Biomimetic piezoelectric hydrogel system for energy metabolism reprogramming in spinal cord injury repair

Rationale: Spinal cord injury (SCI) leads to limited regenerative capacity and severe energy deficiency in the injury microenvironment. This study aimed to develop a biomimetic piezoelectric hydrogel system that could recapitulate the native tissue microenvironment while enabling wireless physical regulation for SCI repair. Methods: A piezoelectric hydrogel was fabricated by integrating K_0.5Na_0.5NbO₃ (KNN) nanoparticles with porous decellularized spinal cord matrix gel (pDG). The hydrogel's effects on vascular endothelial cell migration, neural stem cell differentiation, and ATP synthesis were evaluated in vitro. RNA sequencing was performed to identify key regulatory pathways. The therapeutic efficacy was assessed in a rat model of spinal cord hemisection, examining motor function and angiogenesis. Results: The piezoelectric hydrogel demonstrated excellent biocompatibility and significantly enhanced vascular endothelial cell and neural cell migration. Under ultrasonic stimulation, the hydrogel promoted neural stem cell differentiation into neurons more effectively than control hydrogels. The piezoelectric stimulation increased ATP synthesis and calcium ion flux, activating the Ca2+/Camk2b/PGC-1α signaling axis. In vivo studies showed that implantation of the piezoelectric hydrogel combined with ultrasound stimulation significantly improved motor function recovery and promoted angiogenesis. Conclusion: The piezoelectric hydrogel system presents an effective strategy for SCI repair through energy metabolism reprogramming and demonstrates promising potential in neural tissue engineering applications.