- ºffl º
--- º - ºffl -
Hº º ºfflºffl
Eä# --- #ºffli################
- ºffl L-º-º-º-º-º-º-º-º:
- （º --~~
º - - - º ºffli
º - - ºffl
º º sº
# H ################ º º # º
ºffli Hº #H ºffl
Hä Häß ################### ºffli
--- --- --~~~ - º Häß ºfflº
- º º （
- º ############### º
ºffli - - # º
--- - ------------ º ºffli
H# H Häß º
- ºffl Fº
- º -
ºffl ############
- -- ---
- º
ºffl --------- º
- H ºffli ############### ######################################
º º --- --- º º
--- ºffli - - ---
-
º
º - --
º - ---
--- - - --- -- H ºffl - - --- - ---
º ºffl ################ ºffl ################################################## - ºffli
ºffli º - --- --- --- --- - --- - ---
ºffl ################################### º
ºffli ºffl º - º --- - ############ -------
- - --- º ---
ºffli
ºffl ºffli -- ºffl
--- º --- H --- º ºffli º ºffl
------- ------------ - - - --- º ºffl º
#º º ########### --- H # º
---
- ºffli
- - -
-------------- - ºffli ºffl -
- ºffli - Fº ######## #:
--~~ --- - --- º --
Häß ---
--~~ - ############################ ###########
--~~ ºffli - ºffli ------- -
ºffli -------- - ###########################
---
- ---
---
-
--- º --- --- - ºffl - -
Hiii.
（ H º ######## Hº: ºffl
---------- º ºffl -
Hää
--- -
---
ºffl --- ---
ºffl -
---
H º º
º
-
---
º: - ---
ºffl
ºffli
|-
º
ºffl º
ºffl Eº
ºffl
Fºº..…: ... º.
ca.-- -
ºffl E- - - º:
ºffli - - - - - º
ºfflº - --- | 7 - - - - - - ºffli
==#. - - - - - - ######
-
-----------
-------
ºffl
ºfflº
-----------
---
ºffl
ºffl
º
---
--------
.-
ºffli
ºffl
#.
|
º:
º:
---
. ºfflº
- - - - - - --
ºfflºº - tº rºtºtº
ºffl --~~ -º-º-º-º-º-º-º-
ºffl - Fºº
ºffli º -
º
-
--
**************** -- - ------- ****
ºfflº - º
-- º -º-º-º-º-º:
-:
º
--- º
########## # ºffl
ºffl ################################
--- - ºffl --- ºffli
- - - -
º ---
- - ºffli
ºffl ºffl
Hº
--- ºffli
=########### - ºffl º: ###################
Hº: ºffl# º: #:º
------ ---
ºffl - ºffl - - ºfflº
ºffl --- ºffl Eºº.
ºffli --- -
º:
º
Biºt - -
ºffl
º:
ºffl ºffli
- tº: iii-
ºffl - ºffl
ºffl ºffl
ºffl ##################
-º-º-º-º-º: - - --- -------
--~~~~
º ºffl º - --- - -------- - ---
ºffl Häß º
Häß ºffli
--- - - - - - - º - - - ºfflº
-------------→ ºffl - ---
º --- - ºffl ºffli
--- ######
º ºffli -
=#########
---
- ºffli - -
- --- - #. ºffl º H
- --- --- ºffl º ºffl --
ºffl - --ºi - º - - - ºffli
=# º º ##########:===== # º
- - - - ºffl - ºffl
ºffl º º --~~
ºfflº --- --- -
-º-º: ºffl
º - ºffli --~~~~ º:
ºffl ºffli º == º: º ---
ºffl - - º: - ------------ - - --- - - # -
# =########### ºffl -
- - - º
ºffl ºffl º
ºffli |- ºffl - =#º ºffl
--- - - ºfflº
-
- - - -
- - - - - - --~~~~
- -- - -- --~~ --~~ - -
--- º Häß - ºffli --- - º ºr.
-- ºffl º ºffl ºfflº
- º -
###########
--- - - - -
---
-
- i- |-- --- - º º
ºffl ºfflº - - Häß
Häß. ºffl --~~~~ ºffl
############ º --- º == - - º --~~ º
- ºffl - - E=== º ºffl
ºffl - - - --- - - -
#########iº --- --~~ - ºffl - - ºffl
º º --- ºffli --~~ ---> ºffl
ºffl - -------> - º - ºfflºffl º
º - # - ºffl i- - --- - --- - º º
- º º - ºffl - - º º ºffl -
ºffl - Häß -
ºffl - º ºffl

EXPEDITED ORTHODONTICS:
IMPROVING THE EFFICIENCY OF ORTHODONTIC
TREATMENT THROUGH NOVEL TECHNOLOGIES
This volume includes the proceedings of the
Forty-First Annual Moyers Symposium
March 8–9, 2014
Ann Arbor, Michigan
Editors
Sunil D. Kapila, Jeanne Nervina and Nan Hatch
Associate Editor
Kristin Y. De Koster
Volume 51
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
©2015 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
Expedited Orthodontics: Improving the Efficiency of Orthodontic
Treatment Through Novel Technologies
Volume 51
ISSN 0162 7279
ISBN 0-929921-00-3
ISBN 0-929921–47-X
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
The 41st Annual Moyers Symposium honored two special individ-
uals without whose support and name recognition the Symposium could
not have sustained a successful history or achieved the great heights that
it has: Dr. Verne Primack contributed the original funding that helped to
launch the Symposium in honor of Dr. Robert E. Moyers, whom we honor
with this prestigious symposia annually. In celebration of their contribu-
tions to the success of the Moyers Symposium, members of their families
shared vignettes of their lives,and many accomplishments with the audi-
ence; these are captured in the summaries of the speeches in this vol-
ume. Undoubtedly both the audience at the Symposium and those who
delve into the summary of the speeches on their fascinating lives will gain
Substantial insights and further respect for their legacies and achieve-
ments. This monograph is dedicated to Dr. Verne Primack and Dr. Robert
E. Moyers for their many contributions to dentistry and orthodontics.
Sunil D. Kapila
Ann Arbor, Michigan
December, 2014
SPEECHES FROM THE MOYERS AND PRIMACK FAMILIES
March 8, 2014
Naomi Primack
It brings back such wonderful memories being here today and
I'd like to thank all of you for being here and for participating in this
wonderful symposium.
About 40 years ago, I heard a sermon that still sits inside of me.
It was about life and death. Two questions were posed: “If you were to
die tomorrow, who would care besides your family and friends? What
Contributions have you made outside of your own box to your community,
Society or country?”
Verne Primack was a hero worshiper, maybe one of the last of
a dying breed. He encountered many challenges while in dental school
and found it difficult to find help. Dr. Robert Moyers was head of the
Orthodontics Department and a very fine educator. He had sensitivity,
Compassion and understanding. He made it known to the students that if
they were having a problem, academically or personally, they could make
an appointment and meet with him. Verne took him up on the offer; this
turned out to a lucky day for Verne and even though many of you hadn't
been born, it was also lucky for you. Bob Moyers became his mentor.
As years passed by, Verne decided he wanted to show his appre-
Ciation for this special man and from this came the founding of this sym-
posium. It was created as an interdisciplinary gathering of top presenters
in dental and other related sciences. In this light, Verne even reached out
across campus to ask the head of the Art Department, Tom McClure, to
fabricate a sculpture that Bob and his wife designed, representing growth
and development, spirit and mind. Copies of this sculpture have since
been awarded to presenters and other worthy contributors to the Moyers
Symposium.
Every year, Verne would find at least one pearl of wisdom
from the symposium that he would incorporate into his dental practice
and outside activities, such as founding a free dental clinic in Saginaw,
volunteering as a Court Appointed Special Advocate (CASA) for abused
and troubled children and being appointed by Governor Granholm to the
State Board of Dentistry. After retiring and moving to Denver, he taught
American history to immigrants studying for their U.S. citizenship exams.
Verne contributed both inside his box of dentistry and outside to the
communities and Societies.
One tenet that Verne lived by was: if something good happens
in your life, share it with others so they can also be happy. He graced his
years with courage, strength and truth.
The greatest gift to both of us is our family—our sons: Brian, who
is recovering from a recent heart transplant at Massachusetts General
and not here; and standing beside me, Scott, a physical medicine and
rehabilitative specialist; and Glenn, who is in the world of finance; their
respective wives, Deb and Marla, who were not able to attend; and our
grandchildren: Samantha, a recent U-M graduate; Kyle, Henry and Jacob.
Additionally, you will be hearing from Bob Moyers' daughter, Marty, who
has been a surrogate daughter to us for years; her husband, Frank, is part
of our family as well.
| especially want to thank Jim McNamara, who was a young grad
student when this first started. He has become like a father by nurturing
and sustaining this symposium and the legacy of Bob Moyers so all of you
have the privilege of being a part of it—pass it on! Thank you.
Vi
Marty Moyers
I'm Marty Moyers and Dr. Moyers was my dad.
My dad was like a walking encyclopedia. As a kid, I thought this
was a normal trait all dads possessed. It wasn't until years later that
Came to appreciate what a unique person and special mind my dad had.
Besides being a consummate researcher and professor, he
originated and directed the Center for Human Growth and Development
here at The University of Michigan, which now is celebrating its 50th
anniversary. He also held the roles of pastor, member of the OSS and
being the most highly decorated dentist in World War II.
He loved his adopted county of Greece, reading, writing, music,
art, gardening—particularly hybridizing rhododendrons, faceting gems
and making jewelry, traveling and learning about different cultures, and
my favorite—making perfect buttermilk pancakes.
Dad was born with an insatiable desire to learn. I frequently found
him simultaneously reading, listening to the radio and watching the news
On TV. It was as if he couldn't absorb information quickly enough.
When he decided to go into dentistry, his father said “great, but
you also need to major in the humanities.” As a principal, my grandpa
knew how linearly focused dentists and doctors can become in their
fields, and wanted to be sure his son would be well rounded and able
to understand the importance of finding connections between different
disciplines. Hence laying the foundation of the original intent of this
Symposium!
My dad delighted in sharing his enthusiasm of gathering knowl-
edge with his colleagues and students. He told me he tried to inspire his
Students’ desire to learn by supplying the spark to the fire that was wait-
ing to be lit within them.
While he thoroughly enjoyed his research and writing, teaching
was his true passion. He cared a great deal for his students and encouraged
them all to reach their highest potential.
When Verne was in dental school and needed help, he coura-
geously reached out to my dad for advice. My dad became his mentor
vii
and this act of kindness turned into a wonderful friendship between
these two great men and our families.
As you heard from Naomi, this symposium came to fruition
because my dad had a profound influence on Verne. Verne's desire to
honor my dad in this fashion was an incredible gesture—not only to show
respect for his life's work, but to provide a forum to continue his passion
of collaborative learning. Best of all, my dad was able to enjoy this tribute
while he was alive.
We are all profoundly grateful to the Primacks for their generosity
and inspirational vision in creating this symposium. And also to Dr.
Jim McNamara, Dr. Sunil Kapila, Dr. Mike Rudolph, Michelle Jones and
many others who have been instrumental in organizing, nurturing and
continuing this amazing legacy over the last 41 years.
| also wanted to let you and the recipients of the Moyers
Symposium sculpture know that it was designed by both of my parents
and originally made by our neighbor, Sculptor Tom McClure. Its shape
represents a dividing cell-growth of mind, spirit and body—the perfect
symbolism for this symposium.
The thousands who have come to these symposia have shown
their desire to broaden their horizons; this is precisely what Verne and my
dad wanted. It is my hope that you always have this drive to continue to
learn and share your knowledge with others—just as my dad and Verne
did—and will keep this symposium going for another 41 years.
Verne and my dad loved life. They were both compassionate, good
men who knew that asking for help and extending a hand in kindness can
have such wonderful and unexpected consequences.
We look forward to meeting you and having you participate in
many more years of this symposium. Thank you!
viii
Scott Primack
I was one of the people standing with those who have attended
30+ years of Symposia, as my dad used to drag me out here to undo boxes
to hand out “collaterals,” as he would call them. So, I have a different
angle on this symposium than the rest of my family.
| remember the first symposium was after my bar mitzvah in
1974. My dad said “we’re going to Ann Arbor" and when I asked him why,
he said "because I'm putting on this thing for REM" (Robert E. Moyers was
always “REM” to us).
You have to remember at the time of Orthodontics back in the 70s
that many general dentists used their family as subjects. So, my dad's first
Subject was my brother Brian, who is presently recovering from his heart
transplant. I'll never forget when Brian would have the dental work done
and my dad would take a step back and say, “I have to call REM.” I never
met him until the first symposium and then, of course, I asked my dad,
“Does he have daughters?” And so that's where I met the Moyers family
and Marty's been a dear friend ever since that time.
Dr. McNamara gave me the opportunity to be a research assistant
(he probably doesn’t even remember this) with Dr. Moyers at the Center
for Human Growth and Development and that is where I got my taste for
"Angelo's breakfast.”
Dr. Moyers and Dr. McNamara could dress you down, build you
back up and you would want to work harder. Not many people have the
ability to do that—other than Dr. Moyers and Dr. McNamara.
Coming to these symposia (when I could start pronouncing Some
of the words) really gave me a thirst to do research myself, so I did a
residency of physical medicine and rehabilitation at Northwestern and
then I did my fellowship at the University of Washington.
What's interesting about that is it really gave me a quest for
Outcomes. With my knowledge in engineering, as well as Science, we
actually devised an outcomes program in Denver, Colorado. But it really
Came from here, the Robert E. Moyers Symposium, because it was So
interesting to me. Growing up here as a kid and then being a research
assistant showed me that not only do you need to devise the scientific
means and ways of applying whether a surgical or physical technique for
orthodontics works, you also have the way to measure the outcome. That
is now the key for healthcare.
| appreciate the opportunity to be here, and tell you a little bit of
the stories of me growing up in the symposium. I can tell you that even
during my father's last few days of life, he felt this was one of his amazing
achievements.
So, thank you, Dr. McNamara and the staff for putting this on.
know this will be a great meeting.
Glenn Primack
Good morning:
This is my first symposium, as I'm the baby of the family and I was
locked up in Saginaw, Michigan while all this was happening. I'm honored
to be here in front of a very select group of people ... it's sort of like the
“Lanterns”:
In brightest day
In blackest night
No evil shall escape my sight
Let those who worship evil's might
Beware my power...
Green Lantern's light
Verne Primack, much like Hal Jordan, wore a special ring.
His University of Michigan School of Dentistry ring defined him. The
knowledge gained here allowed him to give great care to his patients as
well as publish research with Dr. Moyers.
My dad didn't know many of the great moments in Michigan
football history ... but Calvin O'Neal and Sam Sward were his patients.
recall one had a “class II molar relationship.”
He couldn't tell you about the Fab Five or the 1989 National
Championship team ... but he understood Coach Frieder had a stressful
job, with a “high I* with teeth grinding” and so probably gave him an
impression for a custom bite plate.
However, my dad could tell people that Michigan was the first
State university to offer education in dentistry. He could name and boast
about four of its faculty members that have been presidents of the
American Dental Association.
And right now, I bet he is smiling from his op-er-uh-towr-ee in
the sky:
What's that dad...close with an oath now? OK.
Xi
“A tartar filled mouth is what I loathe
Fillings, orthodontia, craniofacial growth
An implant here or perhaps a bridge
Damn it, your bite is off a smidge
Wear your retainer, and floss, NO LIES
Moyers and Primack; two great guys"
Thank you Jim! Everyone have a great Symposium.
xii
CONTRIBUTORS
SERCANAKYALCIN, Associate Professor, School of Dentistry, The University
of Texas Health Science Center at Houston, Houston, TX.
SARAH ALANSARI, Orthodontic Resident, Department of Orthodontics,
College of Dentistry, New York University, New York, NY.
MANIALIKHANI, Associate Professor, Director, CTOR, College of Dentistry,
New York University, New York, NY.
MONA ALIKHANI, Postdoctoral Fellow, CTOR, College of Dentistry, New
York University, New York, NY.
FERNANDA ANGELIERI, Associate Professor, Department of Orthodontics,
São Paulo Methodist University, São Bernardo do Campo, Brazil; Visiting
Scholar, Department of Orthodontics and Pediatric Dentistry, School of
Dentistry, The University of Michigan, Ann Arbor, MI.
REBECCA BOCKOW, Affiliate Assistant Professor, Department of Ortho-
dontics, University of Washington School of Dentistry; Diplomate, Ameri-
can Board of Orthodontics; Diplomate, American Board of Periodontics;
private practice, Kenmore, WA.
PAOLO M. CATTANEO, Section of Orthodontics, Department of Dentistry,
Faculty of Health, Aarhus University, Aarhus, Denmark.
LUCIA H.S. CEVIDANES, Assistant Professor, Department of Orthodontics
and Pediatric Dentistry, School of Dentistry, The University of Michigan,
Ann Arbor, MI.
TORU DEGUCHI, Graduate Program Director, Associate Professor, Division
of Orthodontics, College of Dentistry, The Ohio State University, Colum-
bus, OH.
BANU DINCER, Professor, School of Dentistry, Ege University, Izmir, Turkey.
CALOGERO DOLCE, Department of Orthodontics, College of Dentistry,
University of Florida, Gainesville, FL.
ASLIHAN ERTAN ERDINC, Professor, School of Dentistry, Ege University,
Izmir, Turkey.
PADHRAIG S. FLEMING, Senior Clinical Lecturer/Honorary Consultant,
Barts and The London School of Medicine and Dentistry, Oueen Mary
University of London, London, England.
xiii
LORENZO FRANCHI, Research Associate, Department of Surgery and
Translational Medicine, The University of Florence, Florence, Italy; Thom-
as M. Graber Visiting Scholar, Department of Orthodontics and Pediatric
Dentistry, School of Dentistry, The University of Michigan, Ann Arbor, MI.
L. SHANNON HOLLIDAY, Department of Orthodontics, College of Dentistry,
University of Florida, Gainesville, FL; Department of Anatomy and Cell
Biology, College of Medicine, University of Florida, Gainesville, FL.
SARANDEEP HUJA, Professor and Division Chief, Orthodontics, University
of Kentucky, Lexington, KY.
ALEJANDRO IGLESIAS-LINARES, Associate Professor, School of Dentistry,
Complutense University of Madrid, Madrid, Spain.
LAURA R. IWASAKl, Associate Professor, Leo A. Rogers Chair of the De-
partment of Orthodontics and Dentofacial Orthopedics, Departments
of Orthodontics and Dentofacial Orthopedics/Oral and Craniofacial Sci-
ences, School of Dentistry, University of Missouri-Kansas City, Kansas City,
MO.
NANDAKUMAR JANAKIRAMAN, Assistant Professor, Division of Ortho-
dontics, Department of Craniofacial Sciences, School of Dental Medicine,
University of Connecticut, Farmington, CT.
CHUNG HOW KAU, Chair and Professor of Orthodontics, University of
Alabama at Birmingham, Birmingham, AL.
HONGZENG LIU, Post-doctoral Fellow, Departments of Orthodontics and
Dentofacial Orthopedics/Oral and Craniofacial Sciences, School of Den-
tistry, University of Missouri-Kansas City, Kansas City, MO.
KEVIN P. McHUGH, Associate Professor, Department of Periodontology,
College of Dentistry, University of Florida, Gainesville, FL.
JAMES A. McNAMARAJR., Thomas M. and Doris Graber Endowed Profes-
sor Emeritus, Department of Orthodontics and Pediatric Dentistry, School
of Dentistry; Professor Emeritus of Cell and Development Biology, School
of Medicine; Research Professor Emeritus, Center of Human Growth and
Development, The University of Michigan, Ann Arbor, MI.
RAVINDRA NANDA, Professor and Head, Department of Craniofacial Sci-
ences, Alumni Endowed Chair, School of Dental Medicine, University of
Connecticut, Farmington, CT.
Xiv
JEFFREY C. NICKEL, ASSociate Professor, Director of Advanced Education
Program in Orthodontics and Dentofacial Orthopedics, Departments of
Orthodontics and Dentofacial Orthopedics/Oral and Craniofacial Science
es, School of Dentistry, University of Missouri-Kansas City, Kansas City,
MO.
NIKOLAOS PANDIS, Assistant Professor, Department of Orthodontics and
Dentofacial Orthopedics, Dental School/Medical Faculty, University of
Bern, Switzerland; private practice, Corfu, Greece; Ph.D. candidate, De-
partment of Hygiene and Epidemiology, University of loannina School of
Medicine, loannina, Greece.
P. EDWARD PURDUE, Associate Scientist, Hospital for Special Surgery,
New York, NY.
WELLINGTON J. RODY JR., Assistant Professor, Department of Orthodon-
tics, College of Dentistry, University of Florida, Gainesville, FL.
DANIEL ROSEN, Orthodontic Resident, Department of Orthodontics, Col-
lege of Dentistry, New York University, New York, NY.
GEORGIA SALANTI, Assistant Professor, Department of Hygiene and Epi-
demiology, University of loannina School of Medicine, loannina, Greece.
CHINAPA SANGSUWON, Orthodontic Resident, Department of Ortho-
dontics, College of Dentistry, New York University, New York, NY.
RONALDSNYDER, private practice, Apple Valley, MN.
LOUKIA M. SPINELI, Ph.D. candidate, Department of Hygiene and Epide-
miology, University of loannina School of Medicine, loannina, Greece.
CRISTINA C. TEIXEIRA, Associate Professor, Chair, Department of Ortho-
dontics, College of Dentistry, New York University, New York, NY.
FLAVIO URIBE, Associate Professor and Program Director, Charles Bur-
stone Professor, Division of Orthodontics, Department of Craniofacial Sci-
ences, School of Dental Medicine, University of Connecticut, Farmington,
CT.
SHANNON M. WALLET, Associate Professor, Departments of Periodontol-
ogy and Oral Biology, College of Dentistry, University of Florida, Gaines-
ville, FL.
XV
PREFACE
For more than 100 years, orthodontists have strived to identify
and utilize methods to expedite orthodontic treatment. Most of the
current approaches aimed at achieving this goal rely primarily on
physical or surgical techniques and mechanical devices that recently
have gained prominence in the field. However, there is limited cohesive,
comprehensive and objective information on the efficacy of many of these
approaches for expediting orthodontic treatment. Furthermore, the use
of novel technologies and biomedicine in efficient delivery of orthodontic
treatment has not been realized fully.
The 41st Annual Moyers Symposium and Presymposium provided
clinically relevant updates on this intriguing and, in some instances,
controversial topic. In this monograph, the authors present historical
perspectives, scientific evidence and clinical observations on a range of
topics including the contribution of appliance design and physical, surgical
and biomedical approaches to expedite orthodontic treatment.
Sunil D. Kapila
Ann Arbor, Michigan
December, 2014
xvi
TABLE OF CONTENTS
Dedication
Speeches
Contributors
Preface
Incorporating TADs and Sound Mechanics for Efficient
Orthodontic Treatment
Nandakumar Janakiraman, Flavio Uribe and Ravindra Nanda,
University of Connecticut
Effects of Mechanical Stress and Growth on the Velocity of
Human Tooth Movement
Jeffrey C. Nickel, Hongzeng Liu and Laura R. Iwasaki,
University of Missouri-Kansas City
Are We Any Closer to Understanding the Mechanisms of
Expedited Tooth Movement?
Sarandeep Huja, University of Kentucky
A Critical Appraisal of Surgically Facilitated Orthodontics to
Increase the Rate of Tooth Movement
Flavio Uribe and Ravindra Nanda, University of Connecticut
Accelerated Tooth Movement
Mani Alikhani, Daniel Rosen, Sarah Alansari, Chinapa
Sangsuwon, Mona Alikhani and Cristina C. Teixeira,
New York University
Accelerated Orthodontics: The Path from Corticotomy to
Genetics-based Orthodontics
Alejandro Iglesias-Linares,
Complutense University of Madrid, Spain
Goal-oriented Treatment Planning with Corticotomy-facilitated
Orthodontics
Rebecca Bockow, University of Washington
xiii
Xvi
27
47
65
87
105
135
xvii
Efficient Orthodontic Treatment
anchorage preparation (Cope, 2005). Skeletal anchorage devices eliminate
the necessity for traditional methods of intraoral and/or extraoral
anchorage, significantly reducing the need for patient compliance and
thereby making the treatment mechanics and outcomes more predictable
(Melsen, 2011). In addition to the anchorage considerations, the range of
Orthodontic tooth movement has been widened in all three dimensions.
Mini-implants are used most commonly for intrusion of posterior teeth,
distalization, correction of asymmetries, molar protraction and for
providing anchorage in patients with mutilated dentition (Baumgaertel et
al., 2008). Although the use of miniscrew implants has been effective in
treating difficult cases, little evidence regarding the impact of their usage
On treatment time exists.
In the past decade, there has been a significant increase in the
number of adults seeking orthodontic treatment (Melsen, 2011). While
adult patients have reported wanting their orthodontic treatment to be
completed within six to eighteen months (Uribe et al., 2014), numerous
biological factors may prolong the treatment time in adults compared
to younger patients. Among these changes are a decrease in the cellular
activity (Ong and Wang, 2002), presence of dense bone on the pressure
side and the existence of hyalinized zones, which are formed readily in
adult patients (lino et al., 2007).
METHODS TO INCREASE THE RATE OF
ORTHODONTIC TOOTH MOVEMENT
To reduce the treatment time in these subjects, clinicians have
tried different treatment approaches using non-invasive mechanical
devices, adjunctive surgical procedures and pharmacologic agents
(Bartzela et al., 2009) with varying degree of success (Nimeri et al., 2013).
Lasers (Doshi et al., 2012), electrical stimulation (Davidovitch et al., 1980)
and vibration devices (Miles et al., 2012) are the most commonly used non-
invasive methods for increasing the rate of tooth movement. Osteotomy,
periodontal distraction, corticotomy, corticision and piezoincision are
some of the minor surgical procedures for enhancing the speed of tooth
movement (Nimeri et al., 2013). Pharmacologic agents (e.g., parathyroid
hormone, thyroxine, vitamin D3 and prostaglandins) have shown to
increase the velocity of tooth movement (Bartzela, 2009), but may pose
potential risks and side effects to the patients.
Janakiraman et al.
Among the mechanical devices for increasing the rate of tooth
movement, photo-biomodulation or low-level laser therapy in the
wavelength range of 780 to 860 mm and continuous wave mode have
been used routinely in humans. However, various studies on lower level
laser therapy have shown contradictory findings on orthodontic tooth
movement (Kau et al., 2013; Nimeri et al., 2013). Hence, there is a need
for further well-controlled studies to evaluate the effectiveness of lasers
for accelerating the orthodontic tooth movement (Nimeri et al., 2013).
Vibration Appliances
Vibration appliances act by applying cyclical intermittent forces
to the dento-alveolar region and, at the same, may reduce the stick-slip
phenomenon at archwire bracket interface (Miles et al., 2012). Preliminary
studies have shown an increase in orthodontic tooth movement (Nimeri
et al., 2013). On the other hand, Miles and colleagues (2012) found no
significant difference in the rate of tooth movement between the control
and experimental subjects. The study outcome cannot be generalized
with other studies, however, because of difference in the use of vibration
device, vibration frequency and force levels (Miles et al., 2012).
Surgical Approach
Adjunctive surgical procedures during orthodontic treatment
show potential for reducing treatment time. These surgical procedures
have been used for reducing the treatment time in subjects requiring
alleviation of crowding (Wilcko et al., 2001), space closure (lino et al.,
2006) and molar intrusion (Moon et al., 2007). However, the current level
of evidence is limited to few case reports or clinical trials with inadequate
sample size (Long et al., 2012). Although the surgically facilitated
orthodontic tooth movement appears promising, prospective clinical
trials are necessary to evaluate the efficiency of treatment as well as any
short- and long-term complications before they are accepted widely as a
treatment alternative (Buschang et al., 2012).
While current research has focused primarily on increasing the
rate of orthodontic tooth movement by using the non-invasive mechanical
devices, Surgical procedures and pharmacologic agents, no significant ad-
vances at the biomechanical level have been presented, especially with
regard to mandibular molar protraction procedures. Mandibular molar
protraction to close the missing first molar or second premolar extraction
Efficient Orthodontic Treatment
space is challenging and often is difficult to achieve with conventional
anchorage preparation. Although the mini-implant provides absolute an-
chorage for molar protraction, the biomechanics of molar protraction is
understood poorly. Numerous side effects during miniscrew supported
molar protraction are seen including mesial crown tipping of the molar,
mesial-in rotation of the molar, flaring of incisors (Cousley, 2013), midline
shift and lack of tooth movement due to binding. Additionally, the line of
force application, buccal and/or lingual force application, point of force
application, type of force application (elastic chain/Ni Ti coil springs), oc-
clusion, deflection of archwire, type and dimension of arch wire, brackets
and their effect on friction are some of the variables to be considered
carefully for decreasing the treatment time.
Biomechanics of Mandibular Moldr Protraction
The sliding mechanics of the molar protraction is similar to
canine retraction (i.e., in second-order/mesiodistal movement); however,
the inter-bracket span is increased in molar protraction due to the large
extraction space. There are numerous studies (Kojima et al., 2005,
2006, 2010) on canine retraction, but there are limited studies on the
biomechanics of the molar protraction.
Theoretically, the type of tooth movement obtained depends on
the line of action of force and its relation to center of resistance (Cr) of
any specific tooth or group of teeth (Tominaga et al., 2012). However, in
a 3D finite element study, Tominaga and associates (2012) showed that
the line of force when applied at the Cr of anterior teeth did not result
in bodily movement when a full dimension archwire was used. Instead,
application of the force 2 mm below the Cr resulted in translation. When
0.016" x 0.022” archwire was tested, translation was seen when the line
of force was 3.8 mm above the Cr. Based on these findings, applying the
theoretical biomechanical principles may not result in expected tooth
movement in an indeterminate straight wire appliance. Other factors like
archwire bracket play, archwire deflection, bending moment of Cantilever/
power arm may play a significant role in determining the type of tooth
movement (Tominaga et al., 2012).
Recently, Nihara and associates (2014) made an attempt to find
the ideal force system for protraction of mandibular molar with the aid
Janakiraman et al.
of miniscrew anchorage by finite element analysis. They evaluated the
molar protraction in three dimensions and under different experimen-
tal conditions by changing the length of power arm, height of the minis-
crew and the application of lingual and buccal force. They found that the
length of the power arm directly influenced the amount of mandibular
tipping in the second-order dimension. Mesio-distal tipping of the mo-
lar was proportional inversely to length of the cantilever arm. When the
length of the power arm was increased, there was a significant reduction
in second-order tipping of the mandibular molar. In the sagittal plane, the
Cr of the molar is located 1 to 2 mm apically from the furcation (Burstone
et al., 1981). When the power arm extended below the Cr, distal crown
tipping was observed. However, the bucco-lingual tipping and mesial-in
rotation of the mandibular molar were independent of the power arm
length (Nihara et al., 2014).
Mesial-in rotation of the molar can be prevented with the simul-
taneous application of a lingual force, in addition to the buccal force.
Mesial-in rotation was observed in spite of the application of an equal
magnitude of force on either side. Experimentally, when the lingual
force was 1.5 times greater than the buccal force, no mesial rotation was
seen. However, clinically the buccal force is applied from the miniscrews,
whereas the lingual force is applied most commonly from the button
bonded on the molars and canines/premolars. Application of higher force
levels lingually can lead to anchorage loss, which usually is undesirable
(Nihara et al., 2014).
The study by Nihara and associates (2014) gives some important
information for clinicians regarding how to control the side effects in first
and second order. Application of a lingual and buccal force can minimize
the first-order rotation simultaneously. Extending the power arm close
to Cr can reduce the amount of mesio-distal tipping of mandibular mo-
lar. However, the major limitation with this study was the lack of clinical
simulation, as there was no archwire engaged during the molar protrac-
tion. No information regarding the role of friction, dimension of archwire,
effect of increased inter-bracket distance, bending moment of the power
arm and most importantly, the deflection of the archwire could be ex-
trapolated from this finite element analysis (Nihara et al., 2014).
Efficient Orthodontic Treatment
Variables to be Considered During Sliding Mechanics
During sliding mechanics, the deflection of the archwire produces
forces and moments to upright mesially tipped teeth eventually (Figs. 1-2).
Sliding mechanics is an excellent example of an elastic beam supported
at both ends. The deflection of the archwire depends on the inter-bracket
span, cross-section and material, deflecting force and bending moment.
The magnitude of deflection in the center of a simple beam supported at
two ends can be calculated by using the formula in Equation 1:
Equation 1
6 = Flº
48El (Barber, 2011)
where
6 = deflection of beam, F = force, L = length of the beam/inter-bracket
span, E = Young's modulus, I = moment of inertia of beam.
| =bhº
12
where
b = width, h = height for rectangular cross-section wire.
| = n.d.
64
where
d = diameter for round cross-section wire.
Figure 1. A. Force system of mandibular molar protraction. Clockwise moment
due to the force (Mf) is generated as the point of force application was away
from the center of resistance (Cr) of molar. B: Deflection of archwire during the
molar protraction.

Janakiraman et al.
& N.
Mc=f x. WB
Fr -
WB
Figure 2. Archwire molar tube interphase after mesial crown tipping of
molar. After the elastic recovery of deflected archwire, counterclockwise
moment of couple (Mc) and frictional resistance (Fr) are generated.
With the decay of applied force (F), Mc will upright of the molar.
Factors to be Considered During the Mandibular Molar Protraction
From Equation 1, at least theoretically, we can apply and un-
derstand some of the biomechanical variables influencing the molar
protraction. The deflection of the beam is proportional directly to the
Cube length of inter-bracket span. Due to the increased mandibular first
molar extraction space, greater archwire deflection can be anticipated.
Although the inter-bracket span is not under the control of the clinician,
placement of miniscrews in the middle of extraction space could reduce
the archwire deflection.
The increase in archwire deflection may cause resistance to slid-
ing due to binding phenomenon. The type of force application is an im-
portant factor that can increase/decrease the frictional resistance. Niſi
Coil springs and elastomeric chains have been used routinely for space
Closure and molar protraction. The elastic chain force decays after one

Efficient Orthodontic Treatment
week to 50% of its original force magnitude (Nightingale et al., 2003).
With the reduction of protraction force, the intra-bracket couple can aid
in root uprighting after crown tipping. However, with NiTi coil springs,
force decay was observed for six weeks after activation; thereafter, the
force levels plateaued for rest of the activation period (Nightingale et al.,
2003). This constant force after six weeks from the NiTi coil spring can
increase the frictional resistance and may delay the molar uprighting.
Due to the binding phenomenon, the archwire deflection may be
maintained, resulting in a mesial force transferred to the teeth anterior
to the edentulous space. Due to the mesial force, incisor flaring and
midline shift to opposite side has been reported during molar protraction
(Cousley, 2013).
The cross section of the archwire and modulus of elasticity are
related inversely to deflection of the archwire. By using a full dimensional
archwire, archwire deformation can be reduced significantly. Similarly,
a rigid stainless steel archwire will reduce the archwire deformation.
Although, the inter-bracket span has the major influence on the archwire
defection, using rigid full dimensional archwire can reduce the archwire
deformation.
During molar protraction, the molar tips mesially and rotates
mesial-in. The elastic recovery of the archwire after deflection may
prevent this mesial-in rotation and crown mesial tipping. The archwire
deformation will produce an intra-bracket couple in the molar for root
uprighting. The moment due to the couple will produce frictional forces
in all three dimensions. Considering the molar movement in second
order, the moment due to the couple is generated at the archwire
bracket interface as the molar tips mesially (Fig. 2). Frictional forces (Fr
=2p x f are generated due the couple (Mc = W, X f in the molar tube.
For translation of the molar, moment of couple (Mc) should be equal to
moment of force (Mf).
As shown in Equation 2, frictional resistance can be reduced by
altering the variables that are under the control of clinician. Frictional
resistance is proportional directly to force applied, distance from the
Cr to point of force application and inversely related to bracket width.
Higher force levels can increase the magnitude of frictional resistance,
although the threshold force for molar protraction is not known. The
point of force application can be applied closer to the Cr by using a power
Janakiraman et al.
Equation 2
Mc = Mf (for translation), Mc = W, X f Mf = F x d, W, X f = F x d
substituting (Fr = 2 p. x f),
Fr = F x d x 211
W
—b
where
W. =bracket width, Fr = frictional resistance, u = coefficient of friction, F=
force applied, d = perpendicular distance from point of force application
to Cr of the molar. y
arm. As the perpendicular distance from the point of force application
decreases, there will be a significant reduction in friction. Finally, using
wider brackets/molar tubes also may reduce the resistance to sliding.
Understanding basic mechanical principles as presented above
helps to give an insight regarding the role of friction and deflection of
archwire for the clinician. However, orthodontic tooth movement is more
complex and it is difficult to simulate the oral conditions experimentally.
The forces of occlusion, masticatory forces, force decay, permanent
deformation of wire and wear are some of the variables that are
difficult to measure and can make the sliding mechanics unpredictable.
Nevertheless, the basic mechanical concepts and formulas may assist the
orthodontist to deliver appropriate force system for efficient treatment
outcome (Burstone, 2011).
Mandibular Molar Protraction Appliance
Applying the above biomechanical principles, a molar protraction
appliance has been designed by author NJ. The mandibular molar
protraction appliance consists of two rigid stainless Steel round cross-
section of 0.032” soldered to premolar bands and engaged in 0.036”
molar tubes. The width of the molar tubes is 4 mm. The rigid stainless
steel arms are soldered parallel to the center of alveolar ridge, so that
the molar moves through the alveolar ridge. Two hooks are soldered to
the molar band both buccally and lingually, as close as possible to the Cr
of the molar. Similarly, two hooks are soldered at the same height of the
molar band, buccally and lingually on the premolar bands. The premolar
band has a buccal tube for providing indirect anchorage from the mini-
implant placed mesial to this tooth (Fig. 3).
Efficient Orthodontic Treatment
Figure 3. Molar protraction appliance. A: 0.032” stainless steel wires (buccal
and lingual) soldered to premolar bands. B: 0.036” tubes soldered on the molar
bands to receive the 0.032” wires. C. Hooks soldered near the Cr of the molar.
Premolar band has a buccal tube for indirect anchorage.
The point of force application is near the Cr of the molar and
the force is applied buccally and lingually. As the perpendicular distance
from the point of force application is decreased, the resistance to sliding
and mesio-distal tipping can be expected to be minimal. Additionally, the
line of force application, both buccally and lingually, was to prevent the
rotation of mandibular molar in the first order. Bilateral use of round wire
of 0.032” thickness provides the necessary rigidity and prevents archwire
deflection. Also, the friction in round cross-section wire is reduced when
compared to rectangular cross-section (Ogata et al., 1996).
We present two case reports of patients who were treated
by molar protraction using miniscrews. One was treated with direct
anchorage; for the other, a mandibular molar protraction appliance was
designed for indirect anchorage.
Case Report 1
A 27-year-old Hispanic female patient reported to the orthodontic
clinic with a primary concern to straighten her upper front teeth and
close the spaces in her lower dentition. Skeletally and dentally, she had a
Class || malocclusion with a missing mandibular first molar on the left side
and a missing mandibular second molar on the right side. Her soft tissue
profile was convex with competent lips at rest and increased nasolabial
angle. Smile assessment showed her lower lip covering the incisal one
third of maxillary incisors, indicating retroclined maxillary incisors. On
intraoral examination, the lower left first molar and lower right second
molar were missing with an edentulous space of 11 mm on the left side
and 8 to 9 mm of edentulous space on the right side (Fig. 4).

10
Janakiraman et al.
Figure 4. Pre-treatment photographs.
The mandibular midline was shifted by 2 mm to the left side in
relation to the facial midline. Vertically, the overbite was recorded as
4 mm and she had an increased overjet of 6 mm. The cephalometric
analysis showed a Class || skeletal base, soft and hard tissue convexity,
decreased mandibular plane angle and lower anterior facial height. The
maxillary incisors were retroclined in relation to the SN plane. Relative
to Rickets E-line, the upper and lower lips were placed forwardly (Fig. 5;
Table 1). The patient was referred for full-mouth periapical radiograph
(Fig. 6) and periodontal evaluation. Her periodontal status was good with
probing depths not greater than 3 mm.
The patient was presented with the treatment options of
extraction of upper first premolars and molar protraction or restoration
of missing mandibular molar with endo-Osseous implants; she selected
the first option. The treatment plan selected was cost effective because it
obviated the need for restorative implants.
The patient was referred to her general dentist for extraction of
the upper first premolars. After the initial aligning and leveling phases,
two miniscrew implants (1.8 x 8 mm, Unitek, TADS, 3M Unitek, Monro-
via, CA) were placed interdentally between the maxillary first molar and
Second premolar. En masse space closure was initiated in the maxillary
arch by applying a 150g of force from the mini-implants (Fig. 7). After
the mandibular arch was aligned and leveled, a miniscrew implant (1.8
X 8 mm Unitek, TADS, 3M Unitek, Monrovia, CA) was placed interden-
tally between the lower left premolars. A power arm was extended from

11
Efficient Orthodontic Treatment
Figure 5. Pre-treatment lateral cephalogram.
/
Figure 6. Pre-treatment periapical radiographs.


12
Janakiraman et al.
Table 1. Pre-treatment and post-treatment lateral cephalometric analy-
SiS.
Variable Norm Pre-treatment Post-treatment
SNA (*) 82 88.4 87
SNB (*) 80 80.4 80.5
ANB (*) 2 7.9 6.5
MP-SN (*) 32 28.1 29
IMPA (*) 90 100.7 101.1
U1-NA (mm) 4 0.4 -1.2
U1-NA (*) 22 8.2 11
L1-NB (*) 25 32.5 34
L1-NB (mm) 4 6.1 6
Upper lip to E line (mm) –4 -1 –2.7
Lower lip to E line (mm) –2 –0.8 -1.4

the mandibular left second molar auxiliary slot closer to the Cr of the
molar and a NiTi coil spring was placed from the miniscrew to the power
arm (Fig. 8). On the other side for group B space closure, an elastic chain
was placed from the lower right third molar to the left second premolar.
The duration of mandibular molar protraction was 25 months on
both sides (Fig. 9). However, the patient was debonded after 48 months
of treatment as she missed 13 appointments. Good occlusal and esthetic
outcomes with adequate incisor show at rest and smiling with normal
overjet and overbite were attained (Fig. 10).
13
Efficient Orthodontic Treatment
Figure 7. Mini-implants placed interdentally between the maxillary first molar
and second premolar. Immediate loading was performed using NiTi coil spring
for en masse space closure.
Figure 8. Mini-implant placed interdentally between the mandibular premolars
on the left side. Immediate loading was done using a Niſi coil spring for protrac-
tion of left mandibular second molar.


14
Janakiraman et al.
Figure 10. Post-treatment photographs.


15
Efficient Orthodontic Treatment
Figure 11. Post-treatment lateral cephalogram.
Improvement in soft tissue profile, reduction in protrusion of
upper and lower lip in relation to Rickets E-line was evident from the post-
treatment cephalometric analysis (Fig. 11; Table 1). At the completion of
treatment, crestal bone loss mesial to the lower right third molar with no
vertical bony defects was seen from the panoramic radiograph (Fig. 12).
Maxillary and mandibular regional Superimposition showed intrusion and
retraction of the incisors and protraction of mandibular left second molar,
respectively (Fig. 13).
Case Report 2
A 17-year, four-month-old, Southeast Asian male presented to
the dental clinic with the chief complaint of crooked teeth. Extra-orally,
a convex soft tissue profile with skeletal Class || malocclusion was noted
with no gross asymmetry present. He had competent lips at rest, reduced
maxillary incisal show on smiling. Dentally, he presented with a mild
Class III occlusion on the left side and end-on Class II relationship on the

16
Janakiraman et al.
- initial
- Final
- Initial - Initial
- Final - Final
Figure 13. Overall superimposition, maxillary and mandibular regional superim-
position.
right side, overjet of 2 mm and overbite of 2 mm (Fig. 14). His mandibular
midline was shifted to the right side of facial midline. Moderate crowding
in the upper arch and mild crowding in the lower arch was present with
impacted mandibular third molars (Fig. 15). The mandibular right first
molar was decayed grossly.
The patient was presented with the treatment options of either
extraction of lower right first molar followed by protraction of second
molar, or extraction of right first molar followed by endo-osseous
implants based restorations. He selected the first option due to financial
ſeasons. After obtaining the informed consent, the patient was referred
for extraction of mandibular right first molar. Three weeks later, a
miniscrew (Lomas, 2 x 9 mm, Donau, Germany) was placed interdentally
between the premolars on the right side and an aginate impression was



17
Efficient Orthodontic Treatment
Figure 14. Pre-treatment photographs.
Figure 15. Pre-treatment panoramic radiograph.
taken for fabrication of the appliance. On the working model, the
design for mandibular molar protraction appliance was drawn for the
lab technician. On the following visit, the appliance was cemented with
glass ionomer cement (Fuji Ortho LC, GC America). A rigid steel segment
(0.021" x 0.025") was placed connecting the tube on the second premolar
and the miniscrew. Immediate loading of 200g of force from the elastic
chain was placed both buccally and lingually (Fig. 16).
The patient reported to the clinic after four weeks and 2 mm of
the molar protraction was seen (Fig. 17). Elastic chain was replaced to
deliver 200g of force and appliance was checked for integrity and stability.
Nearly 2 mm of the molar protraction space was seen at his subsequent
appointment four weeks later (Fig. 18). Four months later, 3 mm of
space was present for closure and there was minimal loss of anchorage


18
Janakiraman et al.
Figure 17. Mandibular intra-oral occlusal photograph after one month.
(Fig. 19). After seven months, most of the missing mandibular first molar
Space (11 mm) was closed at crown level with the exception of the band
Spaces (Figs. 20-21). Indirect anchorage successfully prevented any an-
Chorage loss of the teeth anterior to edentulous space. The mandibular
protraction appliance was removed, initial aligning and leveling was initi-
ated. To close the residual space, a V bend distal to the lower second pre-
molar (Class V geometry) on 0.017"x0.025" stainless steel archwire was
placed. Elastomeric chain was placed from the right mandibular molar
to the left molar. After twelve months, the molar protraction was com-
pleted (Fig. 22). Panoramic radiograph showed parallel roots of protracted

19
Efficient Orthodontic Treatment
Figure 19. Mandibular intra-oral occlusal photograph after four months.

20
Janakiraman et al.
Figure 21. Panoramic radiograph taken prior to removal of the molar protraction
appliance with a slight mesial tipping of right mandibular second molar.
mandibular right second molar with no bone loss or angular defects (Fig.
23). The patient tolerated the appliance well, despite some bulkiness of
the appliance and some encroachment of the tongue space. The patient
had excellent compliance with the appliance, which greatly contributed
to the successful molar protraction.

21
Efficient Orthodontic Treatment
Figure 22. Mandibular intra-oral occlusal photograph after twelve months
showing complete space closure on the right.
Figure 23. Panoramic radiograph aftertwelve months showing uprightmandibular
second molar on the right side.
CONCLUSION
Understanding the basic biomechanical concepts can help
minimize side effects and improve the overall efficiency of treatment,
potentially shortening the treatment time. By using the described molar
protraction appliance supported by mini-implants, the treatment time for
molar protraction phase was reduced. However, further clinical trials are


22
Janakiraman et al.
needed to evaluate the effectiveness of this appliance. In vitro or finite
element studies are necessary to understand the biomechanical force
System of this appliance. In conclusion, miniscrew implants with efficient
biomechanics may reduce the treatment time.
REFERENCES
Barber JR. Elastic stability. In: Intermediate Mechanics of Materials: Solid
Mechanics and Its Applications. 2nd ed. New York: Springer 2011;511-
558.
Bartzela T, Türp JC, Motschall E, Maltha JC. Medication effects on the rate
of orthodontic tooth movement: A systematic literature review. Am J
Orthod Dentofacial Orthop 2009;135(1):16-26.
Baumgaertel S, Razavi MR, Hans MG. Mini-implant anchorage for the
orthodontic practitioner. Am J Orthod Dentofacial Orthop 2008;133
(4):621-627.
Bonnick AM, Nalbandian M, Siewe MS. Technological advances in
nontraditional orthodontics. Dent Clin North Am 2011;55(3):571-584.
Burstone CJ. Self ligation and friction: Fact and fantasy. In: Kapila SD,
Hatch N, McNamara JA Jr, eds. Effective and Efficient Orthodontic
Tooth Movement. Craniofacial Growth Series, Department of
Orthodontics and Pediatric Dentistry and Center for Human Growth
and Development, The University of Michigan, Ann Arbor 2011;1-25.
Burstone C, Pryputniewicz R, Weeks R. Centers of resistance of the human
mandibular molar (Abstract). J Dent Res 1981;60:515. -
Buschang PH, Campbell PH, Ruso S. Accelerating tooth movement with
corticotomies: Is it possible and desirable? Semin Orthod 2012;18(4);
286-294.
Cope JB. Temporary anchorage devices in orthodontics: A paradigm shift.
Semin Orthod 2005;11(1):3-9.
Cousley RRJ. Molar protraction. In: Cousley RRJ, ed. The Orthodontic Mini-
Implant Clinical Handbook. West Sussex, UK: Wiley Blackwell 2013;83–
98.
Davidovitch Z, Finkelson MD, Steignman S, Shanfeld JL, Montgomery PC,
Korostoff E. Electric currents, bone remodeling, and orthodontic tooth
movement: ||. Increase in rate of tooth movement and periodontal
23
Efficient Orthodontic Treatment
cyclic nucleotide levels by combined force and electric current. Am J
Orthod 1980;77(1):33-47.
Doshi-Mehta G, Bhad-Patil WA. Efficacy of low-intensity laser therapy in
reducing treatment time and orthodontic pain: A clinical investigation.
Am J Orthod Dentofacial Orthop 2012;141(3):289-297.
lino S, Sakoda S, to G, Nishimori T, Ikeda T, Miyawaki S. Acceleration of
orthodontic tooth movement by alveolar corticotomy in the dog. Am J
Orthod Dentofacial Orthop 2007;131(4):448.e1-e8.
lino S, Sakoda S, Miyawaki S. An adult bimaxillary protrusion treated with
corticotomy-facilitated orthodontics and titanium miniplates. Angle
Orthod 2006;76(6):1074-1082.
Kau, CH, Kantarci A, Shaughnessy T, Vachiramon A, Santiwong P. de la
Fuente A, Skrenes D, Ma D, Brawn P. Photobiomodulation accelerates
orthodontic alignment in the early phase of treatment. Prog Orthod
2013;14:30.
Kojima Y, Fukui H. Numerical simulation of canine retraction by sliding
mechanics. Am J Orthod Dentofacial Orthop 2005;127(5):542–551.
Kojima Y, Fukui H. Numerical simulations of canine retraction with T-loop
springs based on the updated moment-to-force ratio. Eur J Orthod
2012:34(1):10-18.
Kojima Y, Fukui H, Miyajima K. The effects of friction and flexural rigidity of
the archwire on canine movement in sliding mechanics: A numerical
simulation with a 3-dimensional finite element method. Am J Orthod
Dentofacial Orthop 2006;130(3):275.e1-e10.
Long H, Pyakurel U, Wang Y, Liao L, Zhou Y, Lai W. Interventions for
accelerating orthodontic tooth movement: A Systematic review. Angle
Orthod 2013;83(1):164-171.
Melsen B. Northcroft Lecture: How has the spectrum of orthodontics
changed over the past decades? J Orthod 2011;38(2):134-143.
Miles P, Smith H, Weyant R, Rinchuse DJ. The effects of a vibrational
appliance on tooth movement and patient discomfort: A prospective
randomised clinical trial. Aust Orthod J 2012;28(2):213–218.
Moon CH, Wee JU, Lee HS. Intrusion of overerupted molars by corticotomy
and orthodontic skeletal anchorage. Angle Orthod 2007;77(6):1119-
1125.
24
Janakiraman et al.
Nightingale C, Jones SP. A clinical investigation of force delivery systems
for orthodontic space closure. J Orthod 2003;30(3):229-236.
Nihara J, Gielo-Perczak K, Cardinal L, Saito I, Nanda R, Uribe F. Finite
element analysis of mandibular molar protraction mechanics using
miniscrews. Eur J Orthod 2014;cjuð17.
Nimeri G, Kau CH, Abou-Kheir NS, Corona R. Acceleration of tooth
movement during orthodontic treatment: A frontier in orthodontics.
Prog Orthod 2013;14:42.
Ogata RH, Nanda RS, Duncanson MG Jr, Sinha PK, Currier GF. Frictional
resistances in stainless steel bracket-wire combinations with effects
of vertical defections. Am J Orthod Dentofacial Orthop 1996;109(5):
535–542.
Ong M, Wang HL. Periodontic and orthodontic treatment in adults. Am J
Orthod Dentofacial Orthop 2002;122(4):420-428.
Tominaga JY, Chiang PC, Ozaki H, Tanaka M, Koga Y, Bourauel C, Yoshida
N. Effect of play between bracket and archwire on anterior tooth
movement in sliding mechanics: A three-dimensional finite element
study. J Dent Biomech 2012;1758736012.461269.
Uribe F, Padala S, Allareddy V, Nanda R. Patients', parents', and
orthodontists' perceptions of the need for and costs of additional
procedures to reduce treatment time. Am J Orthod Dentofacial Orthop
2014;145(4 Supp):S65-S73.
Wilcko WM, Wilcko T, Bouquot J, Ferguson DJ. Rapid orthodontics with
alveolar reshaping. Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001;21(1):9-19.
25
26
EFFECTS OF MECHANICAL STRESS AND GROWTH ON
THE VELOCITY OF HUMAN TOOTH MOVEMENT
Jeffrey C. Nickel, Hongzeng Liu and Laura R. Iwasaki
ABSTRACT
INTRODUCTION: In this study, we investigated the effects of increasing magnitudes
of applied stress and patient growth status on the speed of orthodontic tooth
movement. METHODS: Eighty-two maxillary canines in 41 subjects were retracted
for 84 days by 4, 13, 26, 52 or 78 kPa of stress that was applied continuously
via segmental mechanics. Dental impressions made at intervals of 1 to 14
days resulted in 9 or 10 dental casts per subject. Three-dimensional (3D) tooth
movements were quantified using these casts, custom reference templates and
a measuring microscope. Growth status was determined using serial height
and cephalometric measurements. RESULTS: Linear distal tooth movement had
no lag phase in 96% of the teeth. Speeds averaged 0.028, 0.040, 0.050, 0.054
and 0.061 mm per day (standard errors + 0.004) for 4, 13, 26, 52 and 78 kPa of
stress, respectively. Great individual variation in tooth movement speeds was
seen between individuals, with a maximum difference in speed at 9:1. Teeth
moved significantly faster (P º 0.0001) in growing compared with non-growing
subjects, on average by 1.6 fold. Stress and speed of tooth movement were
related logarithmically, where the magnitude of the applied stress accounted for
47% and 34% of the variability in speed in growing and non-growing subjects,
respectively. Non-linear tooth movements were relatively small, except for the
distopalatal rotation of teeth, which was more than 19” upon 78 kPa of applied
stress. CONCLUSIONS: The speed of tooth retraction increased logarithmically
with higher applied stress and was significantly faster in actively growing subjects
compared with those who were not growing.
KEY WORDS: human, tooth movement, mechanical stress, growth, canine retrac-
tion
INTRODUCTION AND LITERATURE REVIEW
The variables that affect the speed of orthodontic tooth move-
ment (e.g., applied stress magnitude and growth status) remain poorly
27
Mechanical Stress and Growth
understood. Previous reviews of the literature on optimal mechanics for
maximizing the speed of tooth movement have demonstrated the pau-
city of data on this topic. Ouinn and Yoshikawa (1985) proposed 4 hypoth-
eses regarding the relationship between applied stress levels and velocity
of tooth movement: 1) a constant relationship; 2) a positive linear rela-
tionship; 3) a positive linear relationship up to a maximum after which
increases in stress decrease velocity; and 4) a positive linear relationship
up to a maximum after which increases in stress do not increase veloc-
ity further, including tentative support for a linearly increasing speed of
tooth movement up to a maximum at 7 to 14 kPa (100 to 200 cm) for an
average canine).
That available quantitative data are relatively limited on this
topic was illustrated further by a comprehensive review of the literature
through 2001. In this review, only 17 animal studies and 4 human studies
met reasonable inclusion criteria and only 1 human study attempted to
quantify applied stress (Ren et al., 2003). Limited information on the rate
of tooth movement and stress levels has challenged previous attempts
to model these relations. Ren and colleagues (2004) used published
results from dog and human studies to develop a mathematical model
for the relationship between speed and applied force. Their results
showed widely scattered velocities of different-sized teeth moved by
various protocols and in different species. They concluded that there
is a dose-response relationship only for lower forces with a maximum
predicted speed of 0.041 mm per day for 272 cm applied to human
canines. More recently, Van Leeuwen and associates (2010) reported on
tooth translation of first molars and second premolars relative to implant
anchorage in dogs, using a relatively disparate range of systematically
increasing forces. Variability in the speed of tooth movement for an
equivalent force (scaled to account for differences in root surface areas
between molars and premolars) was high between dog's teeth and
estimated at more than 15:1. Despite this high variability, the authors
suggested a logarithmic model where only forces in the low range can
affect the speed of tooth movement. Theoretical models involving finite
element approaches and up-to-date methods for characterizing the
anatomy of the tooth and surrounding structures might be used in the
future to study this clinically important relationship (Reimann et al., 2007;
Cattaneo et al., 2009; Xia and Chen, 2012; Viecilli et al., 2013). However,
28
Nickel et al.
these theoretical approaches currently lack physiological and clinical data
for individual-specific predictions and validation, respectively.
More recently, controlled tooth translational movements in
humans were reported (Iwasaki et al., 2000, 2005, 2006, 2009). Among 68
maxillary canines, the speeds of maxillary canine retraction differed by as
much as 9:1 (Iwasaki et al., 2009). The combined results of these human
studies suggested that 26 kPa was an optimal applied stress and 0.063
mm per day was the average maximum mean speed of tooth movement.
These data also demonstrated that mean speeds of tooth movement
were about 2 times faster in growing subjects compared with subjects
who showed no growth during orthodontic treatment.
To date, no statistically significant mathematical model has been
proposed that relates the speed of tooth movement to applied stress
levels with specific mechanics in humans. Here, we report a model based
on data collected from 41 subjects in whom determinant mechanics were
used to translate the maxillary canines over 84 days.
MATERIALS AND METHODS
The methods for recruitment and data collection were reported
previously (Iwasaki et al., 2000, 2005, 2006, 2009; Hentscher-Johnson,
2011). Briefly, patients with good oral hygiene and at least 6 permanent
teeth in each maxillary quadrant and who required bilateral maxillary
canine retraction into the extracted maxillary first premolar sites were
recruited for the study from the Universities of Nebraska Medical Center
and Missouri-Kansas City Graduate Orthodontic Clinic. Forty-one subjects
gave informed consent to participate according to the ethical standards
of the appropriate institutional review boards. During the study, the
subjects were instructed to rinse orally with chlorhexidine gluconate
twice daily and to avoid taking any other medications.
In each subject, the maxillary posterior teeth were aligned for
Segmental mechanics to translate the bilateral maxillary canines distally,
whereas the mandibular teeth had no appliances. Anchorage included
a Nance appliance and linking of posterior teeth on each side with
passive buccal stainless steel segmental archwires of rectangular cross-
Section (> 0.016" x 0.018"), plus figure-8 ligation (Fig. 1A). Approximately
2 weeks after anchorage placement, the maxillary first premolars were
extracted. At least 2 weeks later, at a time point defined as day 0, active
29
Mechanical Stress and Growth
retraction of the maxillary canines began. In brief, a 0.016" x 0.022”
diameter stainless steel auxiliary wire with a vertical loop just distal to the
maxillary canine was constructed to extend passively from the maxillary
first molar band's auxiliary tube to the canine bracket. The height of this
loop matched the canine's center of resistance, relative to its root length,
which was measured from a periapical radiograph of this tooth corrected
for magnification and according to the relationship in which center of
resistance = 0.24 root length. The vertical-loop auxiliary wire was made
passive initially, ligated to the canine bracket with a stainless steel tie and
an elastomeric tie overlay and then activated by a nickel-titanium (Niſi)
coil spring, calibrated at mouth temperature (see the study of Iwasaki
and coworkers [2000] for details of methods), stretched between hooks
on the molar band and on the auxiliary wire just distal to the loop (Fig.
1B). This caused separation of the vertical legs of the loop, creating both a
retraction force and an apicodistal counter-moment at the canine bracket
that was designed to result in translation of the canine with respect to
the posterior anchorage. The force required for a given stress level (4,
13, 26, 52 or 78 kPa) was determined by dividing the applied stress by
the maxillary canine's estimated distal root surface area (A) that was
involved in periodontal ligament compression during canine retraction.
This estimate took into account root curvature in cross-section, whereby
A = root length X aſ 1 - bº/a”)”, where “a” is half the labiopalatal width of
the canine at the cementoenamel junction and "b" is half the mesiodistal
width of the canine at the cementoenamel junction. On average, loads
corresponded to forces of approximately 18, 60, 120, 240 and 360 cM,
respectively (Fig. 1). A balanced incomplete block study design was used
to assign 2 different stresses per subject and these were assigned further
to right or left sides randomly.
On days 0, 1, 3, #7, 14, 28, 42, 56, 70 and 84, the subjects had
their modified gingival index scored (Lobene et al., 1986), a supragingi-
val oral prophylaxis and a maxillary dental impression made with poly-
vinylsiloxane material in a custom tray. The set of 3 templates for each
subject provided a common axis system and canine reference markers
(Fig. 2) so that three-dimensional (3D) tooth movement measurements
could be calculated from each cast in the series with the templates in
place, using a measuring microscope (MM-11 Measurescope; Nikon,
30
Nickel et al.
Figure 1. A: Maxillary occlusal view showing anchorage appliances. B: Right buccal
view showing height of the vertical loop approximating the estimated center of
resistance of the maxillary canine. Vertical loops activated by calibrated nickel-
titanium (NiTi) coil springs were used to deliver a prescribed continuous force (F)
for a Specified stress (o) to each maxillary canine, according to o = F/A, where A,
is the distal root surface area of the maxillary canine adjusted for root curvature.
Melville, NY) to quantify (Iwasaki et al., 2000). Repeated measurement
errors for this technique were s 0.07 mm and < 0.63°.
For each maxillary canine, movements in 3 linear aspects (distal,
lateral and extrusion) and 3 angular aspects (distal crown tip, lateral
Crown torque and distopalatal rotation) were calculated and plotted
VS. time to assess the nature and amount of tooth movement. Speed
Was Calculated by plotting the amount of tooth movement vs. time.
Craniofacial growth via serial lateral cephalometric superimpositions
and height measurements during orthodontic treatment were used to
determine growth status as positive (grower) or negative (non-grower) by
presence or absence, respectively, of a demonstrated change. Repeated
measures analysis of variance and Tukey-Kramer post-hoc tests were used
to evaluate the effects of mechanical stress and growth status on the
Speed of tooth movement.
RESULTS
Twenty-four female and 17 male subjects participated, ages 10.1
to 30.9 years (mean age = 14.8 + 3.9 years; Table 1). Of these, 30 subjects
Were growers (17 females, 13 males) and 11 subjects were non-growers
(7 females, 4 male; Table 1). Subjects had an average modified gingi-
Val index score of 0.1 + 0.1, indicating good oral hygiene with minimal

31
Mechanical Stress and Growth
Figure 2. Diagram of a maxillary dental cast and custom acrylic
templates: 1 for the posterior anchor teeth and 1 for each maxillary
canine. Markers were embedded in each template: R1, R2 and R3 in
the posterior template defined the origin and 3 orthogonal axes (x, y,
z); C1, C2 and C3 in each canine template allowed serial measurements
of the canines in terms of linear positions (distal, lateral and extrusion)
relative to the origin and angular positions (crown tip, Crown torque and
distopalatal rotation) relative to the axis system. Modified from Iwasaki
et al., 2009.
visible signs of inflammation. Posterior anchorage was preserved (< 1.0
mm change) for all subjects as verified by cephalometric superimposi-
tions before day 0 and after day 84, and by the acceptable fit of the cus-
tom posterior template on all casts for an individual subject. Most sub-
jects came to each scheduled study visit, but 13 subjects came on at least
one day that differed from the scheduled day by 1 to 8 days; 5 subjects
missed 1 day on day 28 or later and 1 subject missed days 42 and 70.

32
Nickel et al.
Table 1. Subject's identification (group, sex, number), age and
growth status with side of the maxillary canine, applied stress and
Slope (Speed) and R* of distal movement vs. time relation, where
F = female and M = male.

Age Growth Stress Speed
Subject (years) || Status Side (kPa) (mm/day) R”
1F1 12.2 Grower Right 4 0.029 0.97
Left 13 0.046 0.97
1F2 14.8 Grower Right 4 0.020 0.97
Left 13 0.018 0.91
1F3 13.2 Grower Right 4 0.048 0.99
Left 13 0.049 0.94
1F4 13.3 Grower Left 4 0.019 0.86
Right 13 0.052 0.97
1F5 14.4 Grower Left 4. 0.022 0.90
Right 13 0.026 0.99
2F1 30.9 Non- Right 13 0.012 0.66
Grower T.HTT-ze 0.013 || 0.73
2F2 15.1 Non- Left 13 0.021 0.88
Grower Tºni 26 0.022 0.93
2F3 16.1 Non- Right 13 0.033 0.96
Grower FT= 52 0.052 0.88
2F4 12.8 Grower Left 13 0.052 0.90
Right 26 0.053 0.84
2F5 10.4 Grower Right 13 0.045 0.86
Left 52 0.056 0.95
3F1 16.1 Grower Right 26 0.067 0.98
Left 52 0.060 0.99
3F2 13.2 Grower Right 26 0.060 0.98
Left 52 0.065 0.99
3F3 24.6 Non- Right 26 0.062 0.99
Grower H=== 0.066 0.99
33
Mechanical Stress and Growth

Age Growth Stress Speed
Subject (years) || Status Side (kPa) (mm/day) R*
3F4 11.5 Grower Left 26 0.091 0.99
Right 52 0.081 0.99
3F5 15.2 Grower Left 13 0.049 0.99
Right 26 0.070 O.99
4F1 13.3 Grower Right 52 0.079 0.97
Left 78 0.090 0.99
4F2 12.8 Grower Right 78 0.059 0.95
Left 52 0.071 0.94
4F3 12.2 Grower Right 26 0.037 0.94
Left 78 0.072 0.98
4F4 11.8 Grower Right 78 0.109 0.98
Left 13 0.075 0.98
4F5 17.9 Non- Right 26 0.028 0.98
grower T.HT-7s 0.029 || 0.87
4F6 10.8 Grower Right 78 0.061 0.96
Left 52 0.048 0.99
5F1 14.2 Non- Right 4. 0.032 0.98
grower Tan T7a 0.049 || 0.92
5F2 17.6 Non- Right 78 0.066 0.98
grower Tien 4. 0.024 0.96
5F3 10.1 Grower Right 4. 0.052 0.92
Left 78 0.094 0.74
1M1 16.2 Grower Left 4. 0.016 0.73
Right 13 0.024 0.90
1M2 13.9 Grower Left 4 0.042 0.87
Right 13 0.066 0.93
2M1 17.9 Non- Left 13 0.015 0.88
Grower Tºni TE, 0.037 || 0.76
2M2 12.9 Grower Right 13 0.057 0.91
Left 26 0.043 0.93
34
Nickel et al.

Age Growth Stress Speed
Subject (years) || Status Side (kPa) (mm/day) R”
2M3 14.2 Grower Left 13 0.068 0.96
Right 52 0.063 0.92
3M1 12.5 Grower Right 26 0.072 0.98
Left 52 0.059 0.99
3M2 13.8 Grower Left 26 0.097 0.99
Right 52 O.084 0.99
3M3 12.2 Grower Right 26 0.090 0.98
Left 52 0.080 0.99
3M4 16.3 Grower Right 26 0.054 0.96
Left 52 0.034 0.99
3M5 14.1 Grower Left 13 0.046 0.99
Right 26 0.058 0.99
4M2 14.2 Grower Right 78 0.065 0.98
Left 13 0.061 0.98
4M3 16.1 Grower Right 13 0.037 0.95
Left 78 0.051 0.92
5M1 12.6 Grower Right 78 0.060 O.97
Left 4. 0.031 0.86
5M2 11.8 Grower Right 4. 0.024 0.80
Left 78 0.093 0.98
5M3 13.7 Grower Right 4 0.046 0.13
Left 78 0.076 0.81
5M4 22.5 Non- Right 78 0.052 0.79
Grower Han 4 0.029 || 0.41
5MS 17.0 Grower Right 4 0.013 0.50
Left 78 0.039 0.94
Overall, the greatest direction of tooth movement occurred in
the distal direction and increased linearly with time (Fig. 3). Plots of
distal tooth movement vs. time point for individual maxillary canines
showed the same general pattern for 79 canines (Fig. 4). Linear
35

Mechanical Stress and Growth
movement began after the application of the load and a lag phase was
evident between days 3 and 28 for only 3 teeth (4% of sample; Fig. 4).
The slope of each plot determined speed (mm/day) and the highly
linear behavior was reflected in the coefficients of determination (R*),
which were on average 0.91 + 0.14. In general, other tooth movements
tended to fluctuate and be relatively small: <+ 0.7 mm for extrusion
(Fig. 5), ºf 4.4° for labial crown torque (Fig. 6) and distal crown tip
(Fig. 7). This was similar for distopalatal rotation, where average tooth
movements associated with applied stresses of 4 to 52 kPa tended to
fluctuate and be ºf 5.3° (Fig. 8). However, progressively increasing
average distopalatal rotations up to 19.4° were seen in teeth moved by
78 kPa (Fig. 8). Lateral tooth movements tended to increase with time
and applied stress magnitude up to a mean of 3.1 mm for teeth moved
by 78 kPa (Fig. 9).
8 -
£ 7 – a 4 kPa
F 6 - • 13 kPa
E. a 26 kPa
# 5 - x 52 kPa
q) - O 78 kPa
> 4
5
E * :
O
º 2
º -
# * * *
º ºf Zº
Q) 0 ºr 1
on
& -1 -
g
ºr -2 -
–3 i I i i i
O 20 40 60 80 100
Approximate Time-point (Day)
Figure 3. Average distal tooth movement (mm) vs. approximate time point (day)
for the 5 applied stress magnitudes. Vertical lines above and below the symbols
indicate 1 standard deviation (SD).
36

Nickel et al.
8 -
7 –
6 - | x 3F152 kPa
$32M1.52 kPa X
5 -
4 -
3 - x
2 - 33
1 - $3 %
o º $3.
X
–2 -
–3 I I I i i
O 20 40 60 80 100
Time-point (Day)
Figure 4. Distal tooth movement (mm) vs. time point (day) for 2 maxillary canines
in different subjects (2M1, 3F1) moved by 52 kPa. Tooth movement for 3F1
(filled X) showed linear movement with time and no lag phase; this pattern was
evident for 79 of 82 teeth. Tooth movement for 2M1 (open X) showed a lag phase
between days 3 and 28; this pattern was evident in only 3 of the 82 teeth.
8 -
7 – a 4 kPa
6 - • 13 kPa
A 26 kPa
5 - x 52 kPa
4 - O 78 kPa
3 -
2 -
º,
. |
–3 i i I i i
O 20 40 60 80 100
Approximate Time-point (Day)
Figure 5. Average extrusive tooth movement (mm) vs. approximate time point
(day) for the 5 applied stress magnitudes. Vertical lines above and below the
Symbols indicate 1 SD.
37
Mechanical Stress and Growth
30 —
25 - - 4 kPa
• 13 kPa
20 – a 26 kPa
x 52 kPa
15 - O 78 kPa
10 -
-15 i I i I i
0 °. 20 40 60 80 100
Approximate Time-point (Day)
Figure 6. Average labial crown torque (") vs. approximate time point (day) for the
5 applied stress magnitudes. Vertical lines above and below the symbols indicate
1 SD.
30 —
– 25 - - 4 kPa
$ • 13 kPa
# 20 - |* 28 kPa
9. x 52 kPa
c. 15 - |o 78 kPa
F-
5 10-
9
º, O --
q) - | |
op
& -5 -
g
* -10
-15 i I i I i
O 20 40 60 80 100
Approximate Time-point (Day)
Figure 7. Average distal crown tip (*) vs. approximate time point (day) for the 5
applied stress magnitudes. Vertical lines above and below the symbols indicate
1 SD.

38
Nickel et al.
30 —
$ 25 - - 4 kPa
Sh • 13 kPa
§ 20 - a 26 kPa (D
- x 52 kPa
º O 78 kPa (D
3. -
ar.
º
# X X .
-
º -
º |
q)
od º
&
º
>
<ſ
-15 i I I i i
O 20 40 60 80 100
Approximate Time-point (Day)
Figure 8. Average distopalatal rotation (*) vs. approximate time point (day) for the
5 applied stress magnitude
1 SD.
s. Vertical lines above and below the symbols indicate
8 –
£ 7 - - 4 kPa
E. 6 - • 13 kPa
E a 26 kPa
# 5 - |x 52 kPa
g 4 - O 78 kPa
O
>
c 3 -
3
9 2 -
º -
i., , ,
º
º 0 & - # I
q)
3 -2 -
–3 I i I i I
O 20 40 60 80 100
Figure 9. Average lateral to
Approximate Time-point (Day)
oth movement (mm) vs. approximate time point (day)
for the 5 applied stress magnitudes. Vertical lines above and below the symbols
indicate 1 SD.

39

Mechanical Stress and Growth
Speeds of linear distal tooth movement ranged from 0.016 to
0.109 mm per day in growers and 0.012 to 0.066 mm per day in non-
growers. Distal linear movement was on average 1.6 times greater and
significantly faster in growers compared to non-growers (P<0.0001; Fig.
10). Tooth movement speeds were approximately 4:1 greater in growers
compared to non-growers at 13 kPa and approximately 5:1 greater in
growers compared to non-growers at 26 kPa. Combining growers with
non-growers, average speeds of distal linear movement were 0.028,
0.040, 0.050, 0.054 and 0.061 mm/day (all standard errors: + 0.004 mm/
day) for 4, 13, 26, 52 and 78 kPa, respectively (Fig. 11). Significantly faster
speeds of distal movement resulted for teeth moved by 26, 52 and 78 kPa
compared with those moved by 4 kPa and for teeth moved by 52 and 78
kPa compared with those moved by 13 kPa (Fig. 11). Average speeds of
distal tooth movement increased logarithmically with stress (R* = 0.99).
However, the logarithmic models (Fig. 12) with raw data indicated that
only 47% and 34%, respectively, of the variances in speed of distal tooth
movement were explained by applied stress for these groups.
Growth Effects
0.07 - P & O.OOOO
1.6:1.0
0.06 -
H
0.05 -
0.04 -
H
0.03 -
0.02 - n = 60 n = 22
0.01 -
Growth No Growth
Growth Status
Figure 10. Average speed of distal tooth movement (mm/day) for the subjects
by growth status. Vertical lines indicate 1 standard error (SE) above and below
the average. Subjects who showed evidence of growth during treatment had
significantly higher speeds of distal tooth movement by a factor of 1.6 compared
to subjects who showed no growth.
40
Nickel et al.
Effect of Stress
* 0.07 - I - – |Fºogool
| P:0.001 | A
§ 0.06: ºn .= 16
E - A as . .
E. 0.05 - 16 - |Fºods
n =
5 0.04 - - P&O.05 | - - -
# " * R2 = 0.9926
> - - - -
c. 0.03 - |
º n = 15 -
o
ºr 0.02 -
o
3 0.01 -
º
>
O i i I t I
0 20 40 60 80 100
Estimated Compressive Stress (kPa)
Figure 11. Average speed of distal movement (mm/day) for the maxillary canines
moved by applied stresses from 4 to 78 kPa. Vertical lines indicate one SE above
and below average. Significant differences in speed were found between teeth
moved by 4 kPa and 26 to 78 kPa, and between teeth moved by 13 kPa and 52 to
78 kPa. Log regression was fitted to averaged data.
Log Model of Stress & Velocity Log Model of Stress & Velocity
1.5 Growers: Both Variables Logged Non Growers: Both Variables Logged
-1.5
-Regression(R*-0.47) -Regression (R = 0.34)
95% Means confidence Limits
-
95% Means confidence Limits
95%. Data Prediction Limits
2.
o
-
-2.
O
-
2.
5.
-
2.
5
-
-4.
5
-
5
o
---
I i i i I ---
1.0 1.5 2.0 2.6 3.0 3.5 4.0 4.5 1.0 1.5 20 2's so 3.5 4.0 4.5
A Log Mechanical Stress B Log Mechanical Stress
Figure 12. Log model of distal linear movement (mm/day) for the maxillary
Canines moved by applied stress ranging from 4 to 78 kPa for (A) growing (R* =
0.47) and (B) non-growing (R2 = 0.34) subjects.
Over time, expected progressive changes were found for distal
movements and, to a smaller degree, for lateral movements. The lat-
ter was expected because most maxillary canines were retracted into
a wider portion of the dental arch (Fig. 1A). Relatively small, fluctuat-
ing changes were seen with time for extrusion, labial crown torque
and distal crown tip. The most remarkable unexpected and clinically
important differences were seen for distopalatal rotation of the teeth















41
Mechanical Stress and Growth
when moved by 78 kPa. At this high applied stress, the constraint con-
ditions of the appliances apparently were outstripped, even though all
vertical loop auxiliary wires were ligated to maxillary canine brackets with
stainless Steel wires and, in most cases, with an elastomeric ligature en-
gaged over the wire ligature. Despite these strict anchorage mechanics,
the highest forces used (about 360 cm) caused over 19° of distopalatal
rotation on average by the end of the study. This amount was 4 to 10
times greater than the distopalatal rotation of canines moved by lower
stress magnitudes.
DISCUSSION
Contrary to previous predictions that 7 to 14 kPa (100 to 200 cM
for an average cañine) might give the fastest tooth movement (Ouinn and
Yoshikawa, 1985), this study showed significantly faster speeds of distal
tooth movement, > 0.050 mm per day (Fig. 11), from stresses between
26 kPa (about 120 cM) and 78 kPa (about 360 cm) compared with lower
stresses. Our results also suggest that human maxillary canine movement
from this range of stresses is more efficient (faster for less load) than
other previously published theoretical predictions (e.g., compared with
0.041 mm per day from a force of 272 cl estimated by the mathematical
model [Ren et al., 2004] based on combined human and dog data and
about 0.030 to 0.035 mm per day for of 120 to 360 cM in dogs [Van
Leeuwen et al., 2010]). However, similar to these previous models (Ren
et al., 2004; Van Leeuwen et al., 2010), this study also demonstrates a
logarithmic relationship between the rate of tooth movement and the
applied load. So far, it is unclear whether rates of tooth movement truly
are maximized 2 26 kPa; further testing of higher magnitude stresses
is indicated to address this. However, as shown by this study, improved
constraint conditions are needed to prevent undesirable rotational effects
for teeth moved by stresses of 78 kPa and higher.
This study demonstrated the advantage of relatively faster tooth
movement in individuals who actively are growing compared to those
who are not growing actively, on average, by a factor of 1.6 fold. When
stress is considered, the speeds of tooth movement in both growers and
non-growers fit a logarithmic model, but only 47% and 34%, respectively,
of the variances in speed of tooth movement were attributable to stress.
42
Nickel et al.
Therefore, other variables must be considered to improve predictions of
rate of orthodontic tooth in the future. The relative amounts of inflam-
matory cytokines in gingival crevicular fluids of moving teeth compared
with control teeth have shown promise in improving such predictions
(Iwasaki et al., 2001). In addition, preliminary studies of single nucleotide
polymorphisms that could account for differences in the inflammatory
responses to similar mechanical stimuli also have shown promise (Iwa-
saki et al., 2009). Undoubtedly, future approaches should include mul-
tiple variables and combine mechanical and biological data in order to
characterize the interactions important to the speed of tooth movement.
Overall, the distal tooth movement vs. time relationship reported
in this study was highly linear, as demonstrated by the average coefficient
of determination (R*) of 0.91 + 0.14. Of note, only 4% of the teeth moved
in our study showed a lag phase. This finding is in contrast to previous
Studies that suggested a 21-day lag phase should be expected from
forces greater than 100 cM (Gianelly and Goldman, 1971). Inter-individual
differences in the speed of distal movement were evident and agreed with
the variability previously reported (Iwasaki et al., 2009). Some maxillary
canines retracted with identical stress magnitudes in people of similar
growth status moved 4 to 5 times faster than others.
Healthcare delivery is trending toward “personalized medicine.”
This involves combining comprehensive data about a person to make
treatment as individualized and effective as possible. The data presented
herein demonstrated as much as a 9:1 difference in the speed of tooth
movement between persons. Future clinical studies that test variable
effects on orthodontic tooth movement must be designed to measure
the effects of mechanics, growth status and biomarkers relevant to the
process.
CONCLUSIONS
Combined data from 82 teeth moved over 84 days in 41 individu-
als demonstrated that the speed of tooth movement was related loga-
rithmically to applied mechanical stress. Greater applied stress leads to
faster tooth movement. In addition, individuals who were growing active-
ly showed significantly faster rates of tooth movement than those who
were not growing, for the same applied mechanics.
43
Mechanical Stress and Growth
ACKNOWLEGEMENTS
We thank Jeff Chandler, Larry Crouch, Whitney DeForest, Krista
Evans, Colin Gibson, Scott Gibson, Jim Haack, Jodi Hentscher-Johnson,
Alistair Hoyt, Aaron Jacobsen, Jay Pandey, Marian Schmid, Bobby Simetich,
Amy Tasca, Sonny Tutor and the subjects in this study; Kim Theesen who
assisted with the figures; and G&H Wire Company (Greenwood, IN)
for donating supplies. This study was funded in part by the American
Association of Orthodontists Foundation. This article was published in:
Nickel JC, Liu H, Marx DB, Iwasaki LR. Effects of mechanical stress and
growth on the velocity of tooth movement. Am J Orthod Dentofacial
Orthop 2014;4(Suppl 1):S74-S81.
REFERENCES
Cattaneo PM, Dalstra M, Melsen B. Strains in periodontal ligament and
alveolar bone associated with orthodontic tooth movement analyzed
by finite element. Orthod Craniofac Res 2009;12(2):120-128.
Gianelly AA, Goldman H.M. Biologic Basis of Orthodontics. Philadelphia:
Lea & Febiger 1971.
Hentscher-Johnson JK. Ouality and intensity of pain associated with
continuously applied orthodontic stresses of relatively high and low
magnitudes. MS Thesis. Kansas City: University of Missouri-Kansas
City 2011. .
Iwasaki LR, Chandler JR, Marx DB, Pandey JP, Nickel JC. IL-1 gene
polymorphisms, Secretion in gingival crevicular fluid, and speed of
human orthodontic tooth movement. Orthod Craniofac Res 2009;12
(2):129-140.
Iwasaki LR, Crouch LD, Tutor A, Gibson S, Hukmani N, Marx D, Nickel JC.
Tooth movement and cytokines in gingival crevicular fluid and whole
blood in growing and adult subjects. Am J Orthod Dentofacial Orthop
2005;128(4):483-491.
Iwasaki LR, Gibson CS, Crouch LD, Marx DB, Pandey JP, Nickel JC. Speed of
tooth movement is related to stress and IL-1 gene polymorphisms. Am
J Orthod Dentofacial Orthop 2006;130(6):698.e1-eg.
Iwasaki LR, Haack JE, Nickel JC, Morton J. Human tooth movement
in response to continuous stress of low magnitude. Am J Orthod
Dentofacial Orthop 2000;117(2):175-183.
44
Nickel et al.
Iwasaki LR, Haack JE, Nickel JC, Reinhardt RA, Petro TM. Human
interleukin-1 beta and interleukin-1 receptor antagonist secretion and
velocity of tooth movement. Arch Oral Biol 2001;46(2):185-189.
Lobene RR, Weatherford T. Ross NM, Lamm RA, Menaker L. A modified
gingival index for use in clinical trials. Clin Prev Dent 1986;8(1):3–6.
Ouinn RS, Yoshikawa DK. A reassessment of force magnitude in
orthodontics. Am J Orthod 1985;88(3):252-260.
Reimann S, Keilig L, Jäger A, Bourauel C. Biomechanical finite-element
investigation of the position of the centre of resistance of the upper
incisors. Eur J Orthod 2007;29(3):219–224.
Ren Y, Maltha JC, Kuijpers-Jagtman AM. Optimum force magnitude for
orthodontic tooth movement: A systematic literature review. Angle
Orthod 2003;73(1):86-92.
Ren Y, Maltha JC, Van't Hof MA, Kuijpers-Jagtman AM. Optimum force
magnitude for orthodontic tooth movement: A mathematic model.
Am J Orthod Dentofacial Orthop 2004;125(1):71-77.
Van Leeuwen EJ, Kuijpers-Jagtman AM, Von den Hoff JW, Wagener FA,
Maltha JC. Rate of orthodontic tooth movement after changing the
force magnitude: An experimental study in beagle dogs. Orthod
Craniofac Res 2010;13(4):238–245.
Viecilli RF, Budiman A, Burstone C.J. Axes of resistance for tooth movement:
Does the center of resistance exist in 3-dimensional space? Am J
Orthod Dentofacial Orthop 2013;143(2):163–172.
Xia Z, Chen J. Biomechanical validation of an artificial tooth-periodontal
ligament-bone complex for in vitro orthodontic load measurement.
Angle Orthod 2013;83(3):410-417.
45
46
ARE WE ANY CLOSER TO UNDERSTANDING THE
MECHANISMS OF EXPEDITED TOOTH MOVEMENTP
Sarandeep Huja
ABSTRACT
The orthodontic profession should aim to reduce the duration of orthodontic
therapy. Currently, increasing numbers, of case reports demonstrate that sub-
stantial reductions in treatment time are achievable. These reports suggest that
Corticotomies, vibration, laser, electric current and controlled localized injury
may have the potential to increase basal metabolic rate and, therefore, reduce
treatment time. The suggested mechanisms by which these adjunctive treat-
ments enhance tooth movement seem to have their basis in tissue-level histo-
logical events. Thus, concepts that are relevant to tissue-level bone biology are
reviewed here. Targeted and stochastic bone remodeling are defined and distin-
guished from bone modeling. The original description and features of regional
acceleratory phenomena (RAP) are discussed, along with the relevance of bone
remodeling rates for expedited tooth movement. Selection of a suitable animal
model to study bone remodeling and adaption is discussed. A brief critical review
of findings from the literature on expedited tooth movement is presented as
related to animal models, bone remodeling and modeling. Finally, a summary
is provided regarding what evidence exists in the literature for many of the pro-
posed mechanisms. The information presented herein will assist in designing fu-
ture experiments and interpreting results from well-designed studies.
KEY WORDS: regional acceleratory phenomena (RAP), remodeling, modeling,
histomorphometry, animal models
INTRODUCTION
The treatment duration for comprehensive orthodontic therapy
is estimated to be 24 to 30 months. Predictable reduction in treatment
time to approximately 12 months would be a significant advance that
would benefit orthodontic patients. Reduction in treatment time would
have the benefit of potentially decreasing the risk of major negative
47
Mechanisms of Expedited Tooth Movement
sequelae of orthodontic therapy (e.g., root resorption and white spot
lesions). Treatment duration has remained unchanged largely for the
last century. With the Synergy of rapid advances in technology and
understanding of the biology of tooth movement, opportunities for
expediting tooth movement seem to be poised on the horizon. A number
of clinical case reports suggest that treatment time can be reduced
for our orthodontic patients; however, hurdles remain before such
claims can be substantiated and become evidence based. For example,
does a reduction in treatment during the initial phases of orthodontics
(initial leveling/alignment or space closure) translate to overall reduced
treatment time? Is it possible that the finishing phase of treatment would
be prolonged in these cases of expedited tooth movement? The cost-to-
benefit ratio of a four- to six-month reduction in treatment and potential
differences in quality of the final result will have to be compared to
cases with traditional treatment approaches. A new model of reduced
treatment time also will impact the practice management component of
orthodontics. Many questions remain unanswered and a major challenge
for Orthodontists is to understand evidence behind the scientific claims
for the many procedures that are being introduced rapidly. This chapter
reviews the current basic tissue-level biology that is cited frequently in
the literature as being the rationale and/or mechanism underlying rapid
tooth movement.
“Mechanisms” suggested as aſthe reason responsible for acceler-
ated tooth movement include:
1. Cortical plates are an impediment to orthodontic
tooth movement (Ren et al., 2007);
2. Regional acceleratory phenomena (RAP) and associ-
ated tissue remodeling (Sebaoun et al., 2008);
. High rates of bone turnover (Sebaoun et al., 2008);
4. Demineralization/remineralization process (Wilcko
et al., 2008);
5. Increase in cortical bone porosity, transient osteo-
penia, osteopenia facilitated rapid tooth move-
ment (Sebaoun et al., 2008);
6. Dramatic increase in trabecular bone turnover (Se-
baoun et al., 2008); and
7. Bone matrix transportation (Wilcko et al., 2008).
3
48
Huja
The basis of Some of these statements lies in beliefs, observations
and/or interpretations of clinical and animal data. However, the word
"mechanism” implies something more proximate, a definitive pathway
without which a process would not occur. A putative mechanism also
allows for experimentation by scientific methods. All of the above listed
"mechanisms” refer to tissue-level histological events and should be
explained by a thorough understanding of bone remodeling (Canalis,
1994) and modeling (Frost, 1990; Roberts et al., 2004) processes.
These two processes are described well in the bone literature, though
they frequently are misunderstood. Thus, in order to understand these
fundamental biological processes, a description of both remodeling and
modeling is provided.
BONE REMODELING
Bone remodeling is a coupled sequential process of bone
resorption followed by bone formation. Bone remodeling occurs both
in cortical and trabecular bone compartments of the skeletal system.
However, there are important differences between bone remodeling in
the cortical versus trabecular bone that are reflected at a tissue level and
revealed by histological studies. Histologically, when viewed in transverse
sections of long bones, the end result of cortical bone remodeling is the
production of a new, circular-shaped osteon (typically 200 to 300 micron
diameter). This type of cortical bone remodeling also can be described as
intracortical secondary osteonal bone remodeling. Thus, this remodeling
occurs in cortical bone within the substance of the cortical bone (in the
intracortical compartment) and away from the periosteal and endosteal
surfaces. In addition, the bone remodeling process results in the formation
of secondary osteons (Roberts, 2012). Secondary osteons have a reversal
line and are in contrast to primary osteons (Martin et al., 1998). Primary
osteons are produced by bone formation and not by a coupled process
of bone resorption and bone formation. Primary osteons, therefore,
histologically resemble secondary osteons, but lack the reversal line
because no bone resorption occurs in the development of a primary
osteon. Intrabecular bone, the bone tissue structure frequently is not wide
enough to accommodate osteons (which are 200 to 300 micron-sized).
Thus, only “hemi-osteonal” surface bone remodeling occurs in trabecular
bone (Parfitt, 1994). However, the trabecular bone remodeling is identical
49
Mechanisms of Expedited Tooth Movement
to that of cortical bone as it follows the same coupled, resorption and
formation process. At a cellular level, bone is resorbed by osteoclasts and
formed by osteoblasts (Robling et al., 2006). In other words, remodeling
of both cortical and trabecular bone involves the coordinated, coupled
activity of osteoclasts and osteoblasts.
Bone remodeling is a homeostatic process that results in the
rejuvenation and replacement of old bone that has served its purpose.
This process is unique to bone and does not occur within the substance
of other mineralized tissues (e.g., enamel, dentin and cementum). This
provides a distinct advantage to bone and makes it a tissue that is capable
of regeneration. Bone remodeling also underlies the immense adaptive
potential of this mineralized and hard tissue, both terms otherwise
potentially implying limited adaptability. From a functional standpoint,
bone remodeling also provides for calcium (Roberts, 2012). From an
evolutionary perspective, bone acts as a calcium reservoir, allowing for
life forms to move away from the sea/salt water. Without this reservoir
and method for mobilization of calcium stores, calcium in the immediate
environment (e.g., sea water) was essential for various cellular functions.
Two terms are used to describe the type of bone remodeling
further: stochastic and targeted (Parfitt, 2002). Stochastic remodeling
occurs rather uniformly throughout the body (i.e., the continuous bone
repair and regeneration process). Stochastic remodeling involves multiple
sites at any one time (e.g., approximately one million by some estimates)
in both trabecular and cortical bone. These remodeling sites provide for
metabolic calcium. During calcium deprivation (Midgett et al., 1981),
bone remodeling is enhanced and the bone remodeling rate is increased
with more “cutting filling cones” or osteons being produced. In contrast,
targeted remodeling occurs at a specific site of injury and not throughout
the entire body. A relevant and easily understandable example of targeted
remodeling for orthodontists is the bone implant interface. In placing a
miniscrew, microdamage (small linear cracks) are created within the bone
due to the insertion of the screw (Huja et al., 1999b). The microdamage, a
manifestation of tissue injury in a mineralized tissue, is repaired by bone
remodeling (Burr et al., 1985). Thus, microdamage production stimulates
bone remodeling at the site of damage (e.g., close to the interface) and
repairs the damaged bone. Another form of bone injury is manifestation
50
Huja
of diffuse damage (Huja et al., 1999a). This damage is not visible as
clearly in histologic sections as microdamage. Corticotomies and/or
injury of both hard and soft tissues produce a localized injury, and repair
is targeted to that specific area. This targeted remodeling probably is
important for expedited orthodontic tooth movement as most therapies
(e.g., vibration, corticotomies) work at Some level through local insult and
subsequently stimulated healing.
BONE MODELING
Bone modeling is a distinct and different process than bone re-
modeling. These two processes are confused frequently, even though
they readily can be distinguished at a histological level. Histologic sec-
tions, labeled with intravital dyes, clearly can distinguish bone remodel-
ing from modeling (Parfitt, 1983; Parfitt et al., 1987). This contrast is not
trivial and the underlying process and controls of bone remodeling and
modeling are different. It is not uncommon to find bone modeling being
measured in studies and being mistaken for bone remodeling. This then
leads to confusion in the literature and, more unfortunately, to incorrect
interpretation of results.
Bone modeling is a surface-specific activity that results in a
change in shape and size (Roberts, 2012). It is an uncoupled process;
bone resorption and formation are not linked or coupled in a sequential
manner. The bone formation and resorption mediated by the osteoblasts
and osteoclasts, respectively, do not occur on the same bone surface.
The processes occur independently of each other on different bone sur-
faces. One example of the end result of bone modeling that can occur
over a duration of years is the difference in the diameter of the dominant
arm of a tennis player from the contralateral non-dominant arm (Jones
et al., 1977). The bone of the dominant arm has a diameter about 1.6-
fold greater than the non-dominant arm. This change in size occurs over
a period of years and, due to modeling events, on the periosteal surface
(and endosteal surface) of the arm. This does not mean that bone remod-
eling cannot occur within the cortical bone (intracortical compartment)
independently or simultaneously; however, they are two different pro-
cesses, each having different control mechanisms (Frost, 1994). There are
numerous other examples of bone modeling, including the formation of
51
Mechanisms of Expedited Tooth Movement
a callus after fracture of a bone (or insertion of an endosseous implant)
and changes we see on the surfaces of bone (changes in shape and size)
that readily are apparent in cephalometric superimposition in a growing
patient. The surface changes result from bone modeling; however, there
is no doubt that bone remodeling is occurring concurrently within the
bone. In fact modeling occurs primarily during growth (on periosteal and
endosteal bone surfaces) and then decreases after maturity. It can be ac-
tivated again during healing and other pathological biological processes
(e.g., bony Cyst-producing expansion).
REGIONAL ACCELERATORY PHENOMENA (RAP)
Regional acceleratory phenomena (RAP) is cited almost
exclusively and frequently in the literature as the basis of accelerated
tooth movement and first was described by Frost (1983) as a complex
reaction to diverse noxious stimuli. He indicated that RAP is an "SOS"
mechanism and acceleration of normal vital tissue processes. In humans,
it is estimated to last for four months in bone and somewhat less in
soft tissues. Importantly, RAP is defined as a process of intermediary
organization of tissues and organs and is not revealed in isolated cells.
This distinction is important and conclusions regarding the occurrence
of RAP cannot be made from experiments or observations on isolated
cells. RAP initially was described in cortical bone tissues and later in
trabecular bone. It typically is not accompanied by osteopenia in the
cortical (Mueller et al., 1991) and trabecular (Bogoch et al., 1993) bone
compartments, as has been described in the orthodontic literature. The
reader is encouraged to review the above two important references
on RAP to understand the process. The osteopenia associated with
orthodontic tooth movement may be unique to the model in which it is
being described and may not be related directly to the RAP phenomena
per se. The contribution of a large rigid structure (the tooth) within the
bone with and without superimposed force application may modify the
response to tissue injury.
Another term that has been introduced in the Orthodontic
literature to describe mechanisms of accelerated tooth movement is
de-mineralization, which implies loss of bone mineral to some extent.
New bone has less mineral content than mature bone. Two phases of
mineral deposition in bone have been described well in the literature
52
Huja
and are referred to as primary and secondary mineralization (Martin et
al., 1998; Roberts, 2012). During primary mineralization (soon after bone
formation), nearly two thirds of bone mineral are thought to be deposited
shortly after the bone matrix has been laid down. During secondary
mineralization (a period that spans approximately four to six months), the
remaining bone mineral is deposited. It is not surprising that new bone
is less rigid and more compliant than mature bone because it contains
fewer minerals. It is implied in the orthodontic literature that mineral is
removed from the bone, the bone matrix remains intact and the tooth is
transported through the matrix without any resistance. Yet, it is unclear
how the bone mineral can be removed exclusively and rapidly without
bone resorption by osteoclasts that also would remove the matrix of
bone; therefore, a decrease in bone volume, rather than a decrease in
mineral per se, seems more plausible. Bone volume can be altered by
osteoclastic resorption or bone formation, rather than by a mechanism
for sole and rapid removal of the mineral.
Bone Remodeling Rate
In order to understand if increases in bone remodeling (aka
bone turnover) rates are responsible for increases in rates of tooth
movement, it will be important to quantify the alterations (increases or
decreases) in the rate of bone remodeling. It is well known that cortical
bone remodels at 2 to 10% per year and the rate of turnover in trabecular
bone is 30 to 35% per year (Parfitt, 1994, 2002). Trabecular bone is active
metabolically and is a primary source of serum calcium. Interestingly, in
the alveolar bone that supports teeth, the physiologic rate of cortical
bone turnover can be as high as 35% per year, which is three- to ten-
fold higher than cortical bone elsewhere (e.g., in the long bones) in the
body (Tricker et al., 2002; Huja et al., 2006). In implant adjacent alveolar
bone, the rate of bone turnover can be as high as 100 to 500% per year,
which suggests intense cortical bone remodeling in implant adjacent
bone (Garetto and Tricker, 2002). It is likely that this elevated turnover
is required to maintain a compliant zone of bone and to buffer for the
modulus mismatch between the implant and bone. This elevated rate of
bone turnover is seen both in mini-implant and implant-adjacent alveolar
bone. During tooth movement, the rate of cortical bone turnover is
estimated to be 100 to 200% per year (Deguchi et al., 2008), which is a
three- to six-fold increase over the physiological rate of bone turnover in
53
Mechanisms of Expedited Tooth Movement
the alveolar process. Currently, there is no quantification of intracortical
bone remodeling in the alveolar process after corticotomies. Thus, we do
not know if the rate of turnover increases, for example, to 1,000% per
year or to any such level. Without this data from cortical and trabecular
bone, it is difficult to confirm that RAP or increased bone turnover is
responsible for or accompanies expedited tooth movement and may be
even the sole mechanism that allows for more rapid tooth movement.
Animal Models and Bone Remodeling
Rodents (mice and rats) and canines (dogs) serve as models
for the study of orthodontic tooth movement. Both of these animal
models have been used extensively in experiments of expedited tooth
movement; however, it is important to understand differences between
these models, each of which has its advantages. More importantly, while
selecting an animal model, it is important to ask the question or test a
hypothesis that can be answered in the particular and suitable animal
model. Rodents possess thin cortical plates (< 0.2 to 0.4 mm; Huja et al.,
2006) and vascular invasion to produce an osteonal system is not required.
The vascular supply from the periosteal and endosteal surfaces suffices to
provide nutrients to all the cells within the bone plates; however, inbred
mice (e.g., C3H mice) have thickened cortical plates and demonstrate
initial evidence of cortical bone remodeling in the femur (Meta et al.,
2008). Additionally, in response to injury and possible microdamage
accumulation, targeted remodeling with appearance of osteons may
occur in rodents (Bentolila et al., 1998). The trabecular bone of the
distal femur and proximal tibia are standard sites to evaluate effects of
interventions or experimental procedures on bone remodeling in mice
and rats by histomorphometric methods, respectively (Huja et al., 2009).
Thus, rodents commonly remodel in the trabecular bone, but not typically
in the intracortical compartment. In the canine model, physiologic
intracortical osteonal remodeling occurs throughout the skeleton, in both
the trabecular and cortical bone compartments (Huja et al., 2006, 2008;
Helm et al., 2010). The canine model animal husbandry is expensive;
however, the dental structures and bone distribution are similar to that
seen in humans. Histomorphometric dynamics in the canine model have
been studied extensively (Allen and Burr, 2007, 2008). It also is possible to
place implants and devices that are used in humans into canines without
54
Huja
scaling the size of the device. While porcine models also demonstrate
intracortical and trabecular bone remodeling, continuous growth and
the ability to obtain older animals for experimental studies remains a
challenge.
CURRENT EVIDENCE FROM EXPERIMENTAL STUDIES
ON RODENTS AND CANINES
This chapter provides a brief critical review of select studies that
previously were reported in the literature. While a multitude of animal
models have been used to study orthodontic tooth movement and
specifically expedited tooth movement, it behooves us to understand and
interpret the results carefully. Such caution will allow us to understand
what research questions still have to be answered and what conclusions
can be drawn from the current literature.
One group of researchers from Boston University has advanced
our understanding of the biology of expedited tooth movement sig-
nificantly in response to injury (e.g., corticotomy, piezocision). In one of
the initial papers by Sebaoun and colleagues (2008), they demonstrated
bone changes subsequent to injury using a rodent/rat model. They
produced an indentation with a burr into the cortical bone of the maxilla
as a representation of the decortication injury commonly used in the
“Wilckodontic” procedure. They demonstrated that the injury results
“disappearance” of bone by three weeks after surgery. The bone between
the roots of the first molar was restored by eleven weeks after surgery
and was similar to that seen in the three-week control group (see Fig.
2A-C in the publication by Sebaoun et al., 2008). They concluded that
their histomorphometric data (intravital bone labels and TRAP staining
for osteoclasts) suggests that modeling of the trabecular bone occurs
and that bone turnover after corticotomy does not involve a linear or
Sequential series of events. In other words, remodeling (coupled bone
formation/resorption) in the rat model is not responsible for the bone
response after decortication as it relates to their specific experimental
conditions. They also demonstrated that the bone appositional width
(also known as mineral apposition rate; Parfitt et al., 1987) is increased at
four weeks after surgery (Fig. 4A-D of the publication by Sebaoun et al.,
2008). In this particular study, the authors did not provide an explanation
on how the mineralized tissue returns to its original state. Also, the bone
55
Mechanisms of Expedited Tooth Movement
labels on the periodontal surface seen in their figures do not assist in
understanding how the bone reappears between the roots of the first
molar. Typically, bone resorption by osteoclasts result in the loss of both
the mineral and the organic matrix of bone. Once bone loss occurs (e.g.,
in trabecular bone of the spine during osteoporosis), reversal of bone loss
and new bone formation does not occur, as no matrix exists from which
new bone formation can occur.
In a Second paper by Baloul and Colleagues (2011), the same group
from Boston University studied corticotomy facilitated tooth movement
by micro-computed tomography (microCT) and the quantification of
selective osteoclast and osteoblast gene expression in their rodent
model. They demonstrated in the split-mouth study design that the rate
of tooth movement initially peaks at seven days in the decortication group
as compared to fourteen days in the non-decortification side. In their
microCT data (Figs. 5-6 of the publication by Baloul et al., 2011), they
demonstrated that apparently greater values of BV, BV/TV, BMC and BMD
occur in their corticotomy-only group compared to the tooth movement
only, or tooth movement plus corticotomy group. This data contradicts
the Sebaoun study (2008) where increases in these parameters from
bone injury are not apparent in their histological data. In this latter study,
they also demonstrated that key osteoblastic and osteoclastic genes are
elevated temporally, suggesting increased bone activity. However, due to
the method of collection of the tissue sample for this gene analysis, it
is not possible to analyze on which surface the bone formation or bone
resorption is occurring. As Frost (1983) indicated, RAP does not occur in
isolated cells, but at a tissue level of organization. The field of molecular
biology did not exist at the time of Frost's publication and current studies
should include region-specific tissue analyses.
In a third paper by Dibart and associates (2013), the Boston
group used piezocision to facilitate the orthodontic tooth movement in
rats. Their histological images demonstrated aggressive/extensive bone
loss that extends beyond the initial piezocision site and that the injury
results in changes in both the cortical and trabecular bone. In Figure 3
from their publication (Dibart et al., 2013), they demonstrated reduction
in percent bone from 60% to virtually 0 to 20% in their three groups. The
question remains if such reductions would result in the devastation of the
bone strength and structure in a human. It also is questionable if tooth
56
Huja
movement could occur in bone that has been compromised so severely.
This may be a limitation of the model and may not detract entirely from
other parts of the data. Also, it is unknown whether a matrix for regaining
the bone would exist in the presence of such severe bone loss. In the
study, however, bone recovery occurred primarily between the 40- to 60-
day period.
The dog/canine animal model also offers valuable insights into
understanding of expedited tooth movement. The concept of cortical
bone resistance impeding tooth movement wastested by undermining the
septal bone in a canine model (Renet al., 2007). This work demonstrated
that the cortical bone structure has to be resorbed during tooth
movement and that surgical removal of this local bone will result in more
rapid tooth movement. Doubling in the rate of tooth movement over a
period of six weeks was demonstrated in a subsequent split-mouth study
in a canine model (Mostafa et al., 2009). This study demonstrated that
the injury (corticotomy) has only a transient effect and a short window
of opportunity exists to effect the tooth movement. Major differences
were seen in the first two weeks between the corticotomy and control
groups, and the authors suggested that there was decreased hyalinization
in the corticotomy groups, based on histology. Their histological images
are different from the rodent model, with no apparent rapid declines in
mineral content of bone. This leads to the question of whether what is
seen in the rodents actually would be observed in humans. In a similar
split-mouth study, greater differences were observed in the rate of tooth
movement in the corticotomy group (Kim et al., 2013). In this canine
model study, the rate of tooth movement was larger in the maxilla than
in the mandible. Similar to the studies cited above, there were greater
differences between experimental and control groups in the first two
to three weeks after corticotomy, after which the differences between
groups diminish in these animal models. The transient nature of the effect
reinforces the need for the tooth movement to begin immediately after
the corticotomy. In humans, if the effect is seen primarily for six weeks,
only a small portion of a phase of treatment (e.g., canine retraction)
would be complete; the question then remains if a second invasive
Surgery would be warranted.
Based on the current literature, there are inconsistencies and
vast differences in histology and interpretations of histology between
rodent and canine models. These inconsistencies pose a problem for
57
Mechanisms of Expedited Tooth Movement
orthodontics, as they leave the mechanism(s) of enhanced tooth move-
ment unclear. The rate-limiting step of orthodontic tooth movement is
resorption of bone by osteoclasts. In rodents, however, the bone mineral
has been shown to “disappear” by a method other than osteoclastic re-
sorption, suggesting that transport of the tooth occurs within the compli-
ant bone matrix. In larger animal models, the corticotomies do not seem
to “devastate” the bone (i.e., the BV/TV does not drop from 60 to 20% in
a matter of weeks).
Molar protraction can take approximately 20 to 24 months, even
when using contemporary methods of anchorage. This type of tooth
movement lends itself to investigation of procedures that enhance the
rate of tooth movement. It is reported clearly in the literature that dense
bone is generated as a two-rooted mandibular molar moves mesially
and that this diminishes the rate of tooth movement (Roberts et al.,
1996). In this chapter, the changes produced in the bone by non-invasive
and additional methods of expedited tooth movement have not been
reviewed (e.g., vibration or Acceledent type of device). It is claimed that
these devices increase the baseline rate of bone remodeling and, thereby,
enhance the rate of tooth movement.
In conclusion, evidence and interpretation of mechanisms under-
lying enhanced tooth movement and potential relevance to orthodontic
practice that were described earlier are summarized as:
1. Cortical plates are an impediment to orthodontic
tooth movement. Canine studies demonstrate that
removal of Cortical bone will increase the rate of tooth
movement. However, it also is possible that the tooth
tips initially and the root-uprighting phase still may
take a considerable time. Thus, the overall reduction
in treatment time may be negligible.
2. RAP and associated tissue remodeling. The RAP is
a non-specific response to tissue injury (i.e., it does
not distinguish between piezocision vs. corticotomy).
Developing more precise methods to enhance tooth
movement will be critical.
3. High rates of bone turnover. It is unknown what the
rate of bone turnover needs to be within the cortical
or trabecular bone compartments for enhanced tooth
58
Huja
movement. One would expect the rate of tooth move-
ment to have somewhat linear relationship to the
bone remodeling rate, though this has to be demon-
strated by research.
4. Demineralization/remineralization process. This pro-
cess does not seem to exist in larger animal models
and seems to be limited to rodents if the interpreta-
tions actually are correct.
5. Increase in cortical bone porosity, transient osteopenia,
osteopenia-facilitated rapid tooth movement. These
observations stem from findings in rodents; however,
clear evidence to support these findings does not exist
in larger animals.
6. Dramatic increase in trabecular bone turnover. The
trabecular bone is scant in the mandible compared to
the maxilla. In addition, there is a thicker Cortical shell
in the mandible when compared to the maxilla. Even
though the amount of trabecular bone in the mandible
is lower than the maxilla, the rate of tooth movement
in the mandible is lower than in the maxilla. It is
unclear what role trabecular bone plays in providing
resistance to orthodontic tooth movement.
7. Bone matrix transportation. This is a term that has de-
veloped from rodent findings; however, it is unclear if
this occurs in humans.
ACKNOWLEDGMENT
The assistance of Dr. Ulas Oz and Dr. Cristina Exposto is acknowl-
edged gratefully.
REFERENCES
Allen MR, Burr DB. Mandible matrix necrosis in beagle dogs after 3 years
of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 2008;
66(5):987–994.
Allen MR, Burr DB. Mineralization, microdamage, and matrix: How
bisphosphonates influence material properties of bone. BoneKey
2007;4(2):49-60.
59
Mechanisms of Expedited Tooth Movement
Baloul SS, Gerstenfeld LC, Morgan EF, Carvalho RS, Van Dyke TE, Kantarci
A. Mechanism of action and morphologic changes in the alveolar bone
in response to selective alveolar decortication-facilitated tooth move-
ment. Am J Orthod Dentofacial Orthop 2011;139(4 Suppl):S83-S101.
Bentolila V, Boyce M, Fyhrie DP, Drumb R, Skerry TM, Schaffler MB.
Intracortical remodeling in adult rat long bones after fatigue loading.
Bone 1998;23(3):275-281.
Bogoch E, Gschwend N, Rahn B, Moran E, Perren S. Healing of cancellous
bone osteotomy in rabbits. Part I: Regulation of bone volume and
the regional acceleratory phenomenon in normal bone. J Orthop Res
1993;11(2):285-291.
Burr DB, Martin RB, Schaffler MB, Radin EL. Bone remodeling in response
to in vivo fatigue microdamage. J Biomech 1985;18(3):189-200.
Canalis E. Regulation of bone remodeling. In: Favus MJ, ed. Primer on the
Metabolic Bone Diseases and Disorders of Mineral Metabolism. New
York, NY; Raven Press 1993:33–37.
Deguchi T, Takano-Yamamoto T, Yabuuchi T, Ando R, Roberts WE, Garetto
LP. Histomorphometric evaluation of alveolar bone turnover between
the maxilla and the mandible during experimental tooth movement in
dogs. Am J Orthod Dentofacial Orthop 2008;133(6):889-897.
Dibart S, Yee C, Surmenian J, Sebaoun JD, Baloul S, Goguet-Surmenian E,
Kantarci A. Tissue response during piezocision-assisted tooth movement:
A histological study in rats. Eur J Orthod 2014;36(4):457-464.
Frost HM. Skeletal structural adaptations to mechanical usage (SATMU):
1. Redefining Wolff's Law: The bone modeling problem. Anat Rec
1990;226(4):403-413.
Frost HM. The regional acceleratory phenomenon: A review. Henry Ford
Hosp Med J 1983;31(1):3-9.
Frost HM. Wolff's Law and bone's structural adapatation to mechanical
usage: An overview for clinicians. Angle Orthod 1994;64(3):175-188.
Garetto LP, Tricker ND. Remodeling of bone surrounding the implant
interface. In: Garetto LP, Turner CH, Duncan RL, Burr DB, eds. Bridging
the Gap Between Dental and Orthopaedic Implants. Third Annual
Indiana Conference, Indianapolis, IN:1998;89-100.
60
Huja
Helm NB, Padala S, Beck FM, D'Atri AM, Huja SS. Short-term zoledronic
acid reduces trabecular bone remodeling in dogs. Eur J Oral Sci 2010;
118(5):460–465.
Huja SS, Fernandez SA, Hill KJ, Li Y. Remodeling dynamics in the alveolar
process in skeletally mature dogs. Anat Rec A Discov Mol Cell Evol Biol
2006;288(12):1243-1249.
Huja SS, Fernandez SA, Phillips C, Li Y. Zoledronic acid decreases bone
formation without causing osteocyte death in mice. Arch Oral Biol
2009;54(9):851-856.
Huja SS, Hasan MS, Pidapartir, Turner CH, Garetto LP, Burr DB. Development
of a fluorescent light technique for evaluating microdamage in bone
subjected to fatigue loading. J Biomech 1999a;32(11):1243-1249.
Huja SS, Katona TR, Burr DB, Garetto LP, Roberts WE. Microdamage
adjacent to endosseous implants. Bone 1999b;25(2):217-222.
Huja SS, Rummel AM, Beck FM. Changes in mechanical properties of bone
within the mandibular condyle with age. J Morphol 2008;269(2):138-
143.
Jones HH, Priest JD, Hayes WC, Tichenor CC, Nagel DA. Humeral hypertro-
phy in response to exercise. J Bone Joint Surg Am 1977;59(2):204-208.
Kim YS, Kim SJ, Yoon HJ, Lee PJ, Moon W, Park YG. Effect of piezopuncture
on tooth movement and bone remodeling in dogs. Am J Orthod
Dentofacial Orthop 2013;144(1):23–31.
Martin RB, Burr DB, Sharkey NA. Skeletal Tissue Mechanics. New York, NY:
Springer-Verlag 1998.
Meta IF, Fernandez SA, Gulati P, Huja SS. Alveolar process anabolic activity
in C3H/He] and C57BL/6] inbred mice. J Periodontol 2008;79(7):1255-
1262.
Midgett RJ, Shaye R, Fruge JF Jr. The effect of altered bone metabolism on
orthodontic tooth movement. Am J Orthod 1981;80(3):256-262.
Mostafa YA, Mohamed Salah Fayed M, Mehanni S, ElBokle NN, Heider AM.
Comparison of corticotomy-facilitated vs standard tooth-movement
techniques in dogs with miniscrews as anchor units. Am J Orthod
Dentofacial Orthop 2009;136(4):570–577.
61
Mechanisms of Expedited Tooth Movement
Mueller M, Schilling T, Minne HW, Ziegler R. A systemic acceleratory phe-
nomenon (SAP) accompanies the regional acceleratory phenomenon
(RAP) during healing of a bone defect in the rat. J Bone Miner Res
1991;6(4):401-410.
Parfitt AM. Osteonal and hemi-osteonal remodeling: The spatial and
temporal framework for signal traffic in adult human bone. J Cell
Biochem 1994;55(3):273-286.
Parfitt AM. Targeted and nontargeted bone remodeling: Relationship to
basic multicellular unit origination and progression. Bone 2002;30
(1):5-7.
Parfitt AM. The physiologic and clinical significance of bone histomorpho-
metric data. In: Recker RR, ed. Bone Histomorphometry: Techniques
and Interpretation. Boca Raton, FL: CRC Press, Inc. 1983;143-224.
Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ,
Ott SM, Recker RR. Bone histomorphometry: Standardization of no-
menclature, symbols, and units. Report of the ASBMR Histomorphom-
etry Nomenclature Committee. J Bone Miner Res 1987;2(6):595-610.
Ren A, Lv T, Kang N, Zhao B, Chen Y, Bai D. Rapid orthodontic tooth
movement aided by alveolar surgery in beagles. Am J Orthod
Dentofacial Orthop 2007;131(2):160.e1-e10.
Roberts WE. Bone physiology, metabolism, and biomechanics in orth-
odontic practice. In: Graber TM, Vanarsdall RL Jr, Vig KWL, eds. Or-
thodontics: Current Principles and Techniques. 5th ed. St. Louis, MO:
Mosby 2012;287-343.
Roberts WE, Arbuckle GR, Analoui M. Rate of mesial translation of man-
dibular molars using implant-anchored mechanics. Angle Orthod
1996;66(5):331-338.
Roberts WE, Roberts JA, Huja SS. Bone modeling: Biomechanics, molecular
mechanisms, and clinical perspectives. Semin Orthod 2004;10(2):123-
161.
Robling AG, Castillo AB, Turner CH. Biomechanical and molecular regula-
tion of bone remodeling. Annu Rev Biomed Eng 2006;8:455-498.
Sebaoun JD, Kantarci A, Turner JW, Carvalho RS, Van Dyke TE, Ferguson
DJ. Modeling of trabecular bone and lamina dura following selective
alveolar decortication in rats. J Periodontol 2008;79(9):1679–1688.
62
Huja
Tricker ND, Dixon RB, Garetto LP. Cortical bone turnover and mineral
apposition in dentate bone mandible. In: Garetto LP, Turner CH,
Duncan RL, Burr DB, eds. Bridging the Gap Between Dental and
Orthopaedic Implants. Indianapolis, IN: School of Dentistry, Indiana
University 2002;226-227.
Wilcko MT, Wilcko JM, Bissada NF. An evidence-based analysis of
periodontally accelerated orthodontic and osteogenic techniques: A
synthesis of scientific perspectives. Semin Orthod 2008;14(4):305-
316.
63
64
A CRITICAL APPRAISAL OF SURGICALLY FACILITATED
ORTHODONTICS TO INCREASE THE RATE OF
TOOTH MOVEMENT
Flavio Uribe and Ravindra Nanda
ABSTRACT
Expediting orthodontic treatment is becoming an expectation of patients and a
new goal for orthodontists. Numerous techniques have been described that claim
to reduce orthodontic treatment duration. The approaches are mainly physical
Stimulations and Surgical procedures applied in conjunction with conventional
orthodontic treatment. Until recently, osteotomies and corticotomies have
been the two main surgical procedures reported to expedite the rate of tooth
movement. Techniques using osteotomies show the fastest tooth displacements,
though this procedure is invasive and requires undermining the bone surrounding
the tooth and that along its path of displacement. Corticotomies, which are less
invasive, appear to increase the rate of tooth movement, but to a lesser extent.
This chapter describes the different surgical techniques to accelerate tooth
movement and the current evidence for their efficacy. Preliminary results of a
randomized control trial involving a corticotomy without a flap (piezocision) also
are presented.
KEY WORDS: osteotomy, corticotomy, piezocision, corticision, surgically facilitated
Orthodontics
INTRODUCTION
Reducing the duration of orthodontic treatment has remained
a goal of the orthodontic profession for decades and recently has ex-
perienced a re-emergence. This desirable goal may be due to the need
to minimize undesirable dental sequelae such white spot lesions (Richter
et al., 2011) and root resorption (Segal et al., 2004), which occur with
prolonged treatment times. Another reason for expediting orthodontic
treatment may be related to an apparent change in society with an
emphasis on instant gratification including when seeking to enhance
dentofacial esthetics.
65
Surgically Facilitated Orthodontics
It is unclear from an evidence-based perspective, however, if
patients undergoing or considering undergoing orthodontic treatment
think that orthodontic treatment will be long or if, in fact, they would like
to reduce its duration. This question was addressed by a recent survey
(Uribe et al., 2014), which captured patients' and parents' perceptions on
the duration of orthodontic treatment. A questionnaire was developed
for adolescent patients, their parents and adult patients of middle
to high socio-economic status in two orthodontic offices of a multi-
doctor practice. Figure 1 summarizes the findings of the perception and
expectation of orthodontic treatment duration for the different groups.
The most interesting findings of the survey were that among
all groups, only the adolescents felt that orthodontic treatment was
too long. Adult patients and parents were neutral about this question.
Furthermore, all groups expected orthodontic treatment to last from
18 to 24 months. When asked how long they wished treatment to last,
however, all groups desired shorter treatment times with most preferring
a range between six to 18 months. Incidentally, the adolescent group
chose the shortest treatment times, with desired mean duration times of
less than six and up to twelve months.
In this study, a questionnaire to orthodontists from the U.S. and
Canada was included to compare their perception to those of patients
and parents regarding treatment duration and preference of methods to
reduce treatment time. In this first survey of its kind, responses of over
650 orthodontists were received. Interestingly, when the orthodontists
were polled regarding the duration of treatment, the majority of
orthodontists were satisfied with the amount of time their patients were
in appliances. This was an unexpected finding, as there appears to be
a significant interest in the profession to accelerate orthodontic tooth
movement (OTM). However, more consistent with this perceived notion
for reduced treatment times, the survey results showed that the majority
of orthodontists indeed were interested in considering techniques that
would be able to reduce treatment duration. Furthermore, the majority
of Orthodontists considered that for a 20 to 40% reduction in treatment
time, they would be open to considering alternative techniques or
approaches that potentially could accelerate tooth movement.
66
Uribe and Nanda
Adult Patients
How long do you expect your orthodontic How long would you wish your
treatment to take? orthodontic treatment to last?
2
s
2
5
# 20 # 20
$ º
E 15 E 15
º c
3. 3.
* 10 * 10
º -
*
0. 0.
- 12 12 to 15 18 to 24 -24 < 6 6 to 12 12 to 18 18 to 24 × 24
months months
Parents
How long do you expect your orthodontic How long would you wish your
treatment to take? orthodontic treatment to last?
90 º 70
80 60
70
- 50 -
# 60 :
$ $ 40
5 50 -
3. 3.
£ 40 tº 30 -
- --
o o
* 30 + 20
20
10 10
o o
< 12 12 to 18 18 to 24 > 24 < 6 6 to 12 12 to 18 18 to 24 × 24
months months
Adolescents
How long do you expect your orthodontic How long would you wish your
treatment to take? orthodontic treatment to last?
80 90
70 80
ºn 60 º, 70
E E. 60
# 50 $
- -
o 50
# 40 3.
º º 40
s 3 30
+ +
20 20
0. 0. -
< 12 12 to 18 18 to 24 > 24 < 6 6 to 12 12 to 18 18 to 24 × 24
months months
Figure 1. Perception of adult and adolescent patients and parents of adolescent
patients on the expected and desired duration of orthodontic treatment.
ALTERNATIVES TO REDUCE DURATION
OF ORTHODONTIC TREATMENT
All of the available options to modulate the velocity of OTM include
both biological and mechanical interventions. Physical intervention
in Conjunction with orthodontic forces to alter the underlying biology
is a new area where a plethora of techniques are emerging. Although
biological modulation holds the most promise in enhancing OTM, the

67
Surgically Facilitated Orthodontics
administration of substances locally to enhance tooth movement,
although available and tested in animal models (Hashimoto et al., 2001;
Chen et al., 2011; Li et al., 2013), may be difficult to apply clinically since
their activity on specific sites or cells (e.g., the osteoclast) also may affect
other cells such as odontoclasts which could contribute to unfavorable
effects such as root resorption (King, 2009). Furthermore, distant skeletal
tissues from the area of interest may be affected unfavorably with these
biological molecules. Therefore, when applied in conjunction with
orthodontic forces, mechanical interventions and physical alterations that
evoke biological responses currently may be the only clinical approaches
available to enhance the speed of tooth movement safely.
Figure 2 illustrates a theoretical layout of the types of physical
or mechanical approaches available to enhance the speed of OTM. The
simplest approach to modulate the rate of tooth movement widely studied
in orthodontics has been related to the variation in the characteristics of
the applied forces. Force magnitude and force constancy are two of these
characteristics that easily can be controlled by the clinician. Although
the literature is ambiguous, it recently has been shown in a human
canine retraction model that it is likely that heavier forces measured as
mechanical stresses per root surface area are able to produce greater
tooth displacement for a given time period (Nickel et al., 2014). Caution
should be exercised in pursuing this strategy, however, since high force
magnitudes may contribute to greater root resorption than lighter forces
(Paetyangkul et al., 2011; Nakano et al., 2014). From a force constancy
perspective, it appears that continuous forces, rather than discontinuous
forces, are able to generate faster tooth movement (Ownan-Moll et al.,
1995, van Leeuwen et al., 1999).
More recently, alternative methods such as vibration, ultrasound
and lasers in combination with traditional Orthodontic mechanics, have
shown some promise in accelerating OTM in animal models and clinical
studies. It is uncertain how these physical modulators affect the biology
in order to potentially result in faster tooth movement. More importantly,
there is a paucity of evidence supporting the ability of any of these
methods to enhance the rate of tooth movement in controlled clinical
trials. Due to the non or low invasiveness of these approaches as compared
to surgical interventions, they may be accepted more readily by patients and
orthodontists than osteotomies and corticotomies.
68
Uribe and Nanda
Physical Efforts
A/fernative Force Surgical Precise
Approaches A/feraſions Meſhod; Appliances
Continuous vs.
ºl.....+. Infermitten/ - - Customized
Vibration Forces Corſicoſomies Appliances
Ultrasound Light tº. - -
Heavy Orfeofomies
Electrica/
Currents
Figure 2. Types of physical/mechanical approaches to accelerate the rate of tooth
mCVerment.
Surgical methods to enhance the speed of tooth movement,
more recently referred to as surgically facilitated orthodontic treatment
(SFOT), were postulated by Bryan (1892) and Cunningham (1893;
both referenced in Merrill and Pedersen, 1976) since the inception of
Orthodontics as a clinical specialty over a century ago. These surgical
methods have undergone resurgence at various time periods in the history
of Orthodontics and oral surgery, and following minor modifications to
the original methods described recently have attracted the interest of
Orthodontists.
TWO Surgical approaches to enhance the rate of tooth movement
that encompass all the techniques within SFOT are osteotomies and
COrticotomies. It is important to define these two specific Surgical
approaches as they often are confused. In an osteotomy, a cut is made
into the cortical bone that continues into the medullary bone. The
Segment is free to be mobilized and requires a significant amount of bone
removal. This contrasts with corticotomies where only the cortical bone is
Penetrated to produce the tooth movement acceleration effect.
Osteotomies have shown to produce the fastest OTM rates in
humans. In the dentoalveolar distraction (DAD) technique, a canine
retraction model has been described after extraction of a first premolar in

69
Surgically Facilitated Orthodontics
which the entire canine receives an osteotomy and the labial cortical bone
of the extracted premolar receives an ostectomy (removal of a part of a
bone; Fig. 3; Kisnisci et al., 2002; Iseri et al., 2005). It is clear in this model
that the resistance to OTM is undermined significantly with this extensive
bone removal, and the application of a force by means of a distractor is
able to retract the canine a full premolar distance (approximately 7 mm) in
two weeks. In fact, this rate of tooth movement represents approximately
15- to 20-fold increase over average retraction rate with conventional
orthodontic treatment.
Periodontal distraction is similar to DAD and involves decreasing
the mechanical resistance of the alveolar bone to the retraction of a
canine following the extraction of a first premolar. In this technique,
an ostectomy is performed in the interdental septal bone distal to the
canine, which facilitates the retraction of the canine with a distraction
device (Liou and Huang, 1998). The retraction time of the canine into the
extraction site is approximately three weeks in this technique. Again, the
rate of tooth movement is expedited significantly in comparison to the
typical canine retraction rates of conventional orthodontics.
It is important to highlight that some degree of canine tipping
accompanies dentoalveolar and periodontal distraction. Therefore, it
is critical to differentiate procedure specific treatment times versus
total treatment time when evaluating rates of tooth movement. For
example, if we consider space closure as the endpoint, the retraction of
the canine will occur in a short period of time with these techniques;
however, the tooth still needs to be uprighted. This root correction could
last longer than the space closure observed at the crown. Furthermore,
once the canine is retracted, the anterior teeth also need to be retracted
in order to complete the orthodontic treatment. This second phase of
anterior teeth retraction, together with the finishing phase, may dilute
the effects of the tooth acceleration achieved by surgical procedure on
the total treatment time. In fact, the clinicians that developed the DAD
technique reported that the total treatment time with this approach was
six to nine months less than conventional orthodontic treatment (IŠeri
et al., 2005). Hence, although the canines were retracted in two weeks,
the treatment completion still required canine root distal tip correction,
incisor retraction and finishing procedures, which partially diminished
the advantages of DAD.
70
Uribe and Nanda
Figure 3. Osteotomy around maxillary canine in the dentoal-
veolar distraction technique.
Procedure-specific times may provide a more valid approach to
evaluate objectively the effectiveness of the different techniques that aim
to decrease orthodontic treatment duration. Reduction in total treatment
time involves many other factors that are more difficult to control (e.g.,
patient compliance, side effects of the mechanics, appliance breakage).
In fact, no clinical study has evaluated total treatment time with either
DAD or periodontal distraction.
Based on the lack of evidence supporting a reduction in total
treatment time and considering the invasiveness of the different
procedures, osteotomies in orthodontics usually are reserved for patients
With ankylosis of a maxillary central incisor (Kofod et al., 2005; Alcan,
2006, Dolanmaz et al., 2010). In these patients, a vertical dentoalveloar
distraction is used to bring the under-erupted tooth into the arch (Fig. 4).
Although the tooth is brought into the arch quickly, the purpose of this
Procedure is not to speed up the tooth movement perse, but to achieve
appropriate vertical height of a tooth that does not respond to traditional
Orthodontic forces.

71
Surgically Facilitated Orthodontics
Other common surgical interventions that will accelerate OTM
and are gaining significant popularity are Corticotomies. It is important to
highlight that not all corticotomies are the same. They can vary in length,
size, location, depth, geometry, pattern and device used to perform
the procedure. Furthermore, the frequency in which corticotomies are
performed also can differ. The length of the corticotomy may range from
extensive when the corticotomy involves the full longitudinal axis of the
tooth from the alveolar crest to its apex, to limited involving a vertical
linear groove of approximately 4 mm in length. In terms of size, it has
been described in the speedy orthodontic technique—which is a series
of extensive corticotomies performed approximately two weeks apart
where the first premolars are extracted and the palatal cortex connecting
them is eliminated (Chung et al., 2009)—range from a 0.5 mm width cut
in a typical corticotomy to the removal of the entire cortical bone over the
entire mesiodistal width of a premolar. Also, in the technique known as
modified corticotomy, the surgical insult extends into the medullary bone
instead of just involving the cortex. The location of the corticotomies in
the alveolar bone may involve just the labial bone or a combination of
both the labial and lingual surfaces. Different geometries (e.g., circular or
linear grooves) and different patterns (e.g., multiple letter “x’s” or "o's")
of cuts also have been suggested (Fig. 5). Additionally, while a high-speed
drill with a bur is the most commonly used device for scoring the bone,
other instruments also have been described for this purpose. Recently, a
piezotome has been suggested as a device that can produce the desired
alveolar bone insult in a predictable manner. In fact, a piezotome can be
used with or or without a gingival flap (Vercellotti and Podesta, 2007;
Dibart et al., 2009). Finally, the frequency with which corticotomies
are performed to maintain their sustained effect on the rate of tooth
movement during orthodontic treatment also can vary. It has been shown
in an animal model that a second corticotomy procedure at a different
time point may enhance even further the rate of tooth movement
(Sandijeh et al., 2010). In this regard, procedures such as piezocision that
do not involve a flap lend themselves better to repeated interventions
relative to those where flaps need to be elevated in order to access the
alveolar bone.
72
Uribe and Nanda
Figure 4. Osteotomy around an ankylosed maxillary incisor to facilitate the
Vertical distraction to the correct incisal plane.
Figure 5. Oval groove corticotomies on the labial aspect of the maxillary alveolar
bone.

73
Surgically Facilitated Orthodontics
Within the different techniques, the surgical procedure not only
may vary, but the magnitude of force applied to move the teeth also may
be different. Overall, the force levels used in the surgical procedures can
be divided into conventional orthodontic (light forces), or orthopedic
(500 to 1000 gms) and distraction forces where the magnitude of force
depends on the resistance of the soft and hard tissues opposing the tooth
movement.
Figure 6 summarizes most of the dentoalveolar-surgical insults
that have been described to accelerate the rate of tooth movement. The
combination of the different types of osteotomies/corticotomies with the
different type of forces yields an abundance of techniques with different
names that may be found in the literature and which may cause some
confusion. In order to provide some guidance into the specific differences
among surgical techniques to accelerate OTM, the following summarizes
Some of the names and their definitions as described in the literature.
1. Modified Corticotomy: A corticotomy not limited to
the cortical bone, which penetrates the medullary
bone (Germec et al., 2006).
2. Surgical Facilitated Orthodontic Therapy (SFOT): Ge-
neric name to the application of corticotomies and
osteotomies to accelerate tooth movement (Roblee
et al., 2009).
3. Speedy Orthodontics: A series of extensive corti-
cotomies performed approximately two weeks apart
where the first premolars are extracted and the pala-
tal cortex connecting them is eliminated. The second
procedure involves the elevation of a labial flap and
resection of the labial bone of the extracted premo-
lars in conjunction of the extension of the corticoto-
mies above the apices of the anterior teeth from one
of the extracted premolars to the contralateral pre-
molar (Chung et al., 2009).
4. Selective Alveolar Decortication: Another name for a
corticotomy.
5. Alveocentesis: Another name for micro-osteo-perfo-
rations. In this technique, three small perforations
74
Uribe and Nanda

OSTEOTOMY- OTHER/
CORTICOTOMY-BASED BASED OSTECTOMY
Modified corticotomy
- Selective alveolar
decortication
- PAOO/AOO - Periodontal
distraction
- Corticision - Dentoalveolar
e tº e distraction
Piezocision - Speedy
Alveocentisis/micro- Orthodontics
osteoperforations
A
FLAP-BASED NON-FLAP-BASED
- Modified corticotomy - Corticision
- Selective alveolar decortication - Piezocision
- PAOO/AOO - Alveocentisis/micro-
B osteoperforations
Figure 6. A: Overview of localized dentoalveolar surgical procedures to expedite
orthodontic treatment. B: Flap- and non-flap-based procedures to produce a
corticotomy.
are performed without a flap adjacent to the area
where enhanced rate of tooth movement is desired
(Fig. 7; Teixeira et al., 2010, Alikhani et al., 2013).
6. Periodontally Accelerated Osteogenic Orthodontics/
Accelerated Osteogenic Orthodontics (PAOO/AOO): A
patented technique where a corticotomy is performed
and a bone allograft is placed covering the intervened
alveolar bone (Wilcko et al., 2001).
7. Corticision: A corticotomy without a flap. An incision
with a scalpel is used to access the alveolar bone. It
has been described primarily in animal models (Fig. 8;
Kim et al., 2009). -
8. Piezocision: A corticision performed with a piezotome
(Fig. 9). Bone grafting material, which is placed on
the labial aspect of the alveolar bone, also has been
described with this technique (Dibart et al., 2009).
75
Surgically Facilitated Orthodontics
Figure 7. Micro-osteoperforations mesial and distal to the maxillary canine to
accelerate the closure of residual spaces. (Courtesy of Dr. Derek Sanders).
|
|
Figure 8. Corticision (green) on the mesial palatal aspect of the first
maxillary molar of a rat.
OBJECTIVE EVALUATION OF THE RATE OF TOOTH MOVEMENT
Defined outcome measures are required to evaluate properly if
any specific therapy may be conducive to a significant reduction in the
duration of orthodontic treatment. There are many factors that influence
total treatment time. Among those are variables such as the interval
between appointment visits, patient compliance, treatment therapy
(extraction versus non-extraction), presence of impacted teeth such as









76
Uribe and Nanda
Figure 9. Corticotomy with a piezotome without a flap (piezocision) on
the labial aspect of the interproximal space between the mandibular
Canine and lateral incisor.
maxillary canines and degree of severity of the malocclusion. Therefore,
it could be difficult to compare all the different therapies systematically to
claim any reduction in treatment time in the presence of these variables.
Therefore, an analysis of treatment duration based on specific procedures
is necessary.
Specific stages in orthodontic treatment are the alignment
phase, Space closure phase (in extraction therapies) and finishing phase.
Among these three phases, the first two have been used systematically
to evaluate the rate of tooth movement. The reason for this is that these
two phases have clear specific end points. For the alignment phase, the
proper alignment of the teeth can be measured objectively against time.
For example, a discrepancy index for incisor irregularity such as Little's
Irregularity Index can be used to evaluate the amount of time it takes
to reduce a moderate or severe degree (5 mm and above) discrepancy
to almost perfect alignment degree (1 mm). This method has been used
in numerous studies that have evaluated the efficiency of self-ligating
brackets in the alignment phase.

77
Surgically Facilitated Orthodontics
The space closure phase also can be evaluated adequately
since it has defined outcome points (e.g., the amount of time it takes to
move a tooth to close an extraction space). Traditionally this has been
used in canine retraction models in periodontal distraction and DAD as
mentioned above. Recently, similar models have been used to evaluate
corticotomies (Aboul-Ela et al., 2011) and micro-osteoperforations
(Alikhani et al., 2013). A controlled model to evaluate tooth movement
in humans, based on a canine retraction model, also has been proposed
by Iwasaki and colleagues (2000). In this model the force delivery and
quantification of stress is determined carefully to evaluate rate of tooth
movement objectively.
Animal Models for Surgical Insults
The majority of animal models evaluating localized surgical insults
to increase the rate of tooth movement have concentrated on procedures
that involve corticotomies with or without a flap. Furthermore, the
majority of animal models have used the rat (Texeira et al., 2010; Baloul
et al., 2011; Iglesias-Linares et al., 2012) with dogs used less commonly
(lino et al., 2007; Mostafa et al., 2009; Sandijeh et al., 2010). Force levels
also have varied from 25 to 100 gms in rats and from 200 to 500 gms in
dogs. The majority of models use springs that deliver an anteroposterior
force from the first molar to the incisors where the anterior displacement
of the first molar is evaluated. The duration of the experimental period
typically has ranged from two to six weeks in rats and four to eight weeks
in dogs. In the majority of the experiments, only one corticotomy has
been performed at the time of delivery of the orthodontic appliance
following which the effects of treatment have been measured after a
specific duration. A few experiments have reported on more than one
surgical insult after a time interval of one week or more to evaluate the
influence of a second procedure (Sanjideh et al., 2010; Murphy et al.,
2014).
From the data gathered from the animal research, it can be
concluded that corticotomy-like procedures appear to enhance the rate
of tooth movement temporarily. It appears that the rate is enhanced
approximately two times compared to controls during the first one or
two weeks after the surgical insult. The rate of tooth movement tends to
normalize after this initial acceleration phase. A second corticotomy may
enhance the rate of tooth movement, but to a lesser degree than the
78
Uribe and Nanda
first. Overall, the findings support that the larger the surgical insult, the
greater the rate of tooth movement.
It is important to highlight the limitations of the animal models
(e.g., difference in size, bone characteristics, orthodontic appliances and
types of tooth movement), which makes the direct extrapolation of their
findings to humans fraught with potential errors. Thus, human models
are important to validate the findings observed in the currently used
animal models.
Human Models of Surgical Insults
As mentioned above, osteotomies have been shown to provide
the fastest rates of tooth movement. Approximately 7 mm of movement
over two and three weeks has been demonstrated with DAD and
periodontal distraction, respectively. With corticotomies, similar models
of canine displacement have shown enhanced movement in the first
month, but not to the same extent. In the study by Alikhani and associates
(2013), where micro-osteoperforations without a flap were performed,
the authors reported twice the rate of maxillary canine distal movement
one month after the surgical procedure compared to the contralateral
side where no surgical procedure was performed. In a similar study by
Aboul-Ela and colleagues (2013) that evaluated a longer duration of
distal canine displacement, it was found that there was approximately
double the rate of tooth movement of the canine on the side that had a
corticotomy during the first month, compared to the contralateral side
with conventional Orthodontics. However, this rate of tooth movement
slowly decreased to 1.5 times the contralateral side after the second
month. In fact, after four months, there was no difference between the
corticotomy and control sides.
In general, these clinical results mimic those observed in the
animal models. This includes an initial significant increase in the rate of
tooth movement soon after the surgical insult up to approximately three
to four months where the acceleration appears to return to baseline levels.
Also, the greater degree of injury associated with osteotomy procedures
yields the fastest movement of all procedures. The reason may be related
to the reduction of the mechanical resistance with the surgery instead of
the biological cascade precipitated with the insult of corticotomy. In fact,
the rate-limiting effects of this biological cascade may be responsible for
the observation that less invasive micro-osteoperforations and the more
79
Surgically Facilitated Orthodontics
extensive Corticotomies appear to produce similar effect of acceleration
in the rate of tooth movement at least in the first month after the
procedure.
RANDOMIZED CLINICAL TRIAL (RCT) ON THE ALIGNMENT OF
LOWER INCISORS WITH A PIEZOTOME-CORTICISION PROCEDURE
Over the past five years, we have been conducting a randomized
clinical trial (RCT) at the University of Connecticut on the effects of
corticision with a piezotome procedure on the rate of alignment of the
lower incisors. The study design of this clinical trial is a parallel arm study
where one group receives piezocision with conventional orthodontics,
while the other group only receives conventional orthodontics. The
primary outcome to be evaluated is the rate of alignment of the
mandibular anterior segment in both groups. Prospective subjects are
excluded if they have any medical condition or are taking a medication
that can affect the rate of tooth movement. Subjects are assigned
randomly to a group where piezocision is performed in conjunction with
orthodontic treatment or to a control group in which only conventional
orthodontic treatment is performed.
The piezosicion procedure is performed by initially using a scalpel
to produce a soft tissue vertical incision of 4 mm in length, 4 mm apical to
the papilla. One incision each is placed between the canines and lateral
incisors, and between the central incisors, for a total of three incisions.
Once the labial alveolar bone is accessed, the tissue is dissected slightly
laterally to confirm the location of the roots of the adjacent teeth. Once
it has been confirmed that the interdental bone is visualized fully, a 4 mm
in length and 1 mm in depth incision into the cortical bone is performed
with a piezotome (Fig. 10). The incison sites are left unsutured and the
wires are placed on the same visit.
For both groups, the teeth are bonded with self-ligating brackets
and a wire sequence of 0.014" Cu NiTi for two visits and 0.014" x 0.025"
Cu Niſi thereafter are placed. The patients are assessed every four to
five weeks until full alignment is observed clinically. The reduction of
Irregularity Index is evaluated by two calibrated blinded examiners.
The primary outcome measure is the amount of time to reduce the
Irregularity Index to an alignment level where there is no deflection on
the 0.014" x 0.025” Cu NiTi wire and where the brackets cannot be re-
80
Uribe and Nanda
Figure 10. Piezocision between the canines and lateral incisors and between the
Central incisors to accelerate the alignment of the lower anterior teeth.
placed to obtain further alignment. This equates with approximately 1 to 2
mm in the Irregularity Index for all patients that have completed the trial.
The decision to define this as the endpoint was determined by a single
blinded examiner. A blinded examiner ensures that the determination of
the endpoint is applied systematically to both groups.
So far in this study, nine patients have been assigned randomly
to the piezocision group and eight to the control group. The amount of
Crowding for has averaged approximately 7 mm for both groups with a
range of 6 to 10 mm. This is considered severe crowding by comparison
to Similar studies.
The preliminary result of this study shows that both groups
achieve the endpoint in approximately a four-month period. There is an
18-day average difference in achieving the stated alignment between the
two groups, with the piezotome group achieving the endpoint slightly
faster at about 108 days of treatment. When the rate of tooth movement
is analyzed, a difference in the rate of tooth movement is observed
between both groups during the first month, which is consistent with the
Other animal and clinical studies on corticotomies.

81
Surgically Facilitated Orthodontics
Based on these preliminary results, this study suggests that the
cost benefit of a piezotome procedure to expedite the alignment of the
mandibular anterior teeth may not be cost effective. It is important to
stress that these are preliminary results with approximately 60% of the
intended sample size enrolled in the study.
CONCLUSIONS
Surgical insults to the alveolar bone to enhance the rate of tooth
movement have become a topic of significant interest for orthodontists
and surgeons. Different techniques have been developed in the last years
where the degree of the surgical insult and the magnitude of forces used
vary. It appears that extensive dentoalveolar surgery that undermines the
bone in the path of tooth movement, combined with heavy forces may
result in the most significant enhancement in the rate of tooth move-
ment. Lesser surgical insult (e.g., corticotomies) seem to enhance the rate
of tooth movement temporarily, with the effect lasting for approximately
three to four months in humans. Within the first month, the corticoto-
mies usually result in twice the rate of tooth movement relative to tra-
ditional orthodontics alone, which then rapidly reduces by about 50% of
this early increase the following month; the enhancements then disap-
pear after four months. These findings in humans are similar to those
shown in animal models following surgical insults. Finally, the preliminary
results of an RCT currently being conducted show a limited effect size of
a corticision with a piezotome in enhancing the rate of alignment of the
mandibular incisors.
ACKNOWLEDGEMENT
We would like to thank the following residents, alumni and col-
laborators through the years of research in this field of SFOT in the Divi-
sion of Orthodontics at the University of Connecticut: Dr. Zachary Librizzi,
Dr. Rana Mehr, Dr. Christopher Murphy, Dr. Zana Kalazjic, Dr. Sunil Wad-
hwa, Dr. Hamed Vaziri, Dr. Preeti Chandhoke, Dr. Leyla Davoody, Dr. Khalid
Almas and Dr. Takanori Sobue. .
82
Uribe and Nanda
REFERENCES
Aboul-Ela SM, El-Beialy AR, El-Sayed KM, Selim EM, El-Mangoury NH,
Mostafa YA. Miniscrew implant-supported maxillary canine retraction
with and without corticotomy-facilitated orthodontics. Am J Orthod
Dentofacial Orthop 2011;139(2):252-259.
Alcan T. A miniaturetooth-borne distractor for the alignment of ankylosed
teeth. Angle Orthod 2006;76(1):77-83.
Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B,
Corpodian C, Barrera LM, Alansari S, Khoo E, Teixeira C. Effect of
micro-osteoperforations on the rate of tooth movement. Am J Orthod
Dentofacial Orthop 2013;144(5):639-648.
Baloul SS, Gerstenfeld LC, Morgan EF, Carvalho RS, Van Dyke TE, Kantarci
A. Mechanism of action and morphologic changes in the alveolar
bone in response to selective alveolar decortication-facilitated tooth
movement. Am J Orthod Dentofacial Orthop 2011;139(4):S83-S101.
Chen RY, Fu MM, Chih YK, Gau CH, Chiang CY, Nieh S, Hsieh YD, Fu E. Effect
of cyclosporine-A on orthodontic tooth movement in rats. Orthod
Craniofac Res 2011;14(4):234-242.
Chung KR, Kim SH, Lee BS. Speedy surgical-orthodontic treatment with
temporary anchorage devices as an alternative to orthognathic
surgery. Am J Orthod Dentofacial Orthop 2009;135(6):787-798.
Dibart S, Sebaoun JD, Surmenian J. Piezocision: A minimally invasive,
periodontally accelerated orthodontic tooth movement procedure.
Compend Contin Educ Dent 2009;30(6):342–344, 346, 348-350. -
Dolanmaz D, Karaman AI, Pampu AA, Topkara A. Orthodontic treatment of
an ankylosed maxillary central incisor through osteogenic distraction.
Angle Orthod 2010;80(2):391-395.
Germec D, Giray B, Kocadereli I, Enacar A. Lower incisor retraction with a
modified corticotomy. Angle Orthod 2006;76(5):882–890.
Hashimoto F, Kobayashi Y, Mataki S, Kobayashi K, Kato Y, Sakai H.
Administration of osteocalcin accelerates orthodontictooth movement
induced by a closed coil spring in rats. Eur J Orthod 2001;23(5):535-545.
83
Surgically Facilitated Orthodontics
Iglesias-Linares A, Yañez-Vico RM, Moreno-Fernandez AM, Mendoza-
Mendoza A, Solano-Reina E. Corticotomy-assisted orthodontic en-
hancement by bone morphogenetic protein-2 administration. J Oral
Maxillofac Surg 2012;70(2):e124-e132.
lino S, Sakoda S, Ito G, Nishimori T, Ikeda T, Miyawaki S. Acceleration of
orthodontic tooth movement by alveolar corticotomy in the dog. Am J
Orthod Dentofacial Orthop 2007;131(4):448.e1-e8.
|Seri H, Kisnisci R, Bzizi N, Tüz H. Rapid canine retraction and orthodontic
treatment with dentoalveolar distraction osteogenesis. Am J Orthod
Dentofacial Orthop 2005;127(5):533–541.
Iwasaki LR, Haack JE, Nickel JC, Morton J. Human tooth movement
in response to continuous stress of low magnitude. Am J Orthod
Dentofacial Orthop 2000;117(2):175-183.
Kim SJ, Park YG, Kang SG. Effects of corticision on paradental remodeling
in orthodontic tooth movement. Angle Orthod 2009;79(2):284-291.
King G. Biomedicine in orthodontics: From tooth movement to facial
growth. Orthod Craniofac Res 2009;12(2):53-58.
Kišnisci RS, Iseri H, Tüz HH, Altug AT. Dentoalveolar distraction osteo-
genesis for rapid orthodontic canine retraction. J Oral Maxillofac Surg
2002;60(4):389-394.
Kofod T, Wurtz V, Melsen B. Treatment of an ankylosed central incisor by
single tooth dento-osseous osteotomy and a simple distraction device.
Am J Orthod Dentofacial Orthop 2005;127(1):72-80.
Li F, Li G, Hu H, Liu R, Chen J, Zou S. Effect of parathyroid hormone on
experimental tooth movement in rats. Am J Orthod Dentofacial Orthop
2013;144(4):523-532.
Liou EJ, Huang C.S. Rapid canine retraction through distraction of the
periodontal ligament. Am J Orthod Dentofacial Orthop 1998;114(4):
372-382.
Merrill RG, Pedersen GW. Interdental osteotomy for immediate
repositioning of dental-osseous elements. J Oral Surg 1976;34(2):118-
125.
Mostafa YA, Mohamed Salah Fayed M, Mehanni S, ElBokle NN, Heider AM.
Comparison of corticotomy-facilitated vs standard tooth-movement
techniques in dogs with miniscrews as anchor units. Am J Orthod
Dentofacial Orthop 2009;136(4):570–577.
84
Uribe and Nanda
Murphy CA, Chandhoke T, Kalajzic Z, Flynn R, Utreja A, Wadhwa S, Nanda
R, Uribe F. Effect of corticision and different force magnitudes on
Orthodontic tooth movement in a rat model. Am J Orthod Dentofacial
Orthop 2014;146(1):55-66.
Nakano T, Hotokezaka H, Hashimoto M, Sirisoontorn I, Arita K, Kurohama
T, Darendeliler MA, Yoshida N. Effects of different types of tooth
movement and force magnitudes on the amount of tooth movement
and root resorption in rats. Angle Orthod 2014;86(6):1079–1085.
Nickel JC, Liu H, Marx DB, Iwasaki LR. Effects of mechanical stress and
growth on the velocity of tooth movement. Am J Orthod Dentofacial
Orthop 2014;145(4 Suppl):S74-S81.
Owman-Moll P, Kurol J, Lundgren D. Continuous versus interrupted
continuous orthodontic force related to early tooth movement and
root resorption. Angle Orthod 1995;65(6):395-401.
Paetyangkul A., Türk T, Elekdag-Türk S, Jones AS, Petocz P. Cheng LL, Dar-
endeliler MA. Physical properties of root cementum: Part 16. Compari-
Sons of root resorption and resorption craters after the application of
light and heavy continuous and controlled orthodontic forces for 4,
8, and 12 weeks. Am J Orthod Dentofacial Orthop 2011;139(3):e279-
e284.
Richter AE, Arruda AO, Peters MC, Sohn W. Incidence of caries lesions
among patients treated with comprehensive orthodontics. Am J
Orthod Dentofacial Orthop 2011;139(5):657-664.
Roblee RD, Bolding SL, Landers JM. Surgically facilitated orthodontic -
therapy: A new tool for optimal interdisciplinary results. Compend
Contin Educ Dent 2009;30(5):264-275.
Sanjideh PA, Rossouw PE, Campbell PM, Opperman LA, Buschang PH.
Tooth movements in foxhounds after one or two alveolar corticotomies.
Eur J Orthod 2010;32(1):106-113.
Segal GR, Schiffman PH, Tuncay OC. Meta analysis of the treatment-re-
lated factors of external apical root resorption. Orthod Craniofac Res
2004;7(2):71-78.
Teixeira CC, Khoo E, Tran J, Chartres I, Liu Y, Thant LM, Khabensky I, Gart
LP, Cisneros G, Alikhani M. Cytokine expression and accelerated tooth
movement. J Dent Res 2010;89(10):1135-1141.
85
Surgically Facilitated Orthodontics
Uribe F, Padala S, Allareddy V, Nanda R. Patients', parents', and orthodon-
tists' perceptions of the need for and costs of additional procedures to
reduce treatment time. Am J Orthod Dentofacial Orthop 2014;145(4
Supply:S65-S73.
van Leeuwen EJ, Maltha JC, Kuijpers-Jagtman AM. Tooth movement with
light continuous and discontinuous forces in beagle dogs. Eur J Oral Sci
1999;107(6):468-474.
Vercellotti T, Podesta A. Orthodontic microsurgery: A new surgically
guided technique for dental movement. Int J Periodontics Restorative
Dent 2007;27(4):325-331.
Wilcko WM, Wilcko T, Bouquot JE, Ferguson DJ. Rapid orthodontics with
alveolar reshaping: Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001:21(1):9-19.
86
ACCELERATED TOOTH MOVEMENT
Mani Alikhani, Daniel Rosen, Sarah Alansari, Chinapa Sangsuwon,
Mona Alikhani and Cristina C. Teixeira
ABSTRACT
The primary goal of contemporary orthodontic treatment is to decrease the
duration of orthodontic treatment time by maximizing the biological response.
There is a general consensus that the rate of tooth movement is controlled by
the rate of bone resorption in the direction of tooth movement, which in turn is
determined by the rate of osteoclast differentiation and activation. Our research
demonstrates that the rate of osteoclast formation is controlled by the activity
of local inflammatory markers (cytokines). In response to orthodontic forces,
there is a transient up-regulation of inflammatory markers that play a key role
in recruitment of osteoclast precursors and their differentiation into active
osteoclasts. Therefore, it is logical to assume that one way to accelerate the
rate of tooth movement is to increase the expression of inflammatory markers
and, therefore, the rate of osteoclastogenesis. In this paper, we report a new
approach to accelerating orthodontic tooth movement, present evidence from
animal and human studies, and discuss biological principles supporting our
results.
KEY WORDS: orthodontics, tooth movement, cytokines, osteoperforations, trans-
lational research
INTRODUCTION
From the Lab to the Clinic
Five years ago, the Consortium for Translational Orthodontic Re-
Search (CTOR; www.orthodonticscientist.org) was created as a nucleus
for the integration of basic science, clinical science and industrial re-
Sources in the field of orthodontics. One of its objectives is to promote
the translation of research findings and biological principles into clinical
applications contributing to the development of more efficient and safer
orthodontic therapies. CTOR has developed and created a network of
87
Accelerated Tooth Movement
orthodontists and scientists around the world with a common goal of
addressing many questions in orthodontics and craniofacial orthopedics.
The focus of these collaborations is to establish a road map to elevate or-
thodontics from an art into a science. CTOR also offers a one- or two-year
intensive, “hands on" research training for healthcare professionals with
an interest in translational research in craniofacial biology. The work pre-
sented here on accelerated tooth movement is a successful example of
this translational effort.
Biology of Tooth Movement
One of the main challenges in orthodontics today is decreasing
treatment time without compromising treatment outcome. To address
this challenge, we need to understand the three variables that can
control the duration of treatment. First, there are practitioner-
dependent factors, such as proper diagnosis and treatment planning,
mechanotherapy, selection of appliances and delivery of treatment in
a timely fashion. Second, we have patient-dependent factors, such as
maintaining appointments, good oral hygiene, integrity of the appliances
and following the practitioner's instructions. The third factor is the
individual’s biology, which is beyond the control of the practitioner
and patient. Assuming the first two factors have been optimized, the
rate of tooth movement will be determined by the body's response to
orthodontic forces. In this regard, understanding the biology of tooth
movement is essential.
In response to the application of orthodontic forces, the peri-
odontal ligament (PDL) will exhibit areas of compression and tension.
Displacement of the tooth due to compression of the PDL causes
immediate constriction of blood vessels and damage to the periodontal
tissues, which results in an aseptic, acute inflammatory response with the
early release of chemokines and several other members of the cytokine
family. Many of these cytokines have pro-inflammatory roles that help to
amplify or maintain the inflammatory response and activation of bone
resorption machinery. In contrast, some proteins have anti-inflammatory
roles, thereby preventing unrestrained progress of the inflammatory
response. Cytokines are produced primarily by inflammatory cells and
secondarily by non-inflammatory cells such as osteoblasts, fibroblasts
and endothelial cells. Many cytokines and chemokines play a significant
role in osteoclastogenesis, recruiting osteoclast precursors from the
88
Alikhani et al.
microvasculature into the extravascular space of the periodontal ligament
and stimulating the differentiation and activation of osteoclasts. These
multinucleated giant cells are responsible for resorption of alveolar
bone, thus allowing specific tooth movements in response to orthodontic
forces.
The importance of cytokines in controlling the rate of tooth
movement can be appreciated through the dramatic results obtained
from studies that block their effects. For example, injections of
interleukin-1 receptor antagonist or tumor necrosis factor alpha receptor
antagonist (TNF-o-RI) results in a 50% reduction in the rate of tooth
movement (Iwasaki et al., 2001; Kesavaluet al., 2002; Jager et al., 2005;
Andrade et al., 2007). Similarly, tooth movement in TNF type II receptor-
deficient mice is reduced compared to wild-type mice (Yoshimatsu et al.,
2006). Animals that are deficient in chemokine receptor 2 (a receptor for
chemokine ligand 2) or chemokine ligand 3 show a significant reduction
in orthodontic tooth movement that may be due in part to a reduced
number of osteoclasts (DeLaurier et al., 2002). Likewise, it is well known
that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the rate
of tooth movement by inhibiting prostaglandin synthesis (Chumbley
and Tuncay, 1986; Knop et al., 2012). Inhibition of other derivatives of
arachidonic acid, such as leukotrienes, also significantly decreases the
rate of tooth movement (Mohammed et al., 1989).
Accelerated Tooth Movement
In general, there are two main methods of increasing the rate of
tooth movement. One approach involves the application of physical and
chemical stimulants to activate pathways that cause an increase in bone
remodeling. Interestingly, these pathways are not the natural pathways
the body utilizes during orthodontic tooth movement; examples are
discussed in the following paragraphs. The second approach involves
intensifying the same pathways that are activated naturally in response
to orthodontic forces.
For physical stimulation of bone remodeling pathways, the use
of light (Tafur and Mills, 2008; Huang et al., 2009), heat (Tweedle, 1965),
electrical currents (Davidovitch et al., 1980, 1984), laser (Kawasaki and
Shimizu, 2000; Cruz et al., 2004; Bjordal et al., 2003, 2008; Bjordal and
Baxter, 2006; Limpanichkul et al., 2006; Tafur and Mills, 2008; Youssef
et al., 2008; Doshi-Mehta and Bhad-Patil, 2012) and vibration (Oxlund et
89
Accelerated Tooth Movement
al., 2003; Nishimura et al., 2008) have been suggested. Unfortunately,
the application of these physical stimuli suffers from a lack of evidence,
poorly studied mechanisms or impracticality. In addition, the increase
in the rate of tooth movement is not significant enough to justify the
application. It is important to note that many of these approaches are in
early stages of development. Thus, these adjunct therapies to accelerate
tooth movement show great promise for future research and clinical
application.
For chemical stimulation of bone remodeling pathways, injections
of parathyroid hormone (Potts and Gardella, 2007), vitamin D, (1,25
dihydroxycholecalciferol; Collins and Sinclair, 1988; Suda et al., 2003),
corticosteroids (Ashcraft et al., 1992; Ong et al., 2000; Angeli et al., 2002;
Kalia et al., 2004), thyroxin (Verna et al., 2000), osteocalcin (Hashimoto
et al., 2001) and relaxin (Madan et al., 2007) have been suggested.
The application of chemicals to accelerate tooth movement has many
drawbacks including root resorption. First, all chemical factors have
systemic effects that raise questions about their safety during clinical
application. Second, the majority of the factors have a short half-life;
therefore, multiple applications of the chemical are required, which is not
practical. In addition, administration of a chemical factor in a manner that
allows an even distribution along the alveolar bone surface is a challenge.
Uneven distribution can change the pattern of resorption and, therefore,
the biomechanics of tooth movement.
Another approach to accelerate the rate of tooth movement
is to intensify the same biological response activated naturally during
application of orthodontic forces. In this regard, if expression of
inflammatory makers plays a critical role in controlling the rate of tooth
movement, it is logical to assume that increasing the activity of these
factors should accelerate tooth movement significantly. Previous studies
have attempted to increase local inflammation during orthodontic tooth
movement by the injection of prostaglandins (Yamasaki, 1984; Lee, 1990;
Leiker et al., 1995; Kale et al., 2004), thromboxanes and prostacyclin
(Gurton et al., 2004) or by systemic application of misoprostol, a
prostaglandin E1 analog (Sekhavat et al., 2002; Seifi et al., 2003) with
mixed results. These methods produced a biological response, but
they possess similar limitations as the injection of the chemical agents
discussed above. For example, injection of prostaglandins requires
multiple applications due to their very short half-life and has undesirable
90
Alikhani et al.
side effects. It has been shown that local injection of prostaglandins can
cause hyperalgesia due to release of histamine, bradykinin, serotonin,
acetylcholine and substance P from nerve endings (Knop et al., 2012).
In addition, because orthodontic tooth movement is a multi-factorial
phenomenon with many up- and down-regulated factors, the application
of one factor to achieve such a complex biological response may be an
oversimplification.
Given the drawbacks and limitations of physical and chemical
Stimulants to increase the rate of Orthodontic tooth movement, a better
approach would be to increase all the required inflammatory markers to
intensify osteoclast activity and bone resorption, thereby increasing the
rate of tooth movement. However, the best approach to producing higher
levels of inflammatory markers is not clear.
Simpler and Safer Approach
Here we suggest a simple and safe approach to stimulate the
body to respond to orthodontic forces at a higher level. This approach
is based on a natural response by the body when it encounters any
physical trauma. Specifically, we hypothesize that introducing controlled
micro-trauma without affecting the integrity and architecture of hard
and soft tissue will stimulate the inflammatory defense mechanism in
the body, which then synergizes with the effects of orthodontic forces to
accelerate the bone remodeling response. Our group first examined this
hypothesis using an animal model of tooth movement before completing
the human clinical trials. Since the objective of this translational research
was establishing a therapeutic modality, the practicality and versatility of
the technique was the focus of these studies. Results of this translational
effort are presented here.
MATERIALS AND METHODS
Animal Study
Thirty-six adult male Sprague-Dawley rats were divided into
three groups. In the experimental group (MOP), animals received a
Spring connecting the first maxillary molar to the incisors to apply a
force to move the first maxillary molar mesially, and three shallow
micro-osteoperforations (MOP) in the cortical bone 5 mm mesial to
the first maxillary molar (Fig. 1A). In the sham group (O), animals
91
Accelerated Tooth Movement
received the exact same force without the MOP. In the control group
(C), animals received passive Springs without any force application. All
animals were anesthetized and Sentalloy closing coil springs (Dentsply
GAC International, Bohemia, NY) exerting a force of 50 CN were placed
between the first maxillary molar and incisors as described by Teixeira
and colleagues (2010). For micro-computed tomography (mCT) analysis,
hemimaxillae were scanned using Scanco Micro CT to evaluate changes
in bone density. For histological analysis and immunohistochemistry
studies, the hemimaxillae were collected, fixed in 10% phosphate buffered
formalin, decalcified and embedded in paraffin blocks that were sectioned
at 5-pum thickness. Hematoxylin and eosin staining was used to evaluate
cell and tissue morphology and areas of bone resorption. Tartrate-
resistant acid phosphatase (TRAP) immunostaining was used to locate
and quantify osteoclast numbers and activity. For fluorescent microscopy,
hemimaxillae were collected and embedded in polymethyl methacrylate.
Blocks were sectioned with 7-pum thickness and viewed under fluorescent
microscopy to evaluate bone formation and mineral deposition. Cytokine
gene expression was evaluated by reverse transcription polymerase
chain reaction analysis (RT-PCR). The hemimaxillae were collected and
immediately frozen in liquid nitrogen for mRNA extraction and analysis. All
methods are described in detail in Teixeira and associates' study (2010).
Human Clinical Trial
A randomized, single-center, single-blinded study was approved
by the Institutional Review Board of New York University. Participants
were recruited from the patient pool that sought comprehensive
orthodontic treatment at the Department of Orthodontics at New York
University College of Dentistry. Twenty patients randomly were divided
into control and experimental groups. Patients' ages ranged from 19.5
to 33.1, with a mean age of 24.7 years for the control group and 26.8 for
the experimental group. The control group consisted of three men and
— Figure 1. MOPs accelerate tooth movement in rats. A: Experimental model.
Rat hemimaxilla showing the location of three MOPS placed 5 mm mesial to the
first molar. B: Comparison of the magnitude of tooth movement after 28 days of
orthodontic force application (C = control; O = orthodontic force only; MOP =
92
Alikhani et al.
Experimental Model
14 r
-k D O group +:
12 - MOP group
10 sk
2
468
C LT a IL 1a |L1b |L 3 |L 6 IL 18
:
:
D
Orthodontic force + MOP). MOPs show greater magnitude of movement. C:
Reverse transcription polymerase chain reaction analysis of cytokine gene
expression. Data is presented as fold increase in cytokine expression in the O
and MOP groups in comparison to C group. Data shown is mean + SEM of three
experiments. D. Histological sections stained with hematoxylin and eosin (top
panels) show increase of periodontal space (p) thickness around the mesiopalatal
root (r) of the first molar and increase in bone (b) resorption both in the O and
MOP groups. Immunohistochemical staining (bottom panels) shows an increase in
Osteoclast activity represented by the increased number of tartrate-resistant acid
phosphatase-positive osteoclasts (arrowhead) in both the O and MOP groups.




93
Accelerated Tooth Movement
seven women whereas five men and five women participated in the
experimental group. All participants had similar malocclusions; for
inclusion criteria, refer to Alikhani and coworkers (2012). Both groups
received similar treatment until the initiation of canine retraction. At
that time, the experimental group received three MOP between the
canine and the second premolar on one side only, while the contralateral
side served as additional control (CL; Fig. 2A). The control group (C)
did not receive MOP on either side. Clinical examination after 24
hours of placing the MOP in the experimental group showed no signs
or Symptoms of trauma. Canine retraction was accomplished using a
calibrated 100-g cM nickel titanium (NiTi) closing spring that connected
the canine via a custom-made power arm extending from the vertical
slot of the canine bracket to the level of the center of resistance, to
a temporary anchorage device (TAD) that was placed between the
second premolar and the first molar. Evaluation of the rate of canine
retraction was achieved through dental cast analysis from impressions
taken immediately before the initiation of canine retraction and 28 days
after the retraction. The distance between the canine and the lateral
incisors was measured at three points: incisal, middle and cervical thirds
of the crown using a digital caliper with an accuracy of 0.01 mm. The
inflammatory response was evaluated by studying the cytokine level
in the gingival crevicular fluid (GCF). Samples were collected from the
distobuccal cervices of the canine before treatment, immediately
before canine retraction and at every subsequent visit. Patient pain and
discomfort were assessed using a numerical scale. Patients were asked
to choose a number from 0 to 10, 0 meaning “no pain” and 10 meaning
“worst possible pain”—on the day of appliance placement, the day of
— Figure 2. MOPs accelerate canine retraction in a human clinical study. A:
Diagram showing the orthodontic setup during canine retraction. A power
arm extending from the vertical slot of the canine bracket to the level of the
center of resistance (CR = green circle) is connected to a TAD (blue circle),
placed between the second premolar and the first molar at the level of the
CR of the canine by a NiTi coil that exerts a continuous force of 50 cM. Three
MOPs (red circles) were placed between the canine and the second premolar
prior to retraction. B: After 28 days of force application, the canine retraction
is significantly greater in the MOP group than in the O group (orthodontic
force alone). C. Canine retraction in MOP group increased by 2.3-fold after
94
Alikhani et d|.
Experimental Model
3 -
5 *
E 2.5
C.
U
9 2 .
$
ºf 15.
º
º
º
§ 1 -
-
ro
--
O 0.5
º
P -
C Control CL MOP
s
E as sk TNF 1 IL 1
S. " O. E. 0.9 B
3 * D Control Sº as D. Control
> 3.5 - MOP 3. 0.7
ºt- > *
£ .. -k § 0.6
Q- -. F 0.5
< - **
g < 0.4 - .
E 1.5 * 03
§ 1. # 0.2
O 0.5 $ 0.1 º
0. Q_0 d |*||
D Before Day 1 Day 7 Day 28 Before Day Day 7 Day 28
28 days of retraction in comparison to the C group and the contralateral side of
the experimental group. D: Expression of inflammatory marker in the gingival
Crevicular fluid (GCF)—as measured by enzyme-linked immunosorbent-based
assay before retraction and 24 hours, 7 days and 28 days after force application–
Shows Significantly higher levels in the MOP group than in the C group. Data is
Presented as pg/ul. * = Significantly higher than control (p<0.05).







95
Accelerated Tooth Movement
canine retraction, and 24 hours, 7 days and 28 days after retraction. For
method details, refer to Alikhani and colleagues (2013).
RESULTS
In the rat study, application of MOP significantly increased
tooth movement by two-fold (p < 0.05) in the MOP group (0.62 mm) in
comparison to the O group (Fig. 1B). At the molecular level, the expression
of cytokines/cytokine receptors increased significantly 24 hours after
force application in the MOP and O groups in comparison to the C group.
In addition, 21 cytokines were significantly higher (p < 0.05) in the MOP
group than the O group (refer to Teixeira et al., 2010 for a complete list
of cytokines/cytokine receptors). Figure 1C shows the results for eight of
these important markers. Histological analysis revealed increased alveolar
bone resorption in both the MOP and O groups when compared to the
C group. However, the MOP group showed a significantly greater rate of
alveolar bone resorption than noted in the O group and a subsequent
increase in PDL thickness (Fig. 1D). Immunohistochemical staining of
TRAP-positive osteoclasts (Fig. 1D) revealed a three-fold increase in the
number of osteoclasts in the MOP group in comparison with the O group
(22 Osteoclasts compared to eight osteoclasts per mmº).
Using a canine retraction model in humans, we were able to
mirror the results of our animal study. In our clinical trial, 28 days after
initiation of canine retraction, we observed a significant increase in the
space between the canine and lateral incisor in the MOP group when
compared to both C group and CL side, where movement was diminutive
(Fig. 2B). Dental cast measurements showed a 2.3-fold increase in canine
retraction in comparison to both C group and CL side (p < 0.05; Fig. 2C).
Protein analysis of the GCF showed an increase in cytokine expression
after 24 hours of force application when compared to the pre-retraction
levels for the same patients. However, in the MOP group, cytokines were
significantly higher than in the C group (p < 0.05; Fig. 2D). After 28 days,
all cytokine levels were decreased back to pre-retraction levels with the
exception of interleukin-1-beta (IL1-3; for a complete list of cytokines and
changes, refer to Alikhani et al., 2013). In the experimental groups, IL1-B
levels still were significantly higher (5.0- and 3.6-fold, respectively) than
their levels before retraction.
96
Alikhani et al.
DISCUSSION
Our animal studies have shown that introducing small holes in
alveolar bone (MOP) during orthodontic tooth movement can stimulate
the expression of inflammatory markers significantly. This was accompa-
nied by a significant increase in the number of osteoclasts and bone re-
Sorption (Fig. 3) as anticipated (Teixeira et al., 2010). We observed that
the increase in bone remodeling was not limited to the area of the mov-
ing tooth, but extended to the tissues surrounding the adjacent teeth
(data not shown). The increase in the number of osteoclasts and, there-
fore, increase in bone resorption and osteoporosity in response to bone
perforations may explain the increase in the rate and magnitude of tooth
movement observed in this study, thereby suggesting that the perfora-
tions do not need to be close to the tooth to be moved to accelerate the
rate of tooth movement.
The results of our human clinical trial were similar to the rat study
(2.3-fold increase in humans, 2-fold increase in rats). Canine retraction
in the presence of MOP resulted in twice as much distalization as the
one observed with the Orthodontic forces alone. This increase in tooth
movement was accompanied by an increase in the level of inflammatory
markers. In addition, we recorded pain and discomfort levels using a
numerical rating scale from 1 to 10, which showed patients that received
canine retraction in presence or absence of microperforations reported
an increase in discomfort levels when compared to pre-retraction levels
(data not shown). However, no significant difference was noted between
the MOP and the C group (orthodontic force alone group). Moreover, after
the placement of the MOP, patients reported only moderate discomfort
that was bearable and did not require any medication (data not shown).
When compared to other surgical approaches to accelerate
tooth movement, it is obvious that MOP offers a number of advantages.
This procedure is minimally invasive and flapless, allowing treatment to
take place in the orthodontic chair. Corticotomies, on the other hand,
require the reflection of a full-thickness flap to expose the buccal and
lingual alveolar bone, followed by interdental cuts through the cortical
bone. A modification of this technique recently has been introduced
where, after selective decortication in the form of lines and points, a
resorbable bone graft is placed over the surgical site. The effect of this
97
Accelerated Tooth Movement
ºn-º-º-º-
-º-º-º-º:
Tooth Periodontalligament Alveolar bone Periodontalligament Tooth
Figure 3. Schematic of the effect of cytokines and MOPs on osteoclastogenesis
and bone resorption. Left side: Inflammatory cells that migrate to the periodontal
ligaments from the bloodstream in response to orthodontic forces, as well as
local cells such as osteoblasts, express nuclear factor KB ligand (RANKL) that
binds to the receptor (RANK) on the surface of osteoclast precursor cells such
as monocytes. This binding initiates the adhesion of these cells to each other
to form osteoclasts that start the bone resorption. Right side: Adding MOPS
increases the expression of inflammatory cytokines and chemokines, which, in
turn, will increase the recruitment of osteoclasts and, therefore, the rate of bone
resorption.
technique has been attributed incorrectly to the shape of the cuts made
into the bone (block concept) and to the bone grafts (Wilcko et al., 2001,
2005, 2009; Fischer, 2007; Nowzari et al., 2008). As previously discussed,
the rate of tooth movement is controlled by osteoclast recruitment and
activation. Therefore, regardless of the shape or the extent of the cut,
bone resorption will not occur unless osteoclasts are activated. This
means that, similar to microperforation, the effectiveness of corticotomy
can be related to the activation of cytokines that are released in response
to the trauma induced during the cuts. The release of cytokines is
expected to be significantly higher in corticotomy in comparison with
microperforation due to the extensive trauma to the bone. Unfortunately,
similar to microperforation, the increased level of cytokines will not be
sustained for a long period of time and eventually will return to normal
levels. Corticotomies cannot be repeated as often as needed to maintain
the desired level of cytokine activity due to the side effects of surgery and
high cost. MOP offers a practical and minimally invasive procedure that
can be repeated as needed. In addition, MOP can be incorporated into
daily mechanics and at different stages of treatment. MOPs can be placed

98
Alikhani et al.
Selectively in the areas where tooth movement is desired and away from
teeth or segments used as anchorage.
REMAINING OUESTIONS
Although many of the approaches described above show promise,
more studies are necessary to evaluate their efficiency and safety. Does
faster tooth movement result in less tipping and more bodily movement
of teeth, since change in bone density can affect the center of resistance?
What are the adverse effects for the teeth and surrounding supporting
tissues? Is there an increase in root resorption as teeth move faster or
decrease in root resorption, since bone density significantly decreases?
Does an increase in osteoclasts and bone remodeling during tooth
movement result in less alveolar bone after treatment or more alveolar
bone due to periosteal stimulation? Is accelerated tooth movement and
faster alignment of teeth less stable or more stable in terms of retention?
Certainly, the CTOR studies discussed here advance our under-
standing of the biology that controls the rate of tooth movement and the
molecular players in a race to shorter treatment time. Current investiga-
tions in the CTOR laboratories are attempting to answer some of these
remaining questions in the field of orthodontics.
REFERENCES
Alikhani M, Khoo E, Alyami B, Raptis M, Salgueiro JM, Oliveira SM, Boskey
A, Teixeira CC. Osteogenic effect of high-frequency acceleration on
alveolar bone. J Dent Res 2012;91(4):413-419.
Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B,
Corpodian C, Barrera LM, Alansari S, Khoo E, Teixeira C. Effect of
micro-osteoperforations on the rate of tooth movement. Am J Orthod
Dentofacial Orthop 2013;144(5):639-648.
Andrade I Jr, Silva TA, Silva GA, Teixeira AL, Teixeira MM. The role of tumor
necrosis factor receptor type 1 in orthodontic tooth movement. J Dent
Res 2007;86(11):1089–1094.
Angeli A, Dovio A, Sartori ML, Masera RG, Ceoloni B, Prolo P, Racca S,
Chiappelli F. Interactions between glucocorticoids and cytokines in the
bone microenvironment. Ann NY Acad Sci 2002;966:97-107.
99
Accelerated Tooth Movement
Ashcraft MB, Southard KA, Tolley EA. The effect of corticosteroid-
induced osteoporosis on orthodontic tooth movement. Am J Orthod
Dentofacial Orthop 1992;102(4):310-319.
Bjordal JM, Baxter GD. Ineffective dose and lack of laser output testing
in laser shoulder and neck studies. Photomed Laser Surg 2006;24(4):
533–534.
Bjordal JM, Couppé C, Chow RT, Tuner J, Ljunggren EA. A systematic
review of low level laser therapy with location-specific doses for pain
from chronic joint disorders. Aust J Physiother 2003;49(2):107-116.
Bjordal JM, Lopes-Martins RA, Joensen J, Couppe C, Ljunggren AE,
Stergioulas A, Johnson Ml. A systematic review with procedural
assessments and meta-analysis of low level laser therapy in lateral
elbow tendinopathy (tennis elbow). BMC Musculoskelet Disord
2008;9:75.
Chumbley AB, Tuncay OC. The effect of indomethacin (an aspirin-like
drug) on the rate of orthodontic tooth movement. Am J Orthod
1986;89(4):312-314.
Collins MK, Sinclair PM. The local use of vitamin D to increase the rate of
orthodontic tooth movement. Am J Orthod Dentofacial Orthop 1988;
94(4):278-284.
Cruz DR, Kohara EK, Ribeiro MS, Wetter NU. Effects of low-intensity laser
therapy on the orthodontic movement velocity of human teeth: A
preliminary study. Lasers Surg Med 2004;35(2):117-120.
Davidovitch Z, Finkelson MD, Steignman S, Shanfeld JL, Montgomery PC,
Korostoff E. Electric currents, bone remodeling, and orthodontic tooth
movement: ||. Increase in rate of tooth movement and periodontal
cyclic nucleotide levels by combined force and electric current. Am J
Orthod 1980;77(1):33-47.
Davidovitch Z, Shanfeld JL, Montgomery PC, Lally E, Laster L, Furst L,
Korostoff E. Biochemical mediators of the effects of mechanical
forces and electric currents on mineralized tissues. Calcif Tissue Int
1984;36(Suppl 1):S86-S97.
DeLaurier A, Allen S, deflandre C, Horton MA, PriceJS. Cytokine expression
in feline osteoclastic resorptive lesions. J Comp Pathol 2002;127(2–
3):169–177.
100
Alikhani et al.
Doshi-Mehta G, Bhad-Patil WA. Efficacy of low-intensity laser therapy in
reducing treatment time and orthodontic pain: A clinical investigation.
Am J Orthod Dentofacial Orthop 2012;141(3):289-297.
Fischer T.J. Orthodontic treatment acceleration with corticotomy-assisted
exposure of palatally impacted canines. Angle Orthod 2007;77(3):417-
420.
Gurton AU, Akin E, Sagdic D, Olmez H. Effects of PGI2 and TXA2 analogs
and inhibitors in orthodontic tooth movement. Angle Orthod 2004;
74(4):526-532. y
Hashimoto F, Kobayashi Y, Mataki S, Kobayashi K, Kato Y, Sakai H. Admin-
istration of osteocalcin accelerates orthodontic tooth movement in-
duced by a closed coil spring in rats. Eur J Orthod 2001; 23(5):535-545.
Huang YY, Chen AC, Carroll JD, Hamblin MR. Biphasic dose response in low
level light therapy. Dose Response 2009;7(4):358-383.
Iwasaki LR, Haack JE, Nickel JC, Reinhardt RA, Petro TM. Human
interleukin-1 beta and interleukin-1 receptor antagonist secretion and
velocity of tooth movement. Arch Oral Biol 2001;46(2):185-189.
Jäger A, Zhang D, Kawarizadeh A, Tolba R, Braumann B, Lossdörfer S, Götz
W. Soluble cytokine receptor treatment in experimental orthodontic
tooth movement in the rat. Eur J Orthod 2005;27(1):1-11.
Kale S, Kocadereli I, Atilla P, Aşan E. Comparison of the effects of 1,25
dihydroxycholecalciferol and prostaglandin E2 on orthodontic tooth
movement. Am J Orthod Dentofacial Orthop 2004;125(5):607-614.
Kalia S, Melsen B, Verna C. Tissue reaction to Orthodontictooth movement
in acute and chronic corticosteroid treatment. Orthod Craniofac Res
2004;7(1):26-34.
Kawasaki K, Shimizu N. Effects of low-energy laser irradiation on bone
remodeling during experimental tooth movement in rats. Lasers Surg
Med 2000;26(3):282-291.
Kesavalu L, Chandrasekar B, Ebersole JL. In vivo induction of proinflam-
matory cytokines in mouse tissue by Porphyromonas gingivalis and
Actinobacillus actinomycetemcomitans. Oral Microbiol Immunol
2002;17(3):177-180.
101
Accelerated Tooth Movement
Knop LA, Shintcovsk RL, Retamoso LB, Ribeiro JS, Tanaka OM. Non-steroidal
and steroidal anti-inflammatory use in the context of orthodontic
movement. Eur J Orthod 2012;34(5):531-535.
Lee WC. Experimental study of the effect of prostaglandin administration
on tooth movement: With particular emphasis on the relationship to
the method of PGE1 administration. Am J Orthod Dentofacial Orthop
1990;98(3):231-241.
Leiker BJ, Nanda RS, Currier GF, Howes RI, Sinha PK. The effects of
exogenous prostaglandins on orthodontic tooth movement in rats.
Am J Orthod Dentofacial Orthop 1995;108(4):380-388.
Limpanichkul W. Godfrey K, Srisuk N, Rattanayatikul C. Effects of low-level
laser therapy on the rate of orthodontic tooth movement. Orthod
Craniofac Res 2006;9(1):38-43.
Madan MS, Liu ZJ, Gu GM, King GJ. Effects of human relaxin on orthodontic
tooth movement and periodontal ligaments in rats. Am J Orthod
Dentofacial Orthop 2007;131(1):8.e1-e10.
Mohammed AH, Tatakis DN, Dziak R. Leukotrienes in orthodontic tooth
movement. Am J Orthod Dentofacial Orthop 1989;95(3):231-237.
Nishimura M, Chiba M, Ohashi T, Sato M, Shimizu Y, Igarashi K, Mitani
H. Periodontal tissue activation by vibration: Intermittent stimulation
by resonance vibration accelerates experimental tooth movement in
rats. Am J Orthod Dentofacial Orthop 2008;133(4):572-583.
Nowzari H, Yorita FK, Chang HC. Periodontally accelerated osteogenic
orthodontics combined with autogenous bone grafting. Compend
Contin Educ Dent 2008;29(4):200-206.
Ong CK, Walsh LJ, Harbrow D, Taverne AA, Symons AL. Orthodontic
tooth movement in the prednisolone-treated rat. Angle Orthod
2000;70(2):118-125.
Oxlund BS, ºrtoft G, Andreassen TT, Oxlund H. Low-intensity, high-
frequency vibration appears to prevent the decrease in strength of
the femur and tibia associated with ovariectomy of adult rats. Bone
2003;32(1):69-77.
Potts JT, Gardella TJ. Progress, paradox, and potential: Parathyroid
hormone research over five decades. Ann NY Acad Sci 2007;1117:
196-208.
102
Alikhani et al.
Seifi M, Eslami B, Saffar AS. The effect of prostaglandin E2 and calcium
gluconate on orthodontic tooth movement and root resorption in rats.
Eur J Orthod 2003;25(2):199-204.
SekhavatAR, Mousavizadeh K, Pakshir HR, Aslani FS. Effect of misoprostol,
a prostaglandin E1 analog, on orthodontic tooth movement in rats.
Am J Orthod Dentofacial Orthop 2002;122(5):542-547.
Suda T, Ueno Y, Fujii K, Shinki T. Vitamin D and bone. J Cell Biochem
2003;88(2):259-266.
Teixeira CC, Khoo E, Tran J, Chartres I, Liu Y, Thant LM, Khabensky I, Gart
LP, Cisneros G, Alikhani M. Cytokine expression and accelerated tooth
movement. J Dent Res 2010;89(10):1135-1141.
Tafur J, Mills PJ. Low-intensity light therapy: Exploring the role of redox
mechanisms. Photomed Laser Surg 2008;26(4):323-328.
Tweedle JA. The effect of local heat on tooth movement. Angle Orthod
1965;35:218-225.
Verna C, Dalstra M, Melsen B. The rate and the type of orthodontic tooth
movement is influenced by bone turnover in a rat model. Eur J Orthod
2000;22(4):343-352.
Wilcko MT, Wilcko WM, Murphy KG, Carroll WJ, Ferguson DJ, Miley DD,
Bouquot JE. Full-thickness flap/subepithelial connective tissue grafting
with intramarrow penetrations: Three case reports of lingual root
coverage. Int J Periodontics Restorative Dent 2005;25(6):561-569.
Wilcko MT, Wilcko WM, Pulver JJ, Bissada NF, Bouquot JE. Accelerated
osteogenic orthodontics technique: A 1-stage surgically facilitated
rapid orthodontic technique with alveolar augmentation. J Oral
Maxillofac Surg 2009;67(10):2149-2159.
Wilcko WM, Wilcko T, Bouquot JE, Ferguson DJ. Rapid orthodontics with
alveolar reshaping: Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001;21(1):9-19.
Yamasaki K, Shibata Y, Imai S, Tani Y, Shibasaki Y, Fukuhara T. Clinical
application of prostaglandin E1 (PGE1) upon orthodontic tooth
movement. Am J Orthod 1984;85(6):508-518.
103
Accelerated Tooth Movement
Yoshimatsu M, Shibata Y, Kitaura H, Chang X, Moriishi T, Hashimoto F,
Yoshida N, Yamaguchi A. Experimental model of tooth movement by
orthodontic force in mice and its application to tumor necrosis factor
receptor-deficient mice. J Bone Miner Metab 2006;24(1):20-27.
Youssef M, Ashkar S, Hamade E, Gutknecht N, Lampert F. Mir M. The
effect of low-level laser therapy during orthodontic movement: A
preliminary study. Lasers Med Sci 2008;23(1):27-33.
104
ACCELERATED ORTHODONTICS:
THE PATH FROM CORTICOTOMY TO
GENETICS-BASED ORTHODONTICS
Alejandro Iglesias-Linares
ABSTRACT
Today's social changes are leading to expectations of instant results in many
areas of everyday life. Such developments are necessitating and popularizing the
development of methods to accelerate orthodontic tooth movement (OTM). As
a result, many papers have been published in the last few decades about tooth
movement acceleration and inhibition and various hypotheses and techniques
proposed for achieving it. Several methods have been advanced for reducing the
length of orthodontic treatment. This chapter will focus on biological approaches
to accelerating OTM, primarily through a review of literature that focuses on
Surgical methods and gene therapy aimed at facilitating this goal.
The RANK/RANKL/OPG pathway constitutes a pivotal regulatory
mechanism in the alveolar bone remodeling process, which facilitates OTM.
RANKL is an upregulator of osteoclast activation, proliferation and survival,
contributing to a cellular cascade in which many other proteins exert their bone
resorptive effect. If molecular pathways involving RANKL are responsible for
regulating the acceleratory process in tooth movement, we would expect that
the transgenic overexpression of this factor would result in sustained acceleration
of OTM. In this chapter, we discuss the results of our experiments in which the
overexpression of RANKL by gene therapy indeed contributed to sustained
acceleration of tooth movement under force over time. This contrasted with
the transient acceleration of OTM at the beginning of therapy observed with
the corticotomy procedure. Thus, selective gene therapy with RANKL offers an
alternative and more effective acceleration of OTM than corticotomy surgery.
KEY WORDS: Surgically facilitated orthodontics, gene therapy, tooth movement,
RANKL
105
Accelerated Orthodontics
THE AGE OF INSTANT GRATIFICATION:
THE NOW GENERATION IN ORTHODONTICSP
The main topic of this chapter, accelerating the rate of
orthodontic tooth movement (OTM), is becoming increasingly popular
in orthodontics. Various factors could account for this growing interest:
the observed improvements in standards of treatment as a whole; an
increasing social need for instant gratification; and perhaps also the
expectations of orthodontists who may consider that the current normal
rates of OTM indeed may be low.
Generally speaking, social values and expectations have changed
considerably over a few decades (Kahle, 1983; Inglehart and Welzel, 2005).
Aspects of the new social expectations in the context of orthodontic
treatment might include patients who request appliances that are more
comfortable, more esthetic, invisible, or for treatments that are painless,
less expensive and, of course, shorter. Studies of self-perception and the
role of orthodontics in people's lives, both of which now are considered
to be important, also show a major shift in trends in recent decades. As
an example, the findings of Klima and colleagues' study (1979) on the
relationship between orthodontics and body image, or self-concept, are
rather different from those of recent similar studies (Henson et al., 2011;
Seehra et al., 2013). This shift has been attributed, to the influence of a
series of factors, one of which is the impact of the media on daily life and
behavior (Stanford et al., 2014).
With respect to these changes, one major social change that is
evident today concerns the concept of instant gratification (Mischel et
al., 1989; Cheng et al., 2012). The impressive technological advances
that are being made constantly and the online social networks that
have been created have a lot to do with this. These advances have had
a considerable impact on everyday life and behavior, and have shaped
the present generation as one with a need for immediate gratification.
There are several examples of such changes in everyday life. Most of uS
have Smartphones with Internet connection and constant email contact
that encourage the need to respond immediately to each and every
message. The culture of e-working has undergone a revolution in the last
fifteen years. Not so long ago, it was almost normal that it should take
a Computer hours, days even, to run a program or video; nowdays, this
106
Iglesias-Linares
would be absolutely unthinkable. Waiting a couple of extra seconds for a
page to load now feels like an eternity.
Krishnan and Sitaraman (2012) studied the viewing habits of 6.7
million people on the internet and, more specifically, how long people
were prepared to wait for a video to load. The results showed that people
would not wait more than a couple seconds for it to download and
after ten seconds, half of the analyzed sample had given up. This clearly
demonstrated that we have come to expect routine aspects of our lives to
happen instantly and, equally importantly, that we have a low threshold
of tolerance for delay and quickly become frustrated if we are made to
wait for a webpage to load or are left on hold. Janakiraman and associates
(2011) highlighted the fact that the need for instant gratification is not
new, but rather that our expectation of ‘immediate' has become faster, so
our patience wears ever thinner.
The demand for instant results is present fully in our lives and not
just in relation to the virtual world. Janakiraman and coworkers' study
(2011) explored how much time the subjects were prepared to wait for
Service. Participants were kept on hold while they waited for a download
and then assistance from a call center. The results showed that most
Subjects who were forced to wait, stopped doing so very quickly. This
helps explain why same-day delivery services are becoming essential
for any shop in a big city, or why instant movie download websites (e.g.,
Netflix) have more than 33 million members streaming videos, compared
with only 8 million who receive DVDs by mail (Stelter, 2014). It also may
explain why many people choose to pay approximately three times the
official price to visit the Vatican Museums and Sistine Chapel just to avoid
waiting in line. As shown by the Pew Research Center for the People
and the Press (2007), these types of behavioral trends in people under
the age of 35 do not come without a cost; we have developed a need
for instant gratification, with sharply decreasing levels of tolerance and
patience expected in this and the next generation.
Of course, such changes in behavior also have a major impact
on economic decisions. Several studies have shown that when offered
a choice between a monetary reward that is larger but deferred, and
one that is smaller but more immediate, people tend to prefer the latter
(Ainslie, 1975; Laibson, 1997; Fredericket al., 2002). Instant access savings
107
Accelerated Orthodontics
accounts are preferred to those that require a period of notice before the
money becomes available (Ainslie, 1975; Laibson, 1997; Frederick et al.,
2002). This kind of choice pattern leads a person to take $10 today rather
than $12 in two weeks' time; nonetheless, the same person would not
prefer $10 in a week's time over $12 in three weeks' time, even though
the difference between the amount of money (two dollars) and the period
of time (two weeks) is the same in both situations (McClure et al., 2007;
Albrecht et al., 2013). Many decisions involve a trade-off between the
quality of an outcome and the time at which that outcome is received,
a phenomenon known as temporal discounting, whereby the subjective
value of a potential reward decreases as the delay to that reward extends
further into the future (Albrecht et al., 2011). In this context, the 'as-
soon-as-possible’, principle (reward without delay) becomes important in
our daily lives, with the loss of patience if our wishes are not immediately
gratified, or if the payoff is deferred (Ainslie, 1975; Fredericket al., 2002;
Albrecht et al., 2011).
Based on these changes in behavior in modern life, we can
assume that things are no different in the present orthodontics market,
in terms of orthodontic treatment, or in dentistry as a whole (Stahl, 2004;
Freedman, 2008). Not only that, healthcare professionals are the first to
call for and offer such results. It is therefore in the context of the need
for instant gratification that accelerated OTM is becoming ever more
popular among patients and those seeking orthodontic treatment from a
scientific and a clinical point of view.
When we translate these concepts to orthodontics, a few ques-
tions arise:
1. Do orthodontists and our patients really want shorter
Orthodontic treatments?
2. Does accelerated OTM require extra effort on the part
of the Orthodontist?
3. Is accelerating OTM desirable at any price in terms of
economics or health?
4. What can orthodontists propose or use to accelerate
tooth movement or to make Orthodontic treatment
shorter without renouncing excellence in finishing?
108
Iglesias-Lindres
The first three questions should be answered together; the
study by Uribe and colleagues (2014) provided evidence to answer
Some of these questions. This research group surveyed a total of 683
orthodontists in the United States of which about 70% responded that
they would be interested in using any additional clinical procedures to
reduce treatment times, irrespective of their practice characteristics.
Not only that, but orthodontists also would be willing to forego 20% of
their present treatment fee in order to be able to offer any improvement
that would reduce the length of orthodontic treatment. This shows
that orthodontists would like to reduce treatment times and that there
is a clear need to make progress in this area of orthodontic treatment.
Nevertheless, if we carefully examine the results of this research, we find
that not all methods presently used to speed up OTM are considered
appropriate or useful, either for the orthodontist or the patient; the more
invasive the procedure proposed, the less acceptable it was considered
in all the groups surveyed. On the other hand, with reference to the
economic cost to the patient as opposed to the health risk inherent to
invasive procedures, the findings showed that patients would be willing
to pay up to 20% more for treatment that would accelerate OTM. The
Study perfectly summarizes the answer to the first three questions with
respect to patient and provider preferences in orthodontics.
The answer to the last question regarding the procedures that
orthodontists may undertake to shorten orthodontic treatment times
without renouncing excellence in finishing opens up a wide range of
possible approaches. Traditional methods of accelerating OTM fall into two
rather arbitrary categories. The first category, appliance-related methods,
includes those that modify or improve the biomechanics of orthodontics
(i.e., the type of appliance, design or alloy used in orthodontic appliances;
Songra et al., 2014). The second category, biological-based methods
(Long et al., 2013; Falkensammer et al., 2014), comprises methods based
on modifying the biology of the orthodontic patient. The literature
Concerning the biological modulation of OTM, groups procedures under
various headings such as surgical methods, vibration methods, systemic
or regional pharmacologic administration, or methods involving the use
of low-energy lasers, electrical currents, pulsed electromagnetic fields,
extracorporeal shock waves and gene therapy. The primary focus of the
109
Accelerated Orthodontics
literature reviewed in this chapter is on the second category of modu-
lator of OTM and specifically biological methods that sustain accelerated
OTM by modifying the patient's alveolar bone turnover, whether via
surgery or by inducing selective expression of genes associated with
tooth movement.
BASICS OF THE BIOLOGY OF OTM
Some excellent review papers have been written in the past
decade about biological responses induced by OTM at molecular, cellular
and tissue levels (Masella and Meister, 2006; Holliday et al., 2009;
Krishnan and Davidovitch, 2009; Yamaguchi, 2009). In order to discuss the
acceleration of tooth movement by changing the biology of the patient, it
is essential to review briefly some of the key basic genetic and molecular
events that take place when orthodontic forces are applied to a tooth to
Cause it to move.
Orthodontic appliances, whether fixed or removable, are the
main physical devices responsible for applying forces to guide a tooth
in the direction we wish it to go. To put it briefly, the mechanical force
applied to the tooth is sensed by the cells and, via the mechanism of
mechanotransduction, subsequently converted into a series of molecular
events (Ingber, 2006; Wang et al., 2007). Osteocytes in the alveolar bone
are thought to be the main mechanoreceptors that react to a mechanical
stimulus to the bone, triggering cellular and molecular changes that
eventually induce an adaptive response at the level of the bone tissue.
The mechanisms of mechanosensation and transduction resulting from
placing a mechanical load on bone have been reviewed in the literature
(Klein-Nulend et al., 2013). Osteocytes, which make up approximately
95% of the bone cell population in an adult animal (Parfitt, 1977), are
the fundamental cells for coordinating the response of adapting to force
(Weinbaum et al., 1994; Bonewald, 2011). Osteocytes are located within
lacunae that are distributed throughout spaces within the mineralized
matrix. About 60 cell extensions radiate out from the lacunae in different
directions, passing through the mineralized matrix in very narrow tunnels
called canaliculi. These cytoplasmic processes, or dendrites, form an
intercellular network, enabling the osteocytes to communicate with each
other, with bone marrow cells and also with cells lining the bone surface
(Sugawara et al., 2005). Although there as yet is no single explanation
110
Iglesias-Linares
for the mechanisms that enable the osteocytes to sense pressure and
coordinate adaptive responses in alveolar bone, it is agreed widely that
applied mechanical loading drives the flow of interstitial fluid through the
incompletely mineralized matrix that surrounds the osteocytes and their
dendritic processes, setting off a signaling cascade (Klein-Nulend et al.,
2013).
The gene and molecular expression profiles of mechanically
loaded osteocytes involve the complex sequenced upregulation of various
bone markers and osteocyte-specific markers that include glucose-6-
phosphate dehydrogenase, c-fos, transforming growth factor 3, insulin-
like growth factor, interleukin-6, E11/gp3.8, dentin matrix protein 1, MEPE
and sclerostin (Krishnan and Davidovitch, 2009; Bakker et al., 2014). All
of these molecular signals coordinate the inhibition and stimulation of
pathways regulating osteoclastogenesis and osteoblastogenesis (Canalis,
2005; Li et al., 2005).
The formation of new alveolar bone secondary to OTM appears
to result in response to the secretion of many growth and transcription
factors and anti-inflammatory cytokines. However, osteoclastogenesis
not only is stimulated by osteocytes, but also by highly differentiated
osteoblasts through the receptor activator of NF-KB ligand (RANKL), a
receptor activator of NF-kB (RANK) pathway (Canalis, 2005). Osteoclasts
are responsible mainly for bone resorption events after mechanical loading
to the tooth. It also has been suggested that osteocytes, both directly
and indirectly through the influence of the osteoblasts, coordinate the
release of a cascade of molecules that lead to osteoclast activity via the
expression of RANKL (Narducci and Nicolin, 2009), macrophage colony-
stimulating factor (M-CSF; Tatsumi et al., 2007) and even osteocyte
apoptosis at the site of microcracks in the alveolar bone (Verborgt et al.,
2002; Bonewald, 2007).
In basal homeostatic conditions RANKL is secreted by osteoblasts.
In other scenarios, in pro-inflammatory diseases or after-induced inflam-
mation (e.g., various immune cells, including T-lymphocytes) cause the
abundant production of RANKL (Boyle et al., 2003).
Although several molecules are involved in the bone resorption
process, the RANK/RANKL pathway is the pivotal regulatory mechanism
for bone resorption and the alveolar bone remodeling process that
facilitates OTM (Yamaguchi, 2009). RANKL, through which many other
111
Accelerated Orthodontics
proteins, hormones and cytokines exert their effects on bone resorption,
upregulates osteoclast activity, proliferation and survival. The binding of
RANKLto its receptor, RANK, promotesthe differentiation of hematopoietic
precursor cells into committed osteoclasts. Osteoprotegerin (OPG) is a
soluble decoy receptor to RANKL Secreted by osteoblasts, which prevents
the binding of RANKL to RANK and inhibits the final stages of osteoclast
commitment and osteoclast activation within the bone matrix, and
also enhances osteoclast apoptosis (Boyle et al., 2003). It is, therefore,
the balance between RANK-RANKL binding and OPG production in the
periodontal ligament during tooth movement that determines the bone
remodeling rate (Yamaguchi, 2009). An in vivo study using a rodent
model showed abundant secretion of RANKL (Shiotani et al., 2001).
These and other-findings suggest that RANKL expression is regulated by
inflammatory cytokines in the periodontal ligament in a time- and force-
dependent manner (Nishijima et al., 2006; Yamaguchi et al., 2006).
Finally, physical contact between the osteoclasts and the
mineralized bone matrix is required for bone remodeling and terminal
osteoclastogenesis. Once differentiated, the ability of an osteoclast
to degrade bone depends on its efficacy in creating an extremely low
pH microenvironment and mobilizing enzymes to demineralize the
mineralized and non-mineralized matrices (Teitelbaum and Ross, 2003;
Teitelbaum, 2007). -
Bone resorption is not the only biological event that facilitates
OTM or is induced by it. Simultaneous non-mineralized tissue responses
take place secondary to mechanical loading. Although it does not form
part of the purpose of this review, it should be mentioned in passing
that fibroblasts are considered to be mechanosensors and transducers
of mechanical force in OTM, mediated by integrin receptors that
reorganize their cytoskeletal structure after affecting their proliferation,
differentiation and gene expression profile (Wang et al., 2007). It has
been suggested that this occurs similarly to the periodontal ligament
when subjected to mechanical strain (Ritter et al., 2007), leading to the
overexpression of genes associated with the production or degradation of
different types of collagen at tension and compression sites, respectively,
during OTM (Takahashi et al., 2003).
112
Iglesias-Lindres
Two of the biologically-based methods, namely corticotomy-
facilitated orthodontics and genetics-based orthodontics in accelerating
OTM, are discussed below.
CORTICOTOMY-FACILITATED ORTHODONTICS
Many articles have been published in recent decades about
accelerating or inhibiting tooth movement using various techniques
and several hypotheses have been proposed on how these approaches
achieve their outcomes. Some of the proposals occasionally have
been controversial or even contradictory. Although several methods
for reducing the length of orthodontic treatment have been reviewed
recently (Long et al., 2013), the following discussion will be limited to
biological methods for accelerating OTM, more specifically using surgical
methods and gene therapy to modulate OTM.
Surgery in orthodontics typically is utilized to correct skeletal
discrepancies of high to moderate severity, which require the repositioning
of fragments of the maxilla and/or mandible in order to achieve a normal
occlusion when growth modification ceases to be possible. Orthognathic
Surgery of this type involves completely cutting through segments of
Cortical and trabecular bone, or osteotomy, with the probability of a
relatively frequent occurrence of secondary risks or complications such
as damage to the nerves and blood supply. Apart from this type of
Orthognathic Surgery, Surgical procedures known as surgically facilitated
orthodontic techniques (SFOTs) recently have been reported in the
literature for speeding up the rate of tooth movement (Liou et al., 2000;
|Seri et al., 2005; Fischer, 2007; Lee et al., 2008; Kim et al., 2009; Kumar et
al., 2009; Mostafa et al., 2009; Wang et al., 2009; Kharkar and Kotrashetti,
2010; Sanjideh et al., 2010). SFOTs include procedures such as bone
distraction, osteotomy and corticotomy and, in some cases, corticotomy
combined with other methods. The results of these studies suggest that
these techniques do accelerate OTM; however, the findings are based
on Small samples and, even though surgical procedures involving risks to
the patient are undertaken, their efficacy has not been proven through
randomized controlled trials.
The corticotomy procedure used as an adjunctive therapy in
expedited orthodontics has gained promienence in the clinical setting and
113
Accelerated Orthodontics
the scientific literature in recent years (Wilcko and Wilcko, 2013; Al-
Nahum et al., 2014; Murphy et al., 2014; Yilmaz et al., 2014). It involves
making shallow cuts or perforations on the cortical alveolar bone with
minimal trabecular bone damage (Murphy et al., 2009). The use of
surgery as adjunctive therapy for enhancing orthodontic treatment is
not exactly a new concept. Cunningham (1893) wrote the first published
report of corticotomy and Guilford's paper (1898) was the first to appear
in English, while Köle (1959) made one of the first detailed descriptions of
the technique. He postulated that the cortical bone was responsible for
slowing down OTM, which is why he thought that tooth movement would
increase once its continuity had been broken. He made vertical interdental
cuts combined with horizontal cuts below the apex, which in the maxilla
tended to resemble an osteotomy, sometimes even reaching as far as
the Schneiderian membrane. In the lower arch, however, the horizontal
incision was not as deep in order to avoid damaging the surrounding
nerves and resemble a corticotomy. According to Köle (1959), leaving
the bone marrow intact prevented periodontal damage, preserved pulp
vitality and avoided root resorption because it was the “bony blocks” that
moved, rather than the teeth. Once the surgery had been performed,
an orthodontic appliance could be placed and the treatment completed
in twelve weeks. A retention device could be used for just six to twelve
months, because of the “extra support” to the teeth provided by bone
healing. Nevertheless, Köle's required such extensive surgery that it was
not well received well in the Orthodontic forums of the time.
Bell and Levy (1972) questioned the desirability of performing a
complete osteotomy to create bony blocks due to the possible ischemia
and long-term blood loss that they claimed resulted when following
Köle's method. Using the Rhesus monkey for their experiments, they
discovered that ischemia and gross necrosis occurred after some weeks,
which was marked particularly in the central incisors and occurred mainly
in the coronal part of the tooth where they found decreased trabecular
width and increased cortical width close to the dental root. Bell and Levy
did not adhere strictly to Köle's protocol, however. More specifically, the
apical cuts were corticotomy-like incisions instead of the full osteotomies
originally described. They observed that the efficacy of the procedure
was the same, but without interrupting the normal blood flow to
the segments. Duker (1975) broadly followed Köle's technique, with
114
Iglesias-Linares
modifications, to investigate the effect of corticotomy on periodontal and
pulp tissues. Interdental cuts were made at least 2 mm away from the
alveolar crest, which the author claimed would minimize periodontal
damage—a concept that was confirmed by the study results. From the
1970s until the 1990s, the technique continued to be developed and
improved by various individuals. Suya (1991), for example, suggested
using forces of high magnitude and completing the OTM in three to four
months by activating the appliances after Surgery and every 10 to 14 days
until the goals of orthodontic treatment had been achieved. According
to Suya and as we now know, the acceleration of tooth movement
from surgical interventions dissipates after this period. Several authors
continued developing and improving the technique to make it easier in
daily practice.
The corticotomy technique currently practiced consists of
making small shallow perforations and cuts on the cortical bone to
trigger acceleration of the tooth movement and usually the addition of
Synthetic bone grafting material (Murphy et al., 2009). But what about
the biological mechanisms underlying acceleration triggered by surgery?
Does Surgical intervention induce any molecular mechanisms that could
be responsable, at least in part, to acceleration of OTM?
The so-called Regional Acceleratory Phenomena (RAP), described
by Frost (1983), provides the traditional scientific support for the
biological mechanism that triggers tooth movement in SFOT. The onset
of RAP is a response to surgical insult on bone and involves enhancing
tooth movement in the brief period when the bone around the dental
roots is demineralized, but before remineralization occurs again. Frost
called it an “alarm system,” the response of tissue to external aggression,
designed to boost local bone healing. Once the tissue is damaged, it
triggers extensive processes such as bone cell renovation and remodeling
of the area around the trauma.
Shin and Norrdin (1985) studied the healing of bone defects
after inflicting surgical wounds on long bones in animals to determine
the Subsequent remodeling process in the bone. They succeeded in
demonstrating that RAP enhanced tissue reorganization around the
wound and increased healing by the temporary formation of mineralized
and non-mineralized tissue following damage to the cortical bone.
Bolander (1992), however, argued that RAP started right after the bone
115
Accelerated Orthodontics
damage under the influence of mechanical, genetic, immunologic and
hormonal factors, the specific behavior of which remains unknown,
although it is agreed that bone passes through several stages of healing
until it is calcified completely. Their study suggests that the low levels of
calcium and reduced bone density during the RAP are possible conditions
underlying the enhanced tooth movement that follows corticotomy
Surgery.
Wilcko and colleagues (2001) developed corticotomy as part
of a technique that they named accelerated osteogenic orthodontics
(AOO), which is based on performing an alveolar corticotomy, followed
by a bone graft made up of deproteinized bovine bone, autogenous bone,
demineralized freeze-dried bone allograft or a combination of all three.
Using this approach they claimed to be able to complete full orthodontic
treatment in a timespan that was three to four times shorter than in
cases that did not use this technique. The main difference between their
approach and earlier techniques was the grafting of synthetic bone to
the alveolar region, which was used for the purpose of minimizing loss of
alveolar crest bone height, protecting the periodontal tissues (receding
gingiva, softtissue adheringtothe bone by mistake, and so on) and inducing
bone formation as demonstrated using computed tomography (CT). When
CT scans were repeated two years after the end of treatment (typically
stated to be accomplished in four to six months), more remineralization
was observed around the roots of younger patients, as opposed to older
ones. It was suggested that this demonstrates accelerated OTM results
from a biological mechanism, which was referred to vaguely as RAP, and
not just to the physical movement of a segment of bone.
Most of the literature about corticotomy consists of case
reports (Wilcko et al., 2005) and little is known about the cellular and
molecular bases contributing to observations of accelerated OTM.
Some authors (Lee et al., 2008; Wang et al., 2009) support the theory
that corticotomy enhances a local response when inflammation due
to trauma leads to transient bone demineralization with an increase
of cytokines, thus facilitating OTM (Fig. 1). lino and coworkers (2007),
Mostafa and associates (2009), Sanjideh and colleagues (2010), Teixeira
and coworkers (2010) and Baloul and associates (2011) studied the effects
of corticotomy on OTM in experiments in rats and dogs and, although
116
Iglesias-Linares
Cellular and mºlecular events
-
º OSTEoc-AST
RANKL |
LTa, IL1a, IL1B, IL3,
IL6, IL,11, L18, TNF
CCL2,CCL9,CCL20, |
CCL5,CCL12
CCR1, CCR5, ºcºl
CX3CR1, L13ra1,
IL6ra, IL18RB, tri-
|
Anti-RAP
Time
Figure 1. Schematic composition representing current knowledge of the
molecular mechanisms underlying the acceleration process triggered by surgery
(e.g., corticotomy [A,B}). There is very little information about the molecular
regulation of the tooth movement acceleration process. As shown in the graph
representing what happens to tooth movement over time following surgery,
the effect of the regional acceleratory phenomenon (RAP) is time-limited. After
the acceleration induced by this phenomenon, an "anti-RAP” phenomenon is
induced in the subject to recover the homeostatic state of cell activity. Less
information is available about the molecular mechanisms that regulate the
deceleration process (C-D), RAP: regional acceleratory phenomenon (Frost,
1983). *Data extracted from different studies at different time points (Iglesias-
Linares et al 2011; Alikhani et al 2013).
the range of forces differed (50 to 200g), they showed similar data, namely
that corticotomy-facilitated treatment results in an approximate doub-
ling of the rate of tooth movement relative to non-corticotmized treat-
ment. Fischer (2007) published a study of six patients with bilateral
impacted canines showing that corticotomy surgery reduced the treat-
ment by 28 to 33% relative to conventional orthodontics. Aboul-Ela and







117
Accelerated Orthodontics
coworkers (2011) found in 13 patients undergoing bilateral canine re-
traction, that corticotomy doubled the rates of OTM compared to con-
tralateral control sites without corticotomy
Nevertheless, as is the case with most local inflammatory
processes, the effects of corticotomy are transitory and the period of
rapid acceleration decreases after a time threshold. It now is considered
that the demineralized state of the bone triggers the acceleration of tooth
movement after a corticotomy and makes the tissue more susceptible to
change. This state is referred to as alveolar osteopenia and is characterized
by increased bone turnover and an enhanced non-mineralized matrix.
In other words, although overall bone mass is maintained, its density
is reduced. Osteopenia is induced by the corticotomy and is reversible
(Krook et al., 1975). In a recent study in a rat model (Iglesias-Linares et
al., unpublished results), we found that the final period of corticotomy-
facilitated OTM acceleration was observed on day 12, which corresponds
to three to four months duration in humans. Consistent with these results,
three phases of bone healing in rats have been described by Wang and
colleagues (2009), namely a resorptive phase at day 3, a replacement
phase at day 21 and a mineralization phase at day 60, which means that
if tooth movement is not complete by this stage, further surgery will
be required between days 20 and 30 to continue to harness its effects
on OTM. Sanjideh and associates (2010) tested the OTM response in
foxhounds after a second surgical intervention 28 days after the first one
and found statistically significant, but clinically non-significant differences
(2.0 mm on control group without corticotomy compared to 2.3 mm on
the group with two corticotomies). Since the RAP is regional, it affects the
site of the trauma and adjacent bone. Thus if tooth movement has to be
performed in entire arch, extensive multiple surgery would be required
with all the attendant risks (Mathews and Kokich, 2013).
The invasive and aggressive nature of these procedures which
require full mucoperiosteal flaps besides cuts in the cortical bone, is an
obvious drawback to their widespread acceptance among orthodontists
and patients (Uribe et al., 2014). Therefore, there has been a general
trend proponed toward reducing the surgical insult to the bone and
more conservative, minimally invasive, even flapless interventions to
cause bone injury. Alikhani and associates (2013) tested the usefulness of
making micro-osteoperforations directly on alveolar bone without a flap
118
Iglesias-Lindres
in a randomized clinical trial and reported a 2.3-fold increase in the rate of
tooth movement during canine retraction. Similarly, Kim and colleagues
(2013) reported a 3.26- and 2.45-fold increase in tooth movement in the
maxillae and mandibles of dogs, respectively, with piezopuncture and
cortical perforations through the soft tissues without requiring a flap.
Corticotomy-facilitated orthodontics has been indicated in
various clinical scenarios for: non-extraction treatment of crowding;
borderline orthognathic patients; extrusion of ankylosed teeth; intrusion
of posterior teeth to close an anterior open bite; canine retraction; and
impacted canines. Corticotomy even has been suggested as a biological
method of providing differential anchorage (Hoogeveen et al., 2014).
GENETICS-BASED ORTHODONTICS
Despite the possible benefits of SFOT, there is a general trend
in orthodontics toward reducing the extent of surgery, particularly
aggressive surgery or insult to the alveolar bone or, if posible, avoiding
the need for surgery altogether. If acceleration of OTM can be achieved
with other non-invasive procedures, these methods are preferred to
Surgical approaches to minimize patient discomfort and guarantee safety
while maintaining treatment efficiency (Alikhani et al., 2013).
According to current theories, surgery is simply a intermediate
Step in altering the biological responses that then facilitate the acceleration
of tooth movement. It largely has been demonstrated that induced
acceleration of tooth movement is facilitated by a biological rather
than a physical change (Frost, 1983; Yaffe et al., 1994). Therefore, the
obvious question to ask is: what specific cellular changes and molecular
mechanisms does surgery trigger to induce expedited orthodontics?
While surgery accelerates tooth movement, the full cascade of molecular
and biological mechanisms underlying the resultant increased rates of
OTM Still is unknown.
Recent studies have shown different in vivo and in vitro experi-
mental approaches to modulate OTM through controlled molecular en-
handement of tooth movement in animal and human models. Toward this
goal, these investigations have utilized a wide range of pharmacological
Compounds or biological agents, alone or in combination, and adminis-
tered locally or systemically. A wide range of bioactive agents have been
119
Accelerated Orthodontics
tested, including prostaglandins (Seifi et al., 2003) and prostaglandin ana-
logs (Gurton et al., 2004), the parathyroid hormone (Soma et al., 2000),
the macrophage colony-stimulating factor (M-CSF; Brooks et al., 2011)
and many others. For the purposes of acceleration, however, none of
these are considered to have real applications in humans for many rea-
sons. One of the main drawbacks is that these drugs often are cleared
quickly in the blood and so are compatible for systemic administration.
The extremely short duration of the possible acceleratory effect, added
to the wide variety of possible side effects caused by the drugs—whether
through a lack of specificity in localization or a lack of specificity about
whether they induce accelerated tooth movement—means that these
experiments serve only as research demonstrations of whether the spe-
cific molecules tested affect OTM or not. Drawing on the experience of
past experimental efforts in the field, we think that perhaps this is not the
best way to achieve biological acceleration of tooth movement in ortho-
dontics for future therapeutic applications.
The recent widespread use of molecular biology techniques
in biomedicine (Nabel, 2004) and the need to reduce the duration of
orthodontic treatment, both call for novel approaches and research in
accelerating tooth movement. Recent advances in molecular medicine
such as gene therapy for biomedical purposes also have opened up new
perspectives for accelerating tooth movement in orthodontics (Ginn et
al., 2013).
Since two sequences of the human genome were announced to
the world on February 12, 2001 and published a few days later in Nature
(International Human Genome Sequencing Consortium, 2001) and Science
(Venter et al., 2001), great progress has been made in various areas of
biomedical research. The idea of gene-based therapeutics, however,
arose some time before then, taking most of its momentum from the
development of recombinant DNA techniques and the capacity to induce
the transfer and expression of exogenous genes in mammalian cells. Gene-
based therapeutics now is defined as the introduction, by means of a
vector, of exogenous nucleic acids that provide a transcriptional template
for the expression of protein- or non-coding nucleic acids into a cell, with
the intention of altering the gene expression of that cell. Gene therapy
can be accomplished by the addition of genes, the modification of gene
expression, gene ablation or some combination of all of these (Kay, 2011).
The vectors, mainly carriers of the target gene, can be administered in
120
Iglesias-Lindres
vivo, in vitro or ex vivo. Depending on the vector, the therapeutic DNA
either integrates into the host chromosomal DNA or exists as an episomal
vector (Kay, 2011).
The inflated expectations of gene therapy generated by the first
clinical trials in the 1980s waned in later decades as a growing number
of obstacles were encountered and the enthusiasm for gene therapy
assumed more realistic proportions. Significant technical problems have
been resolved in recent years, to such an extent that there now are several
successful ongoing clinical trials for the treatment of specific diseases
(Somia and Verma, 2000; Kay, 2011).
In the context of accelerating OTM by modifying the patient's
biological millieu, local gene transfer facilitates lengthy though still time-
limited protein expression (Kaneda et al., 2002). This approach also
overcomes the limitation of traditional pharmacological interventions
that could be short acting due to rapid clearance of the agent. Gene and
protein expression that is prolongad, yet time limited, could be highly
desirable, particularly for orthodontic purposes, since the acceleration
of tooth movement is always a time-limited objective until orthodontic
treatment ends.
The use of gene therapy in modulating OTM has been tested
Successfully using animal models (Kanzaki et al., 2004, 2006; Dunn et al.,
2007; Iglesias-Linares et al., 2011; Hudson et al., 2012; Zhao et al., 2012)
and has been shown to influence key aspects of the biological processes
that enhance or diminish rates of OTM. However, a variety of applied
forces, as well as orthodontic devices, were used during the experiments,
which may become another factor that limits our ability to compare
different methods across experiments and their real efficiency in the
clinical setting. Nevertheless, we can summarize some of the studies'
results by stating that there was a 131.6% increase in OTM in groups with
RANKL gene over-expression, compared to the controls (Kanzaki et al.,
2006) and a 23.6% (p < 0.05) increase when compared with a group of
animals Subjected to surgically facilitated procedures, such as corticotomy
(Iglesias-Linares et al., 2011). In other experimental studies, gene therapy
was used to inhibit OTM and a clear inhibitory effect on OTM (p < 0.05)
was observed in the paradental region when OPG was over-expressed
locally in addition to inhibiting relapse (Dunn et al., 2007; Hudson et al.,
2012).
121
Accelerated Orthodontics
These studies (Kanzaki et al., 2004, 2006; Dunn et al., 2007;
Iglesias-Linares et al., 2011; Hudson et al., 2012; Zhao et al., 2012) taken
together provide evidence that the biomolecular pathways of osteoclast
activation in OTM are linked closely to the RANKL/OPG ratio. Thus elevated
levels of RANKL relative to OPG are associated with increased osteoclast
differentiation, survival and activation and with stimulating alveolar bone
remodeling, as illustrated through experiments in OPG'ſ knockout mouse
model (Oshiro et al., 2002). Corticotomy-assisted orthodontics accelerates
tooth movement, in part because of the increased rate of alveolar bone
remodeling under the RAP phenomenon (Frost, 1983).
On the basis of these studies our research group hypothesized
that the sustained over-expression of RANKL by local gene transfer would
stimulate both osteoclast formation and bone remodeling and, unlike the
corticotomy procedure, also lead to accelerated tooth movement that is
sustained over time, rather than be limited to the beginning of therapy
as occurs in corticotomy-assisted orthodontics (Fig. 2). We designed a
study (Iglesias-Linares et al., 2011), therefore, to test the effect of in vitro
RANKL gene transfection on mineral resorption and compare its effect on
tooth movement in vivo with that of corticotomy-facilitated orthodontics.
We also compared the expression of the RANKL protein in both groups
and the effect of the two therapies on osteoclast counts over time.
That study resulted in the following clinically relevant conclusions.
Both methods, namely, in vivo gene transfection and corticotomy,
initially enhanced RANKL protein expression; however tooth movement,
along with RANKL progressively declined in the surgery group over
the experimental period. RANKL had decreased significantly in the
corticotomy and internal and external control groups but not in the RANKL-
transfected group on the final day of observation. Both the surgical- and
RANKL-transfected OTM groups experienced statistically significant
increases in total tooth movement (p < 0.05) compared to the internal
and external control groups. The RANKL-transfection group showed
the highest total tooth movement, with mean final tooth movement
rates that were 41.3 and 23.6% higher than the external control and
corticotomy groups, respectively. The corticotomy OTM group showed a
21.6% higher final tooth movement rate than the external control group
122
Iglesias-Linares
() Celi nucleus
RANKL cºnia
* Genetherapy vector
- * Mature osteoclast
RANKL protein
- OPG protein
- RANK receptor
A L V E O L.A. R. E. ONE
Figure 2. Simplified schematic view of gene therapy technology applied to the
acceleration of orthodontic tooth movement. Note that gene therapy vectors
(viral or non-viral) are carriers of recombinant DNA (the RANKL transgene in our
experiments). The vectors should incorporate the RANKL transgene into target
host cell DNA. The RANK/RANKL/OPG pathway constitutes a pivotal regulatory
mechanism in the alveolar bone remodeling process. Following successful
transfection/transduction of the transgene, over-expression of the RANKL
protein is expected with further RANKL-RANK binding. Increased RANKL-RANK
binding should lead to enhanced osteoclast activity, which results in accelerated
tooth movement in combination with orthodontic force.
that received only regular orthodontic treatment (Iglesias-Linares et al.,
2011).
Although we initially were excited about the important role that
RANKL played in accelerating the tooth movement and the possibility of
increasing the velocity selectively, we have since begun to reflect more
Critically about the implicit limitations of the study. In this study, we used
a mixed non-viral system for the transfer of RANKL to the periodontal
tissue to take advantage of the capacity of the viral membrane for
fusion and, at the same time, avoid viral recombination, neo-plastic

123
Accelerated Orthodontics
transformation, high toxicity or genome incorporation as consequences
of the viral transfer method. Despite these safeguards, a clinical trial in
humans should be conducted first to ensure that the method is totally
safe. No inflammatory or rejection responses were observed clinically in
the in vivo experiments during the period of observation and the tooth
movement rate increased linearly during the experimental period (Somia
and Verma, 2000; Kay, 2011). It is possible, however, that an immune
response may develop through repeated injections to the viral membrane
system, even if a non-viral method is used. Thus, a longer experimental
period could lead to neutralization of RANKL protein production (Somia
and Verma, 2000; Kay, 2011).
More important than these limitations is the fact that RANKL
is involved directly in processes of tooth eruption and orthodontic
root resorption (Tyrovola et al., 2008), yet reports to date have stated
that root resorption decreases dramatically in surgically-facilitated
orthodontic treatment. We also were somewhat skeptical about the
concept that increased RANKL explains the entire observed effect of
surgery in accelerating OTM. We might speculate that this type of insult
to the alveolar bone necessarily would induce more complex molecular
mechanisms that eventually lead to accelerated tooth movement, but
we do not believe that it provides the whole picture. At this juncture,
we have decided to determine selectively whether some other pathway,
apart from increased RANKL, might contribute to tooth movement
acceleration. The unpublished results of our recent experiments
demonstrate complementary molecular pathways to that of RANKL and
add more details on how corticotomy may enhance OTM.
CONCLUSION
As described earlier, current norms encourage the facilitation
of instant gratification even in orthodontics. We, therefore, have
the responsibility for moving in the direction of new therapies and
improvements that could enhance current results in orthodontics and
even change completely the way we perform orthodontic treatment, not
only in reducing the duration of orthodontic treatment, but also in many
other respects that could improve on current approaches. The history of
the advances that have had greatest significance to humanity tells us that
innovation is the mother of evolution, such that, although we still are a
124
Iglesias-Lindres
long way from translating all the excellent molecular work carried out
by research groups around the world to orthodontics, there is no doubt
that these small steps will pave the way for the implementation of novel
Orthodontic treatments of tomorrow.
REFERENCES
Aboul-Ela SM, El-Beialy AR, El-Sayed KM, Selim EM, El-Mangoury NH,
Mostafa YA. Miniscrew implant-supported maxillary canine retraction
with and without corticotomy-facilitated orthodontics. Am J Orthod
Dentofacial Orthop 2011;139(2):252-259.
Ainslie G. Specious reward: A behavioral theory of impulsiveness and
impulse control. Psychol Bull 1975;82(4):463-496.
Al-Naoum F, Hajeer MY, Al-Jundi A. Does alveolar corticotomy accelerate
orthodontic tooth movement when retracting upper canines? A split-
mouth design randomized controlled trial. J Oral Maxillofac Surg
2014;72(10):1880-1889.
Albrecht K, Volz KG, Sutter M, Laibson Dl, von Cramon DY. What is for me
is not for you: Brain correlates of intertemporal choice for self and
other. Soc Dogn Affect Neurosci 2011;6(2):218-225.
Albrecht K, Volz KG, Sutter M, von Cramon DY. What do I want and when
do I want it: Brain correlates of decisions made for self and other. PloS
One 2013;8(8):e73531.
Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B, Corpodian
C, Barrera LM, Alansari S, Khoo E. Effect of micro-osteoperforations
on the rate of tooth movement. Am J Orthod Dentofacial Orthop
2013;144(5):639-648.
Bakker AD, Kulkarni RN, Klein-Nulend J, Lems WF. IL-6 alters osteocyte
signaling toward osteoblasts but not osteoclasts. J Dent Res 2014;93
(4):394–399.
Baloul SS, Gerstenfeld LC, Morgan EF, Carvalho RS, Van Dyke TE, Kantarci
A. Mechanism of action and morphologic changes in the alveolar bone
in response to selective alveolar decortication-facilitated tooth move-
ment. Am J Orthod Dentofacial Orthop 2011;139(4 Supply:S83-S101.
Bell WH, Levy BM. Revascularization and bone healing after maxillary
corticotomies. J Oral Surg 1972;30(9):640-648.
125
Accelerated Orthodontics
Bolander ME. Regulation of fracture repair by growth factors. Proc Soc
Exp Biol Med 1992;200(2):165-170.
Bonewald LF. Osteocytes as dynamic multifunctional cells. Ann NY Acad
Sci 2007;1116:281–290.
Bonewald LF. The amazing osteocyte. J Bone Miner Res 2011;26(2):229-
238.
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation.
Nature 2003;423(6937):337-342.
Brooks PJ, Heckler AF, Wei K, Gong SG. M-CSF accelerates OTM by targeting
preosteoclasts in mice. Angle Orthod 2011;81(2):277–283.
Canalis E. The fate of circulating osteoblasts. N Engl J Med 2005;352
(19):2014-2016.
Cheng YY, Shein PP, Chiou WB. Escaping the impulse to immediate
gratification: The prospect concept promotes a future-oriented
mindset, prompting an inclination towards delayed gratification. Br J
Psychol 2012;103(1):129-141.
Cunningham G. Methode sofortiger Regulierung von anormalen
Zahnstellungen. Osterr Vjschr Zahnheilkd 1894;19:455.
Düker J. Experimental animal research into segmental alveolar movement
after corticotomy. J Maxillofac Surg 1975;3(2):81–84.
Falkensammer F, Arnhart C, Krall C, Schaden W, Freudenthaler J,
Bantleon HP. Impact of extracorporeal shock wave therapy (ESWT)
on orthodontic tooth movement: A randomized clinical trial. Clin Oral
Investig 2014 [Epub ahead of print].
Fischer T.J. Orthodontic treatment acceleration with corticotomy-assisted
exposure of palatally impacted canines. Angle Orthod 2007; 77(3):417-
420.
Frederick S, Loewenstein G, O'Donoghue T. Time discounting and time
preference: A critical review. J EconLit 2002;40(2):351-401.
Freedman G. Buyers' guide to whitening systems. Instant gratification: In-
office bleaching. Dent Today 2008;27(12):128-133.
Frost HM. The regional acceleratory phenomenon: A review. Henry Ford
Hosp Med J 1983;31(1):3-9.
126
Iglesias-Lindres
Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy
clinical trials worldwide to 2012: An update. J Gene Med 2013;15(2):
65–77.
Guilford SH. Orthodontia, or Malposition of the human teeth: Its preven-
tion and remedy. 3rd ed. Philadelphia: T.C. Davis and Sons 1898.
Gurton AU, Akin E, Sagdic D, Olmez H. Effects of PGI2 and TXA2 analogs
and inhibitors in orthodontic tooth movement. Angle Orthod 2004;
74(4):526-532.
Henson ST, Lindauer SJ, Gardner WG, Shroff B, Tufekci E, Best AM. Influence
of dental esthetics on social perceptions of adolescents judged by
peers. Am J Orthod Dentofacial Orthop 2011;140(3):389–395.
Holliday LS, Ostrov DA, Wronski TJ, Dolce C. Osteoclast polarization and
orthodontic tooth movement. Orthod Craniofac Res 2009;12(2):105-
112.
Hoogeveen EJ, Jansma J, Ren Y. Surgically facilitated orthodontic treat-
ment: A systematic review. Am J Orthod Dentofacial Orthop 2014;145(4
Supply:S51-S64.
Hudson JB, Hatch N, Hayami T, Shin JM, Stolina M, Kostenuik PJ, Kapila
S. Local delivery of recombinant osteoprotegerin enhances post-
orthodontic tooth stability. Calcif Tissue Int 2012;90(4):330-342.
Iglesias-Linares A, Moreno-Fernandez AM, Yañez-Vico R, Mendoza-
Mendoza A, Gonzalez-Moles M, Solano-Reina E. The use of gene
therapy vs. corticotomy surgery in accelerating orthodontic tooth
movement. Orthod Craniofac Res 2011;14(3):138-148.
lino S, Sakoda S, Ito G, Nishimori T, Ikeda T, Miyawaki S. Acceleration of
orthodontic tooth movement by alveolar corticotomy in the dog. Am J
Orthod Dentofacial Orthop 2007;131(4):448.e1-e8.
Ingber DE. Cellular mechanotransduction: Putting all the pieces together
again. FASEB J 2006;20(7):811-827.
Inglehart R, Welzel C. Modernization, Cultural Change and Democracy:
The Human Development Sequence. New York: Cambridge University
Press 2005.
127
Accelerated Orthodontics
International Human Genome Sequencing Consortium. Initial sequencing
and analysis of the human genome. Nature 2001;409(6822):860–921.
|Seri H, Kišnisci R, Bzizi N, Tüz H. Rapid canine retraction and orthodontic
treatment with dentoalveolar distraction osteogenesis. Am J Orthod
Dentofacial Orthop 2005;127(5):533–541.
Janakiraman N, Meyer RJ, Hoch SJ. The psychology of decisions to abandon
waits for service. J Mark Res 2011;48(6):970-984.
Kahle LR, ed. Social Values and Social Change: Adaptation to Life in Amer-
ica. New York: Praeger Publishers 1983.
Kaneda Y, Nakajima T, Nishikawa T, Yamamoto S, Ikegami H, Suzuki N,
Nakamura H, Morishita R, Kotani H. Hemagglutinating virus of Japan
(HVJ) envelope vector as a versatile gene delivery system. Mol Ther
2002;6(2):219–226.
Kanzaki H, Chiba M, Arai K, Takahashi I, Haruyama N, Nishimura M, Mitani
H. Local RANKL gene transfer to the periodontal tissue accelerates
orthodontic tooth movement. Gene Ther 2006;13(8):678-685.
Kanzaki H, Chiba M, Takahashi I, Haruyama N, Nishimura M, Mitani H.
Local OPG gene transfer to periodontal tissue inhibits orthodontic
tooth movement. J Dent Res 2004;83(12):920–925.
Kay MA. State-of-the-art gene-based therapies: The road ahead. Nat Rev
Genet 2011;12(5):316-328. -
Kharkar VR, Kotrashetti SM. Transport dentoalveolar distraction osteo-
genesis-assisted rapid orthodontic canine retraction. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2010;109(5):687-693.
Kim SJ, Moon SU, Kang SG, Park YG. Effects of low-level laser therapy af-
ter corticision on tooth movement and paradental remodeling. Lasers
Surg Med 2009;41(7):524–533.
Kim YS, Kim SJ, Yoon HJ, Lee PJ, Moon W, Park YG. Effect of piezopuncture
on tooth movement and bone remodeling in dogs. Am J Orthod Den-
tofacial Orthop 2013;144(1):23–31.
Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A, Weinbaum S. Mechano-
sensation and transduction in osteocytes. Bone 2013;54(2):182-190.
128
Iglesias-Lindres
Klima RJ, Wittemann JK, McIver JE. Body image, self-concept, and the
orthodontic patient. Am J Orthod 1979;75(5):507–516.
Köle H. Surgical operations on the alveolar ridge to correct oclusal
abnormalities. Oral Surg Oral Med Oral Pathol 1959;12(5):515-529.
Krishnan V, Davidovitch Z. On a path to unfolding the biological mechanisms
of orthodontic tooth movement. J Dent Res 2009;88(7):597–608.
Krishnan S, Sitaraman R. Video stream quality impacts viewer behavior:
Inferring causality using quasi-experimental designs. In: Proceedings
of the 2012 ACM Conference on Internet Measurement Conference
(IMC 12). New York:ACM 2012;211-224.
Krook L, Whalen JP, Lesser GV, Berens DL. Experimental studies on osteo-
porosis. Methods Achiev Exp Pathol 1975;7:72-108.
Kumar PS, Saxena R, Patil S, Keluskar KM, Nagaraj K, Kotrashetti SM. Clini-
cal investigation of periodontal ligament distraction osteogenesis for
rapid orthodontic canine retraction. Aust Orthod J 2009;25(2):147-
152.
Laibson D. Golden eggs and hyperbolic discounting. O J Econ 1997;112
(2):443-477.
Lee W, Karapetyan G, Moats R, Yamashita DD, Moon HB, Ferguson DJ, Yen
S. Corticotomy-/osteotomy-assisted tooth movement microCTs differ.
J Dent Res 2008;87(9):861-867.
Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin
binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem
2005;280(20):19883-19887. -
Liou EJ, Figueroa AA, Polley JW. Rapid orthodontic tooth movement into
newly distracted bone after mandibular distraction osteogenesis in a
canine model. Am J Orthod Dentofacial Orthop 2000;117(4):391-398.
Long H, Pyakurel U, Wang Y, Liao L, Zhou Y, Lai W. Interventions for
accelerating orthodontic tooth movement: A Systematic review. Angle
Orthod 2013;83(1):164-171.
Masella RS, Meister M. Current concepts in the biology of orthodontic
tooth movement. Am J Orthod Dentofacial Orthop 2006;129(4):458-
468.
129
Accelerated Orthodontics
Mathews DP, Kokich VG. Accelerating tooth movement: The case against
corticotomy-induced orthodontics. Am J Orthod Dentofacial Orthop
2013;144(1):5-13.
McClure SM, Ericson KM, Laibson Dl, Loewenstein G, Cohen JD. Time
discounting for primary rewards. J Neurosci 2007;27(21):5796-5804.
Mischel W. Shoda Y, Rodriguez MI. Delay of gratification in children.
Science 1989;244(4907):933–938.
Mostafa YA, Mohamed Salah Fayed M, Mehanni S, ElBokle NN, Heider AM.
Comparison of corticotomy-facilitated vs standard tooth-movement
techniques in dogs with miniscrews as anchor units. Am J Orthod
Dentofacial Orthop 2009;136(4):570–577.
Murphy CA, Chandhoke T, Kalajzic Z, Flynn R, Utreja A, Wadhwa S, Nanda
R, Uribe F. Effect of corticision and different force magnitudes on
orthodontic tooth movement in a rat model. Am J Orthod Dentofacial
Orthop 2014;146(1):55-66.
Murphy KG, Wilcko MT, Wilcko WM, Ferguson DJ. Periodontal accelerated
osteogenic orthodontics: A description of the surgical technique. J
Oral Maxillofac Surg 2009;67(10):2160-2166.
Nabel GJ. Genetic, cellular and immune approaches to disease therapy:
Past and future. Nat Med 2004;10(2):135-141.
Narducci P, Nicolin V. Differentiation of activated monocytes into
osteoclast-like cells on a hydroxyapatite substrate: An in vitro study.
Ann Anat 2009;191(4):349-355.
Nishijima Y, Yamaguchi M, Kojima T, Aihara N, Nakajima R, Kasai K. Levels
of RANKL and OPG in gingival crevicular fluid during orthodontic
tooth movement and effect of compression force on releases from
periodontal ligament cells in vitro. Orthod Craniofac Res 2006;9(2):
63–70.
Oshiro T, Shiotani A, Shibasaki Y, Sasaki T. Osteoclast induction in
periodontal tissue during experimental movement of incisors in
osteoprotegerin-deficient mice. Anat Rec 2002;266(4):218-225.
Parfitt AM. The cellular basis of bone turnover and bone loss: A rebuttal
of the osteocytic resorption—Bone flow theory. Clin Orthop Relat Res
1977;127:236-247.
130
Iglesias-Lindres
Pew Research Center. For the People and the Press. How young people
view their lives, futures, and politics: A portrait of generation next.
Washington DC: Pew Research Center for the People and the Press
2007.
Ritter N, Mussig E, Steinberg T, Kohl A, Komposch G, Tomakidi P. Elevated
expression of genes assigned to NF-kappaB and apoptotic pathways in
human periodontal ligament fibroblasts following mechanical stretch.
Cell Tissue Res 2007;328(3):537-548.
Sanjideh PA, Rossouw PE, Campbell PM, Opperman LA, Buschang PH. Tooth
movements in foxhounds after one or two alveolar corticotomies. Eur
J Orthod 2010;32(1):106-113.
Seehra J, Newton JT, Dibiase AT. Interceptive orthodontic treatment in
bullied adolescents and its impact on self-esteem and oral-health-
related quality of life. Eur J Orthod 2013;35(5):615-621.
Seifi M, Eslami B, Saffar AS. The effect of prostaglandin E2 and calcium
gluconate on orthodontic tooth movement and root resorption in rats.
Eur J Orthod 2003;25(2):199-204.
Stelter B. Netflix stock soars 16% on huge subscriber growth CNN money.
[Internet] 2014. Available from: http://money.cnn.com/2014/01/22/
technology/netflix-earnings/
Shin MS, Norrdin RW. Regional accelerated of remodeling during healing
of bone defect in beagles of various ages. Bone 1985;6(5):377-379.
Shiotani A, Shibasaki Y, Sasaki T. Localization of receptor activator of NF-
kappaB ligand, RANKL, in periodontal tissues during experimental
movement of rat molars. J Electron Microsc (Tokyo) 2001;50(4):365-
369.
Soma S, Matsumoto S, Higuchi Y, Takano-Yamamoto T, Yamashita K, Kurisu
K, Iwamoto M. Local and chronic application of PTH accelerates tooth
movement in rats. J Dent Res 2000;79(9):1717-1724.
Somia N, Verma IM. Gene therapy: Trials and tribulations. Nat Rev Genet
2000;1(2):91-99.
Songra G, Clover M, Atack NE, Ewings P. Sherriff M, Sandy JR, Ireland AJ.
Comparative assessment of alignment efficiency and space closure
of active and passive self-ligating vs. conventional appliances in
131
Accelerated Orthodontics
adolescents: A single-center randomized controlled trial. Am J Orthod
Dentofacial Orthop 2014;145(5):569-578.
Stahl BD. Instant gratification...not so fast. Int J Periodontics Restorative
Dent 2004;24(4):315.
Stanford ND, Ip TB, Durham J. Adult orthodontic patients' views regarding
dentofacial normality: A qualitative study. Am J Orthod Dentofacial
Orthop 2014;145(3):287–295.
Sugawara Y, Kamioka H, Honjo T, Tezuka K, Takano-Yamamoto T. Three-
dimensional reconstruction of chick calvarial osteocytes and their cell
processes using confocal microscopy. Bone 2005;36(5):877-883.
Suya H. Corticotomy in orthodontics. In: Hösl E, Baldauf A, eds. Mechanical
and Biological Basis in Orthodontic Therapy. Heidelberg, Germany:
Huthig Buch Verlag Keidelberg 1991;207-226.
Takahashi I, Nishimura M, Onodera K, Bae JW, Mitani H, Okazaki M,
Sasano Y, Mitani H. Expression of MMP-8 and MMP-13 genes in the
periodontal ligament during tooth movement in rats. J Dent Res
2003;82(8):646–651.
Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita
S, Ikeda K. Targeted ablation of osteocytes induces osteoporosis with
defective mechanotransduction. Cell Metab 2007;5(6):464–475.
Teitelbaum SL. Osteoclasts: What do they do and how do they do it? Am
J Pathol 2007;170(2):427-435.
Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and
function. Nat Rev Genet 2003;4(8):638-649.
Teixeira CC, Khoo E, Tran J, Chartres I, Liu Y, Thant LM, Khabensky I, Gart
LP, Cisneros G, Alikhani M. Cytokine expression and accelerated tooth
movement. J Dent Res 2010;89(10):1135-1141.
Tyrovola JB, Spyropoulos MN, Makou M, Perrea D. Root resorption and
the OPG/RANKL/RANK system: A mini review. J Oral Sci 2008;50(4):
367–376.
Uribe F, Padala S, Allareddy V, Nanda R. Patients', parents', and orthodon-
tists' perceptions of the need for and costs of additional procedures to
reduce treatment time. Am J Orthod Dentofacial Orthop 2014;145(4
Suppl):S65-S73.
132
Iglesias-Lindres
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The
sequence of the human genome. Science 2001;291(5507):1304-
1351.
Verborgt O, Tatton NA, Majeska RJ, Schaffler MB. Spatial distribution of
Bax and Bcl-2 in osteocytes after bone fatigue: Complementary roles
in bone remodeling regulation? J Bone Miner Res 2002;17(5):907-914.
Wang JH, Thampatty BP, Lin JS, Im H.J. Mechanoregulation of gene
expression in fibroblasts. Gene 2007;391(102):1-15.
Wang L, Lee W, Lei DL, Liu YP, Yamashita DD, Yen SL. Tissue responses
in corticotomy- and osteotomy-assisted tooth movements in rats:
Histology and immunostaining. Am J Orthod Dentofacial Orthop 2009;
136(6):770.e1-e11.
Wang Y, McNamara LM, Schaffler MB, Weinbaum S. A model for the role
of integrins in flow induced mechanotransduction in osteocytes. Proc
Natl Acad Sci USA 2007;104(40):15941-15946.
Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes
by mechanical loading-induced bone fluid shear stresses. J Biomech
1994;27(3):339-360.
Wilcko MT, Wilcko WM, Murphy KG, Carroll WJ, Ferguson DJ, Miley DD,
Bouquot JE. Full-thickness flap/subepithelial connective tissue grafting
with intramarrow penetrations: Three case reports of lingual root
coverage. Int J Periodontics Restorative Dent 2005;25(6):561-569.
Wilcko W, Wilcko MT. Accelerating tooth movement: The case for
corticotomy-induced orthodontics. Am J Orthod Dentofacial Orthop
2013;144(1):4-12.
Wilcko WM, Wilcko MT, Bouquot JE, Ferguson DJ. Rapid orthodontics with
alveolar reshaping: Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001;21(1):9-19.
Yaffe A, Fine N, Binderman I. Regional accelerated phenomenon in the
mandible following mucoperiosteal flap surgery. J Periodontol 1994;
65(1):79-83.
Yamaguchi M. RANK/RANKL/OPG during orthodontic tooth movement.
Orthod Craniofac Res 2009;12(2):113-119.
133
Accelerated Orthodontics
Yamaguchi M, Aihara N, Kojima T, Kasai K. RANKL increase in com-
pressed periodontal ligament cells from root resorption. J Dent Res
2006;85 (8):751–756.
Yilmaz HN, Garip H, Satilmis T, Kucukkeles N. Corticotomy-assisted
maxillary protraction with skeletal anchorage and Class III elastics.
Angle Orthod 2014 Jun 10. [Epub ahead of print)
Zhao N, Lin J, Kanzaki H, Ni J, Chen Z, Liang W, Liu Y. Local osteoprotegerin
gene transfer inhibits relapse of orthodontic tooth movement. Am J
Orthod Dentofacial Orthop 2012;141(1):30-40.
134
GOAL-ORIENTED TREATMENT PLANNING WITH
CORTICOTOMY-FACILITATED ORTHODONTICS
Rebecca Bockow
ABSTRACT
Orthodontic therapy combined with alveolar decortication and particulate bone
grafting may provide an alternative treatment option for borderline combined
orthodontic and orthognathic surgical candidates. Combining orthodontics with
selective alveolar decortication and bone grafting allows for a wider range of
tooth movement, while also helping to prevent future periodontal breakdown.
Goal-oriented treatment planning helps identify the indications for applying this
combined technique. Case selection, direction and amount of tooth movement,
and treatment timing all are important factors contributing to favorable
outcomes. The aim of this chapter is to help define the role of surgically facilitated
orthodontics as a treatment modality.
KEY words: orthodontic treatment planning, corticotomy-facilitated orthodontics
INTRODUCTION
Patients seeking orthodontic care may present with dental
crowding and/or skeletal discrepancies. When patients with malocclu-
Sions resulting from underlying skeletal discrepancies seek treatment,
orthodontists may offer a spectrum of treatment options. The treat-
ment modalities offered are based on the clinical diagnosis. As Amster-
dam wrote (1974), for every malocclusion there are multiple treatment
modalities, but only one correct diagnosis. When the etiology for the
malocclusion is based skeletally, a patient's treatment options include
either a combination of orthodontics and orthognathic surgery or orth-
odontic "camouflage” treatment, including extractions and interproximal
reduction (Ackerman et al., 2012; Sarver and Yanosky, 2012). Orthodon-
tists rely on comprehensive orthodontic records—including clinical pre-
sentation, periodontal condition, restorative needs, dental models and
135
Goal-oriented Treatment Planning
three-dimensional (3D) cone-beam computed tomography (CBCT) imag-
ing—to help decide which treatment options and modalities are most ap-
propriate for each patient. Using such diagnostic records, a problem list
is generated, a diagnosis is developed and clear treatment objectives are
outlined (Ackerman et al., 2012; Sarver and Yanosky, 2012). These ob-
jectives will help define treatment strategies that may be appropriate to
achieve the desired treatment outcomes.
When considering the appropriate treatment modality, an
orthodontist must take into consideration the predictability of the
treatment plan, as well as any and all adverse sequelae. Sarver and Proffit
(2005) and Vanarsdall and colleagues (Vanarsdall and Musich, 2000;
Vanarsdall et al., 2012) published on the predictable range and limit of
orthodontic tooth movement with brackets and wires alone. They further
illustrated that dentofacial orthopedics combined with growth allow for
a wider range of tooth position changes, due in part to the growth and
development of skeletal and dentoalveolar structures. Finally, the largest
predictable tooth movement results from a combination of traditional
orthodontics with orthognathic surgery (Vanarsdall and Musich, 2000;
Vanarsdall et al., 2012). The concept that Proffit and Vanarsdall convey
is that there are biologic limits to where orthodontics alone can move
teeth. As many orthodontists and periodontists have seen in their own
patients, the teeth, bone and periodontium all can be lost to some extent
if such biologic limits are not understood and respected.
In a non-growing individual, the biologic limits of orthodontic
tooth movement are defined by the pre-treatment alveolar bone and
surrounding soft tissues (Ackerman and Proffit, 1997; Gracco et al., 2010;
Yagci et al., 2012). Moving teeth outside of the alveolus can result in bony
dehiscences and fenestrations (Wehrbein et al., 1994; Handelman, 1996).
Gingival recession can occur as a consequence during, immediately
following or in the years after treatment (Lund et al., 2012; Renkema
et al., 2013a,b). Adverse sequelae of such tooth movements also may
include root resorption, cessation of tooth movement, horizontal bone
loss and a higher risk of orthodontic relapse (Ten Hoeve and Mulie, 1976;
Wehrbein et al., 1996; Rothe et al., 2006; Ahn et al., 2013).
CBCT scans have begun to illuminate the presence of dehis-
cences, fenestrations and the relationship between teeth and their sur-
rounding alveolar housing in 3D (Nahm et al., 2012). Such 3D information
136
Bockow
helps identify the presence of a pre-existing narrow alveolar arch (in a
bucco-lingual dimension), which may house large or broad tooth roots.
Such anatomic discrepancies may be considered risk factors for future
recession and/or bone loss, particularly in the event of unplanned orth-
odontic tooth movement (Lund et al., 2012; Richman, 2012; Renkema et
al., 2013a,b). While the presence of a dehiscence or fenestration in the
bone automatically does not translate clinically into gingival recession, it
places a patient at greater risk for developing recession over time (Artun
and Krogstad, 1987; Flores-Mir, 2011).
The use of CBCT data helps identify which patients seeking
orthodontic correction can be treated successfully with orthodontic
camouflage. As in all treatment planning, one must perform a virtual
treatment objective (VTO) set-up to determine the ideal final position
of the teeth relative to the skeletal base once treatment is complete.
A VTO can be formulated simply by drawing the proposed tooth
movement on a lateral and P/A ceph to visualize the proposed tooth
movement. If the 3D CBCT data reveals that sufficient alveolar bone is
present to support the proposed tooth movement, then camouflage
treatment—including interproximal tooth reduction, extractions and the
use temporary anchorage devices (TADs) for en-masse movement—may
be an appropriate treatment modality. If the VTO reveals that the final
ideal tooth position will place the roots outside of the available alveolar
bone, as determined by the CBCT, then an advanced surgical treatment
modality may be an appropriate treatment option to consider.
CORTICOTOMY-FACILITATED ORTHODONTICS
AS A TREATMENT ALTERNATIVE
Traditionally, the only treatment option for patients requiring
tooth movement beyond the scope of orthodontic camouflage treatment
was a combination of orthodontics and orthognathic surgery (Arnett
and Gunson, 2010; Musich and Chemello, 2012). Procedures such as
Surgically-assisted rapid maxillary expansion (SARPE), three-piece LeFort
maxillary Surgeries and mandibular advancements and setbacks are all
procedures that orthodontists incorporate into their treatment plans
when indicated. Unfortunately, not all orthodontic patients are candidates
for orthognathic surgery. Patients may decline this treatment modality
due to fear, cost, lifestyle or underlying health issues that prevent them
137
Goal-oriented Treatment Planning
from receiving general anesthesia. We now have an effective treatment
option to offer borderline surgical orthodontic patients.
Corticotomy-facilitated orthodontic treatment modalities have
been published as case reports since the 1950s, with additional publica-
tions in the late 1980s and early 1990s (Kole, 1959; Anholm et al., 1986;
Gantes et al., 1990; Suya, 1991). Wilcko and colleagues (2001, 2009) and
Wilcko and Wilcko (2013) published a combined treatment modality con-
sisting of an in-office surgical procedure combined with orthodontic tooth
movement. Their described method included laying full thickness muco-
periosteal flaps and decorticating the buccal and lingual/palatal sides of
the alveolar bone with a round bur to create bleeding points. They then
added hydrated particulate bone graft material under the periosteum.
The goal of their surgical intervention was to spur a localized osteopenia
and induce rapid bone turnover (Wilcko et al., 2001). They also aimed to
surround the teeth with the additional bony support, adding to the range
of tooth movement and aiding in long-term stability (Wilcko et al., 2001;
Rothe et al., 2006). Following the surgical procedure, the teeth were moved
orthodontically into the grafted bone rapidly. Their published protocol in-
cludes seeing the patient every two weeks for adjustments to maintain
the “bone activation,” rapid bone turnover and rapid tooth movement.
While numerous publications, including studies and case reports,
have highlighted accelerated tooth movement when combining a surgical
insult with orthodontic therapy, some have called into question the need
for periodontal flap procedures solely for the purposes of speed (Mathews
and Kokich, 2013). Variations on the original periodontally-accelerated
osteogenic orthodontics (PAOO) treatment have been published, including
flapless “piezocision” and transmucosal micro-osseous perforations
(Vercelotti and Podesta, 2007; Alikhani et al., 2013; Keser and Dibart,
2013). McBride and associates (2014) report that the greater the surgical
insult, the greater the localized osteopenia, alveolar decalcification and
more rapid the tooth movement. Two recent systematic reviews conclude
that corticotomy-facilitated orthodontics is safe for the oral tissues and
results in a transient phase of accelerated orthodontic tooth movement
(Long et al., 2013; Hoogeveen et al., 2014). Various publications
additionally have described benefits of this procedure including a
thickening of the supporting alveolar bone and periodontal soft tissue
following surgically facilitated orthodontics (Ahn et al., 2012; Shoreibah
et al., 2012; Hoogeveen et al., 2014).
138
Bockow
Patient morbidity and cost are considered drawbacks to the PAOO
procedure (Mathews and Kokich, 2013). While these remain important
concerns for all treatment plans, patient desires and clinical findings must
be taken into account. Adult orthodontic patients frequently require soft
tissue augmentation prior to orthodontic therapy due to pre-existing
gingival recession. With well-planned timing and sequencing, recession
defects can be resolved simultaneously by combining PAOO and gingival
augmentation. An orthodontist can place brackets, the soft tissue can be
augmented and the PAOO procedure can be completed in one simultaneous
Surgical procedure. The orthodontist then can take advantage of the rapid
bone turnover and increased range of tooth movements. Such patients
would have paid for and received gingival grafting (a surgical procedure)
prior to orthodontics. In such cases, PAOO will not add significantly to the
total treatment cost or patient morbidity. Furthermore, for patients who
are borderline candidates for orthognathic surgery, one may argue that an
in-office periodontal procedure including selective alveolar decortication
and bone augmentation may be less costly and less invasive to a patient
than a hospital stay. Additionally, it saves a patient from the associated
Surgical risks and post-operative morbidity encountered with intubation
and orthognathic surgery.
A SEGMENTAL APPROACH
The original PAOO treatment protocol as published by Wilcko
and associates (2001) included buccal and lingual full-thickness mucogin-
gival flaps and decortication of both alveolar walls in both arches. This
renders a great deal of trauma to the bone and soft tissue, and may be
warranted for some treatment plans. A segmental PAOO approach may
be indicated in cases where bone augmentation is required only in the
direction of the proposed tooth movement. Such a conservative approach
decreases patient cost and morbidity, while still allowing for an increased
range of tooth movements. Clinical examples may include a Class ||
Skeletal relationship treated non-surgically where bone augmentation
between the mandibular canines may allow for improved incisor coupling
and a decreased mental-labial fold. Other case examples are patients
with narrow maxillae and end-to-end buccal overjet posteriorly. If these
patients have pre-existing buccal recession, they may either be candidates
for SARPE or for decortication and bone grafting in the buccal maxilla
augmentation in the direction of tooth movement. While controlled
clinical trials have yet to quantify the precise limits of tooth movement
139
Goal-oriented Treatment Planning
with PAOO, predictable success has been observed clinically. Successful
cases thus far have achieved approximately 5 mm or more of dento-alve-
olar expansion bilaterally and up to 6 mm of mandibular incisor proclina-
tion with the employment of segmental decortication and bone grafting
(personal communications, Dr. Colin Richman and Dr. Tom Wilcko).
Clinically, orthodontic diagnosis for PAOO candidates remains the
same as for all orthodontic patients. Dental and skeletal problems are
assessed based on severity and treatment needs, utilizing comprehensive
orthodontic records. Clinical findings and patient desires are considered
in the treatment planning decisions. When malocclusions are severe
enough that they cannot be treated with orthodontic camouflage, but are
not so severe as to warrant orthognathic surgery, PAOO may be a viable
treatment option (Fig. 1).
Patient selection is of the utmost importance for the PAOO treat-
ment plan. In addition to using a VTO in the treatment-planning phase
to determine whether PAOO is indicated, a thorough patient health
history can influence one's choice of treatment modality further. Patients
Treatment Decision Scale
less severe [[IOIG SEVEſº
Is there an underlying skeletal
discrepancy?
Existence of pre-treatment gingival
-
- recession, especially in the -
direction of proposed tooth
Traditional Orthodontic *" - cºcºnathic
rth nt. flage Little to no alveolar bone exists -
Orthodontics Camoufla - in the direction of tooth - Surgery
<- movement -
Orthodontic "camouflage"
treatment may lead to periodontal
complications or a greater chance
of orthodontic relapse
Orthognathic surgery is not an
— option OR the patient declines —-
orthognathic surgery?
Figure 1. Patient dental and skeletal deformities fall within a spectrum of in-
creasing severity. Consequently, orthodontic and surgical treatment decisions
also fall within a similar spectrum. Multiple factors influence treatment deci-
sions, including the patient's pre-treatment periodontal condition, desires and
final treatment goals. This figure highlights many of the pre-treatment clinical
questions with which orthodontists are faced. The answers to each of these
questions and their severity may lead an orthodontist to favor one treatment
modality over another.

140
Bockow
taking certain medications (e.g., as long-term bisphosphonate use,
corticosteroid or NSAID therapy) or blood thinners (e.g., coumadin) are
not candidates. Patients with bleeding disorders as well as immuno-
compromised patients also are not candidates for this procedure.
Additionally, patients must be able to accommodate frequent visits to the
orthodontist (every two to three weeks). The literature shows that the
increased bone turnover lasts approximately four months in an animal
model (Sebaoun et al., 2008; Mostafa et al., 2009). Frost (1983, 1989)
reported that the regional acceleratory phenomenon (RAP) can last 6 to 24
months in humans. Consequently, patients must return to the orthodontist
approximately every two weeks for the first four to six months or longer
after the decortication procedure to maximize both tooth movement and
bone remodeling. Patients must be informed of this during the treatment
planning stages. Without the opportunity for continuous bone activation,
the positive effects that accompany the surgical intervention may be lost.
Patients and treating clinicians often ask what happens to the bone
graft material after the surgery. Does this bone turn into the patient's own
bone? Or do the bone graft particles simply become encapsulated within
the soft tissue? The Wilcko brothers published (2009) re-entry findings on
patients they treated. These case reports demonstrated that the surgery
Successfully corrected pre-existing dehiscences and fenestrations. The
histologic analysis of bone samples from these patients further revealed
that the bone graft particles became incased in native bone upon healing
and maturation (Wilcko et al., 2003, 2009). Araújo and colleagues (2001)
demonstrated that teeth were moved successfully into sites grafted with
Bio-Oss particles in a dog model. Their study showed that the Bio-Oss
particles were degraded and eliminated from the alveolar ridge in the
direction of tooth movement, but remained on the tension side. Based on
this information as well as clinical observations, one can assume that the
bone graft particles are being incorporated into the patient's own alveolar
bone in the direction of tooth movement.
Case Example
Initial Presentation. A 28-year-old female patient presented to
the orthodontic clinic with a chief complaint of “I don’t like my smile and
my open bite.” Her health history was significant only for occasional social
Cigarette smoking. She reported that her teeth never touched in the front
of her mouth. Prior to her initial presentation in our clinic, she had seen
141
Goal-oriented Treatment Planning
two orthodontists and an oral surgeon, all of whom informed her that the
only treatment option was a combination of orthognathic surgery and
orthodontics. Due to fear, she declined all treatment options requiring a
maxillary LeFort surgical procedure.
Problem List. The patient possessed a high mandibular plane angle
(SN-MP = 44°) and a prominent hard and soft tissue pogonion. She had
a history of multiple dental restorations, a complete dentition including
her third molars, a skeletal Class III pattern (Witts Appraisal = -9.9, ANB =
-5.8°) with an anterior open bite, a deficient maxilla in all three dimensions,
four quadrants of facial gingival recession, left temporomandibular joint
clicking with no associated pain, lingually inclined mandibular posterior
teeth, and minor mandibular and moderate maxillary crowding (Figs. 2-3).
NO CRO/MIP shift was noted.
Goals of Treatment. Creating a VTO from the lateral cephalometric
radiograph allowed us to visualize the proposed ideal tooth movements.
Treatment goals were planned around an ideally positioned maxillary
central incisor in three planes of space (Andrews, 2008). The goal was
for the mid-facial point of the central incisor to lie along a vertical plane
coincident with the most prominent portion of the patient's forehead
(Andrews, 2008). The vertical limit of the maxillary central incisor was
planned so that the middle of the crown would be at the same horizontal
level as the wet-dry line of the upper lip (Andrews, 2008). The ideal
root torque was set to 56.8 + 3° from the occlusal plane, as outlined by
Arnett and Gunson (2010, 2013). The goal for the final position of the
mandibular incisors was for them to couple with the ideally positioned
maxillary incisors (Fig. 4).
An ideally positioned maxillary central incisor would need to be
extruded and protracted beyond what was thought to be stable with
traditional fixed orthodontic appliances (Vanarsdall and Musich, 2000,
2012). The maxillary arch required 4 mm of expansion for the palatal
cusps of the maxillary molars to rest in the central fossae of the mandibular
molars when the mandibular molars were positioned upright within the
alveolar bone. All idealized tooth movements, if performed with brackets
and wires alone, would have pushed the tooth roots outside of the
alveolar housing, as visualized in the VTO. However, most of the large
idealized tooth movements were isolated to the maxillary arch.
142
Bockow
Figure 2. Extraoral findings included normal facial symmetry, no chin deviation,
midlines in line with her face, a thin and short upper lip, a high mandibular plane
angle, a slightly long lower facial height and a 90° nasolabial angle.
Figure 3. Intraoral findings included facial gingival recession in all four quadrants, a
thin periodontal phenotype, an open-bite malocclusion with negative overbite and
minimal overjet, moderate maxillary crowding and minor mandibular crowding.
The mandibular posterior teeth had a lingual inclination and the maxillary
90Sterior teeth were upright within their bony housing.
Treatment Plan and Therapy. The goals of orthodontic tooth
movement in the mandible included uprighting the mandibular teeth
to a more stable position in the alveolus combined with conservative
interproximal reduction to manage the crowding. Once the teeth in the
mandibular arch were idealized, they would serve as a template for the


143
Goal-oriented Treatment Planning
Figure 4. The treatment plan started by creating a VTO tracing with the ideal
position of the maxillary central incisor in three planes of space. The final central
incisor crown position was idealized to lie along the same plane as the most
prominent portion of the forehead. Vertically, the maxillary central incisor was
planned such that the middle of the crown would lie at the wet-dry line of the
upper lip. The root torque was idealized to 56.8°, + 3°, as stated by Arnett and
Gunson (2013). The mandibular incisors were traced correspondingly to couple
with the idealized maxillary incisors.
maxillary final tooth position. The goals of tooth movement in the
maxillary arch included transverse expansion and anterior extrusion.
All proposed maxillary tooth movement was in the buccal direction.
Therefore, only the buccal maxilla required segmental decortication and
bone graft augmentation.
Leveling and aligning was completed early during treatment to
progress to a rectangular Niſi wire (Fig. 5). Large bodily tooth movements

144
Bockow
Figure 5. Initial leveling and aligning was accomplished using only brackets and
Wires prior to the decortication and bone grafting procedure. This helped idealize
and upright the lower teeth, allowing them to be a template for the upper tooth
expansion and protraction.
Figure 6. A full-thickness buccal mucoperiosteal flap was prepared, spanning from
the distal line angles of the second molars. The cortical bone was decorticated
to Create bleeding points and induce the RAP of bone turnover. Orthodontic tooth
movement was initiated immediately following the surgical procedure.
Were to be initiated immediately following the corticotomy procedure,
allowing the alveolus and teeth to remodel to the desired new position
during the period of high bone turnover and subsequent healing; such
movements would require a larger archwire for strength and 3D control
(Fig. 5). Following leveling and aligning, a full thickness flap was reflected
and alveolar corticotomies performed along the buccal surfaces of the
maxilla, spanning from molar to molar (Fig. 6). The alveolus was grafted
With rehydrated sterile particulate freeze-dried human bone allograft and
the flaps were repositioned and sutured to place. Healing was uneventful.
Ten days following the in-office procedure, maxillary protraction
and extrusion began with the use of full-time Class III elastics, combined
With anterior vertical elastics at night. The maxillary archwire was expand-
ed to obtain the desired transverse expansion. Progression to a full-sized
Stainless steel archwire helped maintain proper torque. The patient was
Seen every two weeks to assess the treatment progress and to make any


145
Goal-oriented Treatment Planning
- -
Figure 7. Major tooth movement was accomplished in the weeks immediately
following the surgical procedure. The finishing and detailing phase of treatment
was similar to that of a more traditional orthodontic case and required multiple
frequent visits in quick succession.
necessary orthodontic changes. Large tooth movements occurred effi-
ciently within the weeks following the surgery. The final finishing and de-
tailing stages of the patient's treatment were completed within the same
time frame as with any orthodontic case (Fig. 7).
RESULTS
Tooth movement goals as outlined in the original treatment plan
were achieved at the end of treatment (Fig. 8). No extraoral skeletal
changes such as mid-face or chin projection alterations were noted be-
tween pre- and post-treatment records as no orthognathic surgery was
performed (Fig. 9). Total treatment was completed in 13 months. The suc-
cess seen in this case, however, is not from the speed of orthodontics, but
from the dramatic range of tooth movements achieved without adverse
sequelae to the teeth and periodontium. In this patient, only maxillary
buccal bone grafting was utilized, minimizing the surgical intervention.
The final photographs reveal an area of slight marginal gingival recession
around the upper left canine. Proper surgical soft tissue handling, includ-
ing apical flap release, coronally advanced flaps and even simultaneous
soft tissue grafting, all can help prevent the mild recession defects that
were seen in this example. Many patients now are being treated with a
combination of both hard and soft tissue grafting materials, thus chang-
ing the tissue thickness, correcting recession defects and further prevent-
ing future recession. All teeth, occlusal and soft tissue changes remained
stable at the patient's one-year retention visit.

146
Bockow
Figure 8. Tooth movement goals that had been outlined in the original
VTO were accomplished as seen in the final lateral cephalometric film.
Figure 9. No extraoral or skeletal changes were noted because no orthognathic
Surgery was performed. Overall, the patient was satisfied with her treatment
Outcome.


147
Goal-oriented Treatment Planning
CONCLUSIONS
Much of what we know regarding this combined treatment
protocol has been derived from case reports and clinical experiences;
therefore, many surgical and clinical questions remain unanswered. The
potential range of tooth movement and long-term stability with this
combined treatment needs to be defined further by future well-designed
Studies and clinical trials. We have seen, however, that Orthodontics Com-
bined with selective alveolar decortication and bone grafting can lead
to dramatic outcomes and, when appropriate, may be an alternative for
borderline orthognathic surgical candidates. Clear treatment objectives,
proper case selection, goal-oriented orthodontic mechanics, sequencing
and timing all play a role in the successful outcomes of these cases.
REFERENCES
Ackerman JL, Nguyen T, Proffit WR. The decision-making process in
orthodontics. In: Graber LW, Vanarsdall RL, Vig KW, eds. Orthodontics:
Current Principles & Techniques. 5th ed. Philadelphia, PA: Mosby
Elsevier 2012:3-58.
Ackerman JL, Proffit WR. Soft tissue limitations in Orthodontics: Treatment
planning guidelines. Angle Orthod 1997;67(5):327-336.
Ahn HW, Lee DY, Park YG, Kim SH, Chung KR, Nelson G. Accelerated
de-compensation of mandibular incisors in surgical skeletal Class III
patients by using augmented corticotomy: A preliminary study. Am J
Orthod Dentofacial Orthop 2012;142(2):199-206.
Ahn HW, Moon SC, Baek SH. Morphometric evaluation of changes in the
alveolar bone and roots of the maxillary anterior teeth before and
after en masse retraction using cone-beam computed tomography.
Angle Orthod 2013;83(2):212-221.
Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B, Corpo-
dian C, Barrera L., Alansari S, Khoo E, Teixiera C. Effect of micro-osteo-
perforations on the rate of tooth movement. Am J Orthod Dentofacial
Orthop 2013;144(5):639-648.
Amsterdam M. Periodontal Prosthesis. Twenty-five years in retrospect.
Alpha Omegan 1974;67(3):8-52.
Andrews WA. AP relationship of the maxillary central incisors to the
forehead in adult white females. Angle Orthod 2008;78(4):662-669.
148
Bockow
Anholm JM, Crites DA, Hoff R, Rathbun WE. Corticotomy-facilitated or-
thodontics. CDA J 1986;14(12):7-11
Araújo MG, Carmagnola D, Berglundh T, Thilander B, Lindhe J. Orthodontic
movement in bone defects augmented with Bio-Oss: An experimental
study in dogs. J Clin Periodontol 2001;28(1):73-80.
Arnett Gunson Education Materials. 7 step cephalometric treatment plan.
http://www.arnettgunson.com/education-materials/7-step-cephalo-
metric-treatment-plan. Accessed October 27, 2013.
Arnett GW, Gunson MJ. Esthetic treatment planning for orthognathic
surgery. J Clin Orthod 2010;44(3):196-200.
Artun J, Krogstad O. Periodontal status of mandibular incisors following
excessive proclination: A study in adults with surgically treated
mandibular prognathism. Am J Orthod Dentofacial Orthop 1987;91(3):
225-232.
Flores-Mir C. Does orthodontic treatment lead to gingival recession? Evid
Based Dent 2011;12(1):20.
Frost HM The biology of fracture healing: An overview for clinicians. Part
I. Clin Orthop Relat Res 1989;248:283-293.
Frost HM. The regional acceleratory phenomenon: A review. Henry Ford
Hosp Med J 1983;31(1):3-9.
Gantes B, Rathbun E, Anholm M. Effects on the periodontium follow-
ing corticotomy-facilitated orthodontics: Case reports. J Periodontol
1990;61(4):234-238.
Gracco A, Luca L, Bongiorno MC, Siciliani G. Computed tomography
evaluation of mandibular incisor bony support in untreated patients.
Am J Orthod Dentofacial Orthop 2010;138(2):179-187.
Handelman CS. The anterior alveolus: Its importance in limiting orth-
odontic treatment and its influence on the occurrence of iatrogenic
sequelae. Angle Orthod 1996;66(2):95-109.
Hoogeveen EJ, Jansma J, Ren Y. Surgically facilitated orthodontic treat-
ment: A systematic review. Am J Orthod Dentofacial Orthop 2014;
145(4 Supp 1):S51-S64.
Keser El, Dibart S. Sequential piezocision: A novel approach to acceler-
ated orthodontic treatment. Am J Orthod Dentofacial Orthop 2013;
144(6):879-889.
Kole H. Surgical operations on the alveolar ridge to correct occlusal ab-
normalities. Oral Surg Oral Med Oral Pathol 1959;12(5):515-529.
149
Goal-oriented Treatment Planning
Long H, Pyakurel U, Wang Y, Liao L, Zhou Y, Lai W. Interventions for
accelerating orthodontic tooth movement: A systematic review. Angle
Orthod 2013;83(1):164-171.
Lund H, Grondahl K, Grondahl HG. Cone beam computed tomography
evaluations of marginal alveolar bone before and after orthodontic
treatment combined with premolar extractions. Eur J Oral Sci 2012;
120(3):201-211.
Mathews DP, Kokich VG. Accelerating tooth movement: The case against
corticotomy-induced orthodontics. Am J Ortho Dentofacial Orthop
2013;144(1):5-13.
McBride MD, Campbell, PM, Opperman LA, Dechow PC, Buschang PH.
How does the amount of surgical insult affect bone around moving
teeth? Am J Orthod Dentofacial Orthop 2014;145:S92-S99.
Mostafa YA, Mohamed Salah Fayed M, Mehanni S, ElBokle NN, Heider
AM. Comparison of corticotomy-facilitated vs standard tooth-move-
ment techniques in dogs with miniscrews as anchor units. Am J Or-
thod Dentofacial Orthop 2009;136(4):570–577.
Musich DR, Chemello PD. (2012) Orthodontic aspects of orthognathic
Surgery. In: Graber LW, Vanarsdall RL, Vig KW, eds. Orthodontics
Current Principles & Techniques. 5th ed. Philadelphia, PA: Mosby
Elsevier 2012:897–963.
Nahm KY, Kang JH, Moon SC, Choi YS, Kook YA, Kim SH, Huang J. Alveo-
lar bone loss around incisors in Class bidentoalveolar protrusion pa-
tients: A retrospective three-dimensional cone beam CT study. Dento-
maxillofac Radiol 2012;41(6):481-488.
Renkema AM, Fudalej PS, Renkema AA, Abbas F, Bronkhorst E, Katsaros
C. Gingival labial recessions in orthodontically treated and untreated
individuals: A case-control study. J Clin Periodontol 2013;40(6):631-
637.
Renkema AM, Fudalej PS, Renkema A, Kiekens R, Katsaros C. Develop-
ment of labial gingival recessions in orthodontically treated patients.
Am J Orthod Dentofacial Orthop 2013;143(2):206-212.
Richman C. Is gingival recession a consequence of an orthodontic tooth
size and/or tooth position discrepancy? “A paradigm shift.” Compend
Contin Educ Dent 2011;32(4):e.73-e79.
Rothe LE, Bollen AM, Little RM, Herring SW, Chaison JB, Chen CS, Hol-
lender LG. Trabecular and cortical bone as risk factors for orthodontic
relapse. Am J Orthod Dentofacial Orthop 2006;130(4):476-484.
150
Bockow
Sarver D, Yanosky M. Special considerations in diagnosis and treatment
planning. In: Graber LW, Vanarsdall RL, Vig KW, eds. Orthodontics:
Current Principles & Techniques. 5th ed. Philadelphia, PA: Mosby
Elsevier 2012:59–98.
Sarver DM, Proffit WR, Ackerman J. Diagnosis and treatment planning in
orthodontics. In: Graber TM, Vig KL, Vanarsdall RL, eds. Orthodontics:
Current Principles and Techniques. 4th ed. St. Louis, MO: Mosby Else-
Vier 2005:3-115.
Sebaoun JD, Kantarci A, Turner JW, Carvalho RS, Van Dyke TE, Ferguson
DJ. Modeling of trabecular, bone and lamina dura following selective
alveolar decortication in rats. J Periodontol 2008;79(9):1679–1688.
Shoreibah EA, Ibrahim SA, Attia MS, Diab MM. Clinical and radiographic
evaluation of bone grafting in corticotomy-facilitated orthodontics in
adults. J Int Acad Periodontol 2012;14(4):105-113.
Suya H. Corticotomy in orthodontics. In: Hosl E, Baldauf A, eds. Mechanical
and Biological Basis in Orthodontic Therapy. Heidelberg, Germany:
Huthig Buch Verlag 1991:207-226.
Ten Hoeve A, Mulie RM. The effect of antero-postero incisor repositioning
on the palatal cortex as studied with laminagraphy. J Clin Orthod
1976;10(11):804-822.
Vanarsdall RL, Musich DR. Adult interdisciplinary therapy: Diagnosis and
treatment. In: Graber LW, Vanarsdall RL, Vig KW, eds. Orthodontics:
Current Principles & Techniques. 5th ed. Philadelphia, PA: Mosby Else-
Vier 2012:843–896.
Vanarsdall RL, Musich DR. Adult orthodontics: Diagnosis and treatment.
In: Graber LW, Vanarsdall RL, Vig KWL, eds. Orthodontics: Current
Principles & Techniques. 3rd ed. Philadelphia, PA: Mosby Elsevier
2000:908.
Vercellotti T, Podesta A. Orthodontic microsurgery: A new surgically
guided technique for dental movement. Int J Periodontics Restorative
Dent 2007;27(4):325-331.
Wehrbein H, Bauer W, Diedrich P. Mandibular incisors, alveolar bone, and
Symphysis after orthodontic treatment. A retrospective study. Am J
Orthod Dentofacial Orthop 1996;110(3):239-246.
Wehrbein H, Fuhrmann RA, Diedrich PR. Periodontal conditions after
facial root tipping and palatal root torque of incisors. Am J Orthod
Dentofacial Orthop 1994;106(5):455-462.
151
Goal-oriented Treatment Planning
Wilcko MT, Wilcko WM, Pulver JJ, Bissada NF, Bouquot JE. Accelerated
osteogenic orthodontics technique: A 1-stage surgically facilitated
rapid orthodontic technique with alveolar augmentation. J Oral Maxil-
lofac Surg 2009;67(10):2149-2159.
Wilcko W, Wilcko MT. Accelerating tooth movement: The case for corti-
cotomy-induced orthodontics. Am J Orthod Dentofacial Orthop 2013;
144(1):4-12.
Wilcko WM, Ferguson DJ, Bouquot JE, Wilcho T. Rapid orthodontic de-
crowding with alveolar augmentation: Case report. World J Orthod
2003;4(3):197-205.
Wilcko WM, Wilcko MT, Bouquot JE, Ferguson DJ. Rapid orthodontics with
alveolar reshaping: Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001;21(1):9-19.
Yagci A, Velil, Uysal T, Ucar FI, Ozer T, Enhos S. Dehisence and fenestration
in skeletal Class I, II and Ill malocclusions assessed with cone-beam
computed tomography. Angle Orthod 2012;82(1):67-74.
152
THE USE OF PHOTOBIOMODULATION IN
ORTHODONTICS: SOME PERSPECTIVES ON AN
EXTRAORAL DEVICE
Chung How Kau
ABSTRACT
Photobiomodulation is an area of science that incorporates low-level light thera-
py. This is a controversial area in medicine with variable results. Photobiomodu-
lation has been used recently in orthodontics and shown some positive promise.
This chapter describes the use of photobiomodulation and how it is applied to
two orthodontics cases.
KEY WORDS: orthodontics, extraction therapy, photobiomodulation, accelerated
tooth movement, biomechanics
INTRODUCTION
The specialty of orthodontics is practiced on a global scale.
Highly trained professionals routinely perform the specialty and use a
variety of carefully prescribed biomechanical force systems to align teeth
orthodontically. Almost 2.5 million children in the United States receive
orthodontic treatment annually, but there is an increasing demand by
adults for similar treatment.
As the understanding of orthodontics therapy improves, the
focus of treatment now has become about treatment efficiencies (Kau,
2012b). Over the last 25 years, the main innovations have been around
the biomaterial and biomechanical characteristics of the tools of the
trade. These advancements have been at the level of the wire and bracket
interface (Proffit et al., 2012). Newer systems have made significant
improvements in the bracket technologies, examples of which include
friction-free systems using self-ligating brackets (Shivapuja and Berger,
1994) and temporary anchorage devices (TADs; Pace and Sandler, 2014).
There also have been advances to the initial wire properties of alignment
153
Photobiomodulation in Orthodontics
wires (Proffit et al., 2012; Jian et al., 2013) and the introduction of robotic
wire systems (Moles, 2009; Saxe et al., 2010). These innovations have
been present in the marketplace, but one may argue that they have
reached their peak and any further advancement will result in minimal
impact to the length of treatment (Kau, 2012a; Christou et al., 2013).
There has been a significant effort that now is exploring new
approaches to optimize treatment, which hopefully will lead to a
reduction in treatment time (Nimeri et al., 2013). These areas focus on
two main themes to improve treatment efficiencies. The first approach
is to create an accurate road map of the end point of orthodontic
treatment (Kau, 2012b). These treatment plans utilize sophisticated
three-dimensional (3D) virtual plans to simulate and predict the possible
pitfalls in a case. Often, these 3D virtual simulations provide the shortest
pathway between the initial maligned tooth position and the final tooth
position. These plans provide an excellent visualization for the delivery of
the best biomechanical plan and serves as an excellent avenue for patient
education. However, these virtual plans are criticized for not taking the
biology of tooth movement into consideration. The second approach
to improving treatment efficiency utilizes the biological response of the
tooth to mechanical stimulus during orthodontic treatment. A number
of possible methods have been suggested and some early research has
shown tremendous prospect (Kau et al., 2013).
BIOLOGY OF TOOTH MOVEMENT
The biology of tooth movement is a complex process (Krishnan
and Davidovitch, 2006). During orthodontic treatment, numerous
biological mechanisms need to happen before tooth movement can
occur. Some authors suggested that five microenvironments are altered
by orthodontic force: extracellular matrix, cell membrane, cytoskeleton,
nuclear protein and the genome (Masella and Meister, 2006). They also
Suggested that gene activation (or suppression) is the point at which
input becomes output, leading to the necessary changes in the five
environments.
There are four main theories of tooth movement: pressure
tension, biomechanical, piezoelectric and hydrodynamic theories. It is
difficult to go into a detailed account of each theory in this chapter, but
154
Kau
it is important to note that there is no single unifying theory for tooth
movement. Some researchers have postulated that within the first second
of orthodontic treatment, some bone bending occurs, which leads to a
piezoelectric phenomenon (Proffit et al., 2012). As the duration of the
applied force increases, the “force-subjected” progenitor cells in the
PDL differentiate into compression-associated osteoclasts and tension-
associated osteoblasts (Reitan, 1951).
Once tooth movement has been initiated, genes controlling
osteogenesis are upregulated. Many genes release proteins that create
a cascade of events. Some of these proteins include: TF Cbfa1; bone
morphogenetic proteins (BMPs; Winkler et al., 2003); transforming
growth factor-beta (TGF-3); and growth factors. These series of events
lead to resorption and deposition of bone, and ultimately contribute to
tooth movement, which is dependent to the force delivery to the tooth.
METHODS TO ENHANCE TOOTH MOVEMENT
Clinically, three main methods of enhancing tooth movement
(ETM) have been proposed; chemical-led interactions; surgery; and
device assisted therapies (Nimeri et al., 2013).
Chemical-led interventions have been proposed as a mechanism
and fall into four major groups (Krishnan and Davidovitch, 2006). The first
group involves endothelial growth factors (EGF) and vascular endothelial
growth factor (VEGF) for regulating angiogensis. The second involves
a number of major groups. The third group involves bone resorptive
factors like receptor activator of nuclear factor kappa-B ligand (RANKL),
leukotienes and macrophase colony stimulating factors. Studies in
these areas are limited and varied, making the understanding of these
mechanisms difficult.
Two surgical techniques have been described including tra-
ditional osteotomies (for patients with dentofacial deformities) and
corticotomies. The most popular method is the corticotomy (Murphy
et al., 2009; Wilcko and Wilcko, 2013) in which clinicians raise surgical
flaps around the dentoalveolar complex and create selective buccal and
lingual decortications of alveolar bone. The wound sites often are packed
with new bone or bony substitutes, resutured and allowed to heal. Active
orthodontic treatment is applied immediately. The results from studies
employing corticotomies have been variable with strong support in some
155
Photobiomodulation in Orthodontics
instances and less in others (Sebaoun et al., 2008). The most important
finding, however, is that a window period of intervention occurrs following
the surgical procedures. Once the wound resolution of the corticotomy
sites is completed, the effects of the accelerated tooth movement
return to the rates of the control sites (Han et al., 2008). Therefore, the
effects of surgery, though effective, need to be planned carefully with
the orthodontic protocol and timed precisely for maximum effect during
the course of treatment. Furthermore, no randomized clinical trials have
been conducted to understanding the effects of surgical corticotomies.
The last category used in biological enhancing orthodontic tooth
movement involves device-assisted therapy (DAT; Kau et al., 2013). A
number of DAT systems have been suggested including low-level light
therapy (LLLT), electrical currents, cyclic forces and resonance vibration
(Kau et al., 2013).
PHOTOBIOMODULATION OR LIGHT-ACCELERATED
ORTHODONTICS (LAOSs)
Light-accelerated orthodontics is an intervention technique that
falls within the scope of photobiomodulation or low-level light therapy
(LLLT). The term photobiomodulation is favored in this chapter as the
specific wavelength range, intensity and light penetration is specific (Kau
et al., 2013). .
Photobiomodulation is an emerging area of science that shows
promise in producing a non-invasive stimulation of the dentoalveolar
complex (Ross, 2012). It has been postulated that photobiomodulation
may have an effect on the final enzyme in ATP production by the
mitochondrial cells. This enzyme “cytochrome oxidase cº is amenable to
light and its function may be upregulated by specific wavelengths of light,
most commonly in the infrared spectrum. Oron and colleagues (2007)
found a two-fold increase in adenosine triphosphate (ATP) production with
LLLT treatment. An increase to the amount of ATP in a localized site may
allow cells undergoing a remodeling process to benefit from increased
metabolic activity. During the tooth movement phase of orthodontic
treatment, an increase in ATP availability may help cells complete their
tasks more rapidly or “turn over” more efficiently, hence leading to an
increased remodeling process and accelerated tooth movement. A second
156
Kau
postulation of photobiomodulation is the increased vascular activity that
the targeted site might benefit from with the increased light intensity.
A number of clinical case series have showed an enhanced effect
with photobiomodulation (Kau et al., 2013). Youssef and associates
(2008) showed an increased velocity if canine movement and decreased
pain in a laser group with varying dose exposures. Cruz and coworkers
(2004) also showed significantly higher acceleration of the retraction of
treated canines.
MATERIALS AND METHODS: CASE REPORTS
Subject Recruitment
This monograph describes two case reports. Subjects for the
study were recruited from the University of Alabama Birmingham clinical
study on photobiomodulation. The study received Institutional Review
Board approval prior to the start of the individual trials. Both subjects
were patients requiring orthodontic treatment. They met the following
inclusion criteria and were invited to participate in the study:
1. Permanent dentition;
2. Patients who in the opinion of the investigating
orthodontist will be compliant with device use;
3. Class I malocclusion with irregularity score of > 6mm
in either arch;
4. Bicuspid extractions; and
5. Good oral hygiene as determined by the investigating
Orthodontist.
The exclusion criteria for the study were as follows:
1. Any medical or dental condition that, in the opinion
of the investigating orthodontist, could affect study
results negatively during the expected length of the
Study;
2. Patient currently is using an investigational drug or
other investigational device;
3. Patient plans to relocate or move during the treatment
period;
4. Patient has an allergy to acetaminophen (use of aspirin
157
Photobiomodulation in Orthodontics
or non-steroidal anti-inflammatory drugs is excluded
for patients while on the study);
5. Use of bisphosphonates (osteoporosis drugs) during
the study; and
6. Pregnant females.
Device Description
The OrthoPulse is an LLLT device manufactured by Biolux Research
Ltd. (Vancouver, Canada). It is intended to provide stimulation for
accelerating orthodontic movement of teeth, according to the principles
of photobiomodulation. The OrthoPulse produces low levels of light with
a near infrared wavelength of 850 nm and an intensity of less than 100
mW/cm3 continuous wave. Industry standard light emitting diodes (LEDs)
are used to product the light, with arrays of emitters arranged on a series
of treatment arrays to cover the target area of the alveolus of both the
maxilla and mandible.
The OrthoPulse (Fig. 1) consists of three main components:
1. A small, handheld controller that houses the micro-
processor, the menu driven software and the LCD
screen. The controller is programmable by the inves-
tigating orthodontist for the number of treatment
sessions and the session duration. The user interface
indicates to the patient the number of sessions com-
pleted and the remaining time in each session. The
controller plugs into the power mains via a medically
approved, UL-certified power supply.
2. A set of four extraoral treatment arrays, each with
a flexible printed circuit board and a set of LEDs
mounted to a contoured heat sink and infrared-
transmissible plastic lens with conductive cables to
the controller.
3. A headset, similar to an eyeglass support structure,
to be worn by the patient on a daily or weekly basis,
with attachment and adjustment mechanisms for
158
Kau
ºr-nº-ul------------------------- Your Orthopulse Treatment
--------------
º * - --------------- -
-- - - --- -
----------- -
* ------------
The Full ºut-ºu-------
*** * *-ºn-º-º-º-removed ºn-ºn-º-º-º-
- -º-º-º-º-º-º-º-º-º-º-º-º-------
- - - ºn tº uniºn ºn
- - ºneº-
- - ºn-º-º-º-º-º-º-º-º-º-º-º-º-º-º-
- ---------
º - + º-º-º-º-º-º-º-º-º-º-º-º-º:
- *** -º-º-º-º-º-º-º-º-º-
*-tº-º-º-º-º-º-º-º-º-º-º-º-º:
ºn-º-º-º-º-º-º-º-º-º-º-ºn-ºn-
* ------------ ----------
*** -º- ºr -º-º-º-º:
- --------
- *-------- --------------
------------- ---
-------- ---
- - - - -
Z --- -----------
Figure 1. Extraoral photobiomodulation device showing the assembly of the
lights and the controller. Careful instructions are given to the patient to comply
With treatment.
positioning the treatment arrays in the appropriate
location for the given patient.
At no point during this study were the normal orthodontic treatments,
procedures or equipment altered. All light treatments were provided
extraorally with the OrthoPulse device. Any heat generated as a by-
product of light generation was monitored and maintained below
thresholds of electro-medical device safety standards. The device also
monitored and recorded patient compliance by detecting face contact
and only operating the treatment arrays when the patient wore the
device and the investigating orthodontist could obtain compliance data
at each patient visit.
The Orthopulse device is a Class || medical device in the U.S. and
Canada, and a Class 2a device in Europe. For the purpose of this study,
use of the OrthoPulse according to the protocol was determined to be a
non-Significant risk.





159
Photobiomodulation in Orthodontics
DEVICE USAGE BYSUBJECTS
Both subjects in this report received the photobiomodulation de-
vice and used it for 20 minutes per day. The details of the protocol are
presented below.
Tooth Movement Assessments
The alignment phase of orthodontic treatment was evaluated
in this case report. Outcomes assessments were performed every two
weeks for a six-week period and then every four weeks until alignment
was achieved completely.
Tooth movement was assessed primarily by Little's Index of
Displacement. The Little's Index was performed at baseline and each
subsequent visit. Measurements were made at the five contact points for
the anterior teeth located between canine teeth for each arch. The index
recorded in millimeters the displacements for each of the five points.
The changes in tooth position were recorded by designated calibrated
operators at each site.
Clinical Pictures and Compliance Data
Compliance with device usage was captured by an inbuilt micro-
processor embedded within the controller, which recorded the number
of sessions and minutes the Orthopulse device was activated. In addition,
clinical pictures representing the occlusal views and buccal views of the
dentition were recorded at each visit of the case report.
Orthodontic Mechanics Used
Traditional orthodontic brackets and wires were used for both
subjects. The wire sequence consisted of alignment wires followed by
working wires for tooth movement. Once space closure was complete, a
process of individual tooth detailing was carried out to finish the occlu-
SIO'ſ).
Results
Both subjects presented at the time of treatment requiring
bicuspid extractions for crowding or to decompensate the incisor position.
160
Kau
Subject 1
The 13-year-old Hispranic female presented with severe crowd-
ing in the lower arch (Figs. 2-6). To treat the malocclusion, first bicuspids
were extracted to alleviate the crowding. The extractions were complet-
ed before orthodontic appliances were placed. Alignment was carried out
using 0.014" x 17" x 25" Niſi wires. Once complete, 19" x 25" stainless
Steel working wires were used to complete space closure. Detailed finish-
ing bends also were incorporated.
Alignment was complete within ten weeks and the case was
deemed clinically complete (clinical objectives met) in fifteen months of
treatment.
Figure 3. Alignment complete in ten weeks.

161
Photobiomodulation in Orthodontics
Figure 6. Case 1: Final occlusion.

162
Kau
Subject 2
This was a more complex orthodontic case involving a twelve-year-
old African-American female with a vertical maxillary excess and Class bi-
maxillary protrusive dentition (Figs. 7–11). To treat the malocclusion, first
bicuspids were extracted to correct the bi-maxillary protrusive dentition.
Added anchorage was required by the use of a headgear and soldered
transpalatal arch. The extractions were completed before orthodontic
appliances were placed. Alignment was carried out using 0.014" to 17”
x 25" Niſi wires. Once complete, 19" x 25" stainless steel working wires
were used to complete space closure. Detailed finishing bends also were
incorporated.
Figure 8. Alignment and anchorage.

163
Photobiomodulation in Orthodontics
Figure 11. Completion of orthodontic treatment.
Alignment was complete within ten weeks of treatment and the
case was deemed clinically complete meeting the clinical objectives in
eighteen months of treatment.

164
Kau
DISCUSSION
The report on two subjects represented a “start to finish” case
Series. Both subjects used photobiomodulation as adjunctive therapy to
traditional orthodontic therapy.
Photobiomoculation and Past Research
Light therapy in medicine has received mixed reviews (Genc et
al., 2013; Ge et al., 2014). Studies have shown that photobiomodulation
works if the right wavelength and intensities are applied. Ge and
colleagues (2014) showed that light therapy at wavelengths of 660 nm
produced a greater amount of bone mass around the teeth of rats.
Dibart and associates (2014) showed that a laser type semi-conductor
diode emitting infrared laser with a wavelength of 808 nm, 0.25 m W and
ten seconds of exposure produced increased rates of tooth movement
during canine retraction phase of orthodontic treatment. The findings of
increased rates of tooth movement corresponded to studies by Kawasaki
and associates (2000) and Yoshida and colleagues (2009). In these
Studies, a similar rate of tooth movement was recorded in experimental
rats. Faster rates of tooth movement (2.08 fold) were reported by Kim
and coworkers (2009) when studying tooth movement in dogs over a
two-month period. Yoshida and colleagues (2009) showed that a pulsed
method of light delivery, rather than a constant one, produced better
results.
Alignment Rates as Compared to Historical Data
Light and continuous forces applied to the dentoalveolar complex
produce ideal rates of alignment. The efficiency of initial orthodontic
treatment has not been studied extensively and only a small number of
Studies have been reported. Fleming and coworkers (2010) used a 3D
measurement technique and Little's Irregularity Index (Fleming et al.,
2010). Compared to previously reported studies, the rates of alignment in
the OrthoPulse study were significantly faster. The rate of 1.24 mm/week
represented a 100% increase to the control. When comparing the mean
rates of tooth movement in patients undergoing extractions to previous
Studies, the OrthoPulse cohort's rate of tooth movement was much
higher than in the reported studies (Fig. 12). One important aspect of the
previous studies was that the initial LLl was smaller than the OrthoPulse
165
Photobiomodulation in Orthodontics


–
––
c - -
Control Test
Figure 12. Boxplots showing differences in alignment rates (mm/week) between
control and patients using photobiomodulation device (Kau et al., 2013).
groups in these data sets. What is not known is whether the amounts of
crowding and the greater need to overcome displacements of the initial
malocclusion played an important role in the rates of tooth movement.
Kau and colleagues (2013) reported on the alignment rate using the same
device indicated more than a two-fold increase in the rate of alignment.
In this case report, alignment was complete within a ten- to twelve-week
period.

Case Completion
In this report, no controls were presented. It is safe to Say,
however, that most orthodontic treatment requiring extractions takes at
least 24 months of treatment to complete. In these two cases, clinical
case completion rates were reported at eighteen months or less, which
represents an improvement in treatment efficiency.
FUTURE DIRECTION OF ORTHODONTICS
In the near future, photobiomodulation devices might be
administered as intraoral rather than extraoral devices. This advancement
will allow the light to be delivered closer to the target sight and, therefore,
166
Kau
reduce the need for a protracted light exposure time. It is postulated that
light therapy then could be administered for less than three minutes.
In addition to photobiomodulation, orthodontists may combine
3D visualization with targeted orthodontic therapies, thus enhancing
the efficiencies through both a biological and mechanical approach.
A substantial reduction in treatment also potentially will reduce the
unwanted effects of orthodontictreatment that include gingival recession,
decalcification lesions on the surfaces of teeth and patient enthusiasm
for the treatment.
CONCLUSIONS
Biological therapies are being developed constantly in orthodon-
tics. Photobiomodulation represents one of the many types of biology-
modifying devices that may be used in orthodontics. More research and
innovation still are required to comprehend the biological mechanism for
these types of devices fully.
REFERENCES
Christou T, Kau CH, Waite PD, Kheir NA, Mouritsen D. Modified method
of analysis for surgical correction of facial asymmetry. Ann Maxillofac
Surg 2013;3(2):185-191.
Cruz DR, Kohara EK, Ribeiro MS, Wetter NU. Effects of low-intensity laser
therapy on the orthodontic movement velocity of human teeth: A
preliminary study. Lasers Surg Med 2004;35(2):117-120.
Dibart S, Yee C, Surmenian J, Sebaoun JD, Baloul S, Goguet-Surmenian
E, Kantarci A. Tissue response during piezocision-assisted tooth
movement: A histological study in rats. Eur J Orthod 2014;36(4):457-
464.
Fleming PS, DiBiase AT, Lee RT. Randomized clinical trial of orthodontic
treatment efficiency with self-ligating and conventional fixed orth-
odontic appliances. Am J Orthod Dentofacial Orthop 2010;137(6):738–
742.
Ge MK, He WL, Chen J, Wen C, Yin X, Hu ZA, Liu ZP, Zou SJ. Efficacy of
low-level laser therapy for accelerating tooth movement during
orthodontic treatment: A systematic review and meta-analysis. Lasers
MedSci 2014 Feb 20. [Epub ahead of print]
167
Photobiomodulation in Orthodontics
Genc G, Kocadereli I, Tasar F, Kilinc K, El S, Sarkarati B. Effect of low-level
laser therapy (LLLT) on orthodontic tooth movement. Lasers Med Sci
2013;28(1):41-47.
Han XL, Meng Y, Kang N, Lv T, Bai D. Expression of osteocalcin during
surgically assisted rapid orthodontic tooth movement in beagle dogs. J
Oral Maxillofac Surg 2008;66(12):2467-2475.
Jian F, Lai W, Furness S, McIntyre GT, Millett DT, Hickman J, Wang Y. Initial
arch wires for tooth alignment during orthodontic treatment with
fixed appliances. Cochrane Database Syst Rev 2013;4:CD007859.
Kau CH. Biotechnology in orthodontics photo biomodulation. Dentistry
2012a;2:e 108.
Kau CH. Orthodontics in the 21st century: A view from across the pond. J
Orthod 2012b;39(2):75-76.
Kau CH, Kantarci A, Shaughnessy T. Vachiramon A, Santiwong P. de la
Fuente A, Skrenes D, Ma D, Brawn P. Photobiomodulation accelerates
orthodontic alignment in the early phase of treatment. Prog Orthod
2013;14:30.
Kawasaki K, Shimizu N. Effects of low-energy laser irradiation on bone
remodeling during experimental tooth movement in rats. Lasers Surg
Med 2000;26(3):282-291.
Kim SJ, Moon SU, Kang SG, Park YG. Effects of low-level laser therapy after
corticision on tooth movement and paradental remodeling. Lasers
Surg Med 2009;41(7):524–533.
Krishnan V, Davidovitch Z. Cellular, molecular, and tissue-level reactions
to orthodontic force. Am J Orthod Dentofacial Orthop 2006;129(4):
469.e1-e32.
Masella RS, Meister M. Current concepts in the biology of orthodontic
tooth movement. Am J Orthod Dentofacial Orthop 2006;129(4):458-
468.
Moles R. The SureSmile system in orthodontic practice. J Clin Orthod
2009;43(3):161-174.
Murphy KG, Wilcko MT, Wilcko WM, Ferguson DJ. Periodontal accelerated
osteogenic orthodontics: A description of the surgical technique. J Oral
Maxillofac Surg 2009;67(10):2160-2166.
168
Kau
Nimeri G, Kau CH, Abou-Kheir NS, Corona R. Acceleration of tooth
movement during orthodontic treatment: A frontier in orthodontics.
Prog Orthod 2013;14:42.
Oron U, Ilic S, De Taboada L., Streeter J. Ga-As (808 nm) laser irradiation
enhances ATP production in human neuronal cells in culture. Photomed
Laser Surg 2007;25(3):180-182.
Pace A, Sandler J. TADs: An evolutionary road to success. Dent Update
2014;41(3):242-244, 247-249.
Proffit WR, Fields HW, Sarver DM, eds. Contemporary Orthodontics. 5th
ed. St Louis, MO: Mosby Elsevier 2012.
Reitan K. The initial tissue reaction incident to orthodontic tooth
movement as related to the influence of function: An experimental
histologic study on animal and human material. Acta Odontol Scand
Suppl 1951;6:1-240.
Ross G. Photobiomodulation in dentistry. Photomed Laser Surg 2012;30
(10):565-567.
Saxe AK, Louie LJ, Mah J. Efficiency and effectiveness of SureSmile. World
J Orthod 2010;11(1):16-22.
Sebaoun JD, Kantarci A, Turner JW, Carvalho RS, Van Dyke TE, Ferguson
DJ. Modeling of trabecular bone and lamina dura following selective
alveolar decortication in rats. J Periodontol 2008;79(9):1679-1688.
Shivapuja PK, Berger J. A comparative study of conventional ligation and
self-ligation bracket systems. Am J Orthod Dentofacial Orthop 1994;
106(5):472-480. -
Wilcko W, Wilcko MT. Accelerating tooth movement: The case for cor-
ticotomy-induced orthodontics. Am J Orthod Dentofacial Orthop
2013;144(1):4-12.
Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE,
Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby
M, Brunkow ME, Latham JA. Osteocyte control of bone formation via
sclerostin: A novel BMP antagonist. EMBO J 2003 1:22(23):6267-6276.
Yoshida T, Yamaguchi M, Utsunomiya T, Kato M, Arai Y, Kaneda T, Yamamoto
H, Kasai K. Low-energy laser irradiation accelerates the velocity of
tooth movement via stimulation of the alveolar bone remodeling.
Orthod Craniofac Res 2009;12(4):289-298.
169
Photobiomodulation in Orthodontics
Youssef M, Ashkar S, Hamade E, Gutknecht N, Lampert F. Mir M. The
effect of low-level laser therapy during orthodontic movement: A
preliminary study. Lasers MedSci 2008;23(1):27-33.
170
TEN YEARS WITH SURESMILE@:
CLINICAL PROSPECTS AND LIMITATIONS
Ronald J. Snyder
ABSTRACT
As one of the original SureSmile” users with more than 10 years' experience, the
author gives insights into corporate claims relative to university-based outcome
assessment studies performed on the author's treated patients. Once the
university Studies are reviewed, a clear distinction is made between corporate
conclusions and those of independent researchers. Underlying this distinction
is a truncated view of knowledge which is exposed once corporate ends are
understood; knowledge ceases to be knowledge the more ends are limited to
the financial. This chapter contrasts the prospects of robotically bent copper
nickel titanium (NiTi) finishing wires with the limitations inherent in corporate
relationships, continuous arch wires and the patient's skeletal needs.
KEY WORDS: SureSmile”, technology, outcome assessment, ends, knowledge
| began my contractual relationship with SureSmile” in 2003
with my first scan as a beta test site. Since then, I have continued the
relationship, completed over 692 cases and have been involved in
three independent investigations. To date, the only published university
treatment outcome study, completely independent of SureSmile"
(without a potential conflict of interest), has been performed at the
University of Indiana (Alford et al., 2011). Two resident theses also have
been performed at New York's Montefiore Medical Center (Rangwala,
2012) and The University of Michigan (Groth, 2012). Both are treatment
outcome assessment studies of SureSmile” compared to conventional
orthodontic treatment using the American Board of Orthodontics grading
System (Groth, 2012; Rangwala, 2012). The Indiana and Michigan studies
both involved case selection at my private practice in Apple Valley, MN.
This chapter will be limited to their review.
171
Ten Years with SureSmile”
Oral/Metrix", the owner of SureSmile”, promises significant pros-
pects, yet offers little as to their product’s limitations. Having no conflict
of interest, this chapter independently looks at both the prospects and
the limitations of OraſWetrix's" computer-aided designed/computer-aid-
ed manufactured (CAD/CAM) customized orthodontic wires by reviewing
university-based studies from my practice in addition to my personal ex-
perience with the product.
In 2002, Charlene White, orthodontic consultant and owner of
Progressive Concept, Inc., advised me to consider means to leverage the
newer technologies in order to expedite my orthodontic finishing. Her
management review revealed an average of 22 months for each orth-
odontic case with a higher than average number of clinical appointments.
| offer a two-phased solo orthodontic practice with dentofacial manage-
ment that typically precedes the full-braces phase. The braces phase rou-
tinely involves indirect bonding, posterior banding, maxillary and man-
dibular self-ligating lingual arches, arch wire detailing and extraoral aux-
iliaries as needed. As the admissions chair of the Midwest Angle Society
and future American Board of Orthodontics (ABO) examiner, I routinely
studied my final outcomes with model, photograph and cephalometric
review. When OraſWetrix” asked me to become a beta test site, I was in-
terested in reducing my patient's treatment times and improving their
treatment outcomes by leveraging the properties of shape memory alloy
Orthodontic wires.
Based on its in-house studies (www.suresmile.com), Oral/etrix”
claims that the SureSmile” system has the ability to produce finishes that
are of the highest quality while reducing treatment time by up to 40%.
The SureSmile” system is broken down easily into three components:
1. Three-dimensional (3D) scan (intraoral or CBCT) of
brackets/bands after initial leveling/aligning;
2. Virtual finishing; and
3. Robotic wire fabrication of primarily copper NiTi with
options of identical bendable wires—beta titanium,
stainless steel (Elgiloy”).
When assessing the claims by a manufacturer, one must consid-
er the difference in the final mission of a corporation and those of a
172
Snyder
SureSmile
Better quality. Less time. = .
30.7
26.3 23.0
15.8
CFE MOS
29.6
24.1
23.4
22.4
20.8 200
18.5
CFE
21.6
17.0
CRE
UNIV Montefiore º
-º-º-º-º-º- M_i.
Figure 1. University-based outcome comparison studies. CRE = case report ex-
amination; OGS = objective grading system.
MOS
Clinician in search for truth through knowledge. Financial ends naturally
restrict the corporation's view of knowledge, as it must satisfy its
investors. The clinician, on the other hand, has a broader view of things.
This difference is evident in a recent orthodontics trade journal; a typical
Corporate tool used to put forth their unscientific claims. A corporate
profile article (Oral Metrix, 2014) includes a graph (Fig. 1) depicting the
findings of four university-based outcome studies comparing outcomes
of SureSmile" and conventionally treated cases. The graph, titled “Better
quality less time,” is a means to legitimize their corporate claims. Having
personally participated in three of the four university studies shown in
the graph, I readily discovered that the CRE score from the Indiana study
is wrong. Moreover, the UNLV CRE scores and the Indiana CRE scores have
been transposed. Since a 26.3-30.7 CRE score likely would not pass the
ABO, the UNLV study (Saxe et al., 2010) needs to be reviewed closely.
A conflict of interest is apparent readily in the UNLV study (Saxe
et al., 2010) as The Dallas Marketing Group performed the statistical
analyses. SureSmileº's parent company, Oral/etrix", is a client of The
Dallas Marketing Group, thus it is in all of the stakeholders' best interest






173
Ten Years with SureSmile”
to have the Statistical analyses support the conclusion that SureSmile”
offers a superior treatment outcome in a shorter time compared to
conventional brackets.
An example from the Saxe and colleagues' (2010) manuscript
of how the statistics were biased can be found in the methodology. The
treatment groups were reported as n = 38 SureSmile” subjects and n =
24 conventional subjects. Two calibrated graders generated outcome
scores for each group using the ABO Objective Grading System (OGS).
Yet, when the authors assessed the differences in OGS Scores between
the treatment groups (see Tables 2 and 5 in Saxe et al., 2010), they
combined the OGS scores from each grader, thereby doubling the sam-
ple size for each group (n = 76 for SureSmile” treatment and n = 48 for
conventionäl treatment). The authors then claimed that these scores
were independent measurements when, in fact, they were not because
they did not come from 76 and 48 subjects, respectively. This is an ex-
ample of pseudoreplication (Lazic, 2010), which invalidates the “inde-
pendent samples difference of means test” used to analyze differences
between the treatments. Instead, the treatment groups should have
been divided equally between the two graders such that each subject
was graded only once. By doing this, however, the statistical power drops
dramatically because the sample sizes are halved, which makes it likely
that no statistically significant benefit of SureSmile” treatment would be
detected. Thus, by combining the measurements from the two graders
and claiming that each measurement is independent, Saxe and coworkers
(2010) can skew statistical differences between the treatment groups
toward or away from significance in favor of their preferred conclusion
that SureSmile” treatment offers improved outcomes compared to
conventional treatment. Another questionable aspect of this study is
the lack of demographic data on the subjects beyond reporting that they
were treated in three private practices. Publishing an erroneous, bold-
Colored bar graph displaying mean quality assessment numbers that very
likely would not pass the ABO simply is not knowledge.
Properly designed university-based studies, on the other hand,
seek an end entirely independent of the corporation. Dr. Tim Alford, part-
time faculty member at the University of Indiana, in partial fulfillment
of his requirement for admission to the Midwest Component of the
Edward H. Angle Society, and associates (2011) looked into the two
174
Snyder
primary SureSmile" claims: faster treatment and better outcomes. Since
the article is published in the Angle Orthodontist and available in the
Moyers Monograph series (Snyder, 2012), I will give a brief summary of
the investigator's findings.
INDIANA STUDY
Alford and coworkers (2011) analyzed a sample of 132
consecutively finished, cooperative patients treated without extractions
in my practice. The practicing orthodontist and the Indiana investigators
were blinded in the case selection regarding the method of treatment.
Variables studied include: time; the discrepancy index (DI: a degree of
difficulty measure); and the Cast Radiograph Evaluation (CRE) scoring,
otherwise known as the ABO's Objective Grading System (American Board
of Orthodontics, 2012). The findings of the Alford study (2011) showed
that SureSmile” statistically improved treatment time by seven months.
However, the conventional group had more pre-braces orthopedic
treatment compared to the SureSmile” group (62% conventional, 42%
SureSmile”), which suggests that the conventional group includes more
difficult orthodontic cases. This was supported by the DI findings which
showed that the SureSmile” group with a mean of 13.3 had significantly
lower DI mean scores (easier cases) compared to the conventional
mean of 15.8. These scores must be tempered by the fact that the ABO
requires three of the six submitted cases to have Dls of 20 or greater. Vu
and associates (2008) showed that the higher the Dl at the beginning of
treatment, the higher the CRE scoring at the end of treatment. -
When the variable of quality was evaluated, no significant
difference was found; however, a trend emerged that suggested that
SureSmile” improved finishing with a mean CRE score of 18.5 compared
to the conventional group of 20.8. It is important to note that the ABO
does not have strict cutoffs for passing and failing the board exam, though
it commonly is believed that a score of less than 26 will pass and a score
over 30 most likely will fail. Again, these findings must be interpreted in
light of the fact that the SureSmile” group had a lower mean DI and fewer
patients with pre-braces orthopedic treatment.
Shortcomings of the Alford and associates' (2011) study included
a non-randomized sample and the consecutively treated cases were not
175
Ten Years with SureSmile”
started consecutively. Additionally, cases were selected that were without
compliance problems, which effectively entered bias into the consecutive
nature of the sample. Since the sample was not matched for age, DI or
Angle Class, the demographics are unclear. Finally, due to the presence
of pre-braces orthopedic treatment, the sample could be assumed to be
essentially Class I as evident by the mild mean Dl scores.
MICHIGAN STUDY
The author participated in Dr. Christian Groth's multi-center
analysis of finished quality of treated non-extraction cases. He looked at
the difference between a consecutively treated SureSmile” group and
a matched conventional group regarding time management and quality
outcomes. The control matching done by The University of Michigan
sheds new light on the claims of Orametrix”. The control-matching
procedure took into account age, the DI primarily and, if possible, the
Angle Classification. Groth (2012) found no significant difference between
the groups in starting form; therefore, any difference in the final result
can be attributed to the treatment modality. The match produced 89
consecutively and conventionally treated cases from three ABO practices—
one being mine—and 89 consecutively treated SureSmile” cases from
three experienced SureSmile” providers (greater than four years). Groth
was blinded regarding the method when he visited all practices to make
case selection. Potential bias is present if the provider withholds finished
cases, which this author did not. The DI was matched to within one Dl
point positively or negatively. The resulting two treatment groups had
no statistical difference in either the Dl score or Angle Classification
distribution prior to treatment. Inclusion/exclusion criteria included no
early de-bonded patients, no surgical patients, non-extraction, ages 12
to 18 at the start of braces treatment, a full natural dentition and second
molars in occlusion in the finished model. Pre-braces treatment was
permitted since the goal of the study was to examine the finishing phase.
There were no clinically significant differences between the
Dl groups SureSmile” 7.7 and conventional 7.8. The lower scores are
attributed in part to the fact that cephalometric variables were not
included and, in part, due to the fact that “the average case in this
sample is classified as having a mild malocclusion” (Groth, 2012). While
176
Snyder
the distribution of the DI scores showed that the SureSmile” group
contained more patients in the 0 to 5 range and the conventional group
had more patients in the 6 to 10 range, this difference was not significant
(Fig. 2). A Chi-square test was conducted to assess the distribution of
the Angle Classifications between the groups. There was no statistical
difference in the distribution of Angle Classification between the two
groups (p = 0.264); however, Table 1 illustrates that Class I and Class ||
end on account for 86.5% (SureSmile”) and 85.4% (conventional)—
percentages supporting the small D] scores (easy cases). The three
combined SureSmile" practices completed treatment in a statistically
shorter time (15.8 months) compared to the three conventional practices
(23.0 months; Fig. 3). The SureSmile” group finished seven months (40%)
faster and with eight (47%) fewer adjustment appointments. This was a
highly significant difference (p<0.001; Table 2). Finally, linear regression
suggests that as the complexity of the case increased, the SureSmile”
group tended to have higher CRE scores compared to the conventional
group (Fig. 4). Interestingly, all of the SureSmile" practices showed this
positive trend, while the conventional practices did not. The Michigan
group (Groth, 2012) concluded that “the SureSmile” system may not be
as effective in patients with higher levels of pre-treatment difficulty.”
The shortcomings of the Michigan study are similar to those of
the Indiana study (Alford et al., 2011); the sample was not randomized,
Cases were selected without compliance problems and due to the
matching, the sample was essentially Class I. The control matching of
Michigan's multi-center analysis generated a normal total CRE distribution
of relatively mild malocclusions (Fig. 5), many of which would not pass a
typical ABO passing score of 26.
After over ten years as a SureSmile” provider, I see its primary
limitation to be a finishing wire for relatively easy orthodontic cases at best.
The limitation rests in continuous arch side effects of a light force wire in
all dimensions. The advent of computer-aided design for fine orthodontic
tooth movement must acknowledge that finishing in orthodontics rests
primarily in the management of the dentofacial complex. Ouality finishing
is enabled by the correction and control of the skeletal/muscular system.
Angle, Brodie, Tweed, Kesling, Merrifield, Ricketts, Andrews,
Roth, Creekmore and many others went well beyond the limited concept
177
Ten Years with SureSmile"
conventional
| - SureSmile
| T ºn -
0–5 6-10
11-15 16-20 21–25
Discrepancy Index Scores
Figure 2. Discrepancy index distribution (Groth, 2012).
35-
122
5-O-5
1
O.
5
-
º
º
º
SureSmile conventional
Figure 3. Treatment time practice comparison (Groth, 2012).



178
Snyder
Table 1. Illustration that Class I and || end-on account for Angle clas-
sification demographics (Groth, 2012).
SureSmile” Conventional
Angle Classification Number 9% Number %
Class | 69 77.5 61 68.5
Class I end on 8 9.0 15 16.9
Class || 12 13.5 13 14.6
Class || O 0.0 O 0.0
TOTAL 89 100.0 | 89 100.0
Table 2. Adjustment appointment data (Groth, 2012).
Number of Adjustments
Group Mean SD
Conventional (33 male, 56 female) 17.2 2.6
SureSmile" (41 male, 48 female) 9.2 3.5
sº." º
SureSmile
• conventional
SureSmile
5- --------- conventional
O 5 10 15 20 25
Discrepancy Index
Figure 4. Linear regression scatter plot (Groth, 2012).

179

Ten Years With SureSmile"
30
2
5
-SureSmile
ºnconventional
0–5 6–10 11-15 16–20 21-25 || 26–30 31–35 36-40 -40
2
O
5
Cast& Radiograph Evaluation Score
Figure 5. In normal distribution of relatively mild malocclusion, a large percent-
age would not pass the ABO (Groth, 2012).
of finishing through tooth movement alone. For example, the rapidly
maturing ten-year, eight-month-old female in Figure 6 illustrates the
critical contribution of dentofacial management to orthodontic finishing.
The degree of her facial convexity, overjet and mandibular retrognathia
precludes any thought of orthodontic finishing without the management
of her skeletal discrepancy (Fig. 7). However, 18 months of orthopedic
treatment (Fig. 8) with a banded rapid palatal expander and a Mandibular
Anterior Reposition Appliance (MARA) enabled conventional finishing
aimed at uprighting the lower incisors and detailing the occlusion. The
subsequent 17 months of braces were more than reasonable considering
the degree of the pre-treatment skeletal Class || (Figs. 9-11).
Due to the layers of complexity in malocclusions, the notion of
an orthodontic archwire, regardless of its sophistication and capacity for
treating 100% of orthodontic problems to ABO quality outcomes is not
realistic. The fact that Oral/etrix" requires contractual guarantees reveals
that their end is not entirely in the best interest of quality finishing since
quality finishing rests in large part in orthopedic management and the
control of continuous arch side effects (Koenig and Burstone, 1989).
180
Figure 7. Initial lateral cephalometric records.

181
Ten Years With SureSmile"
Figure 9. Serial photographs: initial to final.

182
Snyder
Pre-treatment Post-MARA 18 months *. 17 months
races
Figure 10. Serial lateral cephalograms: initial to final.
Post-MARA 18 months Post-treatment 17 months
braces
Pre-treatment
Figure 11. Good finishing requires good beginnings.
The only university-based studies to date that are independent
of Oral/etrix" entirely have been able to show quality finishing with
the SureSmile" system on Class I and Class || end-on patients, which
are the minority in most specialty practices. The cost does not justify
Contracted case requirements if the system can deliver quality only for
the few. Further, a management problem can exist when states regulate
the duties of orthodontic assistants. The state of Minnesota, for instance,
restricts the removal of the orthodontic archwire to general supervision.
SureSmile" light scans or CBCT imaging that require the removal of
the archwire can be performed only with the doctor in the building.




183
Ten Years with SureSmile”
Another ethical concern surfaces when time is permitted to be a primary
determinant in finishing rather than an outcome-based professional gold
standard. Once patients define outcome, professionalism is reduced to
the particular. Finally, from this more than 10 years user's experience,
quality is more marketable than speed.
When the orthodontist forgets the complexity inherent in
individual malocclusions by the seduction of simplified finishing, highly
sophisticated expensive systems can be counterproductive. The patient in
Figure 12 was referred by a local prosthodontist after a recent traumatic
fracture to tooth #9. The treatment request was to reduce the anterior
overbiteto enable restorative spaceforan osseous implantand subsequent
coronal restoration. Clinical assessment revealed a previously treated
four-bicuspid extraction case with upright incisors, arch constriction
and a hypertonic muscular pattern (Fig. 13). The Class I mildly crowded
malocclusion appears to be a simple exercise in leveling and torqueing
of the upper incisors, which the SureSmile” system most certainly could
execute. Due to the apparent treatment simplicity, the case was bonded
fully without the initial placement of Precision (ORMCO°) lingual arches.
Without lingual arch anchorage, the continuous arch side effects were
manifested; posterior lingual/palatal collapse in the face of hypertonic
musculature. Combined with the posterior intrusive effect of anterior
palatal root torque, treatment time was extended significantly due to
continuous arch side effects. Note that after 18 months of SureSmile”
treatment, the mandibular first molars are collapsing to the lingual and
a posterior open bite is developing secondary to the palatal torque
of the maxillary incisors (Fig. 14). Although palatal root torque can be
accomplished with the SureSmile” system (Fig. 15), the time required for
the biologic change, along with the management of the posterior side
effects, negates the need for highly sophisticated expensive finishing
wires (Fig. 16) since the pre-prosthetic objectives took 41 months to
COrrect.
An area of prospect presented by the author (Snyder, 2006),
however, is the use of copper nickel titanium (NiTi) wires bent robotically
for surgical patients. The simulated positioning of the orthognathic
three-dimensional (3D) models includes both the virtual planning of the
surgical move and the subsequent design of the final shape memory arch
184
Snyder
Figure 12. Prosthodontic referral to openbite and torque incisors/previous ortho-
dontics with four bicuspid extractions/arch constriction hypertonic musculature.
Figure 13. Initial lateral cephalometric records depicting retrusive incisors.


185
Ten Years with SureSmile”
Figure 14. Continuous arch side effects following 18 months SureSmile" torque
without lingual arch support.
Figure 15. Anterior torque change: initial to final.
wires. 3D planning capitalizes fully on the mechanical properties of the
copper Niſi wires during the Rapid Acceleratory Phenomenon (RAP,
Wilcko et al., 2001) since surgical patients commonly wear vertical elastics
post-surgery. With SureSmile” wires in place, post-surgical elastics direct
the dentition to its pre-determined finished position more efficiently
through virtually designed, robotically bent copper Niſi shape memory
wires. Conventionally, the orthodontist cannot consider retroactive wire
manipulation until several months into the RAP phase, which can delay
treatment significantly.


186
Snyder
Figure 16. Final photographs following three years, five months SureSmile"
treatment.
Although my practice's internal statistics (Table 3) show that I have
been able to reduce treatment times on the average by seven months—
including 4.5 fewer adjustments—SureSmile" treatment has been limited
to Class I finishing, which is far from the 100% utilization of the system
advocated by Oral/etrix". The difference between a corporation that
advocates its product through marketing and contractual obligations,
and the clinical realities inherent in the complexities of malocclusion
Correction, rests in the differences of the goals of a corporation and a
Clinician. The corporate goal is restricted to financial ends, while the
Clinician is free to move beyond financial restrictions to the general needs
of the patient. Hence, the corporation can meet its goal in the particular
to meet the needs of the investors. The clinician, not being limited to
the particular, dispenses with the necessity of looking to finances alone
for its end. John Henry Newman, a 19th century educator, said that in
the pursuit of knowledge, the more that it tends to the particular, the
more it ceases to be knowledge. In his educational classic The Idea of a
University, Newman (1852) defined knowledge as:

187
Ten Years with SureSmile”
Table 3. Snyder practice appointment data.
# of # of # of wire H of repair Total Tx # of scans
# of Iff of Appts bracket & - -- p Time in -
Patients (Average) band fails coords inserts visits Braces (active tx)
(Average) || (Average) || (Average) (Average)
(Average) (Average)
*...* 9 18.00 1.55 -1.33 7 1-1 2.89. 1728 22
*...* 692 14 24 2.43 8-14 º 2-3 I-90 1.23
--
* 194 13.72 2,03 13-17 5.33 2,58 21,38
*...* 821 17.39 2.45 1259. 5.85 2.47 21.87
otal - -
• Conventional (5 yrs) SureSmile (10 yrs)
- in E. 82° n = 392
* †e 21.37 months time 14.30 months
adjustments 12.59 adjustments 3.14.
Conventional - 7 more months and 4.5 adjustments
Something intellectual, something which grasps what it
perceives through the senses; something which takes a
view of things; which sees more than the senses convey;
which reasons upon what it sees, and while it sees; which
invests it with an idea. It expresses itself not in a mere
enunciation, but by an enthymene; it is of the nature of
science from the first, and in this consists its dignity.
REFERENCES
Alford TJ, Roberts WE, Hartsfield JK Jr, Eckhardt GJ, Snyder R.J. Clinical
outcomes for patients finished with the SureSmile" method
compared with conventional fixed orthodontic therapy. Angle Orthod
2011;81(3):383–388.
American Board of Orthodontics. 2012. Grading system for dental casts
and radiographs. http://www.americanboardortho.com/profession-
als/downloads/Grading%20System.9%20Casts-Radiographs.pdf

188
Snyder
Groth CG. Computer-Assisted Orthodontics: A Blinded, Multi-Center
Analysis of Finish Ouality in Patients Treated without Extractions. Un-
published Master's Thesis, Department of Orthodontics and Pediatric
Dentistry, The University of Michigan, Ann Arbor 2012.
Koenig HA, Burstone CJ. Force systems from an ideal arch: Large deflection
considerations. Angle Orthod 1989;59(1):11-16.
Lazic SE. The problem of pseudoreplication in neuroscientific studies: Is it
affecting your analysis? BMC Neurosci 2010;11:5.
Newman JH. The laea of a University. Notre Dame, IN: University of Notre
Dame Press, 1982.
Oral/etrix. 2014. Corporate profile. Orthodontic Practice US;5(1):10-12.
http://issuu.com/medmark/docs/opus janfeb14 volS-1/3
Rangwala T. Treatment outcome assessment of SureSmile” compared
to conventional orthodontic treatment using the American Board of
Orthodontics grading system. Graduate research thesis, Department
of Orthodontics, Montefiore Medical Center, Albert Einstein College of
Medicine, New York, June 2012.
Saxe AK, Louie LJ, Mah J. Efficiency and effectiveness of SureSmile”. World
J Orthod 2010;11(1):16-22.
Snyder R. SureSmile”: An eight-year clinical perspective. In: Taking
Advantage of Emerging Technologies in Clinical Practice. McNamara
JA Jr (ed). Monograph 49, Craniofacial Growth Series, Department of
Orthodontics and Pediatric Dentistry and Centerfor Human Growth and
Development, The University of Michigan, Ann Arbor:2012:263-279.
Snyder RJ. Application of computer-assisted archwire fabrication in a
private practice setting. In: Digital Radiography and Three-dimensional
Imaging. McNamara JA Jr, Kapila SD (eds). Monograph 43, Craniofacial
Growth Series, Department of Orthodontics and Pediatric Dentistry
and Center for Human Growth and Development, The University of
Michigan, Ann Arbor:2006:181-197.
Vu CO, Roberts WE, Hartsfield JK Jr, Ofner S. Treatment complexity index
for assessing the relationship of treatment duration and outcomes
in a graduate orthodontics clinic. Am J Orthod Dentofacial Orthop
2008;133(1):9.e1-e13.
189
Wilcko WM, Wilcko T, Bouquot JE, Ferguson DJ. Rapid orthodontics with
alveolar reshaping: Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001;21(1):9-19.
190
SELF-LIGATING BRACKETS AND THEIR EFFECTS ON
EXPANSION, TOROUE AND ALVEOLAR
BONE MORPHOLOGY
Paolo M. Cattaneo
ABSTRACT
This chapter aims to answer some of the open questions about treatment out-
comes using self-ligating brackets. In particular, the focus is on the analysis of:
1) arch width and tipping after the alignment phase and the end of treatment;
2) alveolar buccal bone remodeling at the end of the alignment phase and the
end of treatment; and 3) uprighting and relapse during the retention phase.
The results show that the anticipated translation and buccal bone
remodeling using active or passive SLBS could not be confirmed either at the
end of the alignment phase or the end of treatment. The claimed uprighting of
the dentition during the retention phase could not be confirmed either, though
the expansion and tipping achieved during treatment generally was retained two
years after treatment completion.
A negative correlation was found between the loss of transverse width
during retention and the amount of expansion achieved during treatment,
Suggesting the importance of respecting the patient's individual arch form.
Large inter-individual variations were seen among the patients, indicating that a
patient-specific analysis and treatment plan seem to be mandatory, as individual
factors (e.g., pre-treatment arch dimension and shape, teeth inclination and
occlusion) influence the treatment outcome of each individual patient.
KEY WORDS: CBCT, digital models, ligation, orthodontics, treatment outcome
INTRODUCTION
The influence of the type of orthodontic appliance on the
biological reaction of the alveolar support structure and the subsequent
rate of tooth movement has been a matter of constant discussion (Ren
et al., 2003; Henneman et al., 2008). Among the several new appliances
introduced in the market in recent years, self-ligating brackets (SLBs)
191
Self-ligating Brackets
are gaining more popularity among clinicians compared to conventional
(ligature) brackets.
Despite the recent popularity, the SLB concept is not new
(Fleming et al., 2008): the Boyd band and Ford lock were introduced in
1933. However, it was with the introduction of the SPEED brackets in the
1970s and the In-Ovation (GAC, 2000) and Damon SL (Ormco, 1999) that
the interest for SLBS increased (Harradine, 2008); the latter two were
promoted more as a system than as a bracket (Damon, 2005).
The success of the SLBS is ascribed partly to the claims that the
companies were promoting, among them higher treatment efficiency,
less chair time and stability of treatment (Eberting et al., 2001; Harardine,
2001; Kim et al., 2008). However, these allegations are not accepted
unanimously (Hamilton et al., 2008; Miles, 2009) and a lack of evidence
behind these claims soon was demonstrated (Chen et al., 2010; Celar et
al., 2013).
Because SLBS usually have a slide (passive SLBS Such as Damon
SL) or a spring-clip (active SLBS such as In-Ovation) to close the buccal
aperture of the brackets, the usual steel or elastomeric ligatures no
longer are necessary. This feature combined with the use of high-tech and
high-resilient copper nickel titanium (NiTi) wires was claimed to deliver
light forces and low friction compared to classical brackets (Eberting et
al., 2001; Roth et al., 2005). Yet, from a clinical point of view, the actual
force magnitude exerted by SLBS was found to be similar to conventional
systems (Pandis et al., 2008). Data on frictional resistance are not
unanimous (Ehsani et al., 2009) since friction plays only a negligible role in
sliding mechanics (Kusy and Whitley, 2000). According to the proponents
of the passive SLBS, because of this supposed lower forces associated
with SLBs, they would have the potential advantage of producing a more
physiologic force system relative to conventional systems so that tooth
movement would be generated by a new equilibrium, which would not
overpower the musculature and/or interrupt the periodontal vascular
supply. According to this postulate, the arch then would remodel to
accommodate the teeth, such that the new arch form is determined
by the body and not by the clinician or the system applied. Thus, the
final proposed benefits of this system would be greater alveolar bone
generation, greater amounts of expansion, less proclination of anterior
teeth and less need for extractions. It is not clear, however, how this
192
Cattaneo
purported “system" can deliver such a fine-tuned balance of forces given
the fact that even extremely low forces are sufficient to displace teeth
(Weinstein, 1967).
Another alleged favorable aspect that has been associated with
treatment carried out with SLBS systems is increased arch length achieved
by bodily movement of the teeth or at least with “minimal” tipping. The
play between bracket and wire theoretically can be calculated knowing
the dimension of the bracket's slot and the wire dimension, yet variation
in curvature of the crown, bracket positioning and variation in the
thickness of the adhesive will affect the final bucco-lingual inclination
(Miethke and Melsen, 1999; van Loenen et al., 2005; Mestriner et al.,
2006). In addition, it has been demonstrated that a 0.019" x 0.025"
stainless steel archwire engaged in 0.022” slot of various SLBS is far from
fully engaged; consequently, the prescription cannot be expressed within
clinically relevant angles especially in the case of passive SLBS (Badawi et
al., 2008; Morina et al., 2008; Pandis et al., 2008).
Differences of facial profile associated with an extraction or
non-extraction treatment approach have been evaluated (Young and
Smith, 1993). Particularly in non-extraction cases, control of labio-lingual
torque of the incisors has been found to be of paramount importance
for a successful orthodontic treatment, as lack of control may result in
undesirable flaring. In this respect, the manufacturers of active SLBS
claimed that the active clip renders a better torque control, while the
producers of passive SLBs claimed that a lip-bumper effect could be
achieved as well. The advantages of better torque control of the anterior
dentition have been associated with favorable remodeling of alveolar
bone and surrounding tissues (Damon, 2005), though this claim has never
been confirmed.
To gain space and resolve crowding, thus minimizing the need of
extractions, the majority of SLB systems incorporate transverse expansion
of the maxillary and mandibular posterior teeth. This is achieved using
wires with broad arch form. Because the broad arches apply lateral forces
at the brackets coronal to the center of resistances of teeth, they produce
buccal tipping of the dentition during the initial leveling phase when
round wires are used (Smith and Burstone, 1984). This expansion/tipping
may cause displacement of the roots beyond the actual alveolar bone
envelope, especially in patients with narrow arches, increasing the risk of
193
Self-ligating Brackets
gingival recession and bone dehiscence (Joss-Vassali et al., 2010). Thus,
to achieve stability and minimize the risk of recession, it seems that tooth
uprighting should be beneficial. With SLB systems, it has been suggested
that the first partial uprighting of teeth occurs during the rectangular
wire treatment phase. The final uprighting is stated to occur during
the retention phase and has been attributed to the functional matrix if
fixed and/or removable retainers maintain the expansion that has been
achieved (Damon, 2005), though no direct evidence is available presently
for this claim.
To answer some of the open questions regarding SLBs, research
projects were started at our department (Cattaneo et al., 2011, 2013),
while others were performed in collaboration with São Paulo University,
Bauru, Brazil (De Morais, 2012). This chapter is a summary of these
research lines. Specifically, the following issues will be analyzed:
1. Arch width and tipping after the alignment phase;
2. Alveolar buccal bone remodeling at the end of the
alignment phase;
3. Arch width and tipping after the active treatment
phase;
4. Alveolar buccal bone remodeling of the posterior
segments at the end of treatment; and
5. Uprighting and relapse during retention phase.
SAMPLE DESCRIPTION
To solve the questions previously raised, two different patient
groups were analyzed. The first group consisted of 64 patients, enrolled
at the Orthodontic Department, Aarhus University, Denmark. They were
assigned randomly to be treated either with passive or active SLBs. The
patients were selected carefully in conformity with the guidelines for
Damon” 3 MX passive brackets system (Damon 3 MX Standard torque;
Ormco Corporation, Orange, CA, USA) and In-Ovation R active brackets
system (In-Cvation R, Roth Prescription; GAC International Inc., Bohemia
NY, USA). Patients with severe Class III, an obvious need for extraction,
with periodontal problems and major skeletal discrepancies were
excluded. From the original 32 patients in each group, it was possible to
194

Cattaneo
analyze 21 in the Damon group (mean age = 16.0, SD = 5.7) and 20 in
the In-Ovation group (mean age = 15.0, SD = 3.3). For further details, see
Cattaneo and associates (2011).
For this group of patients, a CBCT scans using a NewTom 3G (OR,
Verona, Italy) with a 12” field of view (FOV), scan time of 36 seconds and
0.36 mm isotropic voxel resolution were taken before treatment started
(TO) and after treatment completion (T1). Also, three sets of digital casts
were produced at T0, T1 and at least after two years in retention (T2;
Table 1). The retention protocol was similar for both groups: bonded
upper and lower retainers plus additional full-time wear of removable
upper retainers for the first six months. The compliance to this protocol
was checked at T2.
The second group consisted of patients enrolled at the Bauru
Dental School, University of São Paulo, Bauru, Brazil. In this group 22
Consecutive young patients (11 to 17 years of age) were included. They
were characterized as being Class I or Class II molar relationship, having
at least 4 mm of crowding in the maxillary arch, treatment planning with-
out extractions and no previous orthodontic treatment. All patients were
treated with Damon 3MX” brackets (Damon3MX standard torque, Ormco
Corporation, Orange, CA, USA).
For this group, one CBCT scan using an i-CAT unit (Imaging Sci-
ences International, Hatfield, PA) with a 13" FOV, scan time of 20 sec-
onds and 0.3 mm isotropic voxel resolution was taken at T1 and a second
CBCT-scan was taken at the end of the alignment phase (TA; i.e., at least
four weeks after insertion of 0.019" x 0.025" stainless steel rectangular
archwire; Table 1).
Table 1. Experiment overview. * = end of alignment (at least four weeks after
insertion of 0.019 x 0.025 SS); ** = more than two years in retention.
Ix Start – TO End Align=TA Tx End – T1
Group CBCT Digital Model CBCT Digital Model CBCT Digital Model CBCT Digital Model
Aarhus Denmark v y - - y v - wº
Bauru Brazil y - wº
195
Self-ligating Brackets
MEASUREMENT TECHNIOUES
Tipping and Expansion
The difference in maxillary and mandibular inter-canine (AE 13-
23 and AE 33–43), inter-first-premolar (AE 14-24 and AE 34-44), inter-
second-premolar (AE 15-25 and AE 35-45) and inter-first molar (AE 16-
26 and AE 36–46) widths was evaluated via a custom-made 3D analysis
by measuring the transverse distance between contralateral teeth,
considering three points (Fig. 1). Using the same points, differences in
bucco-lingual inclinations (AG)) could be evaluated as the angle between
the mesio-distal plane of each tooth and the occlusal plane, digitizing the
procedure previously introduced by Andrews (1989; Fig. 2). Moreover,
the variation of the inter-premolar bucco-lingual inclination (AA) in both
the maxilla and mandible was evaluated by looking at the CBCT scans at
T0 and T1 (Fig. 3).
Analyses of Buccal Bone Changes
Artifacts due to partial volume effect and spatial resolution
easily can hinder the correct evaluation of thin structures such as buccal
alveolar bone (Molen, 2010). In this respect, it is important to understand
what the limits are when measuring alveolar bone thickness on CBCT
images. Indeed, both voxel dimension and voxel quality play important
roles in visualizing alveolar bone structures. To evaluate alveolar bone
morphology and bone thickness, especially on the buccal aspect, it is
important to acknowledge its anatomical characteristics as described
below.
In a previous study performed at our department, alveolar bone
samples of 27 donors (eighteen males, nine females; mean age = 34 years)
were taken at autopsy and micro-CT scanned at high resolution (Laursen
et al., 2013). Buccal bone thickness at various levels of the root apical
to the cement-enamel junction was measured for each tooth from the
micro-CT and CBCT scans. The average thickness of buccal alveolar bone
was evaluated on 3D rendering and on transverse section of the alveolar
supporting structures (Fig. 4) and compared with the measurements
from the CBCT. This comparison was used to generate a color-coded
image of the buccal alveolar bone of the upper and lower dentition
to serve as a visual guide of locations where thickness of the buccal
alveolar bone can be measured reliably (Fig. 5). Because these findings
196
Cattaneo
Figure 1. Three points on each tooth were used to calculate inter-teeth distance
and to determine for each tooth a mesio-distal and bucco-lingual plane.
Figure 2. Tooth-based mesio-distal reference plane used to
assess the bucco-lingual inclination of each tooth (in red) in
relation to the occlusal plane. Blue = bucco-lingual plane.







197
Self-ligating Brackets
Figure 3. Green markers (apex of the root canal) and red mark-
ers (central fossa of the crowns) and angle o and B, where o
and 3 were defined as the angles between the line passing
through the central fossa of the crowns of the 1st premolars
(red markers) and the long axis of left and right 1st premolars,
respectively. The inter-premolar bucco-lingual inclination A
was calculated as Å = 180°- (or + 3).
show that CBCT can be relatively reliably used to measure thickness of
alveolar bone at the maxillary central incisors, maxillary 2nd premo-
lars, maxillary 1st molars and mandibular 2nd premolars, we limited
ourselves to measuring the thickness of buccal alveolar bone at these
locations.

198
Cattaneo
maxillary maxillary maxillary mandibular
Central Incisor canine 1st molar 2nd premolar
Figure 4. Micro-CT scans of four different bone sample. The thickness of the
buccal cortical bone in proximity of a maxillary central incisor, canine and 1st
molar, and of a mandibular 2nd premolar can be appreciated. Note the paper-
thin thickness (~ 0.3 mm) of the buccal alveolar bone of the maxillary canine.
OQs -
º
Figure 5. Color-coded map of the buccal alveolar thickness of each tooth. Green
= buccal bone possible to measure; yellow = buccal bone difficult to measure; red
= buccal bone impossible to measure.
To analyze buccal bone changes on CBCT-scans, various approach-
es can be used. In the present investigation, two different approaches
Were adopted.
Buccal Bone Changes in 2D. A vertical bucco-lingual cross-section
Was generated passing through the center of the pulp apex of (in the
Case of two- or multi-rooted teeth, the buccal root was chosen) and
perpendicular to the buccal cortical bone plate (Fig. 6). On the cross-
Section, a reference line was drawn through the buccal and lingual




199
Self-ligating Brackets
Figure 6. A: A vertical plane is traced through the middle of the root(s) of
the 2nd premolar and the buccal cortical bone. B: On the corresponding
cross-section, two lines are drawn: the 1st line connects the buccal
and lingual cemento-enamel junctions and the 2nd line parallel to the
1st one (in this case, 9 mm apically). The bone area buccal to the 2nd
premolar is outlined. For calibration purposes, a vertical line is traced.
cemento-enamel junction of each tooth. An apical line then is drawn
at fixed distances parallel to the reference line by measuring on the
images as they are calibrated. The area of the buccal bone between the
reference and the apical line was traced and measured using Image] (NIH;
Bethesda, MD). Differences between the bone area measured at TA and
T0, and between T1 to T0, were calculated and reported as percentage
changes relative to the original amount of bone (A bone). For the
Aarhus sample, the buccal bone area was assessed only for the upper 2nd
premolar, while for the Bauru group the bone area was assessed buccal to
the maxillary central incisors, 2nd premolars and 1st molars, and buccal
to the mandibular 2nd premolars.
Buccal Bone Changes in 3D. The CBCT scans were exported via the
DICOM format and imported into ITK-SNAP open-source software (http://
www.itksnap.org; Yushkevich et al., 2006), where3D surface models of the
maxilla and mandible were generated, following the protocol described
by Cevidanes and coworkers (2009). Registration of T1 models to the
corresponding models at T0 was performed using the maximization of
mutual information algorithm. For maxillary superimpositions in non-
growing patients, this method was applied to the anterior cranial base

200
Cattaneo
and the Cranial upper-frontal structures. For growing patients, this
method was applied only on the anterior cranial base (Melsen, 1974; Fig.
7A). For mandibular superimpositions, the model registration utilized
structures that are not modified by growth and/or treatment (internal
part of the mandibular corpus and ramus, the anterior contour of the
chin, and the inner cortical structure of the symphysis; Fig. 7B; Bjork,
1969).
The 3D-registered surface models were overlaid and color maps
were used to visualize alveolar bone changes that occurred during
treatment. Isolines were used to delimit the areas on the models at T1
that display a certain larger than 0.7 mm (i.e., twice the voxel dimensions)
from the model at T0. To account for the spatial resolution, which is
approximately double the voxel size (Molen, 2010), the isoline was set at
0.7 mm (Fig. 8).
OUTCOME AFTER THE ALIGNMENT PHASE (TA-TO)
OF SLB TREATMENT
In this part of the study, only passive SLBS were studied.
Tipping and Expansion of the Lateral Segments
The transverse width increased significantly in maxillary and
mandibular arches (Table 2). The highest increase occurred in the first
premolars region in both arches (approximately 4 mm). All teeth, except
the maxillary canines, demonstrated a statistically significant increase
in buccal tipping (AG)) after alignment (Table 3). After the maxillary
Canines, the molars showed the smallest buccal tipping (mean increase
of approximately 1° and 3.5° for the maxillary and mandibular molars,
respectively).
Tipping of the Front Segments
In both jaws, central and lateral incisors displayed a statistically
Significant increase in labio-lingual proclination in relation to the occlusal
plane (flaring) from T0 to T1 (Table 4). The maximum increase was seen
for the maxillary and mandibular lateral incisors, where the proclination
was in excess of 11°. A pronounced variation in labio-lingual inclination
among incisors within and between individuals in both groups was seen;
this is reflected in the large standard deviation reported.
201
Self-ligating Brackets
Figure 7. A: The anterior cranial base and the upper-frontal structures
of the skull (yellow and light blue masks) were used for registering
and superimposing the 3D models of the maxilla (red) at T0 and T1.
In growing patients, only the anterior cranial base was used (light blue
mask). B: When superimposing the 3D models of the mandible (red),
the structures that are not modified by growth and/or by treatment
(yellow) were used for model registration.
Tim
3.0
0.7
0.0
|soline
-3.0
Figure 8. Example of superimposed T1 over T0 models: the T0 model
is depicted in gray, while the T1 model is shown using a color map
(green = no changes; red = outward expansion). The isoline delimits
the areas on the T1 model that displays a distance from the T0 model
> 0.7 mm.



202

Cattaneo
Table 2. Transverse width increase – AE = mean values (mm). TO = start; TA =
end of alignment phase; T1 = end of treatment; T2 = retention; positive values =
expansion; negative values = relapse; f = 17 patients in passive SLB, 15 patients in
active SLB, f = measured on CBCT; *- Independent sample t-test between passive
and active SLBs; * p < 0.05; ** p < 0.01; NS = non-statistically significant; SD =
standard deviation. The International numbering system is used to identify the
teeth in the top row.
13–23 14-24 15-25 15-25 33–43 34-44 35-45 35-45
- Passive SLB 1.6 4.3 3.6 2.0 2.1. 4.O 3.5 2.1
-
E TA-Tot SD 2.5 1.6 2.8 1.8 2.5 1.6 2.5 1.3
-- wilcoxon TO-TA --- --- --- * --- * * ** ---
T Passive sle 1.4 4.3 4.O. 1.9 2.0 3.2 2.9 1.9
º SD - 1.7 1.6 1.9 1.2 1.6 1.5 1.5 1.4
: Tº TO Active SLB 0.7 4.5 3.3 1.3 1.5 3.4 3.4 1.3
- SD 1.7 1.6 1.8 1.3 2.2 1.7 1.7 1.0
- Passive-Active” NS NS NS NS NS NS NS NS
Passive SLB –0.1 -1.1 -0.6 -O.2 –0.4 –0.7 -1.2 –0.8
º SD 0.7 1.1 o. 7 0.9 0.5 1.2 1.2 0.9
º Tº Tº Active sle –0.4 -1.4 -1.3 –0.4 –0.1 –0.3 -1.3 –0.5
- SD 1.0 1.3 0.8 1.4 O. 9 1.5 2.9 1.4
Passive-Active1 NS NS º: NS NS NS NS NS
Passive sle 1.3 4.1. 3.1 1.4 1.7 3.0 2.8 1.0
º SD 1.4 2.0 1.5 1.4 2.2 1.3 1.3 1.0
# T2-Toº Active SLB 1.O. 2.8 1.9 O.5 O.7 2.2 1.5 O-6
- SD 1.7 2.1 2.1 o. 7 2.1 1.3 1.7 1.2
Passive-Active" NS NS NS * NS NS -k NS
Bone Evaluation
Alveolar buccal bone thickness significantly decreased in proxim-
ity of the maxillary central incisors and for the mesial root of the 1st mo-
lars. A mild, non-significant buccal bone increase was seen for the max-
illary 1st premolars for the distal root of the maxillary 1st molars, and
for the mandibular 2nd premolars. It is worth noticing the large standard
deviation reported (from 19 to 35%; Table 5).
TREATMENT OUTCOME (T1-T0)
In this part of the study, passive and active SLBS were analyzed
and compared.
Tipping and Expansion of the Lateral Segments
Maxilla. At baseline (TO), no statistical significant differences
in inter-teeth distance and teeth bucco-lingual inclination were found
between the passive and active SLB groups.
Looking at the intra-group changes, the differences between T1
and T0 in inter-teeth distances (AE) and bucco-lingual inclinations of teeth
203

Self-ligating Brackets
Table 3. Tooth region, mean values [deg|. T0 = start; TA = end of alignment phase;
T1 = end of treatment, T2 = retention; positive values = proclination; negative
values = relapse; * = independent sample t-test between passive and active SLBs;
AG = bucco-lingual inclination to occlusal plane measured on digital models; AA
= interpremolars angle; t = measured on CBCT, f = 17 patients in passive SLB, 15
patients in active SLB, * p < 0.05; ** p < 0.01; NS = non-statistically significant; SD
= standard deviation. The International numbering system is used to identify the
teeth in the top row.
ao ae an 14- ad an 15- ad ac no anº- no lººs- no
13&23 14&24 24t 15&25 25t 16&26 338.43. 348.44 44t 35&45 45+ 368,46
- Passive SLB 0.3 9.5 - 6.5 - 1.1 4.8 9.1 5.8 - 3.6
-
E TA-T0t SD 8.6 3.9 - 4.9 - 4.1 5.6 5.0 - 5.9 - 6.0
º Wilcoxon To-TA NS -- - --- - - -- -- - -- - --
Passive SLB 1.9 8.2 11.7 6.4 13.5 2.7 4.2 9.9 12.0 7.9 12.2 2.7
º SD 6.5 5.1 9.7. 4.5 8.1 4.4 4.2 4.5 4.8 4.4 6.9 6.8
# Tºº Active SLB 0.6 6.2 11.8 6.2 13.0 1.4 3.2 5.9 9.4 5.4 10.1 3.0
* * SD 7.2 7.8 12.4 5.3 9.1 7.1 4.3 4.1 8.4 6.3 7.0 5.1
- Passive-Active1 NS NS NS NS NS NS NS - Ns NS NS NS
- Passive SLB -0.8 -1.3 - -1.1 - –0.9 -0.1 -1.2 - -1.3 - 1.1
º SD 3.6 4.0 - 3.6 - 4.0 4.0 4.3 - 4.5 - 4.7
: Tº Tº Active SLB -0.6 -1.6 - -1.1 - 0.1 0.5 1.1 - -1.1 - 0.2
º: SD 3.6 3.5 - 3.6 - 5.1 4.1 5.0 - 4.8 - 4.7
p.m. a.º. NS NS - NS - NS NS NS - NS - NS
Passive SLB 1.0 7.3 - 4.9 - 1.6 4.4 8.6 - 5.9 - 3.9
º SD 5.9 4.1 - 4.0 - 3.8 4.3 5.4 - 7.1 - 7.0
: T2-Toº Active SLB 0.0 4.6 - 5.1 - 1.5 3.2 5.0 - 4.2 - 3.2
- SD 4.9 6.9 - 4.6 - 6.3 4.2 3.8 - 5.4 - 4.6
Passive-active" NS NS - NS - NS NS - - NS - NS
Table 4. Tooth region, mean values [deg|. T0 = start; TA = end of alignment phase;
T1 = end of treatment; * = independent sample t-test between passive and
active SLBs; AG) = bucco-lingual inclination to the occlusal plane measured on
CBCT; positive value = proclination; NS = non-statistical significant; SD = standard
deviation. The International numbering system is used to identify the teeth in
the top row.
AO 11&21 AO 21&22 AO 13&24 Ao 238.24
- Passive SLB 6.3 11.1 8.7 11.4
--
# TA-T0
º SD 5.7 9.4 5.0 6.9
Passive SLB - - 6.6 6.9
º SD - - 6.7 7.1
# T1-T0 Active SLB - - 6.3 7.0
º SD - - 6.1 7.1.
Passive-Active” - - NS NS _
204

Cattaneo
Table 5. Tooth region, mean values (%). T0 = start; TA = end of alignment phase;
T1 = end of treatment; NS = non-statistically significant; SD = standard deviation.
The International numbering system is used to identify the teeth in the top row.
Abone 11&12 Abone 15&25 Abone 16&26 M Abone 16&26 D Abone 35&45
- Passive SLB -13 6 –20 7 1.
-
* TA-T0 SD 19 32 30 24 35
--
Passive SLB - –20
- SD - 26
=
º | TO Active SLB - -14
- SD - 27
NS
(AO) were statistically different both for the Damon group and the In-
Ovation group (Table 3). A remarkable expansion took place, especially
at the 1st and 2nd premolars level (up to more than 4 mm for the 1st
premolar in both groups) from T0 to T1. However, looking at the values
measured for AG) (more than 8° in the Damon and more than 6° for the
In-Ovation group for the 1st premolars), it is clear that the achieved
expansion is due mostly to bucco-lingual tipping in both passive and
active SLB systems. This is confirmed by the inter-1st and 2nd premolars
change in inclination (AA) measured on CBCT scans: it increased quite
Substantially for both premolars in both groups (more than 10°).
Mandible. Like the maxillary measurements, no statistical signifi-
Cant differences in inter-teeth distance and teeth bucco-lingual inclina-
tion were found between the two groups at T0.
Looking at the intra-group changes, all the differences between
measurements (i.e., AG) and AE) at T1 were different statistically from T0.
Again, looking at the values of AB (almost 10° in the Damon and 6° for the
In-Ovation group for the 1st premolars), it is clear that the mandibular
arch expansion for the most part was achieved by bucco-lingual tipping
in both SLB systems (Table 3). Also in this case, this is confirmed by the
inter-premolars change in inclination (AA) measured on CBCT scans: it in-
Creased substantially for both the 1st and 2nd premolars in both groups
(more than 9°). The only difference from the maxilla is that in the man-
dible the bucco-lingual tipping at the mandibular 1st premolar levels is
Statistically significant between the active and the passive SLB Systems,
205
Self-ligating Brackets
with the larger increase seen for the passive SLBs. The canines and the
2nd premolars in the passive SLBS group display larger increases com-
pared to the active SLBs, though not statistically significant. This might
be explained by the fact that in the passive SLB system, the archwires
used for the upper and lower arches have the same shape and dimen-
sion, while the archwire used in the mandible of the active SLB system is
Smaller than the one used for the maxilla.
Two different methods were used to assess tipping: changes in
bucco-lingual inclination of one tooth compared to the occlusal plane
(AG)) and the inter-teeth inclination (AA) of two contralateral premolars
with respect to the occlusal plan in the true linguo-buccal direction.
Each method has advantages and disadvantages: AG) represents the true
change in bucco-lingual inclination of the crown of each tooth with respect
to the occlusal plane. While this measurement gives information about
changes in crown inclination, it provides no information about changes
in root inclination. On the other hand, AN measures the change in the
angle formed by the long axes of two contralateral teeth, thus providing
the true inclination of the tooth (i.e., crown and root); yet the calculated
angle represents the angle on the transverse plane of the CBCT image.
Both methods are presented to the readers interested in this topic for
completeness' sake, because each is a valid approach to measure dental
tipping.
Tipping of the Front Segments
No statistically significant differences were found between the
two groups regarding labio-lingual inclination of the lower front dentition
at baseline.
In both SLB systems, mandibular central and lateral incisors
displayed a statistical significant increase in labio-lingual proclination in
relation to the occlusal plane (flaring) from T0 to T1, but no statistical
significant differences were seen between the two SLB systems (Table
4). It is worth noting the pronounced variation in labio-lingual inclination
among incisors within and between individuals in both groups. This is
reflected in the large standard deviations reported.
Buccal Bone Evaluation of the Lateral Segments
Changes in 2D. As mentioned before, the bucco-lingual width of
the buccal bone of many teeth was so thin that the measurement error
206
Cattaneo
Figure 9. Transverse cut through the root of a 2nd premolar
A. Before treatment (T0). B: After treatment (T1). Note the
evident thinning of the buccal alveolar bone.
Surpassed the actual measured area. For this reason only, the bone area
in one selected location was evaluated (2nd maxillary premolar) in this
part of the study. For this location, the buccal bone area at baseline (TO)
Was Similar in both groups.
At T1 a general decrease in buccal bone was seen for both SLB
Systems (Table 5), an example of which is shown in Figure 9.
The results of the calculation of the buccal bone area proximal to
the maxillary 2nd premolar in the Aarhus sample (i.e., performed after
the end of treatment; T1) differ from the ones of the Bauru group (i.e.,
taken immediately after the initial alignment phase; TA). The explanation
for these contrasting results is not understood fully, although some
hypotheses can be proposed. One hypothesis is that these results might

207
Self-ligating Brackets
represent individual patient variability between the two groups. A second
is measurement error given the large standard deviation associated
with the measurement of the buccal bone area. A last hypothesis is the
time it takes for bone resorption and formation to occur: in trabecular
bone one bone resorption cycle takes about 40 days, reaching a depth
of approximately 60pum; bone formation takes about 145 days and the
new formed bone has a thickness of about 60pm (Eriksen et al., 1994).
The Consequence is that the periodontal ligament space generally gets
wider during orthodontic movement. Moreover, its width increases
further following removal of orthodontic forces (Franzen et al., 2013).
The CBCT scans of the Bauru sample were taken at TA, on average 44
weeks after treatment start, while the CBCT scans of the Aarhus sample
were taken at the end of treatment (T1), on average more than 100 weeks
after treatment start. Moreover, as has been shown that in patients
treated with rapid maxillary expansion bone apposition was occurring
some months after treatment completion (Ballanti et al., 2009). To better
understand and explain the above-mentioned discrepancy will require
follow-up assessments of the patients for longer periods after the end of
treatment.
Changes in 3D. Overall, despite a conspicuous increase of the
transverse width, only a modest remodeling of the buccal surface of
the maxillary and mandibular alveolar process in the lateral segments
was seen in both SLB groups (see, as examples, Figs. 10-11). In most of
the patients, despite a large increase measured for the inter-premolar
width, no alveolar bone apposition was seen at all: this easily could be
detected from the T1-T0 isoline, which often was located in proximity to
the cervical bone level.
RETENTION PHASE (T2-T1 AND T2-TO)
In this part of the study, passive and active SLBs were analyzed
and compared. The differences of the transverse width and teeth inclina-
tion from T2 to T1 and from T2 to T0 are presented in Tables 2 and 3.
The transverse width decreases during the retention period (T2
to T1) for all the teeth in both SLB systems. However, this relapse was not
different statistically between the two SLB systems, except for the 2nd
maxillary premolar, where the relapse was greaterfor the active SLB group.
208
Cattaneo
expansion 14–24 = 1.8 mm 3.0
expansion 15-25 = 5.9 mm
0.7
0.0
-3.0
Figure 10. Photos (upper panel) and 3D analysis (lower panel) of a female patient
from the Damon group treated over 16 months. The expansion achieved at the
Occlusal level for 1st and 2nd premolars is reported.
expansion 14–24 = 3.4 mm 3.0
expansion 15-25 = 2.7 mm
0.7
0.0
-3.0
Figure 11. Photos (upper panel) and 3D analysis (lower panel) of a female patient
from the In-Ovation group treated over 20 months. The expansion achieved at
the occlusal level for the 1st and 2nd premolars is reported.







209
Self-ligating Brackets
When considering the changes in bucco-lingual inclination AG)
from T2 to T1 for all the teeth in the lateral quadrants, negative values
were seen (except for the 1st molar in the passive SLB group and canines
and 1st premolars in the active SLB group, all in the lower arches), though
these changes were not significant statistically. This result should not be
interpreted as uprighting of the dentition, as wrongly claimed (Damon,
2005), but simply as a relapse occurring during the retention phase. This
result indeed is confirmed by the transverse width loss seen from T2 to T1.
When looking at the treatment effect two years after treatment
completion (i.e., from T0 to T2), the regions that experienced the largest
increase in transverse width were at the 1st and 2nd premolars, both in
the upper and lower jaws (Table 2). However, in the passive SLB group,
larger increases were seen compared to the active SLB group; these were
different statistically for the maxillary 1st molars and the mandibular 2nd
premolars.
Regarding the changes in bucco-lingual inclination from T0 to
T2, the larger net increases were seen again at the premolars in both
groups (Table 3). On the other hand, the passive SL group displayed a
statistical significantly width increase for the mandibular 1st premolars
when compared to the active SLB system. .
A negative, although not statistically significant, correlation was
found between the loss of transverse width during retention and the
amount of expansion achieved during treatment. This indicates that
greater expansion leads to greater relapse. This correlation suggests the
need to carefully assess each patient's arch forms, thus questioning the
“one arch fits all” approach.
Most of the arch width increase and bucco-lingual inclination
(tipping) achieved during treatment was maintained at T2, meaning
that the treatment results were kept after a minimum of two years in
retention. Though patient compliance using removable retainers could
not be verified directly and was assessed based on patient self-reporting,
the two groups scored similar for the presence of intact bonded retainers
in the upper and lower jaws. Moreover, no direct evidence exists regarding
the difference between a bonded retainer compared to a removable
retainer, and the amount of wear needed for the latter in relation to
treatment stability.
210
Cattaneo
OVERALL DISCUSSION
The idea behind most of the treatments using SLB systems, the
Damon system in particular, to achieve dental arch expansion follows
the same rule proposed by Angle (Tweed, 1936): expanding the dental
arches to accommodate teeth without the need of extractions. The only
difference from then to now is the use of super-elastic copper NiTi wires.
Although it has been shown that extractions have little influence
on stability (Riedel, 1960), the question of whether the alleged pure
expansion achieved using SLBS and copper NiTi wires has the potential
risk of generating bony dehiscences remains. Furthermore, as the cervical
alveolar bone generally is thin, bucco-lingual tipping of the dentition
might increase the risk of bone dehiscences further.
The Aarhus study was set up as an RCT. From the original 64
patients, only 41 completed the treatment according to the planned
treatment plan. Indeed, a considerable number of patients dropped
out. Although patients were selected carefully, an attentive examination
of the CONSORT flow diagram revealed that the reasons for drop out
were related to the fact that the treatment goal could not be achieved
following the original plans. Some patients had to be redirected to
Surgery or extractions became necessary; these were circumstances
that could not be anticipated at treatment start. This highlights the
need to discuss the feasibility of treatment protocols, which only
follow general recommendations, without taking into consideration
the individual characteristics of the patients. This confirms once more
that the orthodontist, not the bracket system philosophy, must make
well-reasoned decisions regarding treatment planning and treatment
advancement.
In the majority of the cases completed with the prescribed wire
Sequence, increased buccal tipping for both the active and the passive
SLBS was seen. By comparing the outcomes at the end of treatment with
the outcomes seen at the end of the alignment phase, it is worth noting
that the major part of transverse expansion and bucco-lingual tipping
already is achieved during the alignment phase. Moreover, that the
amount of transverse expansion is proportional to the amount of tipping:
the teeth that expand the most (i.e., 1st and 2nd premolars) experienced
the largest amount of bucco-lingual tipping.
211
Self-ligating Brackets
The same holds true for the lower anterior teeth, where an almost
true proclination was seen regardless of the SLB system used. This finding
is in agreement with that of Pandis and coworkers (2010), who stated
that alignment with both SLB systems and conventional brackets led to
proclined anterior teeth. This also is in agreement with the fact that only
minor differences exist between the various bracket system prescriptions
with respect to their efficiency in torque delivery (Morina et al., 2008).
In both SLB groups, the change in inclination of mandibular
canines was much smaller than that of the incisors and 1st premolars.
This might be explained by the fact that the canines are surrounded by
a thicker bony alveolar envelope and have a longer and thicker root,
especially when compared to the lower incisors. Moreover, the canines
are positioned at the corner of the dental arch, thus the canines are
tipped both mesially and buccally.
The analysis of buccal bone thickness performed both on
transverse sections and using 3D analysis showed that, despite the
transverse expansion at the occlusal level, the claimed buccal bone
augmentation barely could be detected.
Regarding stability of treatment, even in the non-treated
population. Indeed, it has been shown that occlusion cannot be
anticipated to remain stable. Bishara and colleagues (1996) studied a
sample of normal, untreated sample with an age spanning from 25 to
45 years and found significant changes in tooth size and arch length
discrepancies; they concluded that these changes should be considered
part of the normal evolution process. Later studies corroborated these
findings (Henrikson et al., 2001; Hesby et al., 2006).
Treated populations exhibit similar changes at a period after
treatment, independent from the fact that treatment protocols either
included extractions (Little et al., 1990) or did not include extractions
(Glenn et al., 1987; Freitas et al., 2004).
In the present study, the retention period was just more than
two years; therefore, the results cannot be used to predict the long-term
treatment outcomes. Nevertheless, after two years in retention, only
minor changes were seen. Yet, the purported uprighting of the teeth
in the posterior segments during retention could not be demonstrated
(Damon, 2005).
212
Cattaneo
In the present study, no attempt was made to compare treatment
outcomes of SLB-Systems with conventional bracket systems. The reason
is that we wanted to test arch widening due solely to archwire and bracket
interactions. With conventional brackets, transverse problems usually are
handled differently than by expansion alone, making them unsuitable as
a Control group.
CONCLUSIONS
Treatment Outcome
• Both SL systems achieved considerable arch widen-
ing, both after the alignment phase and at the end
of treatment; however, this expansion was achieved
mainly by bucco-lingual tipping. Therefore, the an-
ticipated bodily tooth movement could not be con-
firmed.
• The passive SLB system seemed to generate more
tipping compared to the active one; however, this
difference is not significant statistically.
• The correction of mandibular anterior crowding pre-
dominantly occurred due to buccal tipping, regardless
of the SLB system.
• Buccal bone analyses revealed that despite a consid-
erable dental expansion at the occlusal level, no or
only mild bone apposition occurred in patients treat-
ed with passive or active SLBS.
Stability at Retention
• Both SLB systems performed equally; yet, the regions
that were expanded the most presented the largest
relapse tendency.
• The purported uprighting of the buccally inclined
posterior teeth did not take place during the two-year
retention period.
213
Self-ligating Brackets
ACKNOWLEDGMENTS
All measurements performed on the Bauru's sample were per-
formed by Juliana Fernandes De Morais, Bauru Dental School, University
of São Paulo, Bauru, Brazil.
| would like to express my gratitude to the (former) post-graduate
students from the Section of Orthodontics at the Department of Den-
tistry, Aarhus University, Denmark; without their help and dedication, this
study would not have been possible to complete. In strictly alphabetical
order, they are: Kim Carlsson, Dimitris Galaktopoulos, Aleksandra Myrda,
Raaid A. Salih, Throstur Thorgeirsson and Marta Treccani. I also would
like to thank Morten Godtfredsen Laursen for the use of Figure 4. Lastly,
I would like to thank our former Professor, Birte Melsen, who inspired,
encouraged and supported me in this study, and Lucia H.S. Cevidanes for
her help in applying the 3D analysis and for her friendship.
REFERENCES
Andrews LF. Straight Wire: The Concept and Appliance. L.A. Wells Co., San
Diego, CA 1989.
Badawi HM, Toogood RW, Carey JP, Heo G, Major PW. Torque expression of
self-ligating brackets. Am J Orthod Dentofacial Orthop 2008;133(5):721-
728.
Ballanti F, Lione R, Fanucci E, Franchi L, Baccetti T, Cozza P. Immediate
and post-retention effects of rapid maxillary expansion investigated
by computed tomography in growing patients. Angle Orthod 2009;
79(1):24-29.
Bishara SE, Treder JE, Damon P. Olsen M. Changes in the dental arches
and dentition between 25 and 45 years of age. Angle Orthod 1996;
66(6):417-422.
Bjork A. Prediction of mandibular growth rotation. Am J Orthod 1969;
55(6):585-599.
Cattaneo PM, Salih RA, Melsen B. Labio-lingual root control of lower
anterior teeth and canines obtained by active and passive self-ligating
brackets. Angle Orthod 2013;83(4):691-697.
Cattaneo PM, Treccani M, Carlsson K, Thorgeirsson T, Myrda A, Cevidanes
LH, Melsen B. Transversal maxillary dento-alveolar changes in patients
214
Cattaneo
treated with active and passive self-ligating brackets: A randomized
clinical trial using CBCT-scans and digital models. Orthod Craniofac Res
2011;14(4):222-233.
Čelar A, Schedlberger M, Dorfler P. Bert M. Systematic review on self-
ligating vs. conventional brackets: Initial pain, number of visits,
treatment time. J Orofac Orthop 2013;74(1):40-51.
Cevidanes LH, Heymann G, Cornelis MA, DeClerck HJ, Tulloch JF.
Superimposition of 3-dimensional cone-beam computed tomography
models of growing patients. Am J Orthod Dentofacial Orthop 2009;
136(1):94-99.
Chen SS, Greenlee GM, Kim JE, Smith CL, Huang GJ. Systematic review
of self-ligating brackets. Am J Orthod Dentofacial Orthop 2010;137(6):
726.e1-e18.
Damon DH. Treatment of the face with biocompatible orthodontics.
In: Graber TM, Vanarsdall RL, Vig KWL, eds. Orthodontics: Current
Principles & Techniques. 4th ed. St Louis, MO: Elsevier-Mosby 2005;
753–831.
de Morais JF. Changes in arch dimensions, buccolingual inclinations and
alveolar bony support during alignment using Damon MX: A CBCT
study. Ph.D. thesis, Bauru Dental School, University of São Paulo,
Bauru, Brazil 2012.
Eberting JJ, Straja SR, Tuncay OC. Treatment time, outcome, and patient
satisfaction comparisons of Damon and conventional brackets. Clin
Orthod Res 2001;4(4):228-234.
Ehsani S, Mandich MA, El Bialy TH, Flores-Mir C. Frictional resistance in
self-ligating orthodontic brackets and conventionally ligated brackets:
A systematic review. Angle Orthod 2009;79(3):592-601.
Eriksen EF, Axelrod DW, Melsen F. Bone Histomorphometry: The American
Society of Bone and Mineral Research. Raven Press, New York, NY 1994.
Fleming PS, DiBiase AT, Lee RT. Self-ligating appliances: Evolution or
revolution? J Clin Orthod 2008;42(11):641–651.
Franzen TJ, Brudvik P. Vandevska-Radunovic V. Periodontal tissue reaction
during orthodontic relapse in rat molars. Eur J Orthod 2013;35(2):152-
159.
215
Self-ligating Brackets
Freitas KM, de Freitas MR, Henriques JF, Pinzan A, Janson G. Postretention
relapse of mandibular anterior crowding in patients treated without
mandibular premolar extraction. Am J Orthod Dentofacial Orthop
2004;125(4):480–487.
Glenn G, Sinclair PM, Alexander RG. Nonextraction orthodontic therapy:
Posttreatment dental and skeletal stability. Am J Orthod Dentofacial
Orthop 1987;92(4):321-328.
Hamilton R, Goonewardene MS, Murray K. Comparison of active self-
ligating brackets and conventional pre-adjusted brackets. Aust Orthod
J 2008;24(2):102-109.
Harradine N. The history and development of self-ligating brackets. Semin
Orthod 2008;14(1):5-18.
Harradine NW. Self-ligating brackets and treatment efficiency. Clin Orthod
Res 2001;4(4):220-227.
Henneman S, Von den Hoff JW, Maltha JC. Mechanobiology of tooth
movement. Eur J Orthod 2008;30(3):299-306.
Henrikson J, Persson M, Thilander B. Long-term stability of dental arch
form in normal occlusion from 13 to 31 years of age. Eur J Orthod
2001;23(1):51-61.
Hesby RM, Marshall SD, Dawson DV, Southard KA, Casko JS, Franciscus
RG, Southard TE. Transverse skeletal and dentoalveolar changes during
growth. Am J Orthod Dentofacial Orthop 2006;130(6):721-731.
Joss-Vassalli I, Grebenstein C, Topouzelis N, Sculean A, Katsaros C.
Orthodontic therapy and gingival recession: A Systematic review.
Orthod Craniofac Res 2010;13(3):127-141.
Kim TK, Kim KD, Baek SH. Comparison of frictional forces during the
initial leveling stage in various combinations of self-ligating brackets
and archwires with a custom-designed typodont system. Am J Orthod
Dentofacial Orthop 2008;133(2):187.e15-e24.
Kusy RP, Whitley JO. Resistance to sliding of orthodontic appliances in the
dry and wet states: Influence of archwire alloy, interbracket distance,
and bracket engagement. J Biomed Mater Res 2000;52(4):797-811.
Laursen MG, Melsen B, Cattaneo PMC. An evaluation of insertion sites for
mini-implants. Angle Orthod 2013;83(2):222-229.
216
Cattaneo
Little RM, Riedel RA, Engst ED. Serial extraction of first premolars:
Postretention evaluation of stability and relapse. Angle Orthod
1990;60(4):255-262.
Melsen B. The cranial base: The postnatal development of the cranial
base studied histologically on human autopsy material. Acta Odontol
Scand Suppl 1974;32(62):1-126.
Mestriner MA, Enoki C, Mucha JN. Normal torque of the buccal surface of
mandibular teeth and its relationship with bracket positioning: A study
in normal occlusion. Braz Dent J 2006;17(2):155-160.
Miethke RR, Melsen B. Effect of variation in tooth morphology and
bracket position on first and third order correction with preadjusted
appliances. Am J Orthod Dentofacial Orthop 1999;116(3):329-335.
Miles PG. Self-ligating brackets in orthodontics: Do they deliver what they
claim? Aust Dent J 2009;54(1):9-11.
Molen AD. Considerations in the use of cone-beam computed tomogra-
phy for buccal bone measurements. Am J Orthod Dentofacial Orthop
2010;137(4 Supply:S130-S135.
Morina E, Eliades T, Pandis N, Jäger A, Bourauel C. Torque expression of
self-ligating brackets compared with conventional metallic, ceramic,
and plastic brackets. Eur J Orthod 2008;30(3):233-238.
Pandis N, Eliades T, Partowi S, Bourauel C. Forces exerted by conventional
and self-ligating brackets during simulated first- and second-order
corrections. Am J Orthod Dentofacial Orthop 2008;133(5):738–742.
Pandis N, Eliades T, Partowi S, Bourauel C. Moments generated during
simulated rotational correction with self-ligating and conventional
brackets. Angle Orthod 2008;78(6):1030-1034.
Pandis N, Polychronopoulou A, Makou M, Eliades T. Mandibular dental
arch changes associated with treatment of crowding using self-ligating
and conventional brackets. Eur J Orthod 2010;32(3):248-253.
Ren Y, Maltha JC, Kuijpers-Jagtman AM. Optimum force magnitude for
orthodontic tooth movement: A systematic literature review. Angle
Orthod 2003;73(1):86-92.
Riedel RA. A review of the retention problem. Angle Orthod 1960;30:179-
199.
217
Self-ligating Brackets
Roth RH, Sapunar A, Frantz RC. The In-ovation bracket for fully adjusted
appliances. In: Graber TM, Vanarsdall RL, Vig KWL, eds. Orthodontics:
Current Principles & Techniques. 4th ed. St. Louis, MO: Elsevier-Mosby
2005;833–853.
Smith RJ, Burstone C.J. Mechanics of tooth movement. Am J Orthod
1984;85(4):294-307.
Tweed CH. The application of the principles of the edgewise arch in the
treatment of Class II, division 1, malocclusion: Part I. Angle Orthod
1936;6:198-208.
van Loenen M, Degrieck J, De Pauw G, Dermaut L. Anterior tooth
morphology and its effect on torque. Eur J Orthod 2005:27(3):258-262.
Weinstein S. Minimal forces in tooth movement. Am J Orthod 1967;
53(12):881-903.
Young TM, Smith RJ. Effects of orthodontics on the facial profile: A
Comparison of changes during nonextraction and four premolar
extraction treatment. Am J Orthod Dentofacial Orthop 1993;103(5):
452-458.
Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, Gerig G. User-
guided 3D active contour segmentation of anatomical structures:
Significantly improved efficiency and reliability. Neuroimage 2006;31
(3):1116-1128.
218
THE USE OF NETWORK META-ANALYSIS IN
ORTHODONTICS: A WORKED EXAMPLE INVOLVING
SELF-LIGATING BRACKETS
Nikolaos Pandis, Padhraig S. Fleming,
Loukia M. Spineli and Georgia Salanti
ABSTRACT
The evidence-based approach for orthodontic clinical practice hinges on three
elements: clinical expertise; best available evidence; and patient preferences and
Circumstances.
High quality randomized controlled trials and systematic reviews of
well-designed trials constitute the highest level of scientific evidence. The goal
of systematic reviews and meta-analyses is to facilitate the integration of the
existing knowledge in a systematic and transparent fashion, and to allow correct
interpretation on the effectiveness and safety of interventions. Traditional meta-
analyses are limited to comparing just two interventions concurrently and are
unable to combine evidence concerning multiple treatments. A relatively recent
extension of the traditional meta-analytical approach is network meta-analysis
(NMA) allowing, under certain assumptions, the quantitative synthesis of all
evidence under a unified framework and across a network of all eligible trials.
NMA combines evidence from direct and indirect information via common
comparators; interventions, therefore, can be ranked in terms of the analyzed
outcome. In this chapter, the NMA approach is implemented in order to compare
and rank the effectiveness of conventional and self-ligating appliances in terms
of initial alignment.
KEY WORDS: network meta-analysis, orthodontic alignment, self-ligating brackets,
conventional brackets
INTRODUCTION
The clinician is confronted on a daily basis with questions such
as: "Are self-ligating brackets more efficient than conventional applianc-
es?,” “Should I use TADs or headgear?” or “Should I implement a two- or
219
Self Ligation
one-stage treatment to treat this Class Il case?" Clinicians are bombarded
constantly by orthodontic companies with often-unsubstantiated claims
of apparently unique products. The practitioner may be influenced by
companies and the public to adopt the latest device or method without
analyzing the evidence for and against using it. In orthodontics, nowhere
has this tension between marketing and clinical decision making been
more prominent than in relation to the clinical use of self-ligating brack-
ets. A variety of competing passive and active self-ligating Systems has
been marketed feverishly with associated claims of faster treatment, di-
minished pain, improved hygiene and less need for extractions. Prospec-
tive studies, however, largely have failed to confirm these claims (Fleming
and Johal, 2010; Fleming and O’Brien, 2013).
A sensible approach to clinical decisions is evidence based, as
it considers the best available scientific evidence on efficacy and safety,
clinical expertise and patient circumstances and preferences (Strauss et
al., 2011). The levels of scientific evidence range from clinical opinion at
the lower level to systematic reviews of high quality clinical trials at the
highest level.
Systematic reviews of interventions aim to collect and accumulate
high-quality evidence on the effects of an intervention in a systematic,
transparent and unbiased manner. This information may be combined
qualitatively or quantitatively in a meta-analysis. Ouantitative analysis
may produce a more precise estimate on the effectiveness and safety of a
therapy and may reconcile misunderstandings and existing controversies
regarding therapies and expose unanswered questions, which may be
addressed in subsequent trials (Higgins et al., 2011).
Traditional meta-analysis compares only two therapies or one
therapy with a control. When several interventions are being tested,
performing multiple pair-wise comparisons restricts the evidence to
just one part of the whole picture. A relatively recent development in
meta-analysis allows the incorporation of all eligible evidence in a unified
framework permitting simultaneous synthesis of all available data,
under certain assumptions. These methods allow direct and indirect
comparisons of diverse interventions in trials using the same outcome to
be combined, increasing the amount of usable information to calculate
pooled estimates (Fig. 1). This type of meta-analysis has been termed
220
Pandis et al.
tº gº sº º sº sº me me gºe| ndirect tº gº tº gº gº º sº º Passive SL
(P)
direct
Conventional
(C)
| AP=AC-PC
Figure 1. Direct and indirect comparisons.
multiple treatments meta-analysis, mixed treatment comparisons or
network meta-analysis (NMA; Lu and Ades, 2004; Caldwell et al., 2005;
Salanti et al., 2008; Cooper et al., 2009; Salanti, 2012; Cipriani et al.,
2013). NMA offers important advantages over conventional meta-
analysis allowing interventions that have not been compared in any
trial to be compared and permitting ranking of interventions in order of
effectiveness. This technique also can improve the precision of the effect
estimates by reducing the width of the confidence intervals compared
with direct evidence alone (Song et al., 2003; Cipriani et al., 2013).
Systematic reviews using NMA are scarce in the dental literature
and, to our knowledge, quantitative syntheses of this nature have not
been reported in orthodontics (Walsh, 2010; Tu et al., 2012; Faggion
et al., 2013). NMA primarily has been undertaken within a Bayesian
framework and long has been inaccessible to non-statisticians. However,
the development of software routines and tutorials in STATA" are likely
to popularize the method (White, 2009; Higgins et al., 2012; White et al.,
2012; Chaimani et al., 2013). The objective of this chapter is to present
the assessment of the effectiveness of initial orthodontic alignment using
different bracket systems under the NMA framework.
METHODS
The following selection criteria were applied:











221
Self Ligation
• Study design: Randomized clinical trials (RCTs),
controlled clinical trials (CCTs) and split-mouth designs
were included.
• Participants: Patients with full-arch, fixed and bonded
orthodontic appliance(s).
• Interventions/comparators: Various types of self-
ligating and conventional brackets.
• Outcome measures: Millimeters of crowding alleviated
during the initial alignment stage per unit of time.
Search Strategy for Identification of Studies
The following electronic databases were searched: MEDLINE
(1966 to December 2012, Appendix 1); EMBASE (1980 to December
2012); the Cochrane Oral Health Group's Trials Register (December
2012); and the Cochrane Central Register of Controlled Trials (CENTRAL,
The Cochrane Library Issue 1, 2013) without language restrictions.
Unpublished literature was searched electronically using www.clinical
trials.gov, the National Research Register (www.controlled-trials.
com) and Pro-Ouest Dissertation Abstracts and Thesis database (www.
produest.com) using the term 'orthodontic.' Conference proceedings
and abstracts also were accessed where possible. Authors were to be
contacted to identify unpublished or ongoing clinical trials and to clarify
results if necessary. Reference lists of the included studies were screened
for relevant research.
Assessment of Comparability and Risk of Bias in the Included Studies and
Data Extraction
Assessment of research for inclusion in the review, risk of bias
assessment and data extraction were performed. Disagreements were
resolved by discussion. Seven criteria were considered to grade risk
of bias of individual studies: random sequence generation; allocation
concealment; blinding of participants and personnel; blinding of
assessors; incomplete outcome data; selective reporting of outcomes;
and other potential sources of bias (Higgins et al., 2011).
A data extraction form was developed to record study design,
observation period, participants, interventions, outcomes and outcome
222
Pandis et al.
data of interest, including use of extractions. The clinical and
methodological heterogeneity of included studies was to be judged by
assessing the treatment protocol, particularly participants and setting,
intervention details (e.g., materials used, follow-up, timing of data
collection and measurement techniques).
The primary outcome assessed was the amount of tooth
movement in millimeters per month. This outcome was calculated in
each primary study by dividing the amount of crowding resolved by the
number of days of follow-up during initial alignment and then scaled to
provide a monthly rate. In instances where the standard deviation of the
mean difference was not reported in the studies, the following formula
was used to approximate it:
Vsd_before’ + sa after” – 2 ºr sa before * sa after
“sd_before” and “sd_after” are the standard deviations before and at
the end of the alignment stage, respectively, and “r” is the correlation
coefficient between the before and after measurements. The correlation
coefficient was calculated from available individual patient data where
necessary (Miles, 2005, 2006; Pandis, 2007; Ong, 2010). To reduce
potential bias due to lack of randomization in CCTs, estimates adjusted for
the impact of potential effect modifiers (e.g., bracket type, age, gender,
and angle classification as co-variates) were calculated from individual
patient data supplied by the trial authors (Miles, 2005, 2006; Pandis,
2007; Ong, 2010). For split mouth designs, the mean difference from the
paired observations was calculated along with the corresponding standard
deviation. The relative treatment effect was calculated as the difference
in the monthly rate of alignment between the compared interventions.
RESULTS
The PRISMA flow chart of the included Studies and the assessment
of the risk of bias of the included RCTs and nonrandomized CCTs are
shown in Figures 2 and 3. The risk of bias of the included randomized
clinical trials (RCTs) and non-randomized controlled clinical trials (CCTs)
are shown in Figures 2-4.
223

Self Ligation
Records identified through Additional records identified
database searching through other sources
(n = 136) (n = 1)
- -
Records after duplicates removed
(n = 132)
-
Records screened J Records excluded
(n = 132) (n = 121)
Full-text articles
Full-text articles excluded, with
assessed for eligibility - reasons
(n = 11) (n = 1, serious
baseline differences)
-
Studies included in
quantitative synthesis
(meta-analysis)
(n = 10, RCTs = 6,
CCTs=4)
\_/IICN\ ^TN
Figure 2. PRISMA flow diagram of trial identification, retrieval and analysis.
A total of eleven trials were identified with one trial omitted
in view of significant between-group baseline differences (Miles, 2005;
Miles et al., 2006; Pandis et al., 2007, 2010; Scott et al., 2008; Fleming
et al., 2009; Miles and Weyant, 2010; Ong et al., 2010; Wahab et al.,
2011; Gaspar-Ribeiro et al., 2012). All trials involved comparisons of
two bracket systems. In total, 588 participants were assigned to one of
these four treatment modalities. In terms of study characteristics, six of
the trials were RCTs, sample size in each group ranged from 14–35 with
a mean of 27 patients per group. The trials were published between
2005-2012 with the majority published in 2010. Most of the studies
investigated mandibular alignment in the anterior (inter-canine) segment.
Participants ranged from 10–18 years in most trials, although one study
had an age range of 14–30 years; 50% of the studies involved extraction-
based treatment. After study selection and data extraction, a network
of four dental bracket systems was generated (Fig. 4). The size of the
224

Pandis et al.
º # * º §
# # # # º
+: -
# ; : § § 3
E * . § ... =
: 3 = E # 3.
5 = 3 º $
: gº 9 ºn E E ºn
º º º º: º º º
-- 5 : 5 º 8 E
º 5 : 5 : E 5
c 3 º E - º º.
º E ºn O : gº 9 to
º º
Fleming 2009 º © () () É # # 5
- º º
Gaspar-Ribeiro 2012 O º |Q|O # § § 5
Miles 2010 º © () () Milºš 2005 O ()|()|()
Pandis 2010 º © |Q|Q)
Miles 2006|Q|(-) © ()|Q)
Pandis 2011 º © |Q|Q)
Scott 2008 |(} |(}) () () () Ong 2010|0|0 () ()|()
Wahab 2012|º |º ©ºlº Pand's 2007|0|0|º |0|0|0|0
Figure 3. Risk of bias summary: judgments for each bias risk item for
individual RCTs (left panel) and CCTS (right panel).
nodes corresponds to the number of trials relating to each particular
bracket system. The larger the number of trials investigating a particular
bracket system, the larger the node representing this group. The directly
Comparable treatments are linked with a line. If there is a dotted line
between two nodes, it means that there are no studies (i.e., no direct
evidence) comparing the two bracket systems. For example, there is
direct evidence for all self-ligating systems vs. conventional, but no
direct evidence for Smart-Clip vs. Damon and In-Ovation-R (Fig. 4). The
observed differences in effect modifiers between the comparisons are
Small, although there are few studies on which to base judgment of
transitivity in terms of study randomization, extractions, age and gender
of the participants and year of trial.
The direct, indirect and mixed relative treatment effects from
the network of the four bracket systems are presented in Table 1; the
Confidence interval for the mixed estimates is narrower than the confi-
dence interval for the direct or indirect estimates. Combining direct and
225
Self Ligation
In-Ovation-R
Smart-Clip
Conventional
º 70
º 6 (335)
Damon
Figure 4. Network of eligible comparisons for the network meta-analysis
(NMA) for effectiveness. The size of the nodes corresponds to the
number of trials relating to each particular bracket system. The larger
the number of trials concerning a particular bracket system, the larger
the node for this intervention. The directly comparable treatments are
linked with a continuous line. The thicker the line connecting the trials,
the larger the number of trials studying this comparison. In the current
figure, it is obvious that the system most frequently encountered is
the conventional followed by Damon; the most frequent comparison
is Damon vs. conventional. The number of trials investigating this
comparison and the total number of randomized participants (included
in parenthesis) are presented on each link.
indirect evidence for the Damon vs. In-Ovation-R comparison reduced
the variance by 36%. The results of the conventional meta-analysis for
the observed pair-wise comparisons are illustrated in Figure 5. The results
for all comparisons are given in Table 2.
As shown in the rankograms (Fig. 6), conventional brackets and
In-Ovation-R are more likely to be among the first two best options, since
they have higher rank probabilities in the first two ranks compared to
Damon and Smart-Clip. On the contrary, Damon and Smart-Clip are more
likely to be the least good options, since they have higher rank probabilities


















226
Pandis et al.
Table 1. Collection of direct, indirect and mixed evidence under Bucher's method.
Direct evidence has been extracted from head-to-head comparisons. Indirect
evidence has been obtained using the consistency equation. Mixed evidence is
the result of the weighting average of the direct and indirect evidence. Parenthesis
= the standard error of the estimate; square brackets = 95% confidence interval.

- Direct Indirect Mixed
Comparisons - - -
evidence evidence evidence
Conventional In-Ovation-R -0.12 (0.39) || 0.18 (0.37) 0.04 (0.26)
VerSUS: [-0.69, 0.45] | [-0.54, 0.90) [-0.48, 0.56]
0.12 (0.14) -0.18 (0.52) 0.10 (0.13)
Damon
[-0.16, 0.40] | [-1.19, 0.83] [–0.16, 0.36]
- 0.16 (0.20) 0.16 (0.20)
Smart-Cl -
Ip [-0.20, 0.52] [-0.20, 0.52]
Damon -0.06 (0.34) 0.24 (0.41) 0.06 (0.26)
In-Ovation-R [-0.51, 0.39] | [-0.57, 1.05] [-0.45, 0.57]
VerSUS: - 0.28 (0.44) 0.28 (0.44)
Smart-Cli -
m p [-0.58, 1.14] [-0.58, 1.14]
- 0.04 (0.24) 0.04 (0.24)
Da . S t–CI -
I77On VerSUS mart-Ullp [-0.44, 0.52] | [-0.44, 0.52]

Table 2. NMA and pair-wise meta-analysis results for the effectiveness of the
bracket systems. NMA mean differences (mm/month) in tooth movement are
presented above the diagonal, while direct meta-analysis results are presented
below the diagonal. Interventions are ordered according to their ranking.
Comparisons between systems are indicated by the column-defining bracket
VS. the rows-defining bracket system. Mean differences above 0 favors the
bracket system in the column. To obtain mean differences for comparisons in the
Opposite direction, negative values should be converted into positive values and
Vice versa. Heterogeneity variance (tº) from NMA was estimated equal to 0.05.
0.03 0.17
C - - "v. -
Onventional (-0.54, 0.48) 0.08 (-0.33, 0.17) (-0.66, 0.32)
- 0.14
-0.12 (-0.69, 0.45) In-Ovation-R 0.05 (-0.52, 0.62) (-0.57, 0.85)
–0.06 (-0.51, 0.09
0.12 (-0.16, 0.40) 0.39) Damon (-0.82, 1.00)
0.16 (-0.20, 0.52) - - Smart-Clip
227
Self Ligation
First treatment Second treatment
Author, year MD (95% CI) N, mean, (SD) N, mean, (SD)
Conventional vs. Damon
Wahab, 2012 - 0.99 (0.17, 1.81) 15, 3.15 (1.17) 14, 2.16 (1.08)
Scott, 2008 - 0.27 (-0.28, 0.82) 28, 1.68 (66) 32, 1.41 (1.41)
Pandis, 2011 He 0.24 (-0.28, 0.76) 25, 222 (.96) 25, 198 (9)
Ong, 2010 -- 0.11 (-0.16, 0.38) 40, 1.57 (.59) 44, 1.46 (65)
Miles, 2006 - 0.09 (-0.27, 0.45) 29, 6 (75) 29, .51 (.66)
Pandis, 2007 --- -0.40 (-0.76, -0.05) 27, 141 (63) 27, 181 (.711)
Subtotal (1-squared = 60.4%, p = 0.027) 0.12 (-0.16, 0.40) 164 171
with estimated predictive interval (-0.71, 0.94)
Conventional vs. Smart-Clip
Miles, 2005 0.34 (-0.26, 0.95) 29, 1.8 (1.29) 29, 146 (1.05)
Fleming, 2009 0.05 (-0.40, 0.50) 32, 1.81 (.984) 33, 1.76 (864)
Subtotal (1-squared = 0.0%, p = 0.455) 0.16 (-0.20, 0.52) 61 62
Conventional vs. In-Ovation-R -
Miles, 2010 - --- -0.12 (-0.69, 0.45) 30, 1.76 (1.05) 30, 1.88 (1.21)
In-Ovation-Rws. Damon
Pandis, 2010 - -0.06 (-0.51, 0.39) 35,228 (99) 35, 2.34 (93)
-T- -
-1.90 -1.00 0.00 1.00 1.90
Favors second treatment Favors first treatment


Figure 5. Forest plots of observed pair-wise comparison results for effectiveness
of initial orthodontic alignment using different bracket systems. Prediction
intervals are estimated only for meta-analysis with more than two studies.
In-Ovation-R Conventional
100 – 100 -
80 - 80 -
60 — 60 -
40 – 40 -
~ 20 – 20 T.
§ 0 – 0 –
§ i i i i I i i —T-
£ 1 2 3 4 1 2 3 4
º
# Damon Smart-Clip
§ 100- 100 -
80 - 80 -
60 — 60 -
40 – 40 -
0 - 0 –
i i i i T- -T-T
1 2 3 4 1 2 3 4
Rank
Figure 6. Rankograms for all interventions. The four possible ranks are on the
horizontal axis and the probability of each treatment to be the first best, the
Second best and so on (rank probabilities) is on the vertical axis.
228
Pandis et al.

100
80
68%
60 56%
43%
40 – - 32%
20 –
In-Ovation-R Conventional Damon Smart-Clip
Figure 7. SUCRA plots of each bracket system with % corresponding to the SUCRA
Value of the respective treatment.
Within the last two ranks. Figure 7 illustrates the SUCRA value of each
alignment in a bar plot. Conventional brackets appear to lead to the most
effective alignment with a SUCRA value of 68%. These are followed by In-
OVation-R, Damon and Smart-Clip with SUCRA values 56%, 43% and 32%,
respectively.

DISCUSSION
Network meta-analyses offer important advantages over Con-
Ventional meta-analysis increasing the precision of the estimated effect
Sizes, allowing interventions that have not been compared in any trial
to be compared and permitting the creation of a hierarchical rank of
interventions. NMA, however, should be used with caution with the
underlying assumptions of the analysis considered carefully. In particular,
the network should be consistent with direct and indirect evidence on
the same comparisons in agreement. Joint analysis of treatments can be
misleading if the network is inconsistent substantially. Inconsistency may
229
Self Ligation
be attributed to an uneven distribution of effect modifiers across groups
of trials comparing different treatments. Therefore, the distribution of
clinical and methodological variables suspected to be potential sources
of either heterogeneity or inconsistency in each comparison or specific
group of trials should be investigated.
This is the first reported usage of multiple treatment meta-
analysis in orthodontic research. Further application of this technique
in orthodontics would be of great value, particularly as a range of
mechanics and treatment alternatives may be depioyed to address
overall malocclusions (e.g., increased overjet) or to effect specific tooth
movements (e.g., Space closure).
Orthodontic treatment rarely involves binary decisions with a
range of options possible in most situations (Ribarevski et al., 1996; Lee et
al., 1999; Cobourne et al., 2012). Individual preferences continue to have
an integral role in treatment planning decisions, with little uniformity in
respect of a range of approaches; consequently, NMA is likely to have
important application in the future of evidence-based orthodontics.
Clinical Interpretation of the Findings
The results from NMA and mixed treatment effects (Tables 1 and
2) display the mean difference in mm per month of alignment achieved
with the different bracket comparisons. The NMA results indicate that
the conventional appliances perform better in alignment efficiency
compared to all other systems with a greater mean improvement
of 0.03, 0.08 and 0.17 mm per month with conventional compared
to In-Ovation-R, Damon and Smart-Clip, respectively. The estimated
differences are not significant statistically since the associated 95%
confidence intervals include the value zero and, more importantly, the
estimates are of little clinical importance. If we assume that an average
duration for initial alignment is approximately four months, the results
suggest that the conventional appliance will be more efficient on average
from between 0.12 to 0.68 mm over the four-month period compared
to the other three-bracket systems. The expected four-month differences
230
Pandis et al.
were calculated by multiplying the minimum and maximum NMA esti-
mates by four (number of months) for the comparisons of conventional
brackets with the other systems (Table 2). The results should be inter-
preted with caution as the number of studies is small and the associated
confidence intervals are relatively wide indicating imprecision of the es-
timated treatment effects. The comparisons between In-Ovation-R, Da-
mon and Smart-Clip yielded differences of limited clinical relevance. This
NMA, therefore, offers further information that self-ligating brackets are
not associated with more rapid treatment than conventional brackets.
CONCLUSIONS
NMA is a relatively new statistical advancement with the potential
for significant application in orthodontics. This technique was applied
in this chapter to illustrate its use in allowing novel, comprehensive,
Concurrent and accurate comparison of a range of treatment modalities.
The key value of NMA lies in the ability to:
• Compare treatments, untested in primary studies, by
using common Comparators;
• Strengthen the evidence base by combining direct
and indirect effects, where applicable; and
• Rank the available interventions for the studied out-
comes. This NMA suggests that self-ligating brackets
are not associated with more efficient treatment than
conventional systems and failed to highlight a differ-
ence among specific self-ligating systems.
ACKNOWLEDGEMENTS
This manuscript is based on the following publication with
permission from Elsevier: Pandis N, Fleming PS, Spineli LM, Salanti G. Initial
Orthodontic alignment effectiveness with self-ligating and conventional
appliances: A network meta-analysis in practice. Am J Orthod Dentofacial
Orthop 2014;145(4 Suppl):S152-S163.
231
Self Ligation
REFERENCES
Caldwell DM, Ades AE, Higgins J.P. Simultaneous comparison of multiple
treatments: Combining direct and indirect evidence. BMJ 2005;331
(7521):897-900.
Chaimani A, Higgins.JP, Mavridis D, Spyridonos P. Salanti G. Graphical tools
for network meta-analysis in STATA. PLoS One 2013;8(10):e76654.
Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical
challenges in network meta-analysis. Ann Intern Med 2013;159(2):
130–137.
Cobourne MT, Fleming PS, DiBiase AT, Ahmad S. Clinical Cases in
Orthodontics. Chichester, UK: Wiley-Blackwell 2012.
Cooper NJ, Sutton AJ, Morris D, Ades AE, Welton NJ. Addressing between-
study heterogeneity and inconsistency in mixed treatment compari-
sons: Application to stroke prevention treatments in individuals with
non-rheumatic atrial fibrillation. Stat Med 2009;28(14):1861-1881.
Faggion CM Jr, Chambrone L, List| S, Tu YK. Network meta-analysis for
evaluating interventions in implant dentistry: The case of peri-
implantitis treatment. Clin Implant Dent Relat Res 2013;15(4):576-588.
Fleming PS, DiBiase AT, Sarri G, Lee RT. Efficiency of mandibular arch
alignment with 2 preadjusted edgewise appliances. Am J Orthod
Dentofacial Orthop 2009;135(5):597–602.
Fleming PS, Johal A. Self-ligating brackets in orthodontics: A systematic
review. Angle Orthod 2010;80(3):575-584.
Fleming PS, O'Brien K. Self-ligating brackets do not increase treatment
efficiency. Am J Orthod Dentofacial Orthop 2013;143(1):11-19.
Lee R, MacFarlane T, O'Brien K. Consistency of orthodontic treatment
planning decisions. Clin Orthod Res 1999;2(2):79-84.
Lu G, Ades AE. Combination of direct and indirect evidence in mixed
treatment comparisons. Stat Med 2004;23(20):3105-3124.
Miles PG. SmartClip versus conventional twin brackets for initial alignment:
Is there a difference? Aust Orthod J 2005;21(2):123-127.
232
Pandis et al.
Miles P, Weyant R. Porcelain brackets during initial alignment: Are self-
ligating cosmetic brackets more efficient? Aust Orthod J 2010;26(1):
21–26.
Miles PG, Weyant RJ, Rustveld L. A clinical trial of Damon 2 vs conventional
twin brackets during initial alignment. Angle Orthod 2006;76(3):480–
485.
Ong E, McCallum H, Griffin MP, Ho C. Efficiency of self-ligating vs
conventionally ligated brackets during initial alignment. Am J Orthod
Dentofacial Orthop 2010;138(2):138.e1-e7.
Pandis N, Polychronopoulou A, Eliades T. Active or passive self-ligating
brackets? A randomized controlled trial of comparative efficiency in
resolving maxillary anterior crowding in adolescents. Am J Orthod
Dentofacial Orthop 2010;137(1):12.e1-e6.
Pandis N, Polychronopoulou A, Eliades T. Self-ligating vs conventional
brackets in the treatment of mandibular crowding: A prospective
clinical trial of treatment duration and dental effects. Am J Orthod
Dentofacial Orthop 2007;132(2):208-215.
Ribarevski R, Vig P, Vig KD, Weyant R, O'Brien K. Consistency of orthodontic
extraction decisions. Eur J Orthod 1996;18(1):77-80.
Salanti G. Indirect and mixed-treatment comparison, network, or
multiple-treatments meta-analysis: Many names, many benefits,
many concerns for the next generation evidence synthesis tool. Res
Synth Method 2012;3(2):80-97.
Salanti G, Higgins JP, Ades AE, Ioannidis JP Evaluation of networks of
randomized trials. Stat Methods Med Res 2008;17(3):279-301.
Scott P. DiBiase AT, Sherriff M, Cobourne MT. Alignment efficiency of
Damon3 self-ligating and conventional orthodontic bracket systems:
A randomized clinical trial. Am J Orthod Dentofacial Orthop 2008;134
(4):470.e1-e8.
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison
for estimating efficacy of competing interventions: Empirical evidence
from published meta-analyses. BMJ 2003;326(7387):472.
Straus SE, Glasziou P, Richardson WS, Haynes BR. Evidence-based
Medicine: How to Practice and Teach lt. 4th ed. Churchill Livingstone,
London 2010.
233
Self Ligation
Tu YK, Needleman I, Chambrone L, Lu HK, Faggion CM Jr. A Bayesian
network meta-analysis on comparisons of enamel matrix derivatives,
guided tissue regeneration and their combination therapies. J Clin
Periodontol 2012;39(3):303-314.
Wahab RM, Idris H, Yacob H, Ariffin SH. Comparison of self- and
conventional-ligating brackets in the alignment stage. Eur J Orthod
2012;34(2):176-181.
Walsh T, Worthington HV, Glenny AM, Appelbe P, Marinho VCC, Shi X.
Fluoride toothpastes of different concentrations for preventing dental
caries in children and adolescents. Cochrane Database Syst Rev
2010(1):CD007868.
White IR. Multivariate random-effects meta-analysis. Stata J 2009;9(1):
40–56.
White IR, Barrett JK, Jackson D, Higgins.JPT. Consistency and inconsistency
in network meta-analysis: Model estimation using multivariate meta-
regression. Res Synth Method 2012;3(2):111-125.
234
THREE-DIMENSIONAL REVIEW OF RAPID MAXILLARY
EXPANSION: LONG-TERM CHANGES IN ANCHOR TEETH
AND ALVEOLAR BONE
Sercan Akyalcin, Banu Dincer and Aslihan Ertan Erdinc
ABSTRACT
AIM: This chapter will review the skeletal and dental changes following rapid
maxillary expansion (RME) therapy with particular emphasis on the alveolar
bone and anchor teeth. METHODS: The records of 26 individuals (16 females, 10
males; mean age 14.1 years) who had RME therapy as part of their orthodontic
treatment were investigated. Coronal and axial slices were created from cone-
beam computed tomography (CBCT) images to perform the skeletal and dental
measurements before (T1) and immediately after (T2) maxillary expansion
therapy and in the retention (T3) period. One-way repeated measures analysis
of variance and post-hoc pairwise comparisons were used for statistical testing.
RESULTS: Significant increases between T1 and T2 and significant decreases
between T2 and T3 were observed in all the dental and skeletal transverse width
measurements. Significant buccal tipping of the maxillary first premolar and
molars and significant bending of maxillary alveolar bone at these sites were
observed between T1 and T2. At T3, some uprighting was observed for both
the teeth and the alveolar bone, mostly with no significant changes. A decrease
between T1 and T2, and an increase between T2 and T3 were found in the buccal
bone thickness of both the maxillary first premolars and maxillary first molars;
however, these changes were not significant. CONCLUSIONS: Transverse width
expansion measured at skeletal structures is retained better than dental width
increases following RME. Buccal tipping of the anchor teeth and bending of the
alveolar bone is a significant aspect of RME and is retained mostly as part of the
treatment OutCOme.
KEY WORDS: rapid maxillary expansion, CBCT, buccal tipping, alveolar bending,
buccal bone
Rapid maxillary expansion (RME) appliances are used to treat
maxillary transverse deficiency, to resolve arch-length discrepancy and
to enhance maxillary protraction by affecting the circum-maxillary suture
235
Rapid Maxillary Expansion
network (McNamara and McNamara, 2009). Throughout the years, many
types of palatal expanders and their effects on facial structures have been
studied (Christie et al., 2010). Following RME therapy in young individuals,
the midpalatal suture separates leading to complex three-dimensional
(3D) changes in the maxillofacial region (Starnbach et al., 1966). Perhaps
the most important outcome that is expected from an RME application is
the achievement of true orthopedic changes via skeletal expansion. Or-
thopedic expansion is not limited to the midpalatal suture alone, but in-
cludes the network of sutures around the maxillary and zygomatic bones.
In a successful RME application, incremental separation of the midpala-
tal suture primarily brings about skeletal expansion of the maxilla and a
subsequent increase in the maxillary dental arch perimeter. It is reported
that every millimeter of palatal width increase in the premolar region
produces a 0.7 mm increase in available maxillary dental arch perimeter
(Adkins et al., 1990).
Common knowledge suggests that separation of the midpalatal
suture does not occur in a uniform pattern. The opening of the suture
is complicated further by the maturation stage of the individual, soft
tissues, cranial structures and other maxillary sutures. Tissue-borne
appliances with reinforced dental anchorage are shown to produce
orthopedically superior results (Haas, 1965, 1980) due to the enhanced
anchorage potential with these types of expanders; however, tooth-borne
expanders (Garib et al., 2005; Huynh et al., 2009; Weissheimer et al.,
2011) are used continuously to correct maxillary transverse discrepancies
for their practicality and hygiene advantage. Additionally, there has been
an increase in the number of clinical trials that evaluate the effectiveness
of incorporating temporary skeletal anchorage devices in the design of
maxillary expanders in efforts to minimize the dental side effects (e.g.,
tipping of teeth, alveolar bending and bite opening; Lee et al., 2010;
Wilmes et al., 2010; Karagkiolidou et al., 2013).
- Regardless of the anchorage setting, dental tipping and related
alveolar bone changes occur in many maxillary expansion applications.
In some cases, these changes may exceed the clinically acceptable levels
resulting in marginal bone loss, buccal fenestrations and gingival prob-
lems (Rungcharassaeng et al., 2007; Akyalçin et al., 2013). The periodon-
tal consequences of RME in the permanent dentition emphasize the
236
Akyalcin et al.
importance of early application since RME produces a greater orthopedic
effect in the deciduous and mixed dentition (Baccetti et al., 2001).
Moreover, heavy buccally-directed forces produce significantly more
resorption than light forces (Paetyangkul et al., 2009; Oh et al., 2011).
Finally, since RME therapy relies on the transmission of heavy forces to
the maxilla by the anchor teeth, root resorption of these teeth is a well-
documented finding in histologic investigations (Langford, 1982; Langford
and Sims, 1982; Odenricket al., 1991).
Studies of RME generally have focused on measuring the changes
observed on dental casts or the two-dimensional (2D) radiographs before
and after treatment to evaluate the short- and long-term skeletal and
dental effects (Handelman et al., 2000; Baccetti et al., 2001; McNamara et
al., 2003). Conventional radiographs (e.g., cephalometric and panoramic
radiograph) are not appropriate for examining buccal bone or periodontal
changes during and after RME therapy. Recently, cone-beam computed
tomography (CBCT) and software reconstruction of the scanned images
in 3D have been valuable for investigating changes induced by RME (Fig.
1; Garrett et al., 2008; Ribeiro et al., 2012). Evaluating buccal bone, dental
and alveolar inclination changes, root resorption, bone density, limits
of absolute skeletal expansion and related airway and sinus changes all
can be achieved using CBCT scans. Reports using CBCT evaluations have
helped expand our knowledge on the effects of RME therapy.
Based on the conclusions of a recent systematic review (Bazargani
et al., 2013), skeletal expansion comprises 22-53% of the screw expansion
as evaluated by 3D methods. However, no consistent evidence is present
whether the suture opening is parallel or triangular. While our classic
knowledge of triangular pattern of skeletal expansion with a wider base
in the anterior region is confirmed (Garrett et al., 2008), parallel opening
of the midpalatal suture also is documented (Ballanti et al., 2010; Christie
et al., 2010). Additionally, the relative contribution of dental, alveolar and
Skeletal changes varies from subject to subject, leading to wider suture
opening either anteriorly and posteriorly depending on the individual
Case (Podesser et al., 2007). The average opening of the midpalatal
suture is between 1.5 to 4.5 mm for both the anterior and posterior
aspects (Podesser et al., 2007; Ballanti et al., 2010; Christie et al., 2010;
Weissheimer et al., 2011).
237
Rapid Maxillary Expansion
Figure 1. Evaluation of buccal alveolar bone cannot be made with conventional
2D radiographs. In this example, a 3D pre-treatment CBCT reconstruction
demonstrates significant bone loss around the maxillary first molar roots.
3D radiographic studies confirm that structures located close to
the midpalatal suture show more width and/or displacement changes
than structures located further from the midline (Bazargani et al., 2013).
The greatest transverse width increase is in the midpalatal suture itself,
followed by basal bone and nasal cavity (Christie et al., 2010). 3D radio-
graphs also provide sufficient resolution to quantitate the separation of
the circum-maxillary suture network resulting directly from midpalatal
suture expansion. Up to 0.5 mm of sutural opening occurs in the Zygo-
maticofrontal, zygomaticomaxillary, frontomaxillary, zygomaticotempo-
ral, nasomaxillary, frontonasal and internasal sutures following 8 mm of
RME Screw expansion (Leonardi et al., 2011). These changes are propoſ-
tional inversely to the age/maturation status of the individual and slightly
higher in those sutures that articulate with the maxilla directly.
While one would predict that circum-maxillary sutures respond
to RME treatment, it is less obvious that distant cranial structures (e.g.,
the orbits and spheno-occipital synchondrosis) also are affected by RME
treatment (Bazargani et al., 2013). All these changes may help assist in
the orthopedic protraction of the maxilla. Some clinical cases show a

238
Akyalçin et al.
Figure 2. Sagittal slices from a CBCT evaluation of an individual with a skeletal
Class Ill tendency. A: Pre-treatment and B: Post-expansion images demonstrate a
downward and forward movement of the maxilla and a subsequent enhancement
in Class III relationship.
Subsequent improvement in the mid-face region following RME therapy
(Fig. 2) with no additional facemask treatment. However, according to the
results of a meta-analysis (Cordasco et al., 2014), no significant differences
exist between individuals that had RME before facemask therapy and
individuals that did not. Interestingly, on average, a stronger orthopedic
effect was found in the group that did not receive preliminary RME. These
findings confirm that RME therapy may be of some value in Class Ill cases,
but certainly is not required in all facemask applications.
The relationship between RME and nasal cavity size and airway
resistance has been a controversial topic in orthodontics. As evident from
the findings of 3D studies, nasal width increases between 0.9 to 2.7 mm,
which accounts for 17–33% of the total screw expansion (Podesser et
al., 2007; Ballanti et al., 2010; Christie et al., 2010; Kartalian et al., 2010;
Darsey et al., 2012). This may sound encouraging when coupled with the
Subjective evaluations (Oliveira De Felippe et al., 2008) that indicate a
decrease in nasal airway resistance following RME therapy. However, 3D
Studies demonstrate that RME has no effect on the nasopharynx volume
(Ribeiro et al., 2012). Additionally, there is no evidence to support the
hypothesis that RME could increase the airway volume in individuals
With narrow oropharyngeal airways (Zhao et al., 2010, Ribeiro et al.,
2012; Zeng and Gao, 2013). Similarly, although a subsequent decrease
in maxillary sinus width is reported (Garrett et al., 2008), total maxillary
Sinus volume appears to remain virtually stable following RME therapy
(Darsey et al., 2012).

239
Rapid Maxillary Expansion
Several authors (Christie et al., 2010; Domann et al., 2011;
Pangrazio-Kulbersh et al., 2012) indicated the importance of buccal
tipping of the anchored teeth and alveolar bending, particularly in banded
RME applications as compared to the bonded RME devices. Specifically,
these authors observed an immediate decrease in buccal bone thickness
and marginal bone levels following RME therapy (Rungcharassaeng et al.,
2007; Domann et al., 2011; Akyalçin et al., 2013; Pangrazio-Kulbersh et
al., 2013). A successful RME application requires careful monitoring of the
patient's age and initial buccal bone thickness so as not to compromise
the periodontal status of the individual. Additionally, slow maxillary
expansion, as opposed to rapid expansion, causes significantly more
vertical and horizontal bone losses (Brunetto et al., 2013). These findings
indicate concerns over the alveolar bone and anchor teeth when
using RME. However, it must be kept in mind that comprehensive
orthodontic treatment starting upon the completion of maxillary
expansion should correct any undesirable side effects (e.g., tipping of
maxillary posterior teeth). It is of great interest to practicing clinicians
to determine what happens to the buccal alveolar bone following fixed
appliance treatment. Therefore, as part of this review, an assessment
of post-treatment effects of maxillary expansion on the dento-alveolar
region and buccal bone using CBCT technology also will be presented.
STUDY SAMPLE
Approval for the study was granted by the Institutional Review
Board of University of Texas Health Science Center at Houston (HSC-
DB-11-0264). The records of orthodontic patients that had constricted
maxillary arches with either uni- or bilateral posterior crossbite between
11 to 16 years were examined at the Department of Orthodontics. The
study sample was formed retrospectively using the records of individuals
that required 5 to 8 mm of maxillary expansion and had a complete set of
images taken pre-expansion (T1), post-expansion (T2) and post-treatment
(2 to 3 years after expansion therapy; T3).
Sample size was determined by using the mean maxillary
expansion measured at the first molars from a preliminary study. The
effect size was calculated with G*Power 3.1 statistical program (Heinrich
Heine Universitat Dusseldorf Institute fur Experimentelle Psychologie,
Dusseldorf, Germany). According to a priori-computed sample size
analysis using the same software program, it is estimated that in order
240
Akyalcin et al.
to detect significant differences (p < 0.05, effect size d:0.77 and with 85%
power) between the three time periods, a total sample size of 24 would be
required. Individuals that had craniofacial anomalies, a need for surgically
assisted RME and previous orthodontic treatment history were excluded
from the sample. A total of 47 patients were identified. Individuals with
incomplete records and compliance issues reported in their charts were
eliminated. The final sample included 26 patients (16 females, 10 males;
mean age 14.1 + SD 0.26 years).
Initial CBCT scans were obtained at the pre-treatment stage (T1)
along with all the other treatment records. Each patient was treated with
a Hyrax appliance and maxillary expansion was started at the beginning
of orthodontic treatment for all patients. The appliance was activated one
to two turns (1/4 mm/turn) per day with a mean screw expansion of 6.98
mm in the study sample. After expansion therapy, post-expansion (T2)
CBCT images were taken. The T3 images were obtained when the patients
were past their 8 to 12 months of retention period after orthodontic
treatment with full-fixed 0.022”-slot appliances—between two to three
years after the completion of maxillary expansion therapy (2.62 + 0.1
years). CBCT images were taken with a Galileos Comfort x-ray unit (Sirona
Dental Systems GmbH, Bensheim, Germany) with exposure parameters
of 85 kVp, 21 mA, 14 seconds, 0.3 voxel size and with volume dimensions
of 15 x 15 x 15 cm3. The image reconstruction time was approximately 4.5
minutes.
The DICOM data sets for T1, T2 and T3 were imported into
OsiriX software (Pixmeo, Geneva, Switzerland). Axial and coronal slices
were created to perform the measurements. Linear measurements were
recorded in millimeters and angular measurements were recorded in
degrees.
MEASUREMENTS
Skeletal Width Measurements
Measurements of linear distances were recorded from the T1
and T2 images: the width of the incisive canal measured from lateral
Wall to lateral wall on the axial image (Fig. 3); and the width of the nasal
cavity measured from the widest points of the anterior bony nasal cavity
perpendicular to the midsagittal plane on the coronal image at the level
of the first premolars (Fig. 4).
241
Rapid Maxillary Expansion
Figure 4. Nasal cavity width.

242
Akyalcin et al.
Dental and Buccal Bone Width Measurements
Bifurcation of the maxillary left and right first premolars and
trifurcation of the left and right maxillary first molars were connected
perpendicular to the midsagittal plane on the axial view. The resulting
coronal slice was used to measure the palatal expansion using the central
fossae of the teeth at the level of maxillary first molars (Fig. 5) and first
premolars (Fig. 6). Buccal alveolar bone width for the maxillary first molars
was measured as the linear distance from the root of the first molar at the
level of trifurcation to the outermost point of the buccal plate for both
left and right sides (Fig. 5). Similarly, linear distance from the root of the
first premolar at the level of bifurcation to the outermost point of the
buccal plate was measured for both left and right sides to determine the
buccal alveolar bone width measurement of the maxillary first premolar
(Fig. 6).
Dental and Alveolar Buccolingual Inclination Changes
The buccolingual inclination of maxillary first premolars and
molars and the alveolar bending at these sites were evaluated on the same
Coronal slices prepared for premolar and molar width measurements.
The axis passing through the palatal apices and the buccal cusp tips of
the teeth was considered as the long axis of the teeth. Another line was
drawn from buccal cusp tips of the teeth to the most inferior aspect of the
hard palate on the midsagittal plane. The angle forming between these
two lines was used to measure the buccolingual inclination of the teeth.
Buccolingual inclination of the alveolar bone was evaluated both on the
palatal and vestibular aspects of the bone surrounding the maxillary first
premolars and molars. The outermost apical and occlusal aspects of the
alveolar bone were connected. Another line was drawn from the most
occlusal point of the alveolar bone to the most inferior point of the hard
palate on the midsagittal plane. This was performed on both the vestibular
and palatal sides of alveolar bone and the formed angles were measured
to evaluate the alveolar buccolingual inclination changes (Figs. 5-6).
A single operator (BD) performed all measurements and was
blinded to the images being measured. The same operator repeated
243
Rapid Maxillary Expansion
Figure 5. a = intermolar width. b = BL inclination of UR6. c = BL inclination buccal
alveolar bone at UR6. d = BL inclination of palatal alveolar bone at UR6, e = buc-
cal alveolar bone width at UR6, f = BL inclination of UL6, g = BL inclination buccal
alveolar bone at UL6, h = BL inclination of palatal alveolar bone at UL6, i = buccal
alveolar bone width at UL6. BL = buccolingual.
Figure 6. a = premolar width, b = BL inclination of UR4, c = BL inclination buccal
alveolar bone at UR4. d = BL inclination of palatal alveolar bone at UR4, e = buc-
cal alveolar bone width at UR4, f = BL inclination of UL4 g = BL inclination buccal
alveolar bone at UL4, h = BL inclination of palatal alveolar bone at UL4, i= buccal
alveolar bone width at UL4. BL = buccolingual.


244
Akyalcin et al.
the measurements using the records of 12 randomly selected patients
at a one-month interval. The intra-observer reliability was tested using
intra-class correlation coefficients (ICCs). Error study was performed
usin Dahlberg's formula. The time periods were compared with one-way
repeated measures analysis of variance. Post-hoc pairwise comparisons
were made using the Bonferroni method. All of the statistical tests were
performed using SPSS for Mac (Version 21; IBM, Armonk, NY). Level of
significance was established at p < 0.05 for all tests.
RESULTS
ICCs for the observer reliability varied between 0.87 to 0.99.
Operator error for angular and linear measurements varied between 0.23
to 0.61° and 0.22 to 0.49 mm, respectively.
The results yielded significant differences between the three
time periods for all investigated parameters, except for palatal alveolar
bone inclination at the maxillary first premolars on the left side (Table 1).
The results of Bonferroni post-hoc pairwise comparisons are
shown in Table 2. The opening of the midpalatal suture was confirmed
in all the subjects. Significant differences were observed for both the
maxillary first premolar and molar widths between T1 and T2 (p <
0.001) and again between T2 and T3 (p < 0.001). On average, only 70%
of the dental width increase was maintained for both the maxillary first
premolars and molars at T3. Similar changes were observed in all the
skeletal width measurements between T1 and T2 (p<0.001) and between
T2 and T3 (p<0.05). However, the width increases in the skeletal variables
were retained at a higher rate than the dental variables at T3 and varied
between 81-87%.
All dental and alveolar inclination measurements indicated con-
siderable buccal tipping between T1 and T2 (p<0.05), except for the buc-
Colingual inclination measurement of the palatal alveolar bone at the lev-
el of maxillary first premolars (p = 0.07). Some uprighting was observed
for all of the variables between T2 and T3. However, significant differ-
ences were observed in only a few of these variables (Table 2). All of these
changes indicated that significant tipping of the anchor teeth and alveolar
bone at these sites occurred at T2 and most of these changes remained at
T3, particularly in the first molar area.
245
Rapid Maxillary Expansion
Table 1. Comparison of the three time periods. UL = upper left; UR = upper right;
BL = buccolingual; NS = not significant.

T1 T2 T3 P
Variables Mean | SD Mean | SD Mean SD
Incisive foramen width (mm) 2.4 0.59 3.5 0.8 3.3 0.7 < 0.001
Nasal cavity width (mm) 19.5 1.8 21.2 1.5 20.9 1.4 < 0.001
Molar width (mm) 42.4 || 3.3 || 47.4 || 2.3 || 45.9 | 1.7 | < 0.001
Premolar width (mm) 33.5 2.5 36.5 1.9 35.6 1.6 < 0.001
BL inclination UR6 (*) 32.6 7.4 27.0 7.4 29.6 6.7 < 0.001
BL inclination of palatal
alveolar bone at UR6 (°)
BL inclination of buccal
alveolar bone at UR6 (°)
31.7 7.8 28.0 8.1 30.6 7.1 0.001
57.2 8.0 52.2 8.4 53.5 7.4 < 0.001
# bone thickness at UR6 2.28 0.72 1.85 0.69 2.16 0.53 NS
BL inclination UL6 (*) 32.0 5.9 28.5 6.1 29.6 5.2 < 0.001
BL inclination of palatal
alveolar bone at UL6 (*)
BL inclination of buccal
alveolar bone at UL6 (*)
34.7 8.9 28.3 6.8 29.6 6.8 < 0.001
67.9 7.4 60.7 7.6 61.0 8.1 < 0.001
# bone thickness at UL6 2.39 0.88 1.82 0.82 2.15 O.77 NS
BL inclination UR4 (°) - 43.8 8.6 38.6 8.8 40.0 7.3 0.002
BL inclination of palatal
alveolar bone at UR4 (*)
BL inclination of buccal
alveolar bone at UR4 (°)
28 6.1 23.2 5.4 25.7 5.2 < 0.001
38.2 10.3 33.7 11.1 35.5 11.3 | < 0.001
# bone thickness at UR4 1.49 0.61 1.04 O.76 1.18 0.70 NS
mm & g e g º e
BL inclination UL4 (°) 44.4 8.8 39.1 9.8 41.5 8.3 0.004
BL inclination of palatal
alveolar bone at UL4 (°) 31.3 10.0 | 27.6 || 10.8 || 28.4 9.9 NS
BL inclination of buccal
alveolar bone at UL4 (°)
# bone thickness at UL4 1.32 0.77 1.09 0.87 1.25 0.72 NS
mm. g e e e * g
38.7 10.4 || 34.7 9.7 36.4 10.8 O.017
When comparing the effect of maxillary expansion on the buccal
plate of the maxillary first molars and maxillary first premolars (Table 1),
no significant changes were recorded for any of the teeth measured (left
and right maxillary first molars and premolars). Upon the completion of
maxillary expansion, a decrease in buccal plate thickness was observed
for all of the teeth; the changes, however, were not significant. At the
post-retention point in time (T3), an increase in buccal plate thickness
was observed for all the teeth; these changes also were not significant.
246
Akyalcin et al.
Table 2. Multiple comparisons of the time periods. UL = upper left; UR = upper
right; BL = buccolingual; NS = not significant.

T1-T2 T2-T3 T1-T3
Variables P P P
Incisive foramen width (mm) < 0.001 < 0.001 < 0.001
Nasal cavity width (mm) < 0.001 0.01 < 0.001
Molar width (mm) < 0.001 < 0.001 < 0.001
Premolar width (mm) < 0.001 < 0.001 < 0.001
BL inclination UR6 (*) < 0.001 < 0.001 < 0.001
BL inclination of palatal alveolar bone at UR6 (*) < 0.001 0.03 NS
BL inclination of buccal alveolar bone at UR6 (*)' < 0.001 NS < 0.001
Buccal bone thickness at UR6 (mm) NS NS NS
BL inclination UL6 (*) < 0.001 NS < 0.001
BL inclination of palatal alveolar bone at UL6 (*) < 0.001 NS < 0.001
BL inclination of buccal alveolar bone at UL6 (*) < 0.001 NS < 0.001
Buccal bone thickness at UL6 (mm) NS NS NS
BL inclination UR4 (*) < 0.001 NS NS
BL inclination of palatal alveolar bone at UR4 (°) < 0.001 < 0.001 NS
BL inclination of buccal alveolar bone at UR4 (°) < 0.001 0.01 0.04
Buccal bone thickness at UR4 (mm) NS NS NS
BL inclination UL4 (°) < 0.001 NS NS
BL inclination of palatal alveolar bone at UL4 (°) NS NS NS
BL inclination of buccal alveolar bone at UL4 (°) 0.02 NS NS
Buccal bone thickness at UL4 (mm) NS NS NS
DISCUSSION
Our results suggest that both the skeletal and dental dimensions
increased with tooth-borne rapid maxillary expansion (RME). This is in
agreement with the findings of recent CBCT investigations (Garib et al.,
2005; Pangrazio-Kulbersh et al., 2012). Although it was suggested to use
tissue-borne RME reinforced with dental anchorage to achieve a better
orthopedic outcome (Haas, 1965, 1980), a CBCT evaluation oftooth tissue-
borne versus tooth-borne expanders in eight individuals demonstrated
that tooth-borne (Hyrax) and tooth tissue-borne (Haas-type) expanders
tended to produce similar orthopedic effects (Garib et al., 2005).
ACCording to the authors, the tooth tissue-borne expander produced a
greater change in the axial inclination of anchorage teeth compared with
the tooth-borne expander (Garib et al., 2005). The main problem of this
Study was the small sample size. In our study, significant buccal tipping of
the anchor teeth and the alveolar bone at these sites occurred as a result
oftooth-borne RME therapy. Similarly, Pangrazio-Kulbersh and colleagues
(2012) signified the importance of dental tipping and alveolar bending
With the use of banded expanders. In our study, we were able to evaluate
247
Rapid Maxillary Expansion
differences between the time period immediately after expansion (T2)
and the retention period following orthodontic treatment (T3) with fixed
appliances. This added to our knowledge from the previous CBCT reports
(Garrett et al., 2008; Pangrazio-Kulbersh et al., 2012; Ribeiro et al., 2012)
that evaluated the effects of RME only within three to six months after
the end of RME appliance activation. Our approach helped us to analyze
the effects of the orthodontic treatment with contemporary edgewise
appliances following RME as well.
The age range in our Sample group was 11 to 16 with an average
of 14.1 years. This may be considered a little high to achieve significant
skeletal changes following RME; however, expansion of the midpalatal
suture was observed in all the individuals. Additionally, the skeletal
measurements demonstrated significant increases between T1 and T2.
When evaluating the retention of these skeletal width changes, significant
differences were noted for both measurements between T2 and T3.
However, these differences were small and varied between 0.2 to 0.3 mm
on average. These changes may have occurred during the reorganization
of the midpalatal suture. It appears that more than 80% of the skeletal
expansion is maintained during this period, while the quality of the newly
formed bone at the midpalatal suture increases over time as suggested
by Petrick and associates (2011). Transverse width increase following RME
in the dental structures superseded the width increase in the skeletal
structures, which previously was reported in the orthodontic literature
(Rungcharassaeng et al., 2007; Garrett et al., 2008; Petrick et al., 2011;
Lione et al., 2013), though a greater percentage of this width increase
was lost between T2 and T3, due in part to the uprighting of the anchor
teeth with the edgewise appliances following orthodontic treatment.
Adkins and coworkers (1990) reported highly variable measurements in
dental tipping after rapid palatal expansion (RPE). The authors found no
significant relationships of buccal crown tipping with age, initial palatal
width, amount of expansion and crossbite. As a result, it was concluded
that buccal tipping of anchor teeth is a consequence of the RPE. Our
results supported their findings and also demonstrated that inclination
changes of the alveolar bone accompany buccal tipping of the anchor
teeth.
Based on our findings, it can be concluded that both dental tip-
ping and alveolar bending occur as a consequence of tooth-borne RME
248
Akyalgin et al.
applications. However, as can be judged by the statistical variability in our
results, the amount and degree of these changes can be specific to the in-
dividual. Figure 7 displays both dental tipping and alveolar bending in the
first premolar area as a result of Hyrax expansion. We also demonstrated
that dental and alveolar tipping induced by tooth-borne RME remained
Variable across the study population, with the variability, depending in
part on the inspected location of the dental arch, even in the retention
period following fixed appliance therapy. Interestingly, at T3, only a small
percentage (11-30%) of our sample group exhibited the same or similar
buccolingual inclinations of the alveolar bone and/or the anchor teeth
recorded at T1. These findings also may suggest that there was an indica-
tion for dental inclination changes at T1 and in some of the individuals,
those changes were retained as needed to achieve harmonious occlusal
relationships. T1 and T3 comparisons revealed that buccolingual incli-
nation changes of the maxillary first molars and the surrounding alveo-
lar bone were significant in all the variables except for the buccolingual
inclination of palatal alveolar bone on the right side. This confirms the
findings that banded RME appliances cause more dental tipping and al-
Veolar bending at the level of the first molars (Pangrazio-Kulbersh et al.,
2012). In contrast, Kartalian and colleagues (2010) found no significant
dental tipping following RME, but significant alveolar bending followed
RME, which may be due to the differences in the sample groups and the
expansion protocols involved. Alveolar bending reported in these studies
Confirmed that the fact that the sutural opening does not occur uniformly
in a bodily fashion.
It recently was shown using cadaver heads that CBCT could be
used to assess buccal bone height and buccal bonethickness quantitatively
Figure 7. Buccal tipping and alveolar bending around the maxillary first
premolar area in an individual treated with a Hyrax expansion device.

249
Rapid Maxillary Expansion
with high precision and accuracy (Timock et al., 2011). In our study,
immediate effects of RME therapy showed reduction in buccal bone at
all the points, but the reduction was not significant. Garib and associates
(2006) presented striking results within the short term after RME
treatment (e.g., significant expansion, buccal crown tipping, loss in the
buccal plate and bone dehiscence). Corbridge and associates (2011)
utilized CBCT images to demonstrate that the teeth moved through
the alveolus with quad-helix appliance therapy, leading to a substantial
decrease in buccal bone thickness and increase in lingual bone thickness.
While our study mainly considered the use of a Hyrax expander and not
a quad-helix, we were not able to verify a substantial decrease in buccal
bone thickness following RME since the changes were not significant.
Moreover, our results demonstrated that after the completion of
orthodontic treatment with fixed appliances, buccal bone width almost
is regained due to subsequent uprighting of the molar and premolar
roots. Figure 8 shows that buccal bone width decreases following RME
therapy. However, the T3 image, which was obtained one year after the
completion of fixed appliance therapy, shows the buccal bone levels for
both the right and left first molars almost equal to the pre-treatment
levels. The variability in the previous studies can be explained by the
findings of Rungcharassaeng and coworkers (2007). They observed using
CBCT images that age, appliance expansion, initial buccal bone thickness
and differential expansion showed not only a significant correlation to
buccal bone changes and dental tipping on the maxillary first molars
and premolars, but that the rate of expansion and retention time also
had no significant association. They also suggested that buccal crown
tipping and reduction in buccal bone thickness of the maxillary posterior
teeth are the only expected immediate effects of RME, which our study
confirmed. Our paper evaluated changes in buccal bone thickness at a
follow-up period that was an average of 2.48 years post-expansion, which
was not determined in the dental literature previously. The addition of a
T3 point in time strengthened this study and confirmed observations that
maxillary expansion can be retained.
One of the strengths of our study was the ability to evaluate the
changes in three different time periods. However, as is the case with
all the other radiographic imaging techniques, CBCT imaging should be
used only after a careful review of the patient's health and imaging his-
tory and the completion of a thorough clinical examination. Outlined
250
Akyalçin et al.
Figure8. Coronal images at the level of the maxillary first molars: A: Pre-treatment;
B: Post-expansion; and C. One year after the completion offixed appliance therapy
demonstrate a decrease following expansion and a subsequentincrease soon after
comprehensive orthodontic treatment was finalized for the buccal alveolar bone.
by an advisory statement from the American Dental Association Council
on Scientific Affairs (2012), it may not be justifiable to obtain CBCT scans
from three time periods on individuals undergoing orthodontic therapy.
However, these images were obtained before such regulatory information
was available as part of the individuals' orthodontic treatment records
and the authors acknowledge that such practice has significant limitations
from a radiation-protection point of view.
CONCLUSIONS
Orthodontic treatment affects the amount of changes that
are induced by RME therapy. Transverse skeletal width increases are
maintained at a higher level than dental width increases following
Orthodontic treatment and in the retention period due to the successful
reorganization of the newly formed bone. Buccal tipping of the anchor
teeth and the alveolar bone is a significant aspect of tooth-borne RME
and is adapted most often as part of the treatment outcome. Clinicians
should be aware that maxillary expansion could reduce the width of the
buccal plate and cause tipping of the maxillary posterior teeth. However,
after the completion of comprehensive orthodontic treatment by means
of full fixed appliances, a subsequent increase in buccal bone width
should be expected.
REFERENCES
Adkins MD, Nanda RS, Currier GF Arch perimeter changes on rapid
maxillary expansion. Am J Orthod Dentofacial Orthop 1990;97(3):194–
199.

251
Rapid Maxillary Expansion
Akyalçin S, Schaefer JS, English JD, Stephens CR, Winkelmann S. A cone-
beam computed tomography evaluation of buccal bone thickness
following maxillary expansion. Imaging Sci Dent 2013;43(2):85-90.
American Dental Association Council on Scientific Affairs. The use of cone-
beam computed tomography in dentistry: An advisory statement from
the American Dental Association Council on Scientific Affairs. J Am
Dent Assoc 2012;143(8):899-902.
Baccetti T, Franchi L, Cameron CG, McNamara JA Jr. Treatment timing for
rapid maxillary expansion. Angle Orthod 2001;71(5):343-350.
Ballanti F, Lione R, Baccetti T, Franchi L, Cozza P. Treatment and
posttreatment skeletal effects of rapid maxillary expansion investigated
with low-dose computed tomography in growing subjects. Am J
Orthod Dentofacial Orthop 2010;138(3):311-317.
Bazargani F, Feldmann I, Bondemark L. Three-dimensional analysis of
effects of rapid maxillary expansion on facial sutures and bones. Angle
Orthod 2013;83(6):1074-1082.
Brunetto M, Andriani Jqa S, Ribeiro GL, Locks A, Correa M, Correa LR.
Three-dimensional assessment of buccal alveolar bone after rapid and
slow maxillary expansion: A clinical trial study. Am J Orthod Dentofacial
Orthop 2013;143(5):633-644.
Christie KF, Boucher N, Chung CH. Effects of bonded rapid palatal
expansion on the transverse dimensions of the maxilla: A cone-beam
computed tomography study. Am J Orthod Dentofacial Orthop 2010;
137(4 Supply:S79-S85.
Corbridge JK, Campbell PM, Taylor R, Ceen RF, Buschang PH. Transverse
dentoalveolar changes after slow maxillary expansion. Am J Orthod
Dentofacial Orthop 2011;140(3):317-325.
Cordasco G, Matarese G, Rustico L, Fastuca S, Caprioglio A, Lindauer SJ,
Nucera R. Efficacy of orthopedic treatment with protraction facemask
on skeletal Class Ill malocclusion: A systematic review and meta-
analysis. Orthod Craniofac Res 2014;17(3):133-143.
Darsey DM, English JD, Kau CH, Ellis RK, Akyalçin S. Does hyrax expansion
therapy affect maxillary sinus volume? A cone-beam computed
tomography report. Imaging Sci Dent 2012;42(2):83-88.
252
Akyalcin et al.
Domann CE, Kau CH, English JD, Xia JJ, Souccar NM, Lee RP. Cone beam
computed tomography analysis of dentoalveolar changes immediately
after maxillary expansion. Orthodontics (Chic.) 2011;12(3):202-209.
Garib DG, Henriques JF, Janson G, de Freitas MR, Fernandes AY. Periodontal
effects of rapid maxillary expansion with tooth-tissue-borne and
tooth-borne expanders: A Computed tomography evaluation. Am J
Orthod Dentofacial Orthop 2006;129(6):749–758.
Garib DG, Henriques JF, Janson G, Freitas MR, Coelho RA. Rapid maxillary
expansion: Tooth tissue-borne versus tooth-borne expanders: A
computed tomography evaluation of dentoskeletal effects. Angle
Orthod 2005;75(4):548–557.
Garrett BJ, Caruso JM, Rungcharassaeng K, Farrage JR, Kim JS, Taylor GD.
Skeletal effects to the maxilla after rapid maxillary expansion assessed
with cone-beam computed tomography. Am J Orthod Dentofacial
Orthop 2008;134(1):8-9.
Haas AJ. Long-term posttreatment evaluation of rapid palatal expansion.
Angle Orthod 1980;50(3):189–218.
Haas AJ. The treatment of maxillary deficiency by opening the midpalatal
suture. Angle Orthod 1965;35:200–217.
Handelman CS, Wang L, BeGole EA, Haas A.J. Nonsurgical rapid maxillary
expansion in adults: Report on 47 cases using the Haas expander.
Angle Orthod 2000;70(2):129-144.
Huynh T, Kennedy DB, Joondeph DR, Bollen AM. Treatment response and
Stability of slow maxillary expansion using Haas, Hyrax, and Ouad-Helix
appliances: A retrospective study. Am J Orthod Dentofacial Orthop
2009;136(3):331-339.
Karagkiolidou A, Ludwig B, Pazera P. Gkantidis N, Pandis N, Katsaros
C. Survival of palatal miniscrews used for orthodontic appliance
anchorage: A retrospective cohort study. Am J Orthod Dentofacial
Orthop 2013;143(6):767-772.
Kartalian A, Gohl E, Adamian M, Enciso R. Cone-beam computerized
tomography evaluation of the maxillary dentoskeletal complex after
rapid palatal expansion. Am J Orthod Dentofacial Orthop 2010;138
(4):486-492.
253
Rapid Maxillary Expansion
Langford SR. Root resorption extremes resulting from clinical RME. Am J
Orthod 1982;81(5):371-377.
Langford SR, Sims MR. Root surface resorption, repair, and periodontal
attachment following rapid maxillary expansion in man. Am J Orthod
1982;81(2):108-115.
Lee KJ, Park YC, Park JY, Hwang WS. Miniscrew-assisted nonsurgical
palatal expansion before orthognathic surgery for a patient with
severe mandibular prognathism. Am J Orthod Dentofacial Orthop
2010;137(6):830–839.
Leonardi R, Sicurezza E, Cutrera A, Barbato E. Early post-treatment
changes of circumaxillary Sutures in young patients treated with rapid
maxillary expansion. Angle Orthod 2011;81(1):36-41.
Lione R, Franchi L, Cozza P. Does rapid maxillary expansion induce adverse
effects in growing subjects? Angle Orthod 2013;83(1):172-182.
McNamara JA Jr, Baccetti T, Franchi L, Herberger TA. Rapid maxillary
expansion followed by fixed appliances: A long-term evaluation of
changes in arch dimensions. Angle Orthod 2003;73(4):344–353.
McNamara JA Jr, McNamara L. Phase I: Early Treatment. In: English JD,
ed. Mosby's Orthodontic Review. St. Louis, MO: Mosby Elsevier 2009;
137-145.
Odenrick L, Karlander EL, Pierce A, Kretschmar U. Surface resorption
following two forms of rapid maxillary expansion. Eur J Orthod 1991;
13(4):264-270.
Oh C, Türk T, Elekdağ-Türk S, Jones AS, Petocz P. Cheng LL, Darendeliler
MA. Physical properties of root cementum: Part 19. Comparison of the
amounts of root resorption between the right and left first premolars
after application of buccally directed heavy orthodontic tipping forces.
Am J Orthod Dentofacial Orthop 2011;140(1):e49–e52.
Oliveira De Felippe NL, Da Silveira AC, Viana G, Kusnoto B, Smith B, Evans
CA. Relationship between rapid maxillary expansion and nasal cavity
size and airway resistance: Short- and long-term effects. Am J Orthod
Dentofacial Orthop 2008;134(3):370-382.
Paetyangkul A, Türk T, Elekdağ-Türk S, Jones AS, Petocz P, Darendeliler
MA. Physical properties of root cementum: Part 14. The amount of
root resorption after force application for 12 weeks on maxillary and
254
Akyalcin et al.
mandibular premolars: A microcomputed-tomography study. Am J
Orthod Dentofacial Orthop 2009;136(4):492.e1-eg.
Pangrazio-Kulbersh V, Jezdimir B, de Deus Haughey M, Kulbersh R, Wine P.
Kaczynski R. CBCT assessment of alveolar buccal bone level after RME.
Angle Orthod 2013;83(1):110-116.
Pangrazio-Kulbersh V, Wine P. Haughey M, Pajtas B, Kaczynski R. Cone
beam computed tomography evaluation of changes in the naso-
maxillary complex associated with two types of maxillary expanders.
Angle Orthod 2012;82(3):448-457.
Petrick S, Hothan T, Hietschold V, Schneider M, Harzer W, Tausche E. Bone
density of the midpalatal suture 7 months after surgically assisted
rapid palatal expansion in adults. Am J Orthod Dentofacial Orthop
2011;139(4 Suppl):S109-S116.
Podesser B, Williams S, Crismani AG, Bantleon HP. Evaluation of the effects
of rapid maxillary expansion in growing children using computer
tomography scanning: A pilot study. Eur J Orthod 2007;29(1):37-44.
Ribeiro ANC, Paiva JB, Neto JR, Filho El, Trivino T, Fantini SM. Upper airway
expansion after rapid maxillary expansion evaluated with cone beam
computed tomography. Angle Orthod 2012;82(3):458–463.
Rungcharassaeng K, Caruso JM, Kan JYK, Kim J, Taylor G. Factors affecting
buccal bone changes of maxillary posterior teeth after rapid maxillary
expansion. Am J Orthod Dentofacial Orthop 2007;132(4):428.e1-e8.
Starnbach H, Bayne D, Cleall J, Subtelny JD. Facioskeletal and dental
changes resulting from rapid maxillary expansion. Angle Orthod
1966;36(2):152-164.
Timock AM, Cook V, McDonald T, Leo MC, Crowe J, Benninger BL, Covell
DA Jr. Accuracy and reliability of buccal bone height and thickness
measurements from cone-beam computed tomography imaging. Am
J Orthod Dentofacial Orthop 2011;140(5):734–744.
Weissheimer A, de Menezes LM, Mezomo M, Dias DM, de Lima EM,
Rizzatto SM. Immediate effects of rapid maxillary expansion with
Haas-type and hyrax-type expanders: A randomized clinical trial. Am J
Orthod Dentofacial Orthop 2011;140(3):366-376.
255
Rapid Maxillary Expansion
Wilmes B, Nienkemper M, Drescher D. Application and effectiveness of
a mini-implant- and tooth-borne rapid palatal expansion device: The
hybrid hyrax. World J Orthod 2010;11(4):323-330.
Zeng J, Gao X. A prospective CBCT study of upper airway changes after
rapid maxillary expansion. Int J Pediatr Otorhinolaryngol 2013;77
(11):1805-1810.
Zhao Y, Nguyen M, Gohl E, Mah JK, Sameshima G, Enciso R. Oropharyngeal
airway changes after rapid palatal expansion evaluated with Cone-
beam computed tomography. Am J Orthod Dentofacial Orthop 2010;
137(4 Supply:S71-S78.
256
EVALUATION OF FACIAL SUTURE MATURATION ON
CBCTS: A PREDICTOR OF MAXILLARY ORTHOPEDIC
TREATMENT RESPONSEP
Fernanda Angelieri, Lucia H.S. Cevidanes, Lorenzo Franchi
and James A. McNamara Jr.
ABSTRACT
Maxillary orthopedic treatment outcome depends in part on the maturational
stage of the maxillary sutures. Recently, the evaluation of the maturation of
midpalatal suture by way of cone-beam computed tomography (CBCT) has been
introduced as a response predictor following rapid maxillary expansion (RME).
Five maturational stages of the midpalatal suture have been described. STAGE
A: Straight high-density sutural line, with no or little interdigitation. STAGE B:
Scalloped appearance of the high-density sutural line. STAGE C: Two parallel,
Scalloped, high-density lines that lie close to each other, separated in some areas
by small low-density spaces. STAGE D: Complete fusion of the palatine bone where
no evidence of a suture is present. STAGE E: Fusion also has occurred anteriorly in
the maxilla. At Stages A and B, more skeletal effects would be expected as there
are no bone bridges, as are observed in Stage C. Surgically assisted RME typically
is a better choice for patients at Stages D and E. This method for evaluation of
midpalatal suture maturation in CBCT images has the potential to be extended
to other maxillary sutures, particularly the zygomaticomaxillary sutures, for
the prediction of the response from facial mask and bone-anchored maxillary
protraction (BAMP) therapies. This diagnostic approach can be used to estimate
the prognosis of these maxillary orthopedic treatments and to avoid unnecessary
corrective jaw surgery in the future.
KEY WORDS: Suture, tomography, orthopedics, rapid maxillary expansion
Orthopedic correction of maxillary growth discrepancies has
been proposed in orthodontics since the mid-1800s (Angell, 1860). For
Class Il malocclusion due to maxillary protrusion, extraoral traction has
been indicated to restrict the anterior midfacial growth (Kloehn, 1947;
Klein, 1957; Blueher, 1959). In Class III malocclusions characterized by
257
Maturation of Facial Sutures
maxillary skeletal retrusion, the facial mask has been shown to stimulate
the anteroposterior growth of the maxilla (Haas, 1973; Petit, 1983;
Hickham, 1991). For transverse discrepancies with a narrow maxilla and
posterior crossbite, rapid maxillary expansion (RME) has been employed
(Angell, 1860; Haas, 1961, 1970).
These maxillary orthopedic treatments promote spatial displace-
ments of the maxilla in relation to the other bones of the Craniofacial
complex, correcting the skeletal malocclusion. Because the maxilla is con-
nected to other facial bones by sutures (Fig. 1), all maxillary orthopedic
treatments depend on the immature maturation of these sutures to be
successful. Clinically, it is known that for adults when the maxillary su-
tures are fused, such effects on the maxilla can be obtained only when
combined with orthognathic surgery.
A number of 2D radiographic and histological studies on maxillary
sutures have been published (Björk, 1966; Latham, 1971; Melsen, 1972,
1975; Persson and Thilander, 1977; Nanda and Hickory, 1984; Cohen,
1993; Sun et al., 2004). The midpalatal suture has been studied extensively
as RME is a frequently used procedure, the success of which depends
fundamentally on the ability of this suture to respond to expansive forces.
Melsen (1975) studied the midpalatal suture in autopsy material,
demonstrating that there are changes in sutural morphology during
growth. During the juvenile period, usually up to ten years of age, the
midpalatal suture is broad and Y-shaped in frontal sections (Cohen,
1993; Sun et al., 2004). From 10 to 13 years of age, this suture assumes a
squamous path, becoming wavier with increased interdigitation at ages
13 to 14 years. In another study, Melsen and Melsen (1982) demonstrated
that more mature stages of the midpalatal suture closure are characterized
by bony bridges and Synostoses that are resistant to expansive forces.
Interestingly, the fusion process of the midpalatal suture starts
with bone spicules from suture margins along with “islands” (i.e., masses
of acellular tissue and inconsistently calcified tissue) in the middle of the
sutural gap (Persson and Thilander, 1977; Persson et al., 1978; Cohen,
1993; Korbmacher et al., 2007). These spicules occur in many places
along the suture, with the number of spicules increasing with matura-
tion (Melsen, 1972; Persson and Thilander, 1977). They form many scal-
loped areas that are close to each other and yet are separated in some
258
Angelieri et al.
Zygomaticomaxillary sutures (yellow arrows), midpalatal suture (red arrow). B:
Midpalatal (red arrow) and palatomaxillary sutures (green arrow). Photos: Per
Kjeldsen.
Zones by connective tissue (Wehrbein and Yildizhan, 2001; Knaup et al.,
2004). With maturation, interdigitation increases (Melsen, 1975; Knaup
et al., 2004) and then fusion occurs earlier in the posterior area of the
Suture and subsequently progresses toward the anterior region (Persson
and Thilander, 1977; Knaup et al., 2004), with resorption of cortical bone
in the sutural ends and the subsequent formation of cancellous bone
(Cohen, 1993; Sun et al., 2004).
The chronological age for the start of fusion of the midpalatal
Suture (i.e., the borderline age for RME success) is controversial in the
literature. According to Wertz and Dreskin (1977), more substantive and
more stable orthopedic changes from RME occur in patients up to 12
years of age. For Baccetti and coworkers (2001), more favorable skeletal
Changes from RME were verified in prepubertal patients compared to
postpubertal patients. On the other hand, Capelozza and associates
(1996) reported success in some adults treated by non-surgically assisted
RME.
Clinically, it is known that it is difficult to obtain success with RME
in subjects older than 25 years of age (Wehrbein and Yildizhan, 2001).
In fact, RME failure is common in late adolescent and young adult pa-
tients (Bishara and Staley, 1987; Fig. 2). Serious pain, mucosal ulcer-
ation or necrosis, and accentuated buccal tipping and gingival reces-
Sion around the posterior teeth (Bell and Epker, 1976; Betts et al., 1995;

259
Maturation of Facial Sutures
Figure 2. A 16-year-old male treated with a Haas-type expander. The midpalatal
suture did not open.


260
Angelieri et al.
Garib et al., 2005; Rungcharassaeng et al., 2007; Kilig et al., 2008) have
been observed after RME failure (Fig. 3).
These clinical findings do not match observations derived from
histological studies. It has been presumed that the presence of sutural
fusion itself is not important to the RME failure, but rather the percentage
of the fusion in the midpalatal suture is more significant (Wehrbein and
Yildizhan, 2001). Persson and Thilander (1977) have speculated that as
little as 5% of suture fusion will restrict the opening of the midpalatal
suture by conventional RME. Nevertheless, many histological studies
have reported percentages of fusion below 5% in patients between ages
18 and 38 (Wehrbein and Yildizhan, 2001). In contrast, no fusion of the
midpalatal suture has been noted in patients ages 27 to 32 (Persson
and Thilander, 1977), 54 years (Knaup et al., 2004) and even 71 years
(Korbmacher et al., 2007). On the other hand, Persson and Thilander
(1977) have observed fusion of the midpalatal suture in the posterior
palate of a 15-year-old female and a 21-year-old male.
These results reveal that fusion of the midpalatal suture is not
related directly to chronological age, particularly in late adolescents
and young adults (Persson and Thilander, 1977; Persson et al., 1978;
Wehrbein and Yildizhan, 2001; Knaup et al., 2004; Korbmacher et al.,
2007). Therefore, individual clinical assessment of the maturation of the
midpalatal suture is essential prior to RME for late adolescents and young
adult patients.
Revelo and Fishman (1994) have proposed the analysis of the fu-
Sion of the midpalatal suture on occlusal radiographs before RME. How-
ever, Wehrbein and Yildizhan (2001) subsequently have demonstrated
that the occlusal radiographs are unreliable for the diagnosis of the fu-
Sion of the midpalatal suture because an invisible suture image does not
match fusion of the midpalatal suture histologically. This artifact occurs
due to the superimposition of the vomer and the structures of the exter-
nal nose in the midpalatal area.
Because there are no clinical parameters for predicting RME
Success in late adolescents and young adults, our research group
(Angelieri et al., 2013) has proposed an individual assessment of the
4– Figure 3. Accentuated buccal inclination of the maxillary posterior teeth after
RME failure.
261
Maturation of Facial Sutures
maturation of the midpalatal suture on cone-beam computed tomography
(CBCT) images. This chapter describes this novel classification method
for individual assessment of the midpalatal suture, as well as clinical
considerations about the maturational stages of the midpalatal suture
regarding individual response to RME.
CLASSIFICATION OF MIDPALATAL SUTURE MATURATION
Baseline diagnostic CBCT images should be analyzed using a
variety of commercially available software that allows visualization of
the images in axial, sagittal and coronal views and that can adjust the
orientation of the head of the patient easily. We will demonstrate our
protocol for classifying midpalatal maturation on CBCT images using
Invivo 5" software (Anatomage, San Jose, CA, USA).
Head orientation should be adjusted in natural head position
in all three planes of space. The cursor (the position indicator) of the
image analysis software is positioned at the midsagittal plane of the
patient in both coronal and axial views (Fig. 4). In the sagittal view,
the patient's head is adjusted so that the anteroposterior long axis of
the palate is horizontal. The vertical and horizontal cursors should be
positioned in the center of palate in axial, coronal and sagittal views.
The most central axial cross-sectional slice is used for sutural
assessment. For selecting this slice in the sagittal plane, the mid-
sagittal cross-sectional slice is used to position the palate horizontally,
parallel to the software's horizontal orange line (Fig. 4B). After placing
the horizontal line along the palate, the most central cross-sectional
slice in the superior-inferior dimension (i.e., from the nasal to the oral
surface) is utilized for classification of the maturational stage of the
midpalatal suture (Fig. 4A).
For subjects who present with a curved palatal contour,
however, the palate should be evaluated in two separate central cross-
sectional axial slices, analyzing the posterior and anterior regions of the
midpalatal suture separately (Fig. 5). On the other hand, for subjects
who presented with a thicker palate, the palate should be evaluated in
the two most central axial slices (Fig. 6).
The classification of the midpalatal suture maturation and the
description of these maturational stages are based on the findings of the
morphology of the midpalatal suture during growth described in pre-
262
Angelieri et al.
… . . .
A. -ºº-ºº: -
| - -- ºf ------ - - . tº i t . , , ,--- . 1 , t , , , , , t ,
Figure 4. Standardization of head position in the axial (A), Sagittal (B) and coronal
planes (C).
Figure 5. Two central cross-sectional axial images should be evaluated for the
posterior and anterior portions for patients with a curved palate.
vious histological studies (Melsen, 1972, 1975; Persson et al., 1978;
Cohen, 1993; Sun et al., 2004) Radiographically, the midpalatal suture
appears as a high density line or area even before sutural interdigitation
and fusion.
All maturational stages of the midpalatal suture are represented
in a schematic drawing (Fig. 7); they are described as follows:
Stage A
At Stage A (Fig. 8), the midpalatal suture appears as an almost
Straight high-density sutural line with no or little interdigitation (Melsen,
1975; Cohen, 1993; Korbmacher et al., 2007; Hahn et al., 2009).
Stage B
In this stage, the midpalatal suture becomes irregular; it appears
as one scalloped high-density line (Fig. 9A). A common finding at Stage
B is the presence of some small areas where two parallel, scalloped,



263
Maturation of Facial Sutures
Figure 6. For patients with a thick palate, the two most central axial slices should
be analyzed.
^_/
Stage A Stage B Stage C Stage D Stage E
Figure 7. Schematic drawing of the maturational stages of the midpalatal suture.
Figure: Chris Jung.


264
Angelieri et al.
Figure 8. The midpalatal suture is almost a straight high-density line in Stage A.
Figure 9. A: The midpalatal suture appears as a scalloped high-density line in
Stage B. B: in some areas, the midpalatal suture appears as two parallel scalloped
high-density lines that lie close to each other and are separated by small low-
density spaces.
high-density lines lie close to each other (Fig. 9B) and are separated by
Small low-density spaces (Korbmacher et al., 2007; Hahn et al., 2009).


265
Maturation of Facial Sutures
Stage C
At Stage C (Fig. 10), the midpalatal suture appears as two parallel,
scalloped, high-density lines that are close to each other, separated by
Small low-density spaces in the maxillary and palatine bones (between
the incisive foramen and the palatomaxillary suture and posterior to the
palatomaxillary suture). The suture may be seen in either a straight or
irregular pattern (Fig. 10).
Stage D
Because the fusion of the midpalatal suture occurs sequentially
from posterior to anterior (Persson and Thilander, 1977; Knaup et al.,
2004), the midpalatal suture cannot be visualized in the palatine bone at
Stage D (Fig. 11). The parasutural bone density is increased (high-density
bone) compared to the density of the maxillary parasutural bone. In the
maxillary portion, the midpalatal suture still appears as two high-density
lines separated by small low-density spaces.
Stage E
At this stage, the midpalatal suture cannot be observed in at
least a portion of the maxilla (Cohen, 1993; Sun et al., 2004), in that at
least partial fusion of this suture has occurred in the maxilla (Fig. 12). The
parasutural bone density is increased, reaching the same level as in other
regions of the palate (Korbmacher et al., 2007).
In order to help clinicians to classify the midpalatal suture matu-
ration, a decision tree has been created, as shown in Figure 13.
CLINICAL CONSIDERATIONS OF
MIDPALATAL SUTURAL MATURATION
It has been a challenge for orthodontists to decide whether
conventional RME intervention or a surgically assisted procedure should
be performed when a late adolescent or young adult needs widening
of the maxilla. No well-defined or well-accepted clinical parameters
for this difficult treatment decision have been established that can
eliminate unnecessary surgical procedures, demanding Costs and risks
for patients; or the side-effects of conventional RME failure (severe pain,
mucosal ulceration or necrosis, accentuated buccal tipping, gingival re-
266
Angelieri et al.
Figure 10. Stage C is characterized as two parallel, scalloped high-density lines
Close to each other and separated by small low-density spaces in either a straight
(A) or an irregular (B) pattern.
Figure 11. In the palatine bone during Stage D, the midpalatal suture cannot be
Visualized and the parasutural bone density is increased.
Cession in the posterior teeth; Bell and Epker, 1976; Betts et al., 1995;
Garib et al., 2005; Rungcharassaeng et al., 2007; Kilig et al., 2008).
As discussed earlier, the use of maxillary occlusal radiographs
has been proposed (Revelo and Fishman, 1994), but with unreliable
findings due to the overlay, the vomer and other external structures of
the nose on the midpalatal area (Wehrbein and Yildizhan, 2001). On the
Other hand, CBCT imaging provides three-dimensional (3D) visualization


267
Maturation of Facial Sutures
Figure 12. The midpalatal suture is not visible in at least a portion of the maxilla
during Stage E.
Can you see the suture along both
the maxillary and palatine bones?
Yes T. No
Are there two high-density Can you see the suture
lines along the suture? along the maxilla only?
No Yes Yes No
|s the one
line you see STAGE C STAGE D STAGE E
scaloped?
No Yes
STAGE A STAGE B
Figure 13. The suggested decision tree that can be used to classify midpalatal
Suture maturation.
of the oral and maxillofacial structures without overlay of the adjacent
structures, which allows the analysis of the midpalatal suture maturation
in patients prior to RME (Angelieri et al., 2013).

268
Angelieri et al.
Analysis of the midpalatal suture maturation by way of CBCT
facilitates the decision either to undertake Conventional RME in late
adolescents and young adults or, on the other hand, to consider Surgically
assisted RME in these patients. Examining a sample of 140 subjects from
5.6 to 58.4 years, Angelieri and colleagues (2013) verified fusion of the
midpalatal suture in girls older than 11 years (Stages D and E) and boys
older than 14 years (Stage D). Clinically, this sexual dimorphism in the
fusion of the midpalatal suture has been observed, with females usually
maturing earlier than males. p
These CBCT findings corroborate the clinical findings of RMEfailure
in late adolescents, mainly in females. Interestingly, histological studies
have shown a lack of fusion of the midpalatal suture in some subjects
in their third through seventh decades of life (Persson and Thilander,
1977; Knaup et al., 2004; Korbmacher et al., 2007). Such findings may be
explained because only the anterior portions of the midpalatal sutures
were analyzed histologically and during which only frontal sections were
evaluated. As the maturation of the midpalatal suture occurs progressively
from the posterior to the anterior regions, those subjects appearing to
have patent midpalatal sutures possibly could have been at Stage D, a
stage characterized by fusion of the posterior portion of the midpalatal
Suture.
In addition, some females from 11 to 14 years of age were
classified at Stage E (Angelieri et al., 2013) because they presented with
a thinner area of the palate in which the midpalatal suture had fused
(Fig. 14). Thus, the anteroposterior evaluation along the long axis of the
midpalatal suture is essential, with no overlay of adjacent structures, to
diagnose properly the stage of maturation of the midpalatal suture. Only
Persson and Thilander (1977) have examined the palatine portion of the
midpalatal suture histologically, observing fusion of this suture in subjects
ranging from 15 to 19 years of age.
The individual assessment of the midpalatal suture maturation
may provide valuable diagnostic guidance in subjects olderthan 11 years of
age, mainly for females. The study performed by Angelieri and associates
(2013) demonstrated great variability between the chronological age and
midpalatal suture maturation, especially in that subjects older than 11
years presented at all maturational stages of the midpalatal suture.
269
Maturation of Facial Sutures
Figure 14. A 13-year-old female with a thinner palate (superoinferiorly) in the
maxillary portion, where the midpalatal suture was fused earlier.
Stage A was identified primarily in subjects younger than 11 years
old (i.e., during the juvenile period). Stage B was observed mainly in
subjects up to 13 years of age, with Stage B also evident in some subjects
from 14 to 18 years and even in an adult female. Stage C was noted mainly
from 11 to 18 years of age, though some adults (4 of 32) also presented at
Stage C (Angelieri et al., 2013).
It can be expected that the complex interdigitation of the
sutural trabeculae and the presence of bony bridges observed in the
later maturational stages of the midpalatal suture will promote more
resistance for conventional RME. Patients at Stages A and B probably
would have less resistance forces and more skeletal effects promoted by
Conventional RME than at Stage C, an observation that corroborates the
findings of Baccetti and colleagues (2001) who verified more favorable
skeletal changes from RME in pre-pubertal patients compared to post-
pubertal patients.
Similar findings were observed by Krukemeyer (2013) who
evaluated the correlation among response to RME, maturational stages
of the midpalatal suture and the stage of cervical vertebral maturation
(CVM). The maturational stages of the midpalatal suture and CVM stages
were correlated inversely with sutural expansion (i.e., the less mature
patient demonstrated the greater sutural expansion, with more skeletal
than dentoalveolar effects of RME).
At Stage C, many initial ossification areas and bone bridges
along the midpalatal suture can be observed; they were described by
Melsen (1972) as “bony islands.” Despite more sutural resistance to
conventional RME and consequently less skeletal effects, patients expand-

270
Angelieri et al.
Figure 15. A 15-year-old male patient at Stage C. Conventional RME was success-
ful.
ed when they were at Stage C still can undergo widening of the maxilla
Orthopedically without simultaneous surgical intervention (Fig. 15).
In addition, having a patient diagnosed at Stage C indicates
that RME treatment should be initiated immediately, in that the start of
fusion of the palatine portion of the midpalatal suture may be imminent.
In contrast, a patient at Stage D may demonstrate an opening of an
interincisal diastema caused by RME, despite no widening of the palate
posteriorly. Patients in Stages D and E often are treated more effectively
by surgically assisted RME, in that the fusion of midpalatal suture already
has occurred partially or totally, hampering the expansive forces of the
RME from opening the midpalatal suture.

271
Maturation of Facial Sutures
The majority of the adults evaluated by Angelieri and coworkers
(2013) presented fusion of the midpalatal suture in the palatine and/or
maxillary portions, findings that corroborate the clinical observations of
high prevalence of RME failure in adults. On the other hand, some adults
were found to be either at Stage B or C, which probably would allow
treatment with conventional RME. Additionally, other factors should be
evaluated for successful conventional RME in adults (e.g., fusion of other
circum-maxillary Sutures).
The individualized assessment of midpalatal suture maturation
has the potential to allow the development of a reliable clinical method
for the prediction of RME success or failure, mainly for late adolescent
and young adult patients for whom the prognosis of this treatment is
questionable. Future studies are necessary to show the clinical meaning
of the different maturational stages of the midpalatal suture and to apply
this method to other circum-maxillary sutures.
APPLICATION TO OTHER ORTHOPEDIC PROCEDURES
Besides RME, the application of reverse traction to the maxilla
comprises an important orthopedic component for skeletal Class ||
malocclusions. Typically, the facial mask associated with various types
of maxillary expanders has been used for the forward movement of the
maxilla (Baik, 1995; Kapust et al., 1998; Baccetti et al., 2000; Westwood
et al., 2003).
Beyond producing forward displacement of maxilla, facial mask
therapy promotes clockwise rotation of the mandible, proclination of
the maxillary incisors and mesialization of the maxillary buccal segments
(Baik, 1995; Kapust et al., 1998; Baccetti et al., 2000; Westwood et al.,
2003).
Clinically, it has been observed that reverse traction of maxilla
should be applied during early childhood to obtain better skeletal
effects in Class Ill malocclusions. Some authors advised facial mask use
until 8 to 10 years of age (Hickham, 1991; Proffit, 1992; Kapust 1998);
others (Franchi et al., 1998, 2004; Baccetti et al., 2000), using the stage
of dental development, have determined the early mixed dentition as
the best time for obtaining maximal skeletal effects. Other investigators
have reported no difference in response to facial mask therapy between
272
Angelieri et al.
pre-pubertal and pubertal stages of maturation (Baik, 1995; Takada et al.,
1993).
To minimize the dentoalveolar effects produced by the facial mask
due to its dentally-supported expander, the bone-anchored maxillary
protraction (BAMP) system was introduced by De Clerck and colleagues
(2009). Miniplates are placed on the left and right infrazygomatic crests
of the maxillary buttress and between the mandibular left and right
lateral incisors and canines. Extensions of the plates perforate the
gingival and intermaxillary elastics are applied to correct the underlying
Class Ill malocclusion. De Clerck and associates (2009) and Nguyen and
Coworkers (2011) have showed forward displacement of both maxilla
and zygomas promoted by BAMP therapy, with favorable results
compared with untreated Class || controls (De Clerck et al., 2010) and
to patients treated with a facial mask (Cevidanes et al., 2010; De Clerck
et al., 2010).
In a 3D CBCT study (Hino et al., 2013), facial mask and BAMP
appliances were shown to promote protraction of the maxilla and
zygomatic processes, with greater maxillary skeletal effects noted for
the BAMP approach. Despite these skeletal effects, Hino and colleagues
(2013) and Nguyen and coworkers (2011) showed substantial variability
in the treatment effects produced by both facial mask and BAMP; for
Some patients, there were greater skeletal effects and for others, more
dentoalveolar effects. This variability in the response from facial mask
and BAMP does not appear to be related to the chronological age or
gender differences among patients (Figs. 16 and 17).
Because the maxilla is connected to other facial bones by sutures,
the skeletal effects from facial mask and BAMP depend on the matura-
tional stage of the circum-maxillary sutural system. The circum-maxillary
Sutures affected are the zygomaticomaxillary sutures, frontomaxillary su-
tures, nasomaxillary sutures, midpalatal suture and palatomaxillary su-
ture. For the forward movement of the maxilla, it has been speculated
that the zygomaticomaxillary sutures play a significant role in determin-
ing the response to facial mask therapy, in that these are the largest max-
illary sutures and are related directly to the orientation of the applied
force system for maxillary protraction (Nanda and Hickory, 1984).
273
Maturation of Facial Sutures
Figure 16. An 8-year-old boy with a good response from facemask therapy.
Images courtesy of Dr. Claudia Toyama Hino.
Figure 17. Poor response from facemask therapy in another 8-year-old boy.
Images courtesy of Dr. Claudia Toyama Hino.
Our research group has investigated the individual assessment
of the zygomaticomaxillary sutures for the response to facial mask and
BAMP. Preliminary results with a pilot study are promising (Figs. 18 and 19),



274
Angelieri et al.
Figure 18. Analysis of the zygomaticomaxillary sutures maturation using CBCT
images. A: Coronal view. B-F: Sagittal view on the right side of the infraorbital (B)
and infrazygomatic (C) portions and left side of infraorbital (D) and infrazygomatic
(E) portions of the 8-year-old boy who responded well to the facial mask (F). The
Zygomaticomaxillary sutures are at Stage B, following the same criteria of the
classification of midpalatal suture maturation.
Figure 19. Classification of the zygomaticomaxillary sutures maturation on CBCT,
On Coronal view (A), and on Sagittal view on right side of infraorbital (superior;
B) and infrazygomatic (inferior; C) portions and left side of infraorbital (D) and
infrazygomatic (E) portions of the 8-year-old boy who responded poorly to facial
mask therapy (F). The zygomaticomaxillary sutures are at Stage C, with many
bony bridges evident.
but more studies should be performed to investigate the influence of the
Zygomaticomaxillary suture maturation and the other maxillary sutures
on the response from the facial mask and BAMP.
CONCLUSIONS
RME has been an unpredictable treatment for late adolescent and
young adults, as is reverse traction of the maxilla for children older than 8
years of age. For these patients, the evaluation of facial suture maturation


275
Maturation of Facial Sutures
on CBCT images is a promising predictor, facilitating the differentiation
between conventional orthopedic treatments and surgically assisted
procedures. Unnecessary surgery, accentuated dental tipping, gingival
recession, severe pain and even necrosis of the palate could be avoided
using this diagnostic approach. CBCT imaging in selected patients for
whom RME is indicated is an important adjunct in the diagnosis and
treatment planning process.
ACKNOWLEDGEMENTS
The authors thank Foundation for Research Support of the
State of São Paulo (FAPESP) and Thomas M. and Doris Graber Endowed
Professorship, the Department of Orthodontics and Pediatric Dentistry at
The University of Michigan for the support. Furthermore, we acknowledge
artist Chris Jung who drew the stages of midpalatal suture maturation
(Fig. 7), photographer Per Kjeldsen for photographs of maxilla (Fig. 1)
and Claudia Toyama Hino for giving us the images from patients seen in
Figures 16 and 17.
REFERENCES
Angelieri F, Cevidanes LH, Franchi L, Gonçalves JR, Benavides E, McNa-
mara JA Jr. Midpalatal suture maturation: Classification method for
individual assessment prior to rapid maxillary expansion. Am J Orthod
Dentofacial Orthop 2013;144(5):759-769.
Angell EC. Treatment of irregularity of the permanent or adult teeth. Dent
Cosmos 1860;1:540-544, 599–600.
Baccetti T, Franchi L, Cameron CG, McNamara JA Jr. Treatment timing for
rapid maxillary expansion. Angle Orthod 2001;71(5):343-350.
Baccetti T, Franchi L, McNamara JA Jr. Treatment and post-treatment
craniofacial changes after rapid maxillary expansion and facemask
therapy. Am J Orthod Dentofacial Orthop 2000;118(4):404-413.
Baik HS. Clinical results of the maxillary protraction in Korean children.
Am J Orthod Dentofacial Orthop 1995;108(6):583-592.
Bell WH, Epker BN. Surgical-orthodontic expansion of the maxilla. Am J
Orthod 1976;70(5):517-528.
276
Angelieri et al.
Betts NJ, Vanarsdall RL, Barber HD, Higgins-Barber K, Fonseca RJ. Diagnosis
and treatment of transverse maxillary deficiency. Int J Adult Orthod
Orthognath Surg 1995;10(2):75-96.
Bishara SE, Staley RN. Maxillary expansion: Clinical implications. Am J
Orthod Dentofacial Orthop 1987;91(1):3-14.
Björk A. Sutural growth of the upper face studied by the implant method.
Acta Odontol Scand 1966;24(2):109-127.
Blueher WA. Cephalometricanalysis of treatment with cervical anchorage.
Angle Orthod 1959;29(1):45-53.
Capelozza Filho L, Cardoso Neto J, da Silva Filho OG, Ursi WJ. Non-surgically
assisted rapid maxillary expansion in adults. Int J Adult Orthodon
Orthognath Surg 1996;11(1):57-70.
Cevidanes L, Baccetti T, Franchi L, McNamara JAJr, De Clerck H. Comparison
of two protocols for maxillary protraction: Bone anchors versus face
mask with rapid maxillary expansion. Angle Orthod 2010;80(5):799-
806.
Cohen MM Jr. Sutural biology and the correlates of craniosynostosis. Am
J Med Genet 1993;47(5):581-616.
De Clerck H, Cevidanes L, Baccetti T. Dentofacial effects of bone-anchored
maxillary protraction: A controlled study on consecutively treated
Class III patients. Am J Orthod Dentofacial Orthop 2010;138(5):577-
581.
De Clerck HJ, Cornelis MA, Cevidanes LH, Heymann GC, Tulloch C.J. Or-
thopedic traction of the maxilla with miniplates: A new prospective
for treatment of midface deficiency. J Oral Maxillofac Surg 2009;
67(10):2123-2129.
Franchi L, Baccetti T, McNamara JA Jr. Post-pubertal assessment of
treatment timing for maxillary expansion and protraction therapy
followed by fixed appliances. Am J Orthod Dentofacial Orthop 2004;
126(5):555-568.
Franchi L, Baccetti T, McNamara JA Jr. Shape-coordinate analysis of skel-
etal changes induced by rapid maxillary expansion and facial mask
therapy. Am J Orthod Dentofacial Orthop 1998;114(4):418-426.
Garib DG, Henriques JF, Janson G, Freitas MR, Coelho RA. Rapid maxillary
expansion tooth-tissue-borne versus tooth-borne expanders: A
277
Maturation of Facial Sutures
computed tomography evaluation of dentoskeletal effects. Angle
Orthod 2005;75(4):548–557.
Haas AJ. Palatal expansion: Just the beginning of dentofacial orthopedics.
Am J Orthod 1970;57(3):219–255.
Haas A.J. Rapid expansion of the maxillary dental arch and nasal cavity by
opening the midpalatal suture. Angle Orthod 1961;31(2):73-90.
Haas A.J. Rapid palatal expansion: A recommended prerequisite to Class ||
treatment. Trans Eur Orthod Soc 1973;49:311-318.
Hahn W, Fricke-Zech S, Fialka-Frickel, Dullin C, Zapf A, Gruber R, Sennhenn-
Kirchner S, Kubein-Meesenburg D, Sadat-Khonsari R. Imaging of the
midpalatal suture in a porcine model: Flat-panel volume computed
tomography compared with multislice computed tomography. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108(3):443-449.
Hickham J.H. Maxillary protraction therapy: Diagnosis and treatment. J
Clin Orthod 1991;25(2):102-13.
Hino CT, Cevidanes LH, Nguyen TT, De Clerck HJ, Franchi L, McNamara
JA Jr. Three-dimensional analysis of maxillary changes associated
with facemask and rapid maxillary expansion compared with bone
anchored maxillary protraction. Am J Orthod Dentofacial Orthop
2013;144(5):705-714.
Kapust A, Sinclair PM, Turley P.K. Cephalometric effects of face mask/
expansion therapy in Class III children: A comparison of three age
groups. Am J Orthod Dentofacial Orthop 1998;113(2):204-212.
Kilig N, Kiki A, Oktay H. A comparison of dentoalveolar inclination treated
by two palatal expanders. Eur J Orthod 2008;30(1):67-72.
Klein PL. An evaluation of cervical traction on the maxilla and upper first
permanent molar. Angle Orthod 1957;27(1):61-68.
Kloehn SJ. Guiding alveolar growth and eruption of teeth to reduce
treatment time and produce a more balanced denture and face. Angle
Orthod 1947;17(1):10–33.
Knaup B, Yildizhan F, Wehrbein H. Age-related changes in the midpalatal
suture: A histomorphometric study. J Orofac Orthop 2004;65(6):467-
474.
278
Angelieri et al.
Korbmacher H, Schilling A, Püschel K, Amling M, Kahl-Nieke B. Age-
dependent three-dimensional micro-computed tomography analysis
of the human midpalatal suture. J Orofac Orthop 2007;68(5):364-376.
Krukemeyer AM. The effects of sutural and cervical vertebral maturation
on dentoalveolar versus skeletal responses to rapid maxillary
expansion. Unpublished master's thesis, Department of Orthodontics
and Pediatric Dentistry, School of Dentistry, The University of Michigan,
Ann Arbor, MI 2013.
Latham RA. The development, structure ànd growth pattern of the human
mid-palatal suture. J Anat 1971;108(Pt 1):31-41.
Melsen B. A histological study of the influence of sutural morphology and
Skeletal maturation on rapid palatal expansion in children. Trans Eur
Orthod Soc 1972;48:499-507.
Melsen B. Palatal growth studied on human autopsy material: A histologic
microradiographic study. Am J Orthod 1975;68(1):42-54.
Melsen B, Melsen F. The postnatal development of the palatomaxillary
region studied on human autopsy material. Am J Orthod 1982;82(4):
329–242.
Nanda R, Hickory W. Zygomaticomaxillary suture adaptations incident to
anteriorly-directed forces in Rhesus monkeys. Angle Orthod 1984;54
(3):199-210.
Nguyen T, Cevidanes L., Cornelis MA, Heymann G, de Paula LK, De Clerck
H.J. Three-dimensional assessment of maxillary changes associated
with bone anchored maxillary protraction. Am J Orthod Dentofacial
Orthop 2011;140(6):790-798.
Persson M, Magnusson BC, Thilander B. Sutural closure in rabbit and
man: A morphological and histochemical study. J Anat 1978;125(Pt
2):313–321.
Persson M, Thilander B. Palatal suture closure in man from 15 to 35 years
of age. Am J Orthod 1977;72(1):42-52.
Petit HP. Adaptation following accelerated facial mask therapy. In:
McNamara JA Jr, Ribbens KA, Howe RP, eds. Clinical Alteration of the
Growing Face. Monograph 14, Craniofacial Growth Series, Center for
Human Growth and Development, The University of Michigan, Ann
Arbor 1983.
279
Maturation of Facial Sutures
Proffit WR, ed. Contemporary Orthodontics. St Louis: CV Mosby 1992.
Revelo B, Fishman LS. Maturational evaluation of Ossification of the
midpalatal suture. Am J Orthod Dentofacial Orthop 1994;105(3):288–
292.
Rungcharassaeng K, Caruso JM, Kan JY, Kim J, Taylor G. Factors affecting
buccal bone changes of maxillary posterior teeth after rapid maxillary
expansion. Am J Orthod Dentofacial Orthop 2007;132(4):428.e1-e8.
Sun Z, Lee E, Herring SW. Cranial sutures and bones: Growth and fusion
in relation to masticatory strain. Anat Rec A Discov Mol Cell Evol Biol
2004;276(2):150-161.
Takada K, Petdachai S, Sakuda M. Changes in dentofacial morphology in
skeletal Class Ill children treated by a modified maxillary protraction
headgear and chin cup: A longitudinal study. Eur J Orthod 1993;15
(3):211-221.
Wehrbein H, Yildizhan F. The mid-palatal suture in young adults: A
radiological-histological investigation. Eur J Orthod 2001;23(2):105-
114.
Wertz R, Dreskin M. Midpalatal suture opening: A normative study. Am J
Orthod 1977;71(4):367-381.
Westwood PV, McNamara JA Jr, Baccetti T, Franchi L, Sarver DM. Long-
term effects of Class Ill treatment with rapid maxillary expansion
and facial mask therapy followed by fixed appliances. Am J Orthod
Dentofacial Orthop 2003;123(3):306–320.
280
BIOMARKERS OF ROOT RESORPTION:
THE CHALLENGES AND OPPORTUNITIES
Wellington J. Rody Jr., Kevin P. McHugh,
P Edward Purdue and Shannon M. Wallet
ABSTRACT
Given the constant demand for shorter treatment, orthodontists have been facing
a dramatic increase in the number of new techniques developed to accelerate
orthodontic treatment. The majority of these novel approaches exacerbate the
inflammatory response of the periodontium to orthodontic forces in order to
enhance tooth movement. Root resorption is also an inflammatory response.
Therefore, orthodontists cannot overlook the impact these techniques may
have on root resorption. Thus, with expanded research in this field of expedited
orthodontics, there is significant need to develop simple and non-invasive tests
that could help to differentiate between acceptable alveolar bone modeling
and individuals at increased risk for root resorption before the damage can be
visualized by a radiograph or cone-beam computed tomography (CBCT) scan. The
main goal of this chapter is to review the current literature on unique biomarkers
of root resorption and explore the challenges and opportunities associated with
this area of research.
KEY WORDS: biomarkers, root resorption, gingival crevicular fluid, odontoclasts,
osteoclasts
Given the Constant demand for shorter treatment, Orthodontists
have been facing a dramatic increase in the number of newly developed
techniques to accelerate tooth movement, including vibratory stimula-
tion (Darendeliler et al., 2007; Nishimura et al., 2008), biological therapy
agents (Kanzaki et al., 2006; Nimeri et al., 2013), low-level laser therapy
(Sousa et al., 2011; Kau et al., 2013; Nimeri et al., 2013; Carvalho-Lobato
et al., 2014), pulsed electromagnetic fields (Showkatbakhsh et al., 2010;
Long et al., 2013), micro-osteoperforations (Teixeira et al., 2010; Alikhani
et al., 2013) and alveolar bone corticotomy (Amit et al., 2012; Mathews
and Kokich, 2013; Wilcko and Wilcko, 2013; Hoogeveen et al., 2014). The
281
Biomarkers of Root Resorption
main goal of these techniques is to maintain sufficient inflammatory re-
sponse for a longer duration in order to enhance alveolar bone remodel-
ing and, therefore, tooth movement. While the hypothesis is sound and
the research thus far is promising, one question remains: What is the bio-
logical cost of accelerated tooth movement?
When it comes to side effects of orthodontic treatment,
orthodontists cannot overlook external root resorption. Although
considered a normal physiological response in deciduous teeth, the
process of root resorption in the permanent dentition is pathological
(Jatania et al., 2012). Specifically, severe root resorption can lead to
mobility and loss of permanent teeth. Clinically, root resorption is
classified as mild, moderate or severe. Generally, severe root resorption
involves the loss of over one third of the root length (Fig. 1). Histologically,
root resorption is manifested as a congregation of multi-nucleated cells
and resorption lacunae along the root surface (Fig. 2). Sections from
orthodontically treated rats demonstrate extensive root resorption
lacunae with enzymatic reaction penetrating the dentine seven days
following appliance activation (Rody et al., 2001). In human teeth,
histological changes associated with root resorption can be observed in
the 3- to 5-week period after initiation of an orthodontic force (Ownan-
Moll et al., 1995). Development of alternative methods for early detection
of root resorption is essential for identifying at-risk individuals.
Figure 1. Radiographic evidence of
severe root resorption in a patient
undergoing orthodontic treatment.

282
Rody et al.
Orthodontic appliance activation. The cluster of dark stained cells represents
Odontoclasts resorbing the root surface. Notice that a significant resorption
lacunae is already formed after 7 days in the rat molar. Bar = 15 um; AB = alveolar
bone; DR = distal root. Reprinted with permission from Elsevier; Rody WJJr, King
GJ, Gu G. Osteoclast recruitment to sites of compression in orthodontic tooth
movement. Am J Orthod Dentofacial Orthop 2001;120(5):477-489.
To date, radiography and computed tomography (CT) are the
Standard techniques used by clinicians to diagnose and monitor root
resorption (Kapila et al., 2011). Yet current radiographic techniques are
inadequate for detection of early signs of resorption. The risks associated
With X-rays also have caused many healthcare professions to curtail
their use. In addition, imaging methods do not indicate if the process
of root resorption is ongoing or historical. Clinicians, therefore, lack an
important diagnostic tool, due to the often asymptomatic nature of the

283
Biomarkers of Root Resorption
root resorption process, which remains undiagnosed in the absence of
a screening technique. With expanded research in the field of clinical
proteomics, there is significant potential to develop simple and non-
invasive tests that could help to diagnose individuals at increased risk
for root resorption (Rody et al., 2012). Indeed, the development of oral
fluid biomarkers offers great potential for the early diagnosis of local
and systemic diseases (Fleissig et al., 2010). The future of this field for
dental applications (e.g., root resorption) will depend on identification
and validation of biomarkers, and their incorporation into state-of-the-
art assays that are reliable, sensitive, specific and cost-effective for broad
implementation in clinical practice.
LITERATURE REVIEW
Saliva and gingival crevicular fluid (GCF) are the most popular
targets for biomarker discovery in oral diseases (Fleissig et al., 2010). Saliva
from healthy humans is composed of a mixture of salivary gland secretion,
GCF, cell debris, microorganisms, serum/blood from sub-clinical wounds,
nasal and bronchial secretions; thus, in terms of proteomic analysis, saliva
is considered a very complex sample (Yan et al., 2009). GCF, on the other
hand, is more site-specific and may provide quantitative biochemical
indicators that reflect the status of mineralized tissue modeling in the
periodontium, including that of root resorption (Ngo et al., 2010, 2013).
GCF is defined as a transudate of interstitial fluid and/or inflammatory
exudates (Suzuki et al., 2008). The constituents of GCF arise from a variety
of sources, including host tissues and cells, microbial plaque and serum-
derived factors (Buduneli and Kinane, 2011). Table 1 summarizes the main
differences between saliva and GCF for diagnostic purposes; readers are
referred to current reviews for a more detailed explanation (Lamster and
Ahlo, 2007; Giannobile et al., 2009; Lee and Wong, 2009; Gupta, 2012,
2013; Malathi et al., 2014).
Although molecular evidence for active bone modeling,
remodeling and soft tissue inflammation can be detected in GCF (Gupta,
2012, 2013), only a handful of biomarkers associated with root resorption
have been described in the literature to date (Table 2) even though a
plethora of potential candidates exist. The categories of biomarkers that
are current and novel potential candidates for root resorption diagnosis
include:
284
Rody et al.
Table 1. Main differences between saliva and gingival crevicular fluid (GCF) for
diagnostic purposes.

Saliva GCF
Mineral
+ - 2+ 2 - 2+ - e -
Composition Na", Cl, Ca”, HPO, A HCO, Mg” and NH, Similar ions
• No body secretion
products
• Body secretion products p • No putrefaction
• Putrefaction products (putrescine, products
cadaverin) • No lipids
º • Lipids (cholesterol, fatty acids) • Proteins:
Organic *
e - tº • Proteins: o Free of amylase
Composition
o Glandular (alpha-amylase, lysozymes, and other glandular
mucins, proline-rich proteins, etc.) proteins
o Plasma-derivatives (Albumin, IgA o Rich in plasma
transferrin) proteins
O Albumin is the most
abundant protein
Methods of • Easy sampling • Minimally invasive
Collection • Non-invasive • Technically challenging
Saliva can reflect the physiologic state
of the body (emotional, endocrinal and More site-specific
metabolic variations)
Diagnostic
Information
Table 2. GCF biomarkers of root resorption reported in the literature.

Biomarker category Name References
Mah and Prasad, 2004
Balducci et al., 2007
Dentin breakdown Dentin Sialoprotein (DSP) Kereshanan et al., 2008
products Dentin Phosphoprotein (DPP) Zuo et al., 2011
Kumar et al., 2013
Sha et al., 2014
Inflammatory cytokines Interleukin-6 (IL-6) Kunii et al., 2013
Receptor activator of nuclear
factor kappa-B ligand (RANKL)
Osteoprotegerin (OPG)
Tyrovola et al., 2008, 2010
George and Evans, 2009
Osteoclastogenesis
related factors
285
Biomarkers of Root Resorption
1.
Dentin breakdown products: To date, the search for
biomarkers for early detection of root resorption has
focused primarily on matrix proteins that are shed into
GCF as a consequence of dentin resorption (Mah and
Prasad, 2004; Balducci et al., 2007; Kereshanan et al.,
2008). Cementum breakdown products in GCF may not
be indicative of the permanent loss of root structure
since focal areas of cementum are resorbed and
subsequently repaired during tooth movement (Owman-
Moll et al., 1995). On the other hand, larger areas of
resorption that include loss of dentin do not repair, thus
making the dentin breakdown products in GCF unique
markers for external root resorption. Of the various
dentin non-collagenous proteins, dentin sialoprotein
(DSP) and dentin phosphoprotein (DPP) are the most
abundant proteins present within dentin. DSP and DPP
are N- and C-terminal proteolytic cleavage products of
dentin sialophosphoprotein (DSPP), respectively (Prasad
et al., 2010). Mah and Prasad (2004) detected DPP and
DSP in GCF of resorbing deciduous molars, non-resorbing
incisors and resorbing incisors during orthodontic
treatment. The concentration of these root-derived
molecules was significantly higher in GCF of teeth with
resorbing roots than in CGF from non-resorbing teeth
(Mah and Prasad, 2004). Later, this finding was confirmed
by other human and animal studies (Balducci et al., 2007;
Kereshanan et al., 2008; Zuo et al., 2011; Kumar et al.,
2013; Sha et al., 2014).
Inflammatory cytokines: Once the microenvironment
of periodontal tissue is disrupted, several key
cytokines are produced to trigger a cascade of cellular
events. Therefore, it is not surprising that increased
concentration of cytokines in human GCF during
orthodontic tooth movement and periodontal disease
has been demonstrated by several studies (Iwasaki et
al., 2005; Giannopoulou et al., 2008; Ren and Vissink,
2008; Iwasaki et al., 2009). Cytokines are extracellular
286
Rody et al.
signaling proteins usually classified as pro-inflammatory
or anti-inflammatory. Some of them, like tumor necrosis
factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6),
interleukin-11 (IL-11) and interleukin-17 (IL-17) play an
important role in bone remodeling and the regulation
of osteoclast activity (Corrado et al., 2013). IL-6 is
particularly important for orthodontic tooth movement
since this cytokine has an autocrine/paracrine activity that
stimulates osteoclast formation and the bone resorbing
activity of preformed osteoclasts (Ren et al., 2007). In
addition, Lee and colleagues (2007) demonstrated that
compression of periodontal ligament cells increased
the expression of IL-6, thus playing a critical role in the
biology of tooth movement. Only recently has cytokine
concentration in GCF been proposed as a biological
indicator of external root resorption (Kunii et al., 2013).
Specifically, a recent in vitro and in vivo study of the
IL-6 family and its role in root resorption observed high
levels of IL-6 in the GCF Collected from five Orthodontic
patients with radiographic signs of severe root resorption
(Kunii et al., 2013). In addition, the study demonstrated
that human periodontal ligament cells release IL-6 under
compressive force. Taken together, the results of this
study indicate that the role of IL-6 as a biomarker of
root resorption not only should be explored further, but
the biological consequences of IL-6 as it relates to root
resorption also should be investigated.
Osteoclastogenesis related factors: Osteoclast differ-
entiation requires the binding of receptor activator of
nuclear factor kappa B ligand (RANKL), primarily pro-
duced by osteoblasts and immune cells, to its receptor,
receptor activator of nuclear factor kappa (RANK), a cell
membrane protein found on osteoclast and osteoclast-
precursor cells. On the other hand, osteoclast differen-
tiation is inhibited by osteoprotegerin (OPG), a soluble
protein acting as a decoy receptor that binds to RANKL
287
Biomarkers of Root Resorption
and prevents the RANKL-RANK association, hence, block-
ing osteoclastogenesis. The balance between RANKL and
OPG is of major importance in bone homeostasis. Ab-
normalities of the RANKL-to-OPG ratio in GCF have been
observed in the presence of periodontitis or during orth-
odontic tooth movement (Mogi et al., 2004; Nishijima et
al., 2006; Chen et al., 2008; Rody et al., 2014b). Previous
Studies also suggest that severe external root resorp-
tion may stimulate cells in the periodontium to express
more RANKL than OPG (Yamaguchi et al., 2006; Nakano
et al., 2010). This finding was supported later by observa-
tions that the RANKL/OPG ratio was statistically higher
in the GCF of human subjects with severe root resorp-
tion than in the control subjects (Tyrovola et al., 2008,
2010; George and Evans, 2009). Again, the role of RANKL,
OPG and/or the RANKL/OPG ratio as a biomarker of root
resorption should be investigated further in future re-
search, along with the biological consequences of their
expression as it relates to root resorption.
The aforementioned studies used standard technologies such
as solid-phase immunoassay (e.g., ELISA and Western blot) to establish
biomarkers of root resorption in GCF. Currently, mass spectrometry
(MS) is becoming the gold standard for biomarker discovery in body
fluids (Good and Coon, 2009). MS analysis consists of using a molecule's
ionization measure its mass-to-charge ratio (m/z). This analysis permits
determination of the mass, composition and primary structure of
molecules, such as proteins, in a sample (Aebersold and Mann, 2003). For
a more comprehensive description of the MS technique and its potential
clinical application in orthodontics, the reader is referred to a current
review (Rody et al., 2012).
The first study using MS to analyze GCF samples collected
from resorbing teeth recently was published by Rody and colleagues
(2014a). This manuscript describes a clinical study in which the protein
composition in GCF was compared between resorbing primary molar
and non-resorbing permanent molar sites. Based on pooled samples,
the authors found that nearly 40 proteins were down-regulated and 60
288
Rody et al.
proteins were up-regulated in the resorbing site compared to the control
site. Among the differentially expressed proteins quantified by MS,
the catalytic subunit of glutamate-cysteine ligase (GCL) and epidermal
growth factor receptor pathway substrate 8 (EPS8) were expressed more
highly in root resorption samples. GCL is the rate-limiting enzyme that
catalyzes the formation of the cellular antioxidant glutathione (GSH),
which in turn plays an important role in a multitude of cellular processes
(Sen, 2003). EPS8 is a molecule that contributes to the promotion of
phagocytosis of collagen fibers (Chen et al., 2012) and, therefore, may
play a role in the collagen degradation observed in the periodontium
during tooth eruption and root resorption. While the results of the study
do not identify practical biomarkers of root resorption definitively, the
article does open new perspectives for the identification of novel protein
markers that may be pursued as novel candidates for an oral fluid-based
test for early detection of root resorption.
THE CHALLENGES
Although considered a normal physiological response in decidu-
ous teeth, the process of dentin resorption in the permanent dentition
is pathological. Bone, on the other hand, is a unique mineralized tissue,
whose resorption and replacement is necessary not only to maintain
integrity of the skeleton, but also to maintain calcium and mineral ho-
meostasis in the body throughout the life span. Because GCF can contain
biomarkers of both bone and teeth, there is a need for the development
of a biomarker panel that is able to distinguish between dentin and bone
resorption (i.e., odontoclastic and osteoclastic activity).
Much controversy exists about the mechanism behind the
cellular resorption of bone versus teeth. The biggest challenge lies in the
fact that the cells that resorb bone ("osteoclasts') and the cells that resorb
dentin ('odontoclasts') belong to the same lineage (Wang and McCauley,
2011). Therefore, there likely will be overlap between biomarkers used to
assess osteoclast and odontoclast activity. For instance, RANKL and OPG
most likely control both cell populations and thus might not be suitable
biomarkers for diagnosis of external root resorption in oral fluids due to
the lack of their specificity. The same problem will arise upon using IL-6
levels in oral fluids, whose expression can be affected significantly by
289
Biomarkers of Root Resorption
bone resorption as well as other inflammatory processes. Dentin matrix
proteins are promising in terms of specificity; however, the identification
of these proteins in oral fluid thus far has had limited success. One
particular challenge is the fact that non-collagenous dentin proteins are
phosphorylated so highly and/or shielded by carbohydrates that they are
not particularly antigenic, which makesthe development of antibodies and,
thus, standard assays for detection particularly challenging. In addition,
whether or not DSP and DPP are highly specific is controversial. Butler and
associates (1992) suggested that DSP is specific to dentin because it is not
found in ameloblasts, bone, cartilage, soft tissues or other components
of the oral tissues. Nevertheless, more recent studies have shown that
dentin proteins have much broader expression patterns and also can be
found in cartilage, cementum, bone and other non-mineralized tissues
(Oin et al., 2002; Baba et al., 2004; Prasad et al., 2011; Liu et al., 2013).
Despite the controversies, DSP and DPP are the most studied biomarkers
in root resorption and their presence in the GCF of patients undergoing
root resorption were reported by many clinical studies (Mah and Prasad,
2004; Balducci et al., 2007; Kereshanan et al., 2008). The controversies
demonstrate a need in the field for the identification of novel biomarkers.
Additionally, it is likely that a panel of biomarkers specific for root
resorption will be more useful than measurements of individual proteins.
THE OPPORTUNITIES
Although current literature indicates that odontoclasts possess
properties shared with osteoclasts, the regulatory mechanisms that
mediate tooth resorption may differ from osteoclastic bone resorption.
In fact, key differences in odontoclastic and osteoclastic activity have
been reported previously in the literature. For example, odontoclasts
are smaller in cell size and have fewer nuclei when compared to
osteoclasts (Hammarstrom and Lindskog, 1985). In addition, osteoclastic
bone resorption is regulated by Systemic factors such as regulated by
parathyroid hormone (PTH), while dentin resorption is not (Harokopakis-
Hajishengallis, 2007). Finally, the response of both processes to drugs is
different. Indomethacin seems to enhance root resorption, but it does
not interfere with bone resorption during orthodontic tooth movement
(Lasfargues and Saffar, 1993; Zhou et al., 1997).
290
Rody et al.
Taken together, these data suggest it may be naïve to assume
that the activities responsible for the resorption of dentin (odontoclastic
activity) and resorption of bone (osteoclastic activity) are identical. In
addition, these results indicate promise for the identification of molecules
specific for odontoclast activity and, thus, root resorption.
Our group has generated preliminary data demonstrating
differential gene expression of human mononuclear precursors cultured
on either dentin (odontoclasts) or bone (osteoclasts). Specifically,
the gene follistatin-like 1 (FSTL1) was induced strongly in human cells
resorbing dentin, but not in bone (Fig. 3A). On the other hand, annexin A8
gene (ANXA8) was upregulated when these cells are cultured specifically
on bone (Fig. 3A). These findings demonstrate that osteoclasts and
odontoclasts display unique gene expression profiles and, thus, possess
distinct markers that would allow for distinction between odontoclastic
and osteoclastic activity.
With expanded research in the field of clinical proteomics, there
is significant potential to develop simple and non-invasive tests that
could help to diagnose individuals at increased risk for root resorption.
Indeed, we have data demonstrating the feasibility of using non-invasive
methods (i.e., collection of GCF) to detect odontoclast activity using
fluid biomarkers. Specifically, we were able to find some of the peptide
products of the differentially genes presented in Figure 3A in human GCF
after an extensive proteome analysis using two-dimensional (2D) liquid-
chromatography mass spectrometry (Fig. 3B). Importantly, the peptide
product of ANXA8 was found at lower levels in the GCF ofteeth undergoing
root resorption (Fig. 3B). Together, these findings are promising in that
they demonstrate that: 1) unique markers of odontoclastic function may
be identified; and 2) once they are identified, non-invasive methods of
Screening for these markers can be achieved.
FUTURE RESEARCH
Future research is required to identify markers that are as-
Sociated uniquely with the root resorption process, while at the same
time developing reagents that could be used to evaluate them in vitro
and in vivo. To address these needs, our group is utilizing an in vitro,
high throughput, phage-display screening method to generate single
chain variable fragments (scFv) that bind with high affinity to molecules
291
Biomarkers of Root Resorption
ad - - FITILCTR
_^
ZT TN
Root resorption (infraction 11) Control (infraction 11)
6500 5.12.2872 7000 512-287.3 6500-
º -
-
: 512.7874
3. 512.7891
-
-
8
P
º
º
c
512.0 513.0 m/z. 512.0 513.0 m/z 5.
4.5eq 33.44 5.0ea 33.51 5 b.
º -
-
8
-
-
º
-
E.
-
8
3
ANXA8 FSTL1 cathk #
D Plastic Bone - Dentine -- *-T- TTTTT-TTTTTTTTTTTTTTTTTTT
A B 33.0 Time, min 340 390 Time, min 340
Figure 3. A: Gene expression (OPCR) of human monocyte-derived cells cultured
on plastic, bone and dentin. The follistatin-like 1 gene (FSTL1) is upregulated
in cells resorbing dentin. The annexin A8 gene (ANXA8) is upregulated when
cells were cultured on bone. No differential expression pattern was noticed for
Cathepsin-k (CATHK). Identical results were obtained with cells from two donors.
B: Comparison of intensity of mass spectrometry (MS) signal between root
resorption and control GCF samples observed during 2D LC-MS acquisitions. MS
signal intensities at peak maximum for FITILCTR a peptide representing annexin
A8 and respective extracted ion chromatograms (XIC- red). Notice a slight down-
regulation of FITILCTR in root resorption samples (33.44 vs. 33.51).
associated with odontoclast activity, but not osteoclast activity (Marks et
al., 1991; Griffiths et al., 1994; Davies and Riechmann, 1995; Ahmad et
al., 2012). ScFV are single polypeptides with the variable heavy (VH) and
variable light (VL) domains of human antibodies attached by a flexible
glycine-serine linker. These variable domains serve as the antigen recog-
nition portions of antibodies (Fig. 4; Reiter et al., 1999; Holt et al., 2003;
Wang et al., 2013).
Traditionally, researchers use a library of scFV to screen for
scFV which bind to a particular molecule of interest. We have modified
the protocol successfully to allow us to create novel scFV that react
with unknown molecules associated with odontoclast activity, but not
Osteoclast activity. We are utilized a phage display library that encodes for


292
Rody et al.
Figure 4. Schematic of single chain fraction variable (scFV) indicating variable
light (VL) and heavy (VH) chains with flexible glycine-serine linker.
Over 100 million different scFV fragments encoded in an ampicillin-re-
Sistant phagemid vector (Nissim et al., 1994). Specifically cell-free cul-
ture Supernatants from odontoclasts and osteoclasts are subjected to
phage-display panning (Fig. 5). Because we are interested in proteins
asSociated only with dentin resorption and not bone resorption, scFV
Will be selected negatively on the supernatant containing bone matrix
and osteoclast-related proteins (Fig 5.1). This leaves a pool of scFV from
which scrv reactive to molecules associated with dentin resorption will
be enriched. To enrich for these scFV, phage are allowed to interact
With the supernatant containing dentin resorption proteins after which
the unbound phage is washed away and the bound material is eluted.
The eluted phage then is reamplified and three additional cycles of pan-
ning is performed (Fig. 5.2). Finally, scFV highly reactive to soluble mark-
ers of dentin resorption will be eluted (Fig 5.3). The specificity of scFV
Will be validated by standard immunoassay techniques and the identi-
fied target will be characterized by MS. This approach will allow us to
achieve two goals: the identification of the protein products to which
SCFV are reactive can serve as novel biomarkers to distinguish between

293
Biomarkers of Root Resorption
Tomlison 1. Absorption
J Library
scFV. N.
"Negative
Selection
- -
Sºo 2:
º
2. Panning
Collect (Repeat 3x)
Supernatant
sº
- Geº — "º º
Osteoclasts Odontoclasts º
(5-day culture) - (5-day culture) 3.
- Eute
scFV with reactivity to soluble
molecules associated with dentin
resorption
Figure 5. Absorption and panning of scFV phage. Marrow derived cells will
be grown on bone (osteoclasts') or on dentin (odontoclasts') after which
osteoclast’-reactive scFV phage will be absorbed out (1) while odontoclast
reactive scFV-phage will be enriched. Following (2) three rounds of panning, (3)
odontoclast reactive scFV-phage will be eluted and their protein target identified
by MS.
dentin and bone resorption; and these scFV identified protein products
potentially can be used for odontoclast specific therapeutics in the fu-
ture.
Another way to approach the problem is to identify pathways
and gene clusters that are unique, or uniquely regulated, in dentin
resorbing odontoclasts. This can be achieved by the characterization of
the genetic molecular signatures of odontoclasts and osteoclasts using
microarray analysis. Since odontoclast and osteoclast differentiation
from bone marrow precursors is controlled by multiple factors produced
by cells within a specialized microenvironment, we believe that the
application of a large-scale analysis of gene expression will allow us to
further understand unique properties of odontoclast differentiation
and function better. Importantly, the results from our preliminary gene
profiling experiments in cells cultured on dentin or bone indicate that the







294
Rody et al.
pattern of gene expression between odontoclast and osteoclasts indeed
are markedly different (Fig. 3).
The development of oral-fluid based diagnostic tests for root
resorption previously has been limited by the lack of a robust biomarker
panel. Therefore, the goal of the aforementioned studies is to use cutting
edge proteomic and genomic techniques to identify multiple markers that
are unique to dentin breakdown, which then will drive the interrogation
and, once the protein targets are identified, we will be able to move from
our unbiased approach to a knowledge-based approach in evaluating the
saliva, serum or GCF content in human subjects. This type of focused,
hypothesis-driven approach allows more powerful statistical analyses and
the capacity to discern differences between healthy and root resorption
fluid samples.
CONCLUSION
Osteoclast and odontoclast function are related closely to
physiological and pathological clinical Scenarios including craniofacial
abnormalities, tooth eruption and root resorption. Understanding the
complex mechanisms that control osteoclast/odontoclast development
and activation will provide insights in early detection and management
of clinical challenges. Although it is believed that odontoclasts possess
Common properties to osteoclasts, the regulatory mechanisms that
mediate tooth resorption may differ from osteoclastic bone resorption.
There are several dental abnormality scenarios that may be related to
clinically altered odontoclast development or function, including root
resorption. Therefore, there is a need to address this fundamental
question in cell biology in order to improve the diagnosis, prevention
and treatment of clinical conditions that are associated with abnormal
odontoclast activity. By harnessing our understanding of the proteomic/
genomic differences between osteoclasts and odontoclasts, clinical care
can be leveraged in three ways:
1. The development of fluid biomarkers for the early
diagnosis of altered odontoclast activity before the
damage can be visualized clinically or by a radiograph/
CBCT Scan.
2. The development of strategies to turn on/off
odontoclastogenesis activation pathways specifically
295
Biomarkers of Root Resorption
and hence, to provide therapeutics for inhibiting tooth
resorption.
3. The development of targeted therapies, which
would be able to interfere with odontoclast function
selectively with fewer side effects on bone and
periodontal ligament cells.
REFERENCES
Aebersold R, Mann M. Mass spectrometry-based proteomics. Nature
2003;422(6928):198-207.
Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NB, Hamid M. scFv
antibody: Principles and clinical application. Clin Dev Immunol 2012;
2012:980.250.
Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B, Corpodian
C, Barrera LM, Alansari S, Khoo E. Effect of micro-osteoperforations
on the rate of tooth movement. Am J Orthod Dentofacial Orthop
2013;144(5):639-648.
Amit G, Jps K, Pankaj B, Suchinder S, Parul B. Periodontally accelerated
osteogenic orthodontics (PAOO): A review. J Clin Exp Dent 2012;4(5):
e292-e296.
Baba O, Oin C, Brunn JC, Jones JE, Wygant JN, McIntyre BW, Butler WT.
Detection of dentin sialoprotein in rat periodontium. Eur J Oral Sci
2004;112(2):163–170.
Balducci L, Ramachandran A, Hao J, Narayanan K, Evans C, George A.
Biological markers for evaluation of root resorption. Arch Oral Biol
2007;52(3):203-208.
Buduneli N, Kinane DF. Host-derived diagnostic markers related to soft
tissue destruction and bone degradation in periodontitis. J Clin
Periodontol 2011;38(Suppl 11):85-105.
Butler WT, Bhown M, Brunn JC, D'Souza RN, Farach-Carson MC,
Happonen RP, Schrohenloher RE, Seyer JM, Somerman MJ, Foster RA.
Isolation, characterization and immunolocalization of a 53-kDal dentin
sialoprotein (DSP). Matrix 1992;12(5):343-351.
Carvalho-Lobato P, Garcia VJ, Kasem K, Ustrell-Torrent JM, Tallón-Walton
V, Manzanares-Céspedes MC. Tooth movement in Orthodontic treat-
296
Rody et al.
ment with low-level laser therapy: A systematic review of human and
animal studies. Photomed Laser Surg 2014;32(5):302-309.
Chen R, Kanzaki H, Chiba M, Nishimura M, Kanzaki R, Igarashi K.
Local osteoprotegerin gene transfer to periodontal tissue inhibits
lipopolysaccharide-induced alveolar bone resorption. J Periodontal
Res 2008;43(2):237-245.
Chen YJ, Hsieh MY, Chang MY, Chen HC, Jan MS, Maa MC, Leu TH. Eps8
protein facilitates phagocytosis by increasing TLR4-MyD88 protein
interaction in lipopolysaccharide-stimulated macrophages. J Biol
Chem 2012;287(22):18806-18819.
Corrado A, Neve A, Maruotti N, Cantatore FP. Bone effects of biologic
drugs in rheumatoid arthritis. Clin Dev Immunol 2013;2013:945945.
Darendeliler MA, Zea A, Shen G, Zoellner H. Effects of pulsed electromag-
netic field vibration on tooth movement induced by magnetic and me-
chanical forces: A preliminary study. Aust Dent J 2007;52(4):282-287.
Davies J, Riechmann L. Antibody VH domains as small recognition units.
Biotechnology (NY) 1995;13(5):475-479.
Fleissig Y, Reichenberg E, Redlich M, Zaks B, Deutsch O, Aframian DJ,
Palmon A. Comparative proteomic analysis of human oral fluids
according to gender and age. Oral Dis 2010;16(8):831-838.
George A, Evans CA. Detection of root resorption using dentin and bone
markers. Orthod Craniofac Res 2009;12(3):229-235.
Giannobile WV, Beikler T, Kinney JS, Ramseier CA, Morelli T, Wong DT.
Saliva as a diagnostic tool for periodontal disease: Current state and
future directions. Periodontol 2000 2009;50:52-64.
Giannopoulou C, Mombelli A, Tsinidou K, Vasqekis V, Kamma J. Detection
of gingival crevicular fluid cytokines in children and adolescents
with and without fixed orthodontic appliances. Acta Odontol Scand
2008;66(3):169-173.
Good DM, Coon JJ. Mass spectrometric analysis of body fluids for
biomarker discovery. Methods Mol Biol 2009;566:277–291.
Griffiths AD, Williams SC, Hartley O, Tomlinson IM, Waterhouse P, Crosby
WL, Kontermann RE, Jones PT, Low NM, Allison TJ, et al. Isolation of
297
Biomarkers of Root Resorption
high affinity human antibodies directly from large synthetic reper-
toires. EMBO J 1994;13(14):3245-3260.
Gupta G. Gingival crevicular fluid as a periodontal diagnostic indicator:
|. Host derived enzymes and tissue breakdown products. J Med Life
2012;5(4):390-397.
Gupta G. Gingival crevicular fluid as a periodontal diagnostic indicator:
ll. Inflammatory mediators, host-response modifiers and chair side
diagnostic aids. J Med Life 2013;6(1):7-13.
Hammarstrom L, Lindskog S. General morphological aspects of resorption
of teeth and alveolar bone. Int Endod J 1985;18(2):93-108.
Harokopakis-Hajishengallis E. Physiologic root resorption in primary
teeth: Molecular and histological events. J Oral Sci 2007;49(1):1-12.
Holt LJ, Herring C, Jespers LS, Woolven BP, Tomlinson IM. Domain
antibodies: Proteins for therapy. Trends Biotechnol 2003;21(11):484-
490.
Hoogeveen EJ, Jansma J, Ren Y. Surgically facilitated orthodontic treat-
ment: A systematic review. Am J Orthod Dentofacial Orthop 2014;145(4
Suppl):S51-S64.
Iwasaki LR, Chandler JR, Marx DB, Pandey JP, Nickel JC. IL-1 gene
polymorphisms, secretion in gingival crevicular fluid, and speed of
human orthodontic tooth movement. Orthod Craniofac Res 2009;12
(2):129-140.
Iwasaki LR, Crouch LD, Tutor A, Gibson S, Hukmani N, Marx DB, Nickel JC.
Tooth movement and cytokines in gingival crevicular fluid and whole
blood in growing and adult subjects. Am J Orthod Dentofacial Orthop
2005;128(4):483-491.
Jatania A, Shivalinga BM, Kiran J. Root resorption after orthodontic
treatment: A review. Int J Orthod Milwaukee 2012;23(2):45-49.
Kanzaki H, Chiba M, Arai K, Takahashi I, Haruyama N, Nishimura M, Mitani
H. Local RANKL gene transfer to the periodontal tissue accelerates
orthodontic tooth movement. Gene Ther 2006;13(8):678-685.
Kapila S, Conley RS, Harrell WE Jr. The current status of cone beam
computed tomography imaging in orthodontics. Dentomaxillofac
Radiol 2011;40(1):24-34.
298
Rody et al.
Kau CH, Kantarci A, Shaughnessy T, Vachiramon A, Santiwong P. de la
Fuente A, Skrenes D, Ma D, Brawn P. Photobiomodulation accelerates
orthodontic alignment in the early phase of treatment. Prog Orthod
2013;14:30.
Kereshanan S, Stephenson P, Waddington R. Identification of dentine
sialoprotein in gingival crevicular fluid during physiological root
resorption and orthodontic tooth movement. Eur J Orthod 2008;30
(3):307-314.
Kumar V, Logani A, Shah N. Dentine sialoprotein expression in gingival
crevicular fluid during trauma-induced root resorption. Int Endod J
2013;46(4):371-378.
Kunii R, Yamaguchi M, Tanimoto Y, Asano M, Yamada K, Goseki T, Kasai
K. Role of interleukin-6 in orthodontically induced inflammatory root
resorption in humans. Korean J Orthod 2013;43(6):294-301.
Lamster IB, Ahlo JK. Analysis of gingival crevicular fluid as applied to the
diagnosis of oral and systemic diseases. Ann NY Acad Sci 2007;1098:
216–229.
LaSfargues JJ, Saffar JL. Inhibition of prostanoid synthesis depresses
alveolar bone resorption but enhances root resorption in the rat. Anat
Rec 1993;237(4):458–465.
Lee YH, Nahm DS, Jung YK, Choi JY, Kim SG, Cho M, Kim MH, Chae CH, Kim
SG. Differential gene expression of periodontal ligament cells after
loading of static compressive force. J Periodontol 2007;78(3):446-452.
Lee YH, Wong DT. Saliva: An emerging biofluid for early detection of
diseases. Am J Dent 2009;22(4):241-248.
Liu O, Gibson MP, Sun H, Oin C. Dentin sialophosphoprotein (DSPP) plays
an essential role in the postnatal development and maintenance of
mouse mandibular condylar cartilage. J Histochem Cytochem 2013;
61(10):749–758.
Long H, Pyakurel U, Wang Y, Liao L, Zhou Y, Lai W. Interventions for
accelerating orthodontic tooth movement: A systematic review. Angle
Orthod 2013;83(1):164-171.
Mah J, Prasad N. Dentine phosphoproteins in gingival crevicular fluid
during root resorption. Eur J Orthod 2004;26(1):25-30.
299
Biomarkers of Root Resorption
Malathi N, Mythili S, Vasanthi HR. Salivary diagnostics: A brief review.
ISRN Dent 2014;2014:158786.
Marks JD, Hoogenboom HR, Bonnert TP, McCafferty J, Griffiths AD, Winter
G. By-passing immunization: Human antibodies from V-gene libraries
displayed on phage. J Mol Biol 1991;222(3):581-597.
Mathews DP, Kokich VG. Accelerating tooth movement: The case against
corticotomy-induced orthodontics. Am J Orthod Dentofacial Orthop
2013;144(1):5-13.
Mogi M, Otogoto J, Ota N, Togari A. Differential expression of RANKL
and osteoprotegerin in gingival crevicular fluid of patients with
periodontitis. J Dent Res 2004;83(2):166-169.
Nakano Y, Yamaguchi M., Fujita S, Asano M, Saito K, Kasai K. Expressions of
RANKL/RANK and M-CSF/c-fms in root resorption lacunae in rat molar
by heavy orthodontic force. Eur J Orthod 2011;33(4):335-343.
Ngo LH, Darby IB, Veith PD, Locke AG, Reynolds EC. Mass spectrometric
analysis of gingival crevicular fluid biomarkers can predict periodontal
disease progression. J Periodontal Res 2013;48(3):331-341.
Ngo LH, Veith PD, Chen YY, Chen D, Darby IB, Reynolds EC. Mass
Spectrometric analyses of peptides and proteins in human gingival
crevicular fluid. J Proteome Res 2010;9(4):1683-1693.
Nimeri G, Kau CH, Abou-Kheir NS, Corona R. Acceleration of tooth
movement during orthodontic treatment: A frontier in orthodontics.
Prog Orthod 2013;14:42.
Nishijima Y, Yamaguchi M, Kojima T, Aihara N, Nakajima R, Kasai K. Levels
of RANKL and OPG in gingival crevicular fluid during orthodontic
tooth movement and effect of compression force on releases from
periodontal ligament cells in vitro. Orthod Craniofac Res 2006;9(2):63-
70.
Nishimura M, Chiba M, Ohashi T, Sato M, Shimizu Y, Igarashi K, Mitani
H. Periodontal tissue activation by vibration: Intermittent stimulation
by resonance vibration accelerates experimental tooth movement in
rats. Am J Orthod Dentofacial Orthop 2008;133(4):572-583.
Owman-Moll P, Kurol J, Lundgren D. Repair of orthodontically induced
root resorption in adolescents. Angle Orthod 1995;65(6):403-408.
300
Rody et al.
Prasad M, Butler WT, Oin C. Dentin sialophosphoprotein in biomineraliza-
tion. Connect Tissue Res 2010;51(5):404-417.
Prasad M, Zhu O, Sun Y, Wang X, Kulkarni A, Boskey A, Feng JO, Oin C.
Expression of dentin sialophosphoprotein in non-mineralized tissues.
J Histochem Cytochem 2011;59(11):1009-1021.
Oin C, Brunn JC, Cadena E, Ridall A, Tsujigiwa H, Nagatsuka H, Nagai N,
Butler WT. The expression of dentin sialophosphoprotein gene in
bone. J Dent Res 2002;81(6):392–394.
Reiter Y, Schuck P. Boyd LF, Plaksin D. An antibody single-domain phage
display library of a native heavy chain variable region: Isolation of
functional single-domain VH molecules with a unique interface. J Mol
Biol 1999;290(3):685-698.
Ren Y, Hazemeijer H, de Haan B, Ou N, de Vos P. Cytokine profiles in
crevicular fluid during orthodontic tooth movement of short and long
durations. J Periodontol 2007;78(3):453-458.
Ren Y, Vissink A. Cytokines in crevicular fluid and orthodontic tooth
movement. Eur J Oral Sci 2008;116(2):89-97.
Rody WJ Jr, Holliday LS, McHugh KP, Wallet SM, Spicer V, Krokhin
O. Mass spectrometry analysis of gingival crevicular fluid in the
presence of external root resorption. Am J Orthod Dentofacial Orthop
2014a;145(6):787-798.
Rody WJ Jr, Iwasaki LR, Krokhin O. Oral fluid-based diagnostics and
applications in orthodontics. In: McNamara JA Jr, ed. Taking
Advantage of Emerging Technologies in Clinical Practice. Monograph
49, Craniofacial Growth Series, Center for Human Growth and
Development, The University of Michigan, Ann Arbor, 2012:223-261.
Rody WJ Jr, King GJ, Gu G. Osteoclast recruitment to sites of compression
in orthodontic tooth movement. Am J Orthod Dentofacial Orthop
2001;120(5):477-489.
Rody WJJr, Wijegunasinghe M, Wiltshire WA, Dufault B. Differences in the
gingival crevicular fluid composition between adults and adolescents
undergoing orthodontic treatment. Angle Orthod 2014b;84(1):120-
126.
Sen CK. The general case for redox control of wound repair. Wound Repair
Regen 2003;11(6):431-438.
301
Biomarkers of Root Resorption
Sha H, Bai Y, Li S, Wang X, Yin Y. Comparison between electrochemical
ELISA and spectrophotometric ELISA for the detection of dentine
sialophosphoprotein for root resorption. Am J Orthod Dentofacial
Orthop 2014;145(1):36-40.
Showkatbakhsh R, Jamilian A, Showkatbakhsh M. The effect of pulsed
electromagnetic fields on the acceleration of tooth movement. World
J Orthod 2010;11(4):e52-e56.
Sousa MV, Scanavini MA, Sannomiya EK, Velasco LG, Angelieri F. Influence
of low-level laser on the speed of orthodontic movement. Photomed
Laser Surg 2011(3);29:191-196.
Suzuki M, Ishihara Y, Kamiya Y, Koide M, Fuma D, Fujita S, Matsumara Y,
Suga T, Kamei H, Hoguchi T. Soluble interleukin-1 receptor type II levels
in gingival crevicular fluid in aggressive and chronic periodontitis. J
Periodontol 2008;79(3):495-500.
Teixeira CC, Khoo E, Tran J, Chartres I, Liu Y, Thant LM, Khabensky I, Gart
LP, Cisneros G, Alikhani M. Cytokine expression and accelerated tooth
movement. J Dent Res 2010;89(10):1135-1141.
Tyrovola JB, Perrea D, Halazonetis DJ, Dontas I, Vlachos IS, Makou
M. Relation of soluble RANKL and osteoprotegerin levels in blood
and gingival crevicular fluid to the degree of root resorption after
orthodontic tooth movement. J Oral Sci 2010;52(2):299-311.
Tyrovola JB, Spyropoulos MN, Makou M, Perrea D. Root resorption and
the OPG/RANKL/RANK system: A mini review. J Oral Sci 2008;50(4):
367–376.
Wang L, Liu X, Zhu X, Wang W, Liu C, Cui H, Sun M, Gao B. Generation of
single-domain antibody multimers with three different self-associating
peptides. Protein Eng Des Sel 2013;26(6):417-423.
Wang Z, McCauley LK. Osteoclasts and odontoclasts: Signaling pathways
to development and disease. Oral Dis 2011;17(2):129-142.
Wilcko W, Wilcko MT. Accelerating tooth movement: The case for
corticotomy-induced orthodontics. Am J Orthod Dentofacial Orthop
2013;144(1):4-12.
Yamaguchi M, Aihara N, Kojima T, Kasai K. RANKL increase in Com-
pressed periodontal ligament cells from root resorption. J Dent Res
2006;85 (8):751–756.
302
Rody et al.
Yan W, Apweiler R, Balgley BM, Boontheung P. Bundy JL, Cargile BJ, Cole S,
Fang X, Gonzalez-Begne M, Griffin TJ, Hagen F, Hu S, Wolinsky LE, Lee
CS, Malamud D, Melvin JE, Menon R, Mueller M, Ojao R, Rhodus NL,
Sevinsky JR, States D, Stephenson JL, Than S, Yates JR, Yu W, Xie H, Xie
Y, Omenn GS, Loo JA, Wong DT. Systematic comparison of the human
saliva and plasma proteomes. Proteomics Clin Appl 2009; 3(1):116-
134.
Zhou D, Hughes B, King GJ. Histomorphometric and biochemical study
of osteoclasts at orthodontic compression sites in the rat during
indomethacin inhibition. Arch Oral Biol 1997;42(10-11):717–726.
Zuo ZG, Hu M, Jiang H, Tian L. [Relationship between orthodontics root
resorption following experimental tooth movement and the level
of dentin sialophosphoprotein and dentin sialoprotein in gingival
crevicular fluid]. Hua Xi Kou Ojang Yi Xue Za Zhi 2011;3:294-298.
303
304
COMPUTATIONAL CHEMISTRY:
A NEW FRONTIER IN ORTHODONTICS
Calogero Dolce and L. Shannon Holliday
ABSTRACT
The ability to augment orthodontic tooth movement by manipulating the
underlying biology is at the cutting edge of the practice of orthodontics. Methods
for speeding tooth movement now in use in the clinic include corticotomy plus
decortification (Wilckodontics), drilling small holes in the alveolar bone (device
marketed by Propel) and using resonant micropulses/vibration (device marketed
by Acceledent). Each is thought to work, at least in part, by stimulating cells in
the bone micro-environment to produce regulatory molecules that increase the
natural response to mechanical force and trigger-increased osteoclastic bone
resorption. Because orthodontic tooth movement requires bone resorption,
it should be possible to achieve rapid tooth movement by directly supplying
stimulators of osteoclastic bone resorption. Alternatively, inhibiting pathways
that promote osteoclast activity could immobilize teeth to use for anchorage. In
animal models, speed of tooth movement has been increased or slowed using
Small molecule therapeutics or biologics, but safety concerns and expense thus
far have prevented translation of these approaches to the clinic. During the past
decade, the convergence of advances in molecular biology (including enhanced
knowledge of processes involved in bone remodeling and orthodontic tooth
movement) and computer technology led to the emergence of computational
chemistry, which allows for new, rational strategies for drug development.
Computational chemistry may prove the ideal tool for identifying specific agents
that are useful for augmenting orthodontics. Here, we will provide a brief
background of computational chemistry and its use in drug discovery. We will
describe the general process of using a computational chemistry approach and
use our own work to illustrate how such a project can develop. Although this
field is in its infancy, therapeutic agents identified by computational chemistry
could revolutionize the practice of orthodontics during the 21st century.
KEY WORDS: bone remodeling, osteoclast, osteoblast, anti-resorptive, virtual
SCreen
305
Computational Chemistry
BIOLOGICAL STRATEGIES FOR SPEEDING AND SLOWING
ORTHODONTIC TOOTH MOVEMENT
Orthodontics has improved smiles and quality of life of countless
patients for more than 2,000 years (Phillippe and Guedon, 2007). Both
Hippocrates (Corpus Hipperaticum) and Aristotle (De Partibus Animalium)
pondered the problem of crowding and misaligned teeth. A mummified
corpse from a Roman tomb in Egypt was found with metal and wires
on the teeth, indicative of an attempt at orthodontic tooth movement
(Phulari, 2013). By the 18th century, orthodontic visionaries like Pierre
Fauchard and Ettienne Bourdet were describing and putting into
practice the rudiments of modern orthodontics (Kowitz and Loevy, 1993;
Vatteone, 1994). During the 19th and 20th centuries, developments in
orthodontic theory and practice, driven in good measure by Angle and
his students, led to the current practice of orthodontics (Peck et al., 1997;
Peck, 2006, 2009a,b). However, the time required for a tooth to move
in response to mechanical force has not changed from the first Greek
or Roman proto-orthodontists to the modern orthodontist, despite
advances in design of orthodontic appliances. For that reason, a simple
orthodontic case always has required one to two years of treatment.
This is a source of frustration for patients and their orthodontists. While
today's multicolored orthodontic grill has become a status symbol for
middle school-aged children, the large increase in adult patients, who
often have specific deadlines for completion of treatment, has increased
the desirability of rapid orthodontics.
It first was reported in the 1950s that corticotomies of bone could
speed orthodontic tooth movement (Kole, 1959). More recently, simple
corticotomy has evolved into a more complex procedure developed by
Wilcko and colleagues (2001) and the Wilcko brothers (2013) involving
corticotomies and decortifications. This surgical adjunct to orthodontic
appliances is called “Wilckodontics.” Additional and more recent
adjunctive approaches include drilling shallow holes in the alveolar
bone (Propel) or vibrating the teeth with 0.25 N/30 Hz micropulses
(Acceledent) to enhance tooth movement. All of these procedures are
thought to trigger the release of signaling molecules that augment the
effect of orthodontic mechanical force on bone resorption, which is the
limiting factor in tooth movement (Fig. 1). There is evidence for this
chain of events in animal studies (Teixeira et al., 2010; Alikhani et al., 2012,
306
Dolce and Holliday
A. E. C
Figure 1. Three marketed techniques for “rapid” orthodontic tooth movement
Currently in use in the clinic. A: Wilckodontics in which corticotomies and
decortications increase the speed of tooth movement. B: Propel provides a
tool to drill small holes in the alveolar bone which increases the rate of tooth
movement. C. Acceledent utilizes daily stimulation (20 minutes) with vibration
to speed tooth movement. All are thought to function by stimulating local pro-
resorptive signaling pathways that increases osteoclastic bone resorption.
2013). Yet, despite many anecdotal accounts, there still is surprisingly
little support for the efficacy of these treatments for enhancing tooth
movement by randomized clinical trials.
USE OF BIOLOGICS AND DRUGS TO ALTER ORTHODONTIC TOOTH
MOVEMENT IN ANIMAL MODELS
Perhaps the most straightforward approach to speeding
tooth movement is by the local introduction of biologic stimulators of
Osteoclasts, such as Receptor Activator of Nuclear Factor Kappa B-Ligand
(RANKL). Osteoclast formation and activity depend on the presence of
RANKL (Hofbauer and Heufelder, 2001). This molecule, which is expressed
On the surface of osteoblasts and immune T-cells, interacts with RANK,
a transmembrane protein expressed on the surface of osteoclasts and
Osteoclast precursor cells (Gallagher and Sai, 2010). Increased RANKL
Stimulation of RANK triggers more bone resorption (Teitelbaum, 2007;
Fig. 2). An approach involving local introduction of RANKL would be
expected to lead to more bone resorption and therefore, more rapid tooth
movement. This idea was investigated in a mouse model of orthodontic
tooth movement by using viral-mediated gene therapy to deliver a
Soluble form of RANKL to the local micro-environment of alveolar bone
and teeth. As predicted, delivery of RANKL by this method enhanced
the rate of tooth movement (Kanzaki et al., 2006). However, it is unlikely
that such a gene therapy approach would be advanced to the clinic in
the near future. One concern is the fact that RANKL also is involved in

307
Computational Chemistry
RANKL OPG
Bone Bone
A C
Figure 2. Balance between Receptor Activator of Nuclear Factor Kappa B-Ligand
(RANKL) and ssteoprotegerin (OPG) is an important determinant of the amount
of bone resorption that occurs in a local micro-environment. Bone resorption
by osteoclasts and bone formation by osteoblasts normally are balanced to
maintain bone mass during remodeling (A). RANKL is the primary stimulator
of bone resorption while osteoprotegerin (OPG) is a competitive inhibitor of
RANKL. An excess of RANKL leads to increased levels of osteoclast activity (B).
Excess OPG inhibits bone resorption (C).
regulation in the immune system (Kong et al., 1999; Takahashi et al.,
1999). Enhanced production of RANKL could alter immune responses
and lead to unforeseen consequences. There also are dangers inherent
to gene therapy delivery methods including that the virus may spread,
trigger an immune response or cause transformation of healthy cells into
cancerous cells.
Inhibiting orthodontic tooth movement also has been
accomplished in animal models of tooth movement using various agents,
including bisphosphonates alendronate (Igarashi et al., 1994; Karras et
al., 2009), risedronate (Adachi et al., 1994) and bis-enoxacin (Toro et al.,
2013) and osteoprotegerin, the natural endogenous competitive inhibitor
of RANKL (Fig. 2). Osteoprotegerin has been injected and delivered
directly by gene therapy (Kanzaki et al., 2004; Dunn et al., 2007; Hudson
et al., 2012). In preventing tooth movement, an important concern is that
anti-resorptive use at high doses is associated with an increased risk of
anti-resorptive-associated oral osteonecrosis of the jaw (ARONJ; McLeod
et al., 2012; Carlson and Schlott, 2014). Anti-resorptives associated


308
Dolce and Holliday
with the condition include nitrogen-containing bisphosphonates and
the RANKL-inhibiting humanized monoclonal antibody Denosumab
(marketed as Prolia, Xgeva), which inhibits RANKL in a manner similar to
osteoprotegerin.
In summary, studies show that it is possible to deliver therapeutic
agents to speed or slow orthodontic tooth movement, but current thera-
peutic agents may not suitable for easy translation to the orthodontic
clinic. Biologics or gene therapy reagents may not be safe, specific or suf-
ficiently affordable for translation in the near future. Better, safer and
more specific therapeutic agents are required. Small molecule therapeu-
tics may prove to be more practical, but new drugs must be identified in
order for this to work.
COMPUTATIONAL CHEMISTRY:
A NEW STRATEGY FOR DRUG DEVELOPMENT
Traditional drug discovery involves developing a simple assay that
can be performed in a high throughput mode for the testing of thousands
to hundreds of thousands of candidate molecules. This process is both
expensive and time consuming. Recent technological developments allow
for a less expensive approach (computational chemistry) that depends
on advances in computer technology and an increased understanding
of biology and protein structure (van der Kamp et al., 2008; de Jong et
al., 2010; Brunk et al., 2011; Ortega et al., 2012; Friedman et al., 2013;
Karaman et al., 2013; Sheng and Zhang, 2013).
Computational chemistry is the branch of chemistry in which
computer simulations are used to solve chemical problems (Bures and
Martin, 1998). Such predictions are intensive computationally; however,
Current supercomputers, which are capable of calculations in the
PetaFLOP range (i.e., 10° or one quadrillion floating point operations per
second), provide the computing power required to perform such intensive
calculations (Yoo and Yin, 2012; Hagiwara et al., 2013). If the atomic level
Structure of a protein is known, it now is possible to use computational
chemistry techniques reliably to reduce the pool of candidate interacting
molecules from hundreds of thousands to hundreds or less (Dias and de
Azevado, 2008; Fukunishi, 2009; Ostrov et al., 2009; Biesiada et al., 2011;
Pons et al., 2012; Chowdhury et al., 2013).
309
Computational Chemistry
The Search for a Selective Small Molecule Inhibitor of Osteoclastic Bone
Resorption
Our group has had a long history of seeking biological approaches
to manipulate tooth movement. We initially tested various known inhibi-
tors of osteoclasts in rats, delivered locally using ELVAX, a bioinert slow-
release delivery agent (Silberstein and Daniel, 1982; Smith et al., 1995;
Bix and Clark, 1997). We found that integrin and matrix metalloprotein-
ase inhibitors could be used to inhibit tooth movement (Dolce et al.,
2003; Holliday et al., 2003). These agents worked best from the selection
of known osteoclast inhibitors that we tested. Unfortunately, integrin and
metalloproteinase inhibitors are only modestly selective for osteoclasts,
even when delivered locally. '
Much work in our research group has focused on the finding that
the vacuolar Hº-ATPase (V-ATPase) is recovered bound to filamentous
actin in osteoclasts, but not in other cell types (Lee et al., 1999). Because
this interaction occurs selectively in osteoclasts, it represents a potential
osteoclast-specific target for inhibiting bone resorption. We found that the
interaction is mediated by an actin-binding site located in the B-subunit
of V-ATPase (Holliday et al., 2000). By 2007, when our computational
chemistry project was initiated, we had shown that: 1) the V-ATPase-
actin filament interaction is selective for osteoclasts; 2) the interaction
is crucial for the transport of V-ATPase to the ruffled plasma membrane
of osteoclasts, which is vital for bone resorption (Zuo et al., 2006); and
3) the precise site of the interaction was within amino acids 29-73 in the
B2-subunit (the B-subunit isoform found in osteoclasts) of the V-ATPase
(Chen et al., 2004). We also generated atomic level models of the actin-
binding site based on crystal structures of the related molecule, ATP
synthase (Ostrov et al., 2009). In addition, we optimized a simple in vitro
assay to test for binding (or inhibition of binding) between recombinant
B2-subunit and actin microfilaments, and a reliable in vitro assays for
osteoclast differentiation and bone resorption.
V-ATPases
Acidification of intracellular compartments is required for recep-
tor-mediated endocytosis, protein degradation, processing of signaling
molecules and other cellular housekeeping functions (Nishi and ForgaC,
310
Dolce and Holliday
2002; Hinton et al., 2009; Saroussi and Nelson, 2009). V-ATPases are
large multi-subunit enzymes that are responsible for acidification. While
most subunits are ubiquitous, several have isoforms that are restricted
to specific cell types (Fig. 3). V-ATPases normally are located in intracel-
lular membranous organelles of the endocytic, exocytic and phagocytic
pathways. They also localize to the plasma membrane in some cell types
including renal intercalated cells (Wagner et al., 2004), osteoclasts (Gluck
et al., 1998) and metastatic cancer cells (Hinton et al., 2009), where they
carry out cell-type specific functions.
Vacuolar Hº-ATPase Isoforms
ADP-Pi - B1 - kidney, epididymis
- B2- ubiquitous, osteoclasts
C1 – ubiquitous
C2a – lung
C2b-kidney
- V1.
E1 – acrosome
E2– ubiquitous
G1 – ubiquitous
G2-synaptic vesicles
G3-kidney
a1 – endomembranes
XXX. F C. Q. C.
a2 – endomembranes
V0 a3– osteoclasts, pancreatic beta cells
--- a4-kidney, epididymis
d1 – ubiquitous
Lumen/ d2 – kidney, osteoclasts, dendritic
Extracellular H* cells
Figure 3. Vacuolar Hº-ATPase (V-ATPase) is an important housekeeping enzyme
that plays vital specialized roles in specific types of cells. The V-ATPase is a rotary
motor powered by ATP hydrolysis. Protons are pumped across a membrane driven
by the rotation of the inner stalk subunit D and the hexagon of Cand C" sub-units.
As noted, some of the subunits are present both as ubiquitous isoforms that are
present in housekeeping enzymes and cell type-specific isoforms that are part
of V-ATPases with specialized functions. For example, a1 and a2 are present in
housekeeping enzymes, while as is present in osteoclasts and pancreatic beta
Cells, and a 4 is present in the kidney and epididymis. Osteoclasts express a1, a2
and a 3, but only the a2-containing V-ATPases are involved in bone resorption
directly.


311
Computational Chemistry
Subcellular Localization of V-ATPase in Resorbing Osteoclasts
Osteoclasts are specialized cells that resorb mineralized tissue in a
highly regulated manner (Teitelbaum, 2007). Contact with bone activates
osteoclast to resorb bone. Upon contact, osteoclasts polarize relative to
the bone and form a specialized resorptive structure called the ruffled
plasma membrane (ruffled membrane, ruffled border), which is encircled
by an equally unusual cytoskeletal structure called the actin ring (Fig. 4;
King and Holtrop, 1975; Blair et al., 1989).
The actin ring is formed by distinct substructures called
podosomes (King and Holtrop, 1975; Saltel et al., 2004). These also
exist in other cells that migrate through tissue (Spinardi and Marchisio,
2006; Saltel et al., 2008) including metastatic tumor cells (Yamaguchi and
Oikawa, 2010). V-ATPases acidify the extracellular space between the
ruffled border and bone surface (Baron et al., 1985). The low pH dissolves
the bone mineral, which allows the acid cysteine proteinase, cathepsin
K, to digest the organic components of the bone (Bromme et al., 1996;
Drake et al., 1996).
From a medicinal chemist perspective, the fact that V-ATPases
in osteoclasts that are involved in bone resorption must be trafficked
to the plasma membrane, while V-ATPases in most other cells types are
excluded from the plasma membrane makes this enzyme a target for drug
development. Our findings (described below) that transport of V-ATPases
to the plasma membrane requires binding to actin microfilaments identify
that interaction as a potential target for osteoclast-specific anti-resorptive
drug development.
CHARACTERIZATION OF V-ATPASE BINDING TO
MICROFILAMENTS THROUGH THE B-SUBUNIT
We identified a direct interaction between V-ATPases and micro-
filaments (Lee et al., 1999) and showed that the B-subunits of V-ATPase
bind tightly to actin (Fig. 5; Holliday et al., 2000). The ability of B-subunits
to bind actin has been demonstrated in mammals, yeast, insects (Man-
duca) and plants (Vitavska et al., 2003; Zuo et al., 2008; Ma et al., 2012).
Although this interaction occurs preferentially in osteoclasts as part of
the process by which V-ATPases reach the ruffled plasma membrane (Zuo
et al., 2006), the actin-binding site likely also is used for other purposes,
such as in response to particular types of stress (Zuo et al., 2008).
312
Dolce and Holliday
Figure 4. Side view of a resorbing osteoclast. Resorbing osteoclasts have a
Specialized subdomain of the plasma membrane called the ruffled membrane,
which is packed with V-ATPases. Actin filaments form the actin-ring structure
that delineates the ruffled membrane. V-ATPases pump protons into the
extracellular resorption compartment, thereby lowering the pH on the surface
of bone. This solubilizes bone mineral and provides a micro-environment where
acid proteinases secreted by the osteoclast can degrade the organic matrix of
the bone.
. . . . . . . . .
|
-
Figure 5. The V-ATPases that enter the ruffled membrane of osteoclasts are
found bound to actin filaments in inactive osteoclasts. This binding is mediated
by actin-binding sites in the B-subunit. This interaction is vital for osteoclasts
ability to resorb bone. Actin filaments illustrated as intracellular blue ovals.





313
Computational Chemistry
To test the role of the actin-binding activity of the V-ATPase
B-subunit in osteoclasts, we introduced wild type B-subunit, or B-subunit
lacking actin-binding activity into cells using adeno-associated virus (Zuo
et al., 2006). We found that the wild type, but not the mutant B-subunit,
was transported to the ruffled plasma membrane (Zuo et al., 2006).
These results suggested that the actin-binding activity of B-subunit is
necessary for V-ATPases to function in osteoclasts. Because localization
of V-ATPase to the ruffled membrane of Osteoclasts is essential for bone
resorption, an inhibitor of the interaction between the B2-subunit and
microfilaments would be expected to inhibit bone resorption (Fig. 6).
INHIBITION OF THE BINDING INTERACTION BETWEEN
V-ATPASE AND MICROFILAMENTS AS A MECHANISM
FOR REGULATING OSTEOCLASTS
To Screen for Small molecule inhibitors of the B2-microfilament
interaction, we made use of a virtual, high confidence atomic-level model
of the actin-binding domain of V-ATPase subunit B2 (Ostrov et al., 2009).
Each of approximately 300,000 small molecules in the “plated set” at the
National Cancer Center Developmental Therapeutics Program repository
of small molecules were positioned in the selected structural pockets of
the B2 structural model in approximately 2,000 different orientations by
the computer program DOCKV6.1.0 (Perola et al., 2004). We identified the
40 small molecules with the highest score and obtained them from the
National Cancer Center.
An actin filament-pelleting assay was used to determine
whether 100 puM of each test molecule could block interaction between
recombinant subunit B2 and rabbit muscle actin filaments (Ostrov et al.,
2009). Two tested molecules inhibited osteoclast formation and activity
with an IC, of approximately 10 pm, without affecting viability of the
cells. Especially important, enoxacin, one of the positive test molecules,
did not affect osteoblast growth and survival, or the ability of osteoblasts
to mineralize (Ostrov et al., 2009).
Enoxacin is a second generation fluoroquinolone antibiotic (Hen-
wood and Monk, 1988). It was withdrawn voluntarily from the market
in the United States because of adverse effects including insomnia (Ra-
falsky et al., 2006), but is still in use in much of the rest of the world
as an antibiotic. For us, this test molecule held two large advantages. First,
314
Dolce and Holliday
Figure 6. A small molecule inhibitor of the V-ATPase-actin filament
interaction could prevent the transport of V-ATPases to the ruffled
membrane and prevent bone resorption. In practice, it also blocks
actin ring formation.
While side effects have been described in humans, they are relatively
rare and mild. Through long clinical usage, enoxacin has proven to be a
relatively safe drug. Second, unlike the other positive test compound,
enoxacin could be obtained in large quantities for modest prices, making
detailed in vitro and in vivo studies possible.
ENOXACIN AND BIS-ENOXACIN: NOVEL ANTI-RESORPTIVES
We initially envisioned enoxacin as a novel therapeutic agent
for the treatment of osteoporosis. However, initial studies did not show
Significant reduction of bone loss in a rat model for post-menopausal
Osteoporosis. We suspected that insufficient enoxacin reached the
bone micro-environment to affect bone loss. To target enoxacin to the
bone micro-environment, a bisphosphonate-ester of enoxacin, which
previously had been described as a tool for delivering enoxacin and other
fluoroquinolone antibiotics to bone to treat osteomyelitis, was made

315
Computational Chemistry
(Herczegh et al., 2002; Tanaka et al., 2008; Toro et al., 2013; Rivera et
al., 2014). We found that bis-enoxacin and enoxacin have similar anti-
osteoclastogenic and anti-resorptive properties in vitro (Toro et al., 2013).
However, bis-enoxacin, like other bisphosphonates, binds to and quickly
becomes associated with bone when introduced into an animal.
Bis-enoxacin was tested for its ability to block orthodontic tooth
movement in a rat model. Because bis-enoxacin acts by a different
mechanism than the bisphosphonates currently used in the clinic, we
reasoned that there is a chance that it will not provoke oral osteonecrosis
and, therefore, may be safe for use in orthodontics. In comparison with
alendronate, we found that bis-enoxacin was similar in its ability to block
tooth movement (Toro et al., 2013).
We next tested bis-enoxacin for its ability to reduce alveolar bone
loss associated with periodontitis. In a rat model of periodontal disease,
bis-enoxacin was more effective than either alendronate or doxycycline
at preventing alveolar bone loss (Rivera et al., 2014). Further work will
be required to determine whether the positive effects on periodontal
disease were due to its anti-resorptive activity, its antibiotic activity or
another activity. In any case, bis-enoxacin proved to be effective.
Very recently, Kerong Dai and colleagues reported that enoxacin
is effective at blocking bone resorption associated with titanium particles
(Liu et al., 2014). This group also confirmed many of our previous findings
regarding the efficacy of enoxacin for inhibiting osteoclasts. In addition,
they reported that enoxacin preferentially suppressed the JNK signaling
pathway, which may be downstream of V-ATPase in a signaling pathway
(Petzoldt et al., 2013).
Enoxacin and Cancer
Our work identified enoxacin as an inhibitor of B-subunit-
microfilament binding. Work by others identified enoxacin as a stimulator
of RNA interference and microRNA activity (Shan et al., 2008a,b). Esteller's
group, which hypothesizes that the pathology of many types of cancer
is due to suppressed microRNA activity (Lujambio and Esteller, 2009;
Davolos and Esteller, 2010; Melo and Esteller, 2011), tested enoxacin
for the treatment of Colorectal cancer due to its microRNA stimulat-
316
Dolce and Holliday
ing activity. They found that enoxacin effectively reduced the growth and
metastasis of human colorectal cancers in a xenobiotic mouse model (Melo
et al., 2011). They attributed the effects to stimulation of microRNAs. It is
not known if microRNA stimulation contributes to the effects of enoxacin
or bis-enoxacin on bone, or if blocking V-ATPase-microfilament binding
Contributes to inhibition of cancer.
Enoxacin: New Roles for an Old Drug?
Enoxacin and bis-enoxacin have been shown to act as anti-
resorptive and anti-tumor agents in animal models. At least three
mechanisms have emerged that might explain their effects: the ability
to block interaction between V-ATPase and microfilaments, the ability to
stimulate microRNAs and their ability to inhibit the JNK signaling pathway.
Further studies will be required to confirm the molecular mechanisms
responsible for their therapeutic activities.
OTHER COMPUTATIONAL CHEMISTRY TARGETS
FOR USE IN ORTHODONTICS
Pharmacologic inhibitors of bone resorption may be useful
in orthodontics by allowing teeth to be fixed in place so that they can
be used for anchorage. However, the “killer application” would be to
develop small molecules that enhance osteoclast activity to speed tooth
movement and shorten treatment time. One promising computational
chemistry approach to enhance bone resorption is to identify small
molecules that bind osteoprotegerin and inhibit the interaction between
RANKL and osteoprotegerin (Fig. 7). Osteoprotegerin regulates osteoclast
activity competitively by binding RANKL and inhibiting binding between
RANKL and RANK. A small molecule that competitively inhibited the
interaction between osteoprotegerin and RANKL would be expected to
stimulate bone resorption. The crystal structure of RANKL in complex with
osteoprotegerin was published recently. This structure provides precise
information regarding which interaction pockets on osteoprotegerin to
target (Luan et al., 2012). Candidate small molecules could be tested
on calcitriol-stimulated mouse bone marrow cell in vitro culture system
to determine whether they promote osteoclast formation, because
this mixed cell culture system is regulated by osteoprotegerin-RANKL
interactions.
317
Computational Chemistry
RANKL OPG RANKL opg (...)
Binding of OPG
inhibitor reduces
OPG pool and
allows increased
bone resorption
Figure 7. A possible pharmacological approach to rapid orthodontics would be
to introduce locally a small molecule that binds OPG and blocks its ability to
bind RANKL. This would increase the effective amount of RANKL available for
stimulating osteoclasts activity and tooth movement.
Inhibitors of the RANKL-osteoprotegerin interaction would have
to be delivered to the micro-environment for Orthodontic use. It is pos-
sible that such a delivery system (e.g., using ELVAX) would be less invasive
and more effective than the current physical approaches (i.e., Wilckodon-
tics, Propel, Acceledent) used to stimulate the speed of tooth movement.
FUTURE PERSPECTIVE
Orthodontics commonly is thought of as a field based upon
using cutting edge materials and mechanical appliances, not biological
techniques. Modern orthodontics provides safe and effective movement
of teeth, which benefits millions of people every year. New approaches to
improve orthodontics, particularly those that use drugs or biologics, must
be very specific, very effective and very safe. There are few parents who
would choose to increase the risk of deleterious side effects even slightly
to reduce treatment time for their children. Advances in understanding
of the biology underlying tooth movement, including involved signaling
pathways, protein-protein interactions and atomic level structures,
coupled with emerging and improving computational chemistry, makes it
plausible that the ability to identify safe and precise molecules required
to manipulate tooth movement may be available in the near future.


3.18
Dolce and Holliday
Moreover, pharmacologic tools that are capable of manipulating tooth
movement inevitably will have other uses in the treatment of bone
pathologies. For the orthodontic researcher, the current times are an
exciting opportunity to advance both the practice of orthodontics and of
medicine in general, using tools at the leading edge of science.
REFERENCES
Adachi H, Igarashi K, Mitani H, Shinoda H. Effects of topical administration
of a bisphosphonate (risidronate) on orthodontic tooth movement in
rats. J Dent Res 1994;73(8):1478-1486.
Alikhani M, Khoo E, Alyami B, Raptis M, Salgueiro JM, Oliveira SM, Boskey
A, Teixeira CC. Osteogenic effect of high-frequency acceleration on
alveolar bone. J Dent Res 2012;91(4):413-419.
Alikhani M, Raptis M, Zoldan B, Sangsuwon C, Lee YB, Alyami B,
Corpodian C, Barrera LM, Alansari S, Khoo E, Teixeira C. Effect of
micro-osteoperforations on the rate of tooth movement. Am J Orthod
Dentofacial Orthop 2013;144(5):639-648.
Baron R, Neff L, Louvard D, Courtoy PJ. Cell-mediated extracellular
acidification and bone resorption: Evidence for a low pH in resorbing
lacunae and localization of a 100-kD lysosomal membrane protein at
the osteoclast ruffled border. J Cell Biol 1985;101(6):2210-2222.
Biesiada J, Porollo A, Velayutham P. Kouril M, Meller J. Survey of public
domain software for docking simulations and virtual screening. Hum
Genomics 2011;5(5):497-505.
Bix GJ, Clark GD. Elvax as a slow-release delivery agent for a platelet-
activating factor receptor agonist and antagonist. J Neurosci Methods
1997;77(1):67-74.
Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption
by a polarized vacuolar proton pump. Science 1989;245(4920):855-
857.
Bromme D, Okamoto K, Wang BB, Biroc S. Human cathepsin O2, a matrix
protein-degrading cysteine protease expressed in osteoclasts: Func-
tional expression of human cathepsin O2 in Spodoptera frugiperda and
characterization of the enzyme. J Biol Chem 1996;271(4):2126-2132.
319
Computational Chemistry
Brunk E, Ashari N, Athri P. Campomanes P. de Carvalho FF, Curchod BF,
Diamantis P. Doemer M, Garrec J, Laktionov A, Micciarelli M, Neri M,
Palermo G, Penfold TJ, Vanni S, Tavernelli I, Rothlisberger U. Pushing
the frontiers of first-principles based computer simulations of chemical
and biological systems. Chimia (Aarau) 2011;65(9):667-671.
Bures MG, Martin YC. Computational methods in molecular diversity and
combinatorial chemistry. Curr Opin Chem Biol 1998;2(3):376-380.
Carlson ER, Schlott BJ. Anti-resorptive osteonecrosis of the jaws: Facts
forgotten, questions answered, lessons learned. Oral Maxillofac Surg
Clin North Am 2014;26(2):171-191.
Chen SH, Bubb MR, Yarmola EG, Zuo J, Jiang J, Lee BS, Lu M, Gluck SL,
Hurst IR, Holliday LS. Vacuolar H+-ATPase binding to microfilaments:
Regulation in response to phosphatidylinositol 3-kinase activity and
detained characterization of the actin-binding site in subunit B. J. Biol
Chem 2004;279(9):7988-7998.
Chowdhury R, Rasheed M, Keidel D, Moussalem M, Olson A, Sanner M,
Bajaj C. Protein-protein docking with F(2) Dock 2.0 and GB-rerank.
PLoS One 2013;8(3):e51307.
Davalos V, Esteller M. MicroRNAs and cancer epigenetics: A macrorevolu-
tion. Curr Opin Oncol 2010;22(1):35-45.
de Jong WA, Bylaska E, Govind N, Janssen CL, Kowalski K, Muller T, Nielsen
IM, van Dam HJ, Veryazov V, Lindh R. Utilizing high performance
computing for chemistry: Parallel computational chemistry. Phys
Chem Chem Phys 2010;12(26):6896–6920.
Dias R, de Azevado WFJr. Molecular docking algorithms. Curr Drug Targets
2008;9(12):1040-1047.
Dolce C, Vakani A, Archer L, Morris-Wiman JA, Holliday LS. Effects of
echistatin and an RGD peptide on orthodontic tooth movement. J
Dent Res 2003;82(9):682-686.
Drake FH, Dodds RA, James IE, Connor JR, Debouck C, Richardson S, Lee-
Rykaczewski E, Coleman L, Rieman D, Barthlow R, Hastings G, Gowen
M. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed
in human osteoclasts. J Biol Chem 1996;271(2):12511-12516.
320
Dolce and Holliday
Dunn MD, Park CH, Kostenuik PJ, Kapila S, Giannobile WV. Local delivery
of osteoprotegerin inhibits mechanically mediated bone modeling in
orthodontic tooth movement. Bone 2007;41(3):446-455.
Friedman R, Boye K, Flatmark K. Molecular modeling and simulations in
cancer research. Biochim Biophys Acta 2013;1836(1):1-14.
Fukunishi Y. Structure-based drug screening and ligand-based drug
screening with machine learning. Comb Chem High Throughput
Screen 2009;12(4):397–408.
Gallagher JC, Sai AJ. Molecular biology of bone remoderling: Impli-
cations for new therapeutic targets for osteoporosis. Maturitas
2010;65(4):301-307.
Gluck SL, Lee BS, Wang SP, Underhill D, Nemoto J, Holliday LS. Plasma
membrane V-ATPases in proton-transporting cells of the mammalian
kidney and osteoclast. Acta Physiol Scand Suppl 1998;643:203-212.
Hagiwara Y, Ohno K, Orita M, Koga R, Endo T, Akiyama Y, Sekijima M.
Accelerating quantum chemistry calculations with graphical processing
units: Toward in high-density (HD) silico drug discovery. Curr Comput
Aided Drug Des 2013;9(3):396–401.
Henwood JM, Monk JP Enoxacin: A review of its antibacterial activity,
pharmacokinetic properties and therapeutic use. Drugs 1988;36(1):
32-66.
Herczegh P, Buxton TB, McPherson JC III, Kovacs-Kulyassa A, Brewer
PD, Sztaricskai F, Stroebel GG, Plowman, KM, Farcasiu D, Hartmann
JF. Osteoadsorptive bisphosphonate derivatives of fluoroquinolone
antibacterials. J Med Chem 2002;45(11):2338-2341.
Hinton A, Bond S, Forgac M. V-ATPase functions in normal and disease
function. Pflugers Arch 2009;457(3):589-598.
Hinton A, Sennoune SR, Bond S, Fang M, Reuveni M, Sahagian GG, Jay
D, Martinez-Zaguilan R, Forgac M. Function of a subunit isoforms of
the V-ATPse in pH homeostasis and in vitro invasion of MDA-MB231
human breast cancer cells. J Biol Chem 2009;284(24):16400-16408.
Hofbauer LC, Heufelder, AE. Role of receptor activator of nuclear factor-
kappaB ligand and osteoprotegerin in bone cell biology. Maturitas
2001;79(5-6):243-253.
321
Computational Chemistry
Holliday LS, Lu M, Lee BS, Nelson RD, Solivan S, Zhang L, Gluck SL. The
amino-terminal domain of the B subunit of vacuolar H+-ATPase
contains a filamentous actin binding site. J Biol Chem 2000;275(41):
32331-32337.
Holliday LS, Vakani A, Archer L, Dolce C. Effects of matrix metalloproteinase
inhibitors on bone resorption and orthodontic tooth movement. J
Dent Res 2003;82(9):687-691.
Hudson JB, Hatch N, Hayami T, Shin JM, Stolina M, Kostenuik PJ,
Kapila S. Local delivery of recombinant osteoprotegerin enhances
postorthodontic tooth stability. Calcif Tissue Int 2012;90(4):330-342.
Igarashi K, Mitani H, Adachi H, Shinoda H. Anchorage and retentive effects
of a bisphosphonate (AHBuBP) on tooth movement in rats. Am J
Orthod Dentofacial Orthop 1994;106(3):279-289.
Kanzaki H, Chiba M, Arai K, Takahashi I, Haruyama N, Nishimura M, Mitani
H. Local RANKL gene transfer to the periodontal tissue accelerates
orthodontic tooth movement. Gene Ther 2006;13(8):678-685.
Kanzaki H, Chiba M, Takahashi I, Haruyama N, Nishimura M, Mitani H.
OPG gene transfer to periodontal tissue inhibits orthodontic tooth
movement. J Dent Res 2004;83(12):920–925.
Karaman R, Fattash B, Otait A. The future of prodrugs: Design by quantum
mechanics methods. Expert Opin Drug Deliv 2013;10(5):713-729.
Karras JC, Miller JR, Hodges JS, Beyer JP, Larson BE. Effect of alendronate
on Orthodontic tooth movement in rats. Am J Orthod Dentofacial
Orthop 2009;136(6):843-847.
King GJ, Holtrop ME. Actin-like filaments in bone cells of cultured mouse
calvaria as demonstrated by binding to heavy meromyosin. J Cell Biol
1975;66(2):445-451.
Kole H. Surgical operations on the alveolar ridge to correct occlusal
abnormalities. Oral Surg Oral Med Oral Pathol 1959;12(3):277–288.
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S,
Oliveira-dos-Santos AJ, Van G, ſtie A, Khoo W, Wakeham A, Dunstan
CR, Lacey DL, MakTW, Boyle WJ, Penninger JM. OPGL is a key regulator
of osteoclastogenesis, lymphocyte development and lymph-node
organogenesis. Nature 1999;397(6717):315-323.
322
Dolce and Holliday
Kowitz AA, Loevy H.T. Paediatric dentistry: Fauchard and before. Int Dent
J 1993;43(3):239-244.
Lee BS, Gluck SL, Holliday LS. Interaction between vacuolar H(+)-ATPase
and microfilaments during osteoclast activation. J Biol Chem 1999;27
(41):29164-29171.
Liu X, Ou X, Wu C, Zhai Z, Tian B, Li H, Ouyang Z, Xu X, Wang W, Fan O,
Tang T, Oin A, Dai K. The effect of enoxacin on osteoclastogenesis and
reduction of titanium particle-induced osteolysis via suppression of
JNK signaling pathway. Biomaterials 2014;35(22):5721-5730.
Luan X, Lu O, Jiang Y, Zhang S, Wang O, Yuan H, Zhao W, Wang J, Wang X.
Crystal structure of human RANKL complexed with its decoy receptor
osteoprotegerin. J Immunol 2012;189(1):245-252.
Lujambio A, Esteller M. How epigenetics can explain human metastasis: A
new role for microRNAs. Cell Cycle 2009;8(3):377-382.
Ma B, Ojan D, Nan O, Tan C, An L, Xiang Y. Arabidopsis vacuolar H+-
ATPase (V-ATPase) B subunits are involved in actin cytoskeleton
remodeling via binding to, bunding, and stabilizing F-actin. J Biol Chem
2012;287(23):19008–19017.
McLeod NM, Brennan PA, Ruggiero SL. Bisphosphonate osteonecrosis of
the jaw: A historical and contemporary review. Surgeon 2012;10(1):
36-42.
Melo SA, Esteller M. Dysregulation of microRNAs in cancer: Playing with
fire. FEBS Lett 2011;585(13):2087-2099.
Melo S, Villanueva A, Moutinho C, Davalos V, Spizzo R, Ivan C, Rossi S,
Setien F, Casanovas O, Simo-Riudalbas L., Carmona J, Carrere J, Vidal
A, Aytes A, Puertas S, Ropero S, Kalluri R, Croce CM, Calin GA, Esteller
M. Small molecule enoxacin is a cancer-specific growth inhibitor that
acts by enhancing TAR RNA-binding protein 2-mediated microRNA
processing. Proc Natl Acad Sci USA 2011;108(11):4394-4399.
Nishi T, Forgac M. The vacuolar (H+)-ATPases: Nature's most versatile
proton pumps. Nat Rev Mol Cell Biol 2002;3(2):94-103.
Ortega SS, Cara LC, Salvador MK. In silico pharmacology for a multidisci-
plinary drug discovery process. Drug Metabol Drug Interact 2012;27
(4):199-207.
Ostrov DA, Magis AT, Wronski TJ, Chan EK, Toro EJ, Donatelli RE, Sajek K,
Haroun IN, Nagib MI, Piedrahita A, Harris A, Holliday LS. Identification
323
Computational Chemistry
of enoxacin as an inhibitor of osteoclast formation and bone resorption
by structure-based virtual screening. J Med Chem 2009;52(16):5144-
5151.
Peck S. A biographical portrait of Edward Hartley Angle, the first specialist
in orthodontics: Part 3. Angle Orthod 2009;79(6):1034–1036.
Peck S. The contributions of Edward H. Angle to dental public health.
Community Dent Health 2009;26(3):130-131.
Peck S. The students of Edward Hartley Angle, the first specialist in
orthodontics: A definitive compilation. J Hist Dent 2006;54(2):70-76.
Peck S, Peck L, Hirsh G. Mandibular lateral incisor-canine transposition in
monozygotic twins. ASDCJ Dent Child 1997;64(6):409–413.
Perola E, Walters WP, Charifson PS. A detailed comparison of current
docking and scoring methods on systems of pharmaceutical relevance.
Proteins 2004;56(2):235–249.
Petzoldt AG, Gleixner EM, Fumagalli A, Vaccari T, Simons M. Elevated
expression of the V-ATPase C subunit triggers JNK-dependent cell
invasion and overgrowth in a Drosophila epithelium. Dis Model Mech
2013;6(3):689-700.
Philippe J, Guedon P. Evolution of orthodontic appliances from 1728 to
2007: Inaugural Conference of the 79th Scientific Meeting of the SFO-
DR at Versailles, 31 May 2007. Orthod Fr 2007;78(4):295-302. (Article
in French)
Phulari BS. History of Orthodontics. Jaypee Brothers, Medical Publishers,
New Delhi, India 2013;1-256.
Pons C, Jimenez-Gonzalez D, Gonzalez-Alvarez C, Servat H, Cabrera-
Benitez D, Aguilar X, Fernandez-Recio J. Cell-Dock: High-performance
protein-protein docking. Bioinformatics 2012;28(18):2394-2396.
Rafalsky V, Andreeva I, Rjabkova E. Ouinolones for uncomplicates acute
cystitis in women. Cochrane Database Syst Rev 2006;3:CD003597.
Rivera MF, Chukkapalli SS, Velsko IM, Lee JY, Bhattacharyya I, Dolce C,
Toro EJ, Holliday LS, Kesavalu L. Bis-enoxacin blocks rat alveolar bone
resorption from experimental periodontitis. PLoS One 2014;9(3):
e92119.
324
Dolce and Holliday
Saltel F, Chabadel A, Bonnelye E, Jurdic P. Actin cytoskeletal organization
in osteoclasts: A model to decipher transmigration and matrix
degradation. Eur J Cell Biol 2008;87(8–9):459-468.
Saltel F. Destaing O, Bard F, Eichert D, Jurdic P. Apatite-mediated actin
dynamics in resorbing osteoclasts. Mol Biol Cell 2004;15(12):5231-
5241.
Saroussi S, Nelson N. Vacuolar H(+)-ATPase: An enzyme for all seasons.
Pflugers Arch 2009;457(3):581–587.
Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, Faghihi MA, Khalil AM,
Lu L, Paroo Z, Chan AW, Shi Z, Liu O, Wahlestedt C, He C, Jin P. A
small molecule enhances RMA interference and promotes microRNA
processing. Nat Biotechnol 2008;26(8):933-940.
Sheng C, Zhang W. Fragment informatics and computational fragment-
based drug design: An overview and update. Med Res Rev 2013;
33(3):554-598.
Silberstein GB, Daniel CW. Elvax 40P implants: Sustained, local release of
bioactive molecules influencing mammary ductal development. Dev
Biol 1982;93(1):272-278.
Smith AL, Cordery PM, Thompson ID. Manufacture and release character-
istics of Elvax polymers containing glutamate receptor antagonists. J
Neurosci Methods 1995;60(1-2):211-217.
Spinardi L, Marchisio PC. Podosomes as smart regulators of cellular
adhesion. Eur J Cell Biol 2006;85(3–4):191-194.
Takahashi N, Udagawa N, Suda T. A new member of tumor necrosis
factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast
differentiation and function. Biochem Biophys Res Commun 1999;
256(3):449-455.
Tanaka KS, Houghton TJ, Kang T, Dietrich E, Delorme D, Ferreira SS, Caron
L, Viens F, Arhin FF, Sarmiento I, Lehoux D, Fadhil I, Laquerre K, Liu J,
Ostiguy V, Poirier H, Moeck G, Parr TR Jr, Rafai FA. Bisphosphonated
fluoroquinolone esters as osteotropic prodrugs for the prevention of
osteomyelitis. Biocrg Med Chem 2008;16(20):9217-9229.
Teitelbaum SL. Osteoclasts: What do they do and how do they do it? Am
J Pathol 2007;170(2):427-435.
325
Computational Chemistry
Teixeira CC, Khoo E, Tran J, Chartres I, Liu Y, Thant LM, Khabensky I, Gart
LP, Cisneros G, Alikhani M. Cytokine expression and accelerated tooth
movement. J Dent Res 2010;89(10):1135-1141.
Toro EJ, Zuo J, Guiterrez A, La Rosa RL, Gawron AJ, Bradaschia-Correa
V, Arana-Chavez V, Dolce C, Rivera MF, Kesavalu L, Bhattacharyya I,
Neubert JK, Holliday LS. Bis-enoxacin inhibits bone resorption and
orthodontic tooth movement. J Dent Res 2013;92(10):925-931.
van der Kamp MW, Shaw KE, Woods CJ, Mulholland AJ. Biomolecular
simulation and modeling: Status, progress and prospects. J R Soc
Interface 2008;5(Suppl 3):S173-S190.
Vatteone MH. The evolution of orthodontic appliances, from Fauchard
to Angle. Rev Museo Fac Odontol B Aires 1994;9(17):38-44. (Article in
Spanish)
Vitavska O, Wieczorek H, Merzendorfer H. A novel role for subunit C in
mediating binding of the H+-V-ATPase to the actin cytoskeleton. J Biol
Chem 2003;278(20):18499-18505.
Wagner CA, Finberg KE, Breton S, Marshansky V, Brown D, Geibel JP, Renal
vacuolar H+-ATPase. Physiol Rev 2004;84(4):1263-1314.
Wilcko W, Wilcko MT. Accelerating tooth movement: The case for
corticotomy-induced orthodontics. Am J Orthod Dentofacial Orthop
2013;144(1):4-12.
Wilcko WM, Wilcko T, Bouquot JE, Ferguson, DJ. Rapid orthodontics with
alveolar reshaping: Two case reports of decrowding. Int J Periodontics
Restorative Dent 2001;21(1):9-19.
Yamaguchi H, Oikawa T. Membrane lipids in invadopodia and podosomes:
Key structures for cancer invasion and metastasis. Oncotarget
2010;1(5):320–328.
Yoo SJB, Yin YW. Review of the low-latency optical interconnect technolo-
gies for peta-scale computing. China Communications 2012;9(8):16-
28.
Zhang O, Zhang C, Xi Z. Enhancement of RNAi by a small molecule
antibiotic enoxacin. Cell Res 2008;18(10):1077–1079.
Zuo J, Jiang J, Chen SH, Vergara S, Gong Y, Xue J, Huang H, Kaku M, Holliday
LS. Actin binding activity of subunit B of vacuolar H+-ATPase is involved
in its targeting to ruffled membranes of osteoclasts. J Bone Miner Res
2006;21(5):714-721.
326
Dolce and Holliday
Zuo J, Vergara S, Kohno S, Holliday LS. Biochemical and functional
characterization of the actin-binding activity of the B subunit of yeast
vacuolar H+-ATPase. J Exp Biol 2008;211(Pt 7):1102-1108.
327
328
EXPERIMENTAL TOOTH MOVEMENT-INDUCED GLIAL
ACTIVATION AND MICROGLIAL MODULATION CAN
ATTENUATE ORTHODOTIC PAIN
Toru Deguchi
ABSTRACT
Microglia and astrocyte in the central nervous system are known to respond
to peripheral injury and release cytokines that induce pain. If an orthodontic
force that generates inflammatory-like response is applied to the tooth,
microglia may respond to the tooth movement causing pain. Several analgesics
are used to control pain during orthodontic treatment; however, most of them
also are known to inhibit tooth movement. Minocyclin is known to disrupt the
activation of microglia selectively to attenuate and delay pain while minimizing
effects on the peripheral system. In this pilot study, we hypothesized that
lasting nociception induced by experimental tooth movement will lead to glial
activation at the medulla and glial inactivation by minocycline medication
will show anti-nociceptive activity. Thirty adult rats divided equally between
minocycline treatment and controls were sacrificed after 3, 5, 7 and 14 days after
experimental tooth movement for immunohistochmestry of OX-42 (microgilia
activation), glial fibrillary acidic protein (GFAP; astrocyte activation) and c-fos
double immunostaining. There was a significant increase in both microglia
and astrocyte activity after tooth movement. Minocycline application resulted
in significant reduction of microglia, astrocyte and c-fos activity associated
with tooth movement. These findings suggest that microglia are potential
contributors for the delay in pain observed during orthodontic treatment.
Furthermore, minocycline may be a new innovative pre-emptive analgesic that
selectively blocks long-lasting pain and effectively contributes to reduced pain
and/or discomfort during orthodontic treatment.
KEY WORDS: experimental tooth movement, pain, microglia, astrocyte, rat
PAIN DURING ORTHODONTIC TOOTH MOVEMENT
The known disadvantages of orthodontic treatment include the
long treatment time, unesthetics appliances, high cost and pain and/or
329
Experimental Tooth Movement
discomfort following appliance activations. To counter some of the dis-
advantages, various studies have attempted to identify methods to accel-
erate tooth movement by targeting bone turnover or mechanotherapy.
These include the use of vibration techniques (Darendeliler et al., 2007),
corticotomy (Hoogeveen et al., 2014) and self-ligation brackets (Čelar et
al., 2013). Esthetic appliances such as clear brackets (Walton et al., 2010),
lingual brackets (Grauer and Proffit, 2011) and Invisalign (Kravitz et al.,
2009) also continue to be introduced to the profession; however, the con-
trol of pain has not received as much attention compared to other disad-
vantages of orthodontic treatment. Orthodontists and patients generally
are aware of pain, but seem to follow the mantra of “no pain, no gain.”
Nevertheless it would be ideal if a drug that specicically reduces pain and/
or discomfort without other side effects was available for mitigating orth-
odontic pain.
Pain and discomfort observed during orthodontic treatment are
different from other types of acute pain such as that following injury or
trauma (Firestone et al., 1999). These sensations are classified into two
responses: the first appears at the moment when the orthodontic force is
applied and then disappears immediately; the second appears much later
with a peak intensity on day one or two following appliance activation
and lasts for a few days (Jones and Chan, 1992). Discomfort can influence
a patient's motivation to undergo orthodontic treatment negatively.
Even though 91% of the patient-experienced pain is a consideration in
whether or not to continue the orthodontic treatment (Lew, 1993), only
a few studies have investigated effective methods to control pain during
orthodontic treatment.
CONTROLLING PAIN DURING ORTHODONTIC TREATMENT
Methods known to reduce pain during orthodontic treatment
include low-level laser therapy (LLLT; Lim et al., 1995) and the use of
analgesics (Hammad et al., 2012). The effects of LLLT in reducing pain
under experimental (Seiryu et al., 2010) and clinical (Fujiyama et al., 2008)
situations have been reported previously by our research group. Fujiyama
and colleagues (2008) were the first to indicate that CO, lasers significantly
reduced the pain level after tooth movement without any damage to the
surrounding tissue. Because these effects were determined only when
using separators, further investigation is necessary to determine whether
330
Deguchi
the CO, laser has a prolonged effect during active orthodontic treatment
involving continuous and more intense pain. The use of analgesics such
as non-steroidal anti-inflammatory drugs (NSAIDs) is the most preferred
method for pain control during orthodontics (Ngan et al., 1994). The
major limitations of NSAIDs are their effects on inflammation associated
with and required for tooth movement (Hammad et al., 2012). The
current trend toward limiting orthodontic pain is directed toward the use
of pre-emptive or pre-operative analgesics, which are administrated at
least one hour before every orthodontic procedure (Arias and Marquez-
Orozco, 2006; Knop et al., 2012). Pre-emptive analgesia blocks the
afferent nerve impulses before they reach the central nervous system
(CNS), abolishing the process of central sensitization. Orthodontic pain
characteristically is long lasting and is not persistently an acute pain. Thus,
pre-emptive analgesia targeting the brain or brainstem might relieve the
orthodontic pain efficiently. However, anti-inflammatory medications
also target inflammation in the peripheral tissues, thereby interfering
with orthodontic tooth movement. Thus, it will be essential to develop
new pre-emptive analgesics that block nociceptive input to the CNS and
reduce pain without any side effects.
CHANGES IN PERIPHERAL AND CENTRAL NERVOUS SYSTEM
DURING ORTHODONTIC TOOTH MOVEMENT
When an orthodontic force is applied to a tooth for a prolonged
period, an inflammatory event occurs within the periodontal ligament
(PDL), resulting in the local release of neuropeptides that are implicated
in the mechanism of pain sensation. In the past, our research group has
identified the presence of several neuropeptides in the peripheral nerve
tissues including the PDL and the tooth pulp (Ichikawa et al., 1994a,b,
1995, 1996.) Furthermore, our research group also has analyzed the
changes of the tissue distribution of one of the neuropeptides (Galanin)
that significantly increases after experimental tooth movement (Deguchi
et al., 2003). Besides the changes in Galanin during tooth movement,
luxation of the teeth also causes a significant increase in Calcitonin gene-
related peptide (CGRP; Nagayama et al., 2012).
The peripheral nociceptive information evoked by experimental
tooth movement is thought to terminate in the CNS (Fig. 1). c-fos is an
331
Experimental Tooth Movement
immediate early gene which encodes the nuclear protein Fos and the
expression of this gene has been utilized as a marker for physiological
activity to identify specific neuronal pathways in the brain (Sagar et al.,
1988). Our research group also has confirmed that the change in the
c-fos expression at the medullary dorsal horn (MDH) after orthodontic
tooth movement significantly correlates with the time when patients
feel pain during orthodontic treatment (Fujiyoshi et al., 2000). The
presence of several neuropeptides is known in other parts of the CNS as
well as in trigeminal ganglion (TG) and tooth pulp, which is innervated
by nociceptive afferents with cell bodies in the TG (Fig. 1). Our research
group has demonstrated the presence of several neuropeptides in the TG
during tooth movement (Ichikawa et al., 1994a,b, 2006). These include
a significant change in Galanin-immuno-reactive (ir) cells at the TG after
the tooth movement (Deguchi et al., 2006). These findings suggest that
these neuropeptides and c-fos would be excellent markers for analyzing
the intensity of pain during experimental movement.
Glia cells are non-neuronal cells in the CNS that have a role in
the initiation and maintenance of persistent pain states. Microglia
and astrocytes have been implicated in various types of pain such as
subcutaneous inflammation and peripheral nerve injury (Watkins and
Maier, 2003). Microglia are the early responding glial cells in the CNS
after injury and release products that activate astroglia (Svensson et al.,
1993). Furthermore, both microglia and astrocytes have the ability to
release cytokines (Aloisi, 2001). These pro-inflammatory cytokines and
prostaglandins, released after microglial activation, play a role in central
sensitization and are implicated in exaggerated pain states (Zhuang et
al., 2005). Thus, microglia and astrocyte may be activated in response to
tooth movement and play a role in releasing cytokines and neuropeptides
to descending peripheral targets (e.g., the tooth pulp and PDL during
orthodontic tooth movement), thereby contributing to aggravation of pain.
POTENTIAL USE OF MINOCYCLINE IN CONTROLLING PAIN
IN ORTHODONTIcTREATMENT
Since NSAIDs cannot cross the blood-brain barrier, their effects
result due to direct activity on the peripheral tissues, rather than at
the level of the CNS (Fig. 2). Only few NSAIDs are recommended pre-
emptively for pain since most of them inhibit bone resorption and inter-
fere with tooth movement (Gonzales et al., 2009; Knop et al., 2012). It
332
Deguchi
Medulla
Figure 1. Schema of response to orthodontic forces. When the forces are applied
within the periodontal ligament (PDL) as an acute inflammatory-like reaction, the
pain information are carried to the medulla via trigeminal ganglion (TG).
EEE
blood–brain barrier (BEE)
–
| Neurotransmitter
Figure 2. Schema of pharmacological management of orthodontic pain. NSAIDs
bind to plasma proteins readily and when bound, cannot cross the blood–brain
barrier.


333
Experimental Tooth Movement
is likely that medication targeting the CNS (e.g., opioid analgesics) that
act at the spinal and supraspinal levels could be effective for mitigating
orthodontic pain; however, such medication for this purpose would be an
over-treatment with too many psychological and physiologic side effects.
In addition, such medication often requires intrathecal administration
because the medicine has to cross the blood–brain barrier.
Minocycline is a semisynthetic tetracycline derivative that exerts
anti-flammatory effects completely distinct from its antimicrobial action
(Tikka and Koistinaho, 2001). Minocycline is a lipophilic molecule that
readily crosses the blood–brain barrier and selectively disrupts the activa-
tion of microglia without directly affecting neurons or astroglia (Raghav-
endra et al., 2003). Minocycline's antihyperalgesic and antiallodynic ef-
fects have been demonstrated in models of arthritis, spinal nerve tran-
section and sciatic inflammatory neuritis (Ledeboer et al., 2005; Shan et
al., 2007). Interestingly, minocycline has no effect on acute inflammation
and nociception, and it attenuates and delays the development of neu-
ropathic pain and formalin-induced inflammatory pain responses (Padi
and Kulkarni, 2008). As mentioned earlier, pain during orthodontic treat-
ment is different from acute pain in that it will last for days and occurs
a few days after initial force application. Thus, medication targeting the
CNS might relieve orthodontic pain effectively. Minocycline is known to
attenuate and delay the development of pain; it also might block the af-
ferent nerve impulses before they reach the CNS, abolishing the process
of central sensitization (Fig. 3).
THE PURPOSE OF THE CURRENT PILOT STUDY
To date, no study has investigated the changes of microglia and
astrocyte after experimental tooth movement or the effect of minocycline
to reduce pain sensation during orthodontic treatment by analyzing
the changes of microglia, astrocyte and c-fos as potential markers of
pain. A new quantitative three-dimensional (3D) evaluation by confocal
laser scanning microscopy that has been described for measuring the
architecture of the osteocyte network in bone was used to investigate
the changes of microglia and astrocyte in CNS. Findings of this study
may suggest an optimal and safe approach in controlling pain in clinical
orthodontics that previously has never been demonstrated.
334
Deguchi
Figure 3. Schema of suggested effect of minocycline. Minocycline may have an
effect directly on MDH that might block central sensitization.
The objective of this pilot study was to investigate the analgesic
effect of minocycline during experimental tooth movement. Two specific
aims were addressed to achieve this objective:
1. Ouantitatively analyze changes of microglia, astro-
cytes and c-fos in the central nervous system after ex-
perimental tooth movement measured by WinROOF
software program.
2. Ouantitatively analyze the effect of systemic adminis-
tration of minocycline in changes of microglia, astro-
cytes and c-fos after experimental tooth movement.
It was hypothesized that lasting-nociception induced by
experimental tooth movement leads to glial activation at the medulla
and glial inactivation by minocycline medication attenuates nociceptive
activity.

335
Experimental Tooth Movement
MATERIALS AND METHODS
Fifteen adult Sprague-Dawley rats (150 to 200g) were used in
this study. The groups included day 0 controls and animals subjected to
experimental tooth movement for 3, 5, 7 and 14 days (n = 3 each). Tooth
movement was preformed with the Waldo method (Waldo and Rothblatt,
1954; Fig. 4A). The rats were anesthetized and perfused transvascularly
at each time point. The lower brain stem then was dissected, immersed
overnight and cryoprotected. The frozen sections were prepared by
cutting 50 pum thickness sections frontally to evaluate the glial activation.
Another fifteen adult Sprague-Dawley rats were used for analyzing
the effect of minocycline (Sigma, St., Louis, MO), which was dissolved
in sterile water and sonicated to ensure complete solubilization. Rats
received an intraperitoneal (i.p.) injection of vehicle or minocycline (50
mg/kg) once per day during the experimental period.
Microglias were identified by anti-CD11b (OX-42; mouse anti-
rabbit, 1:1000; SIGMA), which recognizes cell surface complement
receptor 3 (CR3; He et al., 2001). Astrocytes were identified by anti-glial
fibrillary acidic protein (GFAP; mouse monoclonal, 1:5000; DAKO), which
is expressed in cells of astroglial origin and whose synthesis is modulated
by injury (Tiu et al., 2003). c-fos-ir also was analyzed to evaluate the
orthodontic nociception at the medulla (1:10,000, Oncogene, Cambridge,
MA; Fujiyoshi et al., 2000). The sections were developed using a mixture
of Alexa Fluour 594-conjugated goat anti-rabbit IgG for CD11b and Alexa
488-conjugated goat anti-mouse IgG for GFAP (both from Invitrogen).
For c-fos immunostaining, the sections were exposed to avidin-
biotin horseradish peroxidase complex in 0.1-M PBST. Immunostained
sections were mounted onto gelatin-subbed glass slides.
All except c-fos ABC-stained sections were examined with a
fluorescence microscope. The photographs were taken with a CCD
camera. The images were saved in the TIFF format and managed by a
DP manager. OX-42 and GFAP-ir were evaluated in the rostral-most sec-
tions through the MDH. The outlines of the MDH first were determined
with dark-field illumination (Fig. 4B). These regions also were evaluated
with c-fos-ir to confirm that they were involved in pain processing (Sugi-
moto et al., 1997). The size distribution of the OX-42 and GFAP-ir in
336
Deguchi
Contra
A B
Figure 4. Schema of Waldo method (A) and the region of interest (white box) in
the MDH (B).
the MDH was measured by the WinROOF software program within each
region of interest (400 pum x 300 pum x 50 pum; Sugawara et al., 2005). The
number of c-fos-ir neurons was counted in the rostral-most three sections
through the MDH. The images were processed and the immunoreactive
cells also were quantified using the WinROOF software program, which
automatically traced the fluorescence images.
The difference between groups for GFAP, OX-42 intensity and
c-fos counting were compared using two-way ANOVA followed by a
Tukey's post-hoc test (p<0.05).
RESULTS
In the control (without elastic module), low expression of OX-42
and GFAP was observed in both of the MDH bilaterally. The number of
such OX-42 and GFAP–ir immunoreactivity did not change at the post-
manipulation intervals.
OX-42-ir Immuno-reactivity in the MDH
Experimental tooth movement enhanced OX-42-ir on the
ipsilateral side of the MDH (Fig. 5) and the number of OX-42-ir microglia
significantly increased at 3, 5 and 7 days following initiation of tooth
movement. The highest increase OX-42-ir was observed after 5 days of
tooth movement. However, there was no significant change OX-42-ir on
the contralateral side of the MDH throughout the entire experimental
period.

337
Experimental Tooth Movement
A.
)
(% - Control
2 15 - Tooth movement
9 _ Tooth movement
*F - with minocycline
CN
S. 10 F * = P × 0.05 (to control)
×
O
3
º
Q
E 5 F
He
º
º
0
E O 3 5 7 14 (days)
Figure 5. Change in the OX-42-ir after tooth movement. Significant increase of
OX-42-ir was observed at 3 (B,E), 5 (C,E) and 7 (E) days after the tooth movement
compared to the untreated controls (A,B). Significant reduction of OX-42-
ir was observed after 5 days (D,E) of tooth movement in animals treated with
minocycline relative to PBS-treated tooth movement controls.
GFAP–ir in the MDH
The experimental tooth movement also significantly increased
the expression of GFAP on the ipsilateral side of the MDH (Fig. 6). The
number of GFAP-ir astrocyte significantly increased at 3, 5, 7 and 14 days
after initiating the tooth movement. The greater increase was observed in
the MDH at 5 days of tooth movement. However, there was no significant
change on the contralateral side of the MDH throughout the entire
experimental period.
Effect of Mynocyclin in Microglia, Astrocyte and c-fos-ir Neurons During
Tooth Movement
Minocycline treatment significantly reduced the OX-42-ir from
3 to 7 days and from 3 to 14 days of GFAP-ir during tooth movement
(Figs. 5 and 6D,E). There was no significant change on the contralateral
side of the MDH throughout the entire experimental period. The experi-
mental tooth movement significantly increased of c-fos expression on the
ipsilateral side of the MDH at days 3 and 5 of tooth movement (Fig. 7).



338
Deguchi
| | | |
- Control
(%) - Tooth movement
ºn - _ Tooth movement
ºf 24 F - with minocycline
O
# 20 T +
5 16 F
* 12 H
9
3 8 T
# *= P × 0.05 (to control)
É 4 T
0
E O 3 5 7 14 (days)
Figure 6. Change in the GFAP-ir after tooth movement. Significant increase of
GFAP-ir was observed at 3 (B,E), 5 (C,E), 7 and 14 (E) days after initiating tooth
movement relative to the control (A,B). Significant reduction of GFAP-ir was
observed after minocycline application from 5 to 14 days (D,E) of tooth movement.
A
15 -
+
2
5 10 -
-,
q)
-
3. * :P-0.05(to control)
9 5 -
CŞ º:
D 0 - --_
3 5 7 (day)
Figure 7. Change in the c-fos-ir neurons after tooth movement. Significant in-
crease of c-fos neurons is observed at 3 days (B,D) after tooth movement com-
pared to the control (A.D). Significant decrease of c-fos-ir neurons is observed
after minocycline application (C,D). Black bars represent tooth movement with
no minocycline; gray bars represent tooth movement with minocycline.




339
Experimental Tooth Movement
The greatest increase in c-fos was observed after 3 days. In rats receiv-
ing minocycline, a significant decrease in OX-42, GFAP and c-fos was ob-
served from 3 to 5 days after tooth movement.
DISCUSSION
There was a significant change at the MDH in the number of
OX-42-ir and GFAP-ir after tooth movement. It is known that microglia
and astrocyte are activated by peripheral nerve injury at the spinal dorsal
horn (Narita et al., 2006; Svensson and Brodin, 2010). This hyperactivity
of microglia and astrocytes may be related to pain hypersensitivity at the
CNS. If there is nerve injury or inflammation at the nerve fibers in the PDL
and tooth pulp during tooth movement, this also may result in increased
activation of microglia and astrocytes at the MDH. It also is known that
there is a significant increase in the neurons expressing c-fos in the MDH
after the tooth movement, indicating a nociceptive response in the CNS
by plasticity of nerve fibers in the PDL (Fujiyoshi et al., 2000). Therefore,
experimental tooth movement may result in the increase of the microglia
activity and further activate the astrocyte in the MDH.
In this pilot study, experimental tooth movement contributed
microglia and astrocyte activation after 3 days, peaked at 5 days and
gradually decreased thereafter. In contrast, c-fos expression peaked at
3 days and returned to normal levels at 7 days after after initiation of
tooth movement. c-fos expression is known to have a biphasic pattern
of expression that is observed after approximately 24 hours and at 1 to
3 days after commencing tooth movement (Fujiyoshi et al., 2000). This
temporal change in c-fos expression reflects the time course changes in
pain and peripheral inflammation observed at the PDL and tooth pulp
after orthodontic force application. Even though we did not perform
any analysis after 1 day of tooth movement, it seems obvious that there
is a slight difference between the c-fos expression and microglia activa-
tion. A similar gap in tooth movement-mediated c-fos expression and
microglia activation is observed with a formalin injection study showing
peak c-fos expression within 2 to 4 hours (Presley et al., 1990) and peak
microglia activation after 3 days (Wu et al., 2004). The increased mi-
croglia and astrocyte activation may be responsible for prolonged pain
during orthodontic treatment, rather than the acute pain seen in other
types of injuries.
340
Deguchi
Microglial inhibitor,
Minocycine
Brainstem
Figure 8. Schema of mechanisms by which minocycline may control pain during
tooth movement. Since minocycline can cross the BBB, it selectively disrupts the
activation of glia without affecting neurons.
Administration of minocycline resulted in significant decrease in
the expression of markers of microglia and astrocyte activation during
tooth movement. This, in addition to the decreased c-fos expression may
indicate that the inhibition of glia activation contributes to the reduction
of orthodontic pain sensation during tooth movement (Fig. 8). Micocy-
cline has an anti-hyperalgesic effect in arthritis, spinal nerve injuries and
sciatic inflammatory neuritis (Raghavendra et al., 2003; Ledeboer et al.,
2005; Shan et al., 2007). Moreover, since minocycline selectively inhib-
its microglial activation without affecting other neurons, its reduction
of pain may result from a selective inhibitory effect on microglia. Thus,
microglia and astrocyte may be associated with development of delayed
pain during orthodontic tooth movement.
CONCLUSIONS
Since glial activity in the MDH is elevated by experimental tooth
movement, microglia may play a major role in transmitting pain during
orthodontic treatment. Thus, glial cells in the brain may serve as poten-
tial pharmacological targets for the management of orthodontic pain. Mi-
nocycline application may control nociceptive input effectively, including
delayed pain and could serve as an analgesic in orthodontic treatment.
Further study with a greater sample size and analysis at earlier stages of
experimental tooth movement is necessary for more conclusive findings.
The potential side effects of minocycline on alveolar bone turnover during
tooth movement also remains to be determined.

341
Experimental Tooth Movement
REFERENCES
Aloisi F. Immune function of microglia. Glia 2001;36(2):165-179.
Arias OR, Marquez-Orozco MC. Aspirin, acetaminophen, and ibuprofen;
Their effects on Orthodontictooth movement. Am J Orthod Dentofacial
Orthop 2006;130(3):364-370.
Čelar A, Schedlberger M., Dörfler P, Bert M. Systematic review on self-
ligating vs. conventional brackets: Initial pain, number of visits,
treatment time. J Orofac Orthop 2013;74(1):40-51.
Darendeliler MA, Zea A, Shen G, Zoellner H. Effects of pulsed electromag-
netic field vibration on tooth movement induced by magnetic and me-
chanical forces: A preliminary study. Aust Dent J 2007;52(4):282-287.
Deguchi T, Takeshita N, Balam TA, Fujiyoshi Y, Takano-Yamamoto T.
Galanin-immunoreactive nerve fibers in the periodontal ligament
during experimental tooth movement. J Dent Res 2003;82(9):677-681.
Deguchi T, Yabuuchi T, Ando R, Ichikawa H, Sugimoto T, Takano-Yamamoto
T. Increase of galanin in trigeminal ganglion during tooth movement. J
Dent Res 2006;85(7):658-663.
Firestone AR, Scheurer PA, Bürgin WB. Patients' anticipation of pain and
pain-related side effects, and their perception of pain as a result of
orthodontic treatment with fixed appliances. Eur J Orthod 1999;21
(4):387-396.
Fujiyama K, Deguchi T, Murakami T, Fujii A, Kushima K, Takano-Yamamoto
T. Clinical effect of CO(2) laser in reducing pain in orthodontics. Angle
Orthod 2008;78(2):299-303.
Fujiyoshi Y, Yamashiro T, Deguchi T, Sugimoto T, Takano-Yamamoto T. The
difference in temporal distribution of c-fos immunoreactive neurons
between the medullary dorsal horn and the trigeminal subnucleus
oralis in the rat following experimental tooth movement. Neurosci
Lett 2000;283(3):205-208.
Gonzales C, Hotokezaka H, Matsuo K, Shibazaki T, Yozgatian JH, Daren-
deliler MA, Yoshida N. Effects of steroidal and nonsteroidal drugs on
tooth movement and root resorption in the rat molar. Angle Orthod
2009;79(4):715–726.
342
Deguchi
Grauer D, Proffit WR. Accuracy in tooth positioning with a fully custom-
ized lingual orthodontic appliance. Am J Orthod Dentofacial Orthop
2011;140(3):433-443.
Hammad SM, El-Hawary YM, El-Hawary AK. The use of different analgesics
in orthodontic tooth movements. Angle Orthod 2012;82(5):820–826.
He Y, Appel S, Le W. Minocycline inhibits microglial activation and protects
nigral cells after 6-hydroxydopamine injection into mouse striatum.
Brain Res 2001;909(1-2):187-193.
Hoogeveen EJ, Jansma J, Ren Y. Surgically facilitated orthodontic treat-
ment: A systematic review. Am J Orthod Dentofacial Orthop 2014;145(4
Suppl):S51-S64.
Ichikawa H, Deguchi T, Fujiyoshi Y, Nakago T, Jacobowitz DM, Sugimoto T.
Calbindin-D28k-inmunoreactivity in the trigeminal ganglion neurons
and molar tooth pulp of the rat. Brain Res 1996;715(1-2):71-78.
lchikawa H, Deguchi T, Mitani S, Nakago T, Jacobowitz DM, Yamaai T,
Sugimoto T. Neural parvalbumin and calnetinin in the tooth pulp. Brain
Res 1994a;647(1):124-130.
lchikawa H, Deguchi T, Nakago T, Jacobowitz DM, Sugimoto T. Parvalbumin,
calnetinin and carbonic anhydrase in the trigeminal and spinal primary
neurons of the rat. Brain Res 1994b;655(102):241–245.
lchikawa H, Deguchi T, Nakago T, Jacobowitz DM, Sugimoto T. Parvalbumin-
and calnetinin-immunoreactive trigeminal neurons innervating the rat
molar tooth pulp. Brain Res 1995;679(2):205-211.
lchikawa H, Yabuuchi T, Jin HW, Terayama R, Yamaai T, Deguchi T, Kamioka
H, Takano-Yamamoto T, Sugimoto T. Brain-derived neurotrophic
factor-immunoreactive primary sensory neurons in the rat trigeminal
ganglion and trigeminal sensory nuclei. Brain Res 2006;1081(1):113-
118.
Jones M, Chan C. The pain and discomfort experienced during orthodontic
treatment: A randomized controlled clinical trial of two initial aligning
arch wires. Am J Orthod Dentofacial Orthop 1992;102(4):373-381.
Knop LA, Shintcovsk RL, Retamoso LB, Ribeiro JS, Tanaka OM. Non-steroi-
dal and steroidal anti-inflammatory use in the context of orthodontic
movement. Eur J Orthod 2012;34(5):531-535.
343
Experimental Tooth Movement
Kravitz ND, Kusnoto B, BeGole E, Obrez A, Agran B. How well does
Invisalign work? A prospective clinical study evaluating the efficacy
of tooth movement with Invisalign. Am J Orthod Dentofacial Orthop
2009;135(1):27–35.
Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF,
Watkins LR. Minocycline attenuates mechanical allodynia and proin-
flammatory cytokine expression in rat models of pain facilitation. Pain
2005;115(1-2):71-83.
Lew KK. Attitudes and perceptions of adults towards orthodontic
treatment in an Asian community. Community Dent Oral Epidemiol
1993;21(1):31-35.
Lim HM, Lew KK, Tay DK. A clinical investigation of the efficacy of low
level laser therapy in reducing orthodontic postadjustment pain. Am J
Orthod Dentofacial Orthop 1995;108(6):614-622.
Nagayama T, Seiryu M, Deguchi T, Kano M, Suzuki T, Takano-Yamamoto
T, Ichikawa H. Increase of CGRP-containing nerve fibers in the rat
periodontal ligament after luxation. Cell Mol Neurobiol 2012;32(3):
391-397.
Narita M, Yoshida T, Nakajim M, Narita M, Miyatake M, Takagi T, Yajima
Y, Suzuki T. Direct evidence for spinal cord microglia in the develop-
ment of a neuropathic pain-like state in mice. J Neurochem 2006;97
(5):1337-1348.
Ngan P, Wilson S, Shanfeld J, Amini H. The effect of ibuprofen on the level
of discomfort in patients undergoing orthodontic treatment. Am J
Orthod Dentofacial Orthop 1994;106(1):88-95.
Padi SS, KulkarniSK. Minocycline prevents the development of neuropathic
pain, but not acute pain: Possible anti-inflammatory and antioxidant
mechanisms. Eur J Pharmacol 2008;601(1-3):79-87.
Presley RW, Menétrey D, Levine JD, Basbaum Al. Systemic morphine
suppresses noxious stimulus-evoked Fos protein-like immunoreactivity
in the rat spinal cord. J Neurosci 1990;10(1):323-335.
Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial activation
attenuates the development but not existing hypersensitivity in a rat
model of neuropathy. J Pharmacol Exp Ther 2003;306(2):624–630.
344
Deguchi
Sagar SM, Sharp FR, Curran T. Expression of c-fos protein in brain:
Metabolic mapping at the cellular level. Science 1988;240(4857):
1328–1331.
Seiryu M, Deguchi T, Fujiyama K, Sakai Y, Daimaruya T, Takano-Yamamoto T.
Effects of CO2 laser irradiation of the gingiva during tooth movement.
J Dent Res 2010;89(5):537-542.
Shan S, Oi-Liang MY, Hong C, Tingting L, Mei H, Haili P. Yan-Oing W, Zhi-
Oi Z, Yu-Oju Z. Is functional state of spinal microglia involved in the
anti-allodynic and anti-hyperalgesic effects of electroacupuncture in
rat model of monoarthritis? Neurobiol Dis 2007;26(3):558-568.
Sugawara Y, Kamioka H, Honjo T, Tezuka K, Takano-Yamamoto T. Three-
dimensional reconstruction of chick calvarial osteocytes and their cell
processes using confocal microscopy. Bone 2005;36(5):877-883.
Sugimoto T, Fujiyoshi Y, Xiao C, He YF, Ichikawa H. Central projection
of calcitonin gene-related peptide (CGRP)- and substance P (SP)-
immunoreactive trigeminal primary neurons in the rat. J Comp Neurol
1997;378(3):425-442.
Svensson Cl, Brodin E. Spinal astrocytes in pain processing: Non-neuronal
cells as therapeutic targets. Mol Interv 2010;10(1):25-38.
Svensson M, Eriksson NP, Aldskogius H. Evidence for activation of
astrocytes via reactive microglial cells following hypoglossal nerve
transection. J Neurosci Res 1993;35(4):373-381.
Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against
N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol
2001;166(12):7527-7533.
Tiu SC, Yew DT, Chan WY. Development of the human cerebral cortex: A
histochemical study. Prog Histochem Cytochem 2003;38(1):3-149.
Waldo CM, Rothblatt JM. Histologic response to tooth movement in the
laboratory rat: Procedure and preliminary observations. J Dent Res
1954;33(4):481-486.
Walton DK, Fields HW, Johnston WM, Rosenstiel SF, Firestone AR, Chris-
tensen JC. Orthodontic appliance preferences of children and adoles-
cents. Am J Orthod Dentofacial Orthop 2010;138(6):698.e1-e12.
345
Experimental Tooth Movement
Watkins LR, Maier SF. Glia: A novel drug discovery target for clinical pain.
Nat Rev Drug Discov 2003;2(12):973-985.
Wu Y, Willcockson HH, Maixner W, Light AR. Suramin inhibits spinal cord
microglia activation and long-term hyperalgesia induced by formalin
injection. J Pain 2004;5(1):48-55.
Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neu-
rons, microglia, and astrocytes by spinal nerve ligation and contrib-
utes to mechanical allodynia in this neuropathic pain model. Pain
2005;114(1-2):149-159.
346
UNIVERSITY OF MICHIGAN
3 9015
OO64 1839
1

H
º:
#
º
######## H H
-
--~~
-º-º-º-º:
º
- ºffli
#
#. -
ºffl
---
ºffl
iii.
H
#- H
-- Hº
--- ºffl
H
（H º
Häß - º
Hää H #
- ---
º
- ###### º
---
---
º
º
.
º
º
ºffl
- -- º -
#. # º
ºffl º - H
H # H H
-
#
|-
# -
º º
# º H ---
- Hää i
- i-
- ---
i.
---
- ºffl
-- Häº
--- -
-
------
#########
º
ºffl
#
º
i.
º
--~~
ºffl
º
º
-
º
- --
ºffl
Hä # -
H
º
-
º =#
º
- º
--- -
- º ---
H
- - - --- --- -
- # =###################
- - -
- º
- º --------
H. H.
- - - - - - （ º
º - H - º --- º º
º HHHH - H - H
ºffl i.
-------
ºffli
--- ###########
HH Hº
H
ºfflº- º
ºffl #
º - -- º -
H
º º
---
º º ºffl
Häß
--- ####################
- º - º
-
ºffl º
º
#
#
i- ---
- º
-
--- H H
#
---
--------
- ---
（ ºffli -
- -
H. - º
---
ºffli
ºfflº
ºffl
#
Hä --
ºffl
#
#:
-º-º-º:
-- ºffli
- ############ ---
ºffl
- -
- -
--- º
- - º
Eß.
######
ºffl -
H ==
º Hº: -
º ºffl -
- -
º - --- - ---
º
- ---
（
（--- -
#############
- º - ºffli -
º -- ºffl
# =#|
º
--~~~~
-
---
ºffl
º
-
#
（