Ultrasound-activated piezoelectric hydrogel promotes functional muscle repair by orchestrating myogenesis and reinnervation

Volumetric muscle loss (VML) is a debilitating condition characterized by traumatic tissue loss and a subsequent failure of regeneration, resulting in permanent structural and functional deficits. The microenvironment of VML is characterized by a loss of regenerative cues and supportive infrastructure, which disrupts the coordinated cellular processes of muscle differentiation and nerve integration. Electrical stimulation is a potential therapeutic intervention for VML. Here, we developed a wireless electrotherapy strategy using an injectable, conductive, and piezoelectric KOCC hydrogel for the functional recovery of VML. The hydrogel was engineered by incorporating lead-free piezoelectric (K, Na) NbO₃ (KNN) nanoparticles into a dynamically crosslinked network of oxidized sodium alginate and chitosan hydrochloride and calcium ion. Upon exposure to ultrasound (US), the KOCC hydrogel generated controllable, localized electrical fields without the need for implanted electrodes or external wire connections. In vitro and in vivo experiments demonstrated that US-stimulated electrical signaling promoted myogenic differentiation, enhanced nerve regeneration and neuromuscular junction formation, and reduced excessive inflammation and fibrosis, which ultimately led to functional improvement in a murine VML model. These results demonstrate the potential of this wireless, US-responsive piezoelectric platform for VML treatment by orchestrating myogenesis and nerve reinnervation.