their way into the orthodontic clinic to improve treatment of dentofacial deformities, from simple Class || malocclusion to profound craniofacial anomalies. An in-depth understanding of genomics-epigenomics probably is not important for treatment of unilateral crossbite, flared incisors and Crowding. 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Conventional treatment involves the use of protraction facemask to advance the maxilla. Such appliances often have unwanted side effects, however, including upper incisor proclination and clockwise rotation of the mandible, resulting in an increased vertical dimension. Miniplates can be used for intermaxillary orthopedic traction. Class III elastics can be fixed between a Bollard anchor on the infra-zygomatic crest of the maxilla and another one in the canine region of the mandible of young growing patients. A prospective study on 25 consecutive cases based on the registration On the anterior cranial base of a CBCT before and after orthopedic traction revealed a forward displacement/modelling of the maxillary and zygoma bones as one unit. Because of the pure skeletal anchorage, no dental compensations of the upper incisors were found. Our studies also show that mandibular shape rather than mandibular size was affected by this bone anchored intermaxillary traction. A restriction of forward displacement of the chin by a combination of a slight swing-back of the ramus and closure of the gonial angle commonly was observed. In contrast to the outcome of face mask therapy, there was no posterior rotation of the mandible. Furthermore, a high correlation was found between the remodeling of the anterior and posterior eminence of the glenoid fossa and displacement of the opposed condylar surface. This resulted in a slight posterior relocation of the articular fossa. Treatment outcome after completion of growth will be needed to assess long-term stability of bone anchored orthopedics and which percentage of these patients still needs a surgical correction. KEY WORDS: bone anchors, orthopedics, Class III, growth changes, maxillary protraction 249 Orthopedic Changes INTRODUCTION Malocclusions often are due to an unbalanced growth between the upper and lower jaws. In severe cases, a stable occlusion can be obtained only after repositioning of the jaws within the face. This movement can be accomplished by orthognathic surgery after growth or by modifying the direction and amount of growth of one or both jaws by So-called “orthopedic appliances.” Class Ill malocclusions commonly are associated with a hypo- plastic growth of the maxilla. There is a long clinical tradition attempting to protract the maxilla by an extraoral facemask. Several animal experi- ments have showed by histology that disruption of sutures leads to in- creased bone formation and a forward displacement of the maxilla (Kam- bara, 1977; Nanda, 1978; Jackson et al., 1979). Depending on the orienta- tion of the bone extensions within the suture and the line of force of the extraoral traction, there are zones of tension and zones of compression. This treatment results in a complex response of bone resorption and ap- position along the suture. Resistance against separation of sutures after application of heavy forces is different for each suture. The resistance depends on the total surface of the suture and the complexity of the interdigitation. Furthermore, it is well known that the interdigitation increases with age, so that protraction of the midface can be obtained more easily in young individuals. In the past, extraoral forces could not be applied directly to bone. A maxillary splint covering the entire upper dentition was used to limit the dentoalveolar effects and to transfer the forces to the circummaxillary sutures as much as possible. To avoid irritation of the lips by the elastics connecting the maxillary splint with the facemask, the direction of traction always is slightly downward, with the line of force below the center of resistance of the maxilla. The moment of force generates a slight counterclockwise rotation of the maxilla, which results in a compression of the fronto-nasal suture and stretching of the other circummaxillary sutures. The zygomatico-maxillary suture has the largest surface and interdigitation is complex; resistance against separation by forward traction is high. 250 De Clerck and Timmerman In contrast, the interdigitations of the zygomatico-temporal and zygomatico-frontal suture are weak, and the contact surfaces are small. These findings may explain why huge elongations of the zygomatic arch Were observed in animal experiments (Jackson et al., 1979), suggesting that not only the maxilla is displaced forward by protracting mechanics, but also the zygoma. The opposite happens to the palatine bone. The transverse palatine suture is fragile and easily disrupted. This suture is in Contrast to the tight connection between the pyramidal process of the palatine bone and the pterygoid plates (Melsen and Melsen, 1982). That is why the transverse palatine suture showed the biggest separation in animal experiments of all circummaxillary sutures (Jackson et al., 1979; Kambara, 1977). In contrast to the zygoma, the palatine bone seems not to be affected much by the forward traction, preserving the nasopharyngeal Volume. Skeletal anchorage by miniplates now makes it possible to apply Orthopedic forces directly to the bone surface, close to the sutures. By inserting a miniplate at the infra-zygomatic crest and another in the canine region of the mandible, Class III elastics can be fixed between both jaws. The first advantage is that anteriorly directed forces can be applied to the Sutures 24 hours per day instead of only at night. Because an extraoral device is no longer needed, compliance from the patient is much better. Furthermore, dentoalveolar compensations are eliminated. The effect of this bone-anchored protraction on the growth of the midface initially was evaluated by classical cephalometric analysis. In a later stage of our research, a cone-beam CT (CBCT) image was made at the start and a second after one year of protraction. After segmentation, a three-dimensional (3D) surface model was made from each CBCT and registered on the anterior cranial base. Closest point distances were Computed and color maps were generated (Cevidanes et al., 2011). MAXILLARY GROWTH CHANGES An initial Sample of 25 consecutive growing children, mean age 11.9 years, was treated with intermaxillary elastics fixed between a modified upper miniplate (Bollard", Tita-Link, Brussels, Belgium) on the infrazygomatic crest and another between the lower canine and lateral incisor. Elastics were worn day and night and replaced every morning and 251 Orthopedic Changes evening. The force level was 200-250 grams each side and traction was maintained over a mean period of 1.2 years. A CBCT was made both at the beginning and end of the orthope- dic treatment (Nguyen et al., 2011). Special software was used to obtain lateral cephalograms from the CBCTs. The group treated with bone-an- chored protraction was matched with a control group based on dento- skeletal disharmony, gender distribution, timing of observation and Skel- etal maturation. Compared to the control group, the upper jaw moved 3.9 mm more forward in the group treated by bone supported elastic traction (De Clerck et al., 2010). It generally is accepted that after the age of nine years, the effect of a facemask on the development of the midface is small (Franchi et al., 2004) because of increasing interdigitations of the sutures and high resistance against disruption. Thus, most of the clinical protocols start with a rapid maxillary expansion (RME) before facemask therapy. This initial expansion presumably disarticulates the sutures mechanically and improves the orthopedic outcome. Liou (2005) advocates an alternating 7 mm expansion and Com- pression during nine consecutive weeks to mobilize all maxillary Sutures more. In a randomized prospective clinical trial (Vaughn et al., 2005), however, no different orthopedic outcome was found between a group of patients treated with facemask preceded by RME and another group without expansion. In our protocol, protraction is started after the age of 11 years, when the sutures are supposed to be interdigitated too much to be protracted by a facemask. Without expansion and using light forces (about a third of the traction force used with facemask), twice the amount of maxillary advancement is obtained. Last year, we further reduced the force level to a maximum of 150 grams per side, with a similar growth response. Based on our findings, it seems that higher forces or disarticulation of the sutures by RME seem not to be the key factors to improve midface protraction. The duration of the force application may be of greater significance. With a facemask, heavy forces during the night are interrupted completely during the day. With bone-anchored maxillary protraction, forces can be applied day and night, resulting in greater suture growth. Increased maxillary protraction 252 De Clerck and Timmerman also was found in animal experiments on rabbits (Liu et al., 2010) where Suture separation with continuous forces was higher than separation obtained by intermittent forces. Finally, compliance also may affect the outcome. The wearing of an extraoral facemask has more impact on the psycho-social lives of these young patients and is not accepted as easily as wearing intraoral elastics. Clear separations of the zygomatico-temporal, Zygomatico-fron- tal and transverse palatine suture have been visualized on the 3D images of the face (Nguyen et al., 2011), though the zygomatico-maxillary suture was less affected. CBCTs before and after protraction registeréd on the anterior cranial base showed a high correlation between the forward dis- placement of the maxilla, zygoma and upper dentition. Rather than mov- ing only the maxilla forward, the whole midface seems to be affected by the continuous elastic forces. Teuscher (1986) introduced biomechanics to explain rotations of the upper jaw by headgear; he defined a hypothetical location of the Center of resistance of the maxilla close to the buttress. It now seems more appropriate, however, to define a center of resistance of the midfacial Complex, including the upper dentition, maxilla and zygoma. With our traction protocol, hardly any rotation of the maxilla has been noted. Therefore the center of resistance of the midface must be located at a lower level and more posteriorly than the one defined by Teuscher. This Center of resistance is located closer to the pterygomaxillary complex. MANDIBULAR GROWTH CHANGES The adaptability of sutures to external factors is higher than the adaptability of condylar cartilage (van der Linden et al., 2000). Therefore, Class Ill orthopedics is focused mostly on stimulation of midfacial growth. It should be noted, however, that equal reaction forces are acting in the opposite direction on the mandible. The forces generated by bone anchored intermaxillary elastics pull the chin backward and upward, which is in contrast to the horizontal reaction force from the chincup of a facemask. Such forces acting below the condyles tend to rotate the man- dible backward. This force application often results in an increase of the mandibular plane angle and the lower face height (Toffol et al., 2008). 253 Orthopedic Changes Clockwise rotation of the mandible reduces the prominence of the chin, increases the convexity of the soft tissue profile and often is interpreted as a restriction of the forward growth of the jaw. With bone-anchored traction, no posterior rotation of the mandible was observed (De Clerck et al., 2010). There is no evidence concerning an eventual compression of the condyles by a facemask. It has not been shown that such an intermittent compression at the cellular level of the cartilage restricts the growth potential of the mandible. When the increase in length of the ramus and mandibular body between our clinical sample and a control group was compared, We could find no significant difference. The increase of the linear distance condylion-gonion and gonion-gnathion is not different between patients wearing bone anchored elastics for one year and untreated Class || patients. In contrast, the distance between the condyle and the chin (condylion-gnathion) increased significantly less in the treated group than in the controls. Because both legs (the ramus and the horizontal part of the mandible) grew as much in both groups, this can be explained only by changes in the gonial angle. There was a reduction of the gonial angle in the treated group, whereas the gonial angle slightly increased in the control group. The difference was 4.1°, a highly significant difference (De Clerck et al., 2010). That the gonial angle should be affected by such light forces in only one year's time is amazing, although closure of the gonial angle also has been observed with chincup therapy (Mimura and Deguchi, 1996). In contrast to the facemask, the line of force of the chincup is similar to the line of force of the elastic traction between upper and lower Bollard miniplates. Besides a reduction of the gonial angle, they also found a slight closure of the mandibular plane angle without increase of the mandibular length and also concluded that the shape rather than the size of the mandible was affected by chincup therapy. A closure of the gonial angle alone not only would result in a closure of the mandibular plane angle, but also a more forward projection of the chin. This change in mandibular shape did not happen in our Sample, The chin moved a mean distance of 0.6 mm backward instead of the 2.2 254 De Clerck and Timmerman mm forward growth in the control group (De Clerck et al., 2010). This observation may be explained by a combination of a closure of the gonial angle with a 'Swing back' of the ramus. Such a morphological change also Was observed with chincup therapy. The gonial landmarks showed a clear posterior displacement in contrast with the control group not only in our 3D Superimpositions (De Clerck et al., 2012; Nguyen et al., 2013), but also With the thin-plate spline analysis (Baccetti et al., 2011). The direction of growth of both condyles also may be modified by the force application. Different directions of condylar growth were reported by Björk and Skieller (1972), superimposing growing mandibles on metallic implants. They found anterior, upward and backward growth directions of the condyle and associated them with the vertical growth pattern of the face. Following bone-supported Class Ill traction, Nguyen and col- leagues (2013) found three distinct patterns of posterior condylar dis- placement using shape correspondence analysis: backward or a combina- tion backward-downward or backward-upward. Instead of superimposi- tions of 3D images of the face on the anterior cranial base, superimposi- tion on stable structures in the bony chin may give us better insights in the growth direction of the condyles in the near future and if the direc- tion of growth is related to and can be modified by the direction of elastic traction. The direction of traction is determined not only by the positioning of the miniplates, but also by the severity of the skeletal Class III, which Will change slightly during the orthopedic treatment. To some degree, the direction of traction can be modified by inserting extensions in the tubes of the Bollard miniplates. GLENOID FOSSA REMODELING Superimposition on the anterior cranial base of CBCTs before and after bone anchored elastic traction showed a posterior displace- ment of the condyles in all patients (range 0.1-4.1mm; De Clerck et al., 2012). In Class Ill growing patients, an edge-to-edge bite in the incisor region in centric relation may force the mandible in a functional anterior Shift to obtain a stable occlusion of the molars. After protraction of the midface and upper dentition, the functional shift of the mandible may 255 Orthopedic Changes be eliminated, which could explain the posterior displacement of the condyles. Posterior displacement of the condyles, however, also may be caused by remodeling processes at the glenoid fossa. MRI studies conducted by Ruf and associates (2002) showed bone resorption and apposition in the glenoid fossa, which were attributed to the treatment with Herbst appliances. With color maps of the fossa obtained by registration of two CBCTs on the anterior cranial base, remodeling processes now can be visualized and quantified better. It is possible to link these changes to the displacement of the condyles. We found that the amount of resorption of the posterior wall of the glenoid fossa was correlated highly with the amount of backward displacement of the posterior surface of the condyles. • The amount of bone apposition that was found at the anterior eminence of the fossa also was correlated well with the amount of backward movement of the anterior surface of the condyle (De Clerck et al., 2012). In other words, the movement of the condyles seems to be correlated with a repositioning of the fossa by bone remodeling and not With a functional shift of the mandible. DENTOALVEOLAR CHANGES One of the main advantages of our clinical protocol is the ap- plication of the forces directly to the skeletal base of upper and lower jaw. That is why barely any proclination of the upper incisors was found in contrast to facemask (Nguyen et al., 2011), though some spontaneous proclination of the lower incisors occurred in all cases. Tongue pressure against the lingual surface of the lower incisors after the correction of the skeletal Class III may be a possible explanation. After the orthope- dic phase, a Class Ill occlusion from the start of treatment often is trans- formed into a Class Il malocclusion. Because the miniplates are inserted at the base of the maxilla and at a distance from the dental arch, they also can be used in combination with fixed appliance to distalize the up- per molars and premolars to open space for the eruption of the canines, This tooth movement reduces the need for extractions of upper premo- lars, which may be better in patients with a hypoplastic midface. 256 De Clerck and Timmerman SOFT TISSUE CHANGES The combination of maxillary, mandibular and glenoid fossa changes result in an improvement of the soft tissue profile. The CBCTs registered on the anterior cranial base show that most soft tissue changes occur at the level of the upper lip, which becomes more prominent (Nguyen et al., 2011). Clinically, more vermilion of the upper lip becomes Visible. In most of the cases, the position of the lower lip is not altered and stays at the same level during the one year of intermaxillary traction. Especially in Class Ill growing patients, this finding was not expected, but is due to the complete restriction of forward projection of the bony Chin by the mandibular and fossa changes, as explained above. Finally, a forward and slight upward movement of the tip of the nose often is Observed. Altogether, this results in a reduction of the concavity of the Soft tissue profile. DISCUSSION The changes in the different parts of the face do not happen in a uniform way in all patients treated using our protocol. Some patients mainly show a forward movement of the midface; others have more mandibular response or a combination of both. A huge variation has been found in the modulation of growth of the different units (Nguyen et al., 2011). Variation in patient response also has been found in patients treated by facemask (Hino et al., 2013). Why certain patients show a more favorable response than others is not totally clear yet. Future research Should focus on finding criteria to predict which patient will and will not respond favorably to this orthopedic traction. One possible explanation is the skeletal maturation and the degree of interdigitation of the maxillary sutures. More interdigitation may be expected in older patients; for this reason, it may be advocated to Start the orthopedic treatment as early as possible. However, a higher failure rate of the miniplates in the upper jaw was found in patients treated before the age of 11 because of the thin and fragile cortical bone at the infra-zygomatic crest. Poor mechanical retention of the screws may result in loosening of the plates after loading. For this reason, it is better to start the treatment at an older age. But what is the upper limit? When is the patient too old for an orthopedic approach? Also in this regard, we found a high variability in outcome. 257 Orthopedic Changes Another factor that may lead to failure of the anchorage system is the surgical procedure itself. Insertion of the plates close to the infra- zygomatic crest, good contact with the bone all along the miniplate and perforation of attached gingiva close to the mucogingival border are key factors for long-term stability of the miniplates (De Clerck and Swennen, 2011). Furthermore, all jiggling forces should be avoided. Favorable outcomes were obtained with our approach in a group of patients three to four years older than what was considered the ideal age for growth modulation. This treatment also was possible without RME. Why is it accepted generally that a disarticulation of sutures by RME is mandatory to obtain a favorable response from facemask therapy, while better results were obtained with our protocol in older patients and without RME? Why do we still believe that heavy forces are needed to distract sutures, whereas a better outcome was found with much lighter forces? Based on our findings, the duration of the force application seems to be more important than the magnitude. The best treatment time to obtain maximal changes in the shape of the mandible is unknown. Can mandibular growth still be modified when the sutures already are interlocked partially and protraction of the midface is restrained? Are there any adverse effects produced by these continuous forces? Until now, no subjective complaints have been reported about dysfunction of the temporomandibular joints; however, further research is needed to exclude any side effect. New imaging tools with less radiation for the patients now makeit possible to analyze and better understand growth changes and the result- ing development of the face. But all of these effects have been observed only in the short term. There are relapse tendencies after the active or- thopedic phase, and the degree of relapse also is variable. Some patients need extra intermaxillary elastic traction after fixed appliance treatment at night to compensate for a remaining Class Ill growth potential—some patients do not. This means that this protocol needs a long follow-up, and treatment is finished only when growth is totally complete. Now we have an extra tool to treat Class Ill patients. Much more research is needed, however, to establish guidelines how to choose the best treatment for our patients: facemask at early age, bone-anchored elastic traction at a later stage, dento-alveolar compensation by fixed 258 De Clerck and Timmerman appliance or orthognathic surgery after growth. The best quality of the final outcome must be the main goal, but efficiency as well as the relation between costs and benefits also will have to be evaluated one day for each of these approaches. REFERENCES Baccetti T, De Clerck HJ, Cevidanes LH, Franchi L. Morphometric analysis of treatment effects of bone-anchored maxillary protraction in growing Class Ill patients. Eur J Orthod 2011;33(2):121-125. Björk A, Skieller V. Facial development and tooth eruption: An implant study at the age of puberty. Am J Orthod 1972;62(4):339-383. Cevidanes LH, Oliveira AE, Grauer D, Styner M, Proffit WR. Clinical application of 3D imaging for assessment of treatment outcomes. Semin Orthod 2011;17(1):72-80. De Clerck H, Cevidanes L, Baccetti T. Dentofacial effects of bone-anchored maxillary protraction: A controlled study of consecutively treated Class |ll patients. Am J Orthod Dentofacial Orthop 2010;138(5):577-581. De Clerck H, Nguyen T, de Paula LK, Cevidanes L. Three-dimensional assessment of mandibular and glenoid fossa changes after bone- anchored Class III intermaxillary traction. Am J Orthod Dentofacial Orthop 2012;142(1):25-31. De Clerck EE, Swennen GR. Success rate of miniplate anchorage for bone anchored maxillary protraction. Angle Orthod 2011;81(6):1010-1013. Franchi L, Baccetti T, McNamara JA Jr. Postpubertal assessment of treat- ment timing for maxillary expansion and protraction therapy followed by fixed appliances. Am J Orthod Dentofacial Orthop 2004;126(5):555- 568. Hino CT, Cevidanes LH, Nguyen TT, De Clerck HJ, Franchi L, McNamara JAJr. Three-dimensional analysis of maxillary changes associated with facemask and rapid maxillary expansion compared with bone an- chored maxillary protraction. Am J Orthod Dentofacial Orthop 2013; 144(5):705-714. Jackson GW, Kokich VG, Shapiro PA. Experimental and postexperimen- tal response to anteriorly directed extraoral force in young Macaca nemestrina. Am J Orthod 1979;75(3):318–333. 259 Orthopedic Changes Kambara T. Dentofacial changes produced by extraoral forward force in the Macaca irus. Am J Orthod 1977;71(3):249-277. Liou EJ. Toothborne orthopedic maxillary protraction in Class Ill patients. J Clin Orthod 2005;39(2):68-75. Liu SS, Kyung HM, Buschang PH. Continuous forces are more effective than intermittent forces in expanding sutures. Eur J Orthod 2010;32 (4):371-380. Melsen B, Melsen F. The postnatal development of the palatomaxillary region studied on human autopsy material. Am J Orthod 1982;82(4): 329-342. Mimura H, Deguchi T. Morphologic adaptation of temporomandibular joint after chincup therapy. Am J Orthod Dentofacial Orthop 1996; 110(5):541-546. * Nanda R. Protraction of maxilla in rhesus monkeys by controlled extraoral forces. Am J Orthod 1978;74(2):121-141. Nguyen T, Cevidanes LHS, Cornelis MA, Heymann G, de Paula LK, De Clerck H. Three-dimensional assessment of maxillary changes associated with bone anchored maxillary protraction. Am J Orthod Dentofacial Orthop 2011;140(6):790-798. Nguyen T, Cevidanes L., Paniagua B, Zhu H, Koerich L, De Clerck H. Use of shape correspondence analysis to quantify skeletal changes associa- ted with bone-anchored Class Ill correction. Angle Orthod 2013 Jul 25; Epub ahead of print. Ruf S, Wüsten B, Pancherz H. Temporomandibular joint effects of activator treatment: A prospective longitudinal magnetic resonance imaging and clinical study. Angle Orthod 2002;72(6):527-540. Teuscher U. An appraisal of growth and reaction to extraoral anchorage; Simulation of orthodontic-orthopedic results. Am J Orthod 1986;89 (2):113-121. Toffol LD, Pavoni C, Baccetti T, Franchi L, Cozza P. Orthopedic treatment outcomes in Class Ill malocclusion: A systematic review. Angle Orthod 2008;78(3):561-573. 260 De Clerck and Timmerman Van der Linden FPGM, Radlsanski RJ, McNamara JA Jr. Facial Orthopedics: Dynamics of Orthodontics, CD-ROM. Ouintessence International, Berlin 2000. Vaughn GA, Mason B, Moon HB, Turley PK. The effects of maxillary protraction therapy with or without rapid palatal expansion: A prospective, randomized clinical trial. Am J Orthod Dentofacial Orthop 2005;128(3):299-309. 261 CLINICAL ALTERATION OF MANDIBULAR GROWTH: WHAT WE KNOW AFTER 40 YEARS Lorenzo Franchi, Luca Contardo, Jasmina Primožič, Giuseppe Perinetti ABSTRACT OBJECTIVE: To assess with a meta-analysis if the timing of intervention makes a difference in terms of mandibular changes produced by functional jaw orthope- dics (FJO) in growing Class Il patients. MATERIALS AND METHODS: Both random- ized clinical trials (RCTs) and controlled clinical trials (CCTs, irrespective of being prospective or retrospective) on the mandibular effects produced by removable functional appliances were considered. The search strategy resulted in 2,456 ar- ticles. After Selection according to the inclusionary/exclusionary criteria, ten ar- ticles qualified for meta-analysis. Analysis of supplementary mandibular growth in treated patients with respect to subjects with untreated Class Il malocclu- Sion was reported according to treatment timing (pre-pubertal versus pubertal groups) and shown through a forest plot. Any significant difference in the overall effects between the pre-pubertal and pubertal groups was evaluated. RESULTS: In the samples treated before puberty (Faltin et al., 2003; Baccetti et al., 2005; Al- meida-Pedrin et al., 2007; Singh et al., 2010; Brunharo et al., 2011; Perillo et al., 2013) the overall effect was 1.29 mm (95% CI, 0.89-1.68 mm) while the samples treated at puberty (Baccetti et al., 2000; Faſtin et al., 2003; Cui et al., 2010; Malta et al., 2010; Singh et al., 2010; Martina et al., 2013) showed a significantly great- er overall effect of 4.32 mm (95% CI, 3.65-5.00 mm). CoMcLUsion: Mandibular growth can be stimulated effectively only when FJO is performed at puberty as assessed with a reliable indicator of individual skeletal maturity. KEY WORDS: Class || malocclusion, functional appliances, cephalometric analysis, mandibular growth, meta-analysis 263 Clinical Alteration of Mandibular Growth INTRODUCTION A wide range of functional/orthopedic appliances aimed to stim- ulate mandibular growth by forward posturing of the mandible is avail- able for the correction of Class Il disharmony (McNamara and Brudon, 2001), a type of malocclusion that affects one third of the North Ameri- can population (Proffit et al., 1998). Although many studies in animals have demonstrated that skeletal mandibular changes can be produced by posturing the mandible forward both in the short- and long-term (e.g., McNamara, 1973; McNamara and Bryan, 1987), the effects on humans are more equivocal and controversial. Systematic reviews of the literature (Chen et al., 2002; Cozza et al., 2006; Marsico et al., 2011) on the outcomes of functional jaw orthopedics (FJO) in Class Il malocclusion have shown a substantial variability of reported results. These differences have to be attributed mainly to the type of appliance used (in terms of duration of active treatment needed to achieve Class Il correction and patient's compliance) and to the timing of intervention. A recent systematic review with meta-analysis (Marsico et al., 2011) evaluated the best evidence (randomized clinical trials; RCTs) about the efficacy of functional appliances on mandibular growth in the short term. The quality analysis of these studies showed that the statistical methods were at the medium-to-high level. The results of this meta- analysis showed a statistically significant difference of 1.79 mm in annual mandibular growth of the treatment group compared with the control group. However, the authors concluded that skeletal changes produced by functional appliances versus an untreated Class || controls, though statistically significant, were not significant clinically. With regard to treatment timing as reported by the RCTs included in the systematic review by Marsico and colleagues (2011), it must be stressed that two of them did not include adequate appraisal of skeletal maturity (Jakobsson, 1967; Nelson et al., 1993), while both Tulloch and associates (1997) and O'Brien and coworkers (2003) described results of functional appliances used at a pre-pubertal stage. The lack of clinical significance in the outcomes of these last two RCTs may correlate with the pre-pubertal treatment timing of the reported samples. Similarly, the RCT by Jakobsson (1967) reported outcomes of Activator treatment 264 Franchi et al. performed at an average age of 8.5 years (a very early age with regard to the peak in mandibular growth). Significantly greater effects of FJO have to be expected when treatment is carried out at a later stage of development that corresponds to the pubertal peak in mandibular growth, as detected by a reliable in- dicator of skeletal maturity (hand and wrist analysis, cervical vertebral maturation (CVM) method, analysis of increases in statural height), when Compared to the outcomes of treatment performed before or after the growth spurt (Malmgren et al., 1987; Hägg and Pancherz, 1988; Petrovic et al., 1990; Baccetti et al., 2000; Faltin et al., 2003). However, no system- atic review has been carried out to investigate into the role of treatment timing on the short-term effects produced by FJO in Class Il patients. As for the long-term outcomes of FJO, data available in the litera- ture are much scarcer (DeVincenzo, 1991; Hansen et al., 1991; Hansen and Pancherz, 1992; Rudzki-Janson and Noachtar, 1998; Faltin et al., 2003; Freeman et al., 2009; Malta et al., 2010). While Freeman and associates (2009) and Malta and colleagues (2010) have described a long-term sta- tistically significant increase in mandibular length in patients treated with F]0 over untreated Class || controls of about 3.0 to 3.5 mm, DeVincenzo (1991) and Hansen and Pancherz (1992) have reported lack of significant Changes for the mandible of treated Class II subjects in the long term. In both latter studies, however, the nature of the controls was problematic, with DeVincenzo (1991) utilizing a mixed group of Class || and Class I subjects (some of whom had been treated before or still were in treatment), while Hansen and Pancherz (1992) used values derived from the “Bolton Standards,” a group of subjects highly selected on the basis of ideal occlusions and well-balanced faces. In the literature, there also is lack of information about the role of treatment timing for the long-term outcomes of FJO. Few studies (Hansen et al., 1991; Faltin et al., 2003) have described the long-term effects of FJO at different stages of dentoskeletal development. The aim of the present study, therefore, was to assess with a meta-analysis if the timing of intervention makes a difference in terms of mandibular changes produced by FJO in the short term. The results from a recent study that compared the long-term dentoskeletal changes induced by FJO at two different stages of skeletal maturation (pre-pubertal versus pubertal) also has been reported. 265 Clinical Alteration of Mandibular Growth THE ROLE OF TREATMENT TIMING ON THE EFFECTIVENESS OF FUNCTIONAL JAW ORTHOPEDICS: A META-ANALYSIS Materials and Methods The present meta-analysis used previous systematic reviews as a template (Cozza et al., 2006; Perinetti and Contardo, 2009) and included studies that examined mandibular effects induced by FJO in patients with skeletal Class Il malocclusion treated with removable functional appliances. In particular, the role of treatment timing for FJO (pre- pubertal versus pubertal growth phases) also was considered. A literature survey was carried out using the following data- bases: 1. PubMed SCOPUS 3. Latin American and Caribbean Health Sciences (LILACS) 4. Scientific Electronic Library Online (SciELO) 5. The Cochrane Library 2. The survey covered the period from inceptions to the last access on February 4, 2013, with no language restrictions. The main key words used in the search in each of the database were as follows: "((Orthodontic appliance) or (Functional jaw orthopedics)) AND ((Class Il malocclusion) or (Angle Class II)).’ Finally, a manual search also was performed by scoring the refer- ences within the studies examined and the titles of the papers published over the last twenty years in the following journals: 1. American Journal of Orthodontics and Dentofacial Orthopedics European Journal of Orthodontics Journal of Clinical Orthodontics Journal of Orthodontics Korean Journal of Orthodontics Progress in Orthodontics : 266 Franchi et al. 7. The Angle Orthodontist 8. World Journal of Orthodontics The studies retrieved had to be either RCTs or controlled clinical trials (CCTs) both prospective and retrospective. They had to include healthy subjects treated during either the pre-pubertal or pubertal growth periods. These studies had to investigate the effects on total mandibular length as either a primary or secondary outcome. These studies had to include matched control groups of subjects With untreated Class || malocclusion with similar growth phase. Studies evaluating the long-term effects on total mandibular length from the beginning of the treatment to the end of growth period, thus including a relevant post-pubertal growth phase between the two recordings, were not considered. No restrictions were set regarding the type of removable appli- ance used or the duration of the treatments, or to the cephalometric method used to measure the total mandibular length. Case reports, case Series, reviews and opinion articles were excluded. Of note, studies in Which the diagnosis of Class Il malocclusion was not reported clearly or When a reliable indicator of growth phase (hand and wrist analysis, CVM method, analysis of increases in statural height) was not used also were excluded. Details regarding these inclusion and exclusion criteria are list- ed in Tables 1 and 2. Eligibility assessment and data collection processes were per- formed independently by two authors of this chapter (LF and GP). The data collection was carried without blinding to the authors; intra-examin- er conflicts were resolved by discussion of each article until a consensus was reached. The following data items were collected: study design, sample Size (with age and sex distribution), type of removable appliance, Observation duration and appliance wear, effects on total mandibular length and comments on growth phase (Table 3). The subjects included in these Studies had to show a Class Il malocclusion diagnosed as having One or more of the followings: overjet equal or greater than 7 mm, at least half-cusp molar Class II relationship with an ANB angle greater than 4” and/or full cusp molar Class Il relationship. 267 Clinical Alteration of Mandibular Growth Table 1. Inclusion criteria used in the present review. 1. Prospective or retrospective longitudinal studies on healthy growing subjects treated for skeletal Class || malocclusion due to mandibular retrusion - 2. Use of removable functional orthodontic appliances 3. Use of a reliable indicator of individual skeletal maturity to assess treatment timing that had to be either prepubertal or pubertal 4. Use of matched control groups of subjects with untreated Class || malocclusion with similar growth phase Table 2. Exclusion criteria used in the present review. 1. Case reports, case series with no statistical analysis, studies with less than 10 subjects, comments, letters to the Editor, reviews 2. Studies using the headgear alone or in combination with other functional appliances 3. Studies in which the compared treated groups were subjected to different treatment modalities. 4. Studies in which orthodontic treatments were combined with Surgery 5. Studies without cephalometric analyses (including total mandibular length for meta-analysis) 6. Studies in which a favorable response to treatment was an inclusion Criterion 7. Studies in which control group was based on published reference standard without a specific matching of the groups by age, sex, and other features — Table 3. Design and results of the seven studies on the pre-pubertal subject. RCT = randomized clinical trial; CCT = controlled clinical trial; P = prospective; R = retrospective; F = females; M = males; NA = not available. 268 Franchi et al. Sample size Treatment or Stud Study and mean Appliance observation Comments on y design age in years pp duration/ growth phase (range or SD) appliance wear 23 F. 30 M * J. Bionator 1.3 VearS/NA Tulloch 9.4 + 1.0 years/ Early treatment et al., RCT does not improve 1997 26 F, 35 M Control 1.3 years/NA jaw relationship 9.4 + 1.2 .3 y 11 F. 10M | Twin block | 1.2 + 93 years/ Optimum BacCetti 9.0 + 0.9 full time treatment º et al., | CCT, R appears to be 2000 during or slightly 7 F; 9 M Control 1.3 + 0.6 years/ after the onset of 9.1 + 0.8 NA the pubertal peak e 7 F, 6 M Bionator 1.8 + 0.6 years No significant Faitin 9.7 ± 1.3 skeletal effect et al., CCT, R * during prepubertal 2003 5 F; 6 M period 9.4 + 1.3 Control 2.1 + 0.6 years 15 F; 15 M e 10.35 Bionator 1.52 years / NA Almeida- - e (8.2–11.0) Pedrin et CCT, P None al., 2007 y 5 F; 6 M 9.4 + 1.3 Control 1.49 years / NA e 5 (NA) Twin-block || 2 years/full time Optimal timing Singh NA twin-block during et al., CCT, R or slightly after 2010 5 (NA) the pubertal NA Control 2 years/NA growth spurt 7 F; 12 M Modified 1 year/at least 18 Brunharo 9.5 + 0.8 Twin-block hours per day et al., RCT, P None 2010 7 F; 12 M 9.8 + 1.1 Control 1 year/NA 1.6 + 0.8 years/ - & 17 (NA) FR-2 at least 18 hours Treatment at Perillo 8.9 + 1.1 per day the prepubertal et al., CCT, R growth phase 2013 has minimal 17 (NA) 1.6 + 0.8 years/ g 8.9 + 1.8 Control NA mandibular effects 269 Clinical Alteration of Mandibular Growth To establish the effects of FJO on total mandibular length, supplementary mandibular growth with respect to the untreated control group was calculated. These scores were derived from cephalometric measure of mandibular length as follows: condylion-gnathion, articulare- gnathion, condylion-menton, articulare-menton, condylion-pogonion, articulare-pogonion and expressed in millimeters. Total mandibular length obtained by other recordings, such as that from the Pancherz analysis (1982) was not considered herein because of the difference among the recording methods. Although slightly different, the measures of total mandibular length were combined in the overall effects according to the concept that the supplementary mandibular growth would not be influenced by to the absolute measures from which it was derived. The data were combined for meta-analysis using Statistical Soft- ware (Comprehensive Meta-Analysis software, Biostat Inc., Englewood, NJ). The differences in mean mandibular growth between treated and control groups, along with 95% confidence intervals (CIs), were calcu- lated. Although different treatment durations were from one to two years, with changes reported as either total or annualized, results were combined. To account for this heterogeneity of the results from individ- ual studies (i.e., differences among the retrieved effect sizes), a random effect model was used for the overall effects calculations (Ried, 2006). However, all the relevant information was reported along with the Cor- responding effect size. As no relevant differences were seen between the sexes, these analyses are shown with pooling of the sexes. Moreover, these analyses were reported according to treatment timing (pre-pubertal or pubertal) and shown through a forest plot, a graphical display designed to illustrate the relative strength of treatment effects in multiple quantitative scientific studies addressing the same question. Finally, any significant difference in the overall effects between the two groups of studies (i.e., pre-pubertal versus pubertal studies) also was evaluated. Main Results and Interpretation The present meta-analysis included ten studies (Fig. 1) with the main features and results summarized in Tables 3 and 4. 270 Franchi et al. Medline SCOPUS LILACS Cochrane SciELO (n = 1,870) (n = 2,334) (n = 196) (n = 179) (n = 20) w W ! ! W Records after duplicates removed (n = 2,456) W Full-text articles assessed for eligibility (n = 98) ! Studies included in the systematic review (n = 13) W Studies included in the meta-analysis (n = 10) Figure 1. Flow diagram of the search strategy. In seven studies, patients were treated during the pre-pubertal growth period while in six studies patients were treated during the pubertal growth phase. Five studies (Tulloch et al., 1997; O'Brien et al., 2003; Almeida-Pedrin et al., 2007; Brunharo et al., 2011; Perillo et al., 2013) included specifically pre-pubertal subjects, three studies included Only (Cui et al., 2010; Martina et al., 2013) or mostly (Malta et al., 2010) pubertal subjects and three studies (Baccetti et al., 2000; Faltin et al., 2003; Singh et al., 2010) included both pre-pubertal and pubertal subjects Separately and along with corresponding matched control groups. Three Studies (Tulloch et al., 1997; O'Brien et al., 2003; Martina et al., 2013) Were RCTs, while the rest were CCTs, mostly retrospective. All the studies included both male and female subjects, while Sex distribution was not reported in two studies (Singh et al., 2010; Perillo et al., 2013). The sample sizes ranged from a minimum of five (Singh et al., 2010) to a maximum of 61 (Tulloch et al., 1997). In all the Studies, the mean age for pre-pubertal subjects ranged from 8.9-10.3 271 Clinical Alteration of Mandibular Growth Table 4. Design and results of the six studies on the pubertal subjects. RCT = randomized clinical trial; CCT = controlled clinical trial; P = prospective; R = retrospective; F = females; M = males; CVMS = cervical vertebral maturation Stage; NA = not available. Sample size Study and mean age Treatment or Comments on Study e e Appliance observation duration / design in years appliance wear growth phase (range or SD) pp 6 F, 9 M in- 1.4 + 0.4 years/ - 12.9 + 1.2 Twin-block full time t º - Baccetti º et al., CCT, R alſº or slightly 2000 * 7 ". Control 1.3 + 0.4 years after the Onset of - *-* - - - the pubertal peak * : ". Bionator 2.3 + 1.5 years/NA Optimal timing to - tº * * * * - Start treatment Faltin is immediatel et al., CCT, R before the y 2003 i º, Control 1.8 + 0.7 yars pubertal growth * † - am amº & spurt (CVMS II) 9 º M Twin-block 1.2 years/NA Functional * treatment for Cui et al., CCT, R Class || should be 2010 & performed at the 9 F; 12 M Control 1.2 years pubertal growth 11.3 Spurt 6 F; 14 M Bionator NA/ 10.2 + 1.5 16 hours per day Relevant mandibular effects Malta are seen when et al., CCT, R treatment is 2010 8 F; 12 M performed during Control 9.1 + 1.4 OntrC) NA the pubertal growth phase 29 (NA - - § ) Twin-block 2 years/full time Optimal timing for myofunctional Singh therapy of Class et al., CCT, R Il malocclusion is 2010 29 (NA) during or slightly NA Control 2 years/NA after the pubertal growth spurt 8 F; 15 M Sander bite 1.5 years/ Treatment 10.9 + 1.3 jumping 14 hours per day response was Martina relevant and not et al., RCT influenced by the 2013 12 F; 11 M cervical stage Control 1 Vear/NA 10.5 + 1.2 year/ (3 or 4) among pubertal subjects 272 Franchi et al. years, while for the pubertal subjects the mean age ranged from 9.1-13.6 years. Singh and colleagues' information (2010) regarding the ages of the Subjects was not reported. The removable functional appliances used were Twin-block (Baccetti et al., 2000; Cui et al., 2010; Singh et al., 2010), a modified Twin-block (Brunharo et al., 2011), Bionator (Tulloch et al., 1997; Faltin et al., 2003; Almeida-Pedrin et al., 2007; Malta et al., 2010), Function Regulator (FR-2; Perillo et al., 2013) and a Sander bite jumping (Martina et al., 2013). The mean treatment duration in the pre-pubertal studies ranged from one year (Brunharo et al., 2011) to 2.1 years (Faltin et al., 2003) With the appliance being worn at least 18 hours per day (Brunharo et al., 2011; Perillo et al., 2013) to full-time wear (Baccetti et al., 2000; Singh et al., 2010). However, three pre-pubertal studies (Tulloch et al., 1997; Faltin et al., 2003; Almeida-Pedrin et al., 2007) did not report any information about appliance wear in terms of hours per day. The mean treatment duration in the pubertal studies ranged from one year (Martina et al., 2013) to two years (Singh et al., 2010) with the appliance being worn at least 14 hours per day (Martina et al., 2013) to full-time wear (Baccetti et al., 2000; Singh et al., 2010). Two pubertal studies (Faltin et al., 2003; Cui et al., 2010) did not report the mean appliance wear time. According to the authors' conclusions, no significant supplemen- tary mandibular growth produced by FJO was reported in three pre-pu- bertal studies (Faltin et al., 2003; Almeida-Pedrin et al., 2007; Singh et al., 2010), while three other pre-pubertal studies (Tulloch et al., 1997; Bac- Cetti et al., 2000; Perillo et al., 2013) reported a minimal effect. The last pre-pubertal study (Brunharo et al., 2011) and all pubertal studies (Bac- Cetti et al., 2000; Faltin et al., 2003; Cui et al., 2010; Malta et al., 2010; Singh et al., 2010; Martina et al., 2013) reported significant increases in total mandibular length. Five pre-pubertal studies (Tulloch et al., 1997; Baccetti et al., 2000; Faltin et al., 2003; Singh et al., 2010; Perillo et al., 2013) Concluded that treatment before puberty had zero or minimal skeletal effect on total mandibular length. On the contrary, all pubertal studies 273 Clinical Alteration of Mandibular Growth reported that optimal treatment timing for FJO was during or slightly after the pubertal growth spurt (Baccetti et al., 2000; Faltin et al., 2003; Cui et al., 2010; Malta et al., 2010; Singh et al., 2010; Martina et al., 2013). Finally, two pre-pubertal studies (Almeida-Pedrin et al., 2007; Brunharo et al., 2011) did not comment on treatment timing. The supplementary mandibular growth was retrieved from the distances condylion-gnathion in seven studies (Tulloch et al., 1997; Al- meida-Pedrin et al., 2007; Cui et al., 2010; Malta et al., 2010; Singh et al., 2010; Brunharo et al., 2011; Perillo et al., 2013) and condylion-pogonion in three studies (Faltin et al., 2003; Baccetti et al., 2005; Martina et al., 2013) with a radiographic enlargement of 8% generally in all the studies. Results of the meta-analysis are shown in Figure 2. In only two pre-pubertal studies (Baccetti et al., 2005; Brunharo et al., 2011), the mean value for supplementary mandibular growth and the corresponding 95% CI were slightly above zero. In the other four studies on pre-puberta subjects (Faltin et al., 2003; Almeida-Pedrin et al., 2007; Singh et al., 2010, Perillo et al., 2013), the mean supplementary mandibular growth was in favor of the treated subjects, although the values were not different significantly from zero. For the pre-pubertal studies, the overall effect was 1.29 mm (95% CI; 0.89-1.68 mm). In all pubertal studies (Baccetti et al., 2000; Faltin et al., 2003; Cui et al., 2010; Malta et al., 2010; Singh et al., 2010; Martina et al., 2013), the mean value for supplementary mandibular growth and the corresponding 95% CI were above zero. For these studies, the overal effect was 4.32 mm (95% CI; 3.65-5.00 mm) and was significantly greater than the overall effect of the pre-pubertal studies. The present meta-analysis focused on the mandibular effects in skeletal Class || Subjects produced by FJO according to the growth phase during which treatment was performed. Irrespective of the type of removable appliance used, relevant mandibular effects were observed only when treatment was performed at puberty. In spite of the huge number of clinical studies on skeletal effects induced by FJO in Class Il patients, only ten investigations met the inclusion criteria followed herein. This limited number was due mainly to the lack of clustering of subjects according to growth phase based on a reliable indicator. Moreover, several studies did not include a matched 274 Franchi et al. Tulloch et al., 1997 . | Bionator, 15 months (a) Baccetti et al., 2000 : —H H. Twin-Block, 14 months Faltin et al., 2003 —HH Bionator, 22 months Almeida-Pedrin et al., 2007 —HH- Bionator, 18 months Singh et al., 2010 —-H Twin-Block, 24 months Brunharo et al., 2011 |-HH- Twin-Block, 12 months Perillo et al., 2011 —HH FR-2, 12 months Perillo et al., 2013 —H- FR-2, 19 months Overall prepubertal Baccetti et al., 2000 Twin-Block, 17 months Faltin et al., 2003 Cui et al., 2010 Malta et al., 2010 Singh et al., 2010 Martina et al., 2013 Overall pubertal Bionator, 28 months Twin-Block, 30 months Bionator, 12 months Twin-Block, 24 months Sander BJA, 14.5 months I I I † –2 0 2 4 6 8 mm Figure 2. Forest plots for the supplementary mandibular growth (as mean dif- ference between treated and controls) in treated subjects as compared to un- treated controls according to treatment timing and along with corresponding treatment modalities. Mandibular length was recorded as condylion-gnathion or condylion-pogonion. Blocks = point estimates; lines = 95% confidence inter- Wals. Overall effects based on random models as mean (95% CI): pre-pubertal, 1.29 mm (0.89-1.68 mm); pubertal, 4.32 mm (3.65-5.00 mm); FR-2, function regulator 2; BJA = bite-jumping appliance; a = annualized changes. Control group of subjects with untreated Class || malocclusion or the Controls were comprised of Class I subjects. Finally, some studies did not evaluate the actual mandibular effects through the measure of total mandibular length. Although RCTs provide higher level of evidence as compared to CCTS, for ethical reasons most of the clinical studies on FJO at the pu- bertal growth phase have to be designed as CCTs with a retrospective control group of subjects. For this reason, the merging of RCTs and CCTs 275 Clinical Alteration of Mandibular Growth (prospective or retrospective), as in the present meta-analysis, is neces- sary when evaluating the FJO effects according to the growth phase. Fixed functional appliances were excluded in the present meta-analysis because of the differences in treatment modalities as compared to that provided by removable functional appliances, such as in patient compliance and in daily wear of the different appliances. Further, fixed functional appliances may be used alone (Pancherz, 1982) or in combination (Franchi et al., 2011) with full fixed appliances. Even when limiting the analysis to removable functional appliances, however, differences remain regarding treatment duration or modalities of mandibular advancement. Another potential source of heterogeneity among studies resides in the different methods used to assess total mandibular length, which was defined as the distance condylion-gnathion or condylion-pogonion (see the “Results” of this chapter). For these reasons, a robust random effect model (Ried, 2006) was used in the current meta-analysis to take into account differences among studies. Nevertheless, supplementary mandibular growth was similar among treatments performed within the same growth phase. In the present meta-analysis, the removable functional appliances most investigated were the Twin-Block and Bionator; only two studies focused on the FR-2 appliance of Fränkel (Perillo et al., 2013) and Sander bite jumping appliance (Martina et al., 2013), and treatments lasted generally from one to two years (Tables 2 and 3). When FJO is performed before puberty for the treatment of Class Il malocclusion, it can provide only about 1 mm of supplementary mandibular growth, irrespective of the different treatment modalities (Fig.2). Although this effect statistically was greater than zero (95%CI: 0.89-1.68 mm; Fig. 2), the clinical relevance of such effect would be negligible especially considering the method error encountered in linear cephalometric recording (Battagel, 1993). Furthermore, the authors of these studies (Tulloch et al., 1997; Baccetti et al., 2000; Faltin et al., 2003; Almeida-Pedrin et al., 2007; Singh et al., 2010; Brunharo et al., 2011) consistently reported clinically irrelevant skeletal, other than mandibular, effects produced by the treatment. On the contrary, in studies in which FJO was performed at the 276 Franchi et al. pubertal growth Spurt, Supplementary mandibular growth was greater than 4 mm (Fig. 2). However, when dealing with treatment effects at puberty, because of the heterogeneity among the studies, it was not possible to evaluate the relative efficiency of the different treatment modalities (i.e., type of removable functional appliance). The results reported herein apply to the effects produced by F]0 through removable appliances in the short term. Further meta- analyses are necessary to elucidate the mandibular effects produced by fixed functional appliances in Class subjects according to the growth phase. Moreover, the present meta-analysis has uncovered current limitation of published studies and the need for future investigations to take into account individual skeletal maturity with a reliable biological indicator and to use matched untreated Class II subjects as controls, even retrospectively. THE ROLE OF TREATMENT TIMING ON THE EFFECTIVENESS OF FJO IN THE LONG TERM Subjects and Methods In order to investigate the role of treatment timing on the effectiveness of FJO in the long term, the cephalometric records of 40 patients (22 females, 18 males) with Class Il division 1 malocclusion treated consecutively either with the Bionator or with an Activator were Collected from an orthodontic practice (Bionator) and from the records of the Department of Orthodontics of The University of Rome Tor Vergata (Activator). The non-extraction treatment protocols consisted either of a Bionator constructed without coverage of the lower incisors (Faltin et al., 2003; Malta et al., 2010) or of an acrylic monobloc attached to the upper arch by Adams clasps and with capping of the upper and lower incisors (Cozza et al., 2004). All Subjects underwent approximately one year offixed appliance therapy in the permanent dentition. In order to be included in the study, the patients had to present with lateral cephalograms available at three time periods: T1 = at the start of treatment; T2 = at the end of FJO; and T3 = at long-term observation after completion of growth (Baccetti et al., 2005) including the phase with fixed appliances. The T3 observations Were collected and analyzed regardless of the treatment outcomes in 277 Clinical Alteration of Mandibular Growth terms of correction of Class || malocclusion in the individual patients. The inclusion of all cases assisted in further reducing potential selection bias of the study. The treated sample was divided into two groups according to skeletal maturity at the start of treatment evaluated by means of the CVM method (Baccetti et al., 2005). The Early-Treated Group (ETG) was comprised of 20 subjects (twelve females, eight males) presenting with CS1 at T1. CVM stages at T2 were either CS1 or CS2. Therefore, the peak in growth velocity was not included in the period of treatment with functional appliances for any of the subjects in ETG. At T3, all subjects of the ETG presented with CS6. The Late-Treated Group (LTG) included 20 subjects (10 females and 10 males) presenting with CS3 at T1. Stages in CVM at T2 were either CS4 or CS5. Therefore, the peak in growth velocity was included in the period of treatment with functional appliances for all of the subjects in LTG. Stage in CVM at T3 was CS6 for all the subjects of the LTG. Mean ages of ETG at T1, T2 and T3 were 9.3 + 1.3 years, 11.4 + 1.5 years and 17.8 + 3.5 years, respectively, while the mean duration of T1-T2, T2-T3 and T1-T3 intervals were 2.1 + 1.0, 6.5 + 2.7 and 8.5 + 3.4 years, respectively. Mean ages of LTG at T1, T2 and T3 were 10.7 + 1.3 years, 12.8 + 1.9 years and 19.3 + 3.4 years, respectively, while the mean duration of T1-T2, T2-T3 and T1-T3 intervals were 2.1 + 1.3, 6.5 + 2.9 and 8.5 + 3.4 years, respectively. Lateral cephalograms for each patient at T1, T2 and T3 were digi- tized and a custom cephalometric analysis was used. Twenty variables (13 linear, 7 angular) were generated for each tracing. Lateral cephalo- grams of the treated groups at T1, T2 and T3 were standardized as to magnification factor (8%). Eleven subjects from the final samples (33 cephalograms) were selected at random. All films were retraced and redigitized. Intra-class correlation coefficients were calculated to compare within-subjects variability to between-subjects variability. Correlation coefficients for the dentoskeletal measures were greater than 0.95. Sample size for the treated groups was calculated considering a clinically significant difference of 3.0 mm in the maxillo-mandibular differential with a standard deviation of 2.9 mm, as derived from Malta 278 Franchi et al. and colleagues (2010), a power of 0.80 and alpha of 0.05. The calculated Sample size for the ANOVA test was 19 subjects in each group (SigmaStat 3.5, Systat Software, Point Richmond, CA). Descriptive statistics were calculated in ETG and LTG for all cepha- lometric measures at T1 (starting forms) and for the changes between T1, T2 and T3. All data were checked for normal distribution (Kolmogorov- Smirnov test) and for equality of variances (Levene test). Mann-Whitney Utest was applied to the comparisons between craniofacial starting forms in ETG versus LTG. Analysis of variance (ANOVA) followed by Tukey's post- hoc tests was performed to compare T1-T2, T2-T3 and T1-T3 changes in ETG versus LTG. All statistical computations were calculated with a statis- tical Software package (Statistical Package for the Social Sciences, SPSS, Version 16.0.1 Chicago, IL). Main Results and Interpretation There were no significant differences between ETG and LTG in the Starting forms with the only exception of molar relationship that was Significantly more distal by 1.2 mm in LTG. The comparisons between the ETG versus the LTG (Table 5) revealed that the chin was protruded more significantly in LTG both in the T1-T2 and T1-T3 intervals (Pg to Nasion perpendicular +4.5 mm and +3.9 mm, respectively). The total mandibular length showed significantly greater increases in the LTG versus ETG both in the short- (+5.5 mm) and long-term interval (+4.3 mm). The LTG showed a significant increase in the maxillo-mandibular differential during the T1-T2 interval (+3.1 mm). The mandibular ramus (Co-Go) was increased significantly in the LTG both in the T1-T2 and T1-T3 intervals (+4.8 mm and +3.1 mm, respectively). The Overjet exhibited significant decreases in LTG versus ETG during the T1-T2 interval (-2.4 mm). Distal molar relationship was improved significantly in the LTG both in the short- (+2.1 mm) and long-term (+1.9 mm). The aim of the present study was to assess the long-term dentoskeletal effects of Class Il treatment with functional appliances (Bionator or Activator) followed by fixed appliances at two different Stages of Skeletal maturation (pre-pubertal versus pubertal). The Study by Faltin and coworkers (2003) evaluated differences in the dentoskeletal response of patients treated before or during the peak in 279 Table 5. Descriptive statistics and statistical comparisons for the early vs. late treatment groups at the three observation intervals. ns = not significant; * p < 0.05; ** p < 0.01. EARLY TREATMENT GROUP LATE TREATMENT GROUP STATISTICAL COMPARISONS T1-T2 (E1) T2-T3 (E2) T1-T3 (E3) T1-T2 (L1) T2-T3 (L2) T1-T3 (L3) (ANOVA and Tukey's Cephalometric Skeletal sagittal measureS Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD º º º 3.3 -0.8 2.9 4.2 differential * & - e * 3.3 6.5 Skeletal vertical mandibular Dentoalveolar § Franchi et al. mandibular growth with the Bionator appliance followed by fixed appli- ances. The major limitation of their study was the small number of sub- jects that were included either in the ETG (13 subjects) or in the LTG (10 Subjects). Hansen and associates (1991) compared the long-term den- toskeletal changes induced by the Herbst appliance before, at and just after the peak height velocity. The limitations of the study by Hansen and Colleagues (1991) were that the authors analyzed the specific effects of Herbst treatment without an appraisal of comprehensive treatment of the malocclusion with fixed appliances; moreover, treatment duration with the Herbst appliance was too short (seven months of active treat- ment on average) to allow for the newly formed bone in the condyle and in the glenoid fossa, to mature into more stable bone (Chayanupatkul et al., 2003). Treatment of Class Il malocclusion with functional appliances during the pubertal peak is able to produce significantly greater increases in total mandibular length and ramus height associated with a significant advancement of the bony chin when compared with treatment before puberty. These favorable mandibular changes reached both a statistically and clinically significant level, in both the short- and long-term (about 3-5 mm). Treatment at puberty also is characterized by a greater correction of overjet and molar relationship with respect to treatment before pu- berty, in both the short- and long term (about 2.0–2.5 mm). The results of the current study confirmed that treatment with functional appliance that includes the peak in mandibular growth ap- pears to be more effective than treatment performed before the peak, as it induces more favorable mandibular skeletal modifications (Hägg and Pancherz, 1988; Petrovic et al., 1990; Hansen et al., 1991; Baccetti et al., 2000; Faltin et al., 2003). The present investigation showed that the favorable mandibular modifications induced by pubertal versus pre- pubertal treatment are stable in the long term. A fundamental aspect of the treatment effects produced by functional appliances in Class Il malocclusion is related to the evaluation of the possible improvements in facial esthetics following functional therapy. Patients with Class Il malocclusion treated at the puberty showed a significant advancement of bony chin when compared with patients treated before puberty. As a convex soft-tissue facial profile is the prominent feature in many Class Il malocclusions, one of the aims in 281 Clinical Alteration of Mandibular Growth dentofacial orthopedics is to improve facial appearance by reducing the profile convexity. In this respect, treatment of Class || malocclusion at the pubertal growth spurt appears to be more effective than treatment before puberty. FINAL REMARKS According to the results obtained in the meta-analysis, functional jaw orthopedics in skeletal Class Il patients has favorable effects on mandibular growth when treatment is performed during the pubertal growth phase. On the contrary, early treatment during the pre-pubertal growth phase would have only poor impact on mandibular growth. 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Am J Orthod Dentofacial Orthop 1997;111(4):391-400. 285 TREATMENT TIMING OF HERBST APPLIANCE THERAPY Hans Pancherz ABSTRACT The evidence on optimal treatment timing with the Herbst appliance is discussed by reviewing seven publications (Pancherz and Hägg, 1985; Pancherz, 1994; Kon- ik et al., 1997, Ruf and Pancherz, 1999, 2006; Bock et al., 2010; Bock and Ruf, 2012) that consider early and late therapy in relation to treatment outcome and long-term treatment stability. Consecutively treated Class II, division 1 Herbst pa- tients were analyzed using lateral head films and dental casts. All patients were treated either at The University of Malmö, Lund, Sweden or at The University of Giessen, Germany. The results of the studies revealed the following: 1. The level of somatic maturity at puberty influenced the out- come of Herbst therapy. Sagittal condylar growth changes dominated, on average, in the peak treatment growth period and sagittal incisor tooth movements in the post-peak period. 2. Early treatment in the mixed dentition was prone to relapse more than late treatment in the permanent dentition. 3. Overjet correction in adolescent Herbst patients comprised 27–39% skeletal and 61-73% dental changes. For compari- son, in adult Herbst patients, the skeletal changes were re- duced (21%) and the dental changes were increased (79%). 4. Class II/overjet correction in adult Herbst patients was most successful and showed good stability long term. In conclusion, the following can be said: 1) the ideal period for Herbst therapy is “late,” implying treatment in the permanent dentition after the peak height velocity of pubertal growth; 2) treatment in the mixed dentition is not rec- Ommended due to an increased risk of occlusal relapse; and 3) in young adults, Herbst treatment is most effective and stable and could be an alternative to Class | Surgery. KEY WORDS: Herbst appliance, treatment timing, relapse and stability, early and late treatment, adult treatment 287 Treatment Timing INTRODUCTION One of the most controversial issues in orthodontics and dentofacial orthopedics is that of treatment timing: shall we treat our patients “early” (mixed dentition/preadolescent growth period) or “late" (permanent dentition/adolescent or post-adolescent growth period) in order to get a better and more stable long-term result? In evidence-based orthodontics and dentofacial orthopedics, the Herbst appliance (Herbst, 1934) has been used since 1979 (Pancherz, 1979). After 1979, the appliance has grown to be one of the most popular functional appliances for the therapy of Class Il malocclusions. Considering treatment timing using the Herbst appliance, there exist only a small number of well-designed (prospective and retrospective) studies considering the issue of early or late therapy in relation to treatment outcome and long-term stability (Pancherz and Hägg, 1985; Hägg and Pancherz, 1988; Pancherz and Littmann, 1988; Hansen et al., 1991; Wieslander, 1993; Pancherz, 1994, 1997; Koniket al., 1997; Ruf and Pancherz, 1999, 2003, 2006; Pancherz and Ruf, 2000; Pancherz and Von Bremen, 2002; von Bremen and Pancherz, 2002; Bock et al., 2010; Bock and Ruf, 2012). In this paper, the evidence on optimal treatment timing with the Herbst appliance will be discussed by presenting seven of the publications noted above: 1. Pancherz and Hägg, 1985 . Pancherz, 1994 . Konik et al., 1997 . Ruf and Pancherz, 1999 . Ruf and Pancherz, 2006 . Bock et al., 2010 7. Bock and Ruf, 2012 : PUBLICATION 1: Dentofacial Orthopedics in Relation to Somatic Maturation: An Analysis of 70 Consecutive Cases Treated with the Herbst Appliance (Pancherz and Hägg, 1985) 288 Pancherz Sagittal mandibular Condylar growth changes and Sagittal incisor position changes were related to somatic maturation in 70 consecutive Cases of Class Il malocclusion (52 boys and 18 girls, aged 10 to 16 years) treated with a banded Herbst appliance for an average period of seven months. No post-treatment evaluation was performed. Twenty-three untreated Class || Subjects, all males aged 9–14 years, were used as a Control group. All patients were treated at the Orthodontic Department, University of Malmö (Lund, Sweden). Mouth-open profile roentgenograms (to visualize the condylar head) were analyzed. From all subjects, longitudinal growth' records of Standing height over a five- to ten-year period were available for the assessment of somatic maturation at the time of Herbst treatment. From the growth records, individual velocity curves of standing height were constructed. By visual inspection, the peak height velocity was identified on the growth curves and three growth periods were es- tablished: pre-peak, peak and post-peak (Fig. 1). The examination period in each subject was assigned to one of the three growth periods. The distribution of the Herbst and control subjects in relation to peak height Velocity is shown in Figure 2. Herbst treatment resulted in Class I dental arch relationships in all 70 patients investigated. Sagittal condylar growth was increased (skel- etal effect) and the mandibular incisors were moved anteriorly (dental anchorage loss). When the mandibular skeletal and dental changes were related to the Subjects’ somatic maturation, significant differences between the three growth periods existed in males (Fig. 3): 1. In the pre-peak period, Sagittal condylar growth and anterior incisor position changes were about equally large (Fig. 4). 2. In the peak period, Sagittal condylar growth was rela- tively more pronounced (Fig. 5). 3. In the post-peak period, anterior incisor position changes were relatively more extensive (Fig. 6). 289 Treatment Timing -1 0 +1 years Figure 1. Division of the velocity growth curve of standing height into three growth periods: peak (the period at peak height velocity + one year), pre-peak (the period before peak) and post- peak (the period after peak). Revised from Pancherz and Hägg, 1985. years -1 -3 -2 - 1 PHV + 1 +2 +3. +4 Prepeak Peak Postpeak 290 Pancherz Control Prepeak Prepeak Peak Postpeak TIT Figure 3. Average mandibular condylar and incisor changes in 52 male Herbst subjects and 23 untreated control subjects. Division of the Subjects into the three growth periods: pre-peak, peak and post-peak. * Figure 2. Distribution of 70 Herbst subjects and 23 control subjects in relation * Peak height velocity (PHV) of growth. Division of the subjects into the three Howth periods: pre-peak, peak and post-peak. The length of the examination *"od (–) in each subject is shown. Revised from Pancherz and Hägg, 1985. 291 Treatment Timing Before | | | Velocity 2. N º Prepeak treatment Figure 4. Herbst therapy of a patient treated in the pre-peak growth period. Dental casts, the velocity growth curve of standing height and the superimposed mandibular tracings are shown, depicting the amount of mandibular condylaſ and incisor changes. Revised from Pancherz and Hägg, 1985. Velocity Peak treatment \ - - Figure 5. Herbst therapy of a patient treated in the peak growth period. Dental casts, the velocity growth curve of standing height and the superimpº mandibular tracings are shown, depicting the amount of mandibular condylaſ and incisor changes. Revised from Pancherz and Hägg, 1985. 292 Pancherz Before Figure 6. Herbst therapy of a patient treated in the post-peak growth period. Dental casts, the velocity growth curve of standing height and the superimposed mandibular tracings are shown, depicting the amount of mandibular condylar and incisor changes. Revised from Pancherz and Hägg, 1985. A large individual variation existed, however, for the skeletal and dental changes in all three growth periods (Fig. 7). INTERPRETATIONS OF THE RESULTS (PUBLICATION 1) The level of somatic development influenced the outcome of Herbst therapy. Sagittal condylar growth changes dominated, on average, in the peak treatment period and tooth movements in the post-peak treatment period. These findings are in agreement with those from studies in monkeys fitted with mandibular protrusion splints or a Herbst appliance. In animals in the early growth period, the extent of Condylar 50wth was increased in relation to untreated controls (McNamara and Carlson, 1979; Peterson and McNamara, 2003). In animals in the late ºwth period, on the other hand, the potential of Condylar growth stimulation was reduced (McNamara et al., 1982) and the amount of °mpensatory tooth movements was increased (McNamara, 1975). In the Herbst subjects, the differences in the amount of con- dylar growth seen, when comparing the various maturity groups, ºuld be explained by the difference in the amount of basic condylar 293 Treatment Timing Prepeak Postpeak mm 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 mm Figure 7. Individual mandibular condylar and incisor changes in 52 males ( ) and 18 females (-------- ) treated with the Herbst appliance. The subjects were arranged in relation to the peak height velocity (PHV) of growth in the order given in Figure 2. Revised from Pancherz and Hägg, 1985. growth existing, which is larger in peak than in pre- and post-peak subject. (Hägg et al., 1987). Thus, the increase in sagittal condylar growth seeſ during Herbst treatment was a result of an equal addition of stimulated growth to basic condylar growth, irrespective of the maturation of the Subjects (Hägg et al., 1987; Fig. 8). 294 Pancherz Herbstmales (n=72) controllmales (n=23) 2.7 -3 –2 -1 Peak +1 +2 +3 years Figure 8. Mandibular growth (measured from pogonion to condylion) relative to the growth period in 72 male patients treated with the Herbst appliance for an average period of seven months. The darker areas represent the distribu- " of mandibular growth in 23 male control subjects. Revised from Hägg et al., 1987. The dental changes during Herbst treatment basically were * result of anchorage loss (Pancherz and Hansen, 1988; Weschler and Pancherz, 2005; Martin and Pancherz, 2009). In that it is thought that "euromuscular adaptation will occur less easily in older than in younger Subjects and general muscle strength increases with maturation, the forces exerted upon the dentition by the appliance will be larger in older than in younger Subjects. PUBLICATION 2. Early or Late Treatment with the Herbst Appliance: *ability or Relapse? (Pancherz, 1994) In order to find the optimal time of Herbst treatment with respect to post-treatment stability, the long-term effects of Herbst treatment "ºre assessed in Class II, division 1 subjects treated "early" and “late.” sing the hand-wrist radiographic stages of Hägg and Taranger (1980), early" treatment was defined by the stages MP3-E and F (= pre-peak $100th period) and “late” treatment by the stages MP3-H and (= post- Peak growth period; Fig. 9). 295 Treatment Timing Early" “Late" treatment treatment Figure 9. Hand radiograph and velocity growth curve of standing height. The six developmental stages of the middle phalanx of the third finger (MP3) are shown. Stages E and F represent "early” treatment (before the peak height of pubertal growth) and stages H and I represent “late” treatment (after the peak height of pubertal growth). Revised from Hägg and Taranger, 1980. From the original sample of 118 Class II, division 1 subjects treated with the Herbst appliance at the Department of Orthodontics University of Malmö (Lund, Sweden), those 31 “early” and 24 “late" treated subjects were selected in which a follow-up period of at least five years existed and no other treatment was performed after Herbs: therapy. Dental casts and lateral head films were analyzed from before treatment, six months after treatment, when the occlusion had settled and at follow-up, five to ten years post-treatment. Furthermore, a clinical examination of the function of the masticatory system was performed.” the time of follow-up. With respect to long-term stability or relapse of overjet and Sagº ittal molar relationship at the time of follow-up, the sample of 55 subjeº (31 “early” and 24 “late") was divided into three groups, separately for Overjet and molar relationship: 296 Pancherz 1. Stable • Overjet unchanged or reduced (n = 35) • Molar relation Class I (n = 38) 2. Insignificant relapse • Overjet increased 3 1.5 mm (n = 7) • Molar relation Class I or Class II tendency of less than % premolar width (n = 8) 3. Relapse • Overjet increased - 2 mm (n = 13) • Molar relation Class II of at least 4 premolar width A relapse of overjet and sagittal molar relationship was seen more often in “early” than in “late” treated subjects (Fig. 10). The overjet relapsed in 36% of the “early” and in 8% of the “late” cases. The sagittal molar relationship relapsed in 29% of the “early” and in none of the “late” Cases (Fig. 10). % 100 "Early" (n = 31) “Late" (n = 24) 80 60 - Relapse - Insign. Relapse 40 stable 20 Overjet Molar Relation Overjet Molar Relation Figure 10. Changes of overjet and sagittal molar relationship. Distribution of “early" and “late” treated Herbst subjects with respect to the long-term treatment result: stable, insignificant relapse and relapse. Revised from Pancherz, 1994. 297 Treatment Timing For the assessment of the possible causes of the relapse, the following relapse promoting factors were considered: • E: “early” treatment • H: persisting oral habits (tongue dysfunction, atypical Swallowing) • R: no post-treatment retention • M. mixed dentition treatment • O: occlusal instability post-treatment (insufficient cuspal interdigitation of the teeth) assessed on dental casts from six months post-treatment (after settling of the occlusion) by visual inspection and hand- articulating the models • G: unfavorable growth post-treatment (increase of the ANB angle and “Wits” appraisal) The comparison of all relapse cases with all stable cases revealed that every “relapse-promoting factor” was seen more often in the relapse than in the stable cases. This was true for both the overjet (Fig. 11) and the sagittal molar relationship (Fig. 12). The most frequent combination of factors was “early” treatment (E), habits (H), treatment in the mixed dentition (M) and occlusal instability (O). INTERPRETATIONS OF THE RESULTS (PUBLICATION 2) In several Herbst studies (Pancherz 1982, 1991; Pancherz and Hansen, 1986; Wieslander, 1993), the importance of a stable occlusion for the prevention of a dental and/or skeletal relapse has been stressed. If the maxillary and mandibular teeth are locked in a stable Class cuspal interdigitation, maxillary growth forces and tooth movements are transferred to the mandible or vice versa. Thus, maxillary and mandibular changes may interact as mutually regulating factors, meaning that a stable occlusion after Herbst or any orthodontic therapy could be of greater importance for a long-term stability than the growth period in which the patients are treated. 298 Pancherz % Overjet 100 80 - Relapse (n=13) - Stable (n=35) 60 40 20 0 E H R M O G Figure 11. Long-term effects of Herbst treatment on overjet. Distribution of relapse promoting factors in stable and relapse cases. E = early treatment; H = persisting oral habits; R = no post-treatment retention; M = mixed dentition treatment; O = occlusal instability; G = unfavorable growth post- treatment. Revised from Pancherz, 1994. º Molar retention - Relapse (n=9) 80 - Stable (n=35) 67 60 40 20 E H R M O G Figure 12. Long-term effects of Herbst treatment on sagittal molar relationship. Distribution of relapse promoting factors in stable and relapse *Ses, E = early treatment; H = persisting oral habits; R = no post-treatment ºtention; M = mixed dentition treatment; O = occlusal instability; G = unfavorable growth post-treatment. Revised from Pancherz, 1994. 299 Treatment Timing Early treatment (factor E) was the most frequently noted factor in the overjet and molar relapse cases. This does not mean, however, that early treatment was responsible for the relapse seen, per se. Instead, the reason for the post-treatment relapse most likely was the occlusal instability (factor O), in that treatment in most of the early cases coincided with treatment in the mixed dentition, which makes a stable cuspal interdigitation difficult. Thus, orthodontic treatment in the mixed dentition will endanger a stable treatment result (Wieslander, 1993). Mixed dentition treatment (factor M) and occlusal instability (factor 0) were seen in 67% and 55% of the molar relapse cases, respectively, and equally often (38%) in the overjet relapse cases. An occlusal instability was not diagnosed in any of the stable cases. In the same way, the consequences of persisting oral habits (factor H), seen in many relapse cases, but in none of the stable cases, could be interpreted. The oral habits prevent the teeth to occlude properly and, thus, will result in an occlusal instability. In summary, it can be said that treatment in the mixed dentition is more prone to relapse than treatment in the permanent dentition. PUBLICATION 3: The Mechanism of Class II Correction in Late Herbst Treatment (Konik et al., 1997) PUBLICATION 4: Dentoskeletal Effects and Facial Profile Changes in Young Adults Treated with the Herbst Appliance (Ruf and Pancherz, 1999) PUBLICATION 5: Herbst/Multi-bracket Appliance Treatment of Class II, Di- vision 1 Malocclusions in Early and Late Adulthood: A Prospective Cepha- lometric Study of Consecutively Treated Subjects (Ruf and Pancherz, 2006) In the study by Konikand colleagues (1997), the amount of skeletal and dental changes contributing to overjet correction) was scrutinized in late adolescent patients (Pancherz, 1982). In the study of Ruf and Pancherz (1999), the Class Il correction mechanism was ascertained in early adolescent subjects and in the study of Ruf and Pancherz (2006) in adult patients. 300 Pancherz Early and late adolescent and adult treatment was based on skeletal maturity as assessed on hand radiographs. The epiphyseal region of the MP3 and that of the radius (R) according to the method of Hägg and Taranger (1980) were analyzed. Early adolescent treatment Was defined by the stages MP3–E to -G, late adolescent treatment by the stages MP3-H and - and adult treatment by the stages R-IJ and -J. MP3–E to -G correspond to a time period from before to the maximum of pubertal growth, MP3-H and - to a period after the pubertal maximum of growth and R-IJ and -J to a period at the end of growth (Fig. 13). The subject material comprised of exclusively Class II, divi- Sion 1 malocclusions with a bilateral full Class II molar relationship: 25 patients (four females and 21 males) were treated during early Early Late Young |J J adolescents adolescents adults figure 13. Hand radiograph and velocity growth curve of standing height. The Six developmental stages of the MP3 and the two developmental stages of the distal epiphysis of the radius (R) at the end of growth are shown. The stages MP3–E to LG represent early adolescent treatment (before the peak to the peak height of pubertal growth). The stages MP3-H and - represent late adolescent treatment (after the peak height of pubertal growth). The stages R-II and -j represent young adult treatment (at the end of growth). Revised from Hägg and Taranger, 1980. 301 Treatment Timing adolescence (“early”), 21 patients (15 females and six males) were treated during late adolescence (“late") and 23 patients (19 females and four males) were treated during adulthood (“adult”). The different patient samples came from the Orthodontic Departments at The Universities of Malmö (Lund, Sweden) and Giessen, Germany. All patients were in the permanent dentition and treated during a period of seven months in the “early” group, of eight months in the “late” group and of nine months in the “adult” group. Furthermore, all patients were treated on a non-extraction basis to a Class I occlusion with a normal overjet and overbite. A cast splint Herbst appliance was used in the “early” and “adult” subjects and a banded Herbst appliance in the “late” subjects. The overjet was reduced with a statistically comparable amount in all three groups (“early” = 9.8 mm, “late” = 8.4 mm and “adult” = 10.0 mm; Fig. 14A-C). The skeletal mandibular changes contribution to overjet correction was largest in the “early” group (44%; Fig. 14A), less in the “late” group (28%; Fig. 14B) and smallest in the “adult" group (22%; Fig. 14C). The opposite was true for mandibular dental changes contributing to overjet correction: “early” group (27%), “late” group (42%) and “adult" group (45%). INTERPRETATIONS OF THE RESULTS (PUBLICATIONS 3-5) The patients in the three maturity groups were consecutively treated cases. Konik and associates' study (1997) was a retrospective study, while those of Ruf and Pancherz (1999, 2006) were of a prospective nature. There were more males than females in the “early” group while the opposite was true in the “late” and “adult” groups. These group/ gender differences, however, were not thought to influence the results to a significant degree. Concerning the different anchorage Systems used in treating the patients (banded Herbst in the “late” group and cast splint Herbst in the “early” and “adult” groups), they are not thought to be responsible for the difference in the position changes (proclination) of the mandibular incisors (Pancherz and Hansen, 1986; Weschler and Pancherz, 2005). 302 Pancherz Early adolescent treatment Late adolescent treatment (n=25) (n = 21) Overjet correction Overjet correction 3.4 mm. º - | Mandible 2.4 mm º Young adult treatment (n=23) Overjet correction Figure 14. The mechanism of 100 mm overjet correction (Pancherz, - 1982) in: A:25 early adolescent Herbst patients; B:21 late ado- escent Herbst patients; C:23 young adult Herbst patients. Mººſe Mandible ſºlº Lººſe C --- 2.2 mm ººm .5 mm. 2.2% - As mentioned earlier, mandibular incisor anchorage loss may be related to the age (maturity) of the patients at the time of treatment. The forces exerted on the lower teeth by the appliance will be larger in older than in younger subjects because chewing muscle strength increases With age (Pancherz, 1980). On the other hand, the mandibular skeletal Contribution to overjet correction was more pronounced in the younger than in the older subjects and most likely is a result of a larger underlying 50wthratein youngerthan in olderindividuals. The stimulated mandibular 50wth, on the other hand, is of the same magnitude irrespective of the treatment growth period (Hägg et al., 1987). To summarize the three studies, it was found that overjet *fection in early and late adolescent Herbst patients comprised of ſhore Skeletal than dental changes. In adult patients, the opposite was true: Overjet correction comprised of less skeletal than dental changes. "BLOATION 6: Occlusal Stability of Adult Class II, Division 1 Treatment With the Herbst. Appliance (Bock et al., 2010) 303 Treatment Timing PUBLICATION 7: Dentoskeletal Changes in Adult Class II, Division 1 Herbst Treatment: How Much is Left After the Retention Period (Bock and Ruf 2012) The aim of these two retrospective follow-up studies was to assess the stability of adult Herbst/multi-bracket appliance treatment. Dental casts (Bock et al., 2010) and lateral cephalograms (Bock and Ruf. 2012) were analyzed. The subject material comprised of adult Class II, division 1 maloc- clusions (26 subjects in the 2010 study and 15 subjects in the 2012 study) with a Class || molar relationship of more than or equal to a half cusp bilaterally or a full cusp unilaterally, an overjet of more or equal to 4 mm and no remaining growth pre-treatment. The patients had to be at least 18 years of age and had to present a hand-wrist radiographic stage of R- (complete fusion of the radial epiphysis and diaphysis; Hägg and Tarang- er, 1980). All patients were treated at the Orthodontic Department, Uni- versity of Giessen (Giessen, Germany) using a cast splint Herbst appli- ance followed by a multi-bracket appliance. Retention after treatment was performed with removable appliances in combination with a lower (sometimes also an upper) canine-to-canine retainer. Dental casts (Bock et al., 2010) and lateral head films (Bock and Ruf, 2012) were analyzed before treatment, after treatment and after at least 24 months of retention. At the end of the retention period, the molar relationships were stable in 77.6% and canine relationships in 71.2% of the teeth. True relapses were found in 8.2% (molar relationships) and 1.9% (canine relationships) of the teeth. Overjet was stable in 92.3% and overbite in 96.0% of the patients; true relapses did not occur (Fig. 15). The cephalometric evaluation using the SO-analysis of Pancher. (1982) revealed that overjet correction (6.2 mm) during treatment was accomplished by both skeletal (1.1 mm) and dental (5.1 mm) changes (Fig. 16). There was a minor relapse after treatment (Fig. 16). Looking at the total observation period, the overjet correction comprised of 12% skeletal and 88% dental changes (Fig. 16). 304 Pancherz % 100 80 60 Relapse Insignificant 40 | relapse - stable 20 | 0 Molar. Canine Overjet Overbite relationships relationships Figure 15. Prevalence (%) of stability/relapse for molar relationships (left and ſight side pooled), canine relationships (left and right side pooled), overjet and overbite during the post-treatment period of an average of 32 months. An analysis of 26 adult (21.1 years of age) Class II, division 1 malocclusions treated " the Herbst/multi-bracket appliance for 23.4 months. Revised from Bocket al., 2010. Overjet correction T2-T1: * 6.2 mm T3-T2: - 1.0 mm T3-T1: 4-5.2 mm (100%) Skeletal Dental T2-T1: … 1.4 mm T2-Tº: * 5.4 mm T3-T2. - 0.5 mm T3-T2. - 0.5 mm. T3-T1: * 0.6 mm (+ 1.2%) - T3-T1: * 4.6 mm (+ 88%) figure 16. The mechanism of overjet correction (Pancherz, 1982) in 15 adult (25.6 years of age) Class II, division 1 malocclusions treated with the Herbst/ multi-bracket appliance. T2-T1 = treatment period of 22.9 months; T3-T2 = Pºst-treatment period of 35.5 months; T3–T1 = total observation period of 58.4 "onths. Plus indicates favorable and minus unfavorable changes for overjet °ſſection. Revised from Bock and Ruf, 2012. 305 Treatment Timing INTERPRETATIONS OF THE RESULTS (PUBLICATIONS 6-7) Although the two studies were of a retrospective nature, the treatment protocol was identical in all patients. During the Herbst/multi- bracket appliance therapy, all adult Class II, division 1 subjects were treated successfully to a Class I dental arch relationship. Class Il correction was a result of both skeletal and dental changes. However, the amount of skeletal changes contributing to overjet correction markedly was smaller in the adults when compared to the adolescents (Konik et al., 1997; Ruf and Pancherz, 1999). During the period after active treatment, the occlusion settled. Minor and clinical irrelevant changes were seen for skeletal and dental variables. Therefore, the stability of adult Class II, division 1 Herbst treatment can be considered good. However, it must be remembered that all patients had retainers over the total follow-up period, which could have influenced the stability of overjet by preventing a proclination of the upper and a retroclination of the lower incisors. To summarize the two studies, it can be said that Class || molar and overjet correction in adult Herbst multi-bracket appliance treatment was most successful and resulted mainly from dental changes that, however, showed good stability after active treatment. CLINICAL EXAMPLES The cases of six Herbst patients will be presented to demonstrate the disadvantage of an “early” and the advantage of a “late” treatment approach. Two subjects were treated in the early (Case 1; Fig. 17) and late (Case 2; Fig. 18) mixed dentition, respectively. Both cases relapsed. The patients were retreated with the Herbst appliance in the permanent dentition and remained stable long-term after treatment. The next two patients were treated in the permanent dentition, at or after the pubertal peak of growth (Cases 3 and 4; Figs. 19 and 20). Both cases remained stable long term after therapy. The last two patients were treated successfully in adulthood (Cases 5 and 6; Figs. 21 and 22) and remained stable long term after treatment. 306 Pancherz Figure 1 mixed dentition. Due to relapse, re-treatment was performed in the permanent dentition at the age of 13 years. A. Before the first period of Herbst treatment. B. At the start of treatment. An acrylic splint Herbst appliance was used. C. After six months of treatment. Note the sagittal overcorrection and the lateral open bite, D: Retention with an activator for one year to facilitate tooth eruption and settling the occlusion. E. After retention. Note the Class occlusion, but without a solid interdigitation of the deciduous teeth. F. Four years after retention. Note the Class || relapse, G: Start of the second period of Herbst treatment. A banded Herbst appliance was used. H. Six months after treatment when the occlusion had settled in Class I. Note the solid interdigitation of the permanent teeth. I; Four and a half years post-treatment at the age of 19 years. Note the stable long-term result. The first time Herbst treatment was performed on this girl was ºf eight years of age. At that time, she was in the early mixed dentition tage and in the pre-peak growth period (MP3-E skeletal maturity stage). Therapy was performed with an acrylic splint Herbst appliance that was Worn for six months. Treatment resulted in Class dental arch relation- ships. However, the patient was in the mixed dentition and the lateral teeth were not in occlusion. Therefore, retention with an activator was Performed for nine months in order to promote settling of the occlusion. However, following both Herbst and activator therapy, no stable cus- Painterdigitation of the teeth was present, as the girl remained in the 307 Treatment Timing - - - - Figure 18. Case 2. Herbst appliance treatment of an 11.5-year-old boy in the late mixed dentition. Due to relapse, retreatment was performed in the permanent dentition at the age of 13.5 years. A. Before the first period of Herbst treatment B: At the start of treatment, a banded Herbst appliance was used. C. After Sº months of treatment. Note the incomplete cuspal interdigitation of the teeth, as the primary second lower molar was still in place. D: Six months after treatment Note the Class II relapse of 4 premolar cusp width, as the patient did not usehº retention-activator. E. One year after treatment, before retreatment. F. Start of the second period of Herbst treatment. Again, a banded Herbst appliance W* used. G. After seven months of treatment. Retention for one year with an UP per Hawley plate. H: At the end of retention, one year after treatment. Note the solid Class occlusion. I. Five years post-treatment at the age of 19 years. Notº the stable long-term result. mixed dentition stage. At the age of 13 years, a complete Class || relapse had occurred, and the patient was treated for a second time, again with a banded Herbst appliance. She now was in the permanent dentition stage and in the peak growth period (MP3–G skeletal maturity stage). After post-treatment retention with an activator for six months, the teeth occluded in a stable Class relationship. At the follow"P examination, 4.5 years post-treatment (at 19 years of age), the result remained stable. 308 Pancherz Figure 19. Case 3. Herbst appliance treatment of a 12.5-year-old girl in the Permanent dentition. By treatment a solid Class I cuspal interdigitation was accomplished that remained unchanged long-term. A. Before Herbst treatment. B. At the start of treatment. A banded Herbst appliance was used. C. After three months of treatment. D. After nine months of treatment. E. After Herbst treatment. Note the sagittal Class overcorrection and the unstable cuspal Interdigitation of the teeth. F. Thirteen days after Herbst treatment. Note settling of the teeth in Class I occlusion. G. Six months after Herbst treatment. Note the Solid Class occlusion. H. Three years after Herbst treatment. 1: Six years post- treatment at the age of 19 years. Note the stable long-term result. The first time Herbst treatment was performed on this boy, he Was 11.5 years of age. At that time, he was in the late mixed dentition stage and in the pre-peak growth period (MP3-E skeletal maturity stage). Treatment was undertaken with a banded Herbst appliance that was Worn for six months. Treatment resulted in Class dental arch relation- ships, but with an unstable cuspal interdigitation of the buccal teeth (the Primary lower second molars still were present). The patient was given *" activator for retention, but the appliance was not used. At six months Pºst-treatment, a partial Class || relapse was obvious. The boy was re- treated with a banded Herbst appliance one year post-treatment at the 309 Treatment Timing Figure 20. Case 4. Herbst treatment of a 16-year-old male in the permanent dentition. A solid Class cuspa interdigitation accomplished by treatment remained unchanged long-term. A. Before Herbst treatment. B. At the start of treatment. A banded Herbst appliance was used. C. After Herbst treatment Note the Sagittal Class overcorrection and the unstable cuspal interdigitation of the teeth. D: Six months after Herbst treatment. Note the solid Class occlusion. E: One year after Herbst treatment. F. Five years post-treatment at the age of 21 years. Note the stable long-term result. age of 13.5 years (MP3-F skeletal maturity stage), when all permanent teeth were erupted fully. Treatment lasted for seven months. Post- treatment, the teeth were in a Class occlusion, but with an unstable cuspa interdigitation of the lateral teeth. After retention with an uppº Hawley plate, one-year post-treatment settling of the occlusion and 3 stable Class occlusion was attained. At the follow-up examination, five years post-treatment (at 19 years of age), the occlusion remained Class | 310 Pancherz Figure 21. Case 5. Herbst/multi-bracket appliance treatment of an 18-year-old female. A solid Class cuspa interdigitation accomplished by treatment remained unchanged long-term. A. Before Herbst treatment. B. At the start of treatment. A Cast Splint Herbst appliance was used. C. After four months of treatment. D: After seven months of treatment. Note the sagittal Class overcorrection and the lateral open bite. E. After one month of multi-bracket appliance treatment after Herbst therapy. F. After Herbst/multi-bracket appliance treatment. G: Activator-retention for two years. H. Two years after Herbst/multi-bracket appliance treatment (end of retention). I. Four years post-treatment at the age of 24 years. Note the stable long-term result. Herbst treatment on this girl was performed at 12.5 years of age. At that time, she was in the permanent dentition and post-peak growth Period (MP3-H skeletal maturity stage). Treatment was carried out with a banded Herbst appliance and lasted for nine months. Treatment resulted !" Overcorrected Class I dental arch relationships, but with an unstable *USpal interdigitation of the lateral teeth. For retention, the patient was given an activator for two years. Already 13 days after Herbst treatment, the occlusion had settled in a stable class idental arch relationship. At the follow-up examination, six years post-treatment (at 19 years of age), the Occlusion remained stable in Class I. Herbst treatment on this male was performed at 16 years of age. At that time, he was in the permanent dentition and in the peak growth 3.11 Treatment Timing Figure 22. Case 6. Herbst/multi-bracket appliance treatment of a 28-year old female. A solid Class | cuspal interdigitation accomplished by treatment remained unchanged long-term. A. Before Herbst treatment. Note the missing premolars. B: At the start of treatment. A cast splint Herbst appliance was used. C. After four months of treatment. D. After 13 months of treatment. Note the lateral open bite due to extreme intrusion of the maxillary lateral segment (high-pull headgear effect of the Herbst appliance). E. Start of multi-bracket appliance treatment after Herbst therapy. F: Four months of multi-bracket appliance treatment. G. After Herbst/multi-bracket appliance treatment Activator retention for one year was performed. H. One year after Herbst/multi- bracket appliance treatment (end of retention). I: Three years post-treatment at the age of 33.5 years. Note the stable long-term result. period (MP3-FG skeletal maturity stage). Treatment was done with a banded Herbst appliance and lasted for 5.5 months. Treatment resulted in Class Idental arch relationships, but with an unstable cuspal interdigitation of the lateral teeth. No retention was performed after treatment. At 3% months after Herbst treatment, the occlusion had settled in a stable Class | dental arch relationship. At the follow-up examination five years post- treatment (at 21 years of age), the occlusion remained stable in Class |. Herbst/multi-bracket appliance treatment in this young adult female was performed at 18 years of age. At that time, the growth . considered finished (R-J skeletal maturity stage). Treatment comprlºº 312 Pancherz a cast splint Herbst appliance for seven months followed by a multi- bracket appliance for five months. Treatment resulted in Class I dental arch relationships with a stable cuspal interdigitation of the teeth. For retention, the patient had an activator for two years. At two years post- treatment (after activator retention), the occlusion had settled in a stable Class I dental arch relationship. At the follow-up examination four years after Herbst/multi-bracket appliance therapy (at 24 years of age), the occlusion remained stable in Class I. Herbst/multi-bracket appliance treatment in this adult female Was performed at 28 years of age. At that time, the growth was finished (R-J skeletal maturity stage). She previously had been treated unsuccessfully for nine years. She had a traumatic loss of one maxillary Central incisor and three premolars were extracted. Herbst treatment Was undertaken using a cast splint Herbst appliance for 13 months and followed by a multi-bracket appliance for 16 months. The Herbst phase of therapy resulted in Class I dental arch relationships, but with a lateral Open bite due mainly to an extreme high-pull headgear effect causing an intrusion of the maxillary lateral segments from the canines to the first molars. During the following multi-bracket appliance phase, the dental arches were aligned in the vertical and sagittal plane, the lateral open bite Was closed and the occlusion was stabilized in Class I. For retention, the patient had an activator for two years and a mandibular bonded canine- to-canine retainer for three years. At the follow-up examination, three years after Herbst/multi-bracket appliance therapy (at 33.5 years of age), the occlusion remained stable in Class 1. CONCLUSIONS AND CLINICAL IMPLICATIONS When looking for the best period for Herbst appliance treatment, both dental development and somatic maturation should be taken into Consideration. • The ideal time for Herbst treatment is in the perma- nent dentition after the peak height velocity of puber- tal growth (post-peak growth period). • This “late” treatment approach will promote occlus- al stability after treatment (all permanent teeth are 313 Treatment Timing erupted and a stable cuspal interdigitation is possi- ble) and reduce retention time (the remaining growth period, which could affect the long-term outcome of therapy negatively, is reduced). • An “early” treatment approach in the mixed dentition is not recommended. The risk of occlusal relapse in- creases as a stable cuspal interdigitation of primary teeth and erupting permanent teeth is difficult to at- tain and retention time, thus, must be prolonged. • The Herbst appliance is most effective in non-growing young adults (18–30 years of age). However, in Com- parison to treatment during growth, Class Il correc- tion in adults is achieved by relatively larger dental (80%) and smaller skeletal changes (20%). • In young adult Class || malocclusion cases, the Herbst appliance could be an alternative to orthognathic Surgery. REFERENCES Bock NC, Ruf S. Dentoskeletal changes in adult Class Il division 1 Herbst treatment: How much is left after the retention period? Eur J Orthod 2012;34:747-753. Bock NC, von Bremen J, Ruf S. Occlusal stability of adult Class || Division 1 treatment with the Herbst appliance. Am J Orthod Dentofacial Orthop 2010;138:146-151. Hägg U, Pancherz H. 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Mandibular anchorage in Herbst treatment. Eur J Orthod 1988;10:149-164. 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. Somatisch Reife und morphologische Veránde- rungen des Unterkiefers bei der Herbst-Behandlung. [In German] In- form Orthod Kieferorthop 1988;20:455-470. Pancherz H, Ruf S. The Herbst appliance: Research based updated clinical possibilities. World J Orthod 2000;1:17–31. Pancherz H, von Bremen J. Efficiency of Class II, Division 1 therapy in rela- tion to treatment timing and modality. In: Treatment Timing: Ortho- dontics in Four Dimensions. McNamara JA Jr, Kelly KA, eds. Monograph 39, Craniofacial Growth Series, Department of Orthodontics and Pedi- atric Dentistry and Center of Human Growth and Development, The University of Michigan, Ann Arbor, 2002;25-54. Peterson JE, McNamara JA Jr. Temporomandibular joint adaptations as- sociated with Herbst appliance treatment in juvenile rhesus monkey (Macaca mulatta). Semin Orthod 2003;9:12-25. RufS, Pancherz H. Dentoskeletal effects and facial profile changes in young adults treated with the Herbst appliance. Angle Orthod 1999;69:239- 246. Ruf S, Pancherz H. Herbst/multibracket appliance treatment of Class || 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. When is the ideal period for Herbst therapy: Early or late? Semin Orthod 2003;9:47-56. 316 Pancherz Von Bremen J, Pancherz H. Efficiency of early and late Class || Division 1 treatment. Am J Orthod Dentofacial Orthop 2002;121:31-37. Weschler D, Pancherz H. Efficiency of three mandibular anchorage forms in Herbst treatment: A cephalometric investigation. Angle Orthod 2005;75:23-27. Wieslander L. Long-term effect of treatment with the headgear-Herbst appliance in the early mixed dentition: Stability or relapse? Am J Orthod Dentofacial Orthop 1993;104:319-329. 317 CONTEMPORARY MANAGEMENT OF CRANIOFACIAL ANOMALIES: WILL PAST EXPERIENCES INFLUENCE AND PREDICT THE FUTUREP Katherine W.L. Vig and Ana M. Mercado ABSTRACT This chapter will include a retrospective of previously accepted treatment inter- wentions for the management of craniofacial anomalies and relate them to our Contemporary understanding from the results and conduct of clinical trials in a digital age embraced by telemedicine. Technological advances have influenced diagnostic and treatment methods and the measurement of outcome variables. While clinicians traditionally define their criteria of success on morphological Outcome measures, patients and their parents are more interested in outcomes that reflect their quality of life. The way we evaluate the outcome of clinical in- terventions has moved the field of scientific inquiry in orthodontics from con- Vincing rhetoric to an evidence-based era in the 21st century. The emphasis on evaluating treatment outcomes from the patient's/parent's perspective has re- Sulted in qualitative outcome measures and the development of a field of inquiry embraced by the clinical evaluative sciences. Well-designed randomized clinical trials have provided a high level of evidence to quantitate the outcomes from alternative interventions with estimated probabilities of their risks, costs and benefits. With this wealth of information available, the clinician is required to translate these data into best clinical practices and to inform patients with their treatment options. KEY WORDS: craniofacial anomalies, quality of life, inter-center studies, distraction Osteogenesis, telehealth 319 Craniofacial Anomalies During the past half century, the orthodontic specialty has been influenced by technological advancements and the impact of craniofacial biology in an age of molecular biology and genetic revelations. The impact of science and technology has influenced clinical practice with the development of the clinical evaluative sciences, the prerogative of evidence-based education and the metrics of clinical trials with valid and reliable outcome measures to evaluate alternative treatment interventions. The 1987 Moyers Symposium, entitled Craniofacial Morpho- genesis and Dysmorphogenesis, occurred at a critical time in craniofa- cial biology when the rationale for clinical interventions was derived and extrapolated from animal models. Brodie's genomic paradigm (1941a,b) prevailed, which accepted the immutability of an individual's growth pat- tern established at three months after birth. This concept now was chal- lenged with a paradigm shift to the functional matrix hypothesis (MoSS, 1962) where an individual's genetic blueprint was considered to be influ- enced and modified by environmental factors as the new and widely ac- cepted epigenetic paradigm (Moss, 1981). The rationale for the biologi- cal response is explained by the spectrum of normal biological variation whereas individuals with craniofacial anomalies also have a pathogenesis superimposed on normal biological variation and reflected in a genetic diagnosis of syndromic or non-syndromic. The possibility to modify and redirect craniofacial growth, with an emphasis on stimulating growth of the mandible in skeletal Class || malocclusions, resulted in a resurgence of functional appliances in clinical practice. These appliances had been used extensively with purported success in Europe with the construction of different types of functional appliances and the emergence of the hybrid appliance (Vig and Vig, 1986) in treating asymmetric craniofacial dysmorphology typical of hemifacial microSomia. This chapter will discuss clinical concepts applied to craniofacial dysmorphology with reference to syndromic and non-syndromic cleft lip and/or palate (CL/P) and other craniofacial anomalies (Dixon et al., 2011). Some of the cases illustrated in the Moyers symposium chapter (Vig, 1988) will be compared to the contemporary management of a similar clinical condition. 320 Vig and Mercado Technology advancements and the introduction of an evidence- based approach to quantify clinical interventions has resulted in the Sophisticated methodology of clinical decision analysis and prior probability estimates of the outcomes of alternative interventions. The patient's perspective has become central to informed consent in the 21st century and patients participate in the choice of their alternative treatment options. Additionally, considerable advances have been made in assessing the Health-Related Ouality of Life (HROol) of individuals with Orofacial clefts and other craniofacial anomalies. Oral Health-Related Ouality of Life (OHOOL) studies in children With orofacial clefts have reported significant psychological and social burdens. The adjustment of children with orofacial clefts to facial esthetic Scars and compromised speech and hearing disabilities requires the child to develop additional social skills, which is challenging. In a study by Ward and Coworkers (2013), the impact of orofacial clefts on the quality of life was aSSessed for children and adolescents in different age groups, taking into Consideration whether the caregivers' perception of their children's OHOOL differed from their children's perception of themselves. A control group matched for age, but with no orofacial clefts were enrolled as subjects for Comparison. A valid and reliable questionnaire previously had been developed by Broder and Wilson-Genderson (2007) and the self-reported 38-item Child Oral Health Impact Profile (COHIP) was completed by the Subjects and their caregivers. The results reported a significant impact of an orofacial cleft on the OHOOL in children and their caregivers. Functional Well-being and social-emotional well being also decreased the OHOOL in children and adolescents with orofacial clefts, which was greater in 15- to 18-year-olds than the younger children. Interestingly, the children with Orofacial clefts and their caregivers had similar assessments of the child's OHOOL. These studies from the perspective of the child, adolescent and Caregiver provide much needed information from the patient's perspective and their participation in the choice of alternative treatment options. TEAM MANAGEMENT OF CRANIOFACIAL ANOMALIES: AN INTERDISCIPLINARY APPROACH The team approach was established in the 1940s to treat patients With CL/P in the interdisciplinary context of timing and sequencing of 321 Craniofacial Anomalies treatment. In 1943, the American Cleft Palate Association (ACPA) was established to provide a national forum for disseminating information to teams and as an advocate for patients and parents. By the 1970s, craniofacial teams were established in tertiary centers for the treatment of craniosynostosis and other syndromic patients. From 1960-1980, the orthodontist's alliance with craniofacial biology flourished as animal models simulated clinical interventions and was extrapolated to support clinical practices. The complexity of craniofacial anomalies have included an increasing number of specialists in the 21st century, which has emphasized a more comprehensive team approach for infants born with birth defects (Fig. 1). The ACPA developed a seminal document from an interdisciplinary symposium on “Parameters for Evaluation and Treatment of Patients with Cleft Lip/Palate or other Craniofacial Anomalies;” an updated revision (2009) of which stipulates, “the management of patients with craniofacial anomalies is best provided by an interdisciplinary team of specialists.” In the team approach, the orthodontist collaborates with the other members of the team and treatment is sequenced in the context of other healthcare needs, to provide a comprehensive and prioritized interdisciplinary treatment plan. In the United States, cleft palate care typically is delivered by hospital- or university-based teams or, to a lesser degree, in inde- pendent clinics where multi-disciplinary evaluations and treatment are coordinated. In an effort to improve team care, the ACPA has put forth the document “Standards for Cleft Palate and Craniofacial Teams" that identifies the essential characteristics of quality for team composition and functioning (http://www.acpa-cpf.org/team_care/standards/). Those teams that meet specified standards, as judged by the ACPA Commission on Approval of Teams, are identified and information about their services is provided to patients and families. The Cleft Palate Foundation maintains a list of approved cleft palate-craniofacial teams in the U.S. and around the world (http://www.cleftline.org/parents- individuals/team-care/), Serving as an advocate for children born with craniofacial anomalies and their parents. 322 Vig and Mercado TEAM COORDINATOR CLINICAL DATABASE Research Assistant DENTISTRY SURGERY Orthodontics Plastic Surgery Pediatric Dentistry Neurosurgery ProsthodonticS Oral Maxillofacial Surgery ENT AUDIOLOGY TEAM NURSING APPROACH TO PATIENTS WITH OBSTETRICS GENETICS Perinatologist CRANIOFACIAL Syndromologist Sonologist ANOM ALIES Dysmorphologist SPEECH 8, SOCIAL LANGUAGE SUPPORT PATHOLOGY & SERVICE PEDIATRICS OPHTHALMOLOGY PSYCHOLOGY Figure 1. Components of a cleft palate craniofacial team. In various developing countries of the world, there are no cleft craniofacial teams due to severe shortages in healthcare resources. The access to basic care for indigenous individuals affected with clefts is minimal to non-existent and primary repair of the lip and/or palate often depends on sporadic mission visits from humanitarian surgical teams. The ACPA has outlined standards for international care that are aimed toward assuring that international exchanges or mission-based Cleft lip, cleft palate and craniofacial care are delivered in a safe and high quality manner (http://www.acpa-cpf.org/team_care/position_paper/). Despite the success of the surgical teams in repairing cleft defects in un- derserved countries, several other important aspects of cleft care typical- ly are not addressed in those remote regions. Post-operative follow-up, Speech therapy, audiologic exams, dental care and orthodontic evalua- tions are some of the needs that prevail beyond primary cleft surgery. The advent of the Internet and wireless data exchanges offers oppor- tunities for worldwide connectivity between geographically-separated 323 Craniofacial Anomalies healthcare providers and patients. This technology has opened new hori- zons for international health collaborations in the emerging field of tele- health. TELEHEALTH IN CLEFT PALATE TEAM MANAGEMENT Telehealth is a term that describes the use of technology to facili- tate interactions between healthcare professionals and patients who are separated by geographical distances (Glassman et al., 2012). The model was developed for medical diagnosis and treatment (telemedicine), but the applications have expanded into vision screening, dermatology, men- tal health and telepharmacy, among others. For electronic exchanges, the minimal requirements consist of telecommunication equipment that includes audio and video capabili- ties. In remote regions of developing countries where local access to cleft palate care is limited, telehealth applications help bridge the post-surgi- cal services that patients usually encounter. The field of speech and lan- guage pathology has taken the lead in implementing telehealth practices for evaluation, diagnosis and treatment of patients with clefts. Real-time face-to-face communication for speech therapy requires at least the ac- cess to an Internet-capable personal computer, integrated video camera and microphone, and Internet web-browsing software for both sound and video conferencing (Furr et al., 2011). Patients with clefts in Nicaragua (Glazer et al., 2011) and Perú (Furr et al., 2011) have benefited from the teleconference speech therapy sessions by demonstrating improvements in voice quality and Speech intelligibility. This success is promising as other healthcare disciplines would explore ways to deliver their care to remote regions with underserved cleft populations. Teledentistry has evolved substantially within the U.S. under the lead of several states such as California, Minnesota and Arizona (Fricton and Chen, 2009; Summerfelt et al., 2011; Glassman et al., 2012). Teledentistry currently is being used to provide preventive and diagnostic care of periodontal disease, consultations on temporo- mandibular disorders, orofacial pain and oral maxillofacial pathology (Fricton et al., 2009). These capabilities also could be extrapolated to the examination of children with clefts in remote regions, with intra- oral video or still-digital cameras capturing the dentition, gingival and 324 Vig and Mercado mucosal tissues and then transmitting the images via Internet connection to pediatric dentists for consultation. Another potential field of telehealth exchange in cleft evaluation and management is orthodontics. Studies in the United Kingdom have shown that teleorthodontics is a valid system for accurate diagnoses of malocclusions and positively identifying patients who could benefit from an orthodontic referral (Mandall et al., 2005). In a study of teleorthodontics from The University of Washington (Seattle), Berndt and associates (2008) found that interceptive Orthodontic treatment provided by trained general dentists under remote supervision by orthodontic specialists reduced the severity of malocclusions in children living in underserved regions. These studies give hope to orthodontists in industrialized countries for a future ability to diagnose developing malocclusions remotely and even supervise interceptive treatment of existing malocclusions in children with clefts in developing Countries. Cleft lip and/or palate is the most commonly occurring craniofacial anomaly with an incidence of 1/700 live births in the U.S. The orofacial cleft may be syndromic or non-syndromic. The orthodontist's role in the team management has been divided conveniently into four major time frames and described in textbooks (Vig and Mercado, 2005; Mercado and Wig, 2009). PRENATAL DIAGNOSIS OF OROFACIAL CLEFTS Technological advances have influenced the development of Sophisticated methods of prenatal diagnosis and sonography. The identification of birth defects during fetal development by amniocentesis and ultrasound allows prenatal counseling of parents before the birth. The human genome project that was completed in 2003 has had a Significant impact in the 21st century with proteomics, pharmogenomics and pharmogenetic advances in the current genomic era. These technical advances now are available to clinical syndromologists and dysmorphologists. Although the orthodontist's role is primarily in post-natal care, it is important to know that the diagnosis of an orofacial cleft may be made during prenatal ultrasound examination. With routine transabdominal ul- traSonography, approximately 20% of clefts may be diagnosed correctly 325 Craniofacial Anomalies in utero (Johnson and Sandy, 2003). Three-dimensional (3D) ultrasonog- raphy allows for higher sensitivity in detection due to the generation of lifelike surface rendered images (Ramos et al., 2008). In utero magnetic resonance imaging (MRI) allows precise evaluation not only of the primary palate, but also the secondary palate and, thus, gives better detection ability than routine ultrasound alone (Mailáth-Pokorny et al., 2010). Prenatal diagnosis of a cleft prompts the clinical geneticist to evaluate further and determine whether the defect is non-syndromic or part of over 300 syndromes associated with clefting. The earlier diagnosis and recognition of family members with microforms of the syndrome provides them with prior probability estimates for transmitting the trait to their offspring (Fig.2). This determination has consequences regarding how the patient will be managed and what outcomes can be expected from treatment. With prenatal diagnosis of an orofacial cleft, parents can receive Support and education while preparing for the birth of their child. Identified families are encouraged to schedule a visit at their local cleft craniofacial team to meet with its prenatal support staff, usually composed of a nurse practitioner, feeding specialist, geneticist, social worker, psychologist and the plastic/craniofacial surgeon. A pediatric dentist/orthodontist can discuss with parents the dental and skeletal manifestations associated with clefts and the recommended dental care required at each stage of development. In some instances, prenatal diagnosis of clefts is not possible due to lack of access to ultrasonography technology, lack of expertise of the sonographer in detecting clefts or inability of detection due to unfavorable position of the fetus (Johnson and Sandy, 2003). Parents who have no prenatal knowledge of their baby's defect will be in great need of support from the interdisciplinary cleft team shortly after delivery. It is in the neonatal period when the orthodontist's role typically starts preparing the infants for primary lip and palate surgical repairs. After this early intervention, the orthodontist's role continues to monitor the child's craniofacial growth and development, dental formation and eruption of teeth, and evaluate a malocclusion that may be developing. Orthodontic interventions are sequenced and prioritized 326 Vig and Mercado Figure 2. Mother with Treacher Collins (TC) Syndrome and infant son with phenotypic expression of TC and a variant of Nager Syndrome. Within a comprehensive, integrated treatment plan developed in the team Conferences by all disciplines. When necessary, orthodontic treatment Should be limited to the current stage of skeletodental development, thus avoiding continuous and lengthy course of treatment spanning from the early mixed dentition to the permanent dentition. There are four distinct periods of orthodontic care defined by age and dental development: neonatal period, primary dentition, mixed den- tition and permanent dentition. Neonatal Maxillary Orthopedics Neonatal orthopedics occurs during the early post-natal period, "sually in the first post-natal month unless contraindicated by other con- Benital anomalies or birth defects. This intervention was described and Pioneered by Burston (1958) and McNeil (1961) with the intention of igning the cleft segments in the neonate and avoiding future orthodon- t treatment. This early intervention has gained popularity and resulted "numerous creative appliances, each of which has advantages over the Previous rendition. 327 Craniofacial Anomalies The appliances may be fixed or removable and, as this type of intervention gained popularity, so did the complexity of the appliances increase with both intra- and extraoral components, the least invasive of which was simple extraoral lip taping (Fig. 3). Infant orthopedics has been controversial since it was first introduced and much of the early literature was influenced by primary alveolar bone grafting being performed at the same time as infant orthopedics. When following the patients over their growth, it was difficult to ascribe the findings to the result of neonatal infant orthopedics or the influence of primary bone grafting on the naso-maxillary complex. By the 1980s, neonatal maxillary orthopedics had fallen into disrepute as an intervention for orthodontic alignment of the segments, but was espoused by the surgeons as an adjunctive method of reducing the gap between the vermilion borders of the lip, hence providing the benefits of reduced operating time and dehiscence in the post-surgical repair of the lip. The 1990s was a time of increased enthusiasm for neonatal maxillary orthopedics with the addition of pre-surgical naso- alveolar molding (Grayson et al., 1999). The introduction of naso-alveolar molding (NAM; Grayson et al., 1999; Grayson and Maull, 2004) has allowed inclusion of the columella lengthening in bilateral cleft lip and/or palate and realignment of the extraoral nasal apertures. The bilateral cleft with the tethered columella after primary lip repair may have benefits from NAM and eliminate or reduce future surgical columella lengthening. As with early clinical interventions in the neonate, a lengthy follow-up into adolescence is required to make any judgment on the success of the early intervention during growth of the naso-maxillary complex. With the advances in the methodology of clinical trials and inter- center studies in the 1990s, the Dutch inter-center prospective two-arm randomized clinical trial (RCT) was designed to study the outcome of neonatal maxillary orthopedics in subjects with unilateral cleft lip and palate. It had been reported previously by Shaw and colleagues (2000) from the Eurocleft study that 54% of the 201 European centers were using infant orthopedics as part of comprehensive team management of infants born with clefts of the lip and palate. 328 Vig and Mercado Figure 3. Infant with complete unilateral left cleft lip and palate. A: Defect prior to orthopedic intervention. B: Pre-surgical orthopedics with lip taping to approximate the segments. C. Post-surgical result of definitive lip repair. (Reprinted with permission from Mercado and Vig, 2009.) º A report was published from the RCT comparing the effect of infant orthopedics on maxillary arch dimensions that indicated that infant orthopedics only had a temporary effect (Prahl et al., 2001). Prahl and associates' report (2005) on the effect of infant orthopedics On feeding, weight and length indicated that no significant effect could be found between the two randomized groups on feeding, nutritional Status or somatic growth. This RCT is continuing to follow the subjects longitudinally to evaluate outcome variables comprehensively such as facial and dental development, speech outcome and cost effectiveness. If neonatal orthopedics is recommended, it is completed in the first few months after birth so that definitive surgical lip repair can be achieved for the infant in the first six months of life. Palate repair usually is delayed until the infant is 12–18 months of age. An ongoing controversy is whether the advantages of restoring the anatomy of the palate so the functional aspects of developing the normal phonetic complement of speech outweigh the effects of surgical scar tissue constraining the $100th and development of the naso-maxillary complex. The Dutch cleft clinical trial was started before NAM was popu- larized, so none of the subjects were treated with naso-alveolar molding Appliances. Recent advances in neonatal maxillary orthopedics continue tº be controversial, although the original orthodontic premise of Burston and McNeil in the 1950s no longer is accepted. The Primary Dentition As the deciduous dentition erupts, it is characterized by dental ºfossbites both anterior and posterior. This pattern of eruption reflects the skeletal midface deficiency characteristic of unilateral cleft lip and 329 Craniofacial Anomalies palate (UCLP). Additionally, teeth adjacent to the cleft site may be miss- ing, rotated or erupting ectopically. The bilateral cleft lip and palate (BCLP) occurs less frequently, but may be characterized by the prolabium or pre-maxillary segment being misplaced vertically and mobile with the maxillary incisors in the lower vestibule and the posterior occlusion at a superior occlusal level. In the past, the pre-maxillary segment often was removed surgically, but the prosthetic replacement of the maxillary incisors seldom was successful and the practice of removing the pre-maxillary segment no longer is an alternative intervention to correct the vertically displaced pre-maxilla. To avoid a continuum of treatment, the orthodontist rarely intervenes in the primary dentition because most of the same issues will recur in the mixed dentition when the permanent successors erupt. The primary dentition usually is established by 2%-3 years of age and the chubby infant's face may mask the underlying skeletal midfacial deficiency (Fig. 4). As growth of the naso-maxillary complex lags behind mandibular growth and the soft tissues no longer mask the skeletal midface deficiency, this results in increasing maxillary retrusion. The dentition reflects this pattern with an anterior crossbite with or without a functional mandibular shift. Cases of UCLP tend to have posterioſ transverse collapse of the side of the cleft, whereas BCLP may present | skull radiograph in the primary dentition. Reprinted with permission from Mercado and Vig, 2009. Figure 4. A. Lateral view of a six-year-old girl with repaired BCLP. B. Lateſ? 330 Vig and Mercado Figure 5. A. Five-year-old boy with repaired complete BCLP and severe extrusion of the pre-maxillary segment. B: Frontal intra-oral view showing pre-maxillary Segment out of the vertical plane of occlusion. C. Maxillary occlusal view showing *Vere Constriction of posterior segments and extrusion of the pre-maxillary *śment. Reprinted with permission from Vig and Mercado, 2012. Severe bilateral constriction of the posterior segments with protrusion/ ºtrusion of the mobile pre-maxillary segment (Fig. 5). If the crossbite is associated with a functional mandibular shift, early Orthodontic treatment may be indicated. Maxillary expansion with *W-arch or a Quad-helix will reposition the posterior segments, but care ſeeds to be taken not to stretch the scar tissue from surgical repair of the Palata cleft to result in a fistula or dehiscence. To avoid relapse, delaying Intervention until the mixed dentition is recommended. It is typical for primary maxillary lateral incisors adjacent to the Cleft to erupt ectopically, either facial or palatal, which may be a source º Parental concern. Ectopic primary teeth should be removed if they Interfere with the anterior arms of the maxillary expander, are decayed " are inaccessible to proper oral hygiene by the patient. 331 Craniofacial Anomalies The Mixed Dentition For the orthodontist, the most significant advancement in elim- inating prosthetic replacement of missing teeth and supporting the slumped alar base has been the introduction of secondary alveolar bone grafting to the cleft site. The timing and sequencing varies, but typically is related to eruption of the maxillary canine at 9–11 years of age (Bergland et al., 1986). Occasionally, the cleft site may be mesial to the lateral incisor when the alveolar bone graft will be placed earlier to allow the lateral incisor to erupt through the grafted bone. Although various donor sites have been identified to harvest cancellous bone for the alveolar bone graft, the gold standard in the 21st century is the iliac crest. This procedure is uncomfortable for the child following surgery, typically a sore hip at the donor site and minor discomfort from the recipient intraoral cleft site. Maxillary dental arch collapse, manifested in both the transverse and Sagittal dimensions, occurs secondary to the mucosal scarring origi- nating from surgical repair of the palate. In the primary or early mixed dentition, a protraction facemask in conjunction with tooth-borne appli- ances such as a rapid palatal expander, a labiolingual arch or a Ouad-helix may be used to treat a mild to moderate skeletal midface deficiency. The correction of the incisal relationship results from dentoalveolar proclination of incisors with minimal and often transitory skeletal advancement. With the advent of bone-borne anchorage using miniplates and miniscrews, the orthopedic force from the protraction facemask can be transmitted to the maxilla rather than to the teeth. De Clerck and associates (2009) and Baek and colleagues (2010) placed mini- plates on the zygomatic buttress as anchorage for skeletal protraction of the midface and placed miniscrews in the anterior mandible and in the posterior maxilla as anchorage for the use of intraoral Class Ill elastics, rather than a protraction facemask. Both reports show favorable short- term orthopedic changes in maxilla with minimum side effects such as proclination of the incisors, molar extrusion, bite opening or clockwise rotation of the mandibular plane. Randomized clinical trials currently are in progress and these trials ideally should be extended into adolescence, 332 Vig and Mercado When growth stabilizes, to evaluate the long-term maxillary orthopedic OutCOme. Growth of the naso-maxillary complex continues to lag behind normal mandibular growth, so by the late mixed dentition and in the early permanent dentition, the crossbite relationship tends to recur. A Severe Class Ill malocclusion in the primary or early mixed dentition is unlikely to be corrected with a protraction facemask, so clinicians should Consider the cost and unnecessary burden of care for the patient. Skeletal Correction of severe cases is delayed best until growth stabilizes with the eruption of the permanent dentition. The Permanent Dentition As the permanent successors erupt, the same dental problems of missing teeth, malformed or misplaced teeth recur. Some of these prob- lems are resolved during the mixed dentition, but during adolescence, the establishment of the permanent dentition coincides with the stabi- lization of craniofacial growth. The naso-maxillary complex realizes its growth potential earlier than the mandible following the principle of the Cephalo-Caudal growth maturation. During the mixed dentition, alignment of the permanent teeth is accomplished with either moving the canine into the cleft site after the bone graft or aligning the teeth with ideal crown and root position of the teeth adjacent to the cleft. This treatment prepares the maxillary dentition for replacement of the missing incisor(s) with an implant or prosthesis. During orthodontic treatment, which often is extended from the mixed dentition to the adolescent permanent dentition, a decision needs to be made whether the skeletal discrepancy should be camou- flaged with dentoalveolar compensation or if the skeletal discrepancy is Severe and needs to be corrected with orthognathic surgery or distrac- tion osteogenesis, which may be indicated if the maxillary vascularity is Compromised with excessive scar tissue. Maxillary advancement for improved facial esthetics should be balanced with compromising the velo-pharyngeal mechanism and resulting in hyponasality and reduced intelligibility of speech as an Outcome. The importance of the team management is exemplified With the interaction between the speech and language pathologist, the 333 Craniofacial Anomalies surgeon and the orthodontist in making the decision with objective measures of nasopharyngoscopy and rhinomanometric diagnostic tests. As speech is an important outcome, the contemporary management includes valid and reliable measures, so options and decisions are shared with the patient and parents with an explanation of the risks, costs and benefits of different interventions. TECHNICAL ADVANCES IN CLINICAL PRACTICE The application of 3D images with cone-beam computerized tomography (CBCT) has been embraced rapidly in clinical practice with the contemporary acquisition of diagnostic records. The risk of increased radiation in the child has to be weighed with the benefit of increased information available to the clinician. In infants and children with craniofacial anomalies, this approach often is reconciled with the increased and enhanced diagnostic and treatment planning information available to the surgeon and the orthodontist. Computerized imaging has given us the third dimension and biomaterial advances and innovative approaches to their application in clinical practice have provided new methods to correct skeletal and dental anomalies. Craniofacial Syndromes: Mandibular Deficiency The introduction of distraction osteogenesis (DO) to advance the mandible followed the principle of the Ilizarov technique (1988) developed to correct the length of the limbs following polio or osteomyelitis. This method was adapted to correct the small mandible in infants and was introduced by McCarthy and associates (1995) to advance the mandible and improve the airway and feeding problems in infants who otherwise would need a tracheostomy until the mandible was adequate in size for orthognathic surgery to advance the mandible. DO was a major breakthrough in those infants whose airway and feeding was compromised. Previously, these young infants and children continued to have a tracheostomy until the ramus of the mandible was of a size that would allow a bilateral sagittal split osteotomy (BSSO) to advance the mandible adequately to allow decannalization of the tracheostomy (Figs. 6-7; Vig, 1988; Losken et al., 1996). 334 Vig and Mercado C. -- Dºº Aº Figure 6. A: Child with Hallerman Strief (H-S) Syndrome and tracheostomy Since infancy (courtesy of Monograph 21 Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan). B. Oligodontia that is a feature of H-S syndrome. Stabilization of the surgical advancement With intermaxillary fixation was inadequate due to multiple congenitally absent Permanent teeth. C. Bilateral surgical sagittal advancement with intra- and extra- Oral fixation for stabilization post-surgery. D: Post-surgical advancement with airway restored and tracheotomy stoma closed. While DO is an advancement in the treatment of infants in Whom the airway and feeding is compromised, it also has been claimed as an alternative to orthognathic surgery. While there was considerable ºptimism initially, many surgeons report DO is not as predictable or the ºutcome as stable as orthognathic surgery. If restoring the airway and feeding in the infant and young child is a priority, then DO has definite advantages, especially as technological advances have made intraora distractors less vulnerable and biodegradable materials avoid a second Surgery to remove the intraoral devices. The technical aspects in treating children with cleft lip and pal- ate also includes the burden of care from the patient's/parent's per- *Pectives. Clinicians tend to measure morphological changes as im- Pºrtant outcomes, but consumers measure other outcomes related to their quality of life. This lack of concordance between the consumer and providers of care is being addressed in contemporary measures to 335 Craniofacial Anomalies Figure 7. A: Infant with Nager syndrome treated with distraction osteogeness (Modified and used with permission from Losken et al., 1996.) B: Extraoral uni-directional distractor with surgical corticotomy. C. The same infant after distractor was placed surgically. D: Distraction osteogenesis started With some improvement in mandibular advancement, but the tracheostomy and gastrostomy tube still was in place. E. Distraction osteogenesis to advanº the mandible activated over a four-week period after the latent period. F. Tracheostomy and gastrostomy tubes were removed. Airway established and using oral cavity for feeding and speech acquisition. Note scars on cheeks from extraoral pins. G. Bidirectional extraoral distractor developed to control both vertical and sagittal dimensions, which was not available when this infant W35 treated. The vertical dimension could have been controlled better with the twº corticotomy bidirectional distractor. 336 Vig and Mercado aSSess the outcomes of interventions by developing reliable and valid questionnaires. The methods of deriving evidence to compare different interven- tions in craniofacial anomalies was spearheaded in Europe by six cleft palate teams who agreed to share their outcome data in the Eurocleft Study. This collaborative endeavor was a landmark in comparison of team performance and had far-reaching consequences in making changes to Currently accepted interventions. Results included performance by surgeons with the finding that those teams whose number of patients was small had poorer outcomes thanthose surgeons who had multiple experiences in performing the large number of surgical procedures. These findings resulted in geographically Consolidating teams so that the number of surgeries performed was reflected in the expertise of the surgeons for efficiency and effectiveness. Where uncertainty prevailed, the need for clinical trials was emphasized and an evidence-based approach has been adopted in the 21st Century, although not all procedures are appropriate or ethical for randomized clinical trials (RCTs). Since infant orthopedics has been Controversial for over half a century, the RCT that was initiated in the Netherlands in 1993 (Prahl et al., 2001, 2005) has followed the enrolled Subjects as an intercenter study between Amsterdam, Nijmegen and Rotterdam. The inclusion Criteria were infants with UCLP and the RCT had institutional review board approval, sample size calculation and appro- priate consent and randomization procedures. Multiple outcomes were evaluated with reports that those subjects who had infant orthopedics by 12 years of age did not show any long-term benefit. Other outcomes in- cluding speech showed no significant benefit after the age of three years. However, none of the subjects received infant orthopedics with the NAM appliance and others contend that if a different appliance had been used, the outcomes would have been different and more favorable. Unfortunately, RCTs are expensive to conduct and interventions in the neonatal period require long-term follow up as growth and devel- Opment of the naso-maxillary complex continues until late adolescence. The Dutch cleft prospective RCT challenges and attempts to resolve the 337 Craniofacial Anomalies controversy of neonatal maxillary orthopedics in UCLP. One of the out- comes is that all three centers in the Netherlands now have discontinued infant orthopedics. In the U.S., the Craniofacial Outcomes Registry was supported by NIH/NIDCR to develop a registry of teams and their outcome measures that could provide aggregate data for a comparison of team outcomes. The registry was an ambitious concept and although some outcome measures were developed and multiple teams entered into the registry, no universal acceptance of methods to develop and measure the outcome variables was resolved, resulting in controversy between and among teams. Although this concept was embraced within the national health services in Europe, it was not accepted well in the U.S. in the 1990s. Aless ambitious and less well-funded study than the Craniofacial Outcomes Registry has been based on the Eurocleft study of the 1980s. The six- center Americleft project initiated in 1996 is supported by the ACPA, is less controversial and ultimately has been successful in attracting an additional team to collaborate. Americleft Intercenter Study In children with cleft lip and palate, the typical malocclusion observed during the mixed dentition period involves skeletal Class || relationship, maxillary constriction, crossbites and incisor rotations. In addition, residual facial stigmata are noticeable with nasal asymmetry, lip scarring and concave profile. Some of these problems may present as the cumulative sequelae of procedures that are performed to manage the cleft shortly after birth, such as infant orthopedics and multiple surgical interventions for the lip, alveolus and palate. Such early procedures, often programmed sequentially, are re- ferred to as “primary infant management protocols” and may vary among cleft centers. By the 1990s, the different primary treatment interventions for patients with cleft lip and palate were numerous and it was difficult to identify specific procedures that yielded better results than others. Nevertheless, the Eurocleft project published in 1992 demonstrated the value of conducting inter-center studies to compare treatment outcomes using retrospective records (Asher-McDade et al., 1992; Mars et al., 1992; Mølsted et al., 1992; Shaw et al., 1992a,b). Although not capable of 338 Vig and Mercado identifying which individual procedures within a primary infant manage- ment protocol are responsible for a favorable or unfavorable outcome, inter-center comparisons promote the standardized collection of records at agreed time points and can be a valuable part of quality improvement programs (Shaw et al., 2000). In North America, cleft-craniofacial teams had been unable to develop inter-center, collaborative clinical research even though there are a large number of well-organized centers with high Volumes of patients. In 2006, recognizing the lack of inter-center, collaborative research in North America, the ACPA established a “Task Force on Intercenter Collaborations” as part of its research committee. Support was provided for the initiation of the Americleft study, which was intended to follow the research principles of the landmark Eurocleft study. In the Americleft study, seven key methodological considerations Were established (Long et al., 2011): 1. Sample sizes needed to be in the range of 30-40 sub- jects, as suggested by power analyses. 2. All patients in the study were white and had Com- plete Unilateral Cleft Lip and Palate (CUCLP). 3. CUCLP subjects had to meet the inclusion criteria as having complete clefts and diagnosed as non-syn- dromic. 4. Each center was required to provide evidence that the sample consisted of consecutively enrolled pa- tients, based on patient number or birth date. 5. Clinical records were unlinked to any center of ori- gin and prepared in a standardized fashion to ensure blinding of all raters. 6. All primary surgical management of patients had to be completed at each center of origin. In addition, each center had to describe the sequence of inter- ventions in its protocol and the number of operating surgeons involved in the primary surgeries. 7. All centers had to obtain patient permission and in- stitutional ethics approval for use of clinical records in an inter-center retrospective outcome study. 339 Craniofacial Anomalies Five North American centers (A through E) were chosen to par- ticipate in the Americleft study and had to meet the seven methodologi- cal conditions. Centers A through E used standardized protocols with wide variation among centers. One center used primary bone grafting, two centers used variations of pre-surgical infant orthopedic treatment, one center used two-stage palate repair and there was a wide range of lip/palate repair techniques. Protocols for each of the centers are sum- marized in Table 1. The treatment outcomes assessed were identical to those in the Eurocleft Study: dental arch relationships on dental casts using the Goslon yardstick; skeletal and soft tissue craniofacial morphology using lateral cephalometric analysis; and nasolabial esthetics using the Asher- McDade system. The following is a summary of results for each of the OutCOmeS. Dental Arch Relationships (Hathaway et al., 2011). The Goslon yardstick is a method of classifying the severity of the maxilla-mandibular dental relationships objectively on a scale from 1 = excellent to 5 = very poor (Mars et al., 1987). Center A was included in the analysis and report of dental arch relationships, even though its sample size was less than optimal. A total of 169 dental models were rated by six experienced and calibrated raters. The highest Goslon mean score was for Center B, indicating the poorest outcome in the study and suggesting that patients in this center were at higher risk of needing maxillary orthognathic advancement surgery. The lowest Goslon mean score was for Center C, indicating the best outcome among centers and suggesting a lesseſ likelihood of needing maxillary orthognathic surgery. Craniofacial Morphology Analysis (Daskalogiannakis et al., 2011). Inter-center comparison of skeletal and soft tissue profiles in- cluded 148 lateral cephalometric radiographs of subjects from Americleft Centers B, C, D and E. The radiographs were taken at the same corre- sponding age as the dental models. Significant inter-center differenc- es were found in maxillary prominence, as measured in SNA and ANB angles. Center B had the smallest maxillary prominence while Center C had the highest maxillary prominence. At the soft tissue level, Cen- ter C had the highest ANB angle and soft tissue convexity compared 340 Vig and Mercado Table 1: Sample characteristics and treatment protocols for the Americleft Study CenterS. | Treatment Center A Center B Center C Center D Center E Center G SampleSize 18 40 41 | 38 35 32 and Gender (10M/8F) (28M/12F) (25M:16F) (29M/9F) (21M/14F) (24M/8F) Average Age 9:4 8:6 8:10 9:1 9:2 8:10 y:m Pre-surgical No | Yes” No. Yes” # * iſ Yesº Yeso Orthopedics ; NAM Primary 6-12 wk 2–3 m 3 m 3 m 3-4 m 3-5 m Lip Repair Millard Millard Tennison Millard Millard Modified or 5–6 m Millard Delaire y Primary NO No No NO NO Yes Nasal Repair 3–5 m with - - - - - - - - - - - - - - - - - lip repair Primary No Yes NO NO No NO Bone 6–9 m (GPP in Grafting 5/32) Hard Palate 9-12 m 11–15 m 12 m 12 m 12-14 m 12 m Repair Bardach Hard Vomer Wardill Vorner flap/ Bardach or or Delaire palate flap and Von- 18 m Wardill- Vomer Langenbeck Von- Kilner flap Langenbeck Soft Palate 9-12 m 11-15- m 18 m 12 m 12-14 m 12 m Repair Bardach |VP Or Median Wardill Veau IVP with Or 5-6 m SOme Suture and pushback Bardach or Delaire Furlow (1 With VP Vonner 3-5 m IVP surgeon) flap then V-L at 18 m Secondary 6–7 y 8-9 y 9 y 7–10 y 9-11 y 9-10 y Bone Delaire if needed Grafting - Nose/Lip 4-5y 4-5y 14-20y 4-5) 4-7y None done Revisions on this Sample Surgeons 2 4 1 4 4 2 *Center B. The molding plate was started at 2-3 months and continued through primary bone grafting to the palate repair at 11-15 months. The molding was discontinued at the time of palate repair. **Center E. Infant presurgical orthopedic treatment was done using a modified McNeil technique with extraoral traction. The orthopedic appliance was placed prior to lip repair at 3–4 months and continued until the time of palate repair at 12-14 months. ***Center D. Infant presurgical orthopedictreatment was done using a modified McNeil technique with extraoral traction. The orthopedic appliance was placed prior to lip repair at 3 months and discontinued once lip repair was done. °Center G. NAM with lip taping was started within first 2 wks. Patients wore appliance for 3-4 months until lip repair. GPP = gingivoperiosteoplasty. V-L = Von-Langenbeck. IVP = intravelar veloplasty 341 Craniofacial Anomalies to the other centers. Interestingly, measures of mandibular prominence, vertical dimensions and dental inclinations showed no differences among centers. There was a significant but moderate negative correlation be- tween Goslon rating on the dental models and the corresponding Sub- ject's ANB angle. Nasolabial Aesthetics (Mercado et al., 2011a). Inter-center comparison of naso-labial esthetic outcomes were done on frontal and profile facial images of subjects from Americleft Centers B, C, D and E. All photos were taken at the corresponding age when the dental models and cephalograms were taken. A total of 124 subjects were included in the study. Four features were rated: nasal form, symmetry, profile including the upper lip and shape of the vermilion border (Asher-McDade et al., 1991). Each feature was rated by five experienced and calibrated raters using a scale of 1 = very good to 5 = very poor. The mean scores for each center of the features assessed were in the good to fair range, with no significant differences among centers. The Americleft study, modeled after the 1992 Eurocleft study, demonstrated that the inter-center retrospective cohort approach using common clinical records is capable of discerning dental arch and craniofacial morphologic relationships that yield information about favorable and unfavorable outcomes of treatment protocols for patients with CUCLP. Center B was the only center with a majority of Goslon scores of 4 and 5, resulting in a worse mean score than the other centers. Center B's treatment protocol involved infant orthopedics, primary alveolar bone grafting and secondary surgical revisions prior to the mixed dentition stage. Although it is not possible to assign causality of less favorable results to any of the above interventions, it is important to note that the Eurocleft study also found that centers using primary alveolar bone grafting and infant orthopedics had less favorable outcomes than centers using simpler and less burdensome protocols. Therefore, the results of the Americleft and Eurocleft studies suggest that centers should reconsider the use of infant orthopedics and primary alveolar bone grafting and avoid complicated primary infant management protocols (Russell et al., 2011). This retrospective study supports the results of the prospective Dutchcleft RCT with infant orthopedics in subjects with CUCLP compared to controls with no infant orthopedics. 342 Vig and Mercado EXTENSION OF THE AMERICLEFT INTER-CENTER STUDY After the initial groundbreaking work of the Americleft study was published in 2011, the investigators determined that it was necessary to extend the inter-center comparisons to include other centers whose primary infant management protocols differed substantially from the Original five centers. In particular, it was noted that none of the original Centers performed the infant pre-surgical technique of NAM. The NAM technique has been described thoroughly by its major proponents, Grayson and associates (1999). They advocate that NAM, among other benefits, achieves pre-surgical approximation of the alveolar cleft segments and correction of the deformity in the nasal cartilages, allowing for a more consistent post-operative surgical result without the need for multiple revision surgeries. They also advocate that there is no greater disturbance of maxillary growth than that typically observed in patients with clefts undergoing other traditional treatments (Grayson and Cutting, 2001). The practice of pre-surgical NAM techniques among North American centers and internationally has gained acceptance, but not Without generating some controversies concerning the technique's cost: benefit ratio in relation to its long-term effect on facial growth and naso- labial esthetics. Most of the studies report the results of NAM as part of the primary infant management protocol that have been single-center, intra-center retrospective studies with small sample sizes and short- term follow-up (Wood et al., 1997; Grayson et al., 1999; Maull et al., 1999; Grayson and Cutting, 2001; Singh et al., 2007; Lee et al., 2008; Barillas et al., 2009; Chang et al., 2010). To date, there have been no ran- domized trials of NAM (Uzel and Alparsian, 2011) and no blinded inter- Center comparisons of outcomes resulting from protocols using NAM. As NAM is a relatively new technique in infant orthopedics, an inter-center Study has been designed to compare outcomes of dental arch relation- Ships, Skeletal morphology and naso-labial esthetics among four centers using different primary infant protocols including NAM and applying the Eurocleft and Americleft methodologies (Mercado et al., 2011b). Chosen for this Americleft extension study were Centers B, C, D and G (Table 1). Center G used NAM, Center B used pre-surgical infant Orthopedics and primary bone grafting, Center C used two-stage palate 343 Craniofacial Anomalies repair without any pre-surgical infant orthopedics and Center D used pre-surgical infant orthopedics, but no primary alveolar repair. The inclusion of NAM in the primary infant management protocol resulted in no significant improvement in dental arch relationships or craniofacial morphology when compared to protocols that use other types of pre- surgical infant orthopedics (Peanchitlertkajorn et al., 2010, 2011). For naso-labial esthetic ratings, Center G's mean scores generally were more favorable than those of Centers B, C and D (Mercado et al., 2011b). In conclusion, the data from this Americleft extension study suggests that the naso-labial esthetic outcomes from primary infant management protocols generally are better when the protocols include NAM or secondary revision surgeries. The decision to include NAM during infancy or wait until adolescence for secondary revision surgery to improve naso-labial esthetic outcomes in patients with CUCLP would benefit from a well-designed comparison study to evaluate the burden of care imposed by each procedure. INTERVENTIONS BY SURGEONS: LIP REVISION SURGERY IN PATIENTS WITH CLEFTS After the primary surgical repair of the cleft lip in infancy, continued growth and differential changes in the facial soft tissues due to surgical scars impacts on the child's facial esthetics. During team evaluations, nose and lip revisions may be recommended, but there are no reliable or valid measures to assess the need or evaluate the outcome. Revision surgery is based on the surgeon's experience, training, surgical skills and competence. To determine if there is a concordance among surgeons on their perceptions of naso-labial esthetics before and after lip revision surgery, a single-center retrospective study was conducted (Mercado et al., 2012). Two groups of subjects with repaired cleft lip with or without cleft palate were selected: one group had lip revision surgery (n = 40) and the other did not have surgery (n = 29). The two-dimensional (2D) valid and reliable Asher-McDade scale was used by six experienced surgeons who were blinded to the groups and rated the facial images at baseline and twelve-month follow-up. Concordance among surgeons ranged 344 Vig and Mercado from poor to acceptable and regression analyses demonstrated that the group that underwent revision surgery had significantly higher odds of receiving improved scores at the follow-up visit compared to the group that did not have revision surgery. Regardless of the group allocation, the esthetic scores either did not change or changed by only one unit in the five-unit scale from baseline to follow-up. These findings suggest that the Asher-McDade scale may not be sensitive sufficiently for detecting subtle longitudinal changes in nasolabial esthetics related to revision surgery in a single-center study. Static 2D facial images may limit the raters' ability to visualize facial features when using frontal and profile images. To test this question, six Surgeons were trained to evaluate 3D images of 17 patients with repaired cleft lip and/or palate and images could be rotated by the raters along multiple planes before ascribing a score for each of the features in the Asher-McDade scale (Mercado et al., 2013). Inter-surgeon concordance did not improve in the 3D format compared to the 2D format. Wilcoxon Signed ranksum tests, with Bonferroni’s corrections, revealed that the vast majority of the differences between 2D and 3D ratings for corresponding images statistically were not greater than 0. Taken together, the results from the above two studies (Mercado et al., 2012, 2013) suggest that Subjective methods of assessment are inadequate for evaluating the effects of lip revision surgery. In their study of upper lip movement in patients with surgically repaired cleft lip, Trotman and colleagues (2003) showed that objective measures correlated well with the examiners' perception of facial appear- ance, especially at rest. They suggested that objective measures should be used to supplement subjective evaluations of lip appearance. More recently, Tanikawa and associates (2010) used objective 3D measures to analyze static lip form in patients with and without repaired cleft lip. They found that lip form in patients with repaired cleft lip present greater vari- ation and are different significantly than lip form in patients without cleft lip. This methodology holds promise for assessing outcomes of individual patients before and after lip revision surgery. In summary, several clinical implications can be drawn from these Studies when surgeons recommend lip and nose revisions for patients 345 Craniofacial Anomalies with repaired clefts. Subjective evaluations of naso-labial appearance may be biased by a number of different factors related to the surgeon's experience and competence. Furthermore, the scientific literature lacks valid objective measures that can inform the surgeons adequately on the expected esthetic changes attributed to revision surgery. Ideally, for a patient contemplating revision surgery, accurate 3D facial images at rest should be taken for objective analyses of the residual cleft deformity with comparison to non-cleft patients. This information could be used to supplement the surgeon's subjective perception of disfigurement and thus may lead to more evidence-based discussions with patients on the benefits of revision surgery. CONCLUSIONS This chapter has attempted to summarizethe currentmanagement and future directions in the team approach to the diagnosis, treatment planning and implementation of current clinical interventions in those individuals with craniofacial anomalies. There has been considerable progress in the past decade in the development of outcome measures. This has permitted alternative clinical interventions to be compared and evaluated in a decision analytical context for the risks, costs and benefits including the burden of care from the patient's perspective and their health-related quality of life. Ongoing research initiatives have been discussed and technical advances in biomaterials and genetics will have important clinical implications in our future management of clefts and other craniofacial anomalies, both syndromic and non-syndromic. ACKNOWLEDGEMENTS We are indebted to the following surgeons and their associated cleft palate/craniofacial teams: Dr. Peter Larsen at The Ohio State University, Division of Oral and Maxillofacial Surgery for the surgical management of the mother with Treacher Collins syndrome in Figure 2; Dr. Timothy Turvey at The University of North Carolina Department of Oral and Maxillofacial Surgery for the surgical management of the patient with Hallerman Strieff syndrome shown in Figure 6; and Dr. Wolfgang Losken at The University of Pittsburg, Department of Plastic Surgery for the surgical 346 Vig and Mercado management of the patient in Figure 7. Our gratitude is extended to Dr. John C. Lude for the orthodontic management of the parent in Figure 2 and for the pre-surgical orthopedics of the child in Figure 3. The Americleft studies (2010-2013) were funded by the ACPA and the Cleft Palate Foundation. Dr. Mercado's studies on lip revision Surgery (Mercado et al., 2012, 2013) were funded by a supplemental research-career development NIDCR grant to her as part of parent grant R01 DE13814-01A1 from the NIDCR awarded to Dr. Carroll-Ann Trotman. REFERENCES American Cleft Palate-Craniofacial Association. Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies, Revised Edition November 2009. http://www.acpa-cpf. org/uploads/site/Parameters Rev 2009.pdf Asher-McDade C, Brattström V, Dahl E, McWilliam J, Mølsted K, Plint DA, Prahl-Andersen B, Semb G, Shaw WC. The RPS. A six-center international study of treatment outcome in patients with clefts of the lip and palate: Part 4. Assessment of nasolabial appearance. 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Orthodontics: Current Principles and Techniques. 5th ed. Philadelphia: Elsevier, 2012;973. Wig PS, Vig KWL. Hybrid appliances: A component approach to dentofacial orthopedics. Am J Orthod Dentofacial Orthop 1986;90(4): 273-285. Ward JA, Vig KWL, Firestone AR, Mercado A, Da Fonseca M, Johnston W. Oral health-related quality of life in children with orofacial clefts. Cleft Palate Craniofacial J 2013;50(2):174-181. Wood RJ, Grayson BH, Cutting CB. Gingivoperiosteoplasty and midfacial growth. Cleft Palate Craniofacial J 1997;34(1):17-20. 353 FGF SIGNALING IN CRANIOFACIAL SKELETAL DEVELOPMENT AND THE PATHOGENESIS OF CRANIOSYNOSTOSIS Nan Hatch ABSTRACT For more than a decade, we have known that mutations in specific genes promote craniosynostosis, including those encoding fibroblast growth factor receptors (FGFRs), yet a central hypothesis regarding the etiology of this disorder has not emerged. Ongoing studies involving the use of established mouse models of craniosynostosis should illuminate further molecular mechanisms by which mutations in FGFRs and dysregulation of phosphate homeostasis lead to abnormal craniofacial development and craniosynostosis and provide for the development of biologically rational therapeutics to treat infants and children with this debilitating condition. KEY WORDS: craniosynostosis, fibroblast growth factor receptors, hypophos- phatasia, Cranial suture NORMAL CRANIAL BONE AND SUTURE DEVELOPMENT Development of the cranial bones occurs via intramembranous OSSification and sutural bone apposition. Ossification initiates at sites of mesenchymal condensation that, with continued proliferation followed by osteoblastic differentiation and subsequent matrix mineralization, become the central zones of ossification for each cranial bone (Hall and Miyake, 2000). With continued ossification, the cranial bones increase in Size and ultimately come into a close proximal relationship. At this point, ossification continues to occur via bony apposition along the osteogenic front (outer edge) of each bone, while patency of a non-mineralized fibrous suture between the two adjacent bones 355 FGF Signaling is maintained (Regelsberger et al., 2012). Cranial suture patency is maintained most typically until early adulthood (with the exception of the metopic suture which starts to fuse a few to several months after birth; Cohen, 1993a; Weinzweig et al., 2003). Patent cranial sutures allow for bone growth that facilitates skull expansion to accommodate the enlarging brain and also are believed to provide firm union between distinct bone segments, while also allowing for some freedom of movement between bone segments for dissipation of mechanical stress (such as that which would occur during birth). After cessation of cranial growth, loss of cranial suture patency (fusion of cranial bones) typically occurs via the development of interdigitations between adjacent bones and sometimes can proceed to complete fusion of the adjacent bones (Miura et al., 2009). CRANIOSYNOSTOSIS Craniosynostosis is a debilitating pediatric condition in which cranial suture patency is lost and adjacent cranial bones become fused prematurely. This fusion prevents further cranial bone growth in that area and commonly results in increased intracranial pressure as a result of inadequate skull growth (Renier et al., 2000; Seruya et al., 2011). The premature fusion also leads to abnormal skull shapes resulting from limited growth at fused cranial sutures with compensating overgrowth at non-fused cranial sutures (Kreiborg, 1981a; Morriss-Kay and Wilkie, 2005; Liu, 2013). The severity of the condition and the need for surgical recon- struction depends upon the timing of synostosis and on the number of affected cranial sutures, with earlier synostosis and a greater number of affected sutures leading to a more severe condition (Cohen, 1993a). The condition of craniosynostosis potentially can lead to airway impairments, obstructive sleep apnea (OSA), brain abnormalities, blindness, deafness, seizures and death (Abe et al., 1985; Mixter et al., 1990; Stavrou et al., 1997; Okajima et al., 1999; Shah et al., 2006; Addo et al., 2013; Driessen et al., 2013). Craniosynostosis has a relatively high incidence of approximately 1 in 2500 live births; current treatment options are limited to surgery, genetic Counseling, dental, medical and social support (Rasmussen et al., 2008). Notably, even with an appropriately early and accurate diagnosis, 356 Hatch CranioSynostosis can carry high morbidity, with some patients requiring multiple surgeries throughout childhood for maintenance of an adequate airway, relief of high intracranial pressure, treatment of recurring cranio- Synostosis, achievement of ideal tooth relationships and normalization of skull and facial shapes (Cohen and Kreiborg, 1992; Cunningham et al., 2007; Flapper et al., 2009; Baird et al., 2012). ETIOLOGY OF CRANIOSYNOSTOSIS Several theories regarding the etiology of craniosynostosis have been proposed, including concepts that are biological or mechanical in nature. Mechanical theories involve the contribution of tensile and expansive forces upon suture development, while biological theories more typically propose a role for abnormal cell function in the cranial Suture environment (Cohen, 1993a; Zeiger et al., 2002; Warren et al., 2003). For example, it has been suggested that craniosynostosis occurs Secondary to an aberrant shape of the craniofacial base (Cendekiawan et al., 2010). It also has been suggested that cranioSynostosis is due to an abnormal osteoblastic or pre-osteoblastic phenotype that results from altered intrinsic cellular changes or altered extrinsic signaling to these Cells (such as from the dura) or from a failure of neural crest-mesoderm boundary formation (Morriss-Kay and Wilkie, 2005; Marie, 2012). Notably, it currently is thought that craniosynostosis can occur sporadically (in the absence of additional abnormalities and obvious genetic mutations) or as part of a genetic syndrome. While craniosynostosis is known to occur in association with over One hundred different genetic conditions (Ciurea et al., 2009), several Syndromes classically are noted as having craniosynostosis as their primary phenotypic abnormality. These craniosynostosis syndromes are associated with specific mutations in genes that likely contribute to the proliferation, differentiation, apoptosis, mineralization and/or Other activities of osteoblasts and/or other cells at or near the cranial Suture environment. More specifically, mutations in three members of the fibroblast growth factor receptor (FGFR) gene family, the twist basic helix-loop-helix transcription factor (TWIST) and the homeobox gene Containing transcription factor MSX2 all have been shown to be linked genetically to the classic craniosynostosis syndromes (Jabs et al., 1993; Bellus et al., 1996; el Ghouzzi et al., 1997; Howard et al., 1997). 357 FGF Signaling While mutations in TWIST are thought to result in a loss of function, mutations in both the FGFRS and MSX2 are believed to result in a gain of function. It is worthy to note that while the FGFRs are expressed within cranial bone osteogenic fronts, both TWIST and MSX2 are expressed in the sutural mesenchyme and underlying dura mater (Kim, 1998; Rice et al., 2000, 2003). These findings again support the notion that craniosynostosis results from local abnormalities in cranial bone and suture cells. It is likely that craniosynostosis is both multi-factorial and polygenetic in nature, such that even those forms that presently are believed to be sporadic may have some genetic component. The literature suggests that the craniosynostosis syndromes are, in fact, genetically “plastic” in that the same genetic mutation can result in more than one syndromic phenotype and that different mutations can result in the same syndromic phenotype (Bellus, 1996; DeMoerlooze & Dickson, 1997; Webster and Donoghue, 1997). Existence of “plasticity” supports the idea that these syndromes are polygenetic and multi-factorial in nature, with likely environmental influences, although it also is possible that much of this “plasticity” actually is the result of the inconsistent diagnosis of these craniosynostosis syndromes. These clinical syndromes typically involve the premature fusion of specific sutures with a resultant characteristic skull shape, midface deficiency, hypertelorism and proptosis. Clinical diagnosis of a given syndrome also often is based upon the existence (or lack thereof) of associated limb abnormalities, such as syndactyly. FGFRS AND CRANIOSYNOSTOSIS It has been known for over a decade that mutations in FGFRS promote abnormal craniofacial development and craniosynostosis in humans. Mutations in FGFR2 cause Apert, Crouzon, Jackson-Weiss and Pfeiffer Syndromes, while mutations in FGFR1 cause Pfeiffer Syndrome and mutations in FGFR3 cause Muenke's Craniosynostosis Syndrome and Crouzon Syndrome with Acanthosis Nigricans (Fig. 1). 358 Hatch g1 g2 g3 FGFR1 FGFR2 se- ºr-THTHT- FGFR3 OH H Figure 1. Location of FGFR mutations associated with syndromic craniosynotosis. Each full-length FGFR protein contains an extracellular region, a single transmembrane region and an intracellular region. Cysteine residues present Within each Ig domain maintain the tertiary structure of the receptor via intra- molecular disulfide bonding (S-S). Extracellular immunoglobulin-like domains 1, 2 and 3 are denoted g1, Ig2 and g3. Transmembrane and tyrosine kinase domains are labeled TM, TK1 and TK2, respectively. The location of classic mutations 3850ciated with Apert, Crouzon, Crouzon with Acanthosis Nigricans, Pfeiffer and Muenke Craniosynostosis Syndromes are indicated with dots (red = Apert; yellow Crouzon; blue = Pfeiffer; green = Muenke; orange = Crouzon with Acanthosis Nigricans; pink = Jackson Weiss). Note that both Pfeiffer and Crouzon Syndrome also are associated with numerous other mutations in FGFR2 (see Fig. 4). Craniosynostosis Syndrome-associated mutations in FGFRs are autosomal dominant and exhibit complete penetrance with variable %pression. This means that every person who carries one of these "utations exhibits some degree of the characteristic phenotype and that the phenotype in any given individual can range from quite mild to ºtremely severe. It is a commonly held belief that the craniosynostosis *Sociated FGFR mutations act as gain of function mutations in terms of FGF/FGFR signaling. More specifically, S252W and P253R Apert Syndrome- *Sociated mutations in FGFR2 result in loss of ligand binding specificity (the S252W mutation allows the mesenchymal splice form of FGFR2 359 FGF Signaling (FGFR2||lc) to bind and be activated by the mesenchymally expressed ligands (FGF7 and FGF10) and to increase ligand binding affinity, such that these receptors exhibit increased ligand dependent signaling (Anderson et al., 1998; Yu et al., 2000). Crouzon Syndrome-associated C332Y, Y340H, C342Y, C342R, C342S, S35C, W290G, T341P, C278F mutations and a Crouzon Syndrome- associated 345-361 amino acid deletion in FGFR2 result in ligand- independent autophosphorylation, dimerization and tyrosine kinase activity, such that these mutations are thought to promote ligand independent signaling (Neilson and Friesel, 1995; Galvin et al., 1996; Robertson et al., 1998; Hatch et al., 2006). The P252R mutation in FGFR1 and the analogous P250R mutation in FGFR3 (causative for Pfeiffer and Muenke's Syndrome, respectively) increase ligand-binding affinity without altering ligand-binding specificity (Ibrahimi et al., 2004). Finally, the Crouzon Syndrome with Acanthosis Nigricans- associated A391E mutation in FGFR3 lowers the free energy of FGFR3 dimerization, which may enhance ligand-independent and/or ligand- dependent signaling (Li et al., 2006). In vivo studies also Support the idea that the pathogenesis of FGFR-associated craniosynostosis is mediated by increased receptor signaling. Chemical inhibition of tyrosine kinase signaling was shown to prevent coronal suture fusion in FGFR2°, FGFR2*2W and FGFR2*/* calvaria in organ culture (Perlyn et al., 2006a, Shukla et al., 2007; Yin et al., 2008). Additionally, uncoupling of FGFR2% from Frs.2 signaling via mutation of the FrS2 binding site prevented craniosynostosis in mice that carry this mutation (Eswarakumar et al., 2006). Importantly however, more recent studies have indicated that at least some of the craniofacial defects seen in FGFR2°* mice may be mediated by diminished receptor signaling (Snyder-Warwicket al., 2010). This finding, in combination with the fact that craniosynostosis is evident in FGFR2||lc null mice (Eswarakumar et al., 2002), suggests that FGFR- associated craniofacial abnormalities such as craniosynostosis may result from either too much or too little FGF receptor signaling. It is likely that craniosynostosis is both multi-factorial and polygenetic in nature such that even those forms that presently are believed to be sporadic may have some genetic component. The literature suggests that the craniosynostosis syndromes are, in fact, genetically “plastic” in that the same FGFR mutation can result in more than one 360 Hatch Syndromic phenotype and that different mutations can result in the same Syndromic phenotype (Rutland et al., 1995; DeMoerlooze and Dickson, 1997; Webster and Donoghue, 1997). Existence of “plasticity” supports the idea that these syndromes are polygenetic and multi-factorial in nature, with likely environmental influences, although it also is possible that much of this “plasticity” actually is the result of the inconsistent diagnosis of these craniosynostosis syndromes. These clinical syndromes typically involve the premature fusion of specific sutures with a resultant Characteristic skull shape, midface deficiency, hypertelorism and ocular proptosis. Clinical diagnosis of a given syndrome also often is based upon the existence (or lack thereof) of associated hand and foot abnormalities Such as large and deviated broad toes and/or syndactyly. Pfeiffer Syndrome (OMIMN ID# 101600) can be caused by a P252R mutation in the linker region between the Ig2 and g3 domains of FGFR1 or by mutations in FGFR2 (Muenke et al., 1994; Lajeunie et al., 1995; Rutland et al., 1995; Schell et al., 1995; Kan et al., 2002; Rossi et al., 2003). Classic Pfeiffer Syndrome is characterized by cranio-synostosis, hyperteloric toes, mesial deviation of great toes, brachydactyly and Variable syndactyly. Jackson Weiss Syndrome (OMIM ID #123150) most commonly is associated with an A344G mutation within the Ig3 domain of FGFR2 (Jabs et al., 1994). This syndrome is characterized by variable craniosynostosis, frontal bossing, hypertelorism, strabismus and foot abnormalities, including broad great toes with medial deviation and tarsal-metatarsal Coalescence. Hand anomalies are rare. Most patients are of normal intelligence. Some patients have foot but no craniofacial anomalies. Ocular proptosis usually is mild. The syndrome is considered to exhibit much phenotypic variability (Jackson et al., 1976). Muenke Syndrome (OMIM ID #602849) is caused by a P250R mu- tation in the linker region between the Ig2 and g3 domains of FGFR3 (Muenke et al., 1997). This syndrome commonly is characterized by unicoronal or bicoronal craniosynostosis, midface hypoplasia, hyper- telorism and hand and foot abnormalities, including brachydactyly, thimble-like middle phalanges, coned epiphyses, carpal and tarsal bone fusions. Sensori-neural hearing loss and developmental delay is evident in a minority of cases. While the radiologic findings of hands and feet 361 FGF Signaling can be helpful in the recognition of this syndrome, identification of the P250R mutation in FGFR3 provides for a definitive diagnosis (Kimonis et al., 2007). Crouzon Syndrome is the most common of the FGFR-associated craniosynostosis syndromes. Common features of Crouzon Syndrome (OMIM ID #123500) include bicoronal suture craniosynostosis with occa- Sional pansynostosis, hypertelorism, Severe ocular proptosis, Strabismus, hypoplastic maxilla and relative mandibular prognathism (Reardon et al., 1994). In-depth radiographic analyses of Crouzon Syndrome patients also has revealed a high percentage of patients who have conductive hearing loss, joint stiffness, calcification of the stylohyoid ligament and vertebral fusions (Kreiborg, 1981b). Hydrocephalus also is not uncommon. Crouzon Syndrome is associated with mutations in FGFR2. While mutations that cause Crouzon are distributed across multiple domains of the protein, the vast majority of mutations map to C278 or C342, two residues which are critical for formation of the intramolecular disulfide bridge within the Ig3 domain. Crouzon Syndrome with Acanthosis Nigricans (OMIM ID #612247) is distinct from Crouzon Syndrome both in genotype and phenotype. While Crouzon Syndrome consistently is associated with mutations in FGFR2, Crouzon with Acanthosis Nigricans is associated with an A391E mutation in the transmembrane domain of FGFR3 (Meyers et al., 1995; Wilkes et al., 1996). Patients with this syndrome have the clinical characteristic of Crouzon Syndrome plus Acanthosis Nigricans. The skin abnormalities are of early onset and include velvety hyperplasia, accentuation of skin markings and hyperpigmentation in flexural regions including the neck, axillae, elbow and groin. Additional associated features include choanal atresia and shortened vertebral bodies (Schweitzer et al., 2001). Apert Syndrome is the most severe of the craniosynostosis Syn- dromes (OMIM ID #101.200) and is caused by an S252W or P253R mu- tation in the linker region between the Ig2 and g3 domains of FGFR2 (Wilkie et al., 1995). This syndrome is characterized by craniosynostosis with hypertelorism, down slanting palpebral fissures, midface hypoplasia and widely patent fontanelles. Bony syndactyly of hands and feet with sparing of the thumbs results in a “mitten-like” appearance. Multiple 362 Hatch Central nervous system abnormalities also have been noted including hydrocephalus, ventriculomegaly, megalencephaly and gyral malforma- tions. Defects in the corpus callosum, Septum pellucidum, hippocampus and cerebral cortex also may be present. Cleft palate or a bifid uvula and hearing loss due to fused ossicles may be observed. Mental retardation is not uncommon. Fused cervical vertebrae and elbow ankylosis may be present (Kreiborg et al., 1992; Cohen, 1993b). Most cases of Apert Syn- drome are sporadic and the syndrome is associated with advanced pater- nal age (Glaser et al., 2000). More recent studies indicate that the high frequency of de novo Apert-associated FGFR2 mutations may be due to an increase in the clonal expansion of spermatogonia that carry these mutations (Goriely et al., 2003, 2005). MOUSE MODELS OF FGFR-ASSOCIATED CRANIOSYNOSTOSIS Despite our knowledge in the genetics of craniosynostosis, the biologic pathogenesis by which mutations in FGF receptors lead to the craniosynostosis phenotype remains elusive. FGFR2 is expressed in proliferating and differentiating osteoprogenitor cells, and FGFR1 is expressed in differentiating osteogenic cells along and within the Osteogenic fronts of growing cranial bones, indicating that FGFR activity Could control cranial suture development by altering precursor cell Survival, proliferation, differentiation, cell fate, matrix deposition and/ or mineralization (Iseki et al., 1997, 1999; Rice et al., 1999; Lana-Elola et al., 2007). The development of mouse models of FGFR-associated CranioSynostosis has allowed for an in vivo approach to investigating the molecular mechanism(s) that lead to craniosynostosis. Analyses of these mutant mice provide some insight into the pathogenesis of Craniosynostosis (Zhou et al., 2000; Chen et al., 2003; Eswarakumar et al., 2004; Yin et al., 2008; Liu et al., 2013; Twigg et al., 2009; Tables 1-4). To advance our understanding of mechanisms that lead to CranioSynostosis, we are investigating the Fgfr2°* mouse model of Crouzon Syndrome. Mice carrying this classic Crouzon Syndrome- associated FGFR2°* mutation initially were reported to have Characteristics similar to those of Crouzon Syndrome patients including a dome-shaped skull, wide-set and proptotic eyes, premature fusion of 363 FGF Signaling Table 1. Mouse model of FGFR-associated craniosynostosis (Pfeiffer Syndrome). proliferation and osteoblast differentiation. * Increased calvarial bone mineralization. tº Human Receptor Mutation Syndrome Phenotype References * Viable and fertile with normal long bones. * Craniosynostosis of frontal, Pfeiffer x sagittal and coronal sutures. Dome shaped skull, facial Syndrome aSVmmetr idface, hvpoplasia Zhou et al FGFR1 || FGFR1°250R/* human y y migrace, nypop al., e and hypertelorism. 2000 mutation × d calvarial cellul FGFR1P252R/* Increased Calvarial Cellular * Table 2. Mouse model of FGFR-associated craniosynostosis (Crouzon Syndrome). proliferation. * Increased bone marrow osteoprogenitor numbers. * Enhanced early and inhibited late osteoblast differentiation. * Decreased cranial bone volume and density. Receptor Mutation Human Phenotype References Syndrome * Heterozygotes are viable and fertile. * Midface hypoplasia, ocular proptosis, craniosynostosis and fusion of multiple facial bones. * Homozygotes are lethal at Crouzon P0 with cleft palate, tracheal Eswarakumar Syndrome defects, lung defects, vertebral et al., 2004 FGFR2 FGFR2°3°/* human joint fusions with diminished mutation vertebral body ossification. Liu et al., FGFR2C342Y/+ * Increased coronal suture cell 2013 364 Hatch Table 3. Mouse models of FGFR-associated craniosynostosis (Apert Syndrome). Receptor Mutation Human Syndrome Phenotype References FGFR2 FGFR2S250w Apert Syndrome human mutation FGFR2S252W/* >k × × 2k >k >k xk Viable with decreased fertility of females. Small body size, dome shaped skull, craniosynostosis, hypertelorism, midface hypoplasia. No premature fusion of cranial base synchondroses. No difference in cellular proliferation. No differences in Osteoblast differentiation. Increased coronal bone & suture cell apoptosis. Diminished cranial bone thickness and formation. Chen et al., 2003 FGFR2 FGFR2P253R Apert Syndrome human * Viable and fertile. >k Growth retardation, dome shaped skull, hypertelorism, midface hypoplasia, craniosynostosis, variable syndactyly and delayed fusion of posterior frontal suture. Yin et al., 2008 >k Ectopic cartilage detected in Sagittal suture. * Increased osteopontin expression in coronal suture. * Retarded endochondral growth and ossification. mutation FG FR2P253R/* Coronal and lambdoid sutures, a shortened maxilla and an apparently normal appendicular and axial skeleton (Eswarakumar et al., 2004). Consistency of this phenotype was not reported. Subsequent com- prehensive craniofacial analysis of FGFR2°* mice on a mixed ge- netic background revealed a rather severe phenotype that included 365 FGF Signaling Table 4. Mouse model of FGFR-associated craniosynostosis (Muenke Syndrome). Receptor Mutation sº Phenotype References * Viable and fertile. * Dome shaped skull, facial Muenke bone synostosis, variable craniosynostosis and Syndrome, sensorineural hearing loss Twigg et al P244R/+ * */ FGFR3 FGFR3 human * Delayed calvarial ossification. 2009 mutation * Diminished b g | FGFR3P250R/* Iminisned long pone minera density. * Genetic strain dependent phenotype. obliteration (complete fusion) of the left and right coronal sutures in 90% of mice, obliteration of the sagittal suture in 70% of mice and obliteration of the left and right lambdoid sutures in 30-40% of mice (Perlyn et al., 2006b). The intersphenoidal synchondrosis of the anterior cranial base also was reported as fused in 100% of the mice with complete obliteration in most cases. These mice appear to reflect the more Severe form of Crouzon Syndrome that is reported to occur in some patients (Flippen, 1950; Cunningham et al., 2007). . To investigate biologic mechanisms that lead to craniosynostosis and abnormal craniofacial skeletal development, we created congenic BALB/c FGFR2°* mice (Fig.2). The FGFR2°34” mutation in the BALB/c genetic background leads to a consistent and relatively mild craniofacial phenotype including partial fusion of the Coronal and lambdoid sutures, interSphenoidal Synchondrosis and multiple facial bones, with no fusion of other Craniofacial Sutures (Liu et al., 2013). This phenotype appears to reflect the less severe and more typical form of Crouzon Syndrome that involves significant midface hypoplasia with limited craniosynostosis. Despite this milder phenotype, linear and morphometric analyses demonstrate that FGFR2°42'ſ mice on the BALB/c genetic background differ significantly in form and shape from wild-type mice and that the FGFR2°* mutation effects bones of the face, cranium and cranial base in a similar yet milder manner than that which previously was reported for mice on a mixed genetic background (Perlyn et al., 2006b). 366 Hatch Wild type Crouzon Figure 2. Morphologic differences between FGFR2° Crouzon and wild-type murine craniofacial skeletons. Axial and lateral isosurface images of 18 micron resolution micro-computed tomographic scans of four-week-old, FGFR2°* and FGFR2” mouse skulls reveal significant morphologic differences between the mutant and wild-type littermates. Similar to Crouzon Syndrome patients, the FGFR2°* skull appears dome shaped and shows evidence of significant midface hypoplasia. More specifically, the Crouzon skull is shorter in antero- P08terior dimensions, but longer in lateral and infero-superior dimensions. Note (egions of fusion evident within the coronal suture and the far lateral aspects of the lambdoid suture. Because it is unknown why the FGFR" mutation preferentially affects certain craniofacial bones and sutures over others, and because Previous reports had demonstrated that activating mutations in FGF ſeceptors lead to abnormal osteoblast differentiation and bone formation (LOmri et al., 1998; Fragale et al., 1999; Mansukhanietal., 2000; Zhou et al., 367 FGF Signaling 2000; Chen et al., 2003; ESWarkumar et al., 2004; Yin et al., 2008; Holmes et al., 2009; Twigg et al., 2009; Wang et al., 2010), we also compared effects of the FGFRS*” mutation on frontal versus parietal bone cells and tissues. Our analyses showed that the FGFR2°” mutation promotes abnormal osteoblast differentiation (enhanced early and inhibited late Stage differentiation) and diminished bone formation that is more Severe in the frontal than the parietal bones. These results confirm that FGFR2- asSociated CranioSynostosis occurs in association with diminished cranial bone formation and may provide a potential biologic explanation for the Clinical finding of phenotype consistency that exists between many Crouzon Syndrome patients. It is Striking that the FGFR2°/* mouse model of Crouzon Syndrome, the FGFR2” mouse model of Apert Syndrome and the FGFR2” mouse model of Apert Syndrome all exhibit craniosynostosis, but do not exhibit increased cranial bone formation or mineralization. The mouse model of Muenke's craniosynostosis also exhibits a craniofacial morphological and CranioSynostosis phenotype similar to that seen in human patients, with no enhanced calvarial bone formation. These FGFR3*** mice have a dome-shaped skull with consistent facial bone Synostosis and variable craniosynostosis. Remarkably, these mice also show delayed calvarial ossification and diminished cranial bone-mineral density compared to wild-type littermates (Twigg et al., 2009). In contrast to this, mice carrying the P250R mutation in FGFR1 associated with Pfeiffer Syndrome exhibited a dome-shaped skull, midfacial hypoplasia, hypertelorism and craniosynostosis of multiple cranial sutures, with advanced calvarial bone mineralization, increased proliferation and osteoblastic differentiation of cells within and around the sagittal suture (Zhou et al., 2000). Taken together, these studies indicate that while increased calvarial bone formation and mineralization may be a component of some forms of Craniosynostosis, it certainly is not central to the pathogenesis of all forms of FGFR-associated craniosynostosis. In support of the idea that FGFR-associated craniosynostosis is associated with diminished bone formation and/or mineralization is the finding that craniosynostosis also is seen in multiple human disorders involving severely under-mineralized bone. Human activating mutations in FGFR1 that cause Osteoglophonic Dysplasia lead to dwarfism, craniosynostosis, hypophosphatemia and 368 Hatch Severe demineralization of both endochondral and intramembranous bones (OMIM ID #166250; White et al., 2005). CRANIOSYNOSTOSIS IN ASSOCIATION WITH DYSREGULATED PHOSPHATE HOMEOSTASIS While the diminished Cranial bone formation in these FGFR- associated mouse models of craniosynostosis previously has not been Considered as contributing to the development of craniosynostosis, it is interesting to note that craniosynostosis is known to occur in disorders of low bone mineralization due to dysregulated phosphate homeostasis. For example, craniosynostosis is seen in humans and mice with X-linked hypophosphatemic rickets due to mutations in the phosphate regulating protein, Phex (OMIM ID #307800; Roy et al., 1981; Sabbagh et al., 2000). Patients and mice with Phex mutations have low serum phosphate and defective bone mineralization due to high circulating FGF23 levels and diminished renal phosphate reabsorption. It is unknown how these defects result in craniosynostosis, but similar to studies of human patients with FGFR2-associated Craniosynostosis, these patients also commonly have paradoxical heterotopic calcification of normally non-mineralizing tissues, such as tendons and ligaments (Liang et al., 2009). Additionally, craniosynostosis is seen in at high rates in infants with hypophosphatasia (OMIM ID #171760) due to inactivating mutations in the enzyme, tissue non- specific alkaline phosphatase (TNAP/Alpl/Akp2; Mornet, 2007; Wenkert et al., 2009; Whyte, 2010). These patients have severely deficient bone mineralization (Whyte, 2010). TNAP is a local generator of inorganic phosphate and an established critical mediator of tissue mineralization, but again it is unknown how diminished TNAP activity leads to craniosynostosis (Narisawa et al., 1997; Murshed et al., 2005). Finally, craniosynostosis previously was reported to occur secondary to antacid induced infantile hypophosphatemia (Shetty et al., 1998). Together, these findings indicate that craniosynostosis occurs in multiple disorders involving dysregulated phosphate homeostasis and significantly diminished bone mineralization. 369 FGF Signaling To better understand the pathogenesis of hypophosphatasia- associated craniosynostosis, we currently are investigating the craniofacial morphometric and craniosynostosis phenotype of TNAP knockout mice. This genetically engineered mouse model of hypophosphatasia previously was utilized to investigate the bone and tooth abnormalities that occur in association with hypophosphatasia, and to document that treatment of the mice with a recombinant hydroxyapatite-targeted form of TNAP enzyme can prevent the bone and tooth abnormalities seen in these mice (Narisawa et al., 1997; Yadav et al., 2011, 2012). These mouse-based studies have led to the use of a similar recombinant form of TNAP enzyme for the prevention of bone and tooth defects infants and children born with hypophosphatasia (Whyte et al., 2012). Currently, children who are born without adequate TNAP enzyme are treated by injection with a bone-targeted recombinant form of TNAP enzyme starting a few months to years after birth. While this treatment protocol has been shown to be highly successful for curing the long bone and tooth defects seen in this patient population, many of these children still develop craniosynostosis (Whyte et al., 2012). Importantly, because craniosynostosis can develop during late fetal or early post-natal life, we hypothesize that treatment would need to be initiated at these earlier developmental time points in order to prevent the clinical manifestation of craniosynostosis in these children. Initial studies indicate that the TNAP knockout mouse model of hypophosphatasia exhibits craniosynostosis in the form of coronal suture fusion and that treatment of these mice starting at post-natal day one with a bone-targeted recombinant form of TNAP enzyme can prevent this abnormality (Fig. 3). These findings are of potential clinical significance because they demonstrate that cranioSynostosis potentially can be prevented in hypophosphatasia—if treatment with the recombinant hydroxyapatite-targeted form of TNAP enzyme is initiated shortly after birth. The goal of this line of research is to recommend revision to the current TNAP enzyme replacement therapy protocol in infants, in order to prevent and/or significantly diminish craniosynostosis in these patients. 370 Hatch TNAP+1+ TNAP-1- no treatment no treatment Figure 3. Craniosynostosis in the tissue non-specific alkaline phosphatase (TNAP) knockout mouse model of hypophosphatasia. The TNAP knockout mouse is an established mouse model of hypophosphatasia. Macroscopic views of unstained skulls from three-week-old, TNAP/ and TNAP* mice reveal coronal suture fusion to be evident in TNAP/, but not wild-type littermate calvaria. 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Zeiger JS, Beaty TH, Hetmanski JB, Wang H, Scott AF, Kasch L, Raymond G, Jabs EW, VanderKolk C. Genetic and environmental risk factors for Sagittal craniosynostosis. J Craniofac Surg 2002;13:602-606. Zhou YX, Xu X, Chen L, Li C, Brodie SG, Deng CX. A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of Calvarial sutures. Hum Mol Genet 2000;9:2001-2008. 381 ENVOI: THE MOYERS SYMPOSIUM, A MINER'S CANARY FOR 21st CENTURY ORTHODONTICS Lysle E. Johnston Jr. ABSTRACT The Moyers Symposium is four decades old. Its evolution parallels that of the Orthodontic specialty. It once was known commonly as the “Growth Symposium;” as with the specialty of orthodontics, craniofacial biology was its basic theme. It provided an opportunity to interact the “best and brightest” in and around the specialty. Both Robert Moyers' career and his belief that orthodontics is a science- based service exemplified this linkage between “growth” and orthodontics. Times have changed. The Symposium now tends to feature ways of growing faces without much of a discussion of how faces grow. This disconnect between theory and practice mirrors that seen in contemporary orthodontics, a venerable Calling that seems to have lost its way. The Moyers Symposium is, in effect, a "miner's canary” that reflects the intellectual health of the specialty. The conceit of this short communication is the idea that a return to the Symposium's original message and emphasis may help, in some way, to nudge the specialty back to its historical belief that it is a learned, evidence-based calling. KEY WORDS: facial growth, orthodontic theory versus practice, Robert Moyers, "Growth Symposium” Forty years is a long time, especially for a named symposium in orthodontics. Eponymous societies and meetings come and go; the Moyers Symposium has endured and evolved due in no small measure to the stature of Bob Moyers, the significance of the Symposium to Orthodontics and its self-image, and to the ongoing efforts of Jim McNamara. Indeed, appreciation for Jim's many contributions may in fact be one of the few things upon which he and I can agree. I digress. In this short “personal communication,” I will argue that the Symposium is in effect a miner's canary. To borrow a term from series television, its 383 A Miner's Canary “story arc" mirrors that of the specialty. Its history is a commentary on the health of a specialty whose core ethos was crafted by generations of leaders, one of whom we honor here. | first met Robert Edison Moyers 56 years ago. Indeed, my career started as a research assistant tracing cephalograms from The University of Michigan Elementary and Secondary School Growth Study. This project, among others, was a natural by-product of the prevailing view that “growth” is the basic science of orthodontics. Over the years, Moyers was responsible for a variety of “growth” projects, including The Burlington Study and The Center for Human Growth and Development. Indeed, it can be argued that this present gathering is nearly a half century old, given that one of the first Growth Center projects was the 1967 Conference on Cranio-Facial [sic] Growth, featuring such luminaries as Melvin Moss, Kalevi Koski, Donald Woodside, William Krogman and, to keep everyone on the straight and narrow, perhaps the world's pre-eminent statistician, C.R. Rao (Moyers & Krogman, 1971). An early and ongoing emphasis on facial growth seems to have been a natural by-product of Angle's concept of the specialty and its grounding in science. Save for our “space-age” materials, there is little that is done or thought today that Angle did not do orthink a century ago. Angle removed bone to hasten tooth movement; he resected “peridental fibers” with iridectomy blades; and his treatments were predicated on his concepts of growth or, rather, his concepts of modifying growth. Angle's first appliance capable of producing bodily tooth movement—the "pin-and-tube” appliance—was developed as a “working retainer” to apply labial root torque to flared incisors. It was assumed that this maneuver would grow bone. Angle used Class Il elastics (after convincing his followers that they had been invented by a Dr. Baker, rather than Calvin Suveril Case); however, before this, he employed bite- jumping appliances that almost are identical in effect to the mandibular anterior repositioning appliance and to the Herbst appliance. Indeed, he wrote a letter of complaint (1908) to Wilhelm Herbst (apparently under the assumption that he, rather than his son, Emil, had developed the appliance): - 384 Johnston Why are you a copyist of my appliances, and a bad one, a very bad one at that? Why Can't you add something of real merit to the science of orthodontia? It's a bad comment on your country—the work you and Alfred Korbitz are doing. You could, at least, if you were honorable men, give credit where credit is due, even though you are violators of the law, commercially and ethically. I would be pleased to have your views on this point. Angle's ideas about growth modification were consistent with such contemporary European thought as “Wolff's law” and Roux’s “mor- phological law of functional adaptation.” Angle, however, went beyond isolated mechanical exploits: he assumed that a “Class I” occlusion, how- ever achieved (except, of course, by extraction), would optimize the de- Velopment of facial form. For example, his approach to Class Il malocclu- Sions was to “distalize” the upper molars to achieve a Class I occlusion, which, in turn, would cause favorable mandibular growth, which growth would cure the malocclusion, grow an ideal face and, in the process, bring the upper molars back to their proper position under the “key ridge.” A Century or so ago, it was an exciting, testable hypothesis; its continued Survival in a variety of guises, however, is an indictment of the 21st cen- tury, not the 19th century and certainly not of Edward Hartley Angle. Angle was the first to limit his practice (1892), the first to open a school (1900), and the organizer of the first orthodontic society (The Society of Orthodontists, 1900; now the American Association of Orthodontists). In the process, he developed our sustaining mythology: that orthodontics is a true medical science whose basis is craniofacial growth and its modification by treatment. Orthodontia was serious business: Angle's students were chosen to be serious people of real Substance. For example, Milo Hellman (Angle, 1908) worked both with William King Gregory, Curator, American Museum of Natural History (Our Face From Fish to Man) and Thomas Hunt Morgan, a Nobel Laureate for his work on drosophila genetics. The Carnegie Foundation's Flexner Report (1910) and its Gies Report (1926), however, brought into 385 A Miner's Canary question the quality of proprietary schools. The first orthodontic pro- grams—all of them proprietary—were tarred with the same brush. Orthodontics needed a home. To this end, our sustaining mythol- ogy came to the fore: orthodontics is a science and the proper home for a science is the university...preferably the graduate school of a university. In passing, it is perhaps worth noting that we came to the universities; they didn't come to us. Their business is the creation and husbanding of knowledge; we said that we would be willing, productive contributors. The first master's program was started here at Michigan and its chair, A. LeRoy Johnson, was one of the most respected proponents of the con- cept that both dentistry and orthodontics are true medical sciences. Un- fortunately, just before the outbreak of World War II, the application of the cephalogram to the study of treatment effects called into question many of Angle's growth concepts. One of my teachers, C. Edward Mar- tinek (1945), lamented: Ten years ago we were beginning to question our ability to make bone grow and to “develop the mandible forward.” These phenomena are today doubted, if not repudiated. Brodie (1950) was even more distressed: When the staff at Illinois in 1937 presented its findings on the results of treatment we were all shocked by the revelation that we were influencing only alveolar bone. There was a universal attitude of despair. Drilled in a concept that was as tangible as the occlusion of the teeth, it came as a terrible disillusionment to discover that the concept Igrowing faces] was not tenable. It was of the nature of childhood's chagrin and disappointment upon finding out that there is no Santa Claus. The War served to divert our attention from this looming crisis of faith. When hostilities ceased, it was time for orthodontics to get back to the business of growing faces and being special. In retrospect, it is easy to quote Marx (or was it Engels?), “History repeats itself: the first time as tragedy, the second as farce.” This time, however, our science seemed better (it always does) and our leaders were, above all, serious Scientists; the best and brightest. Enter Robert Edison Moyers. 386 Johnston Moyers' wartime record with “Wild Bill” Donovan and the Office of Special Services is well known (Clemente, 2010). I suspect, however, that, after negotiating the freedom of 900 British prisoners with “Aris” Velouchiotis—the grizzled Communist resistance leader in wartime Greece—a return to lowa must have been a marked anti-climax for a smart young dentist who had already lived a life of adventure. Gingival margin trimmers? Silicate cements? Gingivectomies? From this remove, such a career for Bob Moyers seems inconceivable. Once again, our sustaining mythology apparently came to the rescue: orthodontics (“the thinking man's specialty”) and a basic science Ph.D. were enticing alternatives. It was a path that many of us would follow. We weren't sure where it all Would lead, but if we piled up enough Science, Surely something clinically useful would emerge. Many in my dental class went into orthodontics. For most, Moyers Was the pied piper. I, however, was attracted by the money my parents had paid for my treatment when I was 12. My aspirations were trivial and, it would seem, obviously so. When I was a senior, Moyers told me "I Sure hope you don't plan to apply to orthodontics this year.” Instead, he encouraged me to spend a year studying with James Henderson Scott of the Oueen's University of Belfast, Northern Ireland. Scott had a truly unique intellect; he saw things differently. When he was awarded a personal chair in dental anatomy, he gave his inaugural address, The Making of Mankind, in blank verse, “...because,” as he said, “I believe that it is right that members of a university should every now and then attempt to break away from stereotyped patterns of behaviour" (1965). Although I was clearly out of my league, I think I learned from him what Moyers Wanted me to learn: that there is more to orthodontics than money. After a year and almost according to a prepared script, I returned to Ann Arbor and began an orthodontic program to which I had made no formal application. This time, Moyers had said, “You can fill out the papers when you get here.” Thus began one of many careers in orthodontics that were initiated and nurtured by Bob Moyers. It was what he did. Moyers liked the idea of ideas. He liked to build things (perhaps more than he liked running them). He collected talented associates the Way the rich collect art: Egil Harvold, D. Harvey Jenkins, Fred Bookstein and Stanley Garn, among many others. Much as Boswell interpreted John- Son for 18th century England, Moyers sought to interpret their work for 387 A Miner's Canary 20th century orthodontics. His students — Rolf Behrents, David Carlson, Lee Graber and James McNamara, for example – have gone on to distin- guished careers. He inspired many students in many ways. Among those he inspired was Verne Primack, whose ideas and finances led to this Sym- posium. His was a great contribution to dentistry, orthodontics and the University. For Michigan, it was a golden age; the Symposium, its crown jewel. It was a manifestation of our self-image. The Symposium's exis- tence and its tenor were proof that orthodontics is a true medical science. Treatment presentations were declassé; “how the face grows" was the emphasis. It was fun debating the various growth theories du jour. It was “The Growth Symposium.” It attracted the best and the brightest – Alexandre Petrovic, Birte Melsen, David Sackett, Frans van der Linden, Lorenzo Franchi, Tiziano Badcetti and, yes, Melvin Moss. It also attracted a knowledgeable, intellectually stimulating audience. For many years, my students made a yearly pilgrimage to Ann Arbor for the Presymposium (one year there even was a Pre-Presymposium!) and the Symposium, proper. It was like going to an intellectual spa to take the waters. Indeed, many of my past students from all three schools were here at the 40th; however, things have changed, both in orthodontics and in its doppelgänger, the Moyers Symposium. Despite a heightened preoccupation with bone growing, “how the face grows” rarely is discussed. There are no growth “theories," good or bad. No arguments. No controversy. Moyers' Centerfor Human Growth and Development no longer is the sole sponsor of the Symposium. The Center studies development, but precious little growth. Indeed, I suspect that few in the Center would even know of the Symposium's existence. The Dental School has taken over. Unfortunately, in many schools, the status of the various graduate programs, orthodontics included, has de- clined. Save for gene therapy (which may or may not ever see routine clinical application), our research generally is incapable of competing suc- cessfully for extramural funding, the mother's milk of top tier universities. Research is what they do and it costs money. We have chosen instead to dwell in the land of Nod, considerably east of the mainstream academic Eden. Contemporary meetings seem to reflect this change: both the sub- jects and the cast of characters have changed; so, too, has the audience. 388 Johnston Many of today's orthodontic meetings are little more than info- mercials sponsored by the companies. There are no “theory” presenta- tions. Stability? Everything relapses; do what you want and then glue the teeth together. Etiology? It’s “multi-factorial.” Functional appliances? They “work;” what more need we know? In the past, the occasional presentation by a de-frocked European anthropologist at least made us feel “scientific,” Joseph-Marie de Maistre (1753-1821) observed that, “In a democracy, people get the leaders they deserve.” So it is with ortho- dontics: we are where we are because it seems to be not only what we deserve, but also what we want. Nobody dies from anchorage loss and everything—and apparently anything—works well enough to support a practice. What can be done? Should anything be done? Has our sustain- ing mythology that orthodontics is a science outlived both its utility and its believability? Who can say? Perhaps the time has come for the Sym- posium to go its own way; to stop mirroring the fads and trends of the Specialty. In the words of Jimmy Scott's inaugural address (1965): Education, the passing of knowledge From generation to generation, ls the essential communication Without which progress would be impossible. Mere accumulation of information Would by itself in the end Destroy wisdom. In every generation there must be available Opportunities for meditation, A setting aside for those who appreciate silence; Adequate facilities to escape The continual chatter Of Canteen and market place, The distraction of meaningless words. For a specialty that seems in danger of losing its soul, one that is in desperate need of “adequate facilities to escape the continual chatter of Canteen and market place, the distraction of meaningless words,” this 389 A Miner's Canary can be just such a place. I would suggest, however, that it once again must be a “Growth Symposium.” It must lead rather than follow; it must shine rather than reflect. If the canary thrives, perhaps by some strange cause- effect inversion, there is hope for the miners. In the words of Lincoln's first inaugural address, perhaps at a professional level we once again can be “touched...by the better angels of our nature.” REFERENCES Angle EH. Letter to Wilhelm Herbst. November 20, 1908. In: Peck S (ed). The World of Edward Hartley Angle, MD, DDS. His Letters, Accounts and Patents. 4 Volumes. Boston, MA: E.H. Angle Education and Research Foundation 2007;3:227–228. Brodie AG. Appraisal of present concepts in orthodontia. Angle Orthod 1950;20:24–38. Clemente JD. Robert E. Moyers: OSS dentist with the Greek resistance. OSS J 2010;34–36. Martinek CE. Orthodontics' last decade of progress. Am J Orthod 1945; 31:161-167. Moyers RE, Krogman W.M. (eds.) Craniofacial Growth in Man. Oxford: Pergamon Press 1971. Scott JH. The Making of Mankind: An Indugural Address Delivered Before the Oueen's University of Belfast on 3 November 1965. Belfast: The Oueen's University 1965. Note: The author teaches orthodontic history and has acquired bits and pieces of information over the years whose provenance is lost in the mists of a long academic career. Many details in the present paper, however, were derived/verified from: Wahl N. Who Was Who in Orthodontics: With a Selected Bibliography of Orthodontic History. 1stBooks Library, 2002. 390 ANTI-RESORPTIVE AND BONE ANABOLIC AGENTS FOR PERIODONTAL THERAPY Andrei D. Taut, Riley A. Schaff, Min Oh, William V. Giannobile ABSTRACT Host inflammatory responses, instigated by periodontopathogen infection, result in irreversible destruction of both soft and hard tooth-supporting structures. A Complex network of inflammatory cytokines from the gingival tissue induces a destructive response by activating specific cells that mediate the breakdown of the periodontal ligament and alveolar bone. Host modulation has emerged as a therapeutic strategy by its inhibition of the pro-inflammatory signaling pathways in order to attenuate and prevent irreversible tissue destruction in patients with periodontal disease. Another therapeutic strategy of recent exploration is the use of bone anabolics to increase bone mass. These therapies have been investigated primarily for bone regeneration in cases of progressive periodontal disease and alveolar bone loss. Host modulatory therapies also have potential utility by inhibiting osteoclastic activity for promoting orthodontic anchorage. This chapter explores the known biological mechanisms behind inflammatory and skeletal disorders, as well as clinical and pre-clinical evidence for therapeutic intervention for maintaining periodontal structures and regenerating alveolar bone mass and strength. KEY WORDS: periodontitis, host Tauttion, anti-resorptives, bone formation, re- generative medicine INTRODUCTION The concept of host modulation has emerged as a promising therapeutic strategy for the prevention and treatment of periodontal disease. The pursuit of effective host modulatory therapies has arisen as the causative factors for periodontal breakdown have become elucidated further. Periodontal disease begins with an alteration in the commensal Oral microbiome, typically triggered by a few, highly pathogenic, Gram- negative, anaerobic species (Darveau, 2010). Despite their relative low abundance, these highly invasive species manage to colonize the gingival 391 Periodontal Therapy sulci and create an inflammatory immune response, causing a shift in the oral microbiome (Hajishengallis et al., 2011). This shift further elicits an exuberant immune response from the host, leading to immunologically induced osteoclastogenesis and the production of matrix proteinases that cause soft and hard tissue breakdown (Reynolds et al., 1994; Taubman et al., 2005). Tooth mobility and eventually tooth loss result from this breakdown. Some of the key periodontopathogens responsible for initiating this host response have been characterized well and include Porphy- romonas gingivalis, Treponena denticola and Tannerella forsythia. These three bacterial species were classified as the “red complex" (Socransky et al., 1998), referring to the highly pathogenic nature of these species. Due to the infectious nature of periodontal disease, there have been many antimicrobial therapies employed in hopes of mitigating the colonization of the oral cavity by such pathogens, including scaling and root planing (SRP) and antibiotics (Genco, 1992; Socransky and Haffajee, 1993; Hanes and Purvis, 2003). Though these therapies have been shown to be effective, more insight has been gained into the host response to infection by members of the red complex. As the complex immunological mechanisms of disease potentiation have become clearer, the need for immunomodulatory drugs has increased. Attenuation of the excessive host immune response has proven critical in further reducing the tissue destruction associated with peri- odontal disease. The molecular mechanisms by which the immune re- sponse induces bone resorption also have been clarified more thorough- ly. Receptor activator of nuclear factor-Kſ (RANK) is a key pathway that allows crosstalk between the immune system and agents of bone remod- eling (Gruber, 2010). RANK ligand (RANKL), which is membrane bound to osteoblast surfaces and is secreted by activated T helper cells, binds to RANK, which is present on osteoclast progenitors and dendritic cells and is essential for the induction of osteoclast progenitor differentiation and activation (Lacey et al., 1998; Kong et al., 1999; Suda et al., 1999). Thus, it is important to weaken the immune response not only to reduce inflam- mation in the periodontium, but also to reduce the osteoimmune effects of bone resorption. 392 Taut et al. Many therapeutic strategies have been developed (Tables 1 and 2) and focus on early intervention of these destructive processes that cause irreversible tissue damage. Many of these therapies target Specific upstream cell signaling pathways in order to amplify—either positively or negatively—desired downstream gene transcription and protein expression. There also have been considerable efforts to develop therapies to regenerate both soft and hard tissue lost as a result of periodontal disease. This chapter will focus on the pathways relevant for host modulatory therapies, specifically the potential of new bone anti- resorptive and anabolic therapies. Table 1. Pharmacological agents with potential bone-anabolic actions. IL = inter- leukin; MMP = matrix metallo-proteinase; NO = nitric oxide; NSAID = non-steroi- dal anti-inflammatory drug; OPG = osteoprotegerin; rh = recombinant human; RANK = receptor activator of NF-kſ?; RANKL = receptor activator of NF-kſ ligand. Adapted from Kirkwood et al., 2007, with permission from Blackwell Munks- gaard. BONE ANABOLICS AGENT MECHANISM OF ACTION PERIODONTAL-RELATED REFERENCES EFFECTS Block activin-mediated & e. inhibition of osteoblast Activin differentiation and None published to date antagonists activation of osteoclast formation Inhibit GSK33 (1) Significant inhibition GSK33 phosphorylation and of linear alveolar bone g Ad t al., 2012 inhibitors subsequent proteasomal loss; and amowicz et al., degradation of 3-catenin (2) Gingival inflammation Wnt antagonist Inhibit sclerostin, Dkk1, inhibitor sFrps Significant increase in bone volume and density Taut et al., 2013 Stimulate endogenous Calcilytics secretion of PTH None published to date Miller et al., 1997; * * * * * * Barros et al., 2003: º g (1) Significant gain in z g (1) * Wnt linear bone and clinical º º º 2005. PTH g g; attachment level; ung et al., 2007; (2) Increase serum Ca” (2) Significant reduction i Mair et al., 2009; concentration Ignificant reduction in Bashutski et al., 2010; probing depth Bellido et al., 2010; Jensen et al., 2011 393 Periodontal Therapy Table 2. Pharmacological agents with potential anti-resorptive actions. IL = interleukin; MMP = matrix metallo-proteinase; NO = nitric oxide; NSAID = non- steroidal anti-inflammatory drug; OPG = osteoprotegerin; rh = recombinant human; RANK = receptor activator of NF-kſ; RANKL = receptor activator of NF-kſ ligand. Adapted from Kirkwood et al., 2007, with permission from Blackwell Munksgaard. ANTI-RESORPTIVES AGENT MECHANISM OF ACTION PERIODONTAL- RELATED EFFECTS REFERENCES NSAIDs (1) Inhibition of cyclooxygenase enzymes that participate in arachidonic acid metabolism; (2) Reduction of prostanoid production, especially prostaglandin E2 (1) Significant reduction of alveolar bone loss; (2) Inconsistent benefits on clinical attachment gain or probing depth reduction Vane, 1971; Goldhaber et al., 1973; Gomes et al., 1976; Nyman et al., 1979; Weaks-Dybvig et al., 1982; Williams et al., 1988, 1989; Kornman et al., 1990; Lindsley et al., 1990; Offenbacher et al., 1992, 1993; DeWitt et al., 1993; Hawkey, 1993; Reddy et al., 1993; Jeffcoat et al., 1995; Brägger et al., 1997; Cavanaugh et al., 1998; May and Ghosh, 1998; Ng and Bissada, 1998; Shimizu et al., 1998; Bichara et al., 1999; Buduneli et al., 2002; Vardar et al., 2005 Bisphos-phonates Inhibition of osteoclast function (1) Significant attachment gain and probing depth reduction; (2) Significant alveolar bone gain Brunsvold et al., 1992; Weinreb et al., 1994; Reddy et al., 1995; Fleisch, 1997; Nakaya et al., 2000; Rogers et al., 2000; El-Shinnawi and El-Tantawy, 2003; Lane et al., 2005; Goya et al., 2006; Liu et al., 2006; Sharma and Pradeep, 2012 Reduction of nitric oxide Pre-clinical studies in rats; significant Moncada et al., 1991; No synthase production through inhibition of reduction of bone tohina et al., 1998; inhibitors NO SVnthases loss and gingival Lappin et al., 2000; y - ging de Leitão et al., 2005 inflammation (1) Inhibition of pro- Pre-clinical study in dogs; * - e. rhill-11 inflammatory cytokines and significant reduction of º sº other mediators; tissue attachment and g ---, g - e Martuscelli et al., 2000 (2) Stimulation of TIMP-1 bone loss (1) inhibition of cyclooxygenase and lipooxygenase (arachidonic Pre-clinical studv in rat - acid cascade); re-clinical study in rats; ontº fatty ducti f ) id insignificant reduction of Vardar et al., 2005 (2) Re uction O prostano S bone loss and leukotrienes, especially leukotriene B4 Horowitz et al., 2001; Mogi et al., 2004; Ogasawara et al., 2004; RANKL/ Pre-clinical in mice; Tanaka et al., 2005; RANK/ Inhibits RANKL/RANK-mediated º e º is g--. Soedarsono et al., 2006; * º º significant reduction in - OPG disruption osteoclastogenesis alveolar bone loss Bostanci et al., 2007, 2011; therapeutics Jin et al., 2007; Nagasawa et al., 2007; Chen et al., 2008; Dereka et al., 2010; Zhou and Mei, 2012 394 Taut et al. THERAPEUTIC APPROACHES FOR PERIODONTAL DISEASE MANAGEMENT Recent research demonstrating the importance of the host response in periodontal disease has led to significant interestin modulating the exuberant response with a goal of preventing and treating the disease more effectively. The ever-growing body of knowledge within the field of Cellular biology has led to the development of novel drugs that interact with high specificity in various cellular pathways, among which are those that mediate periodontal breakdown. “Host modulation” is a term that describes this intentional modification of the host response and is used largely within the field of periodontics (Golub et al., 1984; Williams, 1990). However, the concept is used widely across the medical field. Understanding and exploiting the cellular pathways involved in the host inflammatory response are crucial for an effective adjunc- tive treatment of periodontal disease or reducing osteoclastic activity in Orthodontic anchorage (Kirkwood et al., 2007). Another inflammation- mediated disease, rheumatoid arthritis (RA), has many analogous patho- genic mechanisms to periodontal disease (Mercado et al., 2003; Detert et al., 2010). Although an etiological difference exists between the two diseases—RA is autoimmune and periodontal disease is pathogenic—in- flammation, tissue destruction and bone loss all are characteristic of both diseases (Berthelot and Le Goff, 2010; Rutger Persson, 2012). With much Optimism, a series of host-modulating drugs has been developed with the end goal of providing an efficacious therapy for RA. One key approach to the treatment of RA is to modulate the pathways by which cellular stress induces the production of the inflam- matory cytokines important in the development of chronic inflammation. Mitogen-activated protein kinases (MAPKs) are an important subset of Cell-signaling pathways. The p38 MAPK cascade is a specific MAPK path- Way that is important in signaling extra-cellular stress for the induction of inflammatory cytokine production (Lee et al., 1994; Cargnello and Roux, 2011). These cellular pathways are crucial in the development of RA (Schett et al., 2000). A series of drugs has been developed that are known as p38 MAPK inhibitors, which either competitively or non-competitively inhibit 395 Periodontal Therapy the kinase action of the cascade (Hope et al., 2009; Elkhawad et al., 2012). Promising results have been found in pre-clinical trials of p38 MAPK inhibitors, including a decrease in inflammation-mediated tissue destruction in the joints (Hill et al., 2008; Balague et al., 2012). Analogous results have not been found yet in p38 MAPK inhibitor clinical trials, but hope has been placed in upstream modulation of regulators of the p38 MAPK pathway (Hegen et al., 2006; Hammaker and Firestein, 2010; Mourey et al., 2010; Clark and Dean, 2012). Like p38 MAPK inhibitors for the treatment of RA, the focus of many host-modulating therapies for periodontal disease is the immune response elicited by periodontopathogens. This response is characterized by an increase in pro-inflammatory cytokines through both an innate and an adaptive immune response (Graves and Cochran, 2003). These cytokines induce chronic inflammation in the periodontium aimed at attacking the invading pathogens, but it also can result in eventual soft tissue breakdown and bone resorption (Socransky and Haffajee, 1992). This inflammatory response is characterized in Figure 1 as a complex cytokine network that has many points of regulation subject to modulation. These numerous points of regulation present a number of potential means for host modulatory therapies. Upon stimulation by various bacterial components, including lipopolysaccharide (LPS), bacterial DNA or bacterial peptidoglycan, the innate immune system, via pattern-recognition receptors (PRRs), initiates an intracellular signaling cascade. This cascade acts through MAPKs, namely the p38 signaling pathway mentioned previously, leading to phosphorylation of numerous transcription factors (Kikkert et al., 2007). These transcription factors, including nuclear factor-Kſ (NF-kſ?), Elk-1, activated protein-1 and serum response factor (SRF), induce expression of pro-inflammatory cytokines (Ambili et al., 2005; Garcia de Aquino et al., 2009). The increased expression of pro-inflammatory cytokines leads to autocrine and paracrine action through a number of other cell-sig- naling pathways, including MAPK, Janus kinase and signal transducer and activator of transcription (JAK-STAT) and NF-Kſ (O'Neill, 2003; Da- vanian et al., 2012). Through these pathways, cytokines are able to induce bone resorption by immune cell-mediated osteoclastogenesis 396 Taut et al. -> - Intermittent sºlº or terparatide cytº-receptºr- ºcerostºn-up Increased osteoblastic activity BONE FORMATION Transcription actor-activated ºn-ºn NF-B inhibitor- sclerostin * – Il-1- TN- Osteoblast L-1 antagon- - p38 MAPK inhibitors Ax/star inhibitor- Fibroblast or PMN Lymphocytes H |- NF-B inhibitor- * - Transcription | - | actor-activated proinflammatory gene expression cytokines N T-cell-secreted v- Denosumab - RANKL MMP - Activated osteoclast - MMP- inhibitors RANK - Osteoclast precursor - - - - Proinflammatory cytokines differentiation SOFT AND HARD TISSUE DESTRUCTION Activation OPG/sRANKL Bºsphosphonates MMP inhibitors Figure 1. The complexity of the immune response to an invading periodonto- pathogen. Stimulation of pattern recognition receptors by bacterial components triggers a cascade of events, beginning with the initial response from neutrophils. Increased IL-1 and TNFs stimulate the production of more inflammatory Cytokines, which then act to increase the expression of MMPs, thereby increasing Soft and hard tissue destruction, and act to increase osteoclast differentiation and activation. Pathways relevant to bone formation also are shown (green arrows). Potential host modulatory therapies are shown in blue. JAK/STAT = Janus kinase and signal transducer and activator of transcription; MMP = matrix metalloproteinase; NF-Kſ = nuclear factor-kappa B; NSAID = non-steroidal anti- inflammatory drug; OPG = osteoprotegerin; PMN = polymorphonuclear cell; RANK(L) = receptor activator of nuclear factor-Kſ (ligand); SPTH = synthetic parathyroid hormone. and soft tissue destruction by matrix proteinases (Birkedalhansen, 1993; Teng et al., 2000; Kawai et al., 2006). Thus, the goal of the potential host modulatory therapies is to act on these many and various pathways to mitigate the resorptive nature of the highly pro-inflammatory cytokine environment. 397 Periodontal Therapy BONE ANABOLIC THERAPY Skeletal mass, structure and biomechanical properties are regu- lated constantly by bone modeling and remodeling events. During bone modeling processes, bone formation and resorption occur independently to alter overall size and shape in response to functional demands. Ad- ditionally, bone remodeling events also provide lifelong maintenance of bone mass and microarchitecture via paracrine signaling and coupled ac- tivity of osteoclasts and osteoblasts (Fig. 2A,B). Together, these biologi- cal processes establish an overall balance between bone formation and resorption, essential for proper bone formation, turnover and healing. Under pathological conditions, aberrant cell signaling in bone modeling and remodeling pathways can interfere with skeletal homeo- stasis and ultimately lead to a variety of bone disorders, including osteo- porosis (Baron and Hesse, 2012). Osteoporosis is a widespread chronic disease characterized by reduced bone mineral density that predomi- nantly affects postmenopausal women and, to a lesser extent, older men. An imbalance in the bone remodeling process—increased bone resorption compared to bone formation—leads a decrease in bone density, compromised bone microarchitecture and fractures of, among other common sites, the lumbar spine, femoral neck and distal radius (Baron and Hesse, 2012). Therapeutic options for the treatment of osteoporosis and other bone disorders have been limited mainly to anti- resorptive drugs, which work by inhibiting osteoclast activation and bone resorption. Although some anti-resorptives have been shown to reduce fracture risk in certain populations, these drugs have several limitations (Chen and Sambrook, 2012). Most notably, anti-resorptives are believed to induce a state of low bone turnover and have been associated with adverse events such as atypical subtrochanteric femur fractures and, in rare cases, osteonecrosis of the jaw (Khosla et al., 2007; Lenart et al., 2008; Shane, 2010; Hollick and Reid, 2011). Consequently, attention has shifted toward the development of anabolic bone therapies, which are defined by the capacity to stimulate bone formation directly. 398 Taut et al. Bone Remodeling (Skeletal homeostasis) f f Bone formation Bone resorption LCs completed BMU OCs º” º ſº º º º A | resorption | reversal | formation | quiescence Osteoporosis (Bone loss) Bone formationſ? Bone resorption - - : - - -i º - * º _* B Q º ſº -- rhpTH, teriparatide (Bone gain) Bone formation Bone resorption modeling Activated Wnt *" Bone formation Bone resorption (I) modeling pº ſº a º * * Figure 2. Bone modeling and remodeling events during (A) skeletal ho- meostasis, (B) osteoporosis and (C, D) bone anabolic treatment. Blue arrows = relative activity of bone forming and resorptive events. OCS = Osteoclasts; OBs = osteoblasts; LCs = lining cells; OCYS = Osteocytes; BMU = basic multi-cellular unit. Adapted from Baron et al., 2012, with permission from The Endocrine Society. Bone anabolics would increase bone formation and mass through (1) increased bone remodeling favoring osteoblast activity, (2) 399 Periodontal Therapy direct activation of bone modeling events or (3) a combination of the two (Baron and Hesse, 2012). The remainder of the chapter will focus on two bone anabolic pathways—parathyroid hormone (PTH) and WNT signaling—and the associated therapeutic approaches under clinical investigation or in clinical trials. PTH SIGNALING The parathyroid glands secrete PTH in response to low serum calcium ion levels to normalize serum levels of calcium partially by enhancing calcium uptake in the intestine and re-absorption in the kidneys. In addition to augmenting calcium uptake, PTH also stimulates osteoclast-mediated calcium release from bone indirectly by stimulating RANKL secretion (Fig. 3) via Gso-linked CAMP-dependent protein kinase A and Gq/11-linked phosphatidyl inositol-specific (PLC)-protein kinase C signaling pathways (Guo et al., 2010). The role of PTH in bone homeostasis is not catabolic solely, as it recently has been shown to activate canonical Wnt-signaling, which increases osteoblast number and function (Calvi et al., 2003). Analysis of bone specimens from patients exposed to elevated PTH levels for prolonged durations of time revealed both increased bone resorption and formation, as indicated by an increase in osteoblast number. Contrastingly, animal studies then demonstrated that exposure to recombinant human PTH for short durations of time elicited a net anabolic response (Rhee et al., 2002). Thus, PTH has an important role in both bone catabolism and bone anabolism, and its effects are dependent upon the frequency and duration of exposure. Two forms of PTH, rhPTH 1-84 (intact hormone) and rhPTH 1-34 (N-terminal fragment, teriparatide), are the only bone anabolic therapies approved (1-84 approved in Europe and 1-34 approved in Europe and the United States) for the treatment of osteoporosis. Intermittent adminis- tration of rhpTH (1-34) in patients has been shown to lead to increases in cancellous bone mass at early time points, with the net anabolic effect plateauing after 18–24 months. Over the span of a 19-month large clinical trial, rhpTH (1-34) was demonstrated to lower the risk of vertebral fractures by 65% and non-vertebral fractures by 40% compared to placebo (Neer et al., 2001). rhpTH is thought to increase bone formation primarily by increasing anabolic bone-remodeling events early in its therapeutic window. 400 Taut et al. º Osteoclas. proger to: - - º G. HSC Osteogenesis º ºapoptosis º Committed osteoblast progenitor º - Prºosteoblast ©sosº Matrix Lining - mineralization cell as 2- ſº º 2. \ 0 \\ Old bone Figure 3. Diagram outlining crosstalk between bone-lineage cells. Canonical Wnt Signaling is dominant in osteocytes and cells from the osteoblast lineage. RANK/ RANKL/OPG signaling between osteoblast and osteoclast cells. Adapted by per- mission from Macmillan Publishers Ltd: Nature Medicine, Baron and Kneissel, 2013, 2014. However, the stimulatory effects of rhpTH on osteoclastogenesis through RANKL secretion eventually lead to the plateauing of its anabolic potential. In order to address the high costs of growth factor therapy and Some of the limitations associated with subcutaneous delivery, new approaches to PTH therapy have been investigated. Transdermal delivery of rhPTH and calcilytic-induced endogenous PTH secretion has shown promise as alternative approaches for exploiting the bone anabolic potential of PTH for treatment of osteoporosis (Cosman et al., 2010; Widler et al., 2010). MODULATING CANONICAL WNT SIGNALING The canonical Wnt-3-catenin signaling pathway is fundamental to bone formation in humans. Binding of secreted Wnt glycoproteins to their receptors (frizzled) and co-receptors (Lºp5 and Lºpé) leads to the 401 Periodontal Therapy stabilization of intracellular 3-catenin, which translocates to the nucleus to activate the expression of genes involved in bone formation (Fig.2). Wnt antagonists, such as sclerostin and Dickkopf (Dkk) family proteins, can block Wnt signaling by either binding to Wnt proteins or Wnt receptors and co-receptors to inhibit bone formation in response to decreased mechanical loads (Krishnan et al., 2006). Sclerostin, mainly secreted by osteocytes and, thus, preferentially expressed in the skel- eton, has been shown to antagonize Wnt signaling by binding to co-re- ceptors Lrp4/5/6 (Li et al., 2005; Choi et al., 2009). In patients suffering from Sclerosteosis/van Buchem's disease, a sclerostin (SOST) gene loss- of-function mutation leads to dramatic increases in bone mineral density and bone volume over the lifespan of patients. A deeper understanding of these genetic mutation syndromes and Wnt antagonists has led to re- search investigating sclerostin as a therapeutic target for inhibition and development of bone anabolic therapies for osteoporosis. Pharmacological inhibition of sclerostin via monoclonal antibody (Scl-Ab) has been investigated in animal models for osteoporosis, as well as clinically in humans. In an estrogen-deficient, aged, ovariectomized (OVX) rat model for post-menopausal osteo-porosis, five-week Scl-Ab treatment led to increases in both bone mass and strength that restored OVX-induced bone loss to healthy levels at several skeletal sites— including at the femoral diaphysis and lumbar vertebrae—in a dose- dependent manner. Trabecular bone volume and thickness doubled after just five weeks of Scl-Ab treatment at a dose of 25 mg/kg (Liet al., 2009). Additional short-term pre-clinical studies further demonstrated the ability of Scl-Ab to increase trabecular and cortical bone mass, and restore bone structure at various stages of estrogen deficiency (Keet al., 2012). The potent anabolic effects of Scl-Ab treatment also have been shown in an orchiectomized rat model for male osteoporosis, which simulates androgen ablation and bone mineral density (BMD) reduction occurring in aging men. Five weeks of Scl-Ab treatment restored bone mass and bone strength to levels measured in young rats (Liet al., 2010). Evidence of the restorative effects of Scl-Ab also has been shown in non-human primate models for fracture healing and bone repair (Ominsky et al., 2011). The comprehensive pre-clinical data demonstrating the anabolic effects of sclerostin inhibition by monoclonal 402 Taut et al. antibody has been verified in human clinical trials for treatment of post- menopausal osteoporosis. In a randomized, double blind, placebo-controlled, single-dose study, Scl-Ab was delivered to healthy men or post-menopausal women between the ages of 45-59 (Padhi et al., 2011). A single dose of Scl-Ab was shown to lead to significant increases in serum bone-formation markers procollagen type 1 amino-terminal propeptide (P1NP), osteocalcin (OCN) and bone-specific alkaline phosphatase in a dose-dependent manner. Peak concentrations were observed after approximately 30 days of Scl-Ab treatment. Furthermore, the increases in serum markers corresponded with significant increases in the bone mineral density of both men and Women at two skeletal sites—lumbar spine and hip. The bone-anabolic therapeutic potential and long-term effects of Scl-Ab will require further investigation. ANTI-RESORPTIVE AND ANTI-INFLAMMATORY APPROACHES FOR PERIODONTAL DISEASE THERAPY Aside from the therapeutic potential of anabolic agents used to treat osteoporosis, anti-resorptive agents also are promising for the treatment of periodontal disease. With the increasing number of studies Confirming the role of host-response pathways in the progression of periodontal disease, recent investigations have been prompted to develop Such host modulatory therapies to attenuate tissue destruction. Through the recent advancements in host modulatory therapies for periodontal disease, three therapeutic sub-groups have been explored: anti- proteinases, anti-inflammatory agents and bone-sparing drugs (Kirkwood et al., 2007). In this section, each of the approaches to host modulation With respect to periodontal disease will be emphasized. MMP Inhibitors The matrix metalloproteinase family (MMPs) plays a key role Within the periodontium both in normal and pathologic conditions. The MMP family includes collagenases, gelatinases and metalloelastases, Which are involved actively in extracellular matrix (ECM) turnover and maintenance in healthy tissues (Preshaw et al., 2004). However, dur- ing the development of periodontal disease, certain pro-inflammatory 403 Periodontal Therapy cytokines, such as tumor necrosis factor-O (TNF-o), interleukin-13 (IL-13) and interleukin-6 (IL-6), may increase the expression of MMPs leading to local tissue destruction and the development of periodontitis (Golub et al., 1990). Despite their common use as an antibiotic, doxycyclines recently have been shown to reduce MMP activity potently, more specifically MMP-8, MMP-13 and cross-linked carboxyterminal telopeptide of type I collagen (ICTP; Golub et al., 1990; Gapski et al., 2004; Lee et al., 2004; Gürkan et al., 2005; Emingil et al., 2011). This finding led to the development of a subantimicrobial dosage of doxycycline (SDD) as a potential host modulatory therapy for periodontal disease without the development of antibiotic resistance (Golub et al., 1990). Many clinical studies have been conducted to measure the effectiveness of SDD as an adjunctive therapy with SRP, which is a current and well-established non-surgical method to treat periodontal disease. While SRP alone significantly improved the periodontal clinical measurements, the administration of SDD with SRP was shown to be even more beneficial as a therapy for patients with general adult periodontitis (Caton et al., 2000, 2001; Novak et al., 2002; Choi et al., 2004; Gapski et al., 2004; Lee et al., 2004; Preshaw et al., 2004; Gürkan et al., 2005; Górska and Nedzi-Góra, 2006; Tüter et al., 2010; Emingil et al., 2011). This combinatory therapy of SDD with SRP also showed reduction in MMP activity and systemic inflammation through the biochemical analyses of inflammatory and MMP-associated markers with minimal cases of adverse side effects to date (Emingil et al., 2004; Lee et al., 2004; Payne et al., 2011). Considering the extensive investigations of the efficacy and safety of SDD as an adjunctive therapy with SRP, this dual-delivery approach currently is the only host modulatory therapy for periodontal disease. However, the further understanding of new pathways involved in the pathogenesis of periodontitis has identified novel targets to modulate the host response. Non-steroidal Anti-inflammatory Drugs In addition to exploring anti-proteinases to treat for periodontal disease, non-steroidal anti-inflammatory drugs (NSAIDs) also have been 404 Taut et al. investigated as a host-modulation therapy. This family of agents acts to inhibit the formation of prostanoids, some of which have pro-inflammatory properties, particularly through targeting the cyclooxygenases (COX), COX-1 or COX-2 for inhibition (Kirkwood et al., 2007). Evidence suggests that prostaglandin E, a product of the COX pathway, has a role in the inflammatory and bone-resorptive mechanisms of periodontal disease (Offenbacher et al., 1993). Targeting the COX pathway with NSAIDs has been shown to be effective in decreasing the production of prostanoids, as well as reducing alveolar bone resorption in pre-clinical studies (Vane, 1971; Goldhaber et al., 1973; Gomes et al., 1976; Nyman et al., 1979; Weaks-Dybvig et al., 1982; Williams et al., 1988; Kornman et al., 1990; Offenbacher et al., 1992; Shimizu et al., 1998). With extensive clinical testing, NSAIDs have been shown to be effective in host modulation as an adjunctive therapy with SRP (Williams et al., 1989; Reddy et al., 1993; Jeffcoat et al., 1995; Brägger et al., 1997; Cavanaugh et al., 1998; Ng and Bissada, 1998; Bichara et al., 1999). Taking an anti-inflammatory approach through the administration of NSAIDs appears to be promising and effective in Controlling the progression of periodontal disease. COX-2 Inhibitors The administration of NSAIDs, which generally target both COX-1 and COX-2 to inhibit the production of pro-inflammatory prostanoids, has resulted in some adverse effects such as renal toxicity and gastrointesti- nal irritations (Lindsley and Warady, 1990; Hawkey, 1993). To alleviate this issue, selective COX-2 inhibitors (e.g., nimesulide) have been developed for the treatment of periodontal disease. These selective inhibitors spe- cifically target COX-2, an inducible isoform that is expressed primarily in inflammatory cells, without influencing COX-1 expression, which is expressed constitutively in most cells and tissues (DeWitt et al., 1993). Pre-clinical studies in vitro and in a rat periodontal model showed that prostaglandin E, levels decrease when using a selective COX-2 inhibitor (May and Ghosh, 1998; Shimizu et al., 1998). Two recent investigations from Buduneli and colleagues (2002) and Vardar and associates (2003) illustrate the effectiveness of selective COX-2 inhibitors, 405 Periodontal Therapy meloxicam and nimeSulide respectively, as adjunctive periodontal therapeutic agents. They found that, as an adjunctive therapy, meloxicam and nimesulide significantly decreased MMP-8 and prostaglandin E, levels, respectively, in the gingival tissue while improving periodontal clinical measurements. While these selective COX-2 inhibitors are suggested to be advantageous to periodontal health during treatment, further studies must be conducted to explore their efficacy and safety for their potential development into clinical practice. Bisphosphonates As periodontal disease progresses within the gingiva, the combi- nation of microbial and host-response factors sequentially lead to softtis- sue destruction and alveolar bone resorption. When left untreated, the resulting alveolar bone continually will lose mass, density and strength, which may lead to tooth mobility and consequently tooth loss. Therapies to reduce or inhibit bone resorption, also referred to as “bone-sparing” drugs, have been studied extensively as a host modulato- ry therapy for periodontal disease. One major class of these bone-sparing drugs includes bisphosphonates, as they act to interfere with osteoclastic functions of resorbing bone in a direct and indirect manner (Rogers et al., 2000). More specifically, as bisphosphonates share a similar molecular structure as host-derived pyrophosphate, these bone-sparing drugs act to bind to hydroxyapatite crystals within bone to reduce osteoclast func- tion (Rogers et al., 2000). Although bisphosphonates are used primarily to treat osteopo- rosis, Paget's disease and tumor bone disease, recent evidence indicates the potential for these bone-sparing agents as a periodontal host modu- latory therapy (Fleisch, 1997). Pre-clinical studies in vitro (Nakaya et al., 2000; Liu et al., 2006) and in periodontal animal models have suggested that bisphosphonate therapy prevents periodontitis-induced bone loss (Brunsvold et al., 1992; Weinreb et al., 1994; Reddy et al., 1995; Goya et al., 2006). Recently, a few investigations involving human subjects also have indicated benefits of bisphosphonates as an adjunctive periodontal therapy with SRP (El-Shinnawi and El-Tantawy, 2003; Lane et al., 2005; Sharma and Pradeep, 2012); however, there has been some evidence that 406 Taut et al. Contradicts this finding (Graziani et al., 2009). The inability to come to a Consensus clearly indicates the need for future studies to elucidate this issue further. Clinical trials with a larger cohort, as well as exploring the long-term effects of bisphosphonate treatment, ultimately can resolve the issue of whether bisphosphonate therapy can improve periodontal conditions significantly as an adjunctive treatment. In addition to exploring the benefits of bisphosphonate therapy in periodontal disease, recent evidence suggests that a long-term administration of these agents could relate to adverse side effects, including osteonecrosis of the jaw (Marx, 2003; Ruggiero et al., 2004). Although there is therapeutic potential for bisphosphonates, further Studies need to test the efficacy and safety of these bone-sparing agents. RANKL/RANK Disruption Therapeutics The RANKL-RANK interaction, in which the ligands and receptors belong in the tumor necrosis factor (TNF) family, has been studied closely in relation to bone metabolism. The activation of RANK through RANKL results in the downstream activation of genes that activate Osteoclastogenesis, thus promoting bone resorption (Horowitz et al., 2001). Osteoprotegerin (OPG), a decoy receptor expressed by osteoblasts, binds RANKL, inhibiting its interaction with RANK and thus suppressing bone resorption through the attenuation of osteoclastogenesis (Horowitz et al., 2001; Ogasawara et al., 2004). Found to be required for osteoclast formation, the RANKL-RANK axis also has been investigated with regard to periodontal disease and alveolar bone loss (Tanaka et al., 2005). Through analysis of the gingival Crevicular fluid (GCF) of periodontally diseased and healthy patients, RANKL expression was increased and OPG expression was decreased Concomitantly with disease (Mogi et al., 2004). More importantly, Stronger evidence suggests that the ratio between RANKL and OPG, as OPG binds RANKL in competition with RANK, is indicative more of periodontal health, with a higher RANKL:OPG ratio in diseased patients (Soedarsono et al., 2006; Bostanci et al., 2007, 2011; Nagasawa et al., 2007; Dereka et al., 2010). Through these findings, OPG has been implicated as a potential therapy as a “bone-sparing” agent. Recent in vivo studies have shown that treatment of mice with OPG has a significant effect in blocking bone 407 Periodontal Therapy resorption in experimental periodontitis models (Jin et al., 2007; Chen et al., 2008; Zhou and Mei, 2012). Although there have not been any reported clinical trials yet, targeting the RANK-RANKL axis Specifically through OPG may have potential as a host modulatory therapy for periodontal bone loss. Inducible Nitric Oxide Synthase Inhibitors With recent findings and evidence regarding mechanisms that drive the progression of periodontal disease, there have been several new approaches for host modulatory therapeutic agents. Inducible nitric oxide synthases (iWCS), expressed by epithelial and inflammatory cells, produce nitric oxide (NO) to respond to pro-inflammatory cytokines in periodontal disease (Lappin et al., 2000) as well as other inflammatory disorders (Moncada and Palmer, 1991). Recent evidence in the rat ligature-induced periodontitis model suggests that the inhibition of iNOS may have therapeutic potential in reducing alveolar bone resorption as well as gingival inflammation (Lohinai et al., 1998; de Leitão et al., 2005). However, despite its anti- inflammatory and bone-sparing properties, NO has been shown to have cytotoxic effects on host cells, which indicate that further studies must be conducted to explore the safety and efficacy of iNOS inhibitors. Studies have shown that interleukin-11 (IL-11) has anti- inflammatory properties through the inhibition of pro-inflammatory cytokines, such as TNF-o, and the stimulation of tissue inhibitor of metalloproteinases-1 (TIMP-1; Trepicchio et al., 1996; Leng and Elias, 1997). The administration of recombinant human IL-11 (rhlL-11) in dog ligature-induced periodontitis models show that radiographic bone loss and clinical attachment was reduced significantly with the treatment of rhll-11 after eight weeks (Martuscelli et al., 2000). Omega-3 fatty acids have been introduced recently for the treatment of periodontitis to prevent the arachidonic acid cascade through blocking the cyclooxygenase and lipooxygenase pathways, which normally produce pro-inflammatory factors (Vardar et al., 2005). When treating periodontitis-induced rats with omega-3 fatty acids, Vardar and coworkers (2005) showed significant decrease in pro- inflammatory mediators such as prostaglandin E, prostaglandin F, and 408 Taut et al. leukotriene B, Interestingly, when used in conjunction with a selective COX-2 NSAID celecoxin, there was a further decrease in the expression of pro-inflammatory mediators. The usage of mouse anti-human interleukin-6 receptor antibody (MRA) has been investigated in the treatment of RA by restricting the binding between IL-6 and its receptor IL-6R (Choy et al., 2002; Nishimoto et al., 2003). This inhibitory action has been shown to reduce arthritic characteristics and has been compared to anti-TNF-o or anti-interleukin-1 therapies (Nishimoto and Kishimoto, 2004). Despite the therapeutic potential of iNOS inhibitors, rhll-11, omega-3 fatty acids and MRA for the treatment of periodontal disease, further studies must be conducted to test their efficacy and safety. Nevertheless, the further understanding of the host-response mechanisms that exist in periodontal disease give rise to various approaches and targets for the development of therapies. In summary, the variety of approaches and strategies to modu- late the host response in periodontal disease can be divided into three Categories: anti-proteinases, anti-inflammatory agents and bone-sparing drugs. Anti-proteinases act primarily to inhibit MMP activity, which can be destructive in periodontally diseased tissues. SDD, the only current available therapy as a host modulatory therapy for periodontal disease, has been shown to reduce MMP activity effectively and improve clinical parameters. Anti-inflammatory agents, such as NSAIDs, have been shown to reduce pro-inflammatory mediators and have bone-sparing effects in gingival tissues. Evidence has suggested that bone-sparing drugs, such as bisphosphonates, can reduce alveolar bone loss and improve periodon- tal clinical parameters. In addition, a broad range of new therapeutic ap- proaches has been investigated, such as iNOS inhibitors, rhill-11, omega-3 fatty acids and MRA. While further studies are necessary to prove their efficacy and Safety, recent evidence suggests that these new approaches may modu- late the host response in an advantageous, therapeutic manner. Based on emerging strategies, the future of identifying molecular targets that fulfill multiple aspects of this three-part “periodontal host-modulatory triad” offers great promise; however, a multitude of studies must prove their efficacy as well as long-term safety to consider for use in the clini- Cal Setting. 409 Periodontal Therapy Bone Anabolic Therapies for Periodontal-Disease Related Alveolar Bone Loss Like that of new anti-resorptive and anti-inflammatory therapies, research investigating the use of PTH and Scl-Ab for periodontal alveolar bone regeneration is limited somewhat. However, recent pre-clinical and clinical studies provide insight into potential non-invasive strategies for stimulating localized alveolar bone regeneration in the future. Administration of teriparatide, a PTH analog, has demonstrated bone regenerative capabilities as an adjunct therapy to periodontal surgery for the treatment of periodontal disease-related alveolar bone loss. Teriparatide treatment in conjunction with periodontal Surgery resulted in improved clinical outcomes, greater bone regeneration and improved healing of bone within alveolar bone defects compared to placebo (Bashutski et al., 2010). * In a pre-clinical study, Scl-Ab treatment augmented alveolar bone healing following experimental periodontitis-induced bone loss, leading to recovery of bone volume and density after six weeks of treatment (Taut et al., 2013). Additionally, no statistical differences in tooth- supporting alveolar bone volume and density were detected between healthy and Scl-Ab treated disease groups following six weeks of therapy. Serum markers revealed an increase in bone formation, as indicated by elevated concentrations of bone formation markers OCN and P1NP without any measurable up-regulation of Serum bone resorption during Scl-Ab treatment. Furthermore, Scl-Ab treatment facilitated the recovery of alveolar bone microarchitecture in the experimental periodontitis group, indicating increased tooth-structural support at the disease site compared to vehicle treatment (Taut et al., 2013). These bone anabolic agents may offer potential for non-invasive therapies for localized alveolar bone defects from periodontal disease. SUMMARY AND FUTURE DIRECTIONS The maintenance for tooth-supporting structures using bone anabolic and anti-resorptive has been documented well in this chapter, as demonstrated in pre-clinical and clinical investigations. The managing of the host in the face of exuberant microbial challenges during periodontal infection or in cases of controlled tooth movement offers many opportunities patient disease management. 410 Taut et al. The targeting of osteoclast inhibition versus promotion of Osteoblastic or osteocytic activity has offered significant early successes that are having good clinical impacts (Gokhale and Padhye, 2013). Most of these approaches use systemic drug delivery approaches that work at the patient level; however, future therapies may look at enhanced biologic agent targeting at the tooth interface for local bone anabolics/anti- resorptives for periodontal diseases (Chan and McCauley, 2013; Pradeep et al., 2013) and for affecting tooth movement (Dunn et al., 2007; Hudson et al., 2012). The administration of host modulation agents using resorbable polymers such as polylactic acid co-polymers or other degradable agents allow for specifc drug targeting without corresponding Systemic effects. The dose of the drugs may be reduced, while local concentrations of agents are enhanced. The future offers significant potential for the field to impact periodontal regenerative medicine and host management of disease. ACKNOWLEDGEMENTS The laboratory has been supported by grants for the NIH/NIDCR (DE 13397), Colgate-Palmolive Co., Amgen, Inc., and UCB, Pharma related to these described studies. 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As more and more information became electronic, it followed that formerly segregated operations of the orthodontic practice now would become integrated, creating a more streamlined workflow that included the embracing of computer hardware in the orthodontic office and the development of specialized software. WHERE ARE WE Now?' Advancements in bandwidth speed have led to the super-fast transfer of data, adding capability and flexibility to the orthodontic workflow. Business broadband, Wi-Fi, 4G/LTE technologies and Cloud computing all make it possible to work from virtually anywhere without hassle. The introduction of smaller, more capable hardware Such as Smartphones, tablets and laptops has enhanced this experience. WHERE ARE WE HEADED? The original focus of employing technology in the orthodontic practice was on accuracy of diagnosis and results. Future technological advance- ments will help reduce treatment time and perfect results. Along the way, hu- man intervention will be reduced for further automation and accuracy of data gathering and treatment. Traditionally, orthodontics has been one of the most progressive professions and is displaying an even faster rate of adoption moving forward. KEY WORDS: digital orthodontics, practice management, 3D imaging, cloud com- puting, 3D printing INTRODUCTION Technology moves fast and affects everything around us—in- cluding all aspects of the orthodontic practice. It is intriguing to observe 427 Looking Back . . . Looking Forward periodically how far we have progressed, incorporating various technol- ogies into the typical orthodontic workflow. In this chapter, we will at- tempt to provide a digest of the innovations the orthodontic profession has taken on during the last 40 years and boldly will make some predic- tions on how clinicians might employ emerging technologies in the not- too-distant future. WHERE HAVE WE BEENP Three main areas of advancement in the broader market tech- nology have triggered advancements in the dental and specialty profes- sions. First, data access in both imaging and practice management has evolved to provide us with more information from which to diagnose and plan treatment. As more and more information became digitized, it fol- lowed that formerly segregated operations of the orthodontic practice now would become integrated, creating a more streamlined workflow. Second, because digital data demands electronic hardware for access, computers replaced paper, thereby replacing manual tasks with automa- tion—helping to reduce margin for human error in many areas of prac- tice. Lastly, these first two advancements triggered the need for special- ized software that was user friendly and designed specifically for the tasks of the Orthodontist. Imaging The introduction of the first consumer digital camera in 1988 had a global impact on orthodontic practice: diagnostics, treatment planning, practice workflow and record keeping became streamlined and posi- tioned to become integrated. The sudden ability to capture digital data with inexpensive equipment and very little operator instruction meant that orthodontic staff could obtain and create their own patient records, eliminating the need for a third-party vendor (Iwamoto, 2007). In addi- tion, it paved the way for specialized software dedicated to image man- agement. Many software companies took this a step further by devel- oping Complementary imaging and practice management Systems that would integrate with each other, allowing one-stop shopping for practi- tioners looking to streamline their practice. Now that imaging data was digital and easily available, there was so much more that could be done with it. The practitioner could 428 Wang and Randazzo organize a patient's image data such that it was accessible easily and not vulnerable to deterioration brought on by time and environment. Also, S/he could integrate those images with practice management Systems, further customizing patient charts and enhancing all communications such as letters (Weinberger, 2008). Cephalometric Tracing Cephalometrics was introduced in 1931 by Broadbent and re- mains a vital diagnostic tool in orthodontics. Practitioners rely on this System to diagnose, plan treatment and monitor changes resulting from treatment and growth (Broadbent, 1931). Tracing of the cephalogram was performed manually until the early 1970s, when Robert M. Ricketts (Rocky Mountain Data Systems) created a computerized cephalometric tracing/ VTO system. Cephalometric computer programs often contain hundreds of analyses, any number of which can be performed simultaneously under the direction of the operator. This instantaneous access to such a large spectrum of data enhanced the clinician's ability to make a more accurate diagnosis, while also saving Countless hours of labor (Wang and Randazzo, 2010). In 1988, Dolphin Imaging introduced the DigiGraph, which used Sonic technology to gather cephalometric information, thereby eliminat- ing radiation from the process. While this approach was novel, it became apparent before long that the traditional method (x-rays) of gathering the Cephalometric imagery was more practical. Digital Study Models Historically, study models are the major record used for treatment planning. The American Association of Orthodontists (AAO) includes "dental casts (or digital models)” in its list of recommended pre- and post-treatment orthodontic records in the publication Clinical Practice Guidelines for Orthodontics and Dentofacial Orthopedics. The traditional plaster study model can be digitized, allowing the practitioner to process these data and incorporate the data set into the patient's electronic record. In 1999, OrthocAD" was the first company to offer a digitizing Service to the orthodontic community, followed by eModels" in 2001. Digital models also assist in patient education, as the younger generation is comfortable with computer-generated information. This methodology 429 Looking Back . . . Looking Forward serves to improve communication between clinician and patient and en- hances informed consent (Peluso et al., 2004). Cone-beam Computed Tomography Cone-beam computed tomography (CBCT) was introduced for use in dentistry in the early 1999. CBCT provided low-radiation, single- Scan volumetric datasets that gave practitioners access to an enormous amount of accurate anatomical data. In 2001, the NewTom 9000 (Quan- titative Radiology, Verona, Italy) was installed at Loma Linda University, (St. Loma Linda, CA), marking the first U.S. installation of a CBCT scanner for dentistry. Within just a few years, there were a handful of companies producing CBCT machines and the i-CAT” (Imaging Sciences, Hatfield, PA) would become the most popular unit on the market. The CBCT output also could serve as a patient's singular dataset from which to derive all the traditional image views of an orthodontic workup. In fact, studies have shown that landmark identification is more precise when performed on multi-planar views of a CBCT dataset than on a traditional lateral cephalogram (Ludlow et al., 2009). Further, the views could be manipulated onscreen for optimum evaluation. Collectively CBCT emitted less radiation than did a traditional series of images (Lagravére et al., 2008). Practice Management In the 1980s, UNIX and DOS entered the arena, opening the doors to practice management Systems. These computerized databases allowed practices to streamline financial transactions, schedule patient appointments and create electronic treatment cards. In addition, the programs were customizable so that details such as color coding, number of columns, procedure names and sizes of time slots all could be user defined. Software The arrival of digital data prompted the development of special- ized software used to organize, process and integrate the orthdontic practice. Software was developed specifically for an end-user lacking a 430 Wang and Randazzo formal technological background. The dental professional now was em- powered with a lot more information and more sophisticated tools from which to make a more accurate diagnosis and treatment plan. All this changed the flow and décor of the orthodontic practice: Computer monitors and workstations now appear in all areas of the orthodontic office, becoming the primary means for accessing and communicating information not only in the front office, but also in the practice at large. WHERE ARE WE NOWP As technology advanced, so did the means of accessing and processing the data being handled by the technology. Faster bandwidth meant faster download and transfer of data, lending added capability and flexibility to our everyday lives—including the orthodontic workflow. Business broadband, Wi-Fi, 4G/LTE technologies and Cloud computing that offered not only mobility, but also large online storage, all made it possible to work from virtually anywhere without difficulty. Enhancing this experience was the introduction of smaller, more capable hardware Such as Smartphones, tablets and laptops that could be transported easily in a pocket, purse or briefcase. Faster Bandwidth While Internet technology was created in the 1960s by the gov- ernment for military purposes, it did not become available commercially until 1992. Since then, online access and the World Wide Web have be- Come integral to everything that we do. In the last decade, increasing bandwidth speeds coupled with wireless technology have allowed us to become less reliant on wired Internet plugged into our PCs: in 1996, the first mobile phone had Internet and studies showed that more people accessed the Internet via mobile phones in 2008 than through their PCs. While broadband generally is defined as data transfer rates greater than 256Kbps, today’s 4G networks can transfer data at 100Mbps (Stewart, 2011). This increased speed is having a profound effect on what we can do with our practice data and how that, in turn, affects our office work- flow environment. 431 Looking Back . . . Looking Forward Smaller, More Capable Hardware Laptops have become as powerful as any desktop PC, with bat- teries lasting up to 12 hours. Other portable devices such as tablets and Smartphones can provide most or all of the capability of a desktop com- puter with the added benefit of mobility. Because of this portability, more people are opting to work directly from their laptop or other mobile de- vice. These mobile solutions are connected with high-speed Internet, al- lowing access to the latest medical research at the point of care and in- stantaneous communication with colleagues around the world (Burdette et al., 2008; Dala-Ali et al., 2011). Dolphin developed its Dolphin Mobile application in order to ad- dress these needs of the orthodontic community. Dolphin Mobile allows the practitioner to access his/her Dolphin database and operate all Dol- phin programs from Smartphones and tablets with both the Android and iOS operating systems. Depending on the Dolphin products that a prac- tice uses, it can have full access to the practice's calendar and detailed schedule, financial and demographic information, in addition to image records including 3D records. Cloud Computing Cloud computing offers a secure, convenient means for a practice to enjoy all the advantages of information technology without needing to be bothered with technical hassles and costs of maintaining hardware and software. The very concept of Cloud computing eliminates reliance on local hardware and its configuration. Practitioners are able to access their practice data by connecting to the Internet via a device such as a laptop, tablet or Smartphone. A side benefit is the extra space in the office that normally would house the server (Torrieri, 2012). Relatively speaking, Cloud computing is not a new concept. Com- mercial and consumer use of Cloud services began soon after the Inter- net was made available to the public in the 1990s. Email services such as Hotmail and AOL are some of the first examples, while document- sharing services such as Google Docs and Dropbox went a step further, allowing the storage and sharing of files on the Internet—or “Cloud." Photo-storing and photo-sharing sites such as Picasa and Flickr, and 432 Wang and Randazzo Social networking sites like MySpace and LinkedIn, are more examples of Cloud computing. In 2000, Dolphin introduced AnywhereDolphin, a Cloud Service that lets one share patient data online with patients and referrals. Within orthodontics, practice management systems were among the first to migrate to the Cloud, with more products and services following every day. The recent introduction of Dolphin Cloud allows users to access and operate all Dolphin software from anywhere there is an Internet Connection. Paperless Practice Management The term "paperless" often is in reference to the gradual adoption of the Electronic Health Record (EHR) system. However, technology has replaced far more in the medical/dental practice than paper charts and appointment calendars. Innovations such as fingerprint scanning for patient check-in, electronic signature for authorizing consent and other documents, patient educational videos, online payment and email and text messaging for communicating are just a few examples of how far we have come in the quest to conquer paper. Social Media Social media offers a brand new way to interact with patients and referrals, in addition to providing a dynamic platform for marketing your business. In fact, many medical and social media professionals feel that creating and monitoring an online presence is vital for a doctor and practice to maintain patient trust. The Internet has become the resource of choice for patients to gather information about their provider, medical conditions, treatment options and voice opinions about their experience. If a patient is venting online, it is in the provider's best interest to know about it immediately so S/he may deal with it effectively. In addition, there exists a proliferation of questionable health information and advice being made available by “non- experts,” diluting the voice and authority of real medical professionals (Chen, 2013). Interacting with patients on Social media platforms gives you the opportunity to gather feedback and gauge collective attitudes about health conditions, medications and treatments (Dolan, 2012). Popular platforms among patients include Facebook, YouTube and Twitter. 433 Looking Back . . . Looking Forward Digital Impressions, CAD/CAM, 3D Printing 3D printing first was used in dentistry in the 1980s with the sepa- rate contributions of three pioneers of CAD/CAM systems. These included Dr. Werner Moermann, who developed the Sirona CEREC" product that combined a digital impression system with a chairside 3D printer to cre- ate single-visit Ceramic restorations such as crowns, inlays and overlays (Miyazaki et al., 2009). In the late 2000s, more advanced digital impres- sion systems and 3D printing technology made possible a far broader ap- plication of CAD/CAM beyond crowns and overlays. Progressive practices already are using the integration of these technologies to streamline the entire diagnostic, treatment planning and treatment process. As mentioned earlier, study models are an integral tool used by the orthodontist in the treatment planning process. The ability to scan plaster models and import the digital data for a broader range of applications was a huge leap in the data gathering process. Now, digital impression systems such as iTero" use an intraoral scanner to capture data directly from the patient's mouth, completely bypassing the need for traditional PVS impressions. The data sets gathered from intraoral scanning systems can be used to create both stereolithographic and three-dimensional (3D) digital models and have been determined to be a valid and reproducible method for measuring distances in a dentition (Cuperus et al., 2012). The scanners are being used by both doctors and staff, with typical scanning time being reported less than ten minutes for the entire process. These digital files have lots of uses—they can be archived easily, imported to systems such as SureSmile” and Invisalign", and merged with a patient's CBCT scan as part of their comprehensive record. Digital Orthodontics The digitization of data over the last several decades has led to more than the integration of all aspects of the orthodontic practice—it also has allowed for the development of alternate modes of treatment outside of bands and brackets. Examples include: Invisalign", a se- quence of clear aligners that rely on digital data not only to create the 434 Wang and Randazzo appliances, but also customize them for each patient; Incognito" lingual braces, which are customized for each patient; and SureSmile”, which uses 3D imaging, treatment planning software and robotics to create customized wires for each patient. These systems step up from conventional braces in that they address the movement of each tooth individually, while directing all the teeth to move in concert to a more precise result. Most of the products enable the clinician to place virtual brackets and simulate treatment, allowing for the exploration of alternative treatment plans. Some products allow the clinician to reposition or torque each tooth individually. More Capable Software In 1965, Gordon Moore, co-founder of Intel, predicted that the number of transistors on a microchip could double every 24 months (Moore, 1965; Twist, 2005). Known as “Moore's Law,” this prediction has held true for more than 40 years. The consequence of this prediction has been the rapid pace of software evolution, with more powerful Software being released each year. This rapid increase has included more sophisticated solutions for the orthodontist regarding diagnosis, treatment planning, case presentation and patient communication. One example is the dynamic, interactive patient-education systems that have appeared in the last few years. Doctors are discovering that the animated imagery used by these systems greatly enhances a patient's Comprehension of the diagnosis and treatment process. WHERE ARE WE HEADED? Technology in the orthodontic office continues to become more Sophisticated as bandwidths get faster and hardware devices become Smaller and more mobile. In the beginning, the focus of employing technology was to increase accuracy of diagnosis and results; as a result, workflow became more streamlined. Technological advancements in the future will help to reduce treatment time and further perfect results. Along the way, human intervention will be reduced for further automation and accuracy of data gathering and treatment. Traditionally, orthodontics has been one of the most progressive professions. It is displaying an even faster rate of adoption moving forward. 435 Looking Back . . . Looking Forward 3D Imaging Image records are an integral dataset for any practitioner. In the future, the routine gathering of the necessary information will be safer, faster and more comprehensive. Already in use in select emergency cen- ters around the world is Lodox” Statscan (LS), an x-ray machine capable of imaging the entire body in 13 seconds using linear slit scanning radi- ography (LSSR). Currently in limited use for evaluating trauma patients, LS has a future in broader applications due to its high speed, high quality, low dose, single whole-body scans. It delivers up to ten times less harm- ful dose than regular x-ray systems. In addition, it offers 3D reconstruc- tive functionality (Evangelopoulos et al., 2009; Whiley et al., 2012). 3D Printing As mentioned earlier, CAD/CAM technology and 3D printing has progressed in recent years beyond mere restoration to create appliances such as splints and retainers. In the future, we see a far more streamlined process with a single fast, low-resolution body scan providing all the data needed for diagnosis, treatment planning and appliance or prosthesis generation. This scenario really is not so outrageous. True story: in early 2008, The University of Hasselt (Belgium) announced that Belgian and Dutch scientists successfully replaced a lower jaw with a 3D printed model for an 83-year-old woman. According to the researchers, it was the first custom-made implant in the world to replace an entire lower jaw. The mandible of the woman was infected badly and needed to be removed. Considering the age of the patient, a “classical” microSurgical reconstructive surgery takes too long and can be risky. Therefore, a tailor- made implant is the best choice. Normally it takes a few days to produce a custom implant, but with 3D printing technology, it takes only a few hours (Richmond, 2012). With desktop 3D printers already on the market, it is not difficult to predict that one day soon they will be a staple piece of equipment in the orthodontic office for on-site production of study models, retainers and other appliances. 436 Wang and Randazzo Machine 2 Machine (M2M) Machine-to-machine (M2M) technology already is being used in a wide range of applications—from security and surveillance to traffic control and healthcare. M2M uses wired or wireless connectivity to exchange information and communications between Web-connected devices without the need for human intervention. In healthcare, application of M2M involves a remote sensor—usually worn by the patient—that gathers source data such as blood pressure, heart rate and glucose levels, then transfers it via the Internet to a controlling server where it is analyzed and acted upon by a host system such as a medical facility (Bodhani, 2012). Nanomedicine. Nanotechnology is the manipulation of matter at the atomic and molecular scale to create materials with remarkably varied and new properties (Paddock, 2012). Nanomaterials differ from other materials in two aspects: the increase in relative surface area and quantum effects. These two aspects work in tandem in that as size is reduced to the nanoscale, quantum effects begin to dominate affecting the optical, electrical and magnetic behavior of materials. Nanotechnology promises applications in the areas of electron- ics, construction, alternative energy sources, biotechnology and dozens of others including medicine, specifically dentistry. In medicine, nano- materials can be engineered for use in diagnostics, gene therapy, drug delivery, and tissue and bone repair. Dental applications could include local anesthesia, tooth renaturalization, prosthetic and appliance du- rability and more (Kanaparthy and Kanaparthy, 2011). One example of nanotechnology already being employed is Simpliclear” from BioMers Pt Ltd., a medical technology company based in Singapore. Simpliclear uses translucent composite polymer wires made strong through nanotechnol- Ogy (Universidad Carlos Ill de Madrid, 2012). Alternative Computer Control Interface For decades we have been dependent on the mouse, keyboard and carpal/metacarpal dexterity to operate computers and access our data. 437 Looking Back . . . Looking Forward While this system of computer control has become second nature, limita- tions of all three components have spurred development of alternative methods. Interfaces that allow the ability to control the computer using voice, gestures, brain waves, eye movement and just plain physical mo- tion already are being implemented in business and consumer sectors. Apple's iOS personal assistant Siri and Google's Google Voice are wide- spread examples of voice control technology, while Microsoft's motion- sensing Kinect has been a driver in gaming technology. Freeing up the hands and reducing the hardware has benefits beyond mere convenience. It makes computer technology accessible to people with disabilities, reduces the incidence of repetitive stress injury, diminishes the spread of germs and allows for multi-tasking. In medicine, the implications are more far reaching: surgeons routinely refer to patient images and records during Surgery, but stepping away from the operating table to touch a keyboard and mouse can delay the surgery and increase the risk of spreading infection (Venere, 2011). On the opposite side of the healthcare sector, disabled patients have benefited from alternative interfaces since the 1980s. The Eyegaze Edge* Communication and Analysis Systems from LC Technologies (Fairfax, VA) uses eye-tracking technology to help patients with spinal injuries and motor disorders communicate and interact with the world around them. More recently, researchers are exploring the use of brain- computer interfaces (BCIs) for communicating with both Alzheimer's patients and those in a non-responsive, awake condition due to brain trauma. By communicating their brain waves directly to an external device, the disabled patient bypasses the normal output pathways of peripheral nerves and muscles (Liberati et al., 2012; Naci et al., 2012). ACCELERATING CHANGE Forty years ago, Gordon Moore proposed the concept of expo- nential growth in reference to semiconductor circuits. The realization of his predictions allowed for astounding technological advancements that have transformed orthodontics. In 1999, Ray Kurzweil (futurist) applied that concept to a broader range of evolutionary systems including, but not limited to, technology. “... We won't experience 100 years of prog- ress in the 21st century—it will be more like 20,000 years of progress (at 438 Wang and Randazzo today's rate). The ‘returns, such as chip speed and cost-effectiveness, also increase exponentially...” he wrote in a 2001 essay entitled The Law of Accelerating Returns. Kurzweil's vision (2001) includes the eventual merging of biological and non-biological intelligence. Of course, wild predictions such as Kurzweil's are difficult—if even possible—to comprehend today. We know, however, that the one thing we can count on for the future is the profession's continued dedication to help improve patient care, treatment outcomes and overall quality of life for doctor and patient. 20-YEAR VISION: ORTHODONTICS IN 2033 Considering the exponential rate of technological advancement, orthodontic practice in the coming generations is poised to be exception- ally different than it is today. The following is a scenario based on the technologies discussed in this chapter: The patient meets with the clinician either in person or remotely for consultation, preliminary diagnosis and treatment options. The patient then would receive a super-low dose full-body scan, either at the clinician's office or a facility. From this scan, the clinician will finalize a treatment plan and forward it to the patient's personal information device. The patient's personal information device will communicate with an in-home 3D printer that will produce the customized appliances— aligners, brackets (labial or lingual, based on the patient's requirements and suitability), wires and the like. All these items would be personalized Completely in size, shape and materials. Minutes after the appliance kit is completed, the patient will attach the appliances without any assistance: if brackets have been prescribed, they require no adhesive; brackets will be placed in a specialized tray (also generated via in-home 3D printer), that the patient simply places into the mouth. Once inserted, the orthodontic professional (remotely) will activate the brackets. The brackets then would fuse to the teeth automatically via nanotechnology. To remove, the office would issue a command to reverse the process remotely. The attachment would be permanent until it is deactivated by the clinician. 439 Looking Back . . . Looking Forward Nanosensors already would be in embedded in these brackets, wires and aligners, allowing treatment with a single aligner or wire from start to finish. The sensors allow the clinician to evaluate and even make adjustments to the prescription of the appliance remotely, based on the information provided by the nanosensors. Following a schedule set by the clinician, a central control system automatically would check on each patient remotely (on hygiene, position, attachment status) and automatically make any necessary adjustments or correction. It is able to do this because the bracket itself—including the slots—can alter physically in angles and shape (based on the mechanical design of the appliance). The wire length and shape can be altered as well based on the survey from the latest check-up. The automated System also can evaluate the patient's progress in real-time constantly and issue alerts on any necessary interventions. Otherwise, it will be on autopilot treatment/adjustment. Further, by 2053–20 years later—orthodontic gene therapy will be discovered and mastered. Orthodontic specialists in the 2050s would prescribe the patient a new gene that would cause the patient's teeth to move gradually into the correct position and onto perfectly sized and positioned jaw structures. This corrected gene then will be passed to the children and subsequent offspring. Preventive gene therapy also would be available. And so orthodontics—at least as we know the profession today—will cease to exist in our world. Since this will not happen for a couple more generations, we have sufficient of time to prepare for the evolution in this revolution. REFERENCES Bodhani A. M2M in healthcare: Wellness connected. Engineering & Technology Magazine 2012;7(4). http://eandt.theiet.org/magazine/ 2012/04/wellness-connected.cfm Broadbent BH. A new x-ray technique and its application to orthodontia: The introduction to cephalometric radiology. Angle Orthod 1931;1: 45-66. . Burdette SD, Herchline TE, Oehler R. Surfing the web: Practicing medicine in a technological age: Using smartphones in clinical practice. Clin Infect Dis 2008;47(1):117-122. 440 Wang and Randazzo Chen P.W. Doctors and their online reputation. Well Blog, New York Times. 2013 March; http://well.blogs.nytimes.com/2013/03/21/ doctors-and-their-online-reputation/ Cuperus AM, Harms MC, Rangel FA, Bronkhorst EM, Schols JG, Breuning KH. Dental models made with an intraoral scanner: A validation study. Am J Orthod Dentofacial Orthop 2012;142(3):308-313. Dala-Ali BM, Lloyd MA, Al-Abed Y. The uses of the iPhone for surgeons. Surgeon 2011;9(1):44-48. Dolan PL. 4 ways social media can improve your medical practice. American Medical News. 2012 June; www.amednews.com/article/20120625/ business/306259971/4/ Evangelopoulos DS, Deyle S, Zimmermann H, Exadaktylos AK. Personal experience with whole-body, low-dosage, digital X-ray scanning (LODOX-Statscan) in trauma. Scand J Trauma Resusc Emerg Med 2009;17:41. Iwamoto E. Choosing a camera. Dolphin Echoes 2007;2:2. Kanaparthy R, Kanaparthy A. The changing face of dentistry: Nanotech- nology. Int J Nanomedicine 2011;6:2799-2804. Kurzweil R. The law of accelerating returns: Kurzweil accelerating intel- ligence. March 2001; http://www.kurzweilai.net/the-law-of-acceler- ating-returns Lagravére MO, Carey J, Toogood RW, Major PW. Three-dimensional accu- racy of measurements made with software on cone-beam computed tomography images. Am J Orthod Dentofacial Orthop 2008;134(1):112- 116. Liberati G, Dalboni da Rocha JL, van der Heiden L, Raffone A, Birbaumer N, Olivetti Belardinelli M, Sitaram R. Toward a brain-computer inter- face for Alzheimer's disease patients by combining classical condi- tioning and brain state classification. J Alzheimers Dis 2012;31 (Suppl 3):S211-S220. Ludlow JB, Gubler M, Cevidanes L, Mol A. Precision of cephalometric landmark identification: Cone-beam computed tomography vs con- ventional cephalometric views. Am J Orthod Dentofacial Orthop 2009;136(3):312-313. Miyazaki T, Yasuhiro H, Kunii J, Kuriyama S, Tamaki Y. A review of dental CAD/CAM: Current status and future perspective from 20 years of experience. Dent Mater J 2009;28(1):44-56. 441 Looking Back . . . Looking Forward Moore GE. Cramming more components onto integrated circuits. Elec- tronics Magazine 1965;38(3):2. Naci L, Monti MM, Cruse D, Kubler A, Sorger B, Goebel R, Kotchoubey B, Owen AM. Brain-computer interfaces for communication with nonresponsive patients. Ann Neurol 2012;72(3):312-323. Paddock C. Nanotechnology in medicine: Huge potential, but what are the risks? Medical New Today. 2012 May; http://www.medicalnews today.com/articles/244972.php Peluso M, Josell SD, Levine SW, Lorei BJ. Digital models: An introduction. Semin Orthod 2004;10(3):226-238. Richmond S. 3D printer builds new jaw bone for transplant. The Tele- graph. 2012 Feb; http://www.telegraph.co.uk/technology/news/ 9066721/3D-printer-builds-new-jaw-bone-for-transplant.html Stewart B. Historical look at internet speeds. www.tylotimes.com/2011/ 11/historicallookatinternet. Torrieri M. Should your medical practice use cloud-based computing? Physicians Practice. 2011; Dec 23; www.physicianspractice.com Twist J. Law that has driven digital life. BBC News. 2005 Apr; http://news. bbc.co.uk/2/hi/science/nature/4449711.stm Universidad Carlos III de Madrid: Oficina de Información Cientifica (2012, October 29). Nanoparticles provide reinforcement for invisible braces in orthodontics. Science Daily. Retrieved 2013 June 21; http://www. sciencedaily.com/releases/2012/10/121029081839.htm Venere E. Purdue Newsroom. Future surgeons may use robotic nurse, 'gesture recognition.’ 2011 Feb; http://www.purdue.edu/newsroom/ research/2011/110203WachsGestures.html Wang CH, Randazzo L. Digital imaging in orthodontics. In: Karad A, ed. Clinical Orthodontics: Current Concepts, Goals and Mechanics. Haryana, India: Elsevier, 2010;49-65. Weinberger G. Optimizing practice protocols for a new century of ortho- dontics. Dolphin Echoes 2008;1:4. Whiley SP, Mantokoudis G, Ott D, Zimmerman H, Exadaktylos AK. A review of full-body radiography in nontraumatic emergency medicine. Emerg Med Int 2012;2012:108-129. 442 40 YEARS OF MOYERS SYMPOSIA Below are the names of the speakers and discussants from the last 40 Moyers Symposia. The speakers, their specialty/discipline and university/practice affilia- tions are listed. - There are 50 books in the Craniofacial Growth Series (CGS) published by The University of Michigan, Ann Arbor, MI, and distributed by Needham Press (www.needhampress.com). In the listing provided below, only those associated with the Symposium are included. The other books in the CGS are listed sepa- rately at the end of the volume. 1974: Control Mechanisms in Craniofacial Growth Monograph 3, Craniofacial Growth Series (CGS), James A McNamara Jr, editor Frank HT Rhodes, geology and mineralogy; Vice President for Academic Affairs, The University of Michigan: Of Craniofacial Sutures and the Rest of the Uni- VerSe. James F Bosma, medicine, National Institutes for Dental Research, Bethesda, MD: Form and Function of the Mouth and Pharynx. Melvin L Moss, anatomy, Columbia University, New York, NY: Neuro-trophic Regulation of Craniofacial Growth. James A McNamara Jr, anatomy and CHGD, The University of Michigan: Muscle and Bone Interaction in Craniofacial Growth. TM Graber, orthodontics, The University of Chicago, Chicago, IL: Extrinsic Control Factors Influencing Craniofacial Growth. Frans PGM van der Linden, orthodontics, The University of Nijmegen, Nijmegen, The Netherlands: Control Mechanisms Regulating the Development of Denti- tion. Judson Van Wyk, pediatrics, The University of North Carolina, Chapel Hill, NC: Somatomedins: A New Class of Growth Regulating Hormones. 443 List of Symposium Participants Donald G Woodside, orthodontics, The University of Toronto, Toronto, Ontario, Canada: Growth Guidance Appliances. - 1975: Determinants of Mandibular Form and Growth Monograph 4, CGS, James A McNamara Jr, editor Milford H. Wolpoff, physical anthropology, The University of Michigan: Some Aspects of Human Mandibular Evolution. Donald H Enlow, anatomy, University of West Virginia: Rotations of the Mandible during Growth. Robert M Ricketts, private practice of orthodontics, Pacific Palisades, CA: A Series of Inquiries on the Growth of the Mandible. , Alexander G Petrovic, medicine and bone biology, The University of Strasbourg, Strasbourg, France: Control Processes in the Post-natal Growth of the Condylar Cartilage of the Mandible. Egil P Harvold, Center for Craniofacial Anomalies, The University of California, San Francisco, CA: Experiments on Mandibular Morphogenesis. Discussants: Melvin J Baer, orthodontics, The University of Michigan. Richard L. Christiansen, orthodontics, National Institute for Dental Research, Bethesda, MD. Arthur H. Craven, private practice of orthodontics, East Lansing, MI. Stanley M. Garn, genetics and nutrition, CHGD, The University of Michigan. Richard A Litt, orthodontics, The University of Detroit, Detroit, MI. 1976: Factors Affecting the Growth of the Midface Monograph 6, CGS, James A McNamara Jr, editor Alphonse R Burdi, anatomy. The University of Michigan: Biological Forces Which Shape the Human Midface before Birth. Ralph A Latham, orthodontics, The University of Western Ontario, London, Ontario, Canada: An Appraisal of Early Maxillary Growth Mechanism. Arne Björk, orthodontics, Royal Dental College, Copenhagen, Denmark: Postnatal Growth and Development of the Maxillary Complex. 444 40 Years of Moyers Symposia Benjamin C Moffett, anatomy and orthodontics, University of Washington, Seattle, WA: Experimental Studies of Midfacial Growth. Bernard G. Sarnat, plastic surgery, The University of California, Los Angeles, CA: The Postnatal Maxillary-nasal-orbital Complex: Experimental Surgery. Lysle E Johnston Jr, orthodontics, Saint Louis University, St Louis, MO: The Functional Matrix Hypothesis: Reflections in a Jaundiced Eye. Discussants: Robert G Aldrich, private practice of orthodontics, Ann Arbor, MI. TM Graber, orthodontics, The University of Chicago, Chicago, IL. Leif Linge, private practice of orthodontics, Skien, Norway. Melvin L. Moss, anatomy, Columbia University, New York, NY. Raymond C Thurow, orthodontics, Washington University, St. Louis, MO. Jeanne Stutzmann, bone biology, University of Strasbourg, Strasbourg, France. - - 1977: Biology of Occlusal Development Monograph 7, CGS, James A McNamara Jr, editor Antony H Melcher, periodontics, The University of Toronto, Toronto, Ontario, Canada: The Physiology of Tooth Eruption. Coenraad A Moorrees, orthodontics, Forsythe Dental Center, Boston, MA: Pat- terns of Dental Maturation. Frans PGM van der Linden, orthodontics, The University of Nijmegen, Nijmegen, The Netherlands: Models in the Development of the Human Dentition. Stanley M. Garn, CHGD, The University of Michigan: Genetics of Dental Develop- ment. Robert E Moyers, CHGD, The University of Michigan: Skeletal Contributions to Occlusal Development. Richard A Reidel, Orthodontics, The University of Washington, Seattle, WA: Post- pubertal Occlusal Changes. Discussants: James L Ackerman, Pennsylvania, Philadelphia, PA. Sheldon Baumrind, Orthodontics, The University of California, San Francisco, CA. C Loring Brace, anthropology, The University of Michigan. Herman Duterloo, Orthodontics, The University of Nijmegen, Nijmegen, The Netherlands. Robert J Isaacson, orthodontics, The University of Minnesota, Minneapolis, MN. 445 List of Symposium Participants Anders Lündstrom, orthodontics, Karolinska Institute, Stockholm, Sweden. Ram S. Nanda, orthodontics, The University of Oklahoma, Oklahoma City, OK. Robert M Ricketts, private practice of orthodontics, Pacific Palisades, CA. 1978: Muscle Adaptation in the Craniofacial Region Monograph 8, CGS, David Carlson and James A McNamara Jr, editors Carl Gans, biological sciences, The University of Michigan: Concepts of Muscle. John A Faulkner, physiology, The University of Michigan: Adaptations in Skeletal Muscle. • Melvin L Moss, anatomy, Columbia University, New York, NY: The Muscle-bone Interface. William R Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC. The Facial Musculature in Relation to the Dental Occlusion. James A McNamara, anatomy and CHGD, The University of Michigan: Muscle Adaptations Following Orthognathic Surgery. William H. Bell, oral and maxillofacial surgery, Southwestern Medical School, Dallas, TX: Updates in Orthognathic Surgery. Discussants and Panelists: Bruce M Carlson, anatomy, The University of Michigan. Anthony A Gianelly, orthodontics, Boston University, Boston, MA. James R Hayward, oral and maxillofacial surgery, The University of Michigan. Lysle E Johnston Jr, orthodontics, Saint Louis University, St. Louis, MO. Eric Luschei, physiology, The University of Washington, Seattle, WA. Letty Moss-Salentijn, orofacial growth and development, Columbia University, New York, NY. Alexandre G Petrovic, medicine and bone biology, University of Strasbourg, Strasbourg, France. Margareta Ringgvist, orthodontics, Karolinska Institute, Stockholm, Sweden. Sheldon W Rosenstein, orthodontics, Northwestern University, Chicago, IL. Arthur T Storey, orthodontics, University of Manitoba, Winnipeg, Manitoba, Canada. Peter S Vig, orthodontics, The University of North Carolina, Chapel Hill, NC. 446 40 Years of Moyers Symposia - - - - 1979: Naso-respiratory Function and Craniofacial Growth Monograph 9, CGS, James A McNamara Jr, editor Arthur J. Miller, Center for Craniofacial Anomalies, The University of California, San Francisco, CA: Long-term Adaptations to Altered Respiratory Function in the Rhesus Monkey. Sten Linder-Aronson, orthodontics, Karolinska Institute, Stockholm, Sweden: The Growth of the Sagittal Depth of the Bony Nasopharynx. Donald W Warren, dental ecology, The University of North Carolina, Chapel Hill, NC: Airodynamic Studies of the Upper Airway. Egil P Harvold, Center for Craniofacial Anomalies, The University of California, San Francisco, CA: Adaptations in Experimentally Induced Oral Respiration. Charles D Bluestone, otorhinolaryngology, Pittsburgh, PA: The Role of the Tonsils and Adenoids in the Obstruction of Respiration. William R Solomon, internal medicine (allergy), The University of Michigan: Allergic Responses in the Upper Respiratory System. Discussants: Robert S Bushey, orthodontics, The University of Colorado, Denver, CO. Robert J Isaacson, orthodontics, The University of California, San Francisco, CA. Charles J Krause, otorhinolaryngology, The University of Michigan. James A McLean, internal medicine (allergy), The University of Michigan. Robert M Ricketts, private practice of orthodontics, Pacific Palisades, CA. Beni Solow, orthodontics, Royal Dental College, Copenhagen, Denmark. Kenneth L Watkins, speech and hearing, The University of Michigan. 1980: Psychological Implications of Facial Form Monograph 11, CGS, G William Lucker, Katherine A Ribbens, James A McNamara Jr, editors Ellen S Berscheid, psychology, The University of Minnesota, Minneapolis, MN: Psychological Effects of Physical Attractiveness. Gerald R Adams, family and human development, Utah State University, Logan, UT: Effects of Physical Attractiveness on Socialization. 447 List of Symposium Participants G William Lucker, social psychology and CHGD, The University of Michigan: Esthetics and Ouantitative Analysis of Facial Appearance. Lee W Graber, orthodontics, Loyola University, Chicago, IL; Psychological Considerations of Orthodontic Treatment. Anne Redmond, psychiatry, Maryland, Baltimore, MD: Psychological Evaluation of Facial Change Following Orthognathic Surgery. lan R Munro, Surgery, The University of Toronto, Toronto, Ontario, Canada: Psychological Effects of Surgical Treatment of Facial Deformities. Discussants: James R Hayward, oral and maxillofacial surgery, The University of Michigan. Lysle E Johnston Jr, orthodontics, Saint Louis University, St. Louis, MO. Hazel Markus, psychology, The University of Michigan. M Haskell Newman, plastic surgery, The University of Michigan. Howard A Sather, orthodontics, Mayo Medical School, Rochester, MN. Ronald P Strauss, dental ecology, The University of North Carolina, Chapel Hill, NC. Donald M Tilghman, oral and maxillofacial surgery, Johns Hopkins University, Baltimore, MD. - -, 1981: Effects of Surgical Intervention on Craniofacial Growth Monograph 12, CGS, James A McNamara Jr, David S Carlson, Katherine A Ribbens, editors Donald H Enlow, orthodontics, Case Western Reserve University, Cleveland, OH: Craniofacial Growth Mechanisms: Normal and Disturbed. David S Carlson, anatomy and CHGD, The University of Michigan: Experimental Models of Surgical Intervention in the Growing Face. Bernard G Sarnat, oral biology and plastic surgery, The University of California, Los Angeles, CA: Some Correlated Studies of Craniofacial Change after Surgery in the Young and Adult. Bruce N Epker, oral and maxillofacial surgery, John Peter Smith Hospital, Fort Worth, TX: The Effects of Early Surgical Advancement of the Mandible and Maxilla on Subsequent Growth. (3 chapters) Samuel Pruzansky, craniofacial anomalies, The University of Illinois, Chicago, |L: Craniofacial surgery: Experimenting on Nature's Experiments. Joseph G McCarthy, plastic surgery, New York University, New York, NY: Interveſ" tive Surgery on Craniofacial Dysostosis. 448 40 Years of Moyers Symposia Discussants: Howard Aduss, orthodontics and craniofacial anomalies, The University of Illinois, Chicago, IL. Robert J Isaacson, orthodontics, The University of California, San Francisco, CA. Melvin L Moss, anatomy, Columbia University, New York, NY. Robert E Moyers, CHGD, The University of Michigan. Ravindra Nanda, orthodontics, The University of Connecticut, Farmington, CT. William R. Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC. R Bruce Ross, dentistry, Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada. º 1982: Clinical Alteration of Craniofacial Growth Monograph 14, CGS, James A McNamara Jr, Katherine A Ribbens, Raymond P Howe, editors Jan Van Limborgh, Institute of Anatomy and Embryology, The University of Am- sterdam, Amsterdam, The Netherlands: Morphogenic Control of Craniofacial Growth. JRE Mills, orthodontics, Eastman Dental Hospital, London, England: Clinical Con- trol of Craniofacial Growth: A Skeptic's Viewpoint. Egil P Harvold, Center for Craniofacial Anomalies, The University of California, San Francisco, CA: Altering Craniofacial Growth: Force Application and Neuromuscular-bone Interaction. Fred L. Bookstein, statistics and morphometrics, CHGD, The University of Michigan: Measuring Treatment Effects on Craniofacial Growth. Rolf Fränkel, Heinrich Braun Regional Hospital, Zwickau, German Democratic Republic: Biomechanical Aspects of the Form-functional Relationship in Craniofacial Morphogenesis: A Clinician's Approach. TM Graber, Orthodontics, The University of Chicago, Chicago, IL: Evolution of the Concepts Underlying Craniofacial Growth Regulation. Discussants: Rolf G Behrents, orthodontics, Case Western Reserve University, Cleveland, OH. Charles J Burstone, orthodontics, The University of Connecticut, Farmington, CT. Donald R Joondeph, orthodontics, The University of Washington, Seattle, WA. Robert P Scholz, Orthodontics, The University of California, San Francisco, CA. 449 List of Symposium Participants Robert Shaye, orthodontics, Louisiana State University, New Orleans, LA. Peter S Vig, orthodontics, The University of North Carolina, Chapel Hill, NC. Donald G. Woodside, orthodontics, The University of Toronto, Toronto, Ontario, Canada. 1983: Malocclusion and the Periodontium Monograph 15, CGS, James A McNamara Jr and Katherine A Ribbens, editors Antony H Melcher, periodontal physiology, The University of Toronto, Toronto, Ontario, Canada: Cellular Activity in Adaptation of the Periodontium. Per Rygh, orthodontics, The University of Bergen, Bergen, Norway: Periodontal Responses to Orthodontic Forces. • Bjørn U Zachrisson, orthodontics and periodontics, The University of Oslo, Oslo, Norway: Periodontal Changes during Orthodontic Treatment. Cyril Sadowsky, orthodontics, The University of Illinois, Chicago, IL: Long-term Effects of Orthodontic Treatment on the Periodontium During Adolescence. Alan M Polson, periodontics, Eastman Dental Center, Rochester, NY; Long-term Effects of Orthodontic Treatment on the Periodontium. Gunnar K Svanberg, periodontics, The University of Michigan: The Effect of Trau- ma from Occlusion on the Periodontium. Robert L.Vanarsdall, orthodontics and periodontics, The University of Pennsylva- nia, Philadelphia, PA: Management of Canine Impaction. Discussants: Raul Caffesse, periodontics, The University of Michigan. Walter Cohen, periodontics, The University of Pennsylvania, Philadelphia, PA. Richard L. Christiansen, orthodontics, The University of Michigan. Arnold M Geiger, periodontics and orthodontics, Columbia University, New York, NY. John E Horton, periodontics, The Ohio State University, Columbus, OH. Sigurd P. Ramfjord, periodontics, The University of Michigan. - 1984: Developmental Aspects of Temporomandibular Disorders Monograph 16, CGS, David S Carlson, James A McNamara Jr, Katherine A RibbenS, editors 450 40 Years of Moyers Symposia Alfred W Crompton, Museum of Comparative Zoology, Harvard University, Cambridge, MA: Development and Adaptation of the TMJ. William K Solberg, gnathology and occlusion, The University of California, Los Angeles, CA: Current Concepts on the Development of TMJ Dysfunction. Robert E Moyers, CHGD, The University of Michigan: Development of Occlusion and TMJ Disorders. Birgit Thilander, orthodontics, The University of Goteborg, Goteborg, Sweden: Temporomandibular Joint Problem in Children. Arthur T Storey, preventive dental sciences, The University of Manitoba, Win- nipeg, Manitoba, Canada: Neurophysiology of TMD. Jos MH Dibbets, orthodontics. The University of Groningen, Groningen, The Netherlands: TMJ Dysfunction and Craniofacial Growth. - Discussants: Raymond J Fonseca, oral and maxillofacial surgery, The University of Michigan. John M. Gregg, private practice of oral and maxillofacial surgery, Blacksburg, VA. William L Hylander, anatomy and anthropology, Duke University, Durham, NC. Sigurd P Ramfjord, periodontics, The University of Michigan. Christian S Stohler, occlusion, The University of Michigan. Peter S Vig, orthodontics, The University of Michigan. - º 1985: Science and Clinical Judgment in Orthodontics Monograph 19, CGS, Peter S Vig and Katherine A Ribbens, editors Alvan R Feinstein, medicine and epidemiology, Yale, New Haven, CT: The Clinician aS Scientist. Peter S Vig, orthodontics, The University of Michigan: Reflections on the Ratio- nality of Orthodontics: Toward a New Paradigm. David F Ransohoff, medicine and epidemiology, Case Western Reserve University, Cleveland, OH: Science and Diagnosis. Coenraad Moorrees, orthodontics, Harvard University and Forsythe Dental Cen- ter, Cambridge, MA: Scientific Discipline in Diagnosis and Treatment Planning. Lysle E Johnston Jr, orthodontics, Saint Louis University, St. Louis, MO: A Comparative Analysis of Class || Treatments. David L. Sackett, medicine and clinical epidemiology, McMasters University, Hamilton, Ontario, Canada: The Science of the Art of Clinical Management. 451 List of Symposium Participants Discussants: Fred L Bookstein, statistics and morphometrics, CHGD, The University of Michi- gan. Bruce McLain, orthodontics, Bowman Grey Medical School, Wake Forest Univer- sity, Wake Forest, NC. Robert E Moyers, CHGD, The University of Michigan. - - 1986: Craniofacial Growth during Adolescence Monograph 20, CGS, David Carlson and Katherine A Ribbens, editors James Tanner, Institute of Child Health, The University of London, London, England: Growth at Adolescence: An Introduction. Robert P. Kelch, pediatrics, The University of Michigan: Endocrinology of Adoles- CenCe. Urban Hägg, orthodontics, University of Lund, Malmö, Sweden: Pubertal Growth and Orthodontic Treatment. Michael L. Riolo, orthodontics and CHGD, The University of Michigan: Facial Soft Tissue Changes During Adolescence. Sheldon Baumrind, orthodontics, The University of California, San Francisco, CA: Craniofacial Growth During Adolescence: Implications and Applications to Orthodontic Treatment. Darryle E Bowden, Center for Human Growth, The University of Melbourne, Melbourne, Australia: Craniofacial Growth During Adolescence. Discussants: Melvyn J Baer, orthodontics, The University of Michigan. Rolf G Behrents, orthodontics, The University of Tennessee, Memphis, TN. David S Carlson, anatomy and orthodontics, The University of Michigan. A Roberto Frisancho, anthropology and CHGD, The University of Michigan. Stanley M. Garn, genetics and nutrition, CHGD, The University of Michigan. 1987: Craniofacial Morphogensis and Dysmorphogensis Monograph 21, CGS, Katherine WLVig and Alphonse Burdi, editors 452 40 Years of Moyers Symposia Brian K Hall, biology, Dalhousie University, Halifax, Nova Scotia, Canada: Mechanisms of Craniofacial Development. Robert M Pratt, reproduction and developmental toxicology, National Institutes of Health, Research Triangle Park, NC: Environmental Factors Influencing Craniofacial Morphogenesis. David E Poswillo, oral and maxillofacial surgery, Guy's Hospital, London, England: Malformations, Microtia and the Growth of the Mandible. Jeffrey L Marsh, plastic surgery, Washington University, St. Louis, MO: Computer- assisted Imaging in the Diagnosis, Management and Study of Dysmorphic Patients. Katherine WL Vig, orthodontics, The University of Michigan: Orthodontic Per- spective in Craniofacial Dysmorphology. - Joseph G McCarthy, plastic surgery, New York University, New York, NY: Craniofa- cial Dysmorphology: Surgical Treatment. James L Ackerman, orthodontics, The University of Pennsylvania, Philadelphia, PA: Summary: The Perspective of the Clinical Orthodontist. Discussants: Linda L Brinkley, anatomy and cell biology, The University of Michigan. Bruce M Carlson, anatomy and cell biology, The University of Michigan. David S Carlson, anatomy and orthodontics, The University of Michigan. Court Cutting, plastic surgery, New York University, New York, NY. Charles Kremenak, pediatric dentistry, The University of Iowa, Iowa City, IA. ºf m 1988: Orthodontics in an Aging Society Monograph 22, CGS, David S Carlson, editor W Andrew Achenbaum, gerontology, The University of Michigan: The Aging Society. Richard CAdelman, gerontology, The University of Michigan: Myths and Realities of Biological Aging. Jeffrey B Halter, medicine and gerontology, The University of Michigan: Clinical Implication of the Aging Process. Rolf G Behrents, orthodontics, The University of Tennessee, Memphis, TN: The Consequences of Adult Craniofacial Growth. Birte Melsen, orthodontics, The University of Aarhus, Aarhus, Denmark: Orth- odontic Treatment of the Degenerated Dentition. 453 List of Symposium Participants Christian S Stohler, restorative dentistry, The University of Michigan: TMD in the Aged. William R Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC; Orthodontics in an Aging Society: An Overview. Discussants: Brian Burt, public health, The University of Michigan. Chester A Douglass, oral epidemiology and dental public health, Harvard Univer- sity, Cambridge, MA. Donald H Enlow, orthodontics, Case Western Reserve University, Cleveland, OH. Stanley M. Garn, genetics and nutrition, CHGD, The University of Michigan. goºd */ 1989: Craniofacial Growth Theory and Orthodontic Treatment Monograph 23, CGS, David Carlson, editor Donald H Enlow, orthodontics, Case Western Reserve University, Cleveland, OH: Factors in the Intrinsic Control of Facial Growth. Alexandre G Petrovic, medicine and bone biology, The University of Strasbourg, Strasbourg, France: A Mechanism of Craniofacial Growth and Modus Operant of Functional Appliance (Cybernetic Model). Lysle E Johnston Jr, orthodontics, Saint Louis University, St. Louis, MO: Fear and Loathing in Orthodontics: Notes on the Death of a Theory. Rolf G Behrents, orthodontics, The University of Tennessee, Memphis, TN: Orth- odontic Treatment and Temporomandibular Function: Concordance and Con- flict. Jos MH Dibbets, orthodontics, The University of Groningen, Groningen, The Netherlands: Orthodontic Treatment Modalities and TMJ Dysfunction. Arthur T Storey, orthodontics, The University of Texas, San Antonio, TX; Orth- odontic Treatment and Temporomandibular Function: The Etiology of TM Disorders. TM Graber, orthodontics, The University of Chicago, Chicago, IL: Temporoman" dibular Disorders: Concordance and Conflict. 454 40 Years of Moyers Symposia 1990: Clinical Research as the Basis of Clinical Practice Monograph 25, CGS, Katherine A Vig and Peter Vig, editors June Osborn, public health, The University of Michigan: Clinical Application of Biomedical Knowledge (AIDS). Ronald G Marks, biostatistics, The University of Florida, Gainesville, FL: Clinical Epidemiology from a Biostatistical Viewpoint. Peter S Vig, orthodontics, The University of Michigan: Clinical Evidence in Orthodontics: New Clothes for the Emperor? Samuel F Dworkin, oral medicine, Washington University, St. Louis, MO: Studying the Natural History of TMD: Physiological and Psychological Findings. William C Shaw, orthodontics, The University of Manchester, Manchester, England: An Epidemiological Appraisal of the Benefits, Risks and Standards of Orthodontic Treatment. Harold C Slavkin, craniofacial molecular biology, The University of Southern Cali- fornia, Los Angeles, CA: Future Prospects of Craniofacial Molecular Biology. 1991: Bone Biodynamics in Orthodontic and Orthopedic Treatment Monograph 27, CGS, David S Carlson and Steven A Goldstein, editors David B Burr, anatomy, Indiana University, Indianapolis, IN: Orthopedic Principles of Skeletal Growth, Modeling and Remodeling. Stephen A Goldstein, bioengineering, The University of Michigan: Clinical Appli- cation of Bone Remodeling Dynamics. Vincent G. Kokich, orthodontics, The University of Washington, Seattle, WA: Sutural Responses to Orthodontic Forces. WEugene Roberts, orthodontics, Indiana University, Indianapolis, IN: Orthodontic Biomechanics: Metabolic and Mechanical Control Mechanisms. Per Rygh, orthodontics, The University of Bergen, Bergen, Norway: The Responses of the Periodontal Ligament to Orthodontic Forces. Peter M Sinclair, orthodontics, The University of North Carolina, Chapel Hill, NC; Clinical Application of Orthopedic Forces: Current Capabilities and Limita- tions? º 455 List of Symposium Participants moºd 1992: Esthetics and the Treatment of Facial Form Monograph 28, CGS, James A McNamara Jr, editor Rudolph Arnheim, psychology of art, Harvard University, Cambridge, MA: The Face and the Mind Behind It. Clifton Olds, history of art, Bowdoin College, Brunswick, ME: Facial Beauty in Western Art. Robert E Moyers, CHGD, The University of Michigan: Evolution of the Concepts of the Face. William W Taschek, philosophy, The Ohio State University, Columbus, OH: Faces, Masks, and the Grotesque: On Objectivity in Aesthetic Judgment. Sheldon Peck, orthodontics, Harvard University, Cambridge, MA: Facial Realities and Oral Esthetics. Stephen R Cohen, plastic surgery, The University of Michigan: Clinical Ramifica- tions of Esthetic Judgments. Douglas KOusterhaut, dentistry and plastic surgery, The University of California, San Francisco, CA: Aesthetic Contouring of the Upper Face. Henry K Kawamoto, plastic surgery, The University of California, Los Angeles, CA: Aesthetic Plastic Surgery of the Midfacial Skeleton. Bruce N Epker, oral and maxillofacial surgery, John Peter Smith Hospital, Fort Worth, TX: Adjunctive Esthetic Surgery in the Orthognathic Surgery Patient. - º 1993: Biological and Psychological Aspects of Orofacial Pain Monograph 29, CGS, Christian S Stohler and David S Carlson, editors Barry JSessle, orofacial neuroscience, The University of Toronto, Toronto, Ontario, Canada: Trigeminal Nerve Pain: Nociceptive Pathways and Mechanisms. Christian S Stohler, biological and material sciences, The University of Michigan: Effects of Noxious Stimulation of the Jaw Muscles in the Sensory Experiences of Human Volunteers. James P. Lund, stomatology, The University of Montreal, Montreal, Quebec, Canada: Effect of Pain on Muscular Activity in TMD and Related Conditions. Samuel F Dworkin, oral medicine, The University of Washington, Seattle, WA: Behavioral, Emotional and Social Aspects of Orofacial Pain. 456 40 Years of Moyers Symposia Jocelyne S Feine, dental medicine, Montreal, Montreal, Quebec, Canada: Challenges of Measuring the Efficacy of Treatment of Chronic Trigeminal Myofascial Pain. John D Rugh, psychology, The University of Texas, San Antonio, TX: Psychological Management of the Orofacial Pain Patient. Charles G Widmer, oral and maxillofacial surgery, The University of Florida, Gainesville, FL: TMD: Past, Present and Future. 2 0. year: 1994: Orthodontic Treatment: Outcome and Effectiveness Monograph 30, CGS, Carroll-Ann Trotman and James A McNamara Jr, editors - David L. Sackett, medicine and clinical epidemiology, McMaster University, Hamilton, Ontario, Canada: Nine Years Later: A Commentary on Revisiting the Moyers Symposium, and on Identifying the Best Therapy. Lysle E Johnston Jr, orthodontics, The University of Michigan: Clinical Studies in Orthodontics: Taking the Low Road to Scotland. Sheldon Baumrind, orthodontics, The University of California, San Francisco, CA: The Decision to Extract: Preliminary Findings from a Prospective Clinical Trial. Stephen D Keeling, orthodontics, The University of Florida, Gainesville, FL:Timing of Class || Treatment: Rationale, Methods, and Early Results from an Ongoing RCT. JF Camilla Tulloch, orthodontics, The University of North Carolina, Chapel Hill, NC: Early vs. Late Treatment of Class || Malocclusion: Preliminary Results from the UNC Clinical Trial. D David Kinser, orthodontics, The University of Iowa, Iowa City, IA: The Iowa TMD Studies. Katherine WL Vig, orthodontics, The Ohio State University, Columbus, OH: Orthodontic Process and Outcome: Efficacy and Effectiveness Studies. - 1995: Orthodontic Treatment: The Management of Unfavorable Sequelae Monograph 31, CGS, James A McNamara Jr and Carroll-Ann Trotman, editors Rolf G Behrents, orthodontics, The University of Tennessee, Memphis, TN; latro- genic Problems Associated with the Clinical Practice of Orthodontics. 457 List of Symposium Participants Peter A Frensch, psychology, Max Planck Institute, Berlin, Germany: Learning and Expertise: Why People Make Mistakes. Richard L Small, attorney, Bingham Farms, MI; Medico-legal Implications of Unfavorable Orthodontic Treatment Outcomes. William R Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC; Root Resorption Related to Orthodontic Treatment. Sheldon Baumrind, orthodontics, The University of California, San Francisco, CA: Investigating the Correlates of Apical Root Resorption. Ze'ev Davidovich, orthodontics, Harvard University, Cambridge, MA: The Etiology of Root Resorption. Paul M Thomas, private practice of orthodontics and orthognathic Surgery, Durham, NC: Complications Associated with Orthognathic Surgery. 1996: Creating the Compliant Patient Monograph 33, CGS, James A McNamara Jr and Carroll-Ann Trotman, editors Anne C Petersen, psychology, The University of Minnesota, Minneapolis, MN: Understanding Adolescence: Adolescent Development Implications for the Adolescent as a Patient. Lynn KCooper, psychology, The University of Missouri, Columbia, MO: Motivations for Health Behavior Among Adolescents. M Susan Jay, pediatrics, Loyola University, Chicago, IL: Compliance: The Adoles- cent/Provider Partnership. David S. Rosen, pediatrics, The University of Michigan: Creating the Successful Adolescent Patient: A Practical Patient-Oriented Approach. Richard G. “Wick" Alexander, orthodontics, Baylor University, Dallas, TX: Creating the Compliant Patient. Larry W White, private practice of orthodontics, Hobbs NM. Patient Motivation. Douglas S Ramsay, pediatric dentistry and orthodontics, The University of Wash- ington, Seattle, WA: The Role of Technology and Its Application to Orthodon- tics. Lisa A Tedesco, health psychologist, The University of Michigan: Symposium Overview: What Did They Say and What Does It Mean? 1997: Distraction Osteogenesis and Tissue Engineering Monograph 34, CGS, James A McNamara Jr and Carroll-Ann Trotman, editors 458 40 Years of Moyers Symposia Mikhail Samchukov, biomedical sciences, Baylor University, Dallas, TX: Distraction Osteogenesis: Origins and Evolution. Fernando Molina, plastic surgery, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico: Maxillary Distraction: Esthetic and Functional Benefits in Cleft and Prognathic Patients during the Mixed Dentition; and Mandibular Distraction in the Treatment of Patients with Craniofacial Anomalies. (2 chapters) Steven R Cohen, plastic surgery, Center for Craniofacial Disorders, Scottish Rite Children's Medical Center, Atlanta, GA: Distraction Osteogenesis of the Craniofacial Skeleton: Evolving Indications and Techniques. Suzanne McCormick, oral and maxillofacial surgery, New York University, New York, NY: The Effect of Distraction Osteogenesis on the Temporomandibular Joint. Barry H Grayson, orthodontics, New York University, New York, NY: Vector of Device Placement and Trajectory of Mandibular Distraction. Joseph Vacanti, surgery, Harvard University and Children's Hospital of Boston, Cambridge and Boston, MA: Tissue Engineering: Replacement and Repair. Bruce M Carlson, anatomy and cell biology, The University of Michigan: Principles of Tissue Generation and Regeneration. Martha J Somerman, periodontics, The University of Michigan: Promise and Uncertainty in Regeneration of Oral Tissues. David J Mooney, biological sciences, The University of Michigan: Future of Tissue Engineering in the Craniofacial Region. 1998: Growth Modification: What Works, What Doesn’t, and Why Monograph 35, CGS, James A McNamara Jr, editor Harold C Slavkin, craniofacial biology, National Institutes of Dental Research, Bethesda, MD: Possibilities of Growth Modification: Nature vs. Nurture. David S Carlson, biomedical sciences, Baylor College of Dentistry, Texas A&M Health Sciences Center, Dallas, TX: Growth Modification: From Molecules to Mandibles. Lysle E Johnston Jr, orthodontics, The University of Michigan: Growing Jaws for Fun and Profit: A Modest Proposal. Patrick K. Turley, orthodontics, The University of California, Los Angeles, CA: Modification of Midfacial Growth with Maxillary Protraction and Expansion in Class || Malocclusion. 459 List of Symposium Participants James A McNamara Jr, orthodontics and CHGD, The University of Michigan: The Role of the Transverse Dimension in Orthodontic Diagnosis and Treatment Planning. Young H Kim, private practice of orthodontics, Weston, MA: Treatment of Severe Openbite Malocclusions without Surgical Intervention. Stephen A Schendel, plastic surgery, Stanford University, Stanford, CA: Surgical Intervention: A Role in Growth Modification. Lee W Graber, private practice of orthodontics, Vernon Hills, IL; The 25th Moyers Meeting: Reflections, Summary and Perspectives. º - Z - 1999: The Enigma of the Vertical Dimension Monograph 36, CGS, James A McNamara, editor Alan G Hannam, oral biology, The University of British Columbia, Vancouver, British Columbia, Canada: The Form/Function Relationship in the Vertical Dimension. William R Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC; The Development of Vertical Dentofacial Problems: Concepts from Recent Human Studies. Lloyd E Pearson, private practice of orthodontics, Edina, MN: The Management of Vertical Dimension Problems in Growing Patient. Sandro FPalla, masticatory disorders, The University of Zurich, Zurich, Switzerland: The Vertical Dimension: A Prosthodontist's Perspective. Donald W Warren, dental ecology, The University of North Carolina, Chapel Hill, NC: Breathing Behavior and Posture. Young H Kim, private practice of orthodontics, Weston, MA: Treatment of Anterior Openbite and Deep Overbite Malocclusions with the Multi-LOOP Edgewise Arch-Wire (MEAW) Therapy. 2000: Frontiers of Dental and Facial Esthetics Monograph 38, CGS, James A McNamara Jr and Katherine A Kelly, editors Vincent G. Kokich, orthodontics, and Frank M Spear, prosthodontics, The University of Washington, Seattle, WA: Maximizing Anterior Esthetics: An Interdisciplinary Approach. 460 40 Years of Moyers Symposia Jörg Strub, prosthodontics, Albert-Ludwigs University, Freiburg, Germany: Gingival and Dental Esthetics: Mimicking Mother Nature. Preston D Miller, private practice of periodontics, Cincinnati, OH: Periodontal Plastic Surgery in the Orthodontic Patient. Maurice Salama, private practice of orthodontics, Atlanta, GA: Implant Restora- tion of the Dentally-compromised Patient. Myron L Nevins, periodontics, Harvard University, Cambridge, MA: Multidisci- plinary Dental Treatment: Bone Augmentation for the Purpose of Implant Placement. W Eugene Roberts, orthodontics, Indiana University, Indianapolis, IN: Multidis– ciplinary Restoration of the Vertical Dimension of Occlusion: Esthetics, Func- tion, Stability and Complications. 2001: Treatment Timing: Orthodontics in Four Dimensions Monograph 39, CGS, James A McNamara Jr and Katherine A Kelly, editors William R Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC; Treatment Timing: Effectiveness and Efficiency. Hans Pancherz, orthodontics, The University of Giessen, Giessen, Germany: Efficiency of Class || Division 1 Therapy in Relation to Treatment Timing and Modality. James A McNamara Jr, orthodontics and CHGD, The University of Michigan: When to Begin? Variations in Treatment Timing According to Malocclusion Type. David C Hamilton Sr, private practice of orthodontics, New Castle, PA: Early Treatment: How Early is Early? Timothy T. Wheeler, orthodontics, The University of Florida, Gainesville, FL: Results from Federally Funded Class || Randomized Clinical Trials. Kevin O'Brien, orthodontics, The University of Manchester, Manchester, England: Treatment Timing for Class || Malocclusion: The Results from Two UK-based Multi-center Randomized Controlled Trials. Tiziano Baccetti and Lorenzo Franchi, orthodontics, The University of Florence, Florence, Italy: The Use of Maturational Indices for the Identification of Optimal Treatment Timing in Dentofacial Orthopedics. Lee W Graber, private practice of orthodontics, Vernon Hills, IL; Tick-tock, Tick- tock: When Do You Start? 461 List of Symposium Participants - - -A - 2002: Information Technology and Orthodontic Treatment Monograph 40, CGS, James A McNamara Jr, editor Richard Walker, software developer and orthodontist, Dentofacial Software Inc, Toronto, Ontario, Canada: A Nonlinear Approach to Surgical Prediction. David M. Sarver, private practice of orthodontics, Vestavia Hills, AL: Integrating Information Technology into Routine Orthodontic Practice. Paul M Thomas, private practice of orthodontics and oral and maxillofacial surgery, Durham, NC: Digital Treatment Simulation: Science or Sleight-of- hand? Robert J Isaacson, orthodontics and editor, Angle Orthodontist, Edina, MN: How Digital Models Work and What to Expect from Them. David C Hatcher, private practice of oral and maxillofacial radiology, Sacramento, CA: Diagnosis Goes Digital. Mark G. Hans, orthodontics, Case Western Reserve University, Cleveland, OH: Electronic Storage and Retrieval of Cephalometric Radiographs. Orhan C Tuncay, orthodontics, Temple University, Philadelphia, PA: Motion Animation of Dentofacial Structures. Chester Wang, software developer, Dolphin Imaging, Woodland Hills, CA: Going Digital. James Mah, craniofacial biology and healthcare, The University of Southern California, Los Angeles, CA: Information Technology: The Virtual Craniofacial Patient. Robert P Scholz, private practice of orthodontics, San Leandro, CA: Technolocity. - 2003: Growth and Treatment: A Meeting of the Minds Monograph 41, CGS, James A McNamara Jr, editor Rolf G Behrents, orthodontics, Saint Louis University, St. Louis, MO: The Past as Present: What Have We Learned about Facial Growth? Harold C Slavkin, craniofacial molecular biology, The University of Southern California, Los Angeles, CA: Genetics and the Genome Project: Relevance to the Practicing Orthodontist. Timothy ATurvey, oral and maxillofacial surgery, The University of North Carolina, Chapel Hill, NC: Orthognathic Surgery: Past and Current Perspectives. 462 40 Years of Moyers Symposia Robert J Isaacson, orthodontics and editor, Angle Orthodontist, Edina, MN: What Makes Orthodontic Treatment Work? Bjørn U Zachrisson, orthodontics and periodontics, The University of Oslo, Oslo, Norway: Interdisciplinary Cooperation in the Treatment of Adults and Adolescents. David M. Sarver, private practice of orthodontics, Vestavia Hills, AL; The Art/ Science of Appearance and Esthetics. Christian S Stohler, biological and material sciences, The University of Michigan: Facial Pain and Temporomandibular Disorders: Current Concepts and Prac- tices. Lysle E Johnston Jr, orthodontics, The University of Michigan: Overview and Per- spectives. - zoºſa - 2004: Implants, Microimplants, Onplants and Transplants: New Answers to Old Ouestions in Orthodontics Monograph 42, CGS, James A McNamara Jr, editor W Eugene Roberts, orthodontics, Indiana University, Indianapolis, IN: The Biology of Osseointegration and Tissue Engineering. Birte Melsen, orthodontics, University of Aarhus, Aarhus, Denmark: Creative Uses of Implant Technology. Hee-Moon Kyung, orthodontics, Kyungpook National University, Daegu, Korea: Microimplant Anchorage in Orthodontics. Frank Celenza Jr, private practice of orthodontics and periodontics, New York, NY: The Power of Implants in Orthodontics. William F. Hohlt, orthodontics, Indiana University, Indianapolis, IN: Onplants as Anchorage in Orthodontic Treatment. Ward M. Smalley, private practice of orthodontics, Seattle, WA: Treatment of Debilitated Dentitions with Implant Anchorage. Hans Ulrik Paulsen, orthodontics and oral radiology, Karolinska Institute, Stockholm, Sweden: Autotransplantation of Teeth in Orthodontics: A Biological Method to Substitute Missing or Lost Teeth and Alveolar Bone. William M Northway, private practice of orthodontics, Traverse City, MI: Auto- genic Dental Transplants. 463 List of Symposium Participants 2005: Digital Radiography and Three-dimensional Imaging Monograph 43, CGS, James A McNamara Jr and Sunil D Kapila, editors David H Hatcher, private practice of oral and maxillofacial radiology, Sacramento, CA: Three-dimensional Digital Imaging. Robert P Scholz, editor of Technobytes, American Journal of Orthodontics and Dentofacial Orthopedics, Discovery Bay, CA: The Radiology Ouestion: Film, Indirect, Direct or Cone Beam. Chester Wang, software developer, Dolphin Imaging, Chatsworth, CA: Creating Practical Tools for Examining and Measuring 3-dimensional Volumetric Data. Sharon L Brooks, oral and maxillofacial radiology, The University of Michigan: Digital Radiography: Who's in Charge? Regulatory, Quality Assurance, and Li- ability Issues. James Mah, orthodontics, The University of Southern California, Los Angeles, CA: The Cone Beam Decision: Features, Technology and Software of the Four Systems. Joseph M. Caruso, orthodontics, Loma Linda University, Loma Linda, CA: A Report on the Use of CBCT within a Graduate Orthodontic Program. Jacques Triel, Service de Radiologie, Clinique Pasteur, Toulouse, France: The Human Face as a Three-dimensional Model for Cephalometric Analysis. 2006: Early Orthodontic Treatment: Is the Benefit Worth the Burden? Monograph 44, CGS, James A McNamara Jr, editor Rolf G Behrents, orthodontics, Saint Louis University, St. Louis, MO: The Decision of When to Intervene: The Nature of the Ouestion in Terms of Faith, Passion, and Evidence. Katherine WLVig, orthodontics, The Ohio State University, Columbus, OH: Early Orthodontic and Orthopedic Treatment. Lysle E Johnston Jr, orthodontics, The University of Michigan: If Wishes Were Horses.... Lorenzo Franchi, orthodontics, The University of Florence, Florence, Italy. Man" dibular Changes Produced by Functional Appliances in Class || Malocclusion: A Systematic Review. 464 40 Years of Moyers Symposia Patrick KTurley, private practice of orthodontics, Santa Monica, CA: Treatment of Class Ill Malocclusion: Short-term and Long-term Outcomes. Tiziano Baccetti, orthodontics, The University of Florence, Florence, Italy: The Effectiveness of Early Intervention in Class III and Openbite Malocclusions. James A McNamara Jr, orthodontics and CHGD, The University of Michigan: Long- term Stability of Changes in the Transverse Dimension: Is Early Expansion Worth the Effort? James L. Vaden, orthodontics, The University of Tennessee, Memphis, TN: Management of Tooth-size/Arch-size Problems in the Mixed and Early Permanent Dentition. 2007: Microimplants as Temporary Anchorage in Orthodontics Monograph 45, CGS, James A McNamara Jr, editor Birte Melsen, orthodontics, The University of Aarhus, Aarhus, Denmark: What Influence Has Skeletal Anchorage Had on Orthodontics? Hee-Moon Kyung, orthodontics, Kyungpook National University, Daegu, Korea: Microimplant Site Selection and Placement. W Eugene Roberts, orthodontics, Indiana University, Indianapolis, IN: Bone Biology and Biomechanics Applied to Microimplants. Axel Bumann, private practice of orthodontics, Berlin, Germany: 3D Control of Orthodontic Tooth Movement with Segmented Techniques and Mini-pins. Hyo-Sang Park, orthodontics, Kyungpook National University, Daegu, Korea: Application of Microimplants in Various Clinical Situations. Hugo De Clerck, orthodontics, Université Catholique de Louvain, Brussels, Belgium: Modified Miniplates: Temporary Skeletal Anchorage Devices for Orthodontic and Orthopedic Applications. Sarandeep Huja, orthodontics, The Ohio State University, Columbus, OH: Review and Implications of Translational Research to Success of TADs. Shou-Hsin Kuang, orthodontics, Veterans General Hospital, Taipei, Taiwan: Clinical Problems with Microimplant Anchorage. Jason Cope, orthodontics, Baylor Dental College, Texas A&M University, Dallas, TX; Successes and Failures with Miniscrew Implants. James A McNamara Jr, orthodontics and CHGD, The University of Michigan: Overview and Closing Remarks. 465 List of Symposium Participants - 2008: Temporomandibular Disorders and Orofacial Pain: Separating Controversy from Consensus Monograph 46, CGS, James A McNamara Jr and Sunil D Kapila, editors Christian S Stohler, Dean, School of Dentistry, Maryland, College Park, MD: Orofacial Pain: 100 Years of Searching for Causes and Cures. Jeffrey P Okeson, orofacial pain, The University of Kentucky, Lexington, KY: Or- thodontics, Occlusion and TMD: Twenty Years after the Michigan Experience. Linda LeResche, oral medicine, The University of Washington, Seattle, WA: Gen- der and Hormonal Effects on Clinical TMJD Pain. Hans Pancherz, orthodontics, The University of Giessen, Giessen, Germany: TMJ Adaptations in Adults Treated with the Herbst Appliance. David H Hatcher, private practice of oral and maxillofacial radiology, Sacramento, CA: 3D Imaging: Applications for TMD and Orofacial Pain. Charles R Carlson, psychology and orofacial pain, The University of Kentucky, Lexington, KY: Psychological Factors in TMD and Orofacial Pain. Larry M. Wolford, oral and maxillofacial surgery, Baylor Dental College, Texas A&M University, Dallas, TX: TMJ Conditions That Adversely Affect Orthodontic Treatment Outcomes: Diagnosis and Treatment. Charles McNeill, orofacial pain, The University of California, San Francisco, CA: Management of TMD Signs and Symptoms that Develop during Dental/ Orthodontic Treatment. Sunil D Kapila, orthodontics, The University of Michigan: Current and Future Innovations in TMD Diagnostics and Therapeutics. º 2009: Surgical Enhancement of Orthodontic Treatment Monograph 47, CGS, James A McNamara Jr and Sunil D Kapila, editors David M Sarver, private practice of orthodontics, Vestavia Hills, AL; Augmenting and Improving Macro-, Micro- and Mini-esthetics through Surgical Intervention. John J. Graeber, private practice of general dentistry, East Hanover, NJ: The Diode Laser. Indications and Contraindications in Routine Orthodontic and Dental Practice. Myron LNevins, periodontics, Harvard University, Cambridge, MA: Breakthroughs and Pitfalls in Periodontal Regenerative Surgery and Corticotomies. 466 40 Years of Moyers Symposia Louis E Costall, plastic surgery, Medical University of South Carolina, Charleston, SC: Surgical Management of the Facial Soft and Hard Tissues to Enhance Patient Esthetics. Sean P. Edwards, oral and maxillofacial surgery, The University of Michigan: Advances in Computer-based Treatment Planning for Craniomaxillofacial Surgery. Harry L. Legan, orthodontics, Vanderbilt University, Nashville, TN: Treating Obstructive Sleep Apnea: What Works Best? Stephen A Schendel, plastic surgery and oral and maxillofacial surgery, Stanford University, Stanford, CA: The Airway: Anatomy and Structural Changes in Obstructive Sleep Apnea. R Scott Conley, orthodontics, The University of Michigan: The Face of Obstructive Sleep Apnea. - 2010: Effective and Efficient Tooth Movement: Evidence-based Ortho- dontics Monograph 48, CGS, James A McNamara Jr, Nan Hatch, Sunil D Kapila, editors Charles J Burstone, orthodontics, The University of Connecticut, Farmington, CT: Self-ligation and Friction: Fact and Fantasy. Peter Miles, orthodontics, The University of Oueensland, Caloundra, Oueensland, Australia: Self-ligation: Claims versus Evidence. Tiziano Baccetti, orthodontics, The University of Florence, Florence, Italy: Clinical Management of Tooth Eruption Anomalies: Effectiveness and Indications. Nan Hatch, orthodontics, The University of Michigan: Biologic Mediators of Tooth Movement: Recent Advances Support Future Clinical Application. James K Hartsfield, orthodontics, The University of Kentucky, Lexington, KY: Problems beyond the Control of the Clinician: Understanding the Genetics Underlying Orthodontic Treatment. Haluk İşeri, orthodontics, The University of Ankara, Ankara, Turkey: Distraction Osteogenesis and Other Adjuncts to Accelerate Tooth Movement and Orth- Odontic Treatment. Ravindra Nanda, orthodontics, The University of Connecticut, Farmington, CT: Mechanics to Expedite Orthodontic Treatment. Peter H Buschang, orthodontic research, Baylor College of Dentistry, Dallas, TX: Experimental Evidence Supporting the Use of Miniscrews in Orthodontics. Flavio A Uribe, orthodontics, The University of Connecticut, Farmington, CT: Corticotomies and Other Adjuncts to Enhance Orthodontic Tooth Movement: Future Directions. 467 List of Symposium Participants º 2011: Taking Advantage of Emerging Technologies in Clinical Practice Monograph 49, CGS, James A McNamara Jr, editor Daniel E Atkins, research cyberinfrastructure and computer science, The University of Michigan: Computing Technology: A Global Perspective. James Lakes, senior strategist, Microsoft Corporation, Redmond, WA: The Future of Healthcare Delivery: Technology and Healthcare. Kirt Simmons, Arkansas Children's Hospital, Little Rock, AR: The Electronic Patient Record: How it Affects the Private Practitioner. Mary Kay Miller, website and Internet consultant, Rochester, NY: Your Practice Website: Improving Visibility on the Internet. Greg Jorgensen, private practice of orthodontics, Rio Rancho, NM: Social and Business Networking: What Every Clinician Should Know. William D Engilman, orthodontics, The University of Louisville, Louisville, KY: Mobile Computing and VoIP: How They Affect Clinical Practice. Lynnea A Johnson, informatics and innovation, The University of Michigan: Cloud Computing: A Part of Your Practice Future? Robert P Scholz, editor of Technobytes, American Journal of Orthodontics and Dentofacial Orthopedics, Discovery Bay, CA: Technology in Private Practice: Where Do We Go From Here? 2012: CBCT in Orthodontics: Indications, Insights & Innovations Textbook, in press, Sunil D Kapila, editor. (Not a CGS monograph. Includes chapter authors who were not speakers at the 2012 Symposium.) Sunil D Kapila, orthodontics, The University of Michigan: Contemporary Concepts on Cone-beam Computed Tomography in Orthodontics. Om P Kharbanda, orthodontics, Center for Dental Education and Research, A|| India Institute of Medical Studies, New Delhi, India: Functional and Technical Characteristics of Different Cone-beam Computed Tomography Units. Sharon L Brooks, orthodontics, The University of Michigan: Cone-beam Com- puted Tomography in Orthodontics: Perspectives on Radiation Risk. William C. Scarfe, radiology and imaging science, The University of Louisville, Louisville, KY: Development of Evidence-based Selection Criteria for Come" beam Computed Tomography in Orthodontics. Aaron Molen, private practice of orthodontics, Auburn, WA: Protocols for the Use of Cone-beam Computed Tomography in Orthodontic Practice. 468 40 Years of Moyers Symposia Christos Angelopoulos, American Academy of Oral and Maxillofacial Radiology, New York, NY. How to Interpret Cone-beam Computed Tomography Scans. Erika Benavides, periodontics and oral medicine, The University of Michigan: Detection of Incidental Findings in Cone-beam Computed Tomography Imaging and Their Clinical Implications. Juan Martin Palomo, orthodontics, Case Western Reserve University, Cleveland, OH: 3D Orthodontic Diagnosis and Treatment Planning. Anna-Kari Hajati, private practice, Stockholm, Sweden: Application of 3D TMJ Imaging to TMJDs, TMJ Functional Analyses and Orthodontic Treatment OutCOmeS. R Scott Conley, orthodontics and pediatric dentistry, The University of Michigan: Characterization of the Upper Airway Morphology and Its Changes in the Apneic Patient Using Cone-beam Computed Tomography. Sunil D Kapila, orthodontics, The University of Michigan: Alveolar Boundary Conditions in Orthodontic Diagnosis and Treatment Planning. Jeanne M Nervina, orthodontics and pediatric dentistry, The University of Michi- gan: Assessment of Root Position and Morphology by Cone-beam Computed Tomography. Sunil D Kapila, orthodontics, The University of Michigan: 3D Image-aided Diagnosis and Treatment of Impacted and Transposed Teeth. Carlos Flores Mir, orthodontics, The University of Alberta, Edmonton, Alberta, Canada: Effects of Rapid Palatal Expansion on Tooth, Bone and Airway Changes in 3D. Sebastian Baumgaertel, orthodontics, Case Western Reserve University, Cleveland, OH: Planning and Placing Temporary Anchorage Devices with the Aid of Cone- beam Computed Tomography Imaging. Tung Nguyen, orthodontics, University of North Carolina, Chapel Hill, NC: 3D Planning and Treatment Outcomes of Bone-anchored Maxillary Protraction. Sean P. Edwards, oral and maxillofacial Surgery, The University of Michigan: Ap- plications of CBCT Technology in Orthognathic Surgery Treatment Planning. Abeer AlHadidi, dentistry, University of Jordan, Amman, Jordan: 3D Diagnosis and Management of Facial Asymmetries. Bernard Friedland, oral medicine, infection and immunity, Harvard, Cambridge, MA: To Scan or Not to Scan: Medico-legal Implications. Birte Melsen, Aarhus, Aarhus, Denmark: Rational Basis for Transitioning from 2D to 3D Radiographic Imaging in Orthodontic Practice and Research. Yoon-Ji R Kim, orthodontics, Hallym University Medical Center, Seoul, Korea: 3D Assessment of Orthognathic Surgical Outcomes. Snehlata Oberoi, orofacial sciences, The University of California, San Francisco, CA: 3D Imaging in Diagnosis and Treatment Planning in Craniofacial Anomalies. Michael W Vannier, radiology and medicine, The University of Chicago, Chicago, IL; The Future of Cone-beam Computed Tomography and 3D Imaging in Or- thodontics. 469 List of Symposium Participants º 2013: The 40th Moyers Symposium: Looking Back ... Looking Forward Monograph 50, CGS, James A McNamara Jr, editor James A McNamara Jr, orthodontics and CHGD, The University of Michigan: Reflections on the Moyers Symposium: A Living History of Contemporary Orthodontics and Craniofacial Biology. Vincent G. Kokich, The University of Washington, Seattle, WA: Evolution of Adult Orthodontics: The Importance of a Realistic Approach. David M Sarver, private practice of orthodontics, Vestavia Hills, AL: Orthodontic Diagnosis and Treatment from the Outside In. Rolf G Behrents, orthodontics, Saint Louis University, St. Louis, MO: Longitudinal Growth Studies: Comments on the Benefits and the Risks. William R Proffit, orthodontics, The University of North Carolina, Chapel Hill, NC; Skeletal Anchorage: Its Possible Impact on Orthognathic Surgery. Lee W Graber, private practice of orthodontics, Vernon Hills, IL: Periodontal Screening: Practical Protocols for the Orthodontist. David L. Sackett, medicine and epidemiology, McMasters University, Hamilton, Ontario, Canada: On the Vanishing Need for MD Randomized Trialists at Moyers Symposia. Frans PGM van der Linden, orthodontics, Radboud University, Nijmegen, The Netherlands: Development of the Human Dentition: A Life's Work. David S Carlson, Vice President for Research and Dean of the School of Graduate Studies at the Texas A&M Health Science Center, College Station, TX: Toward a Modern Synthesis for Craniofacial Biology: A Genomic-Epigenomic Basis for Dentofacial Orthopedic Treatment. Hugo De Clerck, private practice of orthodontics, Brussels, Belgium: Orthopedic Changes by Bone-anchored Intermaxillary Elastic Traction in Class || Growing Patients. Lorenzo Franchi, orthodontics, The University of Florence, Florence, Italy; Clinical Alteration of Mandibular Growth: What We Know After 40 YearS. Hans Pancherz, orthodontics, The University of Giessen, Giessen, Germany: Treatment Timing of Herbst Appliance Therapy. Katherine WL Vig, orthodontics, The Ohio State University, Columbus, OH: Contemporary Management of Craniofacial Anomalies: Will Past Experiences Influence and Predict the Future? Nan Hatch, orthodontics, The University of Michigan: FGF Signaling in Craniofacial Skeletal Development and the Pathogenesis of Craniosynostosis. 470 40 Years of Moyers Symposia Lysle E Johnston Jr, orthodontics, The University of Michigan and Saint Louis University, St. Louis, MO: Envoi: The Moyers Symposium, A Miner's Canary for 21st Century Orthodontics. Andrei D Taut and William Giannobile, periodontics, The University of Michigan: Anti-Resorptive and Bone Anabolic Agents for Periodontal Therapy. Chester Wang, software developer, Dolphin Imaging, Chatsworth, CA: The Future of Technology in Orthodontic Practice: Looking Back ... Looking Forward. 471 *(/ 4/2Z/º OTHER BOOKS FROM THE CRANIOFACIAL GROWTH SERIES McNamara JA Jr. Neuromuscular and Skeletal Adaptations to Altered Orofacial Function. Monograph 1, Craniofacial Growth Series, Centerfor Human Growth and Development, The University of Michigan, Ann Arbor 1972;184 pages. Riolo ML, Moyers RE, McNamara JA Jr, Hunter WS. An Atlas of Craniofacial Growth: Cephalometric Standards from The University School Growth Study, The University of Michigan. Monograph 2, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1974;379 pages. Moyers RE, van der Linden FPGM, Riolo ML, McNamara JA Jr. Standards of Human Occlusal Development. Monograph 5, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1976;371 pages. Carlson DS, ed. Craniofacial Biology. Monograph 10, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1981;269 pages. van der Linden FPGM, ed. Transition of the Human Dentition. Monograph 13, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1982;149 pages. Behrents RG. Growth in the Aging Craniofacial Skeleton. Monograph 17, Cranio- facial Growth Series, Center for Human Growth and Development, The Uni- versity of Michigan, Ann Arbor 1985;145 pages. Behrents RG. An Atlas of Growth in the Aging Craniofacial Skeleton. Monograph 18, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1985;160 pages. Moyers RE. On the Nature of Orthodontics. Monograph 0, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1985;121 pages. Richardson ER. An Atlas Of Craniofacial Growth in Americans of African Descent. Monograph 26, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1991;256 pages. 473 Other CGS Books WS Hunter, Carlson DS, eds. Essays Honoring Robert E. Moyers. Monograph 27, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1992;371 pages. Luder HU. Postnatal Development, Aging, and Degeneration of the TMJ in Humans and Monkeys and Rats. Monograph 32, Craniofacial Growth Series, Center for Human Growth and Development, The University of Michigan, Ann Arbor 1996;261 pages. Basyouni AA, Nanda SK. An Atlas of the Transverse Dimensions of the Face. Monograph 37, Craniofacial Growth Series, Center for Human Growth and Development and Department of Orthodontics and Pediatric Dentistry, The University of Michigan, Ann Arbor 2000;235 pages. 474 L’ IVERSITY OF MICH 1 |GAN iT 47 | 3 90.15 O064 18