Injectable Fiber-Hydrogel Hybrid Scaffolds for Localized Growth Factor Delivery and Modulation of Vascular and Neuronal Cell Responses

Ischemic stroke is a leading cause of mortality and long-term disability worldwide and is characterized by neuronal loss, vascular impairment, and limited endogenous repair. Recovery after ischemic injury requires coordinated vascular and neural responses. However, the unfavorable post-stroke microenvironment, rapid loss of trophic factors, and poor retention of therapeutic proteins remain major barriers to tissue regeneration. Here, we developed an injectable hierarchical fiber-hydrogel hybrid scaffold for localized delivery of angiogenic and neurotrophic factors. Core-shell gelatin methacryloyl/polycaprolactone (GelMA/PCL) electrospun nanofibers were fabricated by coaxial electrospinning, in which vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF) were encapsulated within the GelMA core, while PCL served as the outer shell. The growth factor-loaded nanofibers were then processed into short fibers and incorporated into a VEGF-containing hydrogel matrix composed of thiol-modified hyaluronic acid/heparin and gelatin. The resulting hybrid scaffold combined an injectable hydrogel network with embedded fibrous components and provided localized release of VEGF and GDNF. In vitro studies showed that the hybrid scaffold promoted endothelial cell migration, supported endothelial cell growth, and maintained angiogenic activity under oxygen-glucose deprivation (OGD) conditions. In addition, the scaffold enhanced SH-SY5Y cell growth and supported PC12 neurite outgrowth. By integrating hydrogel-based injectable support, and localized trophic factor delivery, this scaffold provides a biomaterial platform for modulating vascular and neuronal cell responses under ischemia-mimicking conditions, which is promising for recovery after ischemic injury.