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Periodontitis is a prevalent chronic, destructive inflammatory disease affecting tooth-supporting tissues in humans. Guided tissue regeneration strategies are widely utilized for periodontal tissue regeneration generally by using a periodontal membrane. The main role of these membranes is to establish a mechanical barrier that prevents the apical migration of the gingival epithelium and hence allowing the growth of periodontal ligament and bone tissue to selectively repopulate the root surface. Currently available membranes have limited bioactivity and regeneration potential. To address such challenges, an osteoconductive, antibacterial, and flexible poly(caprolactone) (PCL) composite membrane containing zinc oxide (ZnO) nanoparticles is developed. The membranes are fabricated through electrospinning of PCL and ZnO particles. The physical properties, mechanical characteristics, and in vitro degradation of the engineered membrane are studied in detail. Also, the osteoconductivity and antibacterial properties of the developed membrane are analyzed in vitro. Moreover, the functionality of the membrane is evaluated with a rat periodontal defect model. The results confirmed that the engineered membrane exerts both osteoconductive and antibacterial properties, demonstrating its great potential for periodontal tissue engineering.

Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)–treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro–computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden. [ABSTRACT FROM AUTHOR]

PURPOSE: An analysis of retrospective data was conducted to establish the survival rates of osseointegrated implants used to retain orbital, nasal, and auricular prostheses over a 14-year period and to recommend guidelines in the restorative treatment of such facial defects. MATERIALS AND METHODS: Included in this study were all patients who received implant-retained prostheses for auricular, nasal, or orbital defects from 1987 to 2001 in the Maxillofacial Clinics at the UCLA and City of Hope Medical Centers. Data were obtained from patient charts. Two methods were used to determine survival rates: (1) the percentage of the total exposed implants that survived was determined, and (2) life table analysis was used to calculate cumulative survival rates at different time intervals. RESULTS: A total of 207 implants were placed in 72 patients, and 182 implants had been uncovered. During the study period, 35 implants failed to integrate, and the survival rate for all exposed implants was 80%. Auricular implants showed the highest survival rate (95%), and orbital implants showed the lowest survival rate (53%). The life table analysis demonstrated a cumulative 6-year survival rate of 92% for auricular implants and 87% for piriform/nasal implants. In contrast, the survival rate for orbital implants showed a steady downward trend and reached 59% at 66 months. CONCLUSION: It is possible to achieve high survival rates of implants in the auricular and piriform/nasal sites through careful presurgical and radiographic planning. The less favorable long-term survival of implants in the orbital rim, especially at irradiated sites, requires further study. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaws (ONJ) is a rare but severe complication of antiresorptive medications, such as bisphosphonates, used in the treatment of bone malignancy or osteoporosis. Tooth extraction and dental disease have been strongly associated with ONJ development. Here, we investigated molecular and cellular markers of socket healing after extraction of healthy or teeth with experimental periodontitis (EP) in Wistar-Han rats treated with zoledronic acid (ZA). We included 4 experimental groups: vehicle-treated animals with extraction of healthy teeth or teeth with ligature-induced EP and ZA-treated animals with extraction of healthy teeth or teeth with EP. Animals were pretreated with vehicle or ZA for a week, and EP was induced. Four weeks later, the second maxillary molars were extracted; sockets were allowed to heal for 4 wk; animals were euthanized; and maxillae were isolated. Radiographically, extraction sockets in groups 1, 2, and 3 demonstrated normal healing. Contrary incomplete socket healing was noted after extraction of teeth with EP in ZA-treated rats of group 4. Histologically, persistent inflammation and extensive osteonecrosis were seen in group 4. Disorganization of the collagen network, collagen type III predominance, and lack of collagen fiber insertion in the necrotic bone were associated with impaired socket healing. Cells positive for MMP-9, MMP-13, and α-SMA expression were present at the areas of epithelial invagination and adjacent to osteonecrotic bone. Importantly, human biopsies from patients with ONJ showed similar findings. Our data emphasize the importance of dental disease and tooth extraction in ONJ pathogenesis and help delineate an altered profile in wound-healing markers during ONJ development. [ABSTRACT FROM AUTHOR]

The purpose of this systematic review was to evaluate outcomes related to the number of implants used to support complete-arch fixed prostheses for the maxilla or mandible. This review followed the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The following focus question was developed using the PICO format: In patients with an implantsupported fixed complete dental prosthesis, do implant and prosthetic survival outcomes differ between five or more compared to fewer than five supporting implants? A comprehensive search of the literature was performed electronically and by hand search. Two independent reviewers selected the papers and tabulated results. The primary outcomes analyzed were implant and prosthesis survival. Implant distribution, loading, and type of retention were observed as secondary outcomes, and a meta-analysis was performed to compare results for studies by number of implants. The search strategy identified 1,579 abstracts for initial review. Based on evaluation of the abstracts, 359 articles were identified for full-text evaluation. From these, 93 were selected and included in this review: 9 RCTs, 42 prospective studies, and 42 retrospective studies. Of the 93 selected studies, 28 reported number of implants for the maxilla, 46 for the mandible, and 19 for both the maxilla and mandible. The most reported number of implants for the < 5 group was 4 for the maxilla and 3 or 4 for the mandible, whereas for the ≥ 5 implants group, the most reported number of implants was 6 for the maxilla and 5 for the mandible. No significant differences in the primary outcomes analyzed were identified when < 5 implants per arch were compared to ≥ 5 per arch (P > .05) in a follow-up time ranging from 1 to 15 years (median of 8 years). Evidence from this systematic review and meta-analysis suggests that the use of fewer than five implants per arch compared to five or more implants per arch to support a fixed prosthesis of the completely edentulous maxilla or mandible present similar survival rates, with no statistically significant difference. [ABSTRACT FROM AUTHOR]

The purpose of this retrospective cohort analysis of dental implants was to test the hypothesis that coexisting conditions lead to increased rates of implant failures. A total of 1,140 patients treated with a total of 4,680 implants by a single surgeon, from January 1982 to 2003, were included in this study. Failure was defined as any condition that led to removal of the implant, both short and long term. Risk factors abstracted from the patients record included: gender, age, location, smoking history, coexisting medical conditions (insulin and non-insulin dependent diabetes, hypertension and coronary artery disease, asthema, steroid therapy, history of chemotherapy or head and neck radiation therapy, and treatment (or lack of treatment) with post-menopausal hormones replacement therapy (PMHRT). Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between baseline characteristics and the occurrence of implant failure. A stepwise logistic regression was performed using the significant variables location, sex, age, smoking, hypertension, coronary artery disease, asthma, diabetes, chemotherapy, head and neck radiation therapy, PMHRT, and no PMHRT. Older patients (60 to 79) compared to younger patients (> 40) have a significantly higher risk of implant failure (RR = 2.24, P < .05). Smoking (RR = 1.56), diabetes (RR = 2.75), head and neck radiation (RR = 2.73), and PMHRT (RR = 2.55) were correlated with a significant increase in failure rates. Implant failure was 8.16% in the maxilla compared with 4.93% in the mandible (RR = 1.79, P < .001). [ABSTRACT FROM AUTHOR]

Objectives: The incorporation of retromolar bone grafts used for alveolar ridge augmentation is not well understood. This prospective observational study aims to supply histomorphometrical data from bone graft biopsies taken at the time of retrieval and after a 3-month healing period using patient-matched biopsies., Materials and Methods: In 17 patients, trephine biopsies of the graft were acquired at the time of graft retrieval and after a 3-month healing period. The biopsies were compared histomorphometrically regarding the number of osteocytes, appearance of osteocyte lacunae, quantity, surface area, and activity of the Haversian canals., Results: All grafts appeared clinically stable after screw removal and 17 implants were placed. Histomorphometric analysis revealed no significant difference in the number of osteocytes (p = .413), osteocyte lacunae (p = .611), the ratio of filled/empty osteocyte lacunae (p = .467) and active Haversian canals (p = .495) between the biopsies retrieved after a 3-months healing period with those at the time of grafting. The only significant difference was noted in the mean surface area of the Haversian canals (p = .002). Specifically, the grafts post 3-month healing showed a significantly larger mean area (0.069 mm 2 ) compared to the time of grafting (0.029 mm 2 )., Conclusion: This study demonstrates, compared to other data, a high rate of vital structures in retromolar bone block grafts after 3 months of healing, exhibiting the same histological features in comparison to the biopsies from the native alveolar ridge. Standard histomorphometrical parameters, e.g., the amount of filled or empty osteocyte lacunae for the description of the vitality of the graft need to be reappraised., (© 2024 The Author(s). Clinical Oral Implants Research published by John Wiley & Sons Ltd.)

Demineralized bone matrix (DBM) has been widely used as an allogeneic alternative to autologous bone graft for bone repair. However, more extensive use of DBM is limited due to its particulate nature after demineralization and rapid particle dispersion following irrigation, resulting in unpredictable osteoinductivity. Here, a new design of injectable hydrogel carriers for DBM that combine self-healing ability and osteogenic properties based on the self-assembly of guanidinylated hyaluronic acid and silica-rich nanoclays is reported. The nanoclays serve as reversible linkages to form a dynamic hydrogel network with the guanidine moieties on the polymer chains. Gelation kinetics and mechanical properties can be controlled by altering nanoclay content in the hydrogel. The resulting hydrogel exerts self-healing ability due to its dynamic crosslinks and well retains its overall performance with high DBM loading. The hydrogel exhibits great cytocompatibility and osteogenic effects mediated by the nanoclays. In vivo delivery of DBM using the nanocomposite hydrogel further demonstrates robust bone regeneration in a mouse calvarial defect model in comparison to DBM delivered with aqueous HA. This work suggests a promising hydrogel platform for many applications including therapeutic delivery and tissue engineering., (© 2024 Wiley‐VCH GmbH.)

Computer-aided design and computer-aided manufacturing and digitally simulated surgeries have revolutionized maxillomandibular reconstruction. In particular, this technology has increased the accuracy and facilitated the process of dental implantation in fibula free flaps. Despite the efficacy of virtual planning, there is a minor degree of translational difference between digital and intraoperative measurements, which may affect the precision of implant and fibula orientations. This is especially concerning during the last stage of fibula insetting, where the graft segments have the potential to roll, yaw, or pitch. The objective of this study is to describe an advanced prosthodontic technique that ensures the fibula grafts and implants remain in a restorable position during final insetting. We describe the technique and workflow of the implant-borne articulation splint through a case presentation and demonstrate results at 4 months postoperative and postradiotherapy. Given the degree of investment placed in virtual planning, free flap reconstruction, and endosteal implants, a technique that ensures optimal restorability of each implant is pivotal. Larger studies are still required to fully elucidate the cost-effectiveness and long-term results of the implant-borne articulation splint., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Objectives: The aim of the ITI Consensus Workshop on zygomatic implants was to provide Consensus Statements and Clinical Recommendations for the use of zygomatic implants., Materials and Methods: Three systematic reviews and one narrative review were written to address focused questions on (1) the indications for the use of zygomatic implants; (2) the survival rates and complications associated with surgery in zygomatic implant placement; (3) long-term survival rates of zygomatic implants and (4) the biomechanical principles involved when zygoma implants are placed under functional loads. Based on the reviews, three working groups then developed Consensus Statements and Clinical Recommendations. These were discussed in a plenary and finalized in Delphi rounds., Results: A total of 21 Consensus Statements were developed from the systematic reviews. Additionally, the group developed 17 Clinical Recommendations based on the Consensus Statements and the combined expertise of the participants., Conclusions: Zygomatic implants are mainly indicated in cases with maxillary bone atrophy or deficiency. Long-term mean zygomatic implant survival was 96.2% [95% CI 93.8; 97.7] over a mean follow-up of 75.4 months (6.3 years) with a follow-up range of 36-141.6 months (3-11.8 years). Immediate loading showed a statistically significant increase in survival over delayed loading. Sinusitis presented with a total prevalence of 14.2% [95% CI 8.8; 22.0] over a mean 65.4 months follow-up, representing the most common complication which may lead to zygomatic implant loss. The international experts suggested clinical recommendations regarding planning, surgery, restoration, outcomes, and the patient's perspective., (© 2023. Deutsche Gesellschaft für Implantologie im Zahn‐, Mund‐ und Kieferbereich e.V., Japanese Society of Oral Implantology.)

Background: A guideline panel convened by the American Dental Association Council on Scientific Affairs, American Dental Association Science and Research Institute, University of Pittsburgh School of Dental Medicine, and Center for Integrative Global Oral Health at the University of Pennsylvania conducted a systematic review and meta-analyses and formulated evidence-based recommendations for the pharmacologic management of acute dental pain after 1 or more simple and surgical tooth extractions and the temporary management of toothache (that is, when definitive dental treatment not immediately available) associated with pulp and furcation or periapical diseases in children (< 12 years)., Types of Studies Reviewed: The authors conducted a systematic review to determine the effect of analgesics and corticosteroids in managing acute dental pain. They used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence and the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework to formulate recommendations., Results: The panel formulated 7 recommendations and 5 good practice statements across conditions. There is a small beneficial net balance favoring the use of nonsteroidal anti-inflammatory drugs alone or in combination with acetaminophen compared with not providing analgesic therapy. There is no available evidence regarding the effect of corticosteroids on acute pain after surgical tooth extractions in children., Conclusions and Practical Implications: Nonopioid medications, specifically nonsteroidal anti-inflammatory drugs like ibuprofen and naproxen alone or in combination with acetaminophen, are recommended for managing acute dental pain after 1 or more tooth extractions (that is, simple and surgical) and the temporary management of toothache in children (conditional recommendation, very low certainty). According to the US Food and Drug Administration, the use of codeine and tramadol in children for managing acute pain is contraindicated., (Copyright © 2023 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Objectives: The aims of Working Group 1 were to address the role (i) of the buccolingual bone dimensions after implant placement in healed alveolar ridge sites on the occurrence of biologic and aesthetic complications, and (ii) of soft tissue augmentation (STA) on the stability of clinical, radiographic, and patient-related outcomes of implant treatments., Materials and Methods: Two systematic reviews were prepared in advance of the Consensus Conference and were discussed among the participants of Group 1. Consensus statements, clinical recommendations, recommendations for future research, and reflections on patient perspectives were based on structured group discussions until consensus was reached among the entire group of experts. The statements were then presented and accepted following further discussion and modifications as required by the plenary., Results: Dimensional changes of the alveolar ridge occurred after implant placement in healed sites, and a reduction in buccal bone wall thickness (BBW) of 0.3 to 1.8 mm was observed. In healed sites with a BBW of <1.5 mm after implant placement, increased vertical bone loss, and less favorable clinical and radiographic outcomes were demonstrated. Implants with buccal dehiscence defects undergoing simultaneous guided bone regeneration, showed less vertical bone loss, and more favorable clinical and radiographic outcomes, compared to non-augmented dehiscence defects during initial healing. At healthy single implant sites, probing depths, bleeding and plaque scores, and interproximal bone levels evaluated at 1 year, remained stable for up to 5 years, with or without STA. When single implant sites were augmented with connective tissue grafts, either for soft tissue phenotype modification or buccal soft tissue dehiscence, stable levels of the soft tissue margin, and stable or even increased soft tissue thickness and/or width of keratinized mucosa could be observed from 1 to 5 years. In contrast, non-augmented sites were more prone to show apical migration of the soft tissue margin in the long-term. Favorable aesthetic and patient-reported outcomes after STA were documented to be stable from 1 to 5 years., Conclusions: It is concluded that dimensional changes of the alveolar ridge occur after implant placement in healed sites and that sites with a thin BBW after implant placement are prone to exhibit less favorable clinical and radiographic outcomes. In addition, it is concluded that STA can provide stable clinical, radiographic, aesthetic, and patient-reported outcomes in the medium and long-term., (© 2023 The Authors. Clinical Oral Implants Research published by John Wiley & Sons Ltd.)

Objective: The purpose of the present study was to assess the duration of operative time and outcomes related to patients with an increased American Society of Anesthesiologists (ASA) Physical Status classification in the setting of hospital-based maxillofacial surgical procedures., Study Design: The study was a retrospective multi-institutional cohort study using the American College of Surgeons National Surgical Quality Improvement Program database to enroll patients who underwent maxillofacial procedures between 2012 and 2019. The primary independent variable was ASA Physical Status Classification (I, II, III, IV). Descriptive, univariate, and multiple logistic regression statistics were used to evaluate the relationship between ASA classification, body mass index (BMI), operative time, and perioperative complications., Results: The study cohort was comprised of 1807 patients, with 946 males and 861 females. The ASA Physical Status Classification ranged from class I to IV. On bivariate analysis, patients classified as ASA III (286 [IQR 152-503], P < .001) and ASA IV (412 [IQR 156.5-547.5], P = .003) were associated with longer operative times. The risk of perioperative complications was 2.6% for ASA I patients (n = 19), 6.3% for ASA II (n = 48; P = .005), 24.5% for ASA III (n = 76; P < .001), and 55.0% for ASA IV (n = 11; P < .001). On multivariate-adjusted analysis, using ASA I as the reference, ASA III (β +53.2 minutes, 95% CI +28.6 to +77.8, P < .001) and ASA IV (β +81.5 minutes, 95% CI +21.0 to +141.9, P = .008) were variables associated with longer operative time., Conclusions: Increased ASA Physical Status Classification was associated with increased operative time and perioperative complications., Competing Interests: Declarations of interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this systematic review was to assess the evidence regarding the indications for placement of zygomatic implants to rehabilitate edentulous maxillae., Material and Methods: A focused question using the PIO format was developed, questioning "in patients in need of an implant-supported rehabilitation of the edentulous maxillae, what are the indications for the use of zygomatic implants''. The primary information analyzed and collected was a clear description of the indication for the use of zygomatic implants., Results: A total of 1266 records were identified through database searching. The full-text review was conducted for 117 papers, and 10 were selected to be included in this review. Zygomatic implant indications were extreme bone atrophy or deficiency secondary to different factors. The quad zygoma concept (two zygomatic implants bilaterally placed and splinted) was applied to 107 patients, the classic zygoma concept (one zygomatic implant bilaterally placed and splinted to standard anterior implants) was used in 88 patients, and the unilateral concept (one zygomatic implant on one side, splinted with one or more conventional implants) was employed in 14 patients., Conclusions: The main indication for the use of zygomatic implants was considered extreme maxillary bone atrophy, resulting from many factors. The clear definition of what was considered "extreme bone atrophy" is not uniquely defined in each paper. Further studies are needed to develop clear indications for zygomatic implants., (© 2023. The Author(s).)

Purpose: To evaluate how guided and navigation surgical approaches for implant placement affect survival and accuracy. Materials and Methods: An electronic literature search was conducted in PubMed/Medline and the Cochrane Library. The reviews were refereed by two independent investigators using the following PICO question: population-patients with missing maxillary or mandibular teeth; intervention-dental implant guided surgery, dental implant navigation surgery; comparison-conventional implant surgery or historical control; outcome-implant survival, implant accuracy. Single-arm, weighted meta-analyses were performed on navigational and static guided surgery groups for cumulative survival rate and accuracy of implant placement (ie, angular, depth, and horizontal deviation). Group metrics with less than five reports were not synthesized. The study was compiled under PRISMA 2020 guidelines. Results: A total of 3,930 articles were screened. Full-text review of 93 articles resulted in a total of 56 articles included for quantitative synthesis and analysis. Implant placement with a fully guided approach resulted in the following means and 95% CI: cumulative survival rate of 97% (96%, 98%), angular deviation of 3.8 degrees (3.4 degrees, 4.2 degrees), depth deviation of 0.5 mm (0.4 mm, 0.6 mm), and horizontal deviation at the implant neck of 1.2 mm (1.0 mm, 1.3 mm). Implant placement with a navigation approach resulted in an angular deviation of 3.4 degrees (3.0 degrees, 3.9 degrees), horizontal deviation at the implant neck of 0.9 mm (0.8 mm, 1.0 mm), and horizontal deviation at the implant apex of 1.2 mm (0.8 mm, 1.5 mm). Conclusion: Static guided and navigation surgical approaches for dental implant placement have survival rates comparable to historical controls. Accuracy of implant placement does not differ markedly between these two approaches.

Extracellular vesicles have received a great interest as safe biocarriers in biomedical engineering. There is a need to develop more efficient delivery strategies to improve localized therapeutic efficacy and minimize off-target adverse effects. Here, exosome mimetics (EMs) are reported for bone targeting involving the introduction of hydroxyapatite-binding moieties through bioorthogonal functionalization. Bone-binding ability of the engineered EMs is verified with hydroxyapatite-coated scaffolds and an ex vivo bone-binding assay. The EM-bound construct provided a biocompatible substrate for cell adhesion, proliferation, and osteogenic differentiation. Particularly, the incorporation of Smoothened agonist (SAG) into EMs greatly increased the osteogenic capacity through the activation of hedgehog signaling. Furthermore, the scaffold integrated with EM/SAG significantly improved in vivo reossification. Lastly, biodistribution studies confirmed the accumulation of systemically administered EMs in bone tissue. This facile engineering strategy could be a versatile tool to promote bone regeneration, offering a promising nanomedicine approach to the sophisticated treatment of bone diseases.

Nerve growth factor (NGF) is the best-characterized neurotrophin and is primarily recognized for its key role in the embryonic development of the nervous system and neuronal cell survival/differentiation. Recently, unexpected actions of NGF in bone regeneration have emerged as NGF is able to enhance the osteogenic differentiation of mesenchymal stem cells. However, little is known regarding how NGF signaling regulates osteogenic differentiation through epigenetic mechanisms. In this study, using human dental mesenchymal stem cells (DMSCs), we demonstrated that NGF mediates osteogenic differentiation through p75NTR, a low-affinity NGF receptor. P75NTR-mediated NGF signaling activates the JNK cascade and the expression of KDM4B, an activating histone demethylase, by removing repressive H3K9me3 epigenetic marks. Mechanistically, NGF-activated c-Jun binds to the KDM4B promoter region and directly upregulates KDM4B expression. Subsequently, KDM4B directly and epigenetically activates DLX5, a master osteogenic gene, by demethylating H3K9me3 marks. Furthermore, we revealed that KDM4B and c-Jun from the JNK signaling pathway work in concert to regulate NGF-mediated osteogenic differentiation through simultaneous recruitment to the promoter region of DLX5. We identified KDM4B as a key epigenetic regulator during the NGF-mediated osteogenesis both in vitro and in vivo using the calvarial defect regeneration mouse model. In conclusion, our study thoroughly elucidated the molecular and epigenetic mechanisms during NGF-mediated osteogenesis., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive or antiangiogenic medications, used in the treatment of bone malignancy or osteoporosis. Bone necrosis, mainly represented by osteocytic death, is always present in MRONJ sites; however, the role of osteocyte death in MRONJ pathogenesis is unknown. High mobility group box 1 (HMGB1) is a non-histone nucleoprotein that in its acetylated form accumulates in the cytoplasm, whereas non-acetylated HMGB1 localizes in the nucleus. SIRT1 deacetylase regulates cellular localization of HMGB1. Interestingly, HMGB1 is released during cell necrosis and promotes inflammation through signaling cascades, including activation of the RAGE receptor. Here, we utilized a well-established mouse MRONJ model that utilizes ligature-induced experimental periodontitis (EP) and treatment with either vehicle or zolendronic acid (ZA). Initially, we evaluated HMGB1-SIRT1 expression in osteocytes at 1, 2, and 4 weeks of treatment. Significantly increased cytoplasmic and perilacunar HMGB1 expression was observed at EP sites of ZA versus vehicle (Veh) animals at all time points. SIRT1 colocalized with cytoplasmic HMGB1 and presented a statistically significant increased expression at the EP sites of ZA animals for all time points. RAGE expression was significantly higher in the submucosal tissues EP sites of ZA animals compared with those in vehicle group. To explore the significance of increased cytoplasmic and extracellular HMGB1 and increased RAGE expression in MRONJ pathogenesis, we used pharmacologic inhibitors of these molecules. Combined HMGB1/RAGE inhibition resulted in lower MRONJ incidence with statistically significant decrease in osteonecrotic areas and bone exposure versus non-inhibitor treated ZA animals. Together, our data point to the role of HMGB1 as a central alarmin, overexpressed at early phase of MRONJ pathogenesis during osteocytic death. Moreover, HMGB1-RAGE pathway may represent a new promising therapeutic target in patients at high risk of MRONJ. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws (MRONJ) - formerly referred to as bisphosphonate-related osteonecrosis of the jaws (BRONJ)-were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007, 2009 and 2014. The position papers were developed by a committee appointed by the AAOMS Board of Trustees and comprising clinicians with extensive experience in caring for these patients, as well as clinical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to evolve and expand, necessitating modifications and refinements to the previous position papers. Three members of the AAOMS Committee on Oral, Head, and Neck Oncologic and Reconstructive Surgery (COHNORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze the current literature and revise the guidance as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis and management strategies and highlights the current research status. AAOMS maintains that it is vitally important for this information to be disseminated to other relevant healthcare professionals and organizations., (Copyright © 2022 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Periodontal diseases are caused by microbial infection and the recruitment of destructive immune cells. Current therapies mainly deal with bacteria elimination, but the regeneration of periodontal tissues remains a challenge. Here we developed a modular microneedle (MN) patch that delivered both antibiotic and cytokines into the local gingival tissue to achieve immunomodulation and tissue regeneration. This MN patch included a quickly dissolvable gelatin membrane for an immediate release of tetracycline and biodegradable GelMA MNs that contained tetracycline-loaded poly(lactic-co-glycolic acid) nanoparticles and cytokine-loaded silica microparticles for a sustained release. Antibiotic release completely inhibited bacteria growth, and the release of IL-4 and TGF-β induced the repolarization of anti-inflammatory macrophages and the formation of regulatory T cells in vitro . In vivo delivery of MN patch into periodontal tissues suppressed proinflammatory factors and promoted pro-regenerative signals and tissue healing, which demonstrated the therapeutic potential of local immunomodulation for tissue regeneration., Competing Interests: Declaration of Interests: S.L., M.M.H.-S., T.A., and A.M. have patent applications (periodontal micropatch and uses thereof, U.S. Provisional Patent Application PCT/US20/58069) related to the current study and, thus, may have related financial interests. The other authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins (BMPs). The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B (KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen's pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response., (© 2022. The Author(s).)

Supramolecular hydrogels are widely used as 3D scaffolds and delivery platforms in tissue engineering applications. However, hydrophobic therapeutic agents exhibit weak compatibility in hydrogel scaffolds along with aggregation and precipitation. Herein, simvastatin drugs used as BMP-2 stimulators are encapsulated into the layer space of LAPONITE® via electrostatic interactions and ion exchange efficiently, and supramolecular hydrogels could be fabricated with a self-healing, injectable and sustained drug release nature. Hydrogels encapsulated with 10 μg mL -1 simvastatin drug show good osteogenic differentiation in vitro . Moreover, the loading of demineralized bone matrix particles could enhance the capacity for osteogenesis via improving the expression of BMP-2 synergistically. The integrated hydrogels could be implanted into cranial defect sites for bone regeneration in vivo . This work provides the first demonstration of molecular and supramolecular engineering of hydrogels to load osteoinductive agents hierarchically for bone regeneration, contributing to the development of a brand-new strategy for dealing with compatibility between scaffolds and osteogenic agents.

Osteonecrosis of the jaws (ONJ), a severe side effect of antiresorptive medications, is characterized by exposed, nonhealing bone in the oral cavity. Treatment options for ONJ range from management of symptomology to surgical resection of the affected area. Antiresorptive discontinuation, often termed a "drug holiday," has been used for managing ONJ patients. Antiresorptives can be discontinued prior to oral surgical procedures, such as tooth extraction, to prevent ONJ development or in patients with established ONJ to accelerate healing. Here, our objective was to test these clinical scenarios using the potent bisphosphonate, zoledronic acid (ZA), and the denosumab surrogate for rodents, OPG-Fc, in a rat model of ONJ. Animals were pretreated with antiresorptives or saline, after which we induced ONJ using periapical disease and tooth extraction. In our first experimental design, antiresorptives were discontinued 1 wk prior to tooth extraction, and animals were evaluated 4 wk later for clinical, radiographic, and histologic features of ONJ. In the second experiment, ONJ was established and antiresorptives were discontinued for 4 wk. Discontinuation of OPG-Fc, but not ZA, prior to tooth extraction ameliorated subsequent ONJ development. In contrast, discontinuation of either ZA or OPG-Fc in rats with established ONJ did not lead to ONJ resolution. In conclusion, our findings suggest that antiresorptive discontinuation is dependent on both the type of antiresorptive and the timing of discontinuation.

Medication related osteonecrosis of the Jaws (MRONJ) is a severe complication of antiresorptive and anti-angiogenic medications. Osteoclast inhibition is central in MRONJ pathogenesis. Here, we investigated if local application of RANKL (a key molecule in osteoclast activation) could enhance osteoclast generation and improve extraction socket healing in the presence of bisphosphonates. Thirty Wistar-Han rats received one saline or 66 μg/kg zoledronate (ZA) i.p. dose before surgery. A week later, mandibular molars were extracted bilaterally. Collagen tapes infused with water or RANKL were placed in the extraction sockets of 60 hemimandibles of veh (veh/RANKL-, veh/RANKL+) or ZA treated rats (ZA/RANKL-, ZA/RANKL+). Rats were euthanized 3 or 12 days after surgery. Animals euthanized at 12 days received two additional veh or ZA injections. Clinical, radiographic and histologic assessments were performed. Visually, at the 3-day timepoint, no sockets demonstrated complete healing. At the 12-day timepoint, sockets of veh/RANKL- and veh/RANKL+ rats showed intact mucosa, while mucosal defects were noted in ZA/RANKL- rats. Importantly, ZA/RANKL+ sockets showed absence of bone exposure. RANKL delivery increased bone healing in the ZA/RANKL+ sites 12 days after extraction compared to the ZA/RANKL- sites. Histologically, at the 3-day timepoint, ZA/RANKL- sockets demonstrated extensive bone exposure and osteonecrosis. In contrast, ZA/RANKL+ rats showed granulation tissue coverage and significantly reduced osteonecrosis, similar to the veh groups. Importantly, in the ZA/RANKL+ group, osteoclasts attached to the bone surface and osteoclast numbers were higher compared to ZA/RANKL- sites. At the 12-day timepoint, persistent osteonecrosis and bone exposure were detected in the sockets of ZA/RANKL- animals. Contrary, ZA/RANKL+ rats demonstrated socket epithelialization and reduced osteonecrosis. Significantly more total and bony attached osteoclasts persisted in the ZA/RANKL+ vs the ZA/RANKL- group. We present a novel approach towards improving socket healing, in the presence of ZA, by enhancing osteoclastic numbers and attachment through local RANKL application. Our approach is clinically applicable and could improve treatment outcomes of patients on high-dose ZA therapy., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The objective of this study was to quantify the probability of implant failure over time from intrinsic patient factors using a population of patients from multiple private practices., Materials and Methods: The records for this retrospective, multicenter cohort study were randomly selected from eight private practices. The primary outcome variable was time to event (implant failure or last known follow-up). The included independent variables were age, sex, diabetes status, smoking status, and arch location. Analyses were performed with Cox proportional hazards on three models: univariate, full multivariate, and systemic factor multivariate. The probability of implant survival at 1, 5, and 10 years was calculated using univariate time-to-event modeling on log-normal distribution with 95% CIs and Cox proportional hazard tests for significance. The Kaplan-Meier survival curve was calculated for patients < 71 years of age., Results: Eight hundred thirty-five implant-level records from 378 patients were collected for analyses. The mean patient age was 60 years, and 48% were men, 15% reported a history of smoking, and 16% reported having diabetes. The follow-up time was as long as 17 years, with a mean of 23.1 months, and a median of 7 months. The hazard ratio (HR) for implant failure due to sex (HR = 1.18; 95% CI: 0.52 to 2.66), smoking (HR = 1.30; 95% CI: 0.49 to 3.46), diabetes (HR = 1.17; 95% CI: 0.35 to 3.86), and arch location (HR = 2.13 to 3.39) failed to reach the threshold within any Cox proportional hazards model (P > .05)., Conclusion: The implant survival probability for patients ≤ 70 years of age is 86.4% at 10 years in the course of routine private practice by experienced providers. Cautious interpretation of these results is critical, as the effects of known systemic risk factors are likely tempered by effective modifications in clinical decisions and protocols with short- and long-term follow-up maintenance.

Demineralized bone matrix (DBM), a potential alternative to autologous bone-graft, has been increasingly used for clinical bone repair; however, its application in larger defects isn't successful partly due to the rapid dispersion of DBM particles and relatively lower osteoinductivity. Here, a novel strategy is created to complement the osteoinductivity of DBM by incorporating DBM in biopolymer hydrogel combined with the abrogation of BMP antagonism. Combined treatment of DBM + noggin-suppression displays increased osteogenic potency of human bone marrow mesenchymal stem cells (hBMSCs) in vitro . Injectable chitosan (MeGC)-based hydrogel with heparinization (Hep-MeGC) is further developed to localize and stabilize DBM. Noggin-suppression reveals the significant increase in osteogenesis of hBMSCs in the photopolymerizable Hep-MeGC hydrogels with the encapsulation of DBM. Moreover, the combination of DBM + noggin-suppression in the injectable Hep-MeGC hydrogel displays a robust bone healing in mouse critical-sized calvarial defects in vivo . The mechanistic analysis demonstrates that noggin-suppression increased DBM osteoinductivity by stimulating endogenous BMP/Smad signals. These results have shown promise in DBM's ability as a prominent bone grafting material while being coupled with gene editing mechanism and a localizing three-dimensional scaffold. Together, this approach poses a significant increase in the efficiency of DBM-mediated craniofacial bone repair and dental osteointegration., Competing Interests: Conflict of Interest The authors indicated no potential conflicts of interest.

Bone repair is a complex process involving the sophisticated interplay of osteogenic stem cells, extracellular matrix, and osteoinductive factors, and it is affected by bacterial toxins and oxidative stress. Inspired by the nature of plant-derived phytochemicals and inorganic-organic analogues of the bone extracellular matrix, we report herein the facile design of a nanoclay-organic hydrogel bone sealant (NoBS) that integrates multiple physico-chemical cues for bone regeneration into a single system. Assembly of phytochemical-modified organic chitosan and silica-rich inorganic nanoclay serves as highly biocompatible and osteoconductive extracellular matrix mimics. The decorated phytochemical exerts inherent bactericidal and antioxidant activities, and acts as an intermolecular networking precursor for gelation with injectable and self-healing capabilities. Moreover, the NoBS exerts osteoinductive effects mediated by the nanoclay, which regulates the Wnt/β-catenin pathway, along with the addition of osteoinductive signals, resulting in bone regeneration in a non-healing cranial defect. Engineering of this integrated bone graft substitute with multifunctional properties inspired by natural materials may suggest a promising and effective approach for creating a favorable microenvironment for optimal bone healing.

Administration of exosomes is considered an attractive cell-free approach to skeletal repair and pathological disease treatment. However, poor yield for the production technique and unexpected therapeutic efficacy of exosomes have been obstacles to their widespread use in clinical practices. Here, we report an alternative strategy to produce exosome-related vesicles with high yields and improved regenerative capability. An extrusion approach was employed to amass exosome mimetics (EMs) from human mesenchymal stem cells (hMSCs). The collected EMs had a significantly increased proportion of vesicles positive for the exosome-specific CD-63 marker compared with MSC-derived exosomes. EMs were further obtained from genetically modified hMSCs in which expression of noggin, a natural bone morphogenetic protein antagonist, was down-regulated to enhance osteogenic properties of EMs. Moreover, the administration of hMSC-EMs in conjunction with an injectable chitosan hydrogel into mouse nonhealing calvarial defects demonstrated robust bone regeneration. Importantly, mechanistic studies revealed that the enhanced osteogenesis by EMs in which noggin was suppressed was mediated via inhibition of miR-29a. These findings demonstrate the great promise of MSC-mediated EMs and modulation of small RNA signaling for skeletal regeneration and cell-free therapy.

Biomaterial delivery of bioactive agents and manipulation of stem cell fate are an attractive approach to promote tissue regeneration. Here, smoothened agonist sterosome is developed using small-molecule activators [20 S -hydroxycholesterol (OHC) and purmorphamine (PUR)] of the smoothened protein in the hedgehog pathway as carrier and cargo. Sterosome presents inherent osteoinductive property even without drug loading. Sterosome is covalently immobilized onto three-dimensional scaffolds via a bioinspired polydopamine intermediate to fabricate a hybrid scaffold for bone regeneration. Sterosome-immobilized hybrid scaffold not only provides a favorable substrate for cell adhesion and proliferation but also delivers bioactive agents in a sustained and spatially targeted manner. Furthermore, this scaffold significantly improves osteogenic differentiation of bone marrow stem cells through OHC/PUR-mediated synergistic activation of the hedgehog pathway and also enhances bone repair in a mouse calvarial defect model. This system serves as a versatile biomaterial platform for many applications, including therapeutic delivery and endogenous regenerative medicine., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)