Low-intensity focused ultrasound-activated piezoelectric gel bandage for diabetic wound repair and neuropathic pain relief.

Nociceptive hypersensitivity and prolonged wound healing due to the interaction of peripheral neuropathy and local immune disorders are key issues that need to be addressed in diabetic foot ulcer (DFU) regenerative repair. Here, we present a low-intensity focused ultrasound (LIFU)-activated piezoelectric gel bandage for DFU wound repair and neuropathic pain relief. Acting as an artificial "skin", this self-powered, functionalized bandage not only temporarily shields tissue from external environment, but also serves as a drug reservoir that can in situ release nitric oxide upon LIFU to promote macrophage polarization, generate piezoelectric current to desensitize TRPV1 nociceptor for on demand neuropathic pain relief and produce reactive oxygen species to eliminate pathogens in male rodents. More importantly, this regimen can promote CGRP neuropeptides release from sensory neurons to invigorate M2-like macrophages-mediated protective cutaneous immunity. This LIFU-activated immune-nociceptor modulation strategy is potentially applicable to other non-healing tissue regeneration.