Mechano-bioactive hydrogel bioelectronics for mechanical-electrical-bioenergetic conversion and glia-modulating neural regeneration

Dynamic mechanical cues are crucial for glial neuromodulation and energy metabolism in neural regeneration, yet the mechanisms underlying mechanotransduction and intracellular organelle responses in glia after neurotrauma remain vague. In this study, we develop mechano-bioactive piezoelectric hydrogel bioelectronics (BaTiO₃-embedded collagen-1 hydrogel) and investigate mechanotransduction in astrocytes and Schwann cells. Ultrasound-driven piezoelectric hydrogel bioelectronics exerts electrical signals from mechanical stimulation and upregulates PIEZO1 channel in astrocytes and PIEZO2 channel in Schwann cells. This mechanoelectrical conversion increases calcium influx to activate ATP synthase subunit and promote MFN/OPA1 mediated mitochondrial fusion. Consequently, it enhances ATP synthesis by forming an efficient energy network as a central bioenergetic hub to promote glia mediated neural repair. Furthermore, this mechano-bioactive piezoelectric hydrogel bioelectronics exhibits therapeutic efficacy for treating central and peripheral nervous injuries in multiple animal models (mice, rats, Beagle dogs, and Rhesus monkeys), demonstrating its wide adaptivity and significant translational potential. The findings elucidate a multilevel mechanobiological energy transduction (mechanical-electrical-bioenergetic conversion) design in neural repair as a promising clinical treatment mode.