Hybrid Drug-Eluting Microfluidic Neural Probe for Chronic Drug Infusion

用于慢性药物输注的混合药物洗脱微流控神经探针

• 批准号: 10356848
• 负责人: Jeffrey R Capadona
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356848
• 关键词: Abate; Address; Adverse effects; Affect; Anti-Inflammatory Agents; Antioxidants; Architecture; Attenuated; Autopsy; Back; Chronic; Cicatrix; Clinical; Computer software; Computers; Concentration measurement; Data Set; Deep Brain Stimulation; Detection; Development; Devices; Diffuse; Diffusion; Disease; Distant; Dose; Drug Delivery Systems; Electrodes; Equilibrium; Failure; Goals; Hemorrhage; Hybrids; Implant; Individual; Inflammatory Response; Infusion procedures; Injections; Lead; Length; Limb structure; Measurement; Measures; Mechanics; Mediating; Microelectrodes; Microfluidics; Motor; Motor Cortex; Muscle; Nervous System Trauma; Neurons; Operative Surgical Procedures; Organ; Output; Oxidative Stress; Performance; Peripheral; Permeability; Pharmaceutical Preparations; Polymers; Process; Pump; Quadriplegia; Quality of life; Reporting; Research; Resolution; Resveratrol; Risk; Robotics; Rodent; Running; Safety; Sensory; Signal Transduction; Silicon; Site; Source; Spinal cord injury; Sprague-Dawley Rats; Support System; System; Technology; Therapeutic; Therapeutic Agents; Thinking; Time; Tissues; Transport Process; Traumatic injury; Veterans; arm; base; brain machine interface; clinical application; cost; density; electric impedance; experimental study; field study; image processing; improved; insight; intraperitoneal; motor disorder; nanocomposite; nervous system disorder; neural implant; neuroinflammation; neuronal cell body; neurotransmission; new technology; novel; preclinical study; preservation; prevent; programs; relating to nervous system; response; restoration; robot control; side effect

Intracortical brain-machine interfaces (BMIs) offer the promise of providing independence and an improved quality of life to individuals with severe motor dysfunction resulting from neurologic injury or disease. Despite hardware, software, and surgical advances for BMIs, neural spike activity recordings continue to show high variability and unpredictability and ultimately progressive degradation. A neuroinflammatory tissue response that results in astroglial scarring and neuronal process degradation surrounding the implants is widely regarded as a primary cause of neural recording signal variability and degradation. We propose to use a combination of approaches to mitigate the tissue response to improve neural recording quality and stability. Our Microfluidic/Eluting Neural Drug Delivery System (MENDDS) incorporates a mechanically-adaptive intracortical microelectrode implant with a novel microfluidic-aided eluting architecture. A microfluidic channel embedded within a permeable polymer nanocomposite runs down the length of the probe before U-turning and running back up to the back end of the probe. The contents of the channel diffuse through the polymer nanocomposite walls and out to tissue. Drug delivery directly at the implant site facilitates targeted control of local drug concentration without exposing distant tissue and organs to toxic drug levels. Microfluidic-aided elution allows the implant to distribute therapeutic agents uniformly around the implant. Advantageously, this system elutes anti-inflammatory agents along the length of the probe without suffering from the limited release duration of drug-eluting coatings. The key question this proposal will answer is: does local, chronic (>8 week) anti-oxidant elution from a mechanically-compliant implant inhibit the neuroinflammatory response, improve proximity of neuronal cell bodies near to recording microelectrodes, improve neural recording quality, and preserve functional outputs associated with the implanted region of the cortex? To provide insight into this question, we will first optimize resveratrol delivery profile through the MENDDS to maximize neural recording quality and minimize neuroinflammation and adverse local and peripheral effects. We will then quantify the impact of microfluidic-aided elution on chronic neuroinflammation and neural recording quality. Previous resveratrol-related studies have identified a wide therapeutic concentration range of 0 – 100 µM, while large doses of resveratrol that are regularly administered systemically have been associated with adverse side effects, including hemorrhaging. We endeavor to determine an optimal resveratrol concentration within this range for microfluidic-aided elution from the MENDDS. We will implant one MENDDS device into the primary motor cortex of 216 Sprague-Dawley rats across six concentration groups for either 1, 2, or 4 weeks. An osmotic pump will serve drive resveratrol solutions ranging from 0 - 100 µM through the MENDDS microfluidic channel at a rate 0.25 µL∙h-1. Throughout the implant period, neural recording and electrochemical impedance spectra measurement sessions will take place three times weekly. Neuronal density and glial scarring around the implant will be quantified with post-mortem immunohistology. We will determine the optimal resveratrol concentration via a cost function that balances concentration-dependent improvements in neural recording and neuroinflammation versus costs of potential adverse effects of high concentration or prolonged administration. For the chronic delivery experiments, we will implant 100 microelectrode MENDDS into the primary motor cortex of 5 sets of Sprague-Dawley rats for 2 or 16 weeks. Each set will either be assigned to 1) MENDDS probe with microfluidic-aided resveratrol elution, 2) MENDDS probe with resveratrol intraperitoneal (I.P.) injection, 3) MENDDS probe with no resveratrol delivery, 4) silicon- based NeuroNexus probe with I.P. injection, of 5) NeuroNexus probe with no resveratrol delivery. Our objective is to evaluate the effects of sustained anti-oxidant diffuse drug elution at the mechanically-compliant implant interface on the quality and stability of neural recording, the degree of neuroinflammation.

皮质内脑机接口（BMI）提供了提供独立性和改进的 生活质量的严重运动功能障碍的个人造成的神经损伤或疾病。尽管 硬件，软件和手术的进步，神经尖峰活动记录继续显示高 可变性和不可预测性以及最终的逐步退化。一种神经炎症组织反应 导致植入物周围星形胶质细胞瘢痕形成和神经元突起退化的 作为神经记录信号可变性和退化的主要原因。我们建议使用以下组合 减轻组织反应以提高神经记录质量和稳定性的方法。 我们的微流体/洗脱神经药物递送系统（MENDDS）结合了机械自适应 具有新型微流体辅助洗脱结构的皮质内微电极植入物。微流体通道 嵌入在可渗透的聚合物纳米复合材料中的纳米颗粒在U形转弯之前沿着探针的长度延伸， 流回探测器的后端通道的内容物通过聚合物扩散 纳米复合材料壁和组织。直接在植入部位给药有助于靶向控制 局部药物浓度，而不会使远处组织和器官暴露于毒性药物水平。微流体辅助 洗脱允许植入物将治疗剂均匀地分布在植入物周围。有利地，这 系统沿着探针的长度洗脱抗炎剂， 药物洗脱涂层的持续时间。该提案将回答的关键问题是：局部慢性（>8周） 从机械顺应性植入物中洗脱的抗氧化剂抑制神经炎症反应，改善 神经元细胞体靠近记录微电极，改善神经记录质量，以及 保留与皮质植入区域相关的功能输出？ 为了深入了解这个问题，我们将首先通过MENDDS优化白藜芦醇的传递特性 以最大化神经记录质量并最小化神经炎症和不利的局部和外周效应。 然后，我们将量化微流体辅助洗脱对慢性神经炎症和神经系统炎症的影响。 录音质量。以前的白藜芦醇相关研究已经确定了广泛的治疗浓度范围， 0 - 100 µM，而大剂量的白藜芦醇，定期全身给药， 有不良副作用包括衰老我们奋进确定最佳的白藜芦醇 在此范围内的浓度用于从MENDDS的微流体辅助洗脱。我们将植入一个MENDDS 将装置植入6个浓度组的216只Sprague-Dawley大鼠的初级运动皮层， 两到四周。渗透泵将用于驱动范围为0 - 100 µM的白藜芦醇溶液通过 MEDDS微流体通道以0.25 µL·h-1的速率。在整个植入期间，神经记录和 电化学阻抗谱测量会议将每周进行三次。神经元 植入物周围的密度和神经胶质瘢痕将用死后免疫组织学定量。我们将 通过平衡浓度依赖性的成本函数确定最佳白藜芦醇浓度 神经记录和神经炎症的改善与高剂量的潜在不良反应的成本 浓度或延长给药。对于慢性分娩实验，我们将植入100个 将微电极MEDDS植入5组Sprague-Dawley大鼠的初级运动皮层2或16周。 每组将分配给1）具有微流体辅助白藜芦醇洗脱的MENDDS探针，2）MENDDS 腹腔注射白藜芦醇（I. P.）注射，3）没有白藜芦醇递送的MENDDS探针，4）硅- 5）没有白藜芦醇递送的NeuroNexus探针。我们的目标 是为了评价在机械顺应性植入物处持续抗氧化剂扩散药物洗脱的效果 界面对神经记录的质量和稳定性、神经炎症程度的影响。