A composite sustained-release system with immunomodulatory and synergistic osteogenic differentiation effects for repairing inflammatory alveolar bone defects

Inflammation-associated alveolar bone defects, such as periodontitis, remain a major clinical challenge, as persistent inflammatory microenvironments severely impair bone regeneration and tissue repair. The cathepsin family plays a significant role in inflammatory responses and the clinicopathological process of periodontitis. Studies have shown that the cathepsin K inhibitor, odanacatib (ODN), can repair inflammatory bone defects. However, its administration via oral or local delivery fails to maintain sustained drug concentrations within the periodontal pocket. Here, we report a gel sustained-release system that coordinates immunomodulation with osteogenic induction to overcome inflammation-impaired bone regeneration. We utilized the emulsification-solvent evaporation method to prepare ODN-loaded poly(lactic- co -glycolic acid) (PLGA) microspheres (ODN-MS). These microspheres were thoroughly mixed with gelatin methacryloyl (GelMA) to form a gel composite sustained-release system (ODN-MS-Gel). The ODN-MS-Gel prepared has excellent photopolymerization properties and can achieve sustained release of ODN for a long time, thus enabling local and targeted drug delivery within the periodontal pocket. In vitro, ODN-MS-Gel not only promoted the proliferation, adhesion, and migration of BMSCs but also induced macrophage polarization toward the M2 phenotype, demonstrating a significant ability to promote osteogenic differentiation under inflammatory conditions. Furthermore, this study also distinguished the differences between the two situations of continuous release and non-continuous release and revealed the potential role of macrophage immune regulation in conjunction with stem cell osteogenic differentiation. In vivo, ODN-MS-Gel gradually degraded over time, exhibiting excellent long-term biocompatibility. By using a rat periodontitis model, it was demonstrated that ODN-MS-Gel could reduce inflammatory expression in periodontal tissues under inflammatory conditions and repair the alveolar bone defect to 77% of its normal height. In conclusion, ODN-MS-Gel achieves anti-inflammatory and bone repair effects with a single drug, representing a promising biomaterial for treating inflammatory alveolar bone defects.