Project Summary Recent breakthroughs in neuromodulation for diet and weight control have stimulated a growing interest in the development of new anti-obesity strategies. However, achieving effective, real-time, and maintenance-free electrical neuromodulation with minimal side effects remains a major challenge. To address this challenge, this project proposes to develop a battery-free, flexible, and implantable piezoelectric nanogenerator (NG) that produces closed-loop, biofeedback electrostimulation (ES) on the vagus nerves to control food intake in response to stomach motions. This project builds on the collaborative work by Wang (PI) and Cai (co-I) of an implantable vagus nerve stimulation (VNS) device, which achieved effective diet and weight control in rats. The battery- and electronics-free VNS device is attached to the stomach surface and generates alternative current (AC) ES signals to the vagus nerves only when the stomach moves upon food intake. Our preliminary study demonstrated 38% less weight gain on normal adult rats with the VNS device implantation as compared to controls over a 100-day testing period. Although this efficacy value surpassed most peer reports, the ES signal intensity was 1-2 orders of magnitude smaller compared to those typically used. We hypothesize that tuning the closed-loop ES signal to the typical level of neuromodulation may further increase weight loss efficacy outperforming the currently-used non-natural continuous ES. To test this hypothesis and eventually bring this intriguing technology to clinic, we propose to develop a piezoelectric NG that provides tunable ES pulse signals up to 10 V in response to stomach peristalsis, and remains safe and stable over long- term implantation. We will also optimize the implantation of the VNS device and validate the closed-loop VNS efficacy and advantages to using standard obese rat models. In Specific Aim 1, we will develop a biomaterial- based flexible piezoelectric NGs that can produce tunable ES pulses in response to simulated stomach movements. In Specific Aim 2, we will evaluate the biocompatibility of the NG ex vivo and in vivo on the stomach of rats, and examine implantation sites and in vivo outputs in correlation to stomach motions. In Specific Aim 3, we will quantify and compare the diet and weight control performances on two obese rat models among three different strategies of using on-stomach NGs for VNS: (1) battery-powered open-loop VNS; (2) NG-enabled self- powered closed-loop VNS; (3) NG-switched battery-powered closed-loop VNS. This project will deliver a novel biomaterial-based VNS device that is battery- and electronics-free for weight control. This project uses rat model to test the new VNS devices, providing rapid feedback for device optimization, and quantifying the therapeutic efficacy in correlation to ES signals. Implantation-related technical issues will also be addressed. Together, we will establish an essential biological and engineering f...