Dual-Mode Release of IL-4 and TCP from a PGA-SF Core–Shell Electrospinning Scaffold for Enhanced Bone Regeneration through Synergistic Immunoregulation and Osteogenesis

The successful filling of bone defects remains challenging due to the incongruity between bone graft materials and the dynamic process of bone healing. Developing multifunctional materials matching the dynamic process of bone healing offers a viable solution to the current dilemma. Lines of evidence have shown that engineering osteoimmunomodulatory biomaterials can modulate the function of immune cells and thus promote bone regeneration. Herein, we utilized silk fibroin (SF) and polyglycolic acid (PGA) to create a PGA-SF core-shell fibrous scaffold, incorporating interleukin-4 (IL-4) and tricalcium phosphate (TCP) as a codelivery system (PGA/TCP-SF/IL-4), aiming to achieve an initial rapid release of IL-4 and sustained release of TCP. The PGA/TCP-SF/IL-4 scaffold mimicked the native bone structure and showed superior tenacity in the wetting regime. <i>In vitro</i> studies demonstrated that the PGA/TCP-SF/IL-4 scaffold significantly reduced the inflammatory response by upregulating the M2 macrophages, created a favorable microenvironment for osteogenesis, and facilitated osteogenic differentiation and mineralization. Implantation of the PGA/TCP-SF/IL-4 scaffold into the rat skull defect model notably increased the formation of new bones. IL-4 and TCP acted synergistically in attenuating inflammation and enhancing osteogenic differentiation. Overall, this multifunctional scaffold comprehensively considers the various demands in the bone defect region, which might have a significant potential for application in bone reconstruction.