Microelectrodes for Co-Localized Tunable Drug Delivery and Neural Recording

每年，成千上万的退伍军人经历神经损伤或疾病，导致严重的运动 功能障碍，对受影响的个人及其亲人造成毁灭性的后果。皮质内 脑-机接口（IBMIs）为恢复计算机的意志控制提供了一个令人信服的解决方案 光标、机械臂和功能性电刺激控制肢体。然而，iBMI功能 依赖于我们在留置微电极上检测神经信号的能力， 几十年这一要求受到植入物的生物学反应的挑战， 健康神经元和植入的微电极之间的通信。成功的iBMI临床 翻译，以及由此产生的用户功能独立性的收益，取决于提高质量 以及生物-非生物界面的稳定性。 用于皮质内微电极装置的标准材料是刚性材料，例如硅， 其可引起慢性组织损伤，从而加剧生物反应。一些团体已经发展出 柔性聚合物基装置，尽管这些通常需要加固以防止在 插入。局部药理学递送也可用于控制组织反应，但通常是 或者由于载药涂层耗尽而寿命很短，或者需要复杂和侵入性的流体系统。 我们的方法结合了先进的结构和微电极材料， 这是一种在不需要复杂的流体输送系统的情况下减弱炎症组织反应的方法。 一种机械自适应聚合物纳米复合材料（NC）， 插入皮质，但在插入后几分钟内急剧软化，以最大限度地减少慢性差异 组织应变高度有序的垂直取向的二氧化钛纳米管阵列（TNAs）将同时执行药物- 释放皮质内微电极记录位点。TNA是高度可调的材料， 储存的药物在数周至数月内缓慢扩散到组织中， by the nanotube纳米管geometries几何.化学掺杂工艺增强TNA电导率以促进感测 神经元活动我们假设，将柔软的结构材料与持续的抗炎剂相结合， 药物递送将导致组织反应和长期神经记录质量的协同改善。 我们将首先研究抗炎释放动力学和炎症反应之间的关系。 反应装置包括集成到NC中的TNA微段。地塞米松，抗- 炎性皮质类固醇将被加载到NC或TNA中，以提供快速和持续的治疗。 （>8周）释放曲线。将器械植入野生型小鼠体内，持续1、2、4或8天 周在每个时间点，将对两个实验性组织中的局部炎症标志物进行评价。 组和非释放和蔗糖释放对照。本研究将用于评估时间进程 的炎症反应的两种不同的释放曲线，并评估在体内从TNAs的DEX释放。 在第二项研究中，我们将利用TNAs的药物递送和电特性。 我们将使用TNA作为记录位点来制造具有记录功能的基于NC的神经探针， 哪种神经活动被检测到。将探针植入野生型小鼠的初级运动皮层， 16周在整个植入期间，神经活动、电化学阻抗和精细运动行为 将进行评估，随后对细胞类型进行死后定量。我们将评估 软材料、局部药物干预和微电极记录部位材料的贡献。 我们预期直接从记录位点持续（>8周）药理学释放将导致 神经记录稳定性的实质性改进，这将有助于推动iBMI技术向安全的方向发展。 临床应用长期可靠。

Each year, thousands of Veterans experience neurologic injury or disease resulting in severe motor dysfunction, with devastating consequences for the affected individual and their loved ones. Intracortical brain-machine interfaces (iBMIs) offer a compelling solution for restoring volitional control of computer cursors, robotic arms, and functional electrical stimulation-controlled limbs. However, iBMI functionality is reliant upon our ability to detect neuronal signals at indwelling microelectrodes for a period of years to decades. This requirement is challenged by the biological response to the implant, which impedes communication between healthy neurons and the implanted microelectrodes. Successful iBMI clinical translation, and the resulting gains in functional independence for users, hinges upon improving the quality and stability of the biotic-abiotic interface. The standard materials used for intracortical microelectrode devices are rigid materials, such as silicon, which can cause chronic tissue damage that exacerbates the biological response. Some groups have developed flexible polymer-based devices, though these usually require reinforcement to prevent buckling during insertion. Local pharmacologic delivery can also be used to control the tissue response, though is typically either short-lived as drug-loaded coatings are depleted, or requires complex and invasive fluidic systems. Our approach combines advanced structural and microelectrode materials to provide a two-pronged approach to attenuating the inflammatory tissue response without requiring complex fluidic delivery systems. A mechanically-adaptive polymer nanocomposite (NC) provides a structural material that is sufficiently stiff insert into the cortex, yet dramatically softens within minutes of insertion to minimize chronic differential tissue strain. Highly-ordered, vertically-oriented titania nanotube arrays (TNAs) will perform both drug- releasing intracortical microelectrode recording sites. TNAs are highly tunable materials that can efficiently store pharmacologic agents that slowly diffuse into tissue over weeks to months with a release profile governed by the nanotube geometries. Chemical doping processes enhance TNA conductivity to facilitate sensing neuronal activity. We hypothesize that combining soft structural materials with sustained anti-inflammatory drug delivery will lead to synergistic improvements in tissue response and long-term neural recording quality. We will first investigate the relationship between anti-inflammatory release kinetics and the inflammatory response. Devices comprise TNA microsegments integrated into the NC. Dexamethasone, a representative anti- inflammatory corticosteroid, will be loaded into either the NC or into the TNAs to provide rapid and sustained (>8 weeks) release profiles, respectively. Devices will be implanted into wild-type mice for up to 1, 2, 4 or 8 weeks. At each timepoint, local inflammatory markers in tissue will be evaluated for the two experimental groups and for non-releasing and sucrose-releasing controls. This study will be used to evaluate the time course of the inflammatory response to two different release profiles and assess in vivo DEX release from TNAs. In the second study, we will take advantage of both the drug delivery and electrical properties of the TNAs. We will fabricate NC-based neural probes with recording functionality using the TNAs as the recording sites at which neural activity is detected. Probes will be implanted into the primary motor cortex of wild-type mice for 16 weeks. Throughout the implant period, neural activity, electrochemical impedance, and fine motor behavior will be assessed, which will be followed by post-mortem quantification of cell types. We will evaluate the contributions of soft materials, local pharmacologic intervention, and microelectrode recording site material. We expect that sustained (>8 weeks) pharmacologic release directly from the recording sites will result in substantial improvements in neural recording stability that will help to advance iBMI technology toward safe clinical use with long-term reliability.