Low-intensity pulsed ultrasound for peripheral nerve regeneration: mechanobiological mechanisms and translational potential

Peripheral nerve injury (PNI) remains a major clinical challenge, often resulting in incomplete functional recovery despite advances in microsurgical repair. Low-intensity pulsed ultrasound (LIPUS) has recently gained attention as a noninvasive biophysical therapy capable of enhancing nerve regeneration through mechanical stimulation and cellular activation. This review synthesizes current preclinical evidence on the effects of LIPUS across in vitro and in vivo models and outlines its underlying mechanobiological mechanisms and translational implications. A systematic search identified thirty-four experimental studies evaluating LIPUS in nerve injury models, including crush, transection, autograft, and conduit repair. Collectively, these studies demonstrate that LIPUS accelerates axonal regeneration, promotes remyelination, enhances Schwann cell proliferation and migration, and increases neurotrophic factor expression. LIPUS also facilitates neural stem cell differentiation and neuronal survival by activating key intracellular signaling pathways. Despite encouraging preclinical results, significant challenges remain in translating LIPUS to clinical practice. Variability in stimulation parameters, injury models, and species hampers reproducibility, and regulatory approval for neural applications is still pending. Future research should focus on standardizing dosimetry, validating mechanistic pathways in human tissues, and conducting multicenter clinical trials to establish safety, efficacy, and practical treatment guidelines. The current evidence supports LIPUS as a safe and adaptable mechanotransductive therapy that can modulate cellular behavior and molecular signaling to enhance peripheral nerve regeneration.