Photoresponsive electrospun fiber scaffold enables on-demand cytokine delivery for biomimetic endochondral bone regeneration.

Abstract

Critical-sized bone defect repair remains a formidable challenge because conventional approaches cannot recapitulate the temporally coordinated cascade of endochondral ossification. Here, we report a biomimetic, temporally programmed cytokine delivery scaffold that integrates spatially defined nanofiber architecture with sequential biochemical activation to orchestrate orderly tissue regeneration. The scaffold comprises electrospun polycaprolactone nanofibers with an inner uniaxially aligned layer and an outer random layer. Interleukin-8 (IL-8), strategically loaded into the aligned fibers to reinstate early-stage chemotactic cues markedly diminished in adult bone defect repair, is released in a sustained manner during the initial 14 days, enhancing mesenchymal stem cell recruitment and initiating chondrogenic differentiation. At later stages, bone morphogenetic protein-2 (BMP-2) encapsulated between the fiber layers is released on demand via near-infrared (NIR) stimulation, enabling temporally precise promotion of osteogenesis. In vivo, the staged delivery system led to a 72.1% greater bone volume fraction at 12 weeks compared to controls. IL-8-driven early cartilage formation and BMP-2-induced late-stage bone regeneration were consistent with upregulated expression of chondrogenic markers S100 (3.63-fold) and COL2 (1.57-fold) at 4 weeks and subsequently, osteogenic markers OCN (1.68-fold) and OPN (1.47-fold) at 12 weeks. By reinstating early molecular signals absent in conventional healing and coupling them with on-demand osteogenic stimulation, this programmable delivery strategy offers a potent and adaptable approach for regenerating critical-sized bone defects and potentially other complex tissues requiring staged repair.