Abstract

Current clinical interventions for critical-sized nerve defects face dual challenges of inadequate microenvironmental guidance and passive regenerative response in synthetic neural interfaces. We present an electrotopographic nerve Guidance Conduit with triaxial architectural hierarchy that actively coordinates mechanoelectrical signaling, biochemical modulation, and directional axonotropism through self-sustained piezoelectric dynamics. The trilaminar architecture comprises: an inner piezoelectric PLL-PLLA nanofibrous layer generating endogenous electrical fields under physiological deformation while providing contact guidance via aligned grooves, a collagen-PLLA transitional layer maintaining mechanical compliance matching native perineurium, and an outer anisotropic keratin-gelatin cross-linked sheaths. In rat sciatic nerve defects, the conduit achieved accelerating functional recovery, outperforming autografts in myelinated axon density and motor endplate reinnervation. Through integrated transcriptomics and functional genomics, we identified a piezoelectric-triggered miR-30a-5p/PI3K-AKT axis driving BMSC neurodifferentiation . The directional electroactivity enhanced Schwann cell migration and axonal alignment precision. This work establishes a paradigm-shifting strategy for autologous neuromodulation by harnessing physiological motion-derived electromechanical energy, circumventing external power dependency while achieving spatiotemporal precision in neural repair. The self-sustaining therapeutic system holds translational promise for addressing critical challenges in long-gap nerve reconstruction.