Biological Effects of Orthodontic Tooth Movement on the Periodontium in Regenerated Bone Defects: A Scoping Review

The aim of this scoping review is to analyse the biological effects of the orthodontic tooth movement (OTM) in areas with bone defects that are undergoing regeneration using different types of regenerative materials and techniques. The electronic research was performed on four databases as follows: PubMed, Scopus, EMBASE, and Web of Science. Data were extracted according to publication information, study design, sample characteristics, parameters of OTM, biological repercussions on the periodontium complex, methods of analysis, and conclusions. A total of thirty studies were included in the final review. In twenty-two studies, the most widely adopted grafting materials were alloplastics. In most studies, the orthodontic force used was 10 or 100 g, and the timing of application ranged from immediate to 6 months after grafting surgery. Twenty-four studies showed an increase in osteogenesis; in five studies, the clinical attachment level (CAL) increased; in five others, the probing pocket depth (PPD) decreased; in sixteen studies, there was root resorption of a different magnitude. Though the effects of OTM on the periodontium in the grafted areas were positive, the outcomes should be interpreted with caution as future preclinical and clinical studies are needed to extrapolate more valid conclusions.


Introduction
Bone grafts and substitute materials play a crucial role in regenerating missing hard tissue structures, providing a structural framework for osteo-regenerative processes [1].Autologous bone, whether used alone or in combination with bone substitute materials, and bone substitute materials on their own are well-established materials [2].These substitute materials can be categorised into those of natural origins such as autografts, allografts, and xenografts, or alloplastic materials.While autografts are considered the gold standard for treating bone defects, synthetic grafts remain the most common choice [3].
Orthodontic treatment induces changes in the alveolar bone, affecting the characteristics of the bone differently across various regions of the mouth.Specifically, orthodontic treatment leads to a reduction in bone thickness, particularly on the palatal side and in the incisor region [4].It also produces changes at the gingival tissue level, including gingival recession [5].Root resorption is another side effect of orthodontic movements, especially when continuous and heavy forces or a higher amount of apical movement over a long duration are applied [6].
Teeth can also be moved through bone grafts despite there being a side effect of occasional slight root resorption.However, it is essential to carry out these movements when the bone is adequately prepared [3].Previous studies suggest that allografts and βtricalcium phosphate influence bone homeostasis, resulting in a deceleration of orthodontic tooth movement in regenerated sites [7].The aim of this study is to analyse the biological effects of orthodontic tooth movement on the periodontium in areas with bone defects that are undergoing regeneration.

Protocol and Registration
This scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines [8].

Information Sources and Search Strategy
A comprehensive search strategy was designed, and a thorough computer-based search was performed on 10 November 2023, using the electronic databases as follows: PubMed, Scopus, EMBASE, and Web of Science.An electronic search of the grey literature was made through Opengrey.The strategies designed for each database are shown in Table 1.No limitation of language or publication date was applied in the literature search.

Study Selection and Eligibility Criteria
The electronic search was independently conducted by two investigators (AV and CSF), screening titles and abstracts in parallel to evaluate the studies for eligibility.In case of missing information, full-text reading was necessary for a final decision.A third author (ES) discussed and resolved any discrepancies between the two authors.No language or time limit was applied to the search strategy.The inclusion criteria for the selection of articles had to accomplish the following characteristics: (1) human and animal subjects, (2) orthodontic movement across bone defects repaired with synthetic or natural material grafts, (3) biological and/or biomechanic repercussions on the tooth and/or adjacent tissues to the orthodontic displacement, (4) and the amount of orthodontic tooth movement produced across the bone defects repaired.On the other hand, the exclusion criteria were as follows: (1) in vitro and ex vivo studies, (2) literature reviews, (3) and systematic reviews.

Data Extraction and Synthesis
Two different reviewers (A.V. and C.S.F.) unitedly determined which variables to extract and developed the data-charting form.The data were extracted independently by the same two reviewers.The data were extracted according to the following: publication information (authors of the study and year of publication); study design (type of study); sample characteristics (including species, age, gender, type of defect, defect size, and localization and material of regeneration); parameters of orthodontic tooth movement (including localization of orthodontic tooth movement, timing, direction, magnitude, as well as mode of the force application, total duration of orthodontic tooth movement, and amount of movement achieved); biological repercussions on the periodontium complex (including bone formation/resorption, clinical attachment level, root integrity/resorption, and probing pocket depth as a response to the orthodontic tooth movement); methods of analysis; and conclusions.The extracted outcomes were retrieved from the included studies and then summarised.

Literature Search and Screening Process
The search strategy identified 2627 publications from the PubMed (n = 465), Scopus (n = 763), EMBASE (n = 632), Web of Science (n = 767), and Opengrey (n = 0) databases.Following the removal of duplicated ones, 1113 records remained.After reading the title and abstract, an additional 1044 studies were excluded.Subsequently, the full text of 61 out of the remaining 69 studies was reviewed; 8 studies could not be retrieved.Among the studies whose full text was read, eight were excluded for not studying orthodontic tooth movement through bone substitutes, nine for not analysing the effects on the periodontium and/or describing the parameters of the applied orthodontic force, five for not mentioning and/or not explaining the type of material used to treat the bone defect, and nine for not addressing the topic under study and not meeting the inclusion criteria.In the end, 30 studies were included that met the inclusion criteria for this scoping review.The details of the literature search and selection procedure are shown in a flow chart in Figure 1.

Study Design
Almost all the included studies (n = 27) were experimental studies.Additionally, five case reports [23,28,32,35,37] and only one observational one [15] were included in this scoping review.

Parameters of Orthodontic Tooth Movements
The characteristics related to the analysed parameters of orthodontic tooth movement are described in Table 4.

• Localization of orthodontic movement
The main location where tooth movement was examined was the maxilla (n = 30).In four studies, orthodontic movement in the mandible was also analysed simultaneously with the upper jaw [14,20,31,33].Most studies used the canine as the anchoring unit (n = 12) and the premolar as the unit of movement (n = 10).

Biological Repercussions on the Periodontium Complex and Methods of Analysis
The characteristics related to the biological repercussions on the periodontium complex and the methods of analysis of orthodontic tooth movement are described in Table 5.

• Bone response
In as many as 24 studies, most of the results showed that there was an increase in bone formation compared with that of the control group after an initial phase of bone turnover in the graft zone.Among these, five compared various types of bone grafts with each other.In Ru's three studies [16][17][18], synthetic bone resulted in higher bone regeneration than that observed for xenogenic bone graft substitutes.In Moehlhenrich's 2021 study [27], xenogeneic and autologous bone substitutes exhibited higher bone formation than synthetic substitutes.Two studies converged in stating that conjugating bone marrow stromal cells with Beta tricalcium phosphate resulted in higher bone regeneration than that observed for Beta tricalcium phosphate when it was used alone [12,21].Only one article [33] was explicit in stating that the process of bone regeneration and resorption were in balance.In three studies [10,22,28], no such information was reported, and one study [20] did not detail the bone-level response following grafting.

•
Clinical attachment level (CAL) Most studies did not report the effects of orthodontic movement on CAL.An increase in the clinical attachment level was observed in the area undergoing treatment in only five studies [9, 23,32,36,37].

•
Probing pocket depth (PPD) Regarding probing pocket depth, the majority of the studies also did not mention this parameter.Five studies reported a decreased probing pocket depth [11,23,32,36,37], and only Lee's study observed an increase in the probing pocket depth [31].

• Root integrity/resorption
From the results obtained, root resorption as an effect of orthodontic tooth movement in a bone graft zone was produced in nine studies, albeit with a different degree of magnitude.In seven articles, there was slight or partial root resorption [9, 15,24,25,31,33,34], while in one the extent of resorption was more important [10].In five articles, no root resorption was reported [12,26,28,35,37].In three studies, it was stated that synthetic bone substitutes induced a lower degree of root resorption than that observed for xenografts.No such information was reported in 13 studies.

Discussion
This scoping review describes the biological effects of orthodontic tooth movement on the periodontium in regenerated bone defects, analysing thew bone-level response, clinical attachment level, probing pocket depth, and root integrity.These parameters are found to be influenced by multiple variables as follows: type, location, and size of the defect; graft material; timing and intensity of the force application; and total treatment duration.The size of the bone defect can be highly variable depending on the type of defect and the species analysed.Bone has an inherent ability to heal spontaneously after injury [38].If a large defect goes beyond a certain size, which is known as a critical-size bone defect, the bone is unable to heal spontaneously [39].For this reason, an ideal bone defect model would be one in which the defect only heals with the insertion of the graft material [40].Only three studies [22,24,25] clearly defined how the defects that were surgically created were critical-sized and further included an "empty" or untreated blank control group to confirm the absence of spontaneous healing at the end of the study period.Ideally, a two-walled defect would be better to reproduce a true osteotomy gap, but it would be more challenging to fix the scaffold material in place [30].Most of the included studies showed that the most frequently reproduced and studied type of defect was the extraction socket with predominantly maxillary localization.Regional variations in bone density exist between the maxilla and mandible and between the posterior and anterior regions of the same bone structure, thus making it difficult to compare studies even when they are conducted on living beings of the same species [41].Another variable that plays an important role in the periodontal response to orthodontic tooth movement is the type of bone graft material [11,30,36,42].The degradation of the material depends mainly on the composition of the bone substitute [43].The current gold standard of bone grafts is the autograft since it possesses all the characteristics necessary for new bone growth, namely osteoconductivity, osteogenicity, and osteoinductivity [44].This kind of graft also has several clinical disadvantages due to the need to remove the bone from another area causing possible complications such as pain, risk of infiltration, and scarring [45].The increased use of alloplastic materials found in most of the studies that are included in this review is attributed to the favourable characteristics exhibited by these substitutes including biological stability, volumetric stability, osteoconductivity, degradation, absorption, and an absence of infectious risks [46].When comparing alloplastic grafts and autografts, Hossain's study [9] found that tricalcium phosphate exhibited a higher adaptive remodelling and biodegradative ability in response to orthodontic forces than particulate marrow and cancellous bone (PMCB).In the family of calcium phosphate bioceramics, the absorption rate is linked to the calcium-to-phosphate (Ca/P) ratio [20].A lower Ca/P ratio of β-Tricalcium phosphate [47] in comparison with hydroxyapatite can accelerate its degradation and absorption [48].Although alloplastics may be a viable alternative, the heterogeneity of the studies analysed led to a lack of consensus.According to Moehlhenrich [10], there is no difference between autografts, xenografts, or synthetic bone substitutes used to repair alveolar clefts, thus showing similar effects in orthodontic tooth movement and the degree of root resorption.Once the type of bone substitute was selected, the protocols of the studies analysed indicated the timing of the application of the orthodontic force.The timing ranged from immediate application after grafting surgery to six months later.Some authors suggest that tooth movement should not begin until the regenerated bone has been consolidated for 8 to 12 weeks [49,50].Although most of the included studies began force application after four weeks to avoid an increase in the incidence of root resorption due to the lack of degradation of the bone substitute [51], some experimental studies showed that tooth movement could be applied long before the time of complete material degradation and suggested that the immediate application of force induced better periodontal regeneration by decreasing the risk of orthodontic movement inhibition [30].Moreover, the magnitude of the applied force based on the data analysed was highly variable.This is probably due to the lack of scientific evidence concerning the level of force that may be recommended for optimal efficiency in clinical orthodontics [52].The only observation that could be made was that heavy continuous forces increase the risks of uncontrolled tipping, increased hyalinization, and root resorption [53].Nickeltitanium coil springs release light, continuous forces without causing rapid force decay like elastic chains do, and they do not exert high, intermittent tensile forces like stainless steel coils do [54].After analysing the effects on the periodontium, it was observed that orthodontic tooth movement in the bone graft area promoted bone remodelling of the embedded bone, inducing resorption and subsequent deposition [19].This remodelling depends on the multinucleated cells that play an important role in the resorption and replacement of graft materials [55].In all the studies analysed, even though different types of materials were used, an initial phase of bone turnover in the graft zone could be observed.Moehlhenrich's study [27] stated that autografts and xenografts exhibited a higher degree of bone formation in comparison with that observed for alloplastic substitutes.This is due to the porosity and shape of the particles that increase the surface area of xenografts, making them appropriate scaffolds for the penetration of cells mediating osteogenesis and angiogenesis [56].However, although there was no consensus among the authors in this scoping review, most of them stated the exact opposite and attributing greater properties to the ceramic substitutes as the materials of choice, highly increasing their regenerative capabilities when conjugated with bone marrow mesenchymal stem cells (BMSCs) [12,26].Rokn's comparative study [55] established that there were no statistically significant differences in osteogenesis between xenogeneic and alloplastic grafts.It was more complex to determine the repercussions of orthodontic tooth movement on the clinical attachment level and the probing pocket depth because few studies dealt with these parameters.In all of them, there was an improvement in the clinical attachment level and a reduction in the probing pocket depth.This would be due to the increase in the calcium and phosphate ions that stimulate osteogenesis and cementogenesis [57].This cementogenesis is followed by a reorganization of the periodontal ligament between the new cementum and the bone around the granules of the graft material, which occurs due to to the stimulation of the same material [9].Dental root resorption is another important issue during biomaterial grafting in orthodontic treatment.In most of the cases analysed, root resorptions of different entities were produced from one study to another.Ru's studies [16,17] considered root effects three-dimensionally and found that resorptions were not simply located in the areas of the highest accumulated stress but rather in those root portions subject to accumulated stress based on their surface area.Areas with a smaller surface area had more prominent root tissue craters as a result of resorption.Furthermore, it was stated that ceramic substitutes induced less root resorption than xenografts, thereby preserving the recipient area more [11,16,17].According to some studies, the increased erosion of root cement could depend on two factors as follows: the levels of bone morphogenetic protein (BMP2) present in the alloplastic calcium phosphate graft [24,25] and the high immunogenicity of the material.Xenografts induce higher recruitment of osteoclast-like multinucleated cells promoting higher rhizolysis compared with that observed for the ceramic substitutes [58].
The included articles utilized diverse analytical methods to investigate structural changes in the periodontium resulting from orthodontic treatment.Predominantly, histomorphometry and histological analysis were employed, with Kulak CA et al. (2010) [59] considering them to be the "gold standard."Histomorphometry quantifies newly formed bone and residual graft material percentages, while histological analysis identifies the formation of new bone matrix.Despite their appropriateness, these methods possess limitations, being time-consuming, destructive, and confined to a two-dimensional tissue evaluation [60].Consequently, numerous studies in this scoping review [7,10,11,13,14,16,18,27,29,30] adopted three-dimensional techniques (CBCT, micro-CT, and CT).As asserted by Vandewergh et al. [61], these techniques offer insights into bone microarchitecture, which are non-destructive with excellent resolution.However, despite their advantages, three-dimensional techniques are less effective in distinguishing mineralized bone tissue from newly formed bone, thus necessitating complementary methods like histological and histomorphometric analyses [62].Additional techniques including fluorescence, immunohistochemistry, PCR, and finite element studies were auxiliary.The former three methods helped to define biochemical processes at the cellular level influencing tooth movement [63], while the latter detailed the distribution of forces at the root level [16][17][18].
Although this scoping review includes a substantial number of papers, it has certain limitations due to the loss of several studies which did not describe the effects of such treatment on the periodontium or did not specify the type of material grafted even though they dealt with orthodontic tooth movement on grafted areas.In addition, the included studies had a high level of heterogeneity due to the different methodologies applied, with a lack of protocolization in recreating or determining the key parameters such as the species studied, type and size of the bone defect, and timing in the application of orthodontic force after grafting surgery.The studies performed on human patients especially presented a very weak design, with all of them being case reports with little scientific evidence.Even the effects on the periodontium, which are understood to be the supporting apparatus [64], were only partially studied, with the focus mainly being placed on the bone response in response to the grafted material and with most studies omitting the effects on other structures such as the gingiva, periodontal ligament, and cementum.It is mandatory to emphasize that this scoping review's approach only maps the available evidence in a descriptive and exploratory manner rather than being analytical and explanatory like a systematic review.
Future research should be aimed at improving the design of the studies by applying a more meticulous methodology.This improvement could be achieved by treating some of the parameters evoked in the various studies with higher rigor, which include the following: the species, with it being necessary to give preference to species that are similar in their characteristics to humans by considering the size required to reproduce a bone defect of an adequate size; standardization of the size of bone defects; comparisons between the various families of grafting materials in the same study; applications of light and continuous forces; studying the long-term effects (minimum of 6 months); and a detailed study of the periodontium in its entirety with histological, histomorphometric, three-dimensional analysis methods as well as periodontal clinical examination.Studies on humans this clinical procedure is carried out, especially in branches of patients with a cleft palate and periodontal patients undergoing regenerative techniques and orthodontic treatment, should also be improved and deepened so that more scientific evidence is provided.

Conclusions
Orthodontic tooth movement in areas undergoing bone regeneration has revealed positive biological effects on periodontal health.The occurrence of increased bone formation and elevated clinical attachment levels was consistently found in almost all the studies regardless of the material used, timing, and intensity of the force applied.Although root resorption commonly arises as a complication, it does not appear to significantly impact tooth survival.Nonetheless, it is crucial to approach these findings with caution, underscoring the imperative for future preclinical and clinical studies with refined designs to generate more robust conclusions within the context of periodontal regeneration.

Figure 1 .
Figure 1.Flow chart showing the literature search and selection.

Table 1 .
Search strategy for each database.

Table 2 .
Main characteristics of the studies.

Table 3 .
Type of samples and their characteristics.

Table 4 .
Parameters of orthodontic tooth movement.

Table 5 .
Biological repercussions on the periodontium complex.