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Orthodontic tooth movement (OTM) is generated by a mechanical force that induces an aseptic inflammatory response in the periodontal tissues and a subsequent coordinated process of bone resorption and apposition. In this review, we critically summarize the current knowledge on the immune processes involved in OTM inflammation and provide a novel insight into the relationship between classical inflammation and clinical OTM phases. We found that most studies focused on the acute inflammatory process, which ignites the initial alveolar bone resorption. However, the exact mechanisms and the immune reactions involved in the following OTM phases remain obscure. Recent studies highlight the existence of a typical innate response of resident and extravasated immune cells, including granulocytes and natural killer (NK), dendritic, and γδT cells. Based on few available studies, we shed light on an active, albeit incomplete, process of resolution in the lag phase, supported by continuously elevated ratios of M1/M2 macrophage and receptor activator of nuclear factor κB ligand/osteoprotegerin ratio. This partial resolution enables tissue formation and creates the appropriate environment for a transition between the innate and adaptive arms of the immune system, essential for the tissue's return to homeostasis. Nevertheless, as the mechanical trigger persists, the resolution turns into a low-grade chronic inflammation, which underlies the next, acceleration/linear OTM phase. In this stage, the acute inflammation dampens, and a simultaneous process of bone resorption and formation occurs, driven by B and T cells of the adaptive immune arm. Excessive orthodontic forces or tooth movement in periodontally affected inflamed tissues may hamper resolution, leading to "maladaptive homeostasis" and tissue loss due to uncoupled bone resorption and formation. The review ends with a brief description of the translational studies on OTM immunomodulation. Future studies are necessary for further uncovering cellular and molecular immune targets and developing novel strategies for controlling OTM by local and sustained tuning of the inflammatory process. [ABSTRACT FROM AUTHOR]

Presents an abstract of the article "Tooth Size in Dentitions With Buccal Canine Ectopia," by S. Chausu, S. Sharabi, et al., published in the 2003 issue of "European Journal of Orthodontics."

Presents several abstracts on dentistry. Behavior management needs for the orthodontic treatment of children with disabilities; Attitudes and opinions of European dentists regarding tobacco and oral health; Preschool children's consumption of drinks.

This study was designed to measure motivation for and expectations of proposed orthodontic treatment for disabled children, and to examine the level of satisfaction with the results of this treatment, in the eyes of the parents. A two-part questionnaire was sent to the parents of consecutively treated disabled children. The first part was sent to the parents of all the patients treated, while the second was only sent to those whose child had completed treatment. The response rate was over 90 per cent. The parents expected improvement in the child's appearance with a concomitant improvement in his/her social acceptance. These expectations from the treatment were found to be exaggerated, with only a minority of the parents claiming a marked improvement in their child's everyday functioning (four out of 27), or a significant social improvement (six out of 27). Nevertheless, most of the parents (26 out of 27) were satisfied with the treatment, and reported that 17 of the children themselves, who were aware of a change, considered it an improvement. A majority of the children understood the reasons for treatment, in the most general of terms. Close friends regarded treatment results as positive (20 out of 27). With only one exception, the parents stated that they would repeat the procedure, given the same set of circumstances, and all of them would recommend it for other disabled children. It may be concluded that even though orthodontic treatment in this group of patients does not yield the desired social influence, the individual benefits from the treatment are worthwhile. [ABSTRACT FROM AUTHOR]

Background: The prevailing paradigm posits orthodontic tooth movement (OTM) as primarily a localized inflammatory process. In this study, we endeavor to elucidate the potential ramifications of mechanical force on systemic immunity, employing a time-dependent approach., Materials and Methods: A previously described mouse orthodontic model was used. Ni-Ti. springs were set to move the upper 1st-molar in C57BL/6 mice and the amount of OTM was. measured by µCT. Mice were allocated randomly into four experimental groups, each. corresponding to clinical phases of OTM, relative to force application. Terminal blood. samples were collected and a comprehensive blood count test for 7 cell types as well as. proteome profiling of 111 pivotal cytokines and chemokines were conducted. Two controls. groups were included: one comprised non-treated mice and the other mice with inactivated springs., Results: Serum immuno-profiling unveiled alterations in cellular immunity, manifesting as. changes in percentages of leukocytes, monocytes, macrophages, neutrophils, and. lymphocytes, alongside key signaling factors in comparison to both control groups. The systemic cellular and molecular alterations triggered by OTM mirrored the dynamics previously described in the local immune response., Conclusions: Although the exact interplay between local and systemic immune responses to orthodontic forces require further elucidation, our findings demonstrate a tangible link between the two. Future investigations should aim to correlate these results with human subjects, and strive to delve deeper into the specific mechanisms by which mechanical force modulates the systemic immune response., (© 2024. The Author(s).)

Background: The association between orthodontic treatment and temporomandibular disorders (TMD) has been contentious in the literature., Objectives: To analyse the associations between orthodontic treatment and TMD diagnosis and diseases characteristics., Methods: This case-control study included 291 individuals, 192 TMDs and 99 controls. All patients underwent assessment based on a questionnaire and a clinical examination according to Axis I of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Differences in orthodontic treatment between TMDs and controls, as well as across different TMD diagnoses within the TMD group were analysed. Patients who underwent orthodontic treatment were compared to those who did not, regarding their trauma history, bruxism, aggressive teeth brushing, level of oral hygiene, pain scores, muscle tenderness scores and subjective sleep quality., Results: Of the 291 participants, 119 (40.9%) underwent orthodontic treatment and 172 (59.1%) had no orthodontics experience. Orthodontic treatment included: mandibular orthodontic treatment (102 subjects) and maxillary orthodontic treatment (113 subjects) of those 47 used a headgear. Following multivariate analysis among TMDs, orthodontic treatment was associated with a good level of oral hygiene versus poor (Odds ratio [OR]: 5.17 [1.04-25.59]), lower number of tender muscles [OR = 0.84 (0.74-0.96)] and lower (better) Pittsburgh Sleep Quality Index (PSQI) scores (OR = 0.86 [0.76-0.97]). None of the studied parameters maintained a statistically significant association with orthodontic treatment in the multivariate analysis among the entire study population., Conclusions: Utilising a holistic approach, this study supports the main hypothesis that orthodontic treatment is not associated with TMD diagnosis and disease characteristics., (© 2023 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Objective: To assess if the dental follicle volume of palatally impacted canines (PICs) affects the relative root position of the adjacent lateral incisors (LIs) and first premolars (FPs)., Materials and Methods: A retrospective cross-sectional study of 49 patients with unilaterally PICs with dental follicles who had CBCT imaging previously taken. Four orthodontic centers in different countries provided the sample. A mean difference of 5° between the angular measurements (mesiodistal tip, buccolingual inclination, or mesiodistal rotation) of the LI and FP adjacent to the PIC and the controls was considered clinically relevant. A value of 0.05 was set for significance level and a power of 80%. The minimum sample size was determined to be 26 patients. These patients were further assigned to an LI sample (n = 49) and an FP sample (n = 23), dependent on the direct contact of the dental follicle to that adjacent tooth. A manual segmentation technique was used to obtain the volumetric measurements of the dental follicle. Angular measurements of adjacent teeth were then compared to the contralateral nonimpacted side, which acted as the control. A multivariant regression analysis was performed using IBM SPSS software, and statistical significance was set at α = 0.05., Results: Adequate intra-rater reliability was accomplished. The multivariant regression analysis implied that there is no difference in the mean change in the tip, torque, and rotation of the LI and FP between the impacted and control sides when dental follicle volumes are considered (P = .509 for the LI sample and P = .804 for the FP sample)., Limitations: CBCT imaging of dental follicle border delimitations, partial volume effect, and scattering are limitations. This is a convenience sample where the FP subsample is small., Conclusion: The dental follicle volume of the PICs does not seem to influence the relative position of the adjacent LI and FP mesiodistal tip, buccolingual inclination, and mesiodistal rotation. Early intervention could have been suggested to avoid certain malocclusion traits if significant displacements were demonstrated., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Labiopalatal impacted canines (L-PICs) occur when the canines lie between central and lateral incisors, with their tip palatal to the central incisor and part of their crown labial to the lateral incisor. Because of their unusual position, they are often misdiagnosed, and their orthodontic resolution fails. This study aims to provide clinicians with pathognomonic features for early and accurate positional diagnosis of L-PICs., Methods: The L-PIC sample included 21 subjects with full diagnostic records. The control group of normally erupted canines was taken from a previous study. Clinical photographs, 2-dimensional radiographs, and cone-beam computed tomography were used to evaluate the positions of the adjacent incisors and first premolars, the canine incisor index, and the mesiodistal width of the lateral vs central incisors., Results: Central incisors adjacent to L-PICs showed significant mesial root angulation, labial root inclination, and mesiolabial crown rotation, whereas lateral incisors presented significant distal root angulation, palatal root inclination, and mesiolabial crown rotation, in comparison to controls. The roots of the central and lateral incisors were divergent, in contrast to the controls, in which they were slightly convergent. The first premolar positions were not affected. The mean canine incisor index was significantly bigger in L-PICs vs the controls, suggesting a palatal canine. The lateral incisor widths were similar between the groups., Conclusions: This study provides the orthodontist with evidence-based clinical and radiographic red flags for diagnosing L-PIC, which may allow timely initiation of orthodontic treatment and correct planning of mechanotherapy., (Copyright © 2022 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: Allografts are the most common bone grafts for repairing osseous defects. However, their use is associated with an increased risk for infections, donor disease transmission and osteointegration deficiency. Resolvin D1 (RvD1) is an endogenous lipid with a scientifically proven pivotal role in inflammation resolution and osteoclastogenesis inhibition. Yet, its biological relevance as a potential bone regenerative drug has been scarcely studied. Here, we aim to investigate the RvD1 effect on allograft osteointegration in the alveolar bone regeneration (ABR) murine model., Methods: ABR model consisted of osseous defects that were generated by the extraction of the maxillary first molar in C57BL/6 mice. The sockets were filled with allograft and analyzed via RNA sequencing. Then they were locally injected with either RvD1 or saline via single or repeated administrations. The mice were sacrificed 2W after the procedure, and regenerated sites were analyzed using µ CT and histology. First, MC3T3-E1 preosteoblasts were plated with IL-17 pro-inflammatory medium, and RANKL/OPG ratio was measured. Secondly, the MC3T3-E1 were cultured w/o RvD1, for 3W. Osteoblasts' markers were evaluated in different days, using qRT-PCR and Alizarin Red staining for calcified matrix., Results: In vivo , neither allograft alone nor single RvD1 administration promote bone regeneration in comparison to the control of spontaneous healing and even triggered an elevation in NR1D1 and IL1RL1 expression, markers associated with inflammation and inhibition of bone cell differentiation. However, repeated RvD1 treatment increased bone content by 135.92% ± 45.98% compared to its specific control, repeated sham, and by 39.12% ± 26.3% when compared to the spontaneous healing control group (n=7/group). Histologically, repeated RvD1 reduced the number of TRAP-positive cells, and enhanced allograft osteointegration with new bone formation. In vitro , RvD1 rescued OPG expression and decreased RANKL/OPG ratio in IL-17 pro-inflammatory conditions. Furthermore, RvD1 increased the expression of RUNX2, OSX, BSP and OC/BGLAP2 and the mineralized extracellular matrix during MC3T3-E1 osteoblasts differentiation., Conclusions: Repeated administrations of RvD1 promote bone regeneration via a dual mechanism: directly, via enhancement of osteoblasts' differentiation and indirectly, through reduction of osteoclastogenesis and RANKL/OPG ratio. This suggests that RvD1 may be a potential therapeutic bioagent for osseous regeneration following allograft implantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pinto, Klein, David, Polak, Steinberg, Mizrahi, Khoury, Barenholz and Chaushu.)

The study aimed to investigate the role of RvD1 in acute and prolonged sterile inflammation and bone remodeling. A mouse model of sterile inflammation that involves bone resorption was used to examine endogenous RvD1 kinetics during inflammation. Application of exogenous RvD1 significantly inhibited bone remodeling via osteoclast reduction, alongside an anti-inflammatory secretome shift, increased macrophages recruitment and reduction of T-cytotoxic cells. In vitro and in vivo , RvD1 led to significant reduction in RANK expression which reduce osteoclastogenesis in a dose-dependent manner. Taken together, the data shows a dual role for RvD1, as a potent immunoresolvent agent alongside an osteoresolvent role, showing a potential therapeutic agent in bone resorption associated inflammatory conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Klein, Levin-Talmor, Berkstein, Wald, Meirow, Maimon, Leibovich, Barenholz, Polak and Chaushu.)

Objectives: To evaluate the association between maxillary incisor root inclinations and unilateral canine impaction., Methods: A retrospective cross-sectional study of 59 pre-treatment CBCT scans (23 palatal impactions, 10 buccal impactions, and 26 comparison patients). Using Dolphin 3-D Imaging software (Chatsworth, CA), relative incisor angulations to a 3D palatal plane and the shortest distance between the canine crown and the root of the closest lateral incisor were calculated. A one-way analysis of variance was used to determine whether there were any differences between the three independent groups of impactions concerning the four continuous dependent variables incisor root inclination for each maxillary incisor., Results: Patients with unilaterally impacted maxillary canines demonstrate significant differences in the root inclination position on the ipsilateral (0.0001 > P = 0.002) but not contralateral side. While palatal impactions (PIC) are associated with buccally positioned roots of the ipsilateral lateral (-9.05 degrees) and central incisors (-7.91 degrees), buccal impactions (BIC) are only associated with palatally positioned roots of the ipsilateral lateral incisors (+10.40 degrees) alone. A more labial position of the lateral incisor root was correlated with a more proximally located, coronally positioned, and medially displaced adjacent PIC (0.013 > P < 0.026)., Limitations: This is a retrospective cross-sectional convenience sample., Conclusions: Patients with impacted maxillary canines, whether PIC or BIC, do not show generalized retroclination or proclination of all four maxillary incisor roots. Instead, changes in incisor root inclination were only ipsilateral to the impacted canine. BIC is only associated with palatal displacement of the ipsilateral lateral incisor root, whereas PIC is associated with labial root displacement of both ipsilateral incisors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Basic research in orthodontics is commonly conducted in rodents. However, experimental studies on orthodontic tooth movement (OTM) lack a standard method to examine OTM and periodontal changes. This study describes a unifying protocol for the analysis of OTM and associated bone microarchitectural changes in mice using microcomputed tomography (µCT)., Methods: Mice (10 animals/group) were divided into control and OTM groups. OTM was generated by anchoring a nickel-titanium closed-coil spring to the upper incisors to pull the upper left first molar. A third group of TNFα -/- mice was added since these are known to have slower OTM. Using µCT, we implemented and tested a number of methods to measure OTM distance and examine 3D bone morphometric parameters associated with OTM in mice., Results: In total, we tested five methods to measure the OTM distance in mice. The results indicated that measuring the intermolar diastema, and assessing tooth movement relative to the anterior root of the zygomatic arch, displayed the lowest standard deviation and enabled optimal detection of intergroup differences. We also developed two protocols for µCT analysis of the periradicular bone that yielded no false-positive results. Our results revealed that including the width of the periodontal ligament rather than excluding it from the region of interest in mice detected more statistically significant differences in the morphometric parameters between the OTM and control sides and between WT and TNFα -/- mice despite more subtle differences., Conclusions: We, therefore, propose new guidelines for a standardized μCT-based method to analyse OTM and the extent of the periradicular bone structural changes in mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Irradiation of facial bones is associated with a lifelong risk of osteonecrosis. In a rat model, maxillae were exposed to a single 5 Gy dose of external beam radiation and orthodontic force was applied for 2 weeks on the first maxillary molar; control rats were treated identically without radiation. Tooth movement in irradiated jaws was 30% less than in controls, representing radiation-related damage. Micro-CT, histological, and molecular outcomes of orthodontic tooth movement were studied. Microstructurally, bone parameters (trabecular thickness, bone volume fraction, bone mineral density) were significantly affected by orthodontic force but not by radiation. Histological parameters were influenced only by orthodontic force, especially by an increase in osteoclasts. A molecular study revealed a differential distribution of cells expressing pre-osteoclast markers (RANK+-majority, CD11b+, CD14+-minority), with changes being influenced by orthodontic force (increased CD11b+ and CD14+ cells) and also by radiation (decreased RANK+ cells). The activation status of osteoclasts (TRAP staining) showed an orthodontic-force-related increase, which probably could not fully compensate for the radiation-associated impairment. The overall balance showed that orthodontic force had elicited a substantial microstructural, histological, and functional normalization process in irradiated maxillae but a radiation-induced impact was still conspicuous. Additional studies are needed to validate these findings.

Introduction: The purposes of this study were to characterize the 3-dimensional position of teeth adjacent to impacted canines and examine whether impaction affects canine development using cone-beam computed tomography., Methods: Cone-beam computed tomography images of 34 unilateral maxillary impacted canines (12 males, 22 females; mean age, 16.5 years) were collected. Twenty-one canines were palatally impacted (PIC), and 13 were buccally impacted (BIC). Angular measurements of lateral incisors (LIs), first premolars, and the impacted canines positions relative to a 3-dimensional coordinate system and canines' volume, length, and shape of the roots, were compared between the affected and contralateral control sides. The influence of canine position and severity of impaction was examined. Statistics included the paired t test, Wilcoxon signed rank test, and McNemar test., Results: In the PIC group, LIs showed significant mesiobuccal rotation (-17.1°), mesial angulation (8.4°), and buccal root torque (5°) and first premolars mesiobuccal rotation (6.1°). In the BIC group, LIs displayed mesiobuccal rotation (-18°) and significant palatal root torque (-5°). The canine volumes were similar in BICs and slightly smaller in PICs. The lengths were shorter in both, but root hooks were more prevalent in BICs. The severity of impaction affected the measured variables., Conclusions: The differential position of the adjacent teeth is pathognomonic for PIC vs BIC, and impaction seems to affect canine development. The findings provide evidence-based clinical and radiographical clues for early diagnosis of canine displacement and planning the most efficient treatment strategy. In addition, they support timely orthodontic eruption before the development of the apical third of the root., (Copyright © 2020 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Fusobacterium nucleatum is a common oral bacterium that is enriched in colorectal adenomas and adenocarcinomas (CRC). In humans, high fusobacterial CRC abundance is associated with chemoresistance and poor prognosis. In animal models, fusobacteria accelerate CRC progression. Targeting F. nucleatum may reduce fusobacteria cancer progression and therefore determining the origin of CRC F. nucleatum and the route by which it reaches colon tumors is of biologic and therapeutic importance. Arbitrarily primed PCR performed previously on matched same-patients CRC and saliva F. nucleatum isolates, suggested that CRC F. nucleatum may originate from the oral cavity. However, the origin of CRC fusobacteria as well as the route of their arrival to the tumor have not been well-established. Herein, we performed and analyzed whole genome sequencing of paired, same-patient oral, and CRC F. nucleatum isolates and confirmed that CRC-fusobacteria originate from the oral microbial reservoir. Oral fusobacteria may translocate to CRC by descending via the digestive tract or using the hematogenous route during frequent transient bacteremia caused by chewing, daily hygiene activities, or dental procedures. Using the orthotropic CT26 mouse model we previously showed that IV injected F. nucleatum colonize CRC. Here, we compared CRC colonization by gavage vs. intravenous inoculated F. nucleatum in the MC38 and CT26 mouse orthotropic CRC models. Under the tested conditions, hematogenous fusobacteria were more successful in CRC colonization than gavaged ones. Our results therefore provide evidence that the hematogenous route may be the preferred way by which oral fusobacteria reach colon tumors., (Copyright © 2020 Abed, Maalouf, Manson, Earl, Parhi, Emgård, Klutstein, Tayeb, Almogy, Atlan, Chaushu, Israeli, Mandelboim, Garrett and Bachrach.)

Background: The aim of the study is to examine bone healing following augmentation with allograft or β-tricalcium phosphate (β-TCP) and evaluate orthodontic tooth movement (OTM) into the augmented sites., Methods: The study included two parts. Part I included the alveolar bone regeneration model. Osseous defects were created by extraction of the maxillary first molars in C57BL/6 mice, and the sockets were filled with allograft, β-TCP, or left unfilled (n = 6/group). Mouse allograft was prepared by a novel method using long bones. Maxillae were collected at 2, 4, and 6 weeks for microcomputed tomography (μCT) and histological analysis. In Part II, OTM was performed after full bone healing, through grafted and unfilled sockets (n = 10/group), and the second molar shift was assessed using μCT., Results: Bone volume and trabeculation were reduced in β-TCP compared with allograft and non-grafted groups at 2 and 4 weeks post-grafting, but similar at 6 weeks. Graft particles could be detected at 2 weeks post-grafting for β-TCP, and at 2 and 4 weeks for allograft. Increased osteoclasts' presence was observed in the β-TCP group at 2 and 4 weeks compared with allograft and control. OTM was similar in the two graft groups, but impaired versus the non-grafted controls., Conclusion: β-TCP and allograft induce full normal healing but alter OTM into the regenerated sites., (© 2019 American Academy of Periodontology.)

Orthodontic tooth movement (OTM) is a "sterile" inflammatory process. The present study aimed to reveal the underlying biological mechanisms, by studying the force associated-gene expression changes, in a time-dependent manner. Ni-Ti springs were set to move the upper 1 st -molar in C57BL/6 mice. OTM was measured by μCT. Total-RNA was extracted from tissue blocks at 1,3,7 and 14-days post force application, and from two control groups: naïve and inactivated spring. Gene-expression profiles were generated by next-generation-RNA-sequencing. Gene Set Enrichment Analysis, K-means algorithm and Ingenuity pathway analysis were used for data interpretation. Genes of interest were validated with qRT-PCR. A total of 3075 differentially expressed genes (DEGs) were identified, with the greatest number at day 3. Two distinct clusters patterns were recognized: those in which DEGs peaked in the first days and declined thereafter (tissue degradation, phagocytosis, leukocyte extravasation, innate and adaptive immune system responses), and those in which DEGs were initially down-regulated and increased at day 14 (cell proliferation and migration, cytoskeletal rearrangement, tissue homeostasis, angiogenesis). The uncovering of novel innate and adaptive immune processes in OTM led us to propose a new term "Immunorthodontics". This genomic data can serve as a platform for OTM modulation future approaches.

Background: The aim of this study was to investigate the biological mechanisms underlying alveolar bone regeneration (ABR) and orthodontic tooth movement into bovine bone (BB) regenerated sites., Methods: Two mouse models were established in C57BL/6 mice. The ABR model was based on osseous defects filled with BB. The orthodontic tooth movement-ABR model was used to move a molar into the regenerated site. Osseous morphometric analysis and tooth movement distance were evaluated with micro-CT. Histologic characteristics and osteoclast (OCS) accumulation were evaluated by hematoxylin and eosin and tartrate-resistant acid phosphatase staining (TRAP). Expression and location of the receptor activator of nuclear factor-kappa B (RANKL) and of osteoprotegerin (OPG) were evaluated by immunofluorescent staining., Results: Bone healing peaked at 4 weeks. The distance of the orthodontic tooth movement into the bovine bone was significantly reduced versus that of the nonbovine bone controls. BB particles accumulated along the root's pressure side during orthodontic treatment. Despite the osteoclasts' presence adjacent to the BB particles, no BB resorption was observed. Increased RANKL expression was seen at the orthodontic tooth movement pressure zone, without any change in OPG expression., Conclusion: The two novel mouse models show that the lack of resorption of BB xenografts renders them inadequate for proper orthodontic tooth movement at a later stage., (© 2018 American Academy of Periodontology.)

Purpose: Orthodontically induced inflammatory root resorption (OIIRR) is one of the most prevalent and unavoidable consequence of orthodontic tooth movement. The aim of this study was to discover potential diagnostic protein biomarkers for detection of OIIRR in whole saliva (WS)., Material and Methods: Unstimulated WS was collected from 72 subjects: 48 OIIRR patients and 24 untreated, generally healthy, age and gender matched controls. Radiographic assessment of periapical x-rays of four upper incisors taken before and 9 months after bonding was done. High-abundance proteins were depleted followed by two-dimensional-gel-electrophoresis and quantitative mass spectrometry (qMS). Finally, to initially validate qMS results, Western blotting was performed., Results: qMS revealed differentially expressed proteins in the moderate-to-severe OIIRR group, which have never been found in WS before. Additionally, in the moderate-to-severe young OIIRR group, the pathogenetic mechanisms related to actin cytoskeleton regulation and Fc gamma R- mediated phagocytosis were detected, while in adults- to focal adhesion. Preliminary validation by Western blotting of fetuin-A and p21-ARC indicated expression profile trends similar to those identified by qMS., Conclusion: The significance of WS novel proteomic methodologies is clearly demonstrated for detecting new OIIRR biomarkers as well as for unveiling possible novel pathogenetic mechanisms in both young and adult patients., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)