Optimized Electrical Block of Peripheral Nerves

优化周围神经电阻滞

• 批准号: 10583031
• 负责人: Warren M. Grill
• 金额: $ 45.71万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583031
• 关键词: Address; Algorithms; Anesthesia procedures; Animal Model; Animals; Autonomic Dysfunction; Axon; C Fiber; Cervical; Charge; Complex; Computer Models; Development; Diabetes Mellitus; Diameter; Discontinuous Capillary; Electric Stimulation; Electrodes; Elements; Engineering; Family suidae; Fiber; Frequencies; Geometry; Heart Rate; Heart failure; Horns; Human; Inflammation; Measures; Medical Device; Nature; Nerve; Nerve Block; Nerve Fibers; Neural Conduction; Outcome; Pain management; Performance; Peripheral; Peripheral Nerves; Physiologic pulse; Physiological; Rattus; Shapes; Signal Transduction; Technology; Testing; Training; Translations; Vagus nerve structure; autonomic nerve; bioelectronics; chronic pain management; clinical application; clinical translation; design; engineering design; experimental study; in vivo; in vivo evaluation; neural; neuroregulation; novel; particle; preclinical study; preservation; response; sciatic nerve; therapeutic target; tool

Electrical block of neural conduction has myriad potential clinical applications including treatment of pain and autonomic dysfunction such as heart failure, diabetes and inflammation. However, these therapeutic targets require block of small diameter myelinated Ad- and B-fibers and unmyelinated C-fibers, while the majority of prior studies of block were on block of large diameter myelinated Aa-fibers. The continued development of nerve block and its clinical translation are limited by: (1) the high energy required for conduction block, especially for the small diameter nerve fibers most relevant for bioelectronic therapies, (2) the strong excitatory response that occurs at the onset of blocking signals, which is likely to be exacerbated by the high block thresholds of small diameter axons, and (3) the lack of control over which specific nerve fibers are blocked, such that blocking small diameter axons also results in block of larger diameter axons. We propose rigorous engineering design to optimize the performance of nerve block waveforms and electrodes and in vivo testing of their performance in both small and large animals. Aim 1 is to optimize simultaneously the waveform and electrode geometry to meet each of three distinct performance criteria: minimize energy required for block, minimize onset response associated with the initiation of block, and enable selective block of small diameter axons (myelinated Ad- or B- fibers or unmyelinated C-fibers) while preserving conduction in large diameter Aa-fibers. We will combine validated computational models with engineering optimization via a particle swarm algorithm to design new waveform shapes and electrode geometries to achieve our performance metrics and thereby greatly increase the utility of nerve conduction block. In Aim 2, we will measure the responses of different types of nerve fibers (A-, B-, and C-fibers) in both the vagus nerve and the sciatic nerve of anesthetized rats to compare the performance of optimized block waveforms and electrode geometries to conventional waveform shapes (sinusoids, rectangular pulses) and electrode geometries (bipolar, tripolar) used for block of nerve fiber conduction. In Aim 3 we will measure both nerve fiber responses and physiological responses, including electromyograms and changes in heart rate, to block of the pig vagus nerve to quantify performance, including energy, onset response, and selectivity, in a large, multi-fascicular nerve that represents well human nerves. The outcomes will be novel waveforms and electrode geometries that overcome the performance limitations of current approaches to conduction block including the high energy requirements, the strong excitatory onset response, and the lack of control over which specific nerve fibers are blocked. These enhanced capabilities will advance electrical nerve block as an experimental tool and provide technologies to enable the continued translation of new bioelectronic therapies.

神经传导的电阻滞具有无数潜在的临床应用，包括治疗疼痛和 自主神经功能障碍，如心力衰竭、糖尿病和炎症。然而，这些治疗靶点 需要阻断小直径的有髓鞘的Ad-和B-纤维以及无髓鞘的C-纤维，而大多数先前的 阻断的研究是对大直径有髓Aa纤维的阻断。神经阻滞的继续发展 和其临床转化受到以下限制：（1）传导阻滞所需的高能量，特别是对于 与生物电子治疗最相关的小直径神经纤维，（2） 发生在阻塞信号的开始，这可能会因小的高阻塞阈值而加剧。 直径轴突，和（3）缺乏控制哪些特定的神经纤维被阻断，使得阻断小 直径的轴突也导致较大直径轴突的阻塞。我们提出严格的工程设计， 优化神经阻滞波形和电极的性能，并在体内测试它们的性能， 无论是小型还是大型动物。目标1是同时优化波形和电极几何形状，以满足 三个不同的性能标准：最小化阻滞所需的能量，最小化起始反应 与阻滞的起始相关，并且能够选择性阻滞小直径轴突（有髓鞘的Ad-或B- 纤维或无髓C纤维），同时保持大直径Aa纤维中的传导。我们将联合收割机 通过粒子群算法的工程优化验证计算模型， 波形形状和电极几何形状，以实现我们的性能指标，从而大大提高 神经传导阻滞的效用。在目标2中，我们将测量不同类型神经纤维的反应 (A-，B-和C-纤维），以比较 优化的块波形和电极几何形状与传统波形形状的性能 （正弦波、矩形脉冲）和电极几何形状（双极、三极）用于神经纤维阻滞 传导在目标3中，我们将测量神经纤维反应和生理反应，包括 肌电图和心率的变化，以阻断猪迷走神经来量化表现，包括 能量、起始反应和选择性，在一个大的、多分支的神经中，代表了很好的人类神经。 结果将是新的波形和电极几何形状，克服了性能限制， 目前传导阻滞的方法包括高能量要求、强兴奋性发作 反应，以及缺乏对特定神经纤维被阻断的控制。这些增强的能力将 推进电神经阻滞作为一种实验工具，并提供技术，使持续 新的生物电子疗法的翻译。