Sono-electro-mechanical therapy for peripheral nerve regeneration through piezoelectric nanotracts

Peripheral nerve injuries can cause serious health problems, even life-long disability. Although several engineering modalities have been developed for peripheral nerve regeneration, severe injuries that leave large gaps in peripheral nerves remain challenging to repair. Here, we report a biomaterial-based sono-electro-mechanical therapeutic system for long-gap peripheral nerve repair through harnessing both bioelectric and biomechanical modalities with neural regenerative potential. Applying implantable, biodegradable piezoelectric nanotracts composed of polycaprolactone (PCL) and polyvinylidene fluoride (PVDF), we show significant regenerative performance by the synergy of ultrasound-activated electric stimulation and nanotopography-based contact guidance. Specifically, using cell culture models, we demonstrate sono-electro-mechanical promotion of pro-regeneration Schwann cell functions and neuronal growth in vitro. Mimicking long nerve gaps in humans, we use a rat model with a 15 mm sciatic nerve defect and show restoration of complex motor functions and axonal maturity by our sono-electro-mechanical therapeutic system at levels comparable with standard-of-care autograft treatment in vivo. Together, this study provides a previously unappreciated multimodal engineering strategy with great potential for clinical treatment of long-gap peripheral nerve injuries.