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Ensuring an adequate angiogenic response during wound healing is a prevailing clinical challenge in biomaterials science. To address this, we aimed to develop a pro-angiogenic gene-activated scaffold (GAS) that could activate MSCs to produce paracrine factors and influence angiogenesis and wound repair. A non-viral polyethyleneimine (PEI) nanoparticles carrying a gene encoding for stromal derived factor-1 alpha (SDF-1α) was combined with a collagen-chondroitin sulfate scaffold to produce the GAS. The ability of this platform to enhance the angiogenic potential of mesenchymal stem cells (MSCs) was then assessed. We found that the MSCs on GAS exhibited early over-expression of SDF-1α mRNA with the activation of angiogenic markers VEGF and CXCR4. Exposing endothelial cells to conditioned media collected from GAS supported MSCs promoted a 20% increase in viability and 33% increase in tubule formation (p<0.05). Furthermore, the conditioned media promoted a 50% increase in endothelial cell migration and wound closure (p<0.005). Gene expression analysis of the endothelial cells revealed that the functional response was associated with up-regulation of angiogenic genes; VEGF, CXCR4, eNOS and SDF-1α. Overall, this study shows collagen-based scaffolds combined with SDF-1α gene therapy can provide enhanced pro-angiogenic response, suggesting a promising approach to overcome poor vasculature during wound healing.