Research in Tooth Movement Biology: The

Current Status
Vinod Krishnan, Sajan V. Nair, Ambili Ranjith, and Ze’ev Davidovitch

The increased focus on the biological basis of orthodontics is expanding our

knowledge and is augmenting our understanding of the clinical effects of
mechanical forces on living tissues. This has led to the evolution of a
well-defined technique-oriented profession into a comprehensive specialty,
incorporating facets of all fields of medicine, emphasizing that live human
beings are being treated, not dental typodonts. Research in the field of
orthodontic tooth movement comprised a significant share among articles
published in all orthodontic peer-reviewed journals in the past decade. This
article provides an organized scheme for tooth movement research studies
conducted during the past 5 years, divided into areas such as marker stud-
ies, root resorption, accelerating or decelerating tooth movement, and the
expression of various molecules and cells in the process of mechanical
force-induced tissue remodeling. (Semin Orthod 2012;18:308-316.) © 2012
Elsevier Inc. All rights reserved.

esearch in the field of orthodontic tooth has been delineated.1 This growing attention to
R movement has evolved rapidly in the past
decade, as evidenced by the plethora of manu-
the biological basis of orthodontics expands cur-
rent knowledge and augments understanding of
scripts published in various international peer- the effects of mechanical forces on living tissues
reviewed journals. The fact that judicious appli- in the clinical setting. Due to these develop-
cation of mechanical force can generate optimal ments, orthodontics, which for a long time has
reactions by paradental tissues, at the cellular been viewed as a traditional, established, and
and molecular level, is being documented in well-defined technique-oriented profession, has
current research findings. The importance of steadily evolved into a comprehensive specialty,
each and every tissue, be it alveolar bone, peri- incorporating facets of all fields of medicine,
odontal ligament (PDL), root cementum, and emphasizing that live human beings are being
associated vascular and neural networks, has treated, and not dental typodonts.
been investigated, and the role played by each A search in the PubMed database with the key
words “orthodontic tooth movement” retrieved
5358 articles, and when the search was narrowed
Professor and Head, Department of Orthodontics, Sri Sankara down to “tooth movement” and “orthodontic
Dental College, Trivandrum, Kerala, India. Senior Lecturer, De-
partment of Orthodontics, Sri Sankara Dental College, Trivandrum,
forces,” the number of articles was reduced to
Kerala, India. Reader, Department of Periodontics, PMS College of 672. Most of the articles in this search result
Dental Sciences and Research, Trivandrum, Kerala, India. Clinical were published in the year 2009, followed by
Professor, Department of Orthodontics, School of Dental Medicine, 2011, indicating the significantly increased inter-
Case Western Reserve University, Cleveland, OH; and Chairman
est in this particular area for the past 3-4 years.
Emeritus, Department of Orthodontics, Harvard University School of
Dental Medicine, Boston, MA. This manuscript provides an organized scheme
Address correspondence to Vinod Krishnan, BDS, MDS, MOrth for tooth movement research studies, divided
RCS ED, PhD, Department of Orthodontics, Sri Sankara Dental Col- into areas such as marker studies, root resorp-
lege, Trivandrum, Kerala 659043, India. E-mail: vikrishnan@yahoo. tion, accelerating or decelerating tooth move-
com
© 2012 Elsevier Inc. All rights reserved.
ment, and the expression of various molecules
1073-8746/12/1804-0$30.00/0 and cells in the process of mechanical force-
http://dx.doi.org/10.1053/j.sodo.2012.06.009 induced tissue remodeling. The article focuses

308 Seminars in Orthodontics, Vol 18, No 4 (December), 2012: pp 308-316

 Research in Tooth Movement Biology 309

on research performed in the field of tooth cytokines. Recently, Capelli et al12 examined the
movement for the past 5 years (2006-2011), to GCF levels of MMP-3, MMP-9, MMP-13, and of
provide readers with information about recent the chemokines macrophage inflammatory pro-
research and future research directions. tein (MIP)-1␤, monocyte chemoattractant pro-
tein (MCP)-1, and RANTES (Regulated on Acti-
vation Normal T Cell Expressed and Secreted)
Marker Studies at different time points during orthodontic
tooth movement. Capelli et al12 observed a
Gingival Crevicular Fluid and Orthodontic
statistically significant elevation for MMP-3,
Mechanotherapeutics
MMP-9, and MMP-13 on the compression side of
Gingival crevicular fluid (GCF), a transudate tooth movement after 1 hour of force applica-
from interstitial tissues produced by an osmotic tion, but found it decreasing sharply over the
gradient, consists of a complex mixture of se- next 24 hours. They attributed this finding to an
rum, cells, oral bacteria, and many mediators immediate consumption of enzymes related to
and enzymes of gingival inflammation.2-4 Orth- the degradation of collagen. From 24 hours to
odontic tooth movement–induced tissue remod- 80 days, they observed a progressive increase in
eling is triggered by a sterile inflammatory pro- MMP levels. The findings of Alfaqeeh and Anil13
cess, which increases the vascular permeability as confirmed this progressive increase in collagen
well as the amount of GCF production.5,6 Iwa- degradation with orthodontic force application.
saki and Nickel,6 in a review published in 2009, Alfaqeeh and Anil13 documented an elevation in
provided a detailed list of all markers in the levels of N-telopeptide, a type I collagen degra-
GCF, and categorized them as metabolic prod- dation product, incident to application of orth-
ucts of paradental remodeling, inflammatory odontic forces. Surprisingly, the levels of MCP-1,
mediators, enzymes, and enzyme inhibitors. In- MIP-1␤, and RANTES in GCF did not seem to
creased or elevated levels of prostaglandin E2 be altered by orthodontic force application,12
and interleukin (IL)-1␤ after mechanical force which was contradictory to the previous finding
application were initially described by Saito et that chemokines are upregulated with orth-
al7 and Grieve et al.8 Subsequently, there has odontic force application.14
been a myriad of publications describing the Although the orthodontic literature contains
elevated status of biomolecules in GCF, with me- numerous reports on increased elevation of bio-
chanical force application through orthodontic markers in the GCF after the application of
appliances. Recently, Chibebe et al9 discovered orthodontic forces, the difficulty in sample col-
increased levels of prostaglandin E2 in juveniles, lection, its quantification and localization of
compared with adults, and correlated this find- molecules, interpretation of data, and, more im-
ing with the speed of tooth movement. Accord- portantly, its use in a clinical setting, as well as
ing to Chibebe et al,9 the absence of smoking clinical validity of the results, remain question-
and periodontal disease in juveniles, along with able. Drummond et al,4 through a longitudinal
increased levels of sex hormones, resulted in an randomized split-mouth study, confirmed that
earlier and faster inflammatory response to local the GCF volume, measured with the help of a
changes, leading to a more rapid pace of tooth Periotron 8000 (Oraflow, Inc., Smithtown, NY),
movement. In contrast with juveniles, in adults, after sample collection and comparing with test
with increasing age, there is a decrease in the tooth as well as control tooth at baseline (imme-
proliferation of PDL cells, organic matrix pro- diately before the mounting of the orthodontic
duction, as well as the relative amount of soluble appliance) and after 1 hour, 24 hours, and 7, 14,
collagen and alkaline phosphatase activity. Cel- and 21 days, cannot be taken as a reliable
lular differentiation is also affected with the ag- marker for orthodontic tooth movement, as
ing process, as well as periodontal disease and GCF volume is determined by subclinical inflam-
smoking habits, resulting in a decreased number mation. The results, that GCF volume is not a
of osteoblasts and osteoblast-precursor cells.9-11 reliable marker, suggest that a new, noninvasive,
Enzymes such as matrix metalloproteinases and more reliable procedure needs to be devel-
(MMPs) and leptin have received close attention oped for analyzing and evaluating orthodontic
in the past, as has the role of chemoattractant tooth movement, which will facilitate the stan-
310 Krishnan et al

dardization of the collection, analysis, and clin- excellent textbook by Wong, published in
ical utilization as a powerful diagnostic tool. 2008.17
Although the periodontal literature is replete
with articles on salivary biomarker expression
Salivary Biomarkers and Bone Remodeling patterns in periodontitis patients, orthodontic
publications on this subject are limited in num-
The trend toward the use of body fluids other
ber. Only 2 studies were found in which it was
than blood, such as urine and cerebrospinal
reported that the expression of total proteins is
fluid, to aid in the diagnosis of diseases has been
not altered by mechanical force applied to
replicated in orthodontics by incorporating sa-
teeth.18,19 However, Hussian and Ghaib18 re-
liva as a major diagnostic tool in recent years.
ported a statistically significant decrease in the
The serum components of saliva, which are de-
mean total protein concentration in male sub-
rived primarily from the local vasculature, orig- jects and an insignificant increase in the mean
inating from the carotid arteries, have resulted total protein concentration in female subjects
in saliva being a prodigious fluid source of many while evaluating molecular weight of salivary
molecules found in the systemic circulation, proteins measured with sodium dodecyl sulfate
making it a potentially valuable aid in the diag- polyacrylamide gel electrophoresis in unstimu-
nosis of various systemic diseases.15 Because of lated whole saliva from 50 patients under orth-
the rapid, noninvasive, and easy methods of ac- odontic treatment. Burke et al19 demonstrated a
quiring saliva, which require less manpower and significant difference in cyclic adenosine mono-
materials than for GCF, it is frequently being phosphate-dependent protein kinase subunit
used for diagnosis of periodontal disease. More- (RII) after orthodontic separator placement, in-
over, it represents a pooled sample from all peri- dicating that the cyclic adenosine monophos-
odontal sites, in contrast to GCF. Whole saliva phate pathway is activated after tooth movement
clearly provides an overall assessment of a par- is initiated. It is surprising to see that orthodon-
ticular disease or risk status at the subject level, tic researchers have not used the full potential of
instead of site- or tooth-level assessment in this body fluid, saliva, for assessment of progres-
GCF.16 sive tooth movement with mechanical force ap-
With current advancements in this field of plication.
research, the elevation of or decrease in all host-
derived biomarkers, such as cytokines, chemo-
kines, enzymes, and immunoglobulins, which Markers for Root Resorption
were previously identified from GCF, can be Root resorption is sometimes an unwanted iat-
identified through salivary diagnostics. Peri- rogenic outcome of orthodontic tooth move-
odontal research has used saliva’s potential to ment. Root resorption has been linked to faulty
identify all the biomarkers, such as inflammatory biomechanics and cases where dental roots are
mediators (␤-glucuronidase, C-reactive protein, moved excessively or unnecessarily. Research in
IL-1␤, IL-6, tumor necrosis factor-␣, and MIP- this area suggests several risk factors are associ-
1␣), molecules of connective tissue destruction ated with root resorption, including preexist-
(␣2-macroglobulin, MMPs, tissue inhibitors of ing root conditions, type of tooth movement,
MMPs, aminotransferases, cathepsin, and elas- amount and type of force, and treatment dura-
tase), and bone remodeling biomarkers (alka- tion.20,21 There also exists a racial predilection
line phosphatase, C-terminal cross-linking telo- in its occurrence, with Asians showing fewer pre-
peptide of type I collagen, pyridinoline cross- dilections than whites and Hispanics.5,22,23 Dur-
linked carboxyterminal telopeptide domains of ing the process of root resorption, organic ma-
type I collagen, receptor activator of NF-␬B li- trix proteins and cytokines are released into the
gand [RANKL], osteoprotegerin [OPG], hepa- nearby crevices, and there seems to be a differ-
tocyte growth factors, osteocalcin, and osteonec- ence between levels of these proteins in the GCF
tin), for diagnosis of various stages of disease of subjects undergoing orthodontic treatment
processes.16 For more information on how saliva and with radiographic signs of root resorption
can be used for diagnosis of various systemic and and in those subjects not in treatment and with-
local diseases, the readers are referred to the out radiographic signs of root shortening. Also,
 Research in Tooth Movement Biology 311

differences exist between levels of these pro- Asano et al29 linked the role of the chemo-
teins, such as dentin matrix proteins (DMPs) kines IL-8, cytokine-induced neutrophil che-
and dentin sialoproteins (DSPs), in GCF of sub- moattractant-1, and MCP-1/CCL2 to root re-
jects with mild and severe root resorption, eval- sorption during orthodontic tooth movement.
uated by radiographs.20 Candidate genes associ- The detection of immunoreactivity for cytokine-
ated with external apical root resorption have induced neutrophil chemoattractant-1/CXCR2
been identified, and the list includes IL-1␤, and MCP-1 in odontoclasts and PDL fibroblasts
OPG, RANKL, and osteocalcin, to name a few. It in rats after an orthodontic force of 50 g on day
is likely that differential expression of these mol- 7 was suggestive of the involvement of these
ecules that govern osteoclast/odontoclast func- molecules in root resorption. Extending re-
tion plays a role in determining individual sus- search to the role of antidentine antibodies and
ceptibility to the root resorption process, and the role of autoimmune mechanisms in root
this might be the reason why certain individuals resorption, de Paula Ramos et al30 analyzed se-
may react with exaggerated response.24 rum immunoglobulin G levels and salivary secre-
The importance of biochemical assays in the tory immunoglobulin A (sIgA) levels. They used
early detection of the root resorption process human dentine extract as antigen and showed
was initially demonstrated by Mah and Prasad,25 increased sIgA levels in saliva at the beginning of
who showed elevated levels of dentin phospho- therapy in patients who later showed moderate
proteins in the GCF. Moreover, Balducci et al26 to severe resorption after 6 months of treatment.
reported finding elevated levels of DMP1, DSP, de Paula Ramos et al30 confirmed that in hu-
and dentin phosphophoryn in the GCF of pa- mans, the presence of an abnormal root shape
and initial levels of anti– human dentine extract
tients undergoing orthodontic treatment, in
sIgA in saliva are associated with the degree of
whom there were radiographic signs of root re-
upper central incisor root resorption.
sorption. Because the concentrations of these
The aforementioned discussion suggests that
molecules in the study groups were significantly
dentin degradation products, bone remodeling
higher than those of the control group, the in-
products, cytokines, chemokines, and immuno-
vestigators suggested that these proteins could
globulins, all indicating progressive root resorp-
be potential markers for root resorption. The
tion in patients, can be found in bodily fluids,
findings reported by Mah and Prasad25 were
such as blood, GCF, or salivary samples, and that
recently confirmed by Zuo et al27 in a study on
their fluctuations may reflect an association with
36 Wistar rats, further emphasizing the validity the degree of orthodontic root resorption.31
of DMP1, DSP, and phosphophoryn as markers However, these findings have not yet resulted in
of root resorption during orthodontic treat- widespread use of assays to measure these mark-
ment. George and Evans20 demonstrated the ers in the orthodontic clinic. Further research is
presence of bone matrix proteins, such as osteo- required before the establishment of routine
pontin, cytokines, OPG, and RANKL in subjects tests for the detection of specific biological
showing evidence of root resorption. This rela- markers of orthodontic root resorption. The
tionship of the RANK/RANKL/OPG system avoidance, or minimization, of root resorption
with the root resorption process was further con- may be enhanced by applying appropriate bio-
firmed by Tyrovola et al,28 who had found posi- mechanics in orthodontic tooth movement.
tive correlations between the blood serum
RANKL concentrations and the degree of root
resorption after orthodontic treatment, whereas Altering the Pace and Clinical
blood serum OPG levels declined. These results Electrophysiology of Tooth Movement
suggest that the initial blood serum concentra- Orthodontic tooth movement depends on bone
tions of RANKL/OPG may be used as a predic- remodeling and PDL reorganization along with
tor for root resorption incident to orthodontic neoangiogenesis and excitation of peripheral
treatment. Tyrovola et al28 were the first to re- nerve endings.1 The fundamental principle be-
port on differential levels of RANKL/OPG in hind the efforts to enhance the velocity of tooth
the blood serum of rats with severe orthodontic movement is the concept, emanating from lab-
root resorption. oratory experiments, that has demonstrated that
312 Krishnan et al

cells and tissues in culture are capable of re- cally in human subjects, as these injections were
sponding to ⬎1 stimulus at the same time. The painful and the exaggerated inflammatory re-
cellular response to simultaneous stimuli can be sponse had the possibility of increasing the inci-
inhibitory, additive, or synergistic. In the case of dence of dental root resorption.38,41,42
mechanical force–induced tooth movement, the Although reports on investigations of the ef-
assumption is that the addition of an agent fects of iontophoresis,43 local vibratory stimula-
known to stimulate bone cell activities will en- tion,44 and pulsed electromagnetic fields45 dem-
hance the velocity of tooth movement. Conse- onstrated successful results in accelerating tooth
quently, attempts to shorten orthodontic treat- movement, these methods, likewise, failed to
ment time has attracted increasing interest in gain clinical acceptance because of, at least in
recent years. In a related study, Davidovitch et part, their systemic effects, most commonly dry
al32 applied direct electrical current, noninva- mouth. The current research trend revolves
sively, to cat gingivae near maxillary canines around administration of macrophage colony
while they were being moved for 7 or 14 days, stimulating factor (M-CSF), an early osteoclast
and reported that the combined application of recruitment/differentiation factor, to accelerate
mechanical force and direct electrical current tooth movement.46 Brooks et al46 demonstrated
resulted in significant acceleration of canine that low doses of M-CSF were successful in in-
movement. In addition, an immunohistochemi- creasing the expression of M-CSF downstream
cal examination of the tissues surrounding the genes and tartarate resistant acid phosphatase
canines revealed intense staining for cyclic nu- (TRAP) and increasing the rate of tooth move-
cleotides in gingival fibroblasts and alveolar ment, whereas higher doses failed to do so.
bone periosteal surface cells near the cathode Surgical approaches to accelerate tooth
and anode (Fig 1). Enhanced bone resorption movement date back to 1966, when Byloff-Clar47
was observed near the anode (PDL compression demonstrated, by use of his histologic studies,
site), whereas bone formation was pronounced the advantages of corticotomy-assisted tooth
near the cathode (PDL tension site). In a pre- movement. Tenenbaum, a Spanish orthodontist,
liminary clinical trial in young adult patients, a in 1970, reported the technique in detail.48
similar enhancement of canine movement has Later, articles were published in the orthodontic
been observed (Davidovitch et al, unpublished and related literature, outlining the advanta-
data). Recently, a noninvasive removable enzy- geous nature of surgery, as far as accelerating
matic microbattery, using glucose as a fuel, was tooth movement is concerned.49-53 Recently, al-
developed to administer minute electric cur- veolar augmentation with bone grafting, named
rents to the alveolar bone and oral soft-tissues, periodontally accelerated osteogenic orthodon-
thus becoming a possible source of the electrical tics, has been propagated by Wilcko et al,54
power required for accelerating the velocity of which demonstrated promising acceleration of
orthodontic tooth movement.33 the tooth movement process. Readers are re-
Based on the ability of cells to respond to ferred to the article by Murphy et al55 in this
simultaneously applied stimulatory signals, at- issue of Seminars in Orthodontics for a detailed
tempts were made to accelerate the pace of review of the technique and its historical per-
tooth movement with specific molecules, espe- spective. Iglesias-Linares et al56 compared corti-
cially those that had been found to be intimately cotomy and induced RANKL overexpression
involved in inflammation and bone healing. and concluded that although the corticotomy
One of the first messengers in this regard were group showed a greater initial tooth movement
prostaglandins, the inflammatory mediators increase, it experienced a gradual decrease due
known to be involved in tooth movement. Yama- to the decrease in RANKL levels and the lower
saki et al34 demonstrated accelerated tooth TRAP⫹ cell counts. However, induction of
movement with local application of prostaglan- RANKL overexpression increased tooth move-
din E1, without any adverse effects on local tis- ment to 41.27% compared with the control
sues. This effect was studied further by the same group.
researchers33 and others35-40 and was found to The aforementioned reports strongly suggest
be effective in accelerating tooth movement. that orthodontic treatment can be accelerated
However, the approach was not successful clini- by a combined application of mechanical force
 Research in Tooth Movement Biology 313

Figure 1. (A) Constant direct current, 20 mA, noninvasively, to the gingival and oral mucosa labial to the left
canine of a cat. The right canine (control) received the same electrodes but without electrical current. Both
canines were moved distally by an 80-g tipping force. The right canine, which had been subjected only to
mechanical force, moved distally a smaller distance than the left canine, which had been administered a
combination of mechanical force and electrical current. Transverse section, 6-mm thick, of a 1-year-old female
cat’s mandible, after a 7-day exposure to sham electrodes (B) and constant application of a 20-mA direct current
to the gingival mucosa, noninvasively (C). Bone denotes alveolar bone. The bone surface lining cells near the
anode are flat and most stain lightly for cyclic adenosine monophosphate (⫻640 in B), whereas the bone surface
lining cells near the cathode are larger and more darkly stained for cyclic adenosine monophosphate (⫻640 in
C). (Color version of figure is available online.)

and another stimulatory agent, physical or its incorporation into regular orthodontic prac-
chemical, to teeth that need to be moved. The tice is still in the nascent stages.
research along this avenue is continuing, and
the prize remains the discovery of a practical way Alveolar Bone Density and Tooth
to correct malocclusions in a short time, effi- Movement
ciently, and without creating undesirable side
effects. Current ongoing research on stem cell The use of cone-beam computed tomography
therapy is showing promising results, although and microtomography in orthodontic research
314 Krishnan et al

has provided great insights into alveolar bone tooth movement had no effect on relapse, but a
density changes incident to tooth moving forces. significant positive correlation was found be-
With the help of 3-dimensional computer mod- tween the amount of active tooth movement and
els generated out of cone-beam computed to- both the rate and the total amount of relapse.
mography images, Chang et al57 demonstrated However, a contradictory result was published
maximum bone density reduction toward the recently by Kilic et al,63 who stated that there
side of tooth movement. Contradictory results exists a close relationship between the amount
with microtomography analysis were obtained by of relapse and orthodontic force magnitude.
Zhuang et al,58 who found that the bone fraction They further reported that greater relapse oc-
increased significantly after orthodontic force curred during the initial days after appliance
was applied for 2 weeks, and trabecular separa- removal and emphasized the importance of in-
tion decreased significantly with a higher orth- serting retention devices immediately after the
odontic force (100 g). The results of Zhuang et removal of orthodontic appliances.
al58 suggest that the microarchitecture of the On reviewing the literature on orthodontic
alveolar trabecular bone becomes denser, so it relapse, a significant lack of research data was
can adapt to greater mechanical stresses. This noted regarding this important issue. Moreover,
finding was in concordance with previous find- the existing literature also reports controversial
ings by Garat et al59 in periodontitis patients. findings, introducing much ambiguity regarding
Garat et al59 demonstrated that, after periodon- relapse. This paucity of information weakens the
tal infection is controlled, orthodontic force ap- foundations of orthodontics and indicates the
plication results in increased bone volume with
urgent need for a more structured research ap-
improved quality. All these results indicate the
proach, in both animal models and humans, to
still inconclusive data on how alveolar bone be-
provide clinicians with more evidence-based re-
haves in response to orthodontic force applica-
sults.
tion.

Orthodontic Relapse
Conclusions
Orthodontic relapse, an area of most significant
Basic researchers continue, at an increasing
orthodontic importance, although much less in-
pace, to contribute to the advancement of clin-
vestigated, has been receiving attention recently.
ical orthodontics. These researchers benefit
Maltha and Kuijpers-Jagtman60 reported that
the histologic changes occurring during the im- from the publication of the outcomes of well-
mediate posttreatment period, where maximum planned investigations in every field of medi-
relapse changes are observed, are identical to cine. From these interactions, orthodontic re-
those observed when performing active orth- searchers have selected areas that may be helpful
odontic tooth movement, with creation of pres- in addressing clinical issues faced by the ortho-
sure and tension areas, but in a reverse direc- dontist on a daily basis. The biological unique-
tion. They concluded that the rate of collagen ness of each patient dictates the need for con-
turnover in the PDL ligament and gingiva was tinuous acquisition of knowledge. The present
very fast, ruling out its role in relapse tenden- focus is on areas, such as monitoring the reac-
cies. They suggested the role of other extra- tion of patients to mechanical forces by search-
cellular matrix proteins in producing orth- ing for bone remodeling markers in the GCF,
odontic relapse. In their study on rat incisors, saliva, and blood serum. Attention is paid to the
King et al61 concluded that tooth movement speed of tooth movement, and efforts are made
relapses at a rate of approximately 14 ␮m to enhance it, by adding certain physical and
(0.014 mm) per day after 16 days of orthodon- chemical agents to the mechanical orthodontic
tic treatment. force. Orthodontic researchers have had major
van Leeuwen et al62 investigated the role of accomplishments, but new challenges have
retention in preventing orthodontic relapse in a arisen, requiring continuation of the investiga-
model of adult beagle dogs. They concluded tive effort both in the research laboratory and
that the force magnitude applied during active the associated clinic.
 Research in Tooth Movement Biology 315

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