Regulation of osteoimmune microenvironment via functional dynamic hydrogel for diabetic bone regeneration

Bone regeneration and repair face formidable challenges under diabetic conditions, primarily due to the disruption of macrophage polarization induced by diabetes and the inflammatory imbalance within the bone microenvironment. We have developed a novel dynamic hydrogel system (AG-CD@LINA), constructed through the coordination crosslinking of thiolated gelatin (SH-Gelatin) and gold ions (Au³⁺), followed by grafting with cyclodextrin to load the ligand linagliptin. This hydrogel effectively inhibits the formation of M1 macrophages and the expression of pro-inflammatory cytokines by gradually releasing linagliptin. Simultaneously, it promotes the formation of M2 macrophages and the expression of anti-inflammatory cytokines, thus improving the inflammatory microenvironment of diabetic bone defects. Consequently, it facilitates the migration of mesenchymal stem cells and angiogenic cells, augments osteogenic activity, and promotes vascularization, collectively accelerating the regeneration of diabetic bone tissue. Mechanistically, polarization occurs through the TLR3-NF-κB signaling pathway. In vivo experiments demonstrate that the in-situ injection of the hydrogel enhances the regeneration of bone tissue and the restoration of bone structure in diabetic bone defects, effectively modulating local inflammation and promoting vascular formation. This study suggests that functionalized dynamic hydrogels can improve the inflammatory microenvironment by regulating in situ macrophage polarization, thereby facilitating the reconstruction of bone microstructure. This approach represents a promising novel therapeutic strategy for diabetic bone defects.