Closed-loop neuroelectric control of emesis and gastric motility

胃轻瘫在美国有近80，000人的患病率，并且与显著的 包括慢性恶心和呕吐。目前控制恶心和呕吐的策略 在这个病人群体中，大多数是不成功的。闭环神经调节技术可以 可能为这些患者提供精确的治疗，因为恶心信号与 胃运动的生物电中断和迷走神经的电刺激可以增加胃运动的生物电中断和迷走神经的电刺激。 能动性拟议研究的目标是应用闭环技术，利用神经电 记录和刺激装置，以改善胃运动和抑制呕吐信号。我们将 最初在雪貂中进行临床前测试，以定制记录胃肌电的技术 发出信号并电刺激腹部迷走神经。雪貂将被使用，因为它是"黄金- 呕吐测试的“标准”模型，是少数常用的模型之一， 具有呕吐反射，这是实验室大鼠和小鼠所缺乏的。概念验证后 在雪貂中进行测试，我们将在小型猪中进行良好实验室规范（GLP）研究， 在临床试验前进行安全性试验。我们将完成以下三个目标：（1） 在雪貂体内建立柔性电极连接、记录和刺激参数。研究 将包括测试腹部迷走神经刺激和胃电描记术记录使用超， 精密激光图案化和纳米纤维增强的微袖和共形平面电极阵列; (2)测试雪貂呕吐闭环控制的有效性。动物将植入 用于清醒测试的迷走神经和胃电极。呕吐相关的胃反应将由 胃呕吐刺激以触发胃节律障碍和迷走神经的电刺激;和（3） 对电极植入物和腹部迷走神经电刺激进行GLP安全性测试， 迷你猪动物将植入迷走神经和胃电极，随后进行长期安全性试验。 测试，每天刺激迷走神经。完成我们的目标将产生基本的效力， 和安全性数据，以便向FDA提交试验用器械豁免（IDE）申请， 后续临床试点研究。这个项目意义重大，因为它针对的是一个未满足的治疗 需要患有顽固性胃轻瘫的患者，他们经历了高度厌恶的慢性恶心， 呕吐!

Gastroparesis has a prevalence of nearly 80,000 people in the USA and is associated with significant morbidity, including chronic nausea and vomiting. Current strategies to control nausea and vomiting in this patient group are largely unsuccessful. Closed-loop neuromodulation technology could potentially provide a precision therapy for these patients because nausea signaling is associated with bioelectric disruption of gastric motility and electrical stimulation of the vagus nerve can increase motility. The goal of the proposed research is to apply closed-loop technology using neuroelectric recording and stimulation devices to improve gastric motility and inhibit emetic signaling. We will initially conduct preclinical testing in ferrets to customize the technology to record gastric myoelectric signals and electrically stimulate the abdominal vagus. The ferret will be used because it is the “gold- standard” model for emesis testing by industry and is one of the few commonly used models that possesses an emetic reflex, which is lacking in laboratory rats and mice. After proof-of-concept testing in the ferret, we will perform a good laboratory practice (GLP) study in the minipig, a model species for safety testing prior to clinical trials. We will complete the following three Aims: (1) Establish flexible electrode attachment, recording, and stimulation parameters in the ferret. Studies will include testing abdominal vagus nerve stimulation and electrogastrography recording using ultra- precision laser-patterned, and nano-fiber reinforced micro-cuff and conformal planar electrode arrays; (2) Test the efficacy of closed-loop control of emesis in the ferret. Animals will be implanted with vagus and gastric electrodes for awake testing. Emetic-related gastric responses will be produced by gastric emetic stimuli to trigger gastric dysrhythmia and electrical stimulation of the vagus; and (3) Conduct GLP safety testing of electrode implants and abdominal vagus electrical stimulation in the minipig. Animals will be implanted with vagus and gastric electrodes followed by a long-term safety test, with daily stimulation of the vagus. Completion of our Aims will produce the essential efficacy and safety data to enable an Investigational Device Exemption (IDE) submission to the FDA for a subsequent clinical pilot study. This project is significant because it targets an unmet therapeutic need of patients with refractory gastroparesis who experience highly aversive chronic nausea and vomiting.!