Fiber scaffolds augment aged bone regeneration by modulating energy metabolism, immunity and angiogenesis

Aging-associated bone regeneration failure stems from the vicious cycle of metabolic decline, chronic inflammation, and vascular insufficiency. To break this cycle, we engineered a core-shell electrospun scaffold (Fn-TA-PFC/PCK) integrating three bioinspired strategies: (1) Tannic acid (TA)-anchored fibronectin (Fn) recruit endogenous vascular endothelial growth factor (VEGF) in situ to promote angiogenesis, (2) immunomodulatory-related factors promote the polarization of macrophages toward the regenerative M2 phenotype and reduced ROS levels, and (3) α-ketoglutarate (αKG) reprogram the mitochondrial metabolism in bone marrow mesenchymal stem cells (BMSCs), promoting energy production. In vitro experiments showed that the scaffold enhanced adenosine triphosphate (ATP) production and effectively captured VEGF. Importantly, αKG in the scaffold reduced the expression of senescence-related genes, improved aged microenvironment, and restored the osteogenic potential of aged BMSCs. Subcutaneous implantation demonstrated that in situ capture of VEGF by scaffolds accelerated vascularization, and promoted polarization of M2-type macrophages. Further evaluation in calvarial defect models of aged mice, ovariectomized (OVX) rats, and SD rats demonstrated the scaffold's robust angiogenic and osteogenic activity. Multi-omics analysis attributed this efficacy to activated osteogenic/angiogenic pathways and metabolic rewiring. This multifunctional scaffold pioneers a paradigm shifts from single-factor delivery to endogenous niche engineering, offering a strategy for aging tissue repair.