The role of an ultrasound-responsive injectable piezoelectric hydrogel in promoting nerve regeneration and alleviating neuropathic pain.

BACKGROUND: Neuropathic pain (NP) resulting from peripheral nerve injury (PNI) represents a major clinical challenge. Although electrical stimulation (ES) has demonstrated therapeutic benefits, its clinical translation is limited by the invasiveness of electrode implantation, which often requires large surgical incisions and percutaneous wiring, increasing tissue damage and infection risk. METHODS: This study developed an ultrasound-responsive, injectable, and biodegradable piezoelectric hydrogel (sPLLA-Gel) composed of electrospun poly-L-lactic acid (PLLA) and methacryloyl gelatin (GelMA). The physicochemical characteristics, biocompatibility, and piezoelectric performance were systematically evaluated. In vitro, ultrasound-activated sPLLA-Gel was examined for its ability to promote neural stem cell (NSC) differentiation and regulate macrophage polarization. In vivo, the hydrogel was injected into the sciatic nerve injury site of a chronic constriction injury (CCI) rat model, followed by behavioral, electrophysiological, histological, and transcriptomic analyses. RESULTS: The sPLLA-Gel hydrogel exhibited excellent injectability, biodegradability, and ultrasound-induced electrical responsiveness. In vitro studies confirmed its biocompatibility and demonstrated that ultrasound-activated sPLLA-Gel promoted neural stem cell differentiation, axon-like neurite outgrowth, and favorable macrophage polarization. In vivo, the hydrogel was injected into the injury site of a chronic constriction injury rat model. Behavioral and electrophysiological analyses revealed that ultrasound-stimulated sPLLA-Gel enhanced myelin and axon regeneration, improved motor function, and alleviated NP. These therapeutic effects correlated with reduced spinal glial cell activation and decreased pro-inflammatory cytokine expression. Transcriptomic analysis and further validation suggested that sPLLA-Gel's analgesic and neuroprotective effects may arise from the inhibition of TRPV1 expression and the NF-κB signaling pathway. CONCLUSIONS: This study demonstrates the potential of this ultrasound-responsive piezoelectric hydrogel to promote peripheral nerve regeneration and mitigate NP, offering a promising minimally invasive strategy for treating sciatic nerve injury-related NP.