Spinal cord injury (SCI) is a severe neurological disease resulting in the formation of a harsh microenvironment that hinders neural regeneration. By preserving the components and structure of natural tissues, the decellularized extracellular matrix (dECM) mimics the neural regeneration microenvironment and provides the biochemical signals and structural support for neural regeneration. However, the regenerated neurons lack the ability to autonomously restore neural communication. In this study, we assemble the conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) within spinal cord-derived decellularized extracellular matrix (pdECM) to construct a novel pdECM-based conductive hydrogel for enhancing neural communication among regenerated neurons via biochemical and bioelectrical signaling. This conductive hydrogel induces the differentiation of neural stem cells into neurons, modulates cellular membrane potential, enhances 4-fold cellular calcium activity in neural cells, upregulates expression of calcium-dependent signaling genes, and stimulates BDNF expression. In SCI mice model, the conductive hydrogel promotes endogenous neural regeneration, and sustained activates the secretion of neurotrophic factors and calcium-dependent signaling pathways for enhancing neural communication, thereby accelerating motor function recovery. This study addresses the challenge of neural communication among regenerated neurons by activating calcium-dependent signals, providing a novel strategy for the treatment of SCI through integrated biochemical and bioelectrical signaling.
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