Engineering functional vasculatures to reconstruct sympathetic-parasympathetic circuits for bladder function after spinal cord injury.

Abstract

Spinal cord injury (SCI) leads to severe neurogenic bladder dysfunction, and its recovery highly depends on the restoration of bladder innervation of sympathetic-parasympathetic nerves. Stable blood perfusion is a prerequisite for sustaining neural regeneration, yet functional microvasculature rarely forms within injured spinal tissue. In this study, we engineered an integrating hydrogel-based spinal cord substitute to support vascularization through temporally staged angiogenic signaling combined with immune modulation. Early delivery of vascular endothelial growth factor (VEGF) promoted endothelial activation and sprouting, whereas delayed release of platelet-derived growth factor-bb (PDGFbb) supported pericyte recruitment and vessel maturation. Sustained immune modulation further stabilized nascent vasculature within the implanted segment. The spinal cord substitute supported the formation of structurally mature, non-leaky, and functionally perfused microvascular networks <i>in vivo</i>, accompanied by improved metabolic capacity within the implanted tissue. This vascularized environment enabled autonomic axonal regeneration, myelination, and synaptic organization, leading to re-engagement of bladder-related neural circuits and significant recovery of bladder function after SCI. These findings demonstrate that engineering functional vasculature within an implanted spinal cord substitute is sufficient to support tissue integration and selective autonomic recovery, establishing vascular reconstruction as a critical foundation for restoring complex neural functions after SCI.