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

基本信息

批准号：
10840055
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
项目类别：
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/10840055
关键词：
Abate Acceleration 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 Encapsulated Equilibrium Failure Goals Hemorrhage Hybrids Implant Implantable Pump Implanted Electrodes Individual Inflammatory Response Infusion procedures Integrated Delivery Systems Intraperitoneal Injections Length Limb structure Measurement Measures Mechanics Mediating Microelectrodes Microfluidics Motor Motor Cortex Muscle Nervous System Trauma Neurons Operative Surgical Procedures Organ Osmosis Output Oxidative Stress Performance Peripheral Permeability Pharmaceutical Preparations 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 brain machine interface clinical application cost density electric impedance experimental study field study image processing improved insight meter motor disorder nanocomposite nanopolymer nervous system disorder neural neural implant neuroinflammation neuronal cell body neurotransmission new technology nonhuman primate novel preclinical study preservation prevent programs response restoration robot control side effect

项目摘要

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.

皮质内脑机界面（BMI）提供了提供独立性和改善的承诺神经系统损伤或疾病引起的严重运动功能障碍的个体的生活质量。尽管 BMI的硬件，软件和手术进展，神经尖峰活动记录继续显示高可变性和不可预测性，并最终逐步退化。神经炎性组织反应这会导致星形胶质疤痕和神经元过程的降解被广泛考虑是神经记录信号变异性和降解的主要原因。我们建议将减轻组织反应以改善神经记录质量和稳定性的方法。我们的微流体/洗脱神经药物输送系统（MENDDS）结合了机械适应性的带有新型微流体辅助体系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探针的长度掉落之前，然后跑回探针的后端。通道通过聚合物扩散的内容纳米复合壁，直到组织。直接在植入地点输送药物，促进了针对性的控制局部药物浓度而不将远处的组织和器官暴露于有毒药物水平。微流体辅助洗脱允许植入物在植入物周围均匀分布治疗剂。有利地，这系统在探针的长度上洗脱了抗炎剂，而没有限制释放洗脱涂料的持续时间。该提案将回答的关键问题是：当地，慢性（> 8周）机械符合植入物的抗氧化剂洗脱会抑制神经炎症反应，改善靠近记录微电极附近的神经元细胞体，改善神经元记录质量，并保留与皮质植入区域相关的功能输出？为了洞悉此问题，我们将首先通过Mendds优化白藜芦醇交付资料为了最大程度地提高神经元记录质量并最大程度地减少神经炎症和不良局部和外周效应。然后，我们将量化微流体辅助洗脱对慢性神经炎症和神经的影响记录质量。先前与白藜芦醇相关的研究已经确定了广泛的治疗浓度范围 0 - 100 µm，而经常在系统地使用的大剂量的白藜芦醇已与具有不良副作用，包括出血。我们努力确定最佳白藜芦醇在此范围内的小流体辅助洗脱范围内的浓度。我们将植入一个门德设备进入六个浓度组的216个sprague-dawley大鼠的主要运动皮层，任何一个1 2，或4周。渗透泵将提供驱动白藜芦醇溶液，范围从0-100 µm通过以0.25 µL∙h-1的速率Mendds微流体通道。在植入物期间，神经记录和电化学阻抗光谱测量每周将进行三次。神经元植入物周围的密度和神经胶质疤痕将通过验尸后免疫组织学来量化。我们将通过成本函数确定最佳白藜芦醇浓度，以平衡浓度依赖性神经记录和神经炎症的改善与高潜在不利影响的成本浓度或延长给药。对于慢性交付实验，我们将植入100 Microelectrode Mendds进入5组Sprague-Dawley大鼠的主要运动皮层2或16周。每组将分配给1）用微流体辅助的白藜芦醇洗脱，2）Mendds Mendds探针白藜芦醇腹膜内（i.p.）注射探针，3）MENDDS探针，没有白藜芦醇递送，4）硅 - 基于i.p.的基于神经毒素探针注射，为5）神经毒素探针，没有白藜芦醇递送。我们的目标是评估持续的抗氧化剂扩散药物洗脱的作用关于神经元记录的质量和稳定性的接口，神经炎症的程度。