Project Summary: Muscle electrical stimulation (EStim) is a promising rehabilitation modality for denervated muscles after peripheral nerve injuries. Current muscle EStim devices have limited therapeutic efficacy due to the low EStim intensity they apply. Applying high-intensity EStim to muscles presents a significant challenge. This is because all current devices conduct electron currents. Electrochemical reactions are required to convert the electron currents to the ion currents at the device-tissue interface. These reactions can induce chemical changes and temperature increase that can damage tissues when the EStim intensity is high. Thus, there is a critical need for a new generation of muscle stimulators that can safely apply high-intensity EStim for efficacious preservation of denervated human muscles. The long-term goal is to develop efficacious EStim-based therapy to preserve denervated human muscles after peripheral nerve injuries. The overall objectives of this proposal is to develop a novel EStim device that can safely apply high-intensity EStim to improve the preservation of denervated muscles. In Specific Aim 1, we will determine the optimal EStim device design for safe application of high-intensity EStim. Our working hypothesis is that a wirelessly coupled, ion current-conducting hydrogel ionic circuit (HIC) device does not induce any electrochemical reactions, so it can minimize adverse effects when applying high-intensity EStim. In Specific Aim 2, we will determine the efficacy of high-intensity EStim applied by our device for the preservation of denervated muscles using a pre-clinical rat peripheral nerve injury model. Our working hypothesis is that high- intensity EStim can improve muscle preservation compared to the low-intensity EStim typically used in current studies. The sensory recovery, motor recovery and muscle quality will be evaluated. The rationale for this project is that the development of a wirelessly coupled, completely ion current-based stimulator will significantly increase the EStim intensity that can be applied without causing tissue damage. This will lead to improved muscle rehabilitation outcomes following peripheral nerve injury that is not possible with current stimulators. Our outcome will establish an optimal device design to enable safe and efficient high- intensity EStim application. We will also demonstrate the in vivo efficacy of high-intensity EStim protocol for muscle preservation. Our high impact project will provide a strong justification for further development and testing of our device for treating denervated human muscles following peripheral nerve injuries. This will ultimately lead to better rehabilitation outcomes and improved quality of life for patients suffering from peripheral nerve injury.