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Research in Tooth Movement Biology: TheCurrent StatusVinod 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.

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R esearch in the field of orthodontic toothmovement has evolved rapidly in the past

ecade, as evidenced by the plethora of manu-cripts published in various international peer-eviewed journals. The fact that judicious appli-ation of mechanical force can generate optimaleactions by paradental tissues, at the cellularnd molecular level, is being documented inurrent research findings. The importance ofach and every tissue, be it alveolar bone, peri-dontal ligament (PDL), root cementum, andssociated vascular and neural networks, haseen investigated, and the role played by each

Professor and Head, Department of Orthodontics, Sri SankaraDental College, Trivandrum, Kerala, India. Senior Lecturer, De-partment of Orthodontics, Sri Sankara Dental College, Trivandrum,Kerala, India. Reader, Department of Periodontics, PMS College ofDental Sciences and Research, Trivandrum, Kerala, India. ClinicalProfessor, Department of Orthodontics, School of Dental Medicine,Case Western Reserve University, Cleveland, OH; and ChairmanEmeritus, Department of Orthodontics, Harvard University School ofDental Medicine, Boston, MA.

Address correspondence to Vinod Krishnan, BDS, MDS, MOrthRCS ED, PhD, Department of Orthodontics, Sri Sankara Dental Col-lege, Trivandrum, Kerala 659043, India. E-mail: vikrishnan@yahoo.om

© 2012 Elsevier Inc. All rights reserved.1073-8746/12/1804-0$30.00/0

ihttp://dx.doi.org/10.1053/j.sodo.2012.06.009

308 Seminars in Orthodontics, Vol 18, No

as been delineated.1 This growing attention tohe biological basis of orthodontics expands cur-ent knowledge and augments understanding ofhe effects of mechanical forces on living tissuesn the clinical setting. Due to these develop-

ents, orthodontics, which for a long time haseen viewed as a traditional, established, andell-defined technique-oriented profession, has

teadily evolved into a comprehensive specialty,ncorporating facets of all fields of medicine,mphasizing that live human beings are beingreated, and not dental typodonts.

A search in the PubMed database with the keyords “orthodontic tooth movement” retrieved358 articles, and when the search was narrowedown to “tooth movement” and “orthodonticorces,” the number of articles was reduced to72. Most of the articles in this search resultere published in the year 2009, followed by011, indicating the significantly increased inter-st in this particular area for the past 3-4 years.his manuscript provides an organized scheme

or tooth movement research studies, dividednto areas such as marker studies, root resorp-ion, accelerating or decelerating tooth move-

ent, and the expression of various moleculesnd cells in the process of mechanical force-

nduced tissue remodeling. The article focuses

4 (December), 2012: pp 308-316

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309Research in Tooth Movement Biology

on research performed in the field of toothmovement for the past 5 years (2006-2011), toprovide readers with information about recentresearch and future research directions.

Marker Studies

Gingival Crevicular Fluid and OrthodonticMechanotherapeutics

Gingival crevicular fluid (GCF), a transudatefrom interstitial tissues produced by an osmoticgradient, consists of a complex mixture of se-rum, cells, oral bacteria, and many mediatorsand enzymes of gingival inflammation.2-4 Orth-odontic tooth movement–induced tissue remod-eling is triggered by a sterile inflammatory pro-cess, which increases the vascular permeability aswell as the amount of GCF production.5,6 Iwa-aki and Nickel,6 in a review published in 2009,

provided a detailed list of all markers in theGCF, and categorized them as metabolic prod-ucts of paradental remodeling, inflammatorymediators, enzymes, and enzyme inhibitors. In-creased or elevated levels of prostaglandin E2and interleukin (IL)-1� after mechanical forceapplication were initially described by Saito etal7 and Grieve et al.8 Subsequently, there has

een a myriad of publications describing thelevated status of biomolecules in GCF, with me-hanical force application through orthodonticppliances. Recently, Chibebe et al9 discovered

increased levels of prostaglandin E2 in juveniles,compared with adults, and correlated this find-ing with the speed of tooth movement. Accord-ing to Chibebe et al,9 the absence of smokingand periodontal disease in juveniles, along withincreased levels of sex hormones, resulted in anearlier and faster inflammatory response to localchanges, leading to a more rapid pace of toothmovement. In contrast with juveniles, in adults,with increasing age, there is a decrease in theproliferation of PDL cells, organic matrix pro-duction, as well as the relative amount of solublecollagen and alkaline phosphatase activity. Cel-lular differentiation is also affected with the ag-ing process, as well as periodontal disease andsmoking habits, resulting in a decreased numberof osteoblasts and osteoblast-precursor cells.9-11

Enzymes such as matrix metalloproteinases(MMPs) and leptin have received close attention

in the past, as has the role of chemoattractant t

cytokines. Recently, Capelli et al12 examined theGCF levels of MMP-3, MMP-9, MMP-13, and ofthe chemokines macrophage inflammatory pro-tein (MIP)-1�, monocyte chemoattractant pro-tein (MCP)-1, and RANTES (Regulated on Acti-vation Normal T Cell Expressed and Secreted)at different time points during orthodontictooth movement. Capelli et al12 observed atatistically significant elevation for MMP-3,MP-9, and MMP-13 on the compression side of

ooth movement after 1 hour of force applica-ion, but found it decreasing sharply over theext 24 hours. They attributed this finding to an

mmediate consumption of enzymes related tohe degradation of collagen. From 24 hours to0 days, they observed a progressive increase inMP levels. The findings of Alfaqeeh and Anil13

confirmed this progressive increase in collagendegradation with orthodontic force application.Alfaqeeh and Anil13 documented an elevation inevels of N-telopeptide, a type I collagen degra-ation product, incident to application of orth-dontic forces. Surprisingly, the levels of MCP-1,IP-1�, and RANTES in GCF did not seem to

be altered by orthodontic force application,12

which was contradictory to the previous findingthat chemokines are upregulated with orth-odontic force application.14

Although the orthodontic literature containsnumerous reports on increased elevation of bio-markers in the GCF after the application oforthodontic forces, the difficulty in sample col-lection, its quantification and localization ofmolecules, interpretation of data, and, more im-portantly, its use in a clinical setting, as well asclinical validity of the results, remain question-able. Drummond et al,4 through a longitudinalandomized split-mouth study, confirmed thathe GCF volume, measured with the help of aeriotron 8000 (Oraflow, Inc., Smithtown, NY),fter sample collection and comparing with testooth as well as control tooth at baseline (imme-iately before the mounting of the orthodonticppliance) and after 1 hour, 24 hours, and 7, 14,nd 21 days, cannot be taken as a reliablearker for orthodontic tooth movement, asCF volume is determined by subclinical inflam-ation. The results, that GCF volume is not a

eliable marker, suggest that a new, noninvasive,nd more reliable procedure needs to be devel-ped for analyzing and evaluating orthodontic

ooth movement, which will facilitate the stan-

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310 Krishnan et al

dardization of the collection, analysis, and clin-ical utilization as a powerful diagnostic tool.

Salivary Biomarkers and Bone Remodeling

The trend toward the use of body fluids otherthan blood, such as urine and cerebrospinalfluid, to aid in the diagnosis of diseases has beenreplicated in orthodontics by incorporating sa-liva as a major diagnostic tool in recent years.The serum components of saliva, which are de-rived primarily from the local vasculature, orig-inating from the carotid arteries, have resultedin saliva being a prodigious fluid source of manymolecules found in the systemic circulation,making it a potentially valuable aid in the diag-nosis of various systemic diseases.15 Because ofhe rapid, noninvasive, and easy methods of ac-uiring saliva, which require less manpower andaterials than for GCF, it is frequently being

sed for diagnosis of periodontal disease. More-ver, it represents a pooled sample from all peri-dontal sites, in contrast to GCF. Whole salivalearly provides an overall assessment of a par-icular disease or risk status at the subject level,nstead of site- or tooth-level assessment inCF.16

With current advancements in this field ofresearch, the elevation of or decrease in all host-derived biomarkers, such as cytokines, chemo-kines, enzymes, and immunoglobulins, whichwere previously identified from GCF, can beidentified through salivary diagnostics. Peri-odontal research has used saliva’s potential toidentify all the biomarkers, such as inflammatorymediators (�-glucuronidase, C-reactive protein,L-1�, IL-6, tumor necrosis factor-�, and MIP-�), molecules of connective tissue destruction

(�2-macroglobulin, MMPs, tissue inhibitors ofMMPs, aminotransferases, cathepsin, and elas-tase), and bone remodeling biomarkers (alka-line phosphatase, C-terminal cross-linking telo-peptide of type I collagen, pyridinoline cross-linked carboxyterminal telopeptide domains oftype I collagen, receptor activator of NF-�B li-gand [RANKL], osteoprotegerin [OPG], hepa-tocyte growth factors, osteocalcin, and osteonec-tin), for diagnosis of various stages of diseaseprocesses.16 For more information on how salivaan be used for diagnosis of various systemic and

ocal diseases, the readers are referred to the

xcellent textbook by Wong, published in008.17

Although the periodontal literature is repletewith articles on salivary biomarker expressionpatterns in periodontitis patients, orthodonticpublications on this subject are limited in num-ber. Only 2 studies were found in which it wasreported that the expression of total proteins isnot altered by mechanical force applied toteeth.18,19 However, Hussian and Ghaib18 re-ported a statistically significant decrease in themean total protein concentration in male sub-jects and an insignificant increase in the meantotal protein concentration in female subjectswhile evaluating molecular weight of salivaryproteins measured with sodium dodecyl sulfatepolyacrylamide gel electrophoresis in unstimu-lated whole saliva from 50 patients under orth-odontic treatment. Burke et al19 demonstrated asignificant difference in cyclic adenosine mono-phosphate-dependent protein kinase subunit(RII) after orthodontic separator placement, in-dicating that the cyclic adenosine monophos-phate pathway is activated after tooth movementis initiated. It is surprising to see that orthodon-tic researchers have not used the full potential ofthis body fluid, saliva, for assessment of progres-sive tooth movement with mechanical force ap-plication.

Markers for Root Resorption

Root resorption is sometimes an unwanted iat-rogenic outcome of orthodontic tooth move-ment. Root resorption has been linked to faultybiomechanics and cases where dental roots aremoved excessively or unnecessarily. Research inthis area suggests several risk factors are associ-ated with root resorption, including preexist-ing root conditions, type of tooth movement,amount and type of force, and treatment dura-tion.20,21 There also exists a racial predilectionn its occurrence, with Asians showing fewer pre-ilections than whites and Hispanics.5,22,23 Dur-

ing the process of root resorption, organic ma-trix proteins and cytokines are released into thenearby crevices, and there seems to be a differ-ence between levels of these proteins in the GCFof subjects undergoing orthodontic treatmentand with radiographic signs of root resorptionand in those subjects not in treatment and with-

out radiographic signs of root shortening. Also,

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311Research in Tooth Movement Biology

differences exist between levels of these pro-teins, such as dentin matrix proteins (DMPs)and dentin sialoproteins (DSPs), in GCF of sub-jects with mild and severe root resorption, eval-uated by radiographs.20 Candidate genes associ-ted with external apical root resorption haveeen identified, and the list includes IL-1�,PG, RANKL, and osteocalcin, to name a few. It

s likely that differential expression of these mol-cules that govern osteoclast/odontoclast func-ion plays a role in determining individual sus-eptibility to the root resorption process, andhis might be the reason why certain individuals

ay react with exaggerated response.24

The importance of biochemical assays in theearly detection of the root resorption processwas initially demonstrated by Mah and Prasad,25

who showed elevated levels of dentin phospho-proteins in the GCF. Moreover, Balducci et al26

reported finding elevated levels of DMP1, DSP,and dentin phosphophoryn in the GCF of pa-tients undergoing orthodontic treatment, inwhom there were radiographic signs of root re-sorption. Because the concentrations of thesemolecules in the study groups were significantlyhigher than those of the control group, the in-vestigators suggested that these proteins couldbe potential markers for root resorption. Thefindings reported by Mah and Prasad25 wererecently confirmed by Zuo et al27 in a study on6 Wistar rats, further emphasizing the validityf DMP1, DSP, and phosphophoryn as markersf root resorption during orthodontic treat-ent. George and Evans20 demonstrated the

presence of bone matrix proteins, such as osteo-pontin, cytokines, OPG, and RANKL in subjectsshowing evidence of root resorption. This rela-tionship of the RANK/RANKL/OPG systemwith the root resorption process was further con-firmed by Tyrovola et al,28 who had found posi-tive correlations between the blood serumRANKL concentrations and the degree of rootresorption after orthodontic treatment, whereasblood serum OPG levels declined. These resultssuggest that the initial blood serum concentra-tions of RANKL/OPG may be used as a predic-tor for root resorption incident to orthodontictreatment. Tyrovola et al28 were the first to re-

ort on differential levels of RANKL/OPG inhe blood serum of rats with severe orthodontic

oot resorption.

Asano et al29 linked the role of the chemo-ines IL-8, cytokine-induced neutrophil che-oattractant-1, and MCP-1/CCL2 to root re-

orption during orthodontic tooth movement.he detection of immunoreactivity for cytokine-

nduced neutrophil chemoattractant-1/CXCR2nd MCP-1 in odontoclasts and PDL fibroblastsn rats after an orthodontic force of 50 g on day

was suggestive of the involvement of theseolecules in root resorption. Extending re-

earch to the role of antidentine antibodies andhe role of autoimmune mechanisms in rootesorption, de Paula Ramos et al30 analyzed se-um immunoglobulin G levels and salivary secre-ory immunoglobulin A (sIgA) levels. They useduman dentine extract as antigen and showed

ncreased sIgA levels in saliva at the beginning ofherapy in patients who later showed moderateo severe resorption after 6 months of treatment.e Paula Ramos et al30 confirmed that in hu-

mans, the presence of an abnormal root shapeand initial levels of anti–human dentine extractsIgA in saliva are associated with the degree ofupper central incisor root resorption.

The aforementioned discussion suggests thatdentin degradation products, bone remodelingproducts, cytokines, chemokines, and immuno-globulins, all indicating progressive root resorp-tion in patients, can be found in bodily fluids,such as blood, GCF, or salivary samples, and thattheir fluctuations may reflect an association withthe degree of orthodontic root resorption.31

However, these findings have not yet resulted inwidespread use of assays to measure these mark-ers in the orthodontic clinic. Further research isrequired before the establishment of routinetests for the detection of specific biologicalmarkers of orthodontic root resorption. Theavoidance, or minimization, of root resorptionmay be enhanced by applying appropriate bio-mechanics in orthodontic tooth movement.

Altering the Pace and ClinicalElectrophysiology of Tooth Movement

Orthodontic tooth movement depends on boneremodeling and PDL reorganization along withneoangiogenesis and excitation of peripheralnerve endings.1 The fundamental principle be-hind the efforts to enhance the velocity of toothmovement is the concept, emanating from lab-

oratory experiments, that has demonstrated that

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cells and tissues in culture are capable of re-sponding to �1 stimulus at the same time. Thecellular response to simultaneous stimuli can beinhibitory, additive, or synergistic. In the case ofmechanical force–induced tooth movement, theassumption is that the addition of an agentknown to stimulate bone cell activities will en-hance the velocity of tooth movement. Conse-quently, attempts to shorten orthodontic treat-ment time has attracted increasing interest inrecent years. In a related study, Davidovitch etal32 applied direct electrical current, noninva-sively, to cat gingivae near maxillary canineswhile they were being moved for 7 or 14 days,and reported that the combined application ofmechanical force and direct electrical currentresulted in significant acceleration of caninemovement. In addition, an immunohistochemi-cal examination of the tissues surrounding thecanines revealed intense staining for cyclic nu-cleotides in gingival fibroblasts and alveolarbone periosteal surface cells near the cathodeand anode (Fig 1). Enhanced bone resorptionwas observed near the anode (PDL compressionsite), whereas bone formation was pronouncednear the cathode (PDL tension site). In a pre-liminary clinical trial in young adult patients, asimilar enhancement of canine movement hasbeen observed (Davidovitch et al, unpublisheddata). Recently, a noninvasive removable enzy-matic microbattery, using glucose as a fuel, wasdeveloped to administer minute electric cur-rents to the alveolar bone and oral soft-tissues,thus becoming a possible source of the electricalpower required for accelerating the velocity oforthodontic tooth movement.33

Based on the ability of cells to respond tosimultaneously applied stimulatory signals, at-tempts were made to accelerate the pace oftooth movement with specific molecules, espe-cially those that had been found to be intimatelyinvolved in inflammation and bone healing.One of the first messengers in this regard wereprostaglandins, the inflammatory mediatorsknown to be involved in tooth movement. Yama-saki et al34 demonstrated accelerated toothmovement with local application of prostaglan-din E1, without any adverse effects on local tis-sues. This effect was studied further by the sameresearchers33 and others35-40 and was found to

e effective in accelerating tooth movement.

owever, the approach was not successful clini-

ally in human subjects, as these injections wereainful and the exaggerated inflammatory re-ponse had the possibility of increasing the inci-ence of dental root resorption.38,41,42

Although reports on investigations of the ef-fects of iontophoresis,43 local vibratory stimula-ion,44 and pulsed electromagnetic fields45 dem-

onstrated successful results in accelerating toothmovement, these methods, likewise, failed togain clinical acceptance because of, at least inpart, their systemic effects, most commonly drymouth. The current research trend revolvesaround administration of macrophage colonystimulating factor (M-CSF), an early osteoclastrecruitment/differentiation factor, to acceleratetooth movement.46 Brooks et al46 demonstratedhat low doses of M-CSF were successful in in-reasing the expression of M-CSF downstreamenes and tartarate resistant acid phosphataseTRAP) and increasing the rate of tooth move-ent, whereas higher doses failed to do so.Surgical approaches to accelerate tooth

ovement date back to 1966, when Byloff-Clar47

demonstrated, by use of his histologic studies,the advantages of corticotomy-assisted toothmovement. Tenenbaum, a Spanish orthodontist,in 1970, reported the technique in detail.48

Later, articles were published in the orthodonticand related literature, outlining the advanta-geous nature of surgery, as far as acceleratingtooth movement is concerned.49-53 Recently, al-veolar augmentation with bone grafting, namedperiodontally accelerated osteogenic orthodon-tics, has been propagated by Wilcko et al,54

which demonstrated promising acceleration ofthe tooth movement process. Readers are re-ferred to the article by Murphy et al55 in thisssue of Seminars in Orthodontics for a detailedeview of the technique and its historical per-pective. Iglesias-Linares et al56 compared corti-

cotomy and induced RANKL overexpressionand concluded that although the corticotomygroup showed a greater initial tooth movementincrease, it experienced a gradual decrease dueto the decrease in RANKL levels and the lowerTRAP� cell counts. However, induction ofRANKL overexpression increased tooth move-ment to 41.27% compared with the controlgroup.

The aforementioned reports strongly suggestthat orthodontic treatment can be accelerated

by a combined application of mechanical force

313Research in Tooth Movement Biology

and another stimulatory agent, physical orchemical, to teeth that need to be moved. Theresearch along this avenue is continuing, andthe prize remains the discovery of a practical wayto correct malocclusions in a short time, effi-ciently, and without creating undesirable sideeffects. Current ongoing research on stem cell

Figure 1. (A) Constant direct current, 20 mA, nonincanine of a cat. The right canine (control) receivedcanines were moved distally by an 80-g tipping forcmechanical force, moved distally a smaller distancecombination of mechanical force and electrical currecat’s mandible, after a 7-day exposure to sham electrodto the gingival mucosa, noninvasively (C). Bone denoanode are flat and most stain lightly for cyclic adenosinlining cells near the cathode are larger and more darC). (Color version of figure is available online.)

therapy is showing promising results, although

its incorporation into regular orthodontic prac-tice is still in the nascent stages.

Alveolar Bone Density and ToothMovement

The use of cone-beam computed tomography

ely, to the gingival and oral mucosa labial to the leftsame electrodes but without electrical current. Bothhe right canine, which had been subjected only ton the left canine, which had been administered aransverse section, 6-mm thick, of a 1-year-old female

B) and constant application of a 20-mA direct currentlveolar bone. The bone surface lining cells near the

onophosphate (�640 in B), whereas the bone surfaceained for cyclic adenosine monophosphate (�640 in

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has provided great insights into alveolar bonedensity changes incident to tooth moving forces.With the help of 3-dimensional computer mod-els generated out of cone-beam computed to-mography images, Chang et al57 demonstrated

aximum bone density reduction toward theide of tooth movement. Contradictory resultsith microtomography analysis were obtained byhuang et al,58 who found that the bone fraction

increased significantly after orthodontic forcewas applied for 2 weeks, and trabecular separa-tion decreased significantly with a higher orth-odontic force (100 g). The results of Zhuang etal58 suggest that the microarchitecture of thelveolar trabecular bone becomes denser, so itan adapt to greater mechanical stresses. Thisnding was in concordance with previous find-

ngs by Garat et al59 in periodontitis patients.Garat et al59 demonstrated that, after periodon-tal infection is controlled, orthodontic force ap-plication results in increased bone volume withimproved quality. All these results indicate thestill inconclusive data on how alveolar bone be-haves in response to orthodontic force applica-tion.

Orthodontic Relapse

Orthodontic relapse, an area of most significantorthodontic importance, although much less in-vestigated, has been receiving attention recently.Maltha and Kuijpers-Jagtman60 reported thathe histologic changes occurring during the im-

ediate posttreatment period, where maximumelapse changes are observed, are identical tohose observed when performing active orth-dontic tooth movement, with creation of pres-ure and tension areas, but in a reverse direc-ion. They concluded that the rate of collagenurnover in the PDL ligament and gingiva wasery fast, ruling out its role in relapse tenden-ies. They suggested the role of other extra-ellular matrix proteins in producing orth-dontic relapse. In their study on rat incisors,ing et al61 concluded that tooth movement

relapses at a rate of approximately 14 �m0.014 mm) per day after 16 days of orthodon-ic treatment.

van Leeuwen et al62 investigated the role ofretention in preventing orthodontic relapse in amodel of adult beagle dogs. They concluded

that the force magnitude applied during active

tooth movement had no effect on relapse, but asignificant positive correlation was found be-tween the amount of active tooth movement andboth the rate and the total amount of relapse.However, a contradictory result was publishedrecently by Kilic et al,63 who stated that therexists a close relationship between the amountf relapse and orthodontic force magnitude.hey further reported that greater relapse oc-urred during the initial days after applianceemoval and emphasized the importance of in-erting retention devices immediately after theemoval of orthodontic appliances.

On reviewing the literature on orthodonticelapse, a significant lack of research data wasoted regarding this important issue. Moreover,

he existing literature also reports controversialndings, introducing much ambiguity regardingelapse. This paucity of information weakens theoundations of orthodontics and indicates thergent need for a more structured research ap-roach, in both animal models and humans, torovide clinicians with more evidence-based re-ults.

Conclusions

Basic researchers continue, at an increasingpace, to contribute to the advancement of clin-ical orthodontics. These researchers benefitfrom the publication of the outcomes of well-planned investigations in every field of medi-cine. From these interactions, orthodontic re-searchers have selected areas that may be helpfulin addressing clinical issues faced by the ortho-dontist on a daily basis. The biological unique-ness of each patient dictates the need for con-tinuous acquisition of knowledge. The presentfocus is on areas, such as monitoring the reac-tion of patients to mechanical forces by search-ing for bone remodeling markers in the GCF,saliva, and blood serum. Attention is paid to thespeed of tooth movement, and efforts are madeto enhance it, by adding certain physical andchemical agents to the mechanical orthodonticforce. Orthodontic researchers have had majoraccomplishments, but new challenges havearisen, requiring continuation of the investiga-tive effort both in the research laboratory and

the associated clinic.

315Research in Tooth Movement Biology

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biological mechanisms of orthodontic tooth movement.J Dent Res 88:597-608, 2009

2. Uitto VJ: Gingival crevice fluid—An introduction. Peri-odontol 2000 31:9-11, 2003

3. Pashley DH: A mechanistic analysis of gingival fluid pro-duction. J Periodontal Res 11:121-134, 1976

4. Drummond S, Canavarro C, Perinetti G, et al: The mon-itoring of gingival crevicular fluid volume during orth-odontic treatment: A longitudinal randomized split-mouth study. Eur J Orthod 34:109-113, 2012

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8. Grieve WG, Johnson GK, Moore RN, et al: ProstaglandinE (PGE) and interleukin-1� (IL-1�) levels in gingivalcrevicular fluid during human orthodontic tooth move-ment. Am J Orthod Dentofacial Orthop 105:69-374,1994

9. Chibebe PC, Starobinas N, Pallos D: Juveniles versusadults: Differences in PGE2 levels in the gingival crevic-ular fluid during orthodontic tooth movement. BrazOral Res 24:108-113, 2010

10. Ohzeki K, Yamaguchi M, Shimizu N, et al: Effect ofcellular aging on the induction of cyclooxygenase-2 bymechanical stress in human periodontal ligament cells.Mech Ageing Dev 108:151-163, 1999

11. Ren Y, Maltha JC, Van’t Hof MA, , et al: Cytokine levelsin crevice fluid are less responsive to orthodontic forcein adults than in juveniles. J Clin Periodontol 8:757-762,2002

12. Capelli J Jr, Kantarci A, Haffajee A, et al: Matrix metal-loproteinases and chemokines in the gingival crevicularfluid during orthodontic tooth movement. Eur J Orthod33:705-711, 2011

13. Alfaqeeh SA, Anil S: Osteocalcin and N-telopeptides oftype I collagen marker levels in gingival crevicular fluidduring different stages of orthodontic tooth movement.Am J Orthod Dentofacial Orthop 139:e553-e559, 2011

14. Alhashimi N, Frithiof L, Brudvik P, et al: Chemokinesare upregulated during orthodontic tooth movement.J Interferon Cytokine Res 19:1047-1052, 1999

15. Johnson LR: Salivary secretion, in Johnson LR (ed):Gastrointestinal Physiology. St. Louis, MO, Mosby. (Edi-tion 6), 2001, pp 65-74

16. Miller CS, Foley JD, Bailey AL, et al: Current develop-ments in salivary diagnostics. Biomark Med 4:171-189,2010

17. Wong DT (ed): Salivary Diagnostics. Philadelpha, PA,

John Wiley & Sons, 2008, pp 1-320

18. Hussian SF, Ghaib NH: Expression of secretary proteinsin whole unstimulated saliva before and after placementof orthodontic elastic separators in Iraqi samples (clini-cal study). Iraqi Orthod J 1:xxi-xxii, 2005

19. Burke JC, Evans CA, Crosby TR, et al: Expression ofsecretory proteins in oral fluid after orthodontic toothmovement. Am J Orthod Dentofacial Orthop 121:310-315, 2002

20. George A, Evans CA: Detection of root resorption usingdentin and bone markers. Orthod Craniofac Res 12:229-235, 2009

21. Motokawa M, Sasamoto T, Kaku M, et al: Associationbetween root resorption incident to orthodontic treat-ment and treatment factors. Eur J Orthod 34:350-356,2012

22. Krishnan V: Critical issues concerning root resorption: Acontemporary review. World J Orthod 6:30-40, 2005

23. Abass KS, Hartsfield JK Jr: Orthodontics and externalapical root resorption. Semin Orthod 13:246-256, 2007

24. Krishnan V: Mechanical and biological determinants ofiatrogenic injuries in orthodontics, in Krishnan V, Davi-dovitch Z (eds): Biological Mechanisms of Tooth Move-ment. Oxford, UK, Wiley-Blackwell, 2009, pp 215-233

25. Mah J, Prasad N: Dentine phosphoproteins in gingivalcrevicular fluid during root resorption. Eur J Orthod26:25-30, 2004

26. Balducci L, Ramachandran A, Hao J, et al: Biologicalmarkers for evaluation of root resorption. Arch OralBiol 52:203-208, 2007

27. Zuo ZG, Hu M, Jiang H, et al: Relationship betweenorthodontic root resorption following experimentaltooth movement and the level of dentin sialoph-ospho-protein and dentin sialoprotein in gingival crevicularfluid. Hua Xi Kou Qiang Yi Xue Za Zhi 29:294-298, 2011

28. Tyrovola JB, Perrea D, Halazonetis DJ, et al: Relation ofsoluble RANKL and osteoprotegerin levels in blood andgingival crevicular fluid to the degree of root resorptionafter orthodontic tooth movement. J Oral Sci 52:299-311, 2010

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