Wireless Nerve Stimulation Device To Enhance Recovery After Stroke

摘要 中风非常普遍，使人虚弱，而且缺乏一贯有效的损伤后干预措施。我们有 开发了一种创新的技术，使用在康复期间提供的迷走神经刺激(VNS)进行 增强神经调节回路的可塑性，改善中风后运动和感觉功能的恢复。 我们的临床前研究结果表明，VNS结合康复训练可促进多发性硬化患者的康复。 神经损伤模型，包括缺血性中风、脑出血、创伤性脑损伤和 脊髓损伤。此外，我们最近在慢性中风患者中进行的两项临床研究表明，VNS是安全的 与没有康复的康复相比，上肢功能的恢复显著增加了三倍 VNS。 虽然科学和临床证据令人鼓舞，但用于执行这些研究的VNS设备是 基本上受限于不灵活的刺激模式、铅的脆弱性、电池续航时间有限、大尺寸和高 成本。这些技术限制阻碍了这种潜在的变革性疗法的有效翻译。我们 已经开发出一种新型的低成本、临床级VNS系统，可以弥补这些不足。系统 由一个微型无线、无铅、被动植入式刺激器组成，放置在迷走神经上，并 控制植入式刺激器的外部电源和通信模块。植入型装置 使用FDA批准的用于人类的材料的自动化工艺在晶片级制造 使用和MRI兼容，从而提供可靠性并将成本降低为商用产品的1/25 设备。植入式刺激器被密封地封装在生物兼容玻璃中，体积小50倍 比现有的VNS设备更低，降低了植入手术的侵袭性。而且，植入的装置是 无源和从外部模块获取电力，消除了对笨重的植入电池的需要，并 更换电池的外科翻修。所需的大部分测试已经完成，但最终验证和 验证是允许IDE提交和临床评估所必需的。 在这份提案中，我们概述了一系列关键步骤，以将这一强大、经济高效的设备转化为 切实改善中风患者的生活。在UG3阶段，我们将最终完成验证和确认 并创建设计历史文件。此外，我们将在一项 慢性大型动物研究和最终确定包装无菌测试。一旦完成，我们将获得批准 艾德。在UH3阶段，我们将进行双盲、随机、安慰剂对照的交叉研究，以 评价VNS治疗系统在慢性卒中患者中的应用。该项目的成功完成将推动这一进程 该设备即将转化为人体试验，直接专注于随后的关键试验。

ABSTRACT Stroke is highly prevalent, debilitating, and lacks consistently effective post-injury interventions. We have developed an innovative technique using vagus nerve stimulation (VNS) delivered during rehabilitation to engage plasticity-enhancing neuromodulatory circuits and improve recovery of motor and sensory function after stroke. Our preclinical findings demonstrate that VNS paired with rehabilitative training enhances recovery in multiple models of neurological injury, including ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. Moreover, our two recent clinical studies in chronic stroke patients indicate that VNS is safe and yields a significant three-fold increase in recovery of upper limb function compared to rehabilitation without VNS. While the scientific and clinical evidence is encouraging, the VNS device used to perform these studies is substantially limited by an inflexible stimulation paradigm, lead fragility, limited battery life, large size, and high cost. These technical limitations preclude effective translation of this potentially transformative therapy. We have developed a novel low-cost, clinical-grade VNS system that obviates these deficiencies. The system consists of a miniature wireless, lead-less, passive implantable stimulator that is placed on the vagus nerve and an external power and communications module that controls the implantable stimulator. The implantable device is manufactured at the wafer level using an automated process with materials that are FDA-approved for human use and MRI-compatible, thus providing reliability and lowering cost 25-fold compared to commercially-available devices. The implantable stimulator is hermetically encapsulated in biocompatible glass and is 50 times smaller than existing VNS devices, reducing the invasiveness of the implant surgery. Moreover, the implanted device is passive and harvests power from the external module, eliminating the need for a bulky implanted battery and surgical revision for battery replacement. Much of the required testing is complete, but final verification and validation is necessary to allow IDE submission and clinical evaluation. In this proposal, we outline a series of critical steps to translate this robust, cost-effective device to provide tangible improvements in the lives of stroke patients. In the UG3 phase, we will finalize verification and validation of the embedded software and create a design history file. Additionally, we will confirm biocompatibility in a chronic large animal study and finalize package sterility testing. Once complete, we will gain approval for an IDE. In the UH3 phase, we will perform a double-blind, randomized, placebo-controlled crossover study to evaluate the VNS therapy system in chronic stroke patients. Successful completion of this project will move this device from the verge of translation into human trials with a direct focus on a subsequent pivotal trial.