Treating critical bone defects by using core-shell biological scaffold to regulate Fibrosis-Osteogenic homeostasis.

Critical bone defects pose a significant challenge in the realm of bone defect repair. During the repair process, bone formation is crucial, as the occurrence of invasive tissue growth into the defect, known as fibrosis, is also a possibility. Excessive fibrosis can lead to a "filling effect," wherein fibrous tissue occupies the bone defect area, thereby impeding the bone formation and repair processes. Hence, regulating the dynamic balance between fibrosis and osteogenesis is pivotal to effectively treat critical bone defects. To mitigate the rapid fibrosis rate at the bone defect site, which may result in repair failure, we have devised and fabricated a biomimetic core-shell scaffold-PCL-FAPI/GelMA/HAMA-GBA@plasmid-knockdown SHN-3 (PCL-FAPI/GH-GBA@pk SHN-3)-aimed at modulating fibrosis and vascularization processes within the new callus. The outer "shell" structure of the scaffold employs polycaprolactone (PCL) electrospun nanofibers loaded with fibroblast activating protein inhibitor (FAPI). Utilizing hydrophobic PCL electrospun fibers effectively impedes the growth of exogenous fibrous tissue, while releasing FAPI to inhibit the growth of endogenous fibroblasts. The inner layer "nucleus" structure comprises GelMA/HAMA hydrogel-supported plasmid/polyamideamine (GBA@plasmid-knockdown SHN-3), which enhances the secretion of Slit3 protein and promotes the formation of Type H blood vessels by silencing the SHN-3 gene in osteoblasts. The biomimetic "core-shell" scaffold PCL-FAPI/GH-GBA@pkSHN-3 serves to prevent excessive fibrosis of the callus and foster the formation of Type H blood vessels within the new callus, effectively averting bone nonunion and expediting the repair process of critical bone defects.