A bioinspired anisotropic anti-inflammatory scaffold enhances spinal nerve regeneration and neural circuit reconstruction via FGF13/Ca2+/CaMK2A/CREB pathway

Spinal cord injury (SCI) induces severe neurological impairment, exacerbated by secondary inflammation and disrupted neural circuitry. Inspired by the spinal cord’s electromechanical microenvironment, we developed a biomimetic conductive nerve scaffold via directional freeze-casting of gelatin methacryloyl (GelMA) hydrogel incorporated with N-acetylcysteine-modified silver nanowires (NAC-AgNWs). The scaffold exhibits axially aligned microchannels, tunable mechanical strength, and conductivity akin to native spinal tissue. In a rat model of complete spinal cord transection (2 mm), the scaffold exhibited dual therapeutic effects: (1) early-stage anti-inflammatory modulation (mediated by the synergistic interplay between AgNWs and NAC), and (2) sustained neural reconstruction, evidenced by robust axonal bridging across the lesion, synapse reformation, and significant functional recovery. Integrated transcriptomic analyses revealed the FGF13/Ca 2+ /CaMK2A/CREB axis as the activated pathway driving neurite outgrowth and neural circuit reconstruction. This biomaterial design establishes a novel therapeutic paradigm for SCI repair, integrating structural guidance, immunomodulation, and activation of pro-regenerative signaling. • NAC-AgNWs enhance conductivity in an aligned, soft, biomimetic scaffold. • NAC-AgNWs synergistically drive anti-inflammatory M2 microglial polarization. • Functional recovery through novel FGF13/Ca 2+ /CaMK2A/CREB signaling activation. • Repair strategy integrating immunomodulation with electroactive neural guidance.