archives of oral biology 60 (2015) 347–356
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Review
Influence of orthodontic forces on human dental pulp: A systematic review Fawad Javed a, AbdulAziz A. Al-Kheraif b, Enisa B. Romanos a, Georgios E. Romanos c,* a
Division of General Dentistry, Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA. Research Chair for Dental Biomaterials, Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh 11541, Saudi Arabia c Department of Periodontology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA b
article info
abstract
Article history:
Aim: The aim of the present study was to systematically review the influence of orthodontic force on human dental pulp.
Accepted 17 November 2014
Methods and results: The addressed focused question was ‘‘Do orthodontic forces affect the Keywords:
human dental pulp?’’ which was based on the Preferred Reporting Items for Systematic
Dental pulp
Reviews and Meta-Analyses (PRISMA) guidelines, a specific question was constructed
Growth factors
according to the PICO (Participants, Interventions, Control, Outcomes) principle. Databases
Orthodontic force
were explored from 1952 up to and including August 2014 using different combinations of
Pulpal blood flow
the following keywords: ‘‘orthodontic force’’; ‘‘dental pulp’’; ‘‘reaction’’ and ‘‘tooth movement’’. Literature reviews, letters to the editor, commentaries and case-reports were excluded. Thirty studies were included. Six studies assessed the effect of orthodontic forces on pulpal blood flow and 20 studies investigated the pulpal cellular responses to orthodontic forces. In 4 studies, pulpal responses to orthodontic forces were compared between previously traumatized- and non-traumatized teeth. Conclusions: There is insufficient scientific validation regarding the association between orthodontic forces and human dental pulp. However, a history of dental trauma maybe considered a risk factor for loss of pulp vitality during orthodontic treatment. # 2014 Elsevier Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . Materials and methods . 2.1. Focused question. 2.2. Search protocol . .
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* Corresponding author. Tel.: +1 631 632 8755. E-mail address: [email protected] (G.E. Romanos). http://dx.doi.org/10.1016/j.archoralbio.2014.11.011 0003–9969/# 2014 Elsevier Ltd. All rights reserved.
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4. 5.
1.
archives of oral biology 60 (2015) 347–356
2.3. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Level of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Effect of orthodontic forces on pulpal blood flow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Influence of orthodontic forces on the cellular responses of the human dental pulp . 3.3. Influence of orthodontic forces on the pulpal response in traumatized teeth. . . . . . . 3.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Application of orthodontic forces to teeth for specific time periods has been reported to induce molecular changes in the cells of the periodontal ligament, alveolar bone and the pulp– dentine complex.1–7 Histologic studies have reported depression of pulp tissue respiration, vacuolization, circulatory disturbances, haemorrhage, fibro-hyalinosis and even necrosis as the major pulpal changes that may be encountered following the application of orthodontic forces to teeth.1,2,4 Hamersky et al.7 suggested that excessive and prolonged orthodontic forces when applied to teeth may result in loss of pulp vitality. Laser Doppler flowmetry (LDF) by McDonald and Pitt Ford8 have reported a temporary decrease in pulpal blood flow (PBF). The decrease in PBF has been associated with a drop in the oxygen tension thereby increasing the possibility of cellular injury and apoptosis as determined by alterations in the expression of pulpal markers such as Aspartate Aminotransferase (AST) and alkaline phosphatase (ALP).9–11 However, results by Barwick and Ramsay12 and Brodin et al.13 reported no significant effect of a orthodontic forces (intrusive and/or extrusive) on PBF. Studies5,14–16 have also reported that application of orthodontic forces on teeth for certain periods of time increase the expression of various growth factors (GFs), such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and transforming growth factor beta (TGF-b) in pulpal tissues, which in turn contribute to angiogenesis. High levels of inflammatory mediators, such as interleukin (IL)-6, IL-1b tumour necrosis factor alpha and receptor activator of nuclear factor kappa B have been identified in pulpal tissues of teeth exposed to orthodontic forces.17,18 Levels of inflammatory mediators in the gingival crevicular fluid have also been reported to be significantly elevated during orthodontic therapy.19,20 Therefore, from a clinical perspective, it is hypothesized that long-term application of orthodontic forces jeopardizes pulp vitality. Furthermore, pulpal necrosis (PN) has also been reported after the induction of orthodontic forces such as intrusion, extrusion and retraction.8,21 It is tempting to speculate that the magnitude of pulpal inflammation or injury is directly proportional to the degree of orthodontic force applied on the teeth. The aim of the present study was to systematically review the influence of orthodontic force on human dental pulp.
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2.
Materials and methods
2.1.
Focused question
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Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a specific question was constructed according to the PICO (Participants, Interventions, Control, Outcomes) principle.22 The addressed focused question was ‘‘Do orthodontic forces affect human dental pulp?’’ (P) Participants: It was essential for participants to have undergone orthodontic treatment. (I) Types of interventions: The interventions of interest were orthodontic forces (such as intrusion, extrusion, tipping, arch expansion and retraction). (C) Control intervention: Teeth, which were either not subjected to orthodontic forces or pulp tissues which treated with antibodies other than those used in the test-groups, were considered as controls. (O) Outcome measures: Human pulpal response to orthodontic forces.
2.2.
Search protocol
In order to identify studies relevant to the PICO question, the MEDLINE (OVID) database, the EMBASE database, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Web of Knowledge, The Cumulative Index to Nursing and Allied Health Literature and Google-Scholar databases were electronically searched for available data. Databases were searched from 1954 up to and including August 2014 using different combinations of the following key words: ‘‘orthodontic force’’; ‘‘human dental pulp’’; ‘‘reaction’’ and ‘‘tooth movement’’. Titles and abstracts of studies identified using the above-described protocol were screened by two authors (FJ AAK and GER) and checked for agreement. Fulltexts of studies judged by title and abstract to be relevant were read by authors (FJ AAK and GER) and independently evaluated in accordance with the following eligibility criteria: clinical studies, application of orthodontic force on teeth and assessment of pulp tissues. Kappa scores (Cohen’s kappa coefficient) were employed to determine the level of agreement between the two reviewers.23,24 Letters to the Editor, historic reviews, commentaries, experimental (animal) studies and case-reports were excluded. Hand-searching of potentially relevant original and review articles was also performed. This was done to identify any studies that could
349
Identification
archives of oral biology 60 (2015) 347–356
Records identified through MEDLINE (OVID) (n=44)
Records identified through PubMed CENTRAL (n=78)
Records identified through CINAHL (n=0)
Records identified through Web of Knowledge (n=98)
Records identified through Cochrane Central Register
Records identified through GoogleScholar
(n=2)
(n=79)
Records screened (n = 105 )
Records excluded (n = 60 )
Eligibility
Full-text articles assessed for eligibility (n = 45 )
Full-text articles excluded, with reasons (n = 15 )
Included
Screening
Total number of records (n = 301)
Studies included in qualitative synthesis (n = 30 )
Fig. 1 – Literature search strategy according to the PRISMA guidelines (www.prisma-statement.org).
have remained unidentified in the previous step and checked for disagreement via discussion among the authors. Articles available online in electronic form ahead of print were considered eligible for inclusion. Fig. 1 summarizes the literature search strategy according to the PRISMA guidelines. The pattern of the present systematic review was customized to mainly summarize the relevant data.
end points; and diagnostic reliability tests and reproducibility tests described (all criteria should be met; otherwise, grade C). Grade C (Low)—One or more of the following settings are encountered: poorly defined patient material, unclear diagnosis and end points and large attrition of the samples.
2.3.
2.4.
Quality assessment
Three authors (FJ, AAK and GER) independently assessed the methodological quality of the included studies according to a grading system developed by the Swedish Council on Technology Assessment in Health Care.25 The following criteria were used for assessing the methodological quality of the studies included in the present review:
Grade A (High)—A randomized controlled trial or prospective study, composed of a well-defined control group; defined diagnosis and end points; diagnostic reliability tests and reproducibility tests described; and blinded outcome measurements (all criteria should be met). Grade B (Moderate)—A cohort study or retrospective study, composed of a defined control group; defined diagnosis and
Level of evidence
For each study included in the present review, level of evidence was judged in accordance with the following scale26:
Strong Scientific Support (Evidence Grade 1)—Conclusion is based on at least 2 studies with level A-evidence. Studies with opposite conclusions may lower the evidence grade. Moderately Strong Support (Evidence Grade 2)—Conclusion is based on 1 study with strong evidence (A) and at least 2 with moderately strong evidence (B). Studies with opposite conclusions may lower the evidence grade. Limited Scientific Support (Evidence Grade 3)—Conclusion is based on at least 2 studies with moderately strong evidence (B). If studies contradicting the conclusion exist, the scientific basis is judged as contradictory or insufficient.
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Inconclusive Scientific Support (Evidence Grade 4)—If studies fulfilling the evidence criteria are lacking, the scientific basis for conclusion is considered insufficient.
of orthodontic force in the study by Parris et al.32 and Subay et al.29 reported no evidence of inflammatory reactions in the pulps of orthodontically-moved teeth (Table 2).
3.
Results
3.3. Influence of orthodontic forces on the pulpal response in traumatized teeth
3.1.
Effect of orthodontic forces on pulpal blood flow 4,8,12,13,27,28
Six studies addressed the effect of orthodontic forces on PBF (Table 1). The numbers of study participants ranged between 6 and 21 patients. In 5 studies,4,8,12,13,28 orthodontic forces were applied to achieve extrusion, intrusion and retraction of premolar teeth; whereas in the study by Babacan et al.,27 rapid maxillary expansion (RME) was performed. Five studies4,8,12,13,28 reported the orthodontic force applied to teeth which ranged between 0.5 Newton (N) and 44 N. In one study27 the amount of orthodontic force applied to perform RME was not reported. In these studies,4,8,12,13,27,28 the duration for which orthodontic forces were applied ranged between 20 s and 152 days. Three studies4,13,28 reported that intrusive orthodontic forces temporarily reduce PBF; and in the study by Barwick and Ramsay12 PBF remained unaltered during all orthodontic treatment sessions. In the study by Babacan et al.,27 PBF increased in the first week of RME and decreased significantly by the third week of RME.
3.2. Influence of orthodontic forces on the cellular responses of the human dental pulp Twenty studies1,5,7,9,11,14–16,21,29–37 reported the influence of orthodontic forces on human pulpal cellular responses (Table 2). In 18 studies,1–3,5,7,9,11,14–16,21,29–32,34,36,37 orthodontic forces were applied on premolars and in 2 studies33,35 teeth exposed to orthodontic forces were not reported. The magnitude of orthodontic force ranged between 0.3 N and 6 N for durations ranging between 21 min and 84 days. Intrusion, extrusion and tipping movements were performed in 8,1,11,30,31,34–37 83,5,7,14,16,21,29,33 and 39,15,32 studies, respectively. In one study,2 both intrusion and extrusion forces were applied on premolars. Results by Lazzaretti et al.37 showed that intrusive orthodontic forces caused vascular changes in the pulpal tissue and also increased the presence of fibrosis and the number of pulp calcifications. Four studies1,2,21,36 reported orthodontic forces to cause vacuolization and disruption of osteoblasts in pulpal tissues but without necrosis. Results by Caviedes-Bucheli et al.3 reported orthodontic forces of 0.56 N and 2.24 N to increase the pulpal expression of calcitonin gene-related peptide (CGRP) as compared to the control group. Three studies5,14,16 reported orthodontic forces to increase the expression of GFs in pulpal tissues. Perinetti et al.9 and Veberiene et al.11 reported orthodontic forces to increase pulpal AST activity. In one study,34 pulpal AST levels were comparable with and without mechanical load application. Kucukkeles and Okar31 showed vascular degeneration in the pulps of orthodontically treated teeth; Derringer et al.15 reported angiogenesis to be significantly higher in orthodontically-treated teeth and control teeth. In 4 studies,30,33,35,36 orthodontic forces were reported to cause minor disturbances in pulpal circulation. Concentration of substance P was negatively correlated with the magnitude
Four studies38–41 investigated the pulpal reaction of orthodontic forces on traumatized teeth. Two studies38,40 reported the magnitude of orthodontic force applied on traumatized teeth, which were 0.2 N and 0.15 N. In these studies,38–41 duration of orthodontic treatment in previously traumatized teeth ranged between 22.4 and 54 months. All studies38–41 reported PN to be more frequent when orthodontic treatment was performed in previously traumatized teeth as compared to non-traumatized teeth (Table 3).
3.4.
Quality assessment
Most of the studies were graded as ‘‘moderate to low’’ mainly because of their methodological quality (Tables 1–3). Low grading was mainly based on no randomized assignment to experimental and control treatment groups and no description of reliability tests.
4.
Discussion
Since grading evidence is a complicated issue, we avoided using a scale that allocates points to individual quality items because this approach has proved to be inadequate.42 To our knowledge from indexed literature, a gold standard quality assessment tool is still missing.43,44 Lack of randomized controlled trials and a disharmony in the study protocols are limitations of the studies included in this review. These factors may be held responsible for the moderate to low grading of most studies included in this review. In a systematic review published in the year 2012, von Bohl et al.,45 reported that there is no conclusive scientific evidence for a relation between force level and dental pulp tissue reaction in humans. Authors of this systematic review emphasized that there is a scarcity of long-term results regarding pulpal injury occurring as a result of orthodontic treatment.45 Since there is a debate among clinicians regarding the optimal orthodontic forces that teeth can endure without experiencing massive pulpal inflammation and/or necrosis, we were tempted to re-search indexed literature to identify additional studies (published after the year 2012) that assessed the association between orthodontic force and its effects on human dental pulp tissues. Moreover, in the systematic review by von Bohl et al.45 the effect of orthodontic forces on human dental pulp were assessed in non-traumatized teeth only; however, in the present systematic review, we reviewed pertinent literature regarding the influence of orthodontic forces on human dental pulp tissues of nontraumatized and traumatized teeth. In the present study, a systematic review of pertinent literature was performed in an attempt to assess the effect of orthodontic forces on dental pulp tissues. It was hypothesized that long-term application of orthodontic forces jeopardizes
Table 1 – Studies on the effect of orthodontic forces on pulpal blood flow. Authors et al.
Study subjects
Type of treatment
Sano et al.4,*
Prospective
13
Intrusion
McDonald and Pitt Ford8,*
Prospective
10
Canine retraction
Barwick and Ramsay12,y
Prospective
8
Intrusion
Brodin et al.13,y
Prospective
6
Babacan et al.27,y
Prospective
Ikawa et al.28,*
Prospective
Control group
Force applied (N)
Duration of force
Pulpal blood flow measured by
13 vital teeth without orthodontic force application 10 vital teeth without orthodontic force application None
0.5, 1, 2
14 days
LDF
0.5
Up to 4 days
LDF
0.75, 1.25, 5, 44
112 days
LDF
Intrusion and extrusion
None
0.5
152 days
LDF
21
RME
None
NR
Up to 84 days
LDF
17
Intrusion
None
0.5, 1, 5
20 s
LDF
Results
Quality grade
Intrusive forces temporarily reduced PBF. PBF changes returned to normal at the end of force application PBF increased up to 48 h of load application but returned to preload values within 72 h
B
Baseline PBF remained unchanged during all treatment sessions Extrusion had no significant effect on PBF. Intrusion reduced the pulpal blood flow by 20% during the first minute only PBF increased in the 1st week and decreased significantly by the 3rd week of RME Brief intrusive forces temporarily reduced PBF
A
B
C
B
B
archives of oral biology 60 (2015) 347–356
Design
LDF, laser Doppler flowmetry; NR, not reported; OT, orthodontic treatment; PBF, pulpal blood flow; RME, rapid maxillary expansion. High risk of bias. y Low risk of bias. *
351
352
Table 2 – Studies on the influence of orthodontic forces on the cellular responses of the dental pulp. Authors et al.
Design
Subjects
Number of teeth
Type of movement
Force applied (N)
Control group
Duration of force
Prospective
17
34
Intrusion
0.58
No orthodontic force applied
21 days
Han et al.1,y
Prospective
27
54
Intrusion
0.5, 3
No orthodontic force applied
Up to 84 days
Ramazanza-deh et al.2,*
Prospective
26
52
Intrusion and extrusion
0.25, 0.74
No orthodontic force applied
Up to 21 days
Caviedes-Bucheli et al.3,*
Prospective
NR
30
Extrusion
0.56, 2.24
No orthodontic force applied
1 day
Derringer and Linden5,*
Prospective (In vitro)
20
80
Extrusion
0.5–1
Hamersky et al.7,*
Prospective
17
68
Extrusion
At least 0.6 N
Use of antibodies 14 days other than those for VEGF, FGF2 and TGFbeta No orthodontic 3 days force applied
Perinetti et al.9,*
Prospective
17
17
Tipping
0.3–0.9
No orthodontic force applied
7 days
Veberiene et al.11,*
Prospective
21
42
Intrusion
0.61
No orthodontic force applied
7 days
Derringer and Linden14,y
Prospective (In vitro)
10
10
Extrusion
0.5–1
Co-cultures without anti-h EGF
14 days
There was a significant increase in the number of pulpal nodules in the elements with no difference in the number of blood vessels between the groups In both force groups, odontoblasts disruption, vacuolization and moderate vascular congestion occurred but without PN In both force groups, odontoblasts disruption, vacuolization and moderate vascular congestion occurred but without PN In both force groups, pulpal CGRP expression was increased compared to the control group VEGF, FGF-2, PDGF and TGF-b are released following orthodontic force application Short-term orthodontic forces caused pulpal tissue hypoxia Mean AST activity and EPT values were significantly higher in teeth exposed to mechanical load compared to controls Mean AST activity and EPT values were significantly higher in teeth exposed to mechanical load compared to controls Orthodontic forces stimulate the release of EGF in pulp tissues
Conclusion
Intrusive orthodontic forces caused vascular changes in the pulpal tissue and also increased the presence of fibrosis and the number of pulp calcifications Intrusive orthodontic forces do not jeopardize pulp vitality
Quality grade B
C
Histologic pulpal changes C between baseline and 21 days showed no statistically significant difference Orthodontic forces increase C CGRP expression in human dental pulp Growth factors are expressed in the pulp of teeth exposed to mechanical load Orthodontic forces cause biochemical and biologic pulpal tissue alterations Application of mechanical load to teeth can cause metabolic changes in the pulp
C
Application of mechanical load to teeth can cause metabolic changes in the pulp
A
EGF released following orthodontic force application plays a role in pulpal angiogenic response
B
C
B
archives of oral biology 60 (2015) 347–356
Lazzaretti et al.37,y
Pulpal response
Prospective
NR
30
Tipping
0.5–1
Derringer and Linden16,y
Prospective
18
18
Extrusion
0.5–1
Mostafa et al.21,y
Prospective
18
36
Extrusion
0.5
Subay et al.29,y
Prospective
15
40
Extrusion
0.75
Raiden et al.30,y
Prospective
20
40
Intrusion
1.5
Kucukkeles and Okar31,y
Prospective
2
4
Intrusion
1.5
Parris et al.32,*
Prospective
20
80
Tipping
1.2, 1.4, 1.5, 1.8, 2, 2.1, 2.15, 2.3, 2.45 and 6
Stenvik33,y
Prospective
NR
NR
Extrusion
1–2
No orthodontic force applied
7–14 days
Veberiene et al.34,y
Prospective
13
26
Intrusion
0.65
No orthodontic force applied
14 days
Stenvik and Mjor35,y
Prospective
NR
25
Intrusion
0.5–2.5
No orthodontic force applied
5–28 days
a n d Prospective
NR
NR
Intrusion
0.35–2.5
No orthodontic force applied
4–35 days
Stenvik Mjor36,y
No orthodontic force applied
5 days
There were significantly greater numbers of microvessels in orthodontically treated teeth than control teeth No orthodontic 14 days VEGF, FGF-2, PDGF and TGF-b force applied are released following orthodontic force application No orthodontic Up to 28 Dilated and constricted blood force applied days vessels, odontoblastic degeneration, vacuolization and oedema of the pulp tissues, and fibrotic changes occurred in pulpal tissues No control group 10 days, There was no evidence of in(All teeth were ex- 40 days flammatory reactions and/or truded) reparative dentine formation in all teeth No orthodontic 15–20 Histologic results showed force applied days alterations in predentine, calcium deposition, fibrohyalinosis, congestion, inflammation and haemorrhage No orthodontic 90 days Vascular degeneration force applied occurred in the pulps of orthodontically-treated teeth. No orthodontic 21–78 min Concentrations of ir-ME and force applied ir-SP each correlated negatively with the magnitude of the orthodontic force Minor reactions related to the pulpal circulatory system can occur Mean pulpal AST levels and EPT values similar with and without mechanical load application Minor reactions related to the pulpal circulatory system can occur Vacuolization of the pulp tissue and circulatory disturbances occurred
Growth factors are expressed B in the pulp of teeth exposed to mechanical load Growth factors play a role in pulpal angiogenesis
B
Orthodontic forces can cause B temporary inflammation and fibrosis in pulpal tissues
Extrusive forces do not cause C significant pathological changes in pulp tissues Intrusive forces can cause C congestion, haemorrhage and fibrohyalinosis in the pulp tissues
Intrusive forces jeopardize pulp vitality by causing vascular degeneration. Orthodontic forces and pulpal ir-ME and ir-SP concentrations are interlinked
C
B
Orthodontic forces cause C biochemical and biologic pulpal tissue alterations Orthodontic forces do not A influence pulpal AST activity and EPT values Orthodontic forces cause biochemical and biologic pulpal tissue alterations Orthodontic forces cause biochemical and biologic pulpal tissue alterations
archives of oral biology 60 (2015) 347–356
Derringer et al.15,*
C
C
ALP, alkaline phosphatase; AST, aspartate aminotransferase; Control, mechanical load not applied; CGRP, calcitonin gene-related peptide; EGF, epidermal growth factor; EPT, electric pulp testing; irME, immunoreactive methionine enkephalin; ir-SP, immunoreactive substance P; NR, not reported; PM, premolars. * High risk of bias. y Low risk of bias.
353
354
C
C
C
23.8 24 — 23.7 23.7 — 22.4 — 54 39.6 — OT in 29 patients* with non-traumatized teeth
193 traumatized teeth without OT 26 patients* without dental trauma and OT —
Retrospective Brin et al.41
NR
OT in 269 previously traumatized teeth OT in 54 previously traumatized teeth Retrospective Bauss et al.40
0.15
Retrospective Bauss et al.39
NR
59 teeth traumatized during OT
800 teeth non-traumatized during OT
193 traumatized teeth without OT
Group-1: Group-2: Group-3: Group-1: Group-2: Group-3: Group-1: Group-2: Group-1: Group-2: Group-3:
Group-3 (Control group)
193 traumatized teeth without OT OT in 400 non-traumatized teeth
Group-2 Group-1
OT in 77 previously traumatized teeth 0.2 Retrospective Bauss et al.38
Study groups Force applied (N) Design Authors et al.
Table 3 – Studies on the influence of orthodontic forces on the pulpal response in traumatized teeth.
Duration of OT (months)
Results
PN was more frequent in Group-1 than Group-2 or Group-3 PN was more frequent in Group-1 than Group-2 or Group-3 PN was more frequent in Group-1 than Group-2 Loss of pulp vitality was more frequent among teeth in Group-1 than groups 2 and 3
C
Quality grade
archives of oral biology 60 (2015) 347–356
pulp vitality; however, due to a variation in the magnitude and duration of orthodontic forces exerted on teeth in the studies included, it is exigent to scientifically validate the aforementioned hypothesis. Amongst the studies4,8,12,13,27,28 which assessed the influence of orthodontic forces of PBF, magnitude and duration of orthodontic force applied varied considerably (0.5 N–44 N and 20 s–152 days, respectively). It is allured that a low orthodontic force (for instance 0.5 N) exerted on teeth for a few minutes causes minor or no change in PBF than the same force being applied for longer durations. However, scientific evidence in this regard is still missing. Likewise, it may also be argued that long-term application of intense orthodontic forces to teeth influences PBF to a significantly greater extent than when the same forces are applied for a short duration. Therefore, it is difficult to contemplate a direct association between PBF and magnitude of orthodontic force. It has also been reported that the effects of orthodontic forces on PBF are associated with various factors including patients’age, size of apical foramen, dentinogenic activity and not merely on the magnitude and duration of the force applied.7,12 None of the studies4,8,12,13,27,28 that fulfilled the eligibility criteria assessed the influence of size of apical foramen on PBF in the study groups. It is however pertinent to mention that in these studies4,8,12,13,27,28 age of the study participants was also markedly incoherent. For example, in the study by Sano et al.,4 individuals with age ranging between 27 and 31 years were included; whereas Babacan et al.,27 assessed the effect of orthodontic forces on PBF among 10–15 year old patients. Further clinical trials with standardized parameters (particularly magnitude and duration of force application) are needed to clarify the effect of orthodontic forces on PBF. CGRP is a potent vaso-dilatory peptide that is found in approximately 50% of the neurons of the trigeminal system.46,47 Substance P (SP) is mediator of neurogenic inflammation and causes vasodilatation by direct action over endothelial cells and indirect mast cell stimulation for histamine release, a dual effect shared with CGRP.48 These molecules are capable of provoking a tolerable discomfort among patients following the activation of orthodontic intrusive forces.49 In the study by Caviedes-Bucheli et al.,3 orthodontic extrusion was associated with an increased expression of CGRP in the pulp. However, in this study,3 CGRP levels were measured after 24 h of force application. Likewise, Parris et al.,32 measured pulpal SP levels after 0.3–1.3 h after force application. To assess the significance of the results reported by Caviedes-Bucheli et al.,3 and Parris et al.,32 further studies with long-term application of orthodontic force are warranted. Angiogenesis is defined as the process of development of new blood vessels from preexisting microvasculature. GFs may act either directly or indirectly to regulate the endothelial cell function and expression of other GFs by different cell types.50 Studies5,14–16 have used neutralizing antibodies (antih VEGF, FGF2, PDGF, TGF-b and EGF) to investigate the presence of a combination of GFs in the human dental pulp during orthodontic force application. The neutralizing antibodies significantly reduced the number of microvessels in the evaluated in vitro cultures thereby confirming the presence of GFs in the pulp during orthodontic movement. This is an explanation for the study by Derringer et al.,15 in which the authors showed the presence of significantly greater numbers
archives of oral biology 60 (2015) 347–356
of micro-vessels in orthodontically treated teeth than control teeth. Furthermore, in an experimental study on mice, Kaku et al.,51 investigated the effect of recombinant human VEGF (rhVEGF) on the differentiation of osteoclasts during experimental tooth movement. The results suggested that local administration of rhVEGF enhances the number of osteoclasts and may increase the rate of orthodontic tooth movement. It is known that pulpal fibroblasts and odontoblasts synthesize and release ALP.52,53 Therefore, it is hypothesized that application of orthodontic force on these cells reduces their ALP expression. AST is an essential mediator of inflammatory processes and is expressed in high concentrations in pulpal inflammatory conditions.54 Raiden et al.,30 Perinetti et al.,9 Veberiene et al.,11 reported raised pulpal AST levels following the application of intrusive orthodontic forces, which reflect a state of inflammation in the pulp. However, due to a limited number of studies that have assessed pulpal AST and ALP levels during orthodontic force application, the significance of these enzymes affecting pulpal tissues remains veiled. A critical factor that could have biased the outcome of the studies included in the present review is their design and methodology. For example, in the studies4,8,12,13,27,28 which assessed the influence of orthodontic forces on human dental pulp, magnitude of force applied to teeth varied dramatically among as well as between the studies (0.5–44 N). Similarly, among studies that assessed the cellular response of dental pulp cells to orthodontic forces1,5,7,9,11,14–16,21,29–36; the amount of forces used in these studies also varied (0.3–6 N). It is therefore tempting to speculate that an intense orthodontic force (such as 44 N) when applied to teeth for prolonged durations cause pulpal damage to a greater extent as compared to when a low magnitude force is applied to teeth or the same time frame or even longer. Furthermore, regarding the 4 studies38–41 in which pulpal response to orthodontic treatment in previously traumatized teeth was assessed; the results showed loss of pulp vitality following the application of orthodontic force. It is possible that the traumatic insult (such as periodontal trauma) itself may have damaged the dental pulp tissues even before the application of orthodontic force. Therefore, an in-depth assessment involving parameters such as expression of GFs, AST and ALP may yield pertinent information regarding the pulpal response to orthodontic forces in previously traumatized teeth. It is therefore exigent to depict a relationship between force level and the variables investigated in the studies include in the present systematic review.
5.
Conclusion
There is insufficient scientific evidence to prove that orthodontic forces jeopardize the human dental pulp in terms of reducing PBF and irreversible alterations in pulpal cellular response. However, a history of dental trauma maybe considered a risk factor for loss of pulp vitality during orthodontic treatment.
Funding The authors declare that there was no external source of funding for the present study.
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Competing interest The authors declare that they have no conflict of interest.
Ethical approval Not required.
Acknowledgement The authors extend their appreciation to the Research Center, College of Applied Medical Sciences and Deanship of Scientific Research at King Saud University for funding this research. The authors also thank the Visiting Professor Program at King Saud University, Saudi Arabia for supporting this research project.
references
1. Han G, Hu M, Zhang Y, Jiang H. Pulp vitality and histologic changes in human dental pulp after the application of moderate and severe intrusive orthodontic forces. Am J Orthod Dentofacial Orthop 2013;144(4):518–22. 2. Ramazanzadeh BA, Sahhafian AA, Mohtasham N, Hassanzadeh N, Jahanbin A, Shakeri MT. Histological changes in human dental pulp following application of intrusive and extrusive orthodontic forces. J Oral Sci 2009;51(1):109–15. 3. Caviedes-Bucheli J, Moreno JO, Ardila-Pinto J, Del ToroCarren˜o HR, Saltarı´n-Quintero H, Sierra-Tapias CL, et al. The effect of orthodontic forces on calcitonin gene-related peptide expression in human dental pulp. J Endod 2011;37(7):934–7. 4. Sano Y, Ikawa M, Sugawara J, Horiuchi H, Mitani H. The effect of continuous intrusive force on human pulpal blood flow. Eur J Orthod 2002;24(2):159–66. 5. Derringer KA, Linden RW. Vascular endothelial growth factor, fibroblast growth factor 2, platelet derived growth factor and transforming growth factor beta released in human dental pulp following orthodontic force. Arch Oral Biol 2004;49(8):631–41. 6. Romanyk DL, Melenka GW, Carey JP. Modeling stressrelaxation behavior of the periodontal ligament during the initial phase of orthodontic treatment. J Biomech Eng 2013;135(9):91007. 7. Hamersky PA, Weimer AD, Taintor JF. The effect of orthodontic force application on the pulpal tissue respiration rate in the human premolar. Am J Orthod 1980;77(4):368–78. 8. McDonald F, Pitt Ford TR. Blood flow changes in permanent maxillary canines during retraction. Eur J Orthod 1994;16(1):1–9. 9. Perinetti G, Varvara G, Festa F, Esposito P. Aspartate aminotransferase activity in pulp of orthodontically treated teeth. Am J Orthod Dentofacial Orthop 2004;125(1):88–92. 10. Perinetti G, Varvara G, Salini L, Tete S. Alkaline phosphatase activity in dental pulp of orthodontically treated teeth. Am J Orthod Dentofacial Orthop 2005;128(4):492–6. 11. Veberiene R, Smailiene D, Danielyte J, Toleikis A, Dagys A, Machiulskiene V. Effects of intrusive force on selected determinants of pulp vitality. Angle Orthod 2009;79(6):1114–8. 12. Barwick PJ, Ramsay DS. Effect of brief intrusive force on human pulpal blood flow. Am J Orthod Dentofacial Orthop 1996;110(3):273–9.
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13. Brodin P, Linge L, Aars H. Instant assessment of pulpal blood flow after orthodontic force application. J Orofac Orthop 1996;57(5):306–9. 14. Derringer K, Linden R. Epidermal growth factor released in human dental pulp following orthodontic force. Eur J Orthod 2007;29(1):67–71. 15. Derringer KA, Jaggers DC, Linden RW. Angiogenesis in human dental pulp following orthodontic tooth movement. J Dent Res 1996;75(10):1761–6. 16. Derringer KA, Linden RW. Angiogenic growth factors released in human dental pulp following orthodontic force. Arch Oral Biol 2003;48(4):285–91. 17. Yamaguchi M, Kasai K. Inflammation in periodontal tissues in response to mechanical forces. Arch Immunol Ther Exp (Warsz) 2005;53(5):388–98. 18. Basaran G, Ozer T, Kaya FA, Kaplan A, Hamamci O. Interleukine-1beta and tumor necrosis factor-alpha levels in the human gingival sulcus during orthodontic treatment. Angle Orthod 2006;76(5):830–6. 19. van Gastel J, Teughels W, Quirynen M, Struyf S, Van Damme J, Coucke W, et al. Longitudinal changes in gingival crevicular fluid after placement of fixed orthodontic appliances. Am J Orthod Dentofacial Orthop 2011;139(6):735–44. 20. Ren Y, Hazemeijer H, de Haan B, Qu N, de Vos P. Cytokine profiles in crevicular fluid during orthodontic tooth movement of short and long durations. J Periodontol 2007;78(3):453–8. 21. Mostafa YA, Iskander KG, El-Mangoury NH. Iatrogenic pulpal reactions to orthodontic extrusion. Am J Orthod Dentofacial Orthop 1991;99(1):30–4. 22. Boudin F, Nie JY, Bartlett JC, Grad R, Pluye P, Dawes M. Combining classifiers for robust PICO element detection. BMC Med Inform Decis Mak 2010;10:29. 23. Roberts C. Modelling patterns of agreement for nominal scales. Stat Med 2008;27(6):810–30. 24. Chang CH. Cohen’s kappa for capturing discrimination. Int Health 2014;6(2):125–9. 25. Bondemark L, Holm AK, Hansen K, Axelsson S, Mohlin B, Brattstrom V, et al. Long-term stability of orthodontic treatment and patient satisfaction. A systematic review. Angle Orthod 2007;77(1):181–91. 26. Mohlin B, Axelsson S, Paulin G, Pietila¨ T, Bondemark L, Brattstro¨m V, et al. TMD in relation to malocclusion and orthodontic treatment. Angle Orthod 2007;77(3):542–8. 27. Babacan H, Doruk C, Bicakci AA. Pulpal blood flow changes due to rapid maxillary expansion. Angle Orthod 2010;80(6):1136–40. 28. Ikawa M, Fujiwara M, Horiuchi H, Shimauchi H. The effect of short-term tooth intrusion on human pulpal blood flow measured by laser Doppler flowmetry. Arch Oral Biol 2001;46(9):781–7. 29. Subay RK, Kaya H, Tarim B, Subay A, Cox CF. Response of human pulpal tissue to orthodontic extrusive applications. J Endod 2001;27(8):508–11. 30. Raiden G, Missana L, Santamaria de Torres E, Kozuszko S, Pedroso R. Pulpal response to intrusive orthodontic forces. Acta Odontol Latinoam 1998;11(1):49–54. 31. Kucukkeles N, Okar I. Root resorption and pulpal changes due to intrusive force. J Marmara Univ Dent Fac 1994;2(1):404–8. 32. Parris WG, Tanzer FS, Fridland GH, Harris EF, Killmar J, Desiderio DM. Effects of orthodontic force on methionine enkephalin and substance P concentrations in human pulpal tissue. Am J Orthod Dentofacial Orthop 1989;95(6):479–89. 33. Stenvik A. The effect of extrusive orthodontic forces on human pulp and dentin. Scand J Dent Res 1971;79(6):430–5. 34. Veberiene R, Smailiene D, Baseviciene N, Toleikis A, Machiulskiene V. Change in dental pulp parameters in response to different modes of orthodontic force application. Angle Orthod 2010;80(6):1018–22.
35. Stenvik A, Mjor IA. The effect of experimental tooth intrusion on pulp and dentine. Oral Surg Oral Med Oral Pathol 1971;32(4):639–48. 36. Stenvik A, Mjor IA. Pulp and dentine reactions to experimental tooth intrusion. A histologic study of the initial changes. Am J Orthod 1970;57(4):370–85. 37. Lazzaretti DN, Bortoluzzi GS, Torres Fernandes LF, Rodriguez R, Grehs RA, Martins Hartmann MS. Histologic evaluation of human pulp tissue after orthodontic intrusion. J Endod 2013;9. http://dx.doi.org/10.1016/ j.joen.2013.10.039. 38. Bauss O, Schafer W, Sadat-Khonsari R, Knosel M. Influence of orthodontic extrusion on pulpal vitality of traumatized maxillary incisors. J Endod 2010;36(2):203–7. 39. Bauss O, Rohling J, Meyer K, Kiliaridis S. Pulp vitality in teeth suffering trauma during orthodontic therapy. Angle Orthod 2009;79(1):166–71. 40. Bauss O, Rohling J, Rahman A, Kiliaridis S. The effect of pulp obliteration on pulpal vitality of orthodontically intruded traumatized teeth. J Endod 2008;34(4):417–20. 41. Brin I, Ben-Bassat Y, Heling I, Engelberg A. The influence of orthodontic treatment on previously traumatized permanent incisors. Eur J Orthod 1991;13(5):372–7. 42. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999;282(11):1054–60. 43. Katrak P, Bialocerkowski AE, Massy-Westropp N, Kumar S, Grimmer KA. A systematic review of the content of critical appraisal tools. BMC Med Res Methodol 2004;4:22. 44. Sanderson S, Tatt ID, Higgins JP. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007;36(3):666–76. 45. von Bohl M, Ren Y, Fudalej PS, Kuijpers-Jagtman AM. Pulpal reactions to orthodontic force application in humans: a systematic review. J Endod 2012;38(11):1463–9. 46. Raddant AC, Russo AF. Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med 2011;13:e36. 47. Cady RJ, Glenn JR, Smith KM, Durham PL. Calcitonin generelated peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain 2011;7:94. 48. Fewtrell CM, Foreman JC, Jordan CC, Oehme P, Renner H, Stewart JM. The effects of substance P on histamine and 5hydroxytryptamine release in the rat. J Physiol 1982;330:393–411. 49. Chavarria-Bolanos D, Martinez-Zumaran A, Lombana N, Flores-Reyes H, Pozos-Guillen A. Expression of substance P, calcitonin gene-related peptide, beta-endorphin and methionine-enkephalin in human dental pulp tissue after orthodontic intrusion. Angle Orthod 2013;29. http:// dx.doi.org/10.2319/060313-423.1. 50. Folkman J, Klagsbrun M. Angiogenic factors. Science 1987;235(4787):442–7. 51. Kaku M, Kohno S, Kawata T, Fujita I, Tokimasa C, Tsutsui K, et al. Effects of vascular endothelial growth factor on osteoclast induction during tooth movement in mice. J Dent Res 2001;80(10):1880–3. 52. Kim YS, Min KS, Jeong DH, Jang JH, Kim HW, Kim EC. Effects of fibroblast growth factor-2 on the expression and regulation of chemokines in human dental pulp cells. J Endod 2010;36(11):1824–30. 53. Qin W, Liu P, Zhang R, Huang S, Gao X, Song Z, et al. JNK MAPK is involved in BMP-2-induced odontoblastic differentiation of human dental pulp cells. Connect Tissue Res 2014. http://dx.doi.org/10.3109/03008207.2014.882331. 54. Spoto G, Fioroni M, Rubini C, Tripodi D, Perinetti G, Piattelli A. Aspartate aminotransferase activity in human healthy and inflamed dental pulps. J Endod 2001;27(6):394–5.
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Review
Influence of orthodontic forces on human dental pulp: A systematic review Fawad Javed a, AbdulAziz A. Al-Kheraif b, Enisa B. Romanos a, Georgios E. Romanos c,* a
Division of General Dentistry, Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA. Research Chair for Dental Biomaterials, Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh 11541, Saudi Arabia c Department of Periodontology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA b
article info
abstract
Article history:
Aim: The aim of the present study was to systematically review the influence of orthodontic force on human dental pulp.
Accepted 17 November 2014
Methods and results: The addressed focused question was ‘‘Do orthodontic forces affect the Keywords:
human dental pulp?’’ which was based on the Preferred Reporting Items for Systematic
Dental pulp
Reviews and Meta-Analyses (PRISMA) guidelines, a specific question was constructed
Growth factors
according to the PICO (Participants, Interventions, Control, Outcomes) principle. Databases
Orthodontic force
were explored from 1952 up to and including August 2014 using different combinations of
Pulpal blood flow
the following keywords: ‘‘orthodontic force’’; ‘‘dental pulp’’; ‘‘reaction’’ and ‘‘tooth movement’’. Literature reviews, letters to the editor, commentaries and case-reports were excluded. Thirty studies were included. Six studies assessed the effect of orthodontic forces on pulpal blood flow and 20 studies investigated the pulpal cellular responses to orthodontic forces. In 4 studies, pulpal responses to orthodontic forces were compared between previously traumatized- and non-traumatized teeth. Conclusions: There is insufficient scientific validation regarding the association between orthodontic forces and human dental pulp. However, a history of dental trauma maybe considered a risk factor for loss of pulp vitality during orthodontic treatment. # 2014 Elsevier Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . Materials and methods . 2.1. Focused question. 2.2. Search protocol . .
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* Corresponding author. Tel.: +1 631 632 8755. E-mail address: [email protected] (G.E. Romanos). http://dx.doi.org/10.1016/j.archoralbio.2014.11.011 0003–9969/# 2014 Elsevier Ltd. All rights reserved.
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4. 5.
1.
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2.3. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Level of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Effect of orthodontic forces on pulpal blood flow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Influence of orthodontic forces on the cellular responses of the human dental pulp . 3.3. Influence of orthodontic forces on the pulpal response in traumatized teeth. . . . . . . 3.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Application of orthodontic forces to teeth for specific time periods has been reported to induce molecular changes in the cells of the periodontal ligament, alveolar bone and the pulp– dentine complex.1–7 Histologic studies have reported depression of pulp tissue respiration, vacuolization, circulatory disturbances, haemorrhage, fibro-hyalinosis and even necrosis as the major pulpal changes that may be encountered following the application of orthodontic forces to teeth.1,2,4 Hamersky et al.7 suggested that excessive and prolonged orthodontic forces when applied to teeth may result in loss of pulp vitality. Laser Doppler flowmetry (LDF) by McDonald and Pitt Ford8 have reported a temporary decrease in pulpal blood flow (PBF). The decrease in PBF has been associated with a drop in the oxygen tension thereby increasing the possibility of cellular injury and apoptosis as determined by alterations in the expression of pulpal markers such as Aspartate Aminotransferase (AST) and alkaline phosphatase (ALP).9–11 However, results by Barwick and Ramsay12 and Brodin et al.13 reported no significant effect of a orthodontic forces (intrusive and/or extrusive) on PBF. Studies5,14–16 have also reported that application of orthodontic forces on teeth for certain periods of time increase the expression of various growth factors (GFs), such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and transforming growth factor beta (TGF-b) in pulpal tissues, which in turn contribute to angiogenesis. High levels of inflammatory mediators, such as interleukin (IL)-6, IL-1b tumour necrosis factor alpha and receptor activator of nuclear factor kappa B have been identified in pulpal tissues of teeth exposed to orthodontic forces.17,18 Levels of inflammatory mediators in the gingival crevicular fluid have also been reported to be significantly elevated during orthodontic therapy.19,20 Therefore, from a clinical perspective, it is hypothesized that long-term application of orthodontic forces jeopardizes pulp vitality. Furthermore, pulpal necrosis (PN) has also been reported after the induction of orthodontic forces such as intrusion, extrusion and retraction.8,21 It is tempting to speculate that the magnitude of pulpal inflammation or injury is directly proportional to the degree of orthodontic force applied on the teeth. The aim of the present study was to systematically review the influence of orthodontic force on human dental pulp.
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2.
Materials and methods
2.1.
Focused question
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Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a specific question was constructed according to the PICO (Participants, Interventions, Control, Outcomes) principle.22 The addressed focused question was ‘‘Do orthodontic forces affect human dental pulp?’’ (P) Participants: It was essential for participants to have undergone orthodontic treatment. (I) Types of interventions: The interventions of interest were orthodontic forces (such as intrusion, extrusion, tipping, arch expansion and retraction). (C) Control intervention: Teeth, which were either not subjected to orthodontic forces or pulp tissues which treated with antibodies other than those used in the test-groups, were considered as controls. (O) Outcome measures: Human pulpal response to orthodontic forces.
2.2.
Search protocol
In order to identify studies relevant to the PICO question, the MEDLINE (OVID) database, the EMBASE database, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Web of Knowledge, The Cumulative Index to Nursing and Allied Health Literature and Google-Scholar databases were electronically searched for available data. Databases were searched from 1954 up to and including August 2014 using different combinations of the following key words: ‘‘orthodontic force’’; ‘‘human dental pulp’’; ‘‘reaction’’ and ‘‘tooth movement’’. Titles and abstracts of studies identified using the above-described protocol were screened by two authors (FJ AAK and GER) and checked for agreement. Fulltexts of studies judged by title and abstract to be relevant were read by authors (FJ AAK and GER) and independently evaluated in accordance with the following eligibility criteria: clinical studies, application of orthodontic force on teeth and assessment of pulp tissues. Kappa scores (Cohen’s kappa coefficient) were employed to determine the level of agreement between the two reviewers.23,24 Letters to the Editor, historic reviews, commentaries, experimental (animal) studies and case-reports were excluded. Hand-searching of potentially relevant original and review articles was also performed. This was done to identify any studies that could
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Identification
archives of oral biology 60 (2015) 347–356
Records identified through MEDLINE (OVID) (n=44)
Records identified through PubMed CENTRAL (n=78)
Records identified through CINAHL (n=0)
Records identified through Web of Knowledge (n=98)
Records identified through Cochrane Central Register
Records identified through GoogleScholar
(n=2)
(n=79)
Records screened (n = 105 )
Records excluded (n = 60 )
Eligibility
Full-text articles assessed for eligibility (n = 45 )
Full-text articles excluded, with reasons (n = 15 )
Included
Screening
Total number of records (n = 301)
Studies included in qualitative synthesis (n = 30 )
Fig. 1 – Literature search strategy according to the PRISMA guidelines (www.prisma-statement.org).
have remained unidentified in the previous step and checked for disagreement via discussion among the authors. Articles available online in electronic form ahead of print were considered eligible for inclusion. Fig. 1 summarizes the literature search strategy according to the PRISMA guidelines. The pattern of the present systematic review was customized to mainly summarize the relevant data.
end points; and diagnostic reliability tests and reproducibility tests described (all criteria should be met; otherwise, grade C). Grade C (Low)—One or more of the following settings are encountered: poorly defined patient material, unclear diagnosis and end points and large attrition of the samples.
2.3.
2.4.
Quality assessment
Three authors (FJ, AAK and GER) independently assessed the methodological quality of the included studies according to a grading system developed by the Swedish Council on Technology Assessment in Health Care.25 The following criteria were used for assessing the methodological quality of the studies included in the present review:
Grade A (High)—A randomized controlled trial or prospective study, composed of a well-defined control group; defined diagnosis and end points; diagnostic reliability tests and reproducibility tests described; and blinded outcome measurements (all criteria should be met). Grade B (Moderate)—A cohort study or retrospective study, composed of a defined control group; defined diagnosis and
Level of evidence
For each study included in the present review, level of evidence was judged in accordance with the following scale26:
Strong Scientific Support (Evidence Grade 1)—Conclusion is based on at least 2 studies with level A-evidence. Studies with opposite conclusions may lower the evidence grade. Moderately Strong Support (Evidence Grade 2)—Conclusion is based on 1 study with strong evidence (A) and at least 2 with moderately strong evidence (B). Studies with opposite conclusions may lower the evidence grade. Limited Scientific Support (Evidence Grade 3)—Conclusion is based on at least 2 studies with moderately strong evidence (B). If studies contradicting the conclusion exist, the scientific basis is judged as contradictory or insufficient.
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Inconclusive Scientific Support (Evidence Grade 4)—If studies fulfilling the evidence criteria are lacking, the scientific basis for conclusion is considered insufficient.
of orthodontic force in the study by Parris et al.32 and Subay et al.29 reported no evidence of inflammatory reactions in the pulps of orthodontically-moved teeth (Table 2).
3.
Results
3.3. Influence of orthodontic forces on the pulpal response in traumatized teeth
3.1.
Effect of orthodontic forces on pulpal blood flow 4,8,12,13,27,28
Six studies addressed the effect of orthodontic forces on PBF (Table 1). The numbers of study participants ranged between 6 and 21 patients. In 5 studies,4,8,12,13,28 orthodontic forces were applied to achieve extrusion, intrusion and retraction of premolar teeth; whereas in the study by Babacan et al.,27 rapid maxillary expansion (RME) was performed. Five studies4,8,12,13,28 reported the orthodontic force applied to teeth which ranged between 0.5 Newton (N) and 44 N. In one study27 the amount of orthodontic force applied to perform RME was not reported. In these studies,4,8,12,13,27,28 the duration for which orthodontic forces were applied ranged between 20 s and 152 days. Three studies4,13,28 reported that intrusive orthodontic forces temporarily reduce PBF; and in the study by Barwick and Ramsay12 PBF remained unaltered during all orthodontic treatment sessions. In the study by Babacan et al.,27 PBF increased in the first week of RME and decreased significantly by the third week of RME.
3.2. Influence of orthodontic forces on the cellular responses of the human dental pulp Twenty studies1,5,7,9,11,14–16,21,29–37 reported the influence of orthodontic forces on human pulpal cellular responses (Table 2). In 18 studies,1–3,5,7,9,11,14–16,21,29–32,34,36,37 orthodontic forces were applied on premolars and in 2 studies33,35 teeth exposed to orthodontic forces were not reported. The magnitude of orthodontic force ranged between 0.3 N and 6 N for durations ranging between 21 min and 84 days. Intrusion, extrusion and tipping movements were performed in 8,1,11,30,31,34–37 83,5,7,14,16,21,29,33 and 39,15,32 studies, respectively. In one study,2 both intrusion and extrusion forces were applied on premolars. Results by Lazzaretti et al.37 showed that intrusive orthodontic forces caused vascular changes in the pulpal tissue and also increased the presence of fibrosis and the number of pulp calcifications. Four studies1,2,21,36 reported orthodontic forces to cause vacuolization and disruption of osteoblasts in pulpal tissues but without necrosis. Results by Caviedes-Bucheli et al.3 reported orthodontic forces of 0.56 N and 2.24 N to increase the pulpal expression of calcitonin gene-related peptide (CGRP) as compared to the control group. Three studies5,14,16 reported orthodontic forces to increase the expression of GFs in pulpal tissues. Perinetti et al.9 and Veberiene et al.11 reported orthodontic forces to increase pulpal AST activity. In one study,34 pulpal AST levels were comparable with and without mechanical load application. Kucukkeles and Okar31 showed vascular degeneration in the pulps of orthodontically treated teeth; Derringer et al.15 reported angiogenesis to be significantly higher in orthodontically-treated teeth and control teeth. In 4 studies,30,33,35,36 orthodontic forces were reported to cause minor disturbances in pulpal circulation. Concentration of substance P was negatively correlated with the magnitude
Four studies38–41 investigated the pulpal reaction of orthodontic forces on traumatized teeth. Two studies38,40 reported the magnitude of orthodontic force applied on traumatized teeth, which were 0.2 N and 0.15 N. In these studies,38–41 duration of orthodontic treatment in previously traumatized teeth ranged between 22.4 and 54 months. All studies38–41 reported PN to be more frequent when orthodontic treatment was performed in previously traumatized teeth as compared to non-traumatized teeth (Table 3).
3.4.
Quality assessment
Most of the studies were graded as ‘‘moderate to low’’ mainly because of their methodological quality (Tables 1–3). Low grading was mainly based on no randomized assignment to experimental and control treatment groups and no description of reliability tests.
4.
Discussion
Since grading evidence is a complicated issue, we avoided using a scale that allocates points to individual quality items because this approach has proved to be inadequate.42 To our knowledge from indexed literature, a gold standard quality assessment tool is still missing.43,44 Lack of randomized controlled trials and a disharmony in the study protocols are limitations of the studies included in this review. These factors may be held responsible for the moderate to low grading of most studies included in this review. In a systematic review published in the year 2012, von Bohl et al.,45 reported that there is no conclusive scientific evidence for a relation between force level and dental pulp tissue reaction in humans. Authors of this systematic review emphasized that there is a scarcity of long-term results regarding pulpal injury occurring as a result of orthodontic treatment.45 Since there is a debate among clinicians regarding the optimal orthodontic forces that teeth can endure without experiencing massive pulpal inflammation and/or necrosis, we were tempted to re-search indexed literature to identify additional studies (published after the year 2012) that assessed the association between orthodontic force and its effects on human dental pulp tissues. Moreover, in the systematic review by von Bohl et al.45 the effect of orthodontic forces on human dental pulp were assessed in non-traumatized teeth only; however, in the present systematic review, we reviewed pertinent literature regarding the influence of orthodontic forces on human dental pulp tissues of nontraumatized and traumatized teeth. In the present study, a systematic review of pertinent literature was performed in an attempt to assess the effect of orthodontic forces on dental pulp tissues. It was hypothesized that long-term application of orthodontic forces jeopardizes
Table 1 – Studies on the effect of orthodontic forces on pulpal blood flow. Authors et al.
Study subjects
Type of treatment
Sano et al.4,*
Prospective
13
Intrusion
McDonald and Pitt Ford8,*
Prospective
10
Canine retraction
Barwick and Ramsay12,y
Prospective
8
Intrusion
Brodin et al.13,y
Prospective
6
Babacan et al.27,y
Prospective
Ikawa et al.28,*
Prospective
Control group
Force applied (N)
Duration of force
Pulpal blood flow measured by
13 vital teeth without orthodontic force application 10 vital teeth without orthodontic force application None
0.5, 1, 2
14 days
LDF
0.5
Up to 4 days
LDF
0.75, 1.25, 5, 44
112 days
LDF
Intrusion and extrusion
None
0.5
152 days
LDF
21
RME
None
NR
Up to 84 days
LDF
17
Intrusion
None
0.5, 1, 5
20 s
LDF
Results
Quality grade
Intrusive forces temporarily reduced PBF. PBF changes returned to normal at the end of force application PBF increased up to 48 h of load application but returned to preload values within 72 h
B
Baseline PBF remained unchanged during all treatment sessions Extrusion had no significant effect on PBF. Intrusion reduced the pulpal blood flow by 20% during the first minute only PBF increased in the 1st week and decreased significantly by the 3rd week of RME Brief intrusive forces temporarily reduced PBF
A
B
C
B
B
archives of oral biology 60 (2015) 347–356
Design
LDF, laser Doppler flowmetry; NR, not reported; OT, orthodontic treatment; PBF, pulpal blood flow; RME, rapid maxillary expansion. High risk of bias. y Low risk of bias. *
351
352
Table 2 – Studies on the influence of orthodontic forces on the cellular responses of the dental pulp. Authors et al.
Design
Subjects
Number of teeth
Type of movement
Force applied (N)
Control group
Duration of force
Prospective
17
34
Intrusion
0.58
No orthodontic force applied
21 days
Han et al.1,y
Prospective
27
54
Intrusion
0.5, 3
No orthodontic force applied
Up to 84 days
Ramazanza-deh et al.2,*
Prospective
26
52
Intrusion and extrusion
0.25, 0.74
No orthodontic force applied
Up to 21 days
Caviedes-Bucheli et al.3,*
Prospective
NR
30
Extrusion
0.56, 2.24
No orthodontic force applied
1 day
Derringer and Linden5,*
Prospective (In vitro)
20
80
Extrusion
0.5–1
Hamersky et al.7,*
Prospective
17
68
Extrusion
At least 0.6 N
Use of antibodies 14 days other than those for VEGF, FGF2 and TGFbeta No orthodontic 3 days force applied
Perinetti et al.9,*
Prospective
17
17
Tipping
0.3–0.9
No orthodontic force applied
7 days
Veberiene et al.11,*
Prospective
21
42
Intrusion
0.61
No orthodontic force applied
7 days
Derringer and Linden14,y
Prospective (In vitro)
10
10
Extrusion
0.5–1
Co-cultures without anti-h EGF
14 days
There was a significant increase in the number of pulpal nodules in the elements with no difference in the number of blood vessels between the groups In both force groups, odontoblasts disruption, vacuolization and moderate vascular congestion occurred but without PN In both force groups, odontoblasts disruption, vacuolization and moderate vascular congestion occurred but without PN In both force groups, pulpal CGRP expression was increased compared to the control group VEGF, FGF-2, PDGF and TGF-b are released following orthodontic force application Short-term orthodontic forces caused pulpal tissue hypoxia Mean AST activity and EPT values were significantly higher in teeth exposed to mechanical load compared to controls Mean AST activity and EPT values were significantly higher in teeth exposed to mechanical load compared to controls Orthodontic forces stimulate the release of EGF in pulp tissues
Conclusion
Intrusive orthodontic forces caused vascular changes in the pulpal tissue and also increased the presence of fibrosis and the number of pulp calcifications Intrusive orthodontic forces do not jeopardize pulp vitality
Quality grade B
C
Histologic pulpal changes C between baseline and 21 days showed no statistically significant difference Orthodontic forces increase C CGRP expression in human dental pulp Growth factors are expressed in the pulp of teeth exposed to mechanical load Orthodontic forces cause biochemical and biologic pulpal tissue alterations Application of mechanical load to teeth can cause metabolic changes in the pulp
C
Application of mechanical load to teeth can cause metabolic changes in the pulp
A
EGF released following orthodontic force application plays a role in pulpal angiogenic response
B
C
B
archives of oral biology 60 (2015) 347–356
Lazzaretti et al.37,y
Pulpal response
Prospective
NR
30
Tipping
0.5–1
Derringer and Linden16,y
Prospective
18
18
Extrusion
0.5–1
Mostafa et al.21,y
Prospective
18
36
Extrusion
0.5
Subay et al.29,y
Prospective
15
40
Extrusion
0.75
Raiden et al.30,y
Prospective
20
40
Intrusion
1.5
Kucukkeles and Okar31,y
Prospective
2
4
Intrusion
1.5
Parris et al.32,*
Prospective
20
80
Tipping
1.2, 1.4, 1.5, 1.8, 2, 2.1, 2.15, 2.3, 2.45 and 6
Stenvik33,y
Prospective
NR
NR
Extrusion
1–2
No orthodontic force applied
7–14 days
Veberiene et al.34,y
Prospective
13
26
Intrusion
0.65
No orthodontic force applied
14 days
Stenvik and Mjor35,y
Prospective
NR
25
Intrusion
0.5–2.5
No orthodontic force applied
5–28 days
a n d Prospective
NR
NR
Intrusion
0.35–2.5
No orthodontic force applied
4–35 days
Stenvik Mjor36,y
No orthodontic force applied
5 days
There were significantly greater numbers of microvessels in orthodontically treated teeth than control teeth No orthodontic 14 days VEGF, FGF-2, PDGF and TGF-b force applied are released following orthodontic force application No orthodontic Up to 28 Dilated and constricted blood force applied days vessels, odontoblastic degeneration, vacuolization and oedema of the pulp tissues, and fibrotic changes occurred in pulpal tissues No control group 10 days, There was no evidence of in(All teeth were ex- 40 days flammatory reactions and/or truded) reparative dentine formation in all teeth No orthodontic 15–20 Histologic results showed force applied days alterations in predentine, calcium deposition, fibrohyalinosis, congestion, inflammation and haemorrhage No orthodontic 90 days Vascular degeneration force applied occurred in the pulps of orthodontically-treated teeth. No orthodontic 21–78 min Concentrations of ir-ME and force applied ir-SP each correlated negatively with the magnitude of the orthodontic force Minor reactions related to the pulpal circulatory system can occur Mean pulpal AST levels and EPT values similar with and without mechanical load application Minor reactions related to the pulpal circulatory system can occur Vacuolization of the pulp tissue and circulatory disturbances occurred
Growth factors are expressed B in the pulp of teeth exposed to mechanical load Growth factors play a role in pulpal angiogenesis
B
Orthodontic forces can cause B temporary inflammation and fibrosis in pulpal tissues
Extrusive forces do not cause C significant pathological changes in pulp tissues Intrusive forces can cause C congestion, haemorrhage and fibrohyalinosis in the pulp tissues
Intrusive forces jeopardize pulp vitality by causing vascular degeneration. Orthodontic forces and pulpal ir-ME and ir-SP concentrations are interlinked
C
B
Orthodontic forces cause C biochemical and biologic pulpal tissue alterations Orthodontic forces do not A influence pulpal AST activity and EPT values Orthodontic forces cause biochemical and biologic pulpal tissue alterations Orthodontic forces cause biochemical and biologic pulpal tissue alterations
archives of oral biology 60 (2015) 347–356
Derringer et al.15,*
C
C
ALP, alkaline phosphatase; AST, aspartate aminotransferase; Control, mechanical load not applied; CGRP, calcitonin gene-related peptide; EGF, epidermal growth factor; EPT, electric pulp testing; irME, immunoreactive methionine enkephalin; ir-SP, immunoreactive substance P; NR, not reported; PM, premolars. * High risk of bias. y Low risk of bias.
353
354
C
C
C
23.8 24 — 23.7 23.7 — 22.4 — 54 39.6 — OT in 29 patients* with non-traumatized teeth
193 traumatized teeth without OT 26 patients* without dental trauma and OT —
Retrospective Brin et al.41
NR
OT in 269 previously traumatized teeth OT in 54 previously traumatized teeth Retrospective Bauss et al.40
0.15
Retrospective Bauss et al.39
NR
59 teeth traumatized during OT
800 teeth non-traumatized during OT
193 traumatized teeth without OT
Group-1: Group-2: Group-3: Group-1: Group-2: Group-3: Group-1: Group-2: Group-1: Group-2: Group-3:
Group-3 (Control group)
193 traumatized teeth without OT OT in 400 non-traumatized teeth
Group-2 Group-1
OT in 77 previously traumatized teeth 0.2 Retrospective Bauss et al.38
Study groups Force applied (N) Design Authors et al.
Table 3 – Studies on the influence of orthodontic forces on the pulpal response in traumatized teeth.
Duration of OT (months)
Results
PN was more frequent in Group-1 than Group-2 or Group-3 PN was more frequent in Group-1 than Group-2 or Group-3 PN was more frequent in Group-1 than Group-2 Loss of pulp vitality was more frequent among teeth in Group-1 than groups 2 and 3
C
Quality grade
archives of oral biology 60 (2015) 347–356
pulp vitality; however, due to a variation in the magnitude and duration of orthodontic forces exerted on teeth in the studies included, it is exigent to scientifically validate the aforementioned hypothesis. Amongst the studies4,8,12,13,27,28 which assessed the influence of orthodontic forces of PBF, magnitude and duration of orthodontic force applied varied considerably (0.5 N–44 N and 20 s–152 days, respectively). It is allured that a low orthodontic force (for instance 0.5 N) exerted on teeth for a few minutes causes minor or no change in PBF than the same force being applied for longer durations. However, scientific evidence in this regard is still missing. Likewise, it may also be argued that long-term application of intense orthodontic forces to teeth influences PBF to a significantly greater extent than when the same forces are applied for a short duration. Therefore, it is difficult to contemplate a direct association between PBF and magnitude of orthodontic force. It has also been reported that the effects of orthodontic forces on PBF are associated with various factors including patients’age, size of apical foramen, dentinogenic activity and not merely on the magnitude and duration of the force applied.7,12 None of the studies4,8,12,13,27,28 that fulfilled the eligibility criteria assessed the influence of size of apical foramen on PBF in the study groups. It is however pertinent to mention that in these studies4,8,12,13,27,28 age of the study participants was also markedly incoherent. For example, in the study by Sano et al.,4 individuals with age ranging between 27 and 31 years were included; whereas Babacan et al.,27 assessed the effect of orthodontic forces on PBF among 10–15 year old patients. Further clinical trials with standardized parameters (particularly magnitude and duration of force application) are needed to clarify the effect of orthodontic forces on PBF. CGRP is a potent vaso-dilatory peptide that is found in approximately 50% of the neurons of the trigeminal system.46,47 Substance P (SP) is mediator of neurogenic inflammation and causes vasodilatation by direct action over endothelial cells and indirect mast cell stimulation for histamine release, a dual effect shared with CGRP.48 These molecules are capable of provoking a tolerable discomfort among patients following the activation of orthodontic intrusive forces.49 In the study by Caviedes-Bucheli et al.,3 orthodontic extrusion was associated with an increased expression of CGRP in the pulp. However, in this study,3 CGRP levels were measured after 24 h of force application. Likewise, Parris et al.,32 measured pulpal SP levels after 0.3–1.3 h after force application. To assess the significance of the results reported by Caviedes-Bucheli et al.,3 and Parris et al.,32 further studies with long-term application of orthodontic force are warranted. Angiogenesis is defined as the process of development of new blood vessels from preexisting microvasculature. GFs may act either directly or indirectly to regulate the endothelial cell function and expression of other GFs by different cell types.50 Studies5,14–16 have used neutralizing antibodies (antih VEGF, FGF2, PDGF, TGF-b and EGF) to investigate the presence of a combination of GFs in the human dental pulp during orthodontic force application. The neutralizing antibodies significantly reduced the number of microvessels in the evaluated in vitro cultures thereby confirming the presence of GFs in the pulp during orthodontic movement. This is an explanation for the study by Derringer et al.,15 in which the authors showed the presence of significantly greater numbers
archives of oral biology 60 (2015) 347–356
of micro-vessels in orthodontically treated teeth than control teeth. Furthermore, in an experimental study on mice, Kaku et al.,51 investigated the effect of recombinant human VEGF (rhVEGF) on the differentiation of osteoclasts during experimental tooth movement. The results suggested that local administration of rhVEGF enhances the number of osteoclasts and may increase the rate of orthodontic tooth movement. It is known that pulpal fibroblasts and odontoblasts synthesize and release ALP.52,53 Therefore, it is hypothesized that application of orthodontic force on these cells reduces their ALP expression. AST is an essential mediator of inflammatory processes and is expressed in high concentrations in pulpal inflammatory conditions.54 Raiden et al.,30 Perinetti et al.,9 Veberiene et al.,11 reported raised pulpal AST levels following the application of intrusive orthodontic forces, which reflect a state of inflammation in the pulp. However, due to a limited number of studies that have assessed pulpal AST and ALP levels during orthodontic force application, the significance of these enzymes affecting pulpal tissues remains veiled. A critical factor that could have biased the outcome of the studies included in the present review is their design and methodology. For example, in the studies4,8,12,13,27,28 which assessed the influence of orthodontic forces on human dental pulp, magnitude of force applied to teeth varied dramatically among as well as between the studies (0.5–44 N). Similarly, among studies that assessed the cellular response of dental pulp cells to orthodontic forces1,5,7,9,11,14–16,21,29–36; the amount of forces used in these studies also varied (0.3–6 N). It is therefore tempting to speculate that an intense orthodontic force (such as 44 N) when applied to teeth for prolonged durations cause pulpal damage to a greater extent as compared to when a low magnitude force is applied to teeth or the same time frame or even longer. Furthermore, regarding the 4 studies38–41 in which pulpal response to orthodontic treatment in previously traumatized teeth was assessed; the results showed loss of pulp vitality following the application of orthodontic force. It is possible that the traumatic insult (such as periodontal trauma) itself may have damaged the dental pulp tissues even before the application of orthodontic force. Therefore, an in-depth assessment involving parameters such as expression of GFs, AST and ALP may yield pertinent information regarding the pulpal response to orthodontic forces in previously traumatized teeth. It is therefore exigent to depict a relationship between force level and the variables investigated in the studies include in the present systematic review.
5.
Conclusion
There is insufficient scientific evidence to prove that orthodontic forces jeopardize the human dental pulp in terms of reducing PBF and irreversible alterations in pulpal cellular response. However, a history of dental trauma maybe considered a risk factor for loss of pulp vitality during orthodontic treatment.
Funding The authors declare that there was no external source of funding for the present study.
355
Competing interest The authors declare that they have no conflict of interest.
Ethical approval Not required.
Acknowledgement The authors extend their appreciation to the Research Center, College of Applied Medical Sciences and Deanship of Scientific Research at King Saud University for funding this research. The authors also thank the Visiting Professor Program at King Saud University, Saudi Arabia for supporting this research project.
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