Ultrasound-activated piezoelectric muscle constructs for tissue-engineered regenerative peripheral nerve interfaces

Regenerative peripheral nerve interfaces (RPNIs) are emerging platforms capable to translate neural activity into controllable myoelectric signals. However, current clinical RPNIs rely on muscle autografts, limiting their scalability and extensive adoption. Here, we report a bioactive, ultrasound-responsive piezoelectric muscle biomaterial designed as a fully tissue-engineered alternative to autologous grafts. The construct consists of fibrinogen-based muscle tissues enriched with barium titanate nanoparticles (BTNPs, diameter∼60 nm) and supported by a biodegradable surgical membrane that promotes the formation of aligned, multinucleated myotubes. The incorporation of BTNPs imparts intrinsic piezoelectric activity to the construct, and the nanoparticles are taken up by developing myotubes, enabling remote mechanoelectrical tissue stimulation under low-intensity pulsed ultrasound (LIPUS). In vivo, piezoelectric constructs implanted around the rat peroneal nerve for two months undergo LIPUS-driven activation of internalized BTNPs, which enhances muscle maturation, and electromechanical responsiveness, yielding myoelectrical signals up to 3.2 mV upon nerve activation. Histological analyses confirm improved structural organization, increased desmin expression, and evidence of neovascularization and axonal regeneration within the engineered interface. These findings suggest that the piezoelectric constructs form stable, functional biointerfaces with peripheral nerves, and that LIPUS-driven activation of embedded BTNPs provides a non-invasive strategy to potentiate muscle development and signal transduction. This study positions LIPUS-responsive, engineered piezoelectric muscle constructs as a donor-free, bioactive platform alternative to traditional autografts for next-generation human-machine interfaces and regenerative bioelectronics.