Hybrid Drug-Eluting Microfluidic Neural Probe for Chronic Drug Infusion

皮质内脑机接口(BMI)提供了提供独立性和改进的 因神经损伤或疾病而导致严重运动功能障碍的个人的生活质量。尽管 BMI的硬件、软件和外科技术的进步，神经棘波活动的记录继续显示高 可变性和不可预测性，最终导致逐步退化。神经炎性组织反应 这会导致种植体周围的星形胶质细胞瘢痕形成和神经元突起退化，这一点被广泛认为 作为神经记录信号变异性和退化的主要原因。我们建议结合使用 减轻组织反应以提高神经记录质量和稳定性的方法。 我们的微流控/洗脱神经递送系统(MENDDS)结合了机械自适应 皮质内微电极植入与一种新型微流控辅助洗脱架构。一种微流控通道 嵌入在可渗透的聚合物纳米复合材料中，在U形转向之前沿着探头的长度延伸并 回到探测器的后端。通道的内容物通过聚合物扩散 纳米复合体的壁和组织。直接在植入部位给药有助于靶向控制 局部药物浓度，而不会使远端组织和器官暴露于有毒药物水平。微流控技术 洗脱允许植入物在植入物周围均匀分布治疗剂。有利的是，这 系统沿探头长度洗脱抗炎剂，而不会受到有限释放的影响 药物洗脱涂层的持续时间。这项提议将回答的关键问题是：本地的、慢性的(&gt；8周) 抗氧化剂洗脱从机械顺应性植入物抑制神经炎性反应，改善 神经元胞体靠近记录微电极，提高神经记录质量 保留与大脑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优化白藜芦醇的给药方案 以最大限度地提高神经记录质量，最大限度地减少神经炎症和不良的局部和外周影响。 然后我们将量化微流体辅助洗脱对慢性神经炎和神经的影响。 录制质量。此前的白藜芦醇相关研究发现，白藜芦醇具有广泛的治疗浓度范围 0-100微米，而定期全身给药的大剂量白藜芦醇与 有副作用，包括出血。我们努力确定最佳的白藜芦醇 在此范围内的浓度用于从MENDDS进行微流控辅助洗脱。我们将植入一枚MENDDS 装置植入216只SD大鼠的初级运动皮质，共分为6个浓度组，每组1， 2周或4周。渗透泵将用于驱动白藜芦醇溶液，范围从0-100微米到 方法微流控通道，L，流速0.25ug/∙h~(-1)。在整个植入期间，神经记录和 电化学阻抗谱测量将每周进行三次。神经元 植入物周围的密度和胶质瘢痕将通过死后免疫组织学进行量化。我们会 通过平衡浓度依赖关系的成本函数确定白藜芦醇的最佳浓度 神经记录和神经炎症的改善与HIGH潜在不良反应的成本 注意力集中或长时间给药。对于慢性给药实验，我们将植入100 微电极植入5只SD大鼠的初级运动皮质，持续2周或16周。 每组将被分配到1)带有微流控白藜芦醇洗脱的MENDDS探针，2)MENDDS 白藜芦醇腹膜腔内注射探头注射，3)无白藜芦醇输送的MENDDS探针，4)硅- 5)不注射白藜芦醇的NeuroNexus探头。我们的目标 目的是评价持续抗氧化剂扩散药物在机械顺应性种植体上的洗脱效果 界面对神经记录的质量和稳定性、神经炎症程度的影响。

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.