Human physical and mental health are significantly impacted by maxillofacial alveolar bone defects. The emergence of additive manufacturing metamaterial scaffolds provides a new treatment strategy for this. Due to the complexity of the jawbone and the difficulty in preparing bionic hierarchical gradient scaffolds, most current research focuses on human long bones. This study first proposes a metamaterial scaffold that simulates the jawbone. The stratified scaffolds (G300-600, G300-750,G300-900) adopt the Gyroid structure of the triply periodic minimum surfaces (TPMS), with the upper and lower layers respectively simulating the cortical bone and cancellous bone of the jawbone. And a large-aperture uniform scaffold (G750) was designed as a control. And it is prepared through digital light processing (DLP) 3D printing technology. The results show that sintering the scaffold to 1170℃ and holding it for 48 hours can improve the mechanical properties and biocompatibility of the scaffold, making it match. G300-600 not only improves in vitro neovascularization and new bone formation, but also features a high level of compressive strength (9.86MPa) and outstanding degradability. This gradient metamaterial scaffold has a structure, mechanical properties and biological activity that conform to the jawbone, providing a new strategy for bone defects in the maxillofacial region.

Current treatments for oral tissue defects restore structure but rarely restore sensory nerves. Tissues without innervation lose protective reflexes and long-term stability. This review examines neuro-instructive hydrogels designed to guide nerve regeneration in oral tissues. We discuss four design mechanisms: physical cues that direct axon growth, spatiotemporal release of neurotrophic signals, regulation of oral stem cells and Schwann cells, and immunomodulation that supports a pro-regenerative niche. We then map these mechanisms onto three clinical scenarios: regeneration of the dentin-pulp complex, reconstruction of innervated jawbone, and repair of oral mucosal nerves. The oral environment imposes specific constraints (saliva, chewing forces, and a rich microbiome) that call for wet-adhesive, antibacterial, and mechanically adaptable designs. Bioprinting offers a route to patient-specific constructs with controlled architecture, and emerging tools such as stimuli-responsive release and machine learning guided formulation may further improve precision. Key next steps include scalable production under Good Manufacturing Practice, large-animal validation, and objective clinical endpoints for sensory recovery. The central goal is to move oral tissue repair from structural filling toward restoration of sensation.

Hypophosphatasia (HPP) is a rare inherited disorder caused by inactivating variants in the ALPL gene, resulting in defective mineralization of bone and teeth. Dental manifestations include early exfoliation of fully rooted primary teeth as a result of cementum dysplasia, premature loss of permanent teeth, and hypomineralization of enamel, dentin, and jawbone. However, genotype-dependent dental phenotypes and severity-based treatment strategies remain poorly defined. The aim of this study was to generate knock-in mouse models harboring clinically relevant ALPL variants and to characterize their dental and periodontal phenotypes in relation to serum tissue-nonspecific alkaline phosphatase (TNAP) activity. We analyzed mice that were compound heterozygous for a null variant and a hypomorphic variant (Alpl[c.1559delT/p.F327L]) and mice that were heterozygous for a dominant-negative variant (Alpl[+/p.R184W]). Dental and alveolar phenotypes were assessed using micro-CT, histological analyses, and periodontal ligament traction experiments. Alpl[c.1559delT/p.F327L] mice exhibited reduced serum TNAP levels, mild skeletal abnormalities, and severe dental defects, including hypomineralization of enamel, dentin, and cementum, decreased alveolar BMD, and an increased distance from the cemento-enamel junction to the alveolar bone crest. In contrast, Alpl[+/p.R184W] mice showed isolated dental abnormalities characterized by dentin and cementum hypomineralization and decreased alveolar bone BMD without overt skeletal involvement. Periodontal tissue fragility was increased in both models. These knock-in mouse models recapitulate genotype-dependent dental manifestations of HPP and indicate that dental phenotypes are influenced not only by circulating TNAP levels but also by the functional effects of individual ALPL variants. This platform provides a valuable framework for elucidating the mechanisms underlying genotype-dependent dental manifestations and for developing dental treatment strategies tailored to disease severity.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains a challenging complication of bisphosphonate therapy because jaw extraction sockets exposed to bisphosphonates represent impaired wound environments rather than ordinary bone defects. This narrative review summarizes clinical, cellular, animal, and biomaterial evidence on the mechanisms that limit BRONJ repair and discusses how these pathological barriers can inform local material design. Current evidence suggests that BRONJ repair is constrained by impaired osteoclast-mediated remodeling, osteocyte and osteoblast dysfunction, oxidative stress, unresolved inflammation, angiogenic insufficiency, microbial challenge, mucosal instability, and changes in bone material properties. Biomaterial strategies investigated to date include local delivery of regenerative factors, restoration of remodeling activity, extracellular vesicles, nucleic acid nanostructures, platelet-derived matrices, antibacterial and ion-releasing hydrogels, angiogenic or lymphangiogenic systems, and mechanically adaptive scaffolds. Most studies remain preclinical and are based on rodent extraction or mandibular defect models, and few establish a direct causal link between a specific material property and durable BRONJ resolution. Future materials should be judged not only by their ability to enhance bone formation, but also by whether they can re-establish a sealed, vascularized, immune-balanced, and remodeling-competent socket capable of sustained jawbone repair.

Periosteal cells (PCs) play a crucial role in bone regeneration. Currently, the spatial landscapes of jaw-bone periosteum during bone grafting remains unclear. In this study, we propose a modified guided bone regeneration (GBR) model and integrate single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to dissect its spatial characteristics. We identify a functional subset of Ctsk[+]Fmod[+] PCs within the jaw-bone periosteum of rat and human. In addition, we describe a spatial niche around the bone graft substitute, characterized by massive infiltration of macrophages interacting with Ctsk[+]Fmod[+] PCs. Notably, SPP1 secreted by macrophages attenuates the osteogenic capacity of Ctsk[+]Fmod[+] PCs. The discovery of this Ctsk[+]Fmod[+] subcluster, characterized by osteoprogenitor features and close interactions with macrophages, sheds light on the composition of the subperiosteal microenvironment and the heterogeneity of jaw-bone PCs.

Background: This exploratory study assessed the frequency of study-defined focal low-trabeculation/low-density intramedullary findings (FLDIFs) in a selected clinical cohort referred for cone-beam computed tomography (CBCT) and examined their associations with demographic, systemic, and radiographic variables. CBCT depicts mineralized trabecular architecture and relative attenuation but cannot directly demonstrate marrow fat or establish osteonecrosis; FDOJ/MFI were therefore considered only possible interpretations rather than imaging diagnoses. Methods: A single-center retrospective analysis included 1000 adults whose CBCT examinations met the study image-quality and anatomical-coverage requirements. FLDIF was defined as a descriptive radiological phenotype and was not considered a diagnosis of fatty degenerative osteonecrosis of the jaw (FDOJ), marrow fatty infiltration (MFI), or another specific disorder. Patients were classified as positive when at least one study-defined finding was present; one largest index finding per positive patient was used for finding-level analyses. Results: FLDIFs were identified in 452/1000 patients (45.2%; 95% CI: 42.1-48.3%) within this CBCT-referred cohort. Age was associated with finding presence in the multivariable model (OR 1.015 per year, 95% CI: 1.006-1.025; p = 0.001). Diabetes mellitus also showed an adjusted association (OR 1.647, 95% CI: 1.022-2.686; p = 0.042), which should be regarded as exploratory because of residual confounding and retrospective disease ascertainment. Panoramic radiographs were available for all 452 index findings; 180 (39.8%) were judged visible and 272 (60.2%) not visible. Visible index findings were larger (median 9.2 vs. 8.1 mm; pFDR = 0.003; |rank-biserial r| = 0.19), whereas the relative CBCT gray-scale comparison was not significant after FDR correction. Most index findings (412/452, 91.2%) were located in the mandibular retromolar regions. Conclusions: The 45.2% value represents the frequency of a study-defined, nonspecific radiological phenotype within a selected CBCT-referred cohort and should not be interpreted as population prevalence or as the prevalence of histopathologically confirmed FDOJ/MFI. The findings are hypothesis-generating; they do not establish a screening indication for CBCT based on age or diabetes. The biological and clinical significance of the imaging phenotype remains uncertain and requires external validation in independent cohorts and, when clinically indicated, histopathological or complementary imaging correlation.

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a known side effect of antiresorptive agents. Although the jawbone has been extensively investigated, histopathological changes in the overlying oral mucosa remain poorly characterized. We previously reported small bone fragments located within the oral mucosa of a patient with MRONJ. This study aimed to investigate the presence and histopathological characteristics of those fragments in other patients with surgically treated MRONJ. Case Presentation: This retrospective case series included six patients with stage 3 mandibular MRONJ who underwent marginal or segmental resection. Archived histological sections from these patients were examined. Oral mucosal specimens had been separated from the underlying osseous lesions for independent histological evaluation. In this study, small intramucosal sequestra were defined as small bone fragments that appeared to be completely surrounded by mucosal connective tissue in individual two-dimensional sections. All sections had been stained with hematoxylin and eosin, and additional von Kossa staining had been performed on oral mucosal sections from five of the six cases. Histopathological evaluation of small intramucosal sequestra included the presence, size range, and association with pseudoepitheliomatous hyperplasia (PEH). Results: Small intramucosal sequestra were identified in all six patients. They were present either singly or in clusters within the connective tissue beneath the oral epithelium. The intramucosal sequestra exhibited empty osteocytic lacunae, indicating devitalized bone, and were positive for von Kossa staining in all five examined cases, confirming their mineralized nature. In two patients, PEH was observed in direct contact with the small sequestra, some of which appeared to be embedded within the advancing epithelial fronts. Conclusions: Small intramucosal sequestra were a recurrent histopathological finding in this selected series of surgically resected stage 3 mandibular MRONJ. Their presence highlights histopathological changes in the oral mucosa overlying necrotic jawbone that have received limited attention. Further studies including broader patient populations and appropriate comparison groups are needed to determine the generalizability and disease specificity of this finding and its potential relevance to MRONJ pathogenesis.

Bisphosphonates (BPs) and Denosumab (DMB) are antiresorptive agents (AA) commonly used in treatment of osteoporosis, multiple myeloma (8.0%), breast cancer (3.3%), prostate cancer (2.9%) and other malignancies (0.7%), bone metastases, and cancer-induced hypercalcemia. However, this therapy is associated with a significant risk of medication-related osteonecrosis of the jaw (MRONJ), particularly after tooth extraction. The aim of this narrative review was to summarize current evidence on measures aimed to reduce the risk of MRONJ after tooth extraction, and to critically discuss the strength of evidence supporting each of these measures. Articles published in the years 2013-2025 were reviewed using PubMed, Scopus, Web of Science databases. Available studies were categorized and compared with the use of selected prevention methods. The duration of the treatment, route of administration, dosage and type of AA have a significant impact on the risk of developing MRONJ. Antibiotic prophylaxis is considered in most published preventive protocols. However, the evidence supporting a single optimal regimen is limited. Patients from a high-risk group of MRONJ, demonstrating cancer, who were administered intravenous antiresorptive agents for longer than three years or zoledronic acid, or those with a history of jawbone necrosis or inflammation require prolonged antibiotic therapy (started before the procedure and continued up to 14 days after the procedure). Moreover, studies on the use of platelet-rich fibrin (PRF) and Concentrated Growth Factors (CGF) as a preventive measure have shown promising results in observational studies, along with antibiotic prophylaxis and optimal oral hygiene. Pentoxifylline with tocopherol and low-level laser therapy (LLLT) are recognized as potentially useful non-invasive preventions. However, evidence is limited due to the small sample sizes and heterogenous protocols. Vitamin D levels should be monitored, and oral supplementation should be considered if needed. AA therapy suspension prior to the surgical procedure must always be consulted with the attending physician. A multidisciplinary approach along with well-planned pre- and postoperative care is essential for safe tooth extraction in patients receiving AA therapy.