Spatiotemporal Immunomodulation and Biphasic Osteo‐Vascular Aligned Electrospun Membrane for Diabetic Periosteum Regeneration

Abstract Under diabetic conditions, blood glucose fluctuations and exacerbated immunopathological inflammatory environments pose significant challenges to periosteal regenerative repair strategies. Responsive immune regulation in damaged tissues is critical for the immune microenvironment, osteogenesis, and angiogenesis stabilization. Considering the high‐glucose microenvironment of such acute injury sites, a functional glucose‐responsive immunomodulation‐assisted periosteal regeneration composite material—PLA（Polylactic Acid）/COLI(Collagen I）/Lipo(Liposome）‐APY29 (PCLA)—is constructed. Aside from stimulating osteogenic differentiation, owing to the presence of surface self‐assembled type I collagen in the scaffolds, PCLA can directly respond to focal area high‐glucose microenvironments. The PCLA scaffolds trigger the release of APY29‐loaded liposomes, shifting the macrophages toward the M2 phenotype, inhibiting the release of inflammatory cytokines, improving the bone immune microenvironment, and promoting osteogenic differentiation and angiogenesis. Bioinformatics analyses show that PCLA enhances bone repair by inhibiting the inflammatory signal pathway regulating the polarization direction and promoting osteogenic and angiogenic gene expression. In the calvarial periosteal defect model of diabetic rats, PCLA scaffolds induce M2 macrophage polarization and improve the inflammatory microenvironment, significantly accelerating periosteal repair. Overall, the PCLA scaffold material regulates immunity in fluctuating high‐glucose inflammatory microenvironments, achieves relatively stable and favorable osteogenic microenvironments, and facilitates the effective design of functionalized biomaterials for bone regeneration therapy in patients with diabetes.