Implantable Self-Powered Biofeedback Vagus Nerve Stimulator for Weight Control

项目摘要 最近在用于饮食和体重控制的神经调节方面的突破刺激了对以下方面的日益增长的兴趣： 开发新的抗肥胖策略。然而，实现有效、实时和免维护的 具有最小副作用的电神经调节仍然是一个主要的挑战。为了应对这一挑战， 该项目提出开发一种无电池，灵活，可植入的压电纳米发电机（NG）， 在迷走神经上产生闭环生物反馈电刺激（ES）以控制食物摄入 对胃部运动的反应。该项目建立在王（PI）和蔡（co-I）的合作基础上， 一种可植入的迷走神经刺激（VNS）装置，在大鼠中实现了有效的饮食和体重控制。 无电池和电子设备的VNS装置附着在胃表面，并产生替代性的电刺激。 电流（AC）ES仅在胃在食物摄入时移动时向迷走神经发出信号。 我们的初步研究表明，使用VNS装置的正常成年大鼠的体重增加减少了38 在100天的测试期内，与对照组相比，虽然这一功效值超过了大多数 同行报告，ES信号强度比通常使用的信号强度小1 - 2个数量级。我们 假设将闭环ES信号调谐到神经调节的典型水平可以进一步增加 减肥功效优于目前使用的非天然连续ES。为了验证这一假设， 最终将这种有趣的技术应用于临床，我们建议开发一种压电NG， 可调谐ES脉冲信号高达10 V，可响应胃痉挛，并在长时间内保持安全稳定， 术语植入。我们还将优化VNS装置的植入并验证闭环VNS 使用标准肥胖大鼠模型的有效性和优点。在具体目标1中，我们将开发一种生物材料- 基于柔性压电NG，可以响应模拟胃产生可调ES脉冲， 动作在特定目标2中，我们将评价NG在胃上的离体和体内生物相容性 的大鼠，并检查植入部位和体内输出与胃运动的相关性。在具体目标3中， 我们将量化和比较三种肥胖大鼠模型中两种肥胖大鼠的饮食和体重控制表现， 使用胃内NG进行VNS的不同策略：（1）电池供电的开环VNS;（2）NG启用的自 动力闭环VNS;（3）NG开关电池动力闭环VNS。 该项目将提供一种新型的生物材料为基础的VNS设备，是电池和电子免费的重量 控制本项目采用大鼠模型对新型VNS装置进行测试，为装置优化提供快速反馈， 和量化与ES信号相关的治疗功效。与植入相关的技术问题将 也要解决。我们将共同建立一个必不可少的生物和工程基础， 我们将迅速进入大型动物模型体内研究的下一步，最终导致人体试验。

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 foundation that will allow us to move rapidly to the next step of in vivo studies in large animal models, eventually leading to human trials.