GelMA/PEDOT:DSS@H-ADSCs hydrogel enhances functional recovery after sciatic nerve injury via synergistic immunomodulation, angiogenesis, and neural remodeling

Peripheral nerve injury frequently causes neural tissue loss and impairs sensory and motor functions, resulting in significant clinical complications. The regenerative process is severely impeded by a hostile post-injury microenvironment characterized by prolonged inflammation, ischemia, and an absence of directional guidance. We developed an injectable, electrically conductive hydrogel by integrating poly(3,4-ethylenedioxythiophene) doped with dextran sulfate sodium (PEDOT:DSS) into a gelatin methacryloyl (GelMA) network to produce a GelMA/PEDOT: DSS (GP) hydrogel. The GP hydrogel demonstrated good injectability, biocompatibility, and stable electrical conductivity, serving as a three-dimensional electroactive matrix for neural regeneration. We further loaded this platform with hypoxia-preconditioned adipose-derived stem cells (H-ADSCs) to form a GP@H-ADSCs hydrogel. In a rat sciatic nerve crush injury model, the GP@H-ADSCs hydrogel more effectively coordinated multiple regenerative events than H-ADSCs alone. It polarized macrophages toward an M2 phenotype, enhanced angiogenesis and vascular maturation, activated Schwann cells, and promoted axonal regrowth and remyelination. Animal studies demonstrated that, compared with H-ADSCs alone, GP@H-ADSCs hydrogel treatment significantly improved electrophysiological recovery, restored sensory and motor functions, and attenuated denervation-induced muscle atrophy and fibrosis. These findings demonstrate an integrated strategy that combines an electroconductive hydrogel with preconditioned stem cells to modulate the regenerative microenvironment, enabling both structural and functional repair of peripheral nerves. This platform offers a more effective bioactive strategy for peripheral nerve repair than H-ADSCs alone.