Regulation Energy Metabolism of Fiber Scaffolds Orchestrates Osteoimmunomodulation and Angio/Osteogenesis

Bone formation is a highly metabolic process, involving extensive biosynthesis and biomineralization, both of which require substantial amounts of energy. Additionally, the regulation of the immune microenvironment and the development of a neovascularization network are equally crucial in bone formation. Inspired by the high energy demands of the bone formation process, a core–shell electrospun fiber scaffold (PFC/PCK) capable of sustainably releasing a metabolic regulator (αKG) and biomineralizing ions (CaP) is developed. In vitro experiments show that the PFC/PCK fiber scaffolds can induce hyperpolarization of mitochondrial membrane potential in bone marrow mesenchymal stem cells (BMSCs), increase energy supply, effectively regulate immune microenvironment, and remarkably promote expression of angiogenesis and osteogenesis markers. In vivo evaluation further confirms the outstanding immunoregulatory and osteo/angio-genesis capabilities of the fabricated fiber scaffolds. Importantly, transcriptome analysis identifies that the fiber scaffolds upregulate genes and signaling pathways associated with M2 macrophage activation, energy generation, angiogenesis, and osteogenesis. Additionally, metabolomics analysis confirms that the fiber scaffolds enhance bone formation by promoting the expression of osteogenic metabolites. The versatile fiber scaffolds developed in current study demonstrates a new strategy for functional bone regeneration.