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A biologic is a therapeutic agent with biological activity that is administered to achieve an enhanced regenerative or reparative effect. The use of biologics has progressively become a core component of contemporary periodontal practice. However, some questions remain about their safety, indications, and effectiveness in specific clinical scenarios. Given their availability for routine clinical use and the existing amount of related evidence, the goal of this American Academy of Periodontology (AAP) best evidence consensus (BEC) was to provide a state-of-the-art, evidence-based perspective on the therapeutic application of autologous blood-derived products (ABPs), enamel matrix derivative (EMD), recombinant human platelet-derived growth factor BB (rhPDGF-BB), and recombinant human bone morphogenetic protein 2 (rhBMP-2). A panel of experts with extensive knowledge on the science and clinical application of biologics was convened. Three systematic reviews covering the areas of periodontal plastic surgery, treatment of infrabony defects, and alveolar ridge preservation/reconstruction and implant site development were conducted a priori and provided the foundation for the deliberations. The expert panel debated the merits of published data and exchanged experiential information to formulate evidence-based consensus statements and recommendations for clinical practice and future research. Based on an analysis of the current evidence and expert opinion, the panel concluded that the appropriate use of biologics in periodontal practice is generally safe and provides added benefits to conventional treatment approaches. However, therapeutic benefits and risks range based on the specific biologics used as well as patient-related local and systemic factors. Given the limited evidence available for some indications (e.g., gingival augmentation therapy, alveolar ridge preservation/reconstruction, and implant site development), future clinical studies that can expand the knowledge base on the clinical use of biologics in periodontal practice are warranted.

With technological advancements in reconstructive periodontology, traditional protocols for the treatment of gingival recessions (GRs) can be challenged. This manuscript presents preliminary findings of a novel minimally-invasive approach for the regenerative treatment of multiple adjacent GR defects.Two healthy adults were treated as part of this study. Multiple adjacent GRs in both subjects (1 in the mandible, and 1 in the maxilla) were treated employing a tunneled coronally advanced flap (TCAF) design, with the application of a cross-linked collagen matrix (CCM) that was enriched with recombinant human platelet-derived growth factor-BB (PDGF-BB) that was also applied on the prepared root surfaces. Clinical, ultrasonographic, esthetic, and patient-reported outcomes were observed at approximately 6- and 18-month time points.All sites healed uneventfully after the treatments. Complete root coverage was achieved and maintained throughout the follow-up observations, from 6 to 18 months. Patients reported minimal discomfort and reduction of dentinal hypersensitivity at the augmented sites. The areas augmented with CCM + PDGF-BB revealed an increased soft tissue thickness relative to baseline (pretreatment) measures, as well as reduction in the level of the facial bone dehiscences.This article describes the success of two cases of a novel minimally invasive regenerative approach for the treatment of multiple adjacent GR defects by the TCAF, using a CCM loaded with PDGF-BB. This approach offers potential as a minimally-invasive method to repair multiple adjacent GRs.

Periodontitis is a disease characterized by tooth-associated microbial biofilms that drive chronic inflammation and destruction of periodontal-supporting tissues. In some individuals, disease progression can lead to tooth loss. A similar condition can occur around dental implants in the form of peri-implantitis. The immune response to bacterial challenges is not only influenced by genetic factors, but also by environmental factors. Epigenetics involves the study of gene function independent of changes to the DNA sequence and its associated proteins, and represents a critical link between genetic and environmental factors. Epigenetic modifications have been shown to contribute to the progression of several diseases, including chronic inflammatory diseases like periodontitis and peri-implantitis. This review aims to present the latest findings on epigenetic influences on periodontitis and to discuss potential mechanisms that may influence peri-implantitis, given the paucity of information currently available.

To assess the prognostic value of soft tissue phenotype modification following root coverage procedures for predicting the long-term (10-year) behaviour of the gingival margin.Participants from six randomized clinical trials on root coverage procedures at the University of Michigan were re-invited for a longitudinal evaluation. Clinical measurements were obtained by two calibrated examiners. A data-driven approach to model selection with Akaike information criterion (AIC) was carried out via multilevel regression analyses and partial regression plotting for changes in the level of the gingival margin over time and interactions with the early (6-month) results of soft tissue phenotypic modification.One-hundred and fifty-seven treated sites in 83 patients were re-assessed at the long-term recall. AIC-driven model selection and regression analyses demonstrated that 6-month keratinized tissue width (KTW) and gingival thickness (GT) influenced the trajectory of the gingival margin similarly in a concave manner; however, GT was the driving determinant that predicted significantly less relapse in the treatments, with stability of the treated gingival margin obtained beyond values of 1.46 mm.Among a compliant patient cohort, irrespective of the rendered therapy, the presence of at least 1.5 mm KTW and 1.46 mm GT was correlated with the long-term stability of the gingival margin.

Aim To assess the association between peri-implantitis and cardiovascular diseases (CVD). Methods 128 patients with dental implants were recruited to evaluate the prevalence of peri-implantitis in patients with or without CVD (Cases, n = 82, Controls, n = 46, respectively). Diagnosis of peri-implantitis followed the 2017 World Workshop guideline and the severity was defined as mild, moderate, and severe form when the radiographic bone loss (RBL) was 4 mm. Multivariable logistic regression was performed to test the association between two diseases. Results A trend of higher prevalence of peri-implantitis defined by detectable RBL beyond the physiologic bone remodeling was found in the "Cases" group (64.6%) when compared to the "Controls" (56.5%). A significant higher prevalence (48.8%) of moderate to severe peri-implantitis was identified in "Cases" compared to "Controls"(30.4%) with a significant crude association between moderate to severe peri-implantitis and CVD (odds ratio = 2.18, 95% CI = 1.02 to 4.67, p = 0.04). The CVD group had a trend of higher prevalence of deep pockets (≥ 7mm) and higher numbers of sites with bleeding upon probing (BOP) (> 66%) when compared to "Controls" (p> 0.05). However, after controlling for multiple confounders including age, hypertension, smoking, family history of heart attack, and periodontitis, the significant association was not found. Conclusions CVD group had significantly higher prevalence of moderate to severe peri-implantitis (RBL ≥ 2mm). The association between the two diseases did not exist after controlling multiple confounders for CVD. Future studies with a larger sample size controlling for the patient- and implant-related confounders are needed to better understand the link between peri-implantitis and cardiovascular disease. This article is protected by copyright. All rights reserved.

Palatal-tissue harvesting is a routinely performed procedure in periodontal and peri-implant plastic surgery. Over the years, several surgical approaches have been attempted with the aim of obtaining autogenous soft-tissue grafts while minimizing patient morbidity, which is considered the most common drawback of palatal harvesting. At the same time, treatment errors during the procedure may increase not only postoperative discomfort or pain but also the risk of developing other complications, such as injury to the greater palatine artery, prolonged bleeding, wound/flap sloughing, necrosis, infection, and inadequate graft size or quality. This chapter described treatment errors and complications of palatal harvesting techniques, together with approaches for reducing patient morbidity and accelerating donor site wound healing. The role of biologic agents, photobiomodulation therapy, local and systemic factors, and genes implicated in palatal wound healing are also discussed.

To evaluate the efficacy of recombinant human platelet-derived growth factor (rhPDGF)-BB combined with a cross-linked collagen matrix (CCM) for the treatment of multiple adjacent gingival recession type 1 defects (MAGRs) in combination with the coronally advanced flap (CAF).Thirty patients were enrolled in this triple-blind, randomized, placebo-controlled trial and treated with either CAF + CCM + rhPDGF, or CAF + CCM + saline. The primary outcome was mean root coverage (mRC) at 6 months. Complete root coverage, gain in gingival thickness (GT), keratinized tissue width, volumetric and ultrasonographic changes, and patient-reported outcome measures were also assessed. Mixed-modelling regression analyses were used for statistical comparisons.At 6 months, the mRC of the CCM + rhPDGF and CCM alone groups were 88.25% and 77.72%, respectively (p = .02). A significant gain in GT was consistently observed for both treatment arms, and more so for the patients receiving the matrix containing rhPDGF through time (0.51 vs. 0.80 mm, on average, p = .01). The rhPDGF + CCM treated patients presented greater volume gain, higher soft tissue thickness, and a superior aesthetic score.rhPDGF enhances the clinical, volumetric, and aesthetic outcomes of MAGRs above the results achieved with CAF + CCM alone (ClinicalTrials.gov NCT04462237).

Periodontal tissue engineering involves a multi-disciplinary approach towards the regeneration of periodontal ligament, cementum and alveolar bone surrounding teeth, whereas bone regeneration specifically applies to ridge reconstruction in preparation for future implant placement, sinus floor augmentation and regeneration of peri-implant osseous defects. Successful periodontal regeneration is based on verifiable cementogenesis on the root surface, oblique insertion of periodontal ligament fibers and formation of new and vital supporting bone. Ultimately, regenerated periodontal and peri-implant support must be able to interface with surrounding host tissues in an integrated manner, withstand biomechanical forces resulting from mastication, and restore normal function and structure. Current regenerative approaches utilized in everyday clinical practice are mainly guided tissue/bone regeneration-based. Although these approaches have shown positive outcomes for small and medium-sized defects, predictability of clinical outcomes is heavily dependent on the defect morphology and clinical case selection. In many cases, it is still challenging to achieve predictable regenerative outcomes utilizing current approaches. Periodontal tissue engineering and bone regeneration (PTEBR) aims to improve the state of patient care by promoting reconstitution of damaged and lost tissues through the use of growth factors and signaling molecules, scaffolds, cells and gene therapy. The present narrative review discusses key advancements in PTEBR including current and future trends in preclinical and clinical research, as well as the potential for clinical translatability.

Rationale: The endemic of peri-implantitis affects over 25% of dental implants. Current treatment depends on empirical patient and site-based stratifications and lacks a consistent risk grading system. Methods: We investigated a unique cohort of peri-implantitis patients undergoing regenerative therapy with comprehensive clinical, immune, and microbial profiling. We utilized a robust outlier-resistant machine learning algorithm for immune deconvolution. Results: Unsupervised clustering identified risk groups with distinct immune profiles, microbial colonization dynamics, and regenerative outcomes. Low-risk patients exhibited elevated M1/M2-like macrophage ratios and lower B-cell infiltration. The low-risk immune profile was characterized by enhanced complement signaling and higher levels of Th1 and Th17 cytokines. Fusobacterium nucleatum and Prevotella intermedia were significantly enriched in high-risk individuals. Although surgery reduced microbial burden at the peri-implant interface in all groups, only low-risk individuals exhibited suppression of keystone pathogen re-colonization. Conclusion: Peri-implant immune microenvironment shapes microbial composition and the course of regeneration. Immune signatures show untapped potential in improving the risk-grading for peri-implantitis.

The new classification of periodontal diseases recognizes the key role of the interdental clinical attachment for defining the periodontal status and the extent of disease severity. Regenerating interdental clinical attachment not only improves the prognosis of the tooth, but it also lessens the severity of the disease condition. This manuscript provides a state-of-the-art review on surgical reconstructive approaches for treating papillary deficiency associated with soft and hard tissue interproximal defects. Combination therapy of papilla preservation, connective tissue grafting, and coronally advanced flaps may result in regeneration of the intrabony defect coupled with root coverage. Future research highlighted in this review may have the potential especially in combination approaches to repair challenging interproximal soft and hard tissue deficiencies.

Destruction of the alveolar bone in the jaws can occur due to periodontitis, trauma or following tumor resection. Common reconstructive therapy can include the use of bone grafts with limited predictability and efficacy. Romosozumab, approved by the FDA in 2019, is a humanized sclerostin-neutralizing antibody (Scl-Ab) indicated in postmenopausal women with osteoporosis at high risk for fracture. Preclinical models show that Scl-Ab administration preserves bone volume during periodontal disease, repairs bone defects surrounding dental implants, and reverses alveolar bone loss following extraction socket remodeling. To date, there are no studies evaluating Scl-Ab to repair osseous defects around teeth or to identify the efficacy of locally-delivered Scl-Ab for targeted drug delivery. In this investigation, the use of systemically-delivered versus low dose locally-delivered Scl-Ab via poly(lactic-co-glycolic) acid (PLGA) microspheres (MSs) was compared at experimentally-created alveolar bone defects in rats. Systemic Scl-Ab administration improved bone regeneration and tended to increase cementogenesis measured by histology and microcomputed tomography, while Scl-Ab delivered by MSs did not result in enhancements in bone or cemental repair compared to MSs alone or control. In conclusion, systemic administration of Scl-Ab promotes bone and cemental regeneration while local, low dose delivery did not heal periodontal osseous defects in this study.

Aim To develop and internally validate a nomogram built on a multivariate prediction model including parameters from the new classification of periodontal diseases, able to predict, at baseline, the occurrence of tooth loss due to periodontal reason (TLP). Materials and methods A total of 315 individuals diagnosed with periodontal disease and receiving a minimum of one annual supportive periodontal therapy visit were included in the study. Patients were staged and graded based upon baseline data. The population was divided into a development (254 patients) and a validation (61 patients) cohort to allow subsequent temporal validation of the model. According to the TLP at the 10-year follow-up, patients were categorized as "low tooth loss" (≤ 1 TLP) or "high tooth loss" (≥ 2 TLP). Bootstrap internal validation was performed on the whole data set to calculate an optimism-corrected estimate of performance. Results The generated nomogram showed a strong predictive capability (AUC = 0.81) and good calibration with an intercept = 0 and slope = 1. These findings were confirmed by internal validation using bootstrapping (average bootstrap AUC = 0.83). Conclusions The clinical implementation of the present nomogram guides the prediction of patients with high risk of disease progression and subsequent tooth loss for personalized care.

Background The peri-implant soft tissue phenotype (PSP) encompasses the keratinized mucosa width (KMW), mucosal thickness (MT), and supracrestal tissue height (STH). Numerous approaches to augment soft tissue volume around endosseous dental implants have been investigated. To what extent PSP modification is beneficial for peri-implant health has been subject of debate in the field of implant dentistry. The aim of this systematic review was to analyze the evidence regarding the efficacy of soft tissue augmentation procedures aimed at modifying the PSP and their impact on peri-implant health. Methods A comprehensive search was performed to identify clinical studies that involved soft tissue augmentation around dental implants and reported findings on KMW, MT, and/or STH changes. The effect of the intervention on peri-implant health was also assessed. Selected articles were classified based on the general type of surgical approach to increase PSP, either bilaminar or an apically positioned flap (APF) technique. A network meta-analysis including only randomized-controlled trials (RCTs) reporting on PSP outcomes was conducted to assess and compare different techniques. Results A total of 52 articles were included in the qualitative analysis, and 23 RCTs were included as part of the network meta-analysis. Sixteen RCTs reported the outcomes of PSP modification therapy with bilaminar techniques, whereas 7 involved the use of APF. The analysis showed that bilaminar techniques in combination with soft tissue grafts (connective tissue graft [CTG], collagen matrix [CM], and acellular dermal matrix [ADM]) resulted in a significant increase in MT compared to non-augmented sites. In particular, CTG and ADM were associated with higher MT gain as compared to CM and non-augmented sites. However, no significant differences in KMW were observed across different bilaminar techniques. PSP modification via a bilaminar approach utilizing either CTG or CM showed beneficial effects on marginal bone level stability. APF-based approaches in combination with free gingival graft (FGG), CTG, CM, or ADM showed a significant KMW gain compared to non-augmented sites. However, compared to APF alone, only FGG exhibited a significantly higher KMW gain. APF with any evaluated soft tissue graft was associated with with reduction of probing depth, soft tissue dehiscence and plaque index compared to non-augmented sites compared to non-augmented sites. The evidence regarding the effect of PSP modification via APF-based approaches on peri-implant marginal bone loss or preservation is inconclusive. Conclusions Bilaminar approach involving CTG or ADM obtained the highest amount of MT gain, whereas APF in combination with FGG was the most effective technique for increasing KMW. KMW augmentation via APF was associated with a significant reduction in probing depth, soft tissue dehiscence and plaque index, regardless of the soft tissue grafting material employed, whereas bilaminar techniques with CTG or CM showed beneficial effects on marginal bone level stability.

Aim: The use of recombinant human platelet-derived growth factor–BB (rhPDGF) has received Food and Drug Administration approval for the treatment of periodontal and orthopedic bone defects and dermal wound healing. Many studies have investigated its regenerative potential in a variety of other oral clinical indications. The aim of this systematic review was to assess the efficacy, safety, and clinical benefit of recombinant human platelet-derived growth factor (rhPDGF) use for alveolar bone and/or soft tissue regeneration. Material and Methods: Comprehensive electronic and manual literature searches according to the PRISMA guidelines were performed to identify interventional and observational studies evaluating the regenerative applications of rhPDGF-BB. The primary outcomes were the safety, efficacy, and overall clinical benefit of rhPDGF use in oral regenerative procedures. Results: Sixty-three human clinical studies (mean ± SD follow-up period of 10.7 ± 3.3 mo) were included in the qualitative analysis. No serious adverse effects were reported in any of the 63 studies, aside from the postoperative complications routinely associated with surgical therapy. Use of rhPDGF was shown to be beneficial when combined with allografts, xenografts, and alloplasts (the latter tricalcium phosphate [β-TCP]) for the treatment of periodontal defects and gingival recession. The use of rhPDGF also led to favorable clinical outcomes when combined with allografts or xenografts for guided bone regeneration (GBR) and alveolar ridge preservation. While favorable clinical results support the use of the combination of rhPDGF plus allograft or xenograft for GBR, ARP, and sinus floor augmentation, current data support the use of rhPDGF and alloplasts (e.g., β-TCP) only in periodontal defects and gingival recession. Conclusions: Based on the clinical evidence, rhPDGF is safe and provides clinical benefits when used in combination with bone allografts, xenograft, or β-TCP for the treatment of intrabony and furcation periodontal defects and gingival recession or when used with allografts or xenograft for GBR and ARP (PROSPERO CRD42020142446). Knowledge Transfer Statement: Clinicians should be aware that rhPDGF is a safe and effective approach for the treatment of intrabony and furcation periodontal defects and gingival recession or when used with allografts or xenograft for bone regeneration and alveolar ridge preservation. With consideration of cost and patient preference, this result could lead to more appropriate therapeutic decisions.

Made available in DSpace on 2020-12-12T02:41:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-12-01 After chronic low back pain, Temporomandibular Joint (TMJ) disorders are the second most common musculoskeletal condition affecting 5 to 12% of the population, with an annual health cost estimated at $4 billion. Chronic disability in TMJ osteoarthritis (OA) increases with aging, and the main goal is to diagnosis before morphological degeneration occurs. Here, we address this challenge using advanced data science to capture, process and analyze 52 clinical, biological and high-resolution CBCT (radiomics) markers from TMJ OA patients and controls. We tested the diagnostic performance of four machine learning models: Logistic Regression, Random Forest, LightGBM, XGBoost. Headaches, Range of mouth opening without pain, Energy, Haralick Correlation, Entropy and interactions of TGF-β1 in Saliva and Headaches, VE-cadherin in Serum and Angiogenin in Saliva, VE-cadherin in Saliva and Headaches, PA1 in Saliva and Headaches, PA1 in Saliva and Range of mouth opening without pain; Gender and Muscle Soreness; Short Run Low Grey Level Emphasis and Headaches, Inverse Difference Moment and Trabecular Separation accurately diagnose early stages of this clinical condition. Our results show the XGBoost + LightGBM model with these features and interactions achieves the accuracy of 0.823, AUC 0.870, and F1-score 0.823 to diagnose the TMJ OA status. Thus, we expect to boost future studies into osteoarthritis patient-specific therapeutic interventions, and thereby improve the health of articular joints. University of Michigan Department of Orthodontics and Pediatric Dentistry School of Dentistry São Paulo State University (UNESP) Department of Pediatric Dentistry School of Dentistry Kitware Inc. University of North Carolina Department of Psychiatry and Computer Science University of North Carolina Department of Biostatistics University of Michigan Department of Periodontics and Oral Medicine School of Dentistry University of Michigan Department of Oral and Maxillofacial Surgery and Hospital Dentistry School of Dentistry University of North Carolina Department of Orthodontics University of Michigan Center for Integrative Research in Critical Care and Michigan Institute for Data Science Department of Computational Medicine and Bioinformatics São Paulo State University (UNESP) Department of Pediatric Dentistry School of Dentistry

The purpose of the study was to explore the influence of leadership training programs on career development and to gain insight into the perspectives on faculty training programs according to the current US dental school deans.This prospective study analyzed the results of a questionnaire distributed to 67 active Deans of U.S dental schools using a survey instrument that explored the areas of leadership programs that were useful, the support mechanisms received from institutions, and the necessity to integrate formal leadership development programs into training programs for faculty and students.Among 33 participants (49.3% participation rate) in the study, 97% of responders strongly or somewhat agreed that leadership development programs could improve the quality of leadership and administrative skills. The respondents found that the most useful areas in leadership training were conflict resolution, communication skills, organizational change, diversity, inclusion, and belonging. The findings highlighted that critical barriers to accessing leadership training are financial support and lack of protected time for faculty. The results also showed that 73% strongly or somewhat agreed that the leadership training should be integrated into the predoctoral program and 87% into the postdoctoral graduate programs.Participation in formal leadership development programs for faculty leaders in dental education is viewed as beneficial and could offer dental educators leadership training to better navigate the academic environment. The findings suggest the need to further explore the availability and effectiveness of leadership development opportunities for developing current and future educators and administrative leaders.

ImportanceAlthough many academic institutions have implemented infection control and prevention protocols, including regular asymptomatic self-testing, in response to the COVID-19 pandemic, the outcomes of mandatory surveillance testing programs at academic dental institutions that offer direct patient-facing clinical care has not yet been reported.ObjectiveTo report the findings of a comprehensive surveillance COVID-19 testing program at an academic dental institution by assessing SARS-CoV-2 positivity rates and the potential association of test positivity with individual-level characteristics such as age, sex, and role.Design, Setting, and ParticipantsA retrospective cohort study was conducted using SARS-CoV-2 self-testing data from a mandatory surveillance program at the Harvard School of Dental Medicine. Test results obtained between August 24, 2020, and February 28, 2022, from students, faculty, and staff members were analyzed. Testing cadence varied from 1 to 3 times per week depending on risk status. The association of individual characteristics with test positivity was evaluated with univariate analyses and a bayesian multilevel logistic regression model.ExposuresAge by decade, sex, and role or position category (staff members, faculty, and students stratified by their involvement in clinical care activities), testing cadence, and testing date.Main Outcomes and MeasuresPositive results from SARS-CoV-2 real-time reverse transcription–polymerase chain reaction self-tests were assessed.ResultsOf the 390 study participants, 210 (53.8%) were women. Participants were grouped by age as follows: 20 to 29 years (190 [48.7%]), 30 to 39 years (88 [22.6%]), 40 to 49 years (44 [11.3%]), 50 to 59 years (42 [10.8%]), and 60 years or older (26 [6.7%]). Test results demonstrated an overall 0.27% positivity rate (61 test-positive cases), with a peak weekly positivity rate of 5.12% in the first week of January 2022. The mean (SD) test positivity rate among those involved in clinical activities was 0.25% (0.04) compared with 0.36% (0.09) among nonclinical participants. When adjusting for all considered covariates, test positivity was significantly associated with testing frequency (3 times vs 1 time per week: odds ratio [OR], 1.51 [95% credible interval (CrI), 1.07-3.69]) and timing of the test (after vs during the Alpha wave: OR, 0.33 [95% CrI, 0.11-0.88]; and Omicron vs Alpha: OR, 11.59 [95% CrI, 6.49-22.21]) but not with individual characteristics (age, sex, and role).Conclusions and RelevanceThese findings suggest that implementing an adaptive testing cadence based on the risk status of individuals may be effective in reducing the risk of SARS-CoV-2 infection within an institution. In this study, involvement in clinical activities did not pose additional risk of SARS-CoV-2 infection compared with other in-person activities in the presence of these control measures.

To investigate the pro-inflammatory cytokine profiles in patients with or without cardiovascular disease (CVD) and with or without peri-implantitis.Serum, peri-implant crevicular fluid (PICF), and gingival crevicular fluid (GCF) were collected from patients with (n = 82) or without CVD (n = 46) at the most severe peri-implantitis site including sites with periodontitis. A panel of proinflammatory molecules including high-sensitivity C-reactive protein (hsCRP), fibrinogen, interleukin-1 beta (IL-1β), IL-6, plasma tumor necrosis factor-alpha (TNF-α), matrix metallo-proteinase-8 (MMP-8), osteoprotegerin (OPG), vascular endothelial growth factor (VEGF), IL-17, IL-8, tissue inhibitor of metalloproteinase-2 (TIMP-2), myeloperoxidase (MPO), and prostaglandin ESerum IL-1β, TNF-α and fibrinogen were significantly higher in CVD patients than those without. Serum fibrinogen displayed a trend of higher concentration in patients with radiographic bone loss (RBL) ≥2 mm (P = 0.08). PICF TNF-α exhibited a significantly higher detection level in the CVD patients that is coincided with the local peri-implant inflammation. In addition, PICF MMP-8 was significantly higher in the RBL ≥2 mm sites than the healthy implants; whereas IL-1β, IL-8, MMP-8, and TIMP-2 proved to be the significant predictors for peri-implant disease. GCF TNF-α collected from patients with periodontitis was significantly associated with CVD cases.The augmented expression of local and systemic pro-inflammatory cytokines found in the current study supports the weak association between the chronic peri-implantitis with increasing severity and CVD.

Current regenerative strategies for alveolar bone and periodontal tissues are effective and well adopted. These are mainly based on the use of a combination of synthetic/natural scaffolds and bioactive agents, obviating the incorporation of cells. However, there are some inherent limitations associated with traditional techniques, and we hypothesized that the use of cell-based therapies as part of comprehensive regenerative protocols may help overcome these hurdles to enhance clinical outcomes. We conducted a systematic review of human controlled clinical trials investigating the clinical and/or histological effect of the use of cell-based therapies for alveolar bone and periodontal regeneration and explored the translational potential of the different cell-based strategies identified in the included trials. A total of 16 studies (11 randomized controlled trials, 5 controlled clinical trials) were included for data synthesis and qualitative analysis with meta-analyses performed when appropriate. The results suggest a clinical benefit from the use of cell therapy. Improved outcomes were shown for alveolar ridge preservation, lateral ridge augmentation, and periodontal regeneration. However, there was insufficient evidence to identify best-performing treatment modalities amongst the different cell-based techniques. In light of the clinical and histological outcomes, we identify extraction socket and challenging lateral and vertical bone defects requiring bone block grafts as strong candidates for the adjuvant application of mesenchymal stem cells. Given the complexity, invasiveness, and costs associated with techniques that include “substantial manipulation” of tissues and cells, their additional clinical benefit when compared with “minimal manipulation” must be elucidated in future trials. Stem Cells Translational Medicine 2019;8:1286&1295

This manuscript provides a state-of-the-art review on the efficacy of biologics in root coverage procedures, including enamel matrix derivative, platelet-derived growth factor, platelet concentrates, and fibroblast-growth factor-2. The mechanism of action and the rationale for using biologics in periodontal plastic surgery, as well as their anticipated benefits when compared with conventional approaches are discussed. Although the clinical significance is still under investigation, preclinical data and histologic evidence demonstrate that biologic-based techniques are able to promote periodontal regeneration coupled with the provision of tooth root coverage.

Aim To explore the M1/M2 status of macrophage polarization from healthy, gingivitis, and periodontitis patient samples. Materials and methods Gingival biopsies were collected from 42 individuals (14 gingivitis, 18 periodontitis, and 10 healthy samples) receiving periodontal therapy. Histomorphology analysis was performed with haematoxylin and eosin staining. Immunofluorescence was performed using a combination of CD68 (macrophages), iNOS (M1), and CD206 (M2) in order to acquire changes in macrophage polarization at a single-cell resolution. Macrophages were quantified under microscopy using narrow wavelength filters to detect Alexa 488, Alexa 568, Alexa 633 fluorophores, and Hoechst 33342 to identify cellular DNA content. Results Gingivitis and periodontitis samples showed higher levels of macrophages compared with healthy samples. Unexpectedly, periodontitis samples displayed lower levels of macrophages dispersed in the stromal tissues compared with gingivitis samples; however, it remained higher than healthy tissues. The polarization of macrophages appears to be reduced in periodontitis and showed similar levels to those observed in healthy tissues. Conclusions Our study found that gingivitis and periodontitis differ from each other by the levels of macrophage infiltrate, but not by changes in macrophage polarization.

Background and Aims: To describe the biology of alveolar bone regeneration.Material and Methods: Four comprehensive reviews were performed on (a) mesenchymal cells and differentiation factors leadi ...

Few university-based regenerative medicine innovations in the dental, oral, and craniofacial (DOC) space have been commercialized and affected clinical practice in the United States. An analysis of the commercial translation literature and National Institute for Dental and Craniofacial Research’s (NIDCR’s) portfolio identified barriers to commercial translation of university-based DOC innovations. To overcome these barriers, the NIDCR established the Dental Oral Craniofacial Tissue Regeneration Consortium. We provide generalized strategies to inform readers how to bridge the “valley of death” and more effectively translate DOC technologies from the research laboratory or early stage company environment to clinical trials and bring needed innovations to the clinic. Three valleys of death are covered: 1) from basic science to translational development, 2) from translational technology validation to new company formation (or licensing to an existing company), and 3) from new company formation to scaling toward commercialization. An adapted phase-gate model is presented to inform DOC regenerative medicine teams how to involve regulatory, manufacturability, intellectual property, competitive assessments, business models, and commercially oriented funding mechanisms earlier in the translational development process. An Industrial Partners Program describes how to conduct market assessments, industry maps, business development processes, and industry relationship management methods to sustain commercial translation through the later-stage valley of death. Paramount to successfully implementing these methods is the coordination and collaboration of interdisciplinary teams around specific commercial translation goals and objectives. We also provide several case studies for translational projects with an emphasis on how they addressed DOC biomaterials for tissue regeneration within a rigorous commercial translation development environment. These generalized strategies and methods support innovations within a university-based and early stage company-based translational development process, traversing the many funding gaps in dental, oral, and craniofacial regenerative medicine innovations. Although the focus is on shepherding technologies through the US Food and Drug Administration, the approaches are applicable worldwide.

Aim To describe the application of power Doppler Ultrasonography (US) for evaluating blood flow at implant and palatal donor sites following soft tissue augmentation with the connective tissue graft (CTG). Materials and methods Five patients exhibiting a peri-implant soft tissue dehiscence received treatment with a coronally advanced flap and corresponding CTG. Power Doppler US was used for assessing blood volume at baseline, 1 week, 1 month, 6 months and 12 months post-surgery for assessing blood-flow dynamics at the implant and palatal donor sites. The speed-weighted and power-weighted colour pixel density (CPPD) were computed from colour velocity (CV) and colour power (CP), respectively. Results A mean increase in CV of 199.25% was observed at the midfacial region of the implant sites after 1 week compared to baseline. CV and CP were increased in all sites at 1 week and 1 month. At 6 and 12 months, the mean CV appeared lower than baseline at the implant sites. CCPD was increased at the palatal donor sites and at the great palatine foramen areas at the 1-week and 1-month post-operative evaluations. Conclusions Power Doppler US is a non-invasive and valuable tool for estimating tissue perfusion and CPPD variation during different phases of intra-oral soft tissue graft healing.

The precise mechanism by which oral infection contributes to the pathogenesis of extra-oral diseases remains unclear. Here, we report that periodontal inflammation exacerbates gut inflammation in vivo. Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation. In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut. When in the gut, Th17 cells of oral origin can be activated by translocated oral pathobionts and cause development of colitis, but they are not activated by gut-resident microbes. Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells.

Destruction of the alveolar bone in the jaws can occur due to periodontitis, trauma or following tumor resection. Common reconstructive therapy can include the use of bone grafts with limited predictability and efficacy. Romosozumab, approved by the FDA in 2019, is a humanized sclerostin-neutralizing antibody (Scl-Ab) indicated in postmenopausal women with osteoporosis at high risk for fracture. Preclinical models show that Scl-Ab administration preserves bone volume during periodontal disease, repairs bone defects surrounding dental implants, and reverses alveolar bone loss following extraction socket remodeling. To date, there are no studies evaluating Scl-Ab to repair osseous defects around teeth or to identify the efficacy of locally-delivered Scl-Ab for targeted drug delivery. In this investigation, the use of systemically-delivered versus low dose locally-delivered Scl-Ab via poly(lactic-co-glycolic) acid (PLGA) microspheres (MSs) was compared at experimentally-created alveolar bone defects in rats. Systemic Scl-Ab administration improved bone regeneration and tended to increase cementogenesis measured by histology and microcomputed tomography, while Scl-Ab delivered by MSs did not result in enhancements in bone or cemental repair compared to MSs alone or control. In conclusion, systemic administration of Scl-Ab promotes bone and cemental regeneration while local, low dose delivery did not heal periodontal osseous defects in this study.

BACKGROUND Peri-implantitis is a challenging condition to manage and is frequently treated using non-surgical debridement. The local delivery of antimicrobial agents has demonstrated benefit in mild to moderate cases of peri-implantitis. This study compared the safety and efficacy of chlorhexidine gluconate 2.5 mg chip (CHX chips) as an adjunctive treatment to subgingival debridement in patients afflicted with peri-implantitis. METHODS A multicenter, randomized, single-blind, two-arm, parallel Phase-3 study was conducted. Peri-implantitis patients with implant pocket depths (IPD) of 5-8 mm underwent subgingival implant surface debridement followed by repeated bi-weekly supragingival plaque removal and chlorhexidine chips application (ChxC group) for 12 weeks, or similar therapy but without application of ChxC (control group). All patients were followed for 24 weeks. Plaque and gingival indices were measured at every visit whereas IPD, recession, and bleeding on probing were assessed at 8, 12, 16, 24 week. RESULTS A total of 290 patients were included: 146 in the ChxC group and 144 in the control. At 24 weeks, a significant reduction in IPD (P = 0.01) was measured in the ChxC group (1.76 ± 1.13 mm) compared with the control group (1.54 ± 1.13 mm). IPD reduction of ≥2 mm was found in 59% and 47.2% of the implants in the ChxC and control groups, respectively (P = 0.03). Changes in gingival recession (0.29 ± 0.68 mm versus 0.15 ± 0.55 mm, P = 0.015) and relative attachment gain (1.47 ± 1.32 mm and 1.39 ± 1.27 mm, P = 0.0017) were significantly larger in the ChxC group. Patients in the ChxC group that were

Tooth extraction results in alveolar bone resorption and is accompanied by postoperative swelling and pain. Maresin 1 (MaR1) is a proresolving lipid mediator produced by macrophages during the resolution phase of inflammation, bridging healing and tissue regeneration. The aim of this study was to examine the effects of MaR1 on tooth extraction socket wound healing in a preclinical rat model. The maxillary right first molars of Sprague-Dawley rats were extracted, and gelatin scaffolds were placed into the sockets with or without MaR1. Topical application was also given twice a week until complete socket wound closure up to 14 d. Immediate postoperative pain was assessed by 3 scores. Histology and microcomputed tomography were used to assess socket bone fill and alveolar ridge dimensional changes at selected dates. The assessments of coded specimens were performed by masked, calibrated examiners. Local application of MaR1 potently accelerated extraction socket healing. Macroscopic and histologic analysis revealed a reduced soft tissue wound opening and more rapid re-epithelialization with MaR1 delivery versus vehicle on socket healing. Under micro–computed tomography analysis, MaR1 (especially at 0.05 μg/μL) stimulated greater socket bone fill at day 10 as compared with the vehicle-treated animals, resulting in less buccal plate resorption and a wider alveolar ridge by day 21. Interestingly, an increased ratio of CD206+:CD68+ macrophages was identified in the sockets with MaR1 application under immunohistochemistry and immunofluorescence analysis. As compared with the vehicle therapy, local delivery of MaR1 reduced immediate postoperative surrogate pain score panels. In summary, MaR1 accelerated extraction wound healing, promoted socket bone fill, preserved alveolar ridge bone, and reduced postoperative pain in vivo with a rodent preclinical model. Local administration of MaR1 offers clinical potential to accelerate extraction socket wound healing for more predictable dental implant reconstruction.

At present, various tissue engineering strategies in the regenerative medicine have been developed for multiple tissue regeneration and integrative structure formations in musculoskeletal system. However, the regenerations of dental tissues or tooth-supportive structures are still challenging due to the micro-interfacial compartmentalization of multiple tissues, their integrations for systematic responses, and spatiotemporal organizations of engineered fibrous tissues. In particular, the biomaterial-based approaches are limitedly investigated for spatiotemporal controls of periodontal regenerations and challenging to promote micron-scaled interfacial tissue compartmentalization with their integrations for functioning restorations. This chapter demonstrates biomaterial applications for periodontal tissue engineering and the advanced 3D fabrication technologies for preclinical applications and the limited clinical trial using 3D scaffolding systems.

To fully regenerate the periodontal tissues remains a challenge in our daily practice. Periodontal regeneration is a complex process involving a series of cellular and molecular events. In the last two decades, significant advances have been made in applying proteins and peptides to treat periodontal osseous defects. Several products are currently available and a few others are under development. Stem cell therapy has also been vigorously investigated for regenerating craniofacial tissues including periodontia. In this chapter, we review the current status of protein- and cell-based therapies for periodontal regeneration, with an emphasis on products that have been tested in clinical studies.

Background The periodontal phenotype consists of the bone morphotype, the keratinized tissue (KT), and gingival thickness (GT). The latter two components, overlying the bone, constitute the gingival phenotype. Several techniques have been proposed for enhancing or augmenting KT or GT. However, how phenotype modification therapy (PMT) affects periodontal health and whether the obtained outcomes are maintained over time have not been elucidated. The aim of the present review was to summarize the available evidence in regard to the utilized approaches for gingival PMT and assess their comparative efficacy in augmenting KT, GT and in improving periodontal health using autogenous, allogenic, and xenogeneic grafting approaches. Methods A detailed systematic search was performed to identify eligible randomized clinical trials (RCTs) reporting on the changes in GT and KT (primary outcomes). The selected articles were segregated into the type of approach based on having performed a root coverage, or non-root coverage procedure. A network meta-analysis (NMA) was conducted for each approach to assess and compare the outcomes among different treatment arms for the primary outcomes. Results A total of 105 eligible RCTs were included. 95 pertaining to root coverage (3,539 treated gingival recessions [GRs]), and 10 for non-root coverage procedures (699 total treated sites). The analysis on root coverage procedures showed that all investigated techniques (the acellular dermal matrix [ADM], collagen matrix [CM], connective tissue graft [CTG]) are able to significantly increase the GT, compared with treatment with flap alone. However, KT was only significantly increased with the use of CTG or ADM. Early post-treatment GT was found to inversely predict future GR. For non-root coverage procedures, only the changes in KT could be analyzed; all investigated treatment groups (ADM, CM, free gingival graft [FGG], living cellular construct [LCC], in combination with an apically positioned flap [APF]), resulted in significantly more KT than treatment with APF alone. Additionally, the augmented GT was shown to be sustained, and KT displayed an incremental increase over time. Conclusions Within its limitations, it was observed that any graft material was able to significantly enhance GT, while KT in root coverage procedures was significantly enhanced with CTG and ADM, and in non-root coverage procedures, with ADM, CM, FGG, and LCC compared with APF alone. The autogenous soft tissue graft (CTG/FGG) proved to be superior in all comparisons for both outcomes of GT and KT.