Development of a VEGF-activated scaffold with enhanced angiogenic and neurogenic properties for chronic wound healing applications†

Chronic wounds remain in a state of disrupted healing, impeding neurite outgrowth from injured nerves and poor development of new blood vessels by angiogenesis. Current therapeutic approaches primarily focus on the restoration of vascularization and overlook the need of nerve regeneration for complete healing. Vascular endothelial growth factor (VEGF) is a critical growth factor supporting angiogenesis in wound healing, promoting vascularization and has also demonstrated neuro-protective capabilities in both central and peripheral nervous system. While the delivery of pro-regenerative recombinant growth factors has shown promise, gene delivery offers greater stability, reduced off-target side effects, diminished cytotoxicity, and lower production costs. In this context, the overarching goal of this study was to develop a VEGF-activated scaffold with the potential to provide a multifaceted response that enhances both angiogenesis and nerve repair in wound healing through the localized delivery of plasmid encoding VEGF (pVEGF) encapsulated within the GET peptide system. Initially, delivery of pVEGF/GET nanoparticles to dermal fibroblasts led to higher VEGF protein expression without a compromise in cell viability. Transfection of dermal fibroblasts and endothelial cells on the VEGF-activated scaffolds resulted in enhanced VEGF expression, improved endothelial cell migration and organization into vascular-like structures. Finally, the VEGF-activated scaffolds consistently displayed enhanced neurogenic ability through improved neurite outgrowth from neural cells in in vitro and ex vivo models. Taken together, the VEGF-activated scaffold demonstrates multifaceted outcomes through the induction of pro-angiogenic and neurogenic responses from dermal, vascular and neural cells, illustrating the potential of this platform for the healing of chronic wounds.