Enhanced Bone Regeneration via Dual Immune‐Modulatory Scaffold: Integrating Lipopolysaccharide/Gelatin Methacrylate and Proanthocyanidins/Polylactic Acid to Enhance Macrophage Recruitment and M2 Phenotype Polarization

The initiation of bone repair inherently involves inflammation, a key regulator of the healing cascade. However, uncontrolled or excessive inflammation can hinder the natural bone repair process. By modulating the immune response, focusing particularly on macrophage recruitment and polarization, the injury microenvironment can be transformed by facilitating conditions more conducive to rapid bone regeneration. Thus, we developed a composite scaffold comprising biocompatible gelatin methacrylate incorporated with lipopolysaccharide (LPS) and an oligomeric proanthocyanidin (OPC)-loaded polylactic acid scaffold. This novel design leverages the release of LPS from gelatin, rapidly attracting macrophages and transforming them into the M1 phenotype. Subsequently, OPC facilitates the polarization of macrophages from the M1 to the M2 phenotype, leading to the release of anti-inflammatory factors that promote the proliferation and differentiation of bone marrow mesenchymal stem cells. Furthermore, the strong antioxidant properties of OPC effectively mitigate the generation of reactive oxygen species at the injury site, facilitating an environment more conducive to healing. In vivo experiments showed significantly increased expression of osteogenic factors 8 weeks after scaffold implantation, promoting neovascularization and bone regeneration via immune regulation. These findings highlight the substantial potential of leveraging macrophage recruitment and immune modulation as an innovative therapeutic strategy for bone defect repair.