Bone tissue engineering, as an important branch of regenerative medicine, integrates multidisciplinary knowledge from cell biology, materials science, and biomechanics, aiming to develop novel biomaterials and technologies for functional repair and regeneration of bone tissue. Hydrogels are among the most commonly used scaffold materials; however, conventional hydrogels exhibit significant limitations in physical properties such as strength, tensile strength, toughness, and fatigue resistance, which severely restrict their application in load-bearing bone defect repair. As a result, the development of high-strength hydrogels has become a research hotspot in the field of bone tissue engineering. This paper systematically reviews the latest research progress in this area: First, it delves into the physicochemical characteristics of high-strength hydrogels at the molecular level, focusing on core features such as their crosslinking network structure, dynamic bonding mechanisms, and energy dissipation principles. Next, it categorically summarizes novel high-strength hydrogel systems and different types of biomimetic hydrogels developed based on various reinforcement strategies. Furthermore, it provides a detailed evaluation of the application effects of these advanced materials in specific anatomical sites, including cranial reconstruction, femoral repair, alveolar bone regeneration, and articular cartilage repair. This review aims to provide systematic theoretical guidance and technical references for the basic research and clinical translation of high-strength hydrogels in bone tissue engineering, promoting the effective translation of this field from laboratory research to clinical application.

Purpose: Due to the lack of effective local therapeutic strategies for oral squamous cell carcinoma (OSCC), this study aimed to develop a novel gelatin/lignin hydrogel loaded with mesenchymal stem cell (MSC)-derived exosomes enriched in microRNA-185 (miR-185 EV) for intraoral delivery, followed by systematic evaluation of its therapeutic efficacy and underlying molecular mechanisms. Materials and Methods: The gelatin/lignin hydrogel was prepared and subsequently loaded with miR-185 EV. The physicochemical properties of the hydrogel, including microstructure, swelling behavior, chemical composition, and rheological characteristics, were systematically evaluated. Next, the stability, viscosity, biocompatibility, and exosome release kinetics of the hydrogel were further assessed. A 4-nitroquinoline-1-oxide (4NQO)-induced mouse tongue carcinogenesis model was established to assess the in vivo antitumor activity of the hydrogel via intraoral administration. Moreover, a proteomic analysis was conducted to investigate the molecular mechanisms of miR-185 EV on OSCC. Results: The miR-185 EV-loaded gelatin/lignin hydrogel exhibited favorable physicochemical properties, stability, and biocompatibility while prolonging the tissue retention time of miR-185 EV. In vivo antitumor efficacy experiments showed that the miR-185 EV-loaded hydrogel significantly inhibited tumor occurrence and alleviated epithelial dysplasia. Immunohistochemical analyses revealed significant suppression of tumor proliferation and epithelial–mesenchymal transition (EMT) of the hydrogel. Proteomic analysis indicated that miR-185 EV suppressed OSCC progression by downregulating interleukin-1β (IL-1β), consequently inhibiting the NF-κB signaling pathway. Conclusion: The findings demonstrate the successful development of the miR-185 EV-loaded gelatin/lignin hydrogel that represents an effective nanomedicine platform for intraoral drug delivery, providing a promising strategy for the clinical treatment of OSCC.

Oral squamous-cell carcinoma (OSCC) is a prevalent malignancy of the head and neck region. A delay in the diagnosis of OSCC often results in a high metastatic tendency, which is the main reason for the high patient mortality. Dynamic monitoring and management of the onset and progression of OSCC are critical for improving patient survival rates. Liquid biopsy technology—characterized by its non-invasive nature, procedural convenience, and capacity for longitudinal monitoring—is a promising adjunct to histopathological examination for the early diagnosis of OSCC. Epigenetic alterations, characterized by reversibility and long-term stability in physiological fluids, are critical enablers of liquid biopsy and its clinical utility. Advances in detection technologies, including quantitative polymerase chain reaction (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and electrochemical biosensors, have significantly facilitated the research and clinical translation of epigenetic biomarkers in oral liquid biopsies. However, translating epigenetic biomarkers from research discovery to clinical practice for OSCC remains hindered by several critical challenges: the scarcity of large-scale, rigorously designed cohort studies, limited multicenter validation, inconsistent preprocessing protocols, and a lack of harmonized analytical platforms. Finally, we propose a conceptual framework to outline potential clinical application models for these biomarkers.

Aging is a major risk factor for impaired bone-defect healing, and dysregulation of the immune microenvironment, especially macrophage dysfunction, is closely linked to this process. Interleukin-34 (IL-34) plays a crucial role in macrophage biology; however, its role in aging-related bone-defect healing remains elusive. Herein, young and aged male C57BL/6 mice were utilized to establish a tibial bone defect model. Microcomputed tomography, histological staining, flow cytometry, RNA sequencing and in vitro cell experiments were conducted to explore the role and mechanism of action of IL-34 in aging-impaired bone healing. Aging markedly decreased bone mass, inhibited osteogenic differentiation and impaired bone defect healing in mice. Moreover, aging reduces macrophage numbers at bone defects and suppresses M2 polarization, with the drop likely driven by recruitment, survival or proliferation defects rather than impaired recruitment exclusively. IL-34 was a key differentially expressed gene that was downregulated in aged mice, which was further confirmed at the protein level. Furthermore, aging decreased IL-34 secretion by macrophages and impaired macrophage proliferation and M2 polarisation. Thus, aging impairs tibial bone-defect healing by downregulating IL-34 expression, decreasing macrophage infiltration, and inhibiting M2 polarisation. Furthermore, IL-34 acts as a pro-reparative cytokine that promotes bone healing by regulating macrophage function, suggesting its role as a potential therapeutic target for enhancing age-related bone repair.

Bisphosphonates (BPs) are cornerstone therapeutic agents for the management of metabolic bone disorders and skeletal complications associated with malignant tumors. However, their long-term administration is accompanied by the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). In recent years, the pathogenesis of BRONJ has remained a major focus at the intersection of osteoimmunology and oral medicine. This review systematically summarizes the latest advances in the understanding of BRONJ pathogenesis, including the direct disruption of osteoclast differentiation and bone remodeling coupling by bisphosphonates, the systemic reprogramming of immune cell subsets and inflammatory signaling pathways, the multifaceted suppression of angiogenesis and the endothelial–stromal–immune axis, and the toxic impairment of oral soft tissue repair capacity. Building upon these mechanistic insights, we further discuss the modifying and synergistic effects of local oral risk factors, microbial dysbiosis, systemic comorbidities, and genetic susceptibility on the initiation and progression of BRONJ. Furthermore, emerging therapeutic strategies targeting these pathogenic mechanisms are highlighted, including restoration of small GTPase prenylation through modulation of metabolic pathways, reconstruction of T-cell subset homeostasis via immunomodulatory approaches, enhancement of local vascularization through pro-angiogenic interventions, and preservation of soft tissue barrier integrity. Collectively, this review provides a comprehensive and multidimensional overview of the pathological landscape of BRONJ and offers a theoretical framework for clinical risk stratification and the development of personalized prevention and treatment strategies.