Ultrasound-driven in vivo electrical stimulation based on biodegradable piezoelectric nanogenerators for enhancing and monitoring the nerve tissue repair

In vivo electrical stimulation (ES) has shown great promise in promoting tissue repair for various tissue engineering applications. However, a significant limitation of current long-term ES technique is that the existing postoperative protocols with transcutaneous leads have great risk of infection and need second operation to remove the tethered electrical-interface. Herein, we explored an ultrasound-driven in vivo ES technique based on the biodegradable piezoelectric nanogenerator (PENG) without any transcutaneous leads for the repair of peripheral nerve injuries. The piezoelectric nanogenerator contains biodegradable piezoelectric materials, including potassium sodium niobate (KNN) nanowires, poly (L-lactic acid) (PLLA), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), biodegradable encapsulation layers, such as Poly (lactic acid) (PLA) or poly-ɛ-caprolactone (PCL) films, as well as biodegradable magnesium (Mg) electrodes and molybdenum (Mo) wires. Owing to the merits of ultrasound (US) in biomedical engineering, such as deep tissue penetration and predominant clinical security, US was selected as an exterior wireless energy source to drive the implantable nanogenerators which were fabricated with dissolvable piezoelectric films. With mechanical excitation remotely activated by programmable US pulses, the implanted piezoelectric nanogenerator can deliver adjustable ES to the biodegradable conductive conduits of peripheral nerves beyond the intraoperative period. Moreover, upon in-situ ES of the recovered nerves by the implanted nanogenerator, the nerve repairing process can be monitored in real-time with recorded muscle electrophysiology response. With a sciatic nerve injury model, our comprehensive investigation on neurologic function recovery analysis, histological assessment and microstructure analysis confirmed the great enhancement in nerve regeneration by the ultrasound-driven in vivo ES. This work provides a novel strategy with ultrasound-responsive biodegradable piezoelectric nanogenerator to deliver in vivo ES for tissue engineering applications.