A Co-Axial Electrospun Polycaprolactone/Gelatin Scaffold Loaded with VEGF-Releasing Nanoparticles for Vascularized Bone Tissue Regeneration in Critical-Sized Femoral Defects

Critical-sized bone defects present significant clinical challenges in orthopedic surgery due to non-union and delayed vascularization. In this study, we engineered a novel biofunctional scaffold utilizing co-axial electrospinning to generate polycaprolactone (PCL) core / gelatin shell nanofibers embedded with vascular endothelial growth factor (VEGF)-releasing poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The structural core-shell design provided initial mechanical stability while enabling controlled, sustained release kinetics of VEGF over a 28-day period. In vitro characterization demonstrated that the composite scaffolds exhibited a tensile modulus of 28.5 ± 2.1 MPa, rapid cell attachment, and excellent cytocompatibility with both human umbilical vein endothelial cells (HUVECs) and bone marrow-derived mesenchymal stem cells (BMSCs). Tubulogenesis assays revealed enhanced capillary-like network formation in HUVECs cultured with scaffold extracts. Concurrently, BMSC osteogenic differentiation was significantly upregulated, as evidenced by increased alkaline phosphatase activity, elevated calcium deposition, and enhanced expression of osteogenic markers (RUNX2 and osteocalcin). In a rat critical-sized femoral defect model, micro-computed tomography and histological evaluations revealed accelerated bone bridging, superior bone volume fraction (42.3 ± 3.8% at 8 weeks post-implantation), and enhanced microvessel density in defects treated with the VEGF nanoparticle-loaded co-axial scaffolds compared to acellular and growth-factor-free controls. These findings demonstrate that co-axially electrospun PCL/gelatin scaffolds loaded with VEGF nanoparticles provide an effective osteo-angiogenic microenvironment for functional vascularized bone regeneration.