A hydrogel ionic circuit electrical stimulation system to restore denervated muscle following long-gap peripheral nerve injury.

Electrical stimulation (EStim) has been used to exercise denervated muscle pending nerve regeneration, to prevent muscle atrophy. However, higher EStim intensity is required to achieve maximal therapeutic efficacy, which is challenging because conventional electrodes generate heat and alter pH, potentially causing tissue damage. Here, we developed and utilized a novel hydrogel ionic circuit (HIC)-based EStim system that is ionically conductive and prevents tissue damage. This HIC was safely used to deliver a high EStim intensity of 32 mA both in vitro and in vivo without substantial cell death or tissue damage. The high EStim intensity promoted the differentiation of myoblasts into myotubes, increased growth factor production, and enhanced the release of extracellular vesicles. In a long-gap sciatic nerve rat model, high-intensity EStim reduced muscle atrophy, stabilized the neuromuscular junction, and upregulated regenerative proteins, while also promoting nerve regeneration. Conclusively, these findings demonstrate that the HIC provides a safe and effective platform for high-intensity EStim to enhance neuromuscular regeneration and functional recovery.