Microelectrodes for Co-Localized Tunable Drug Delivery and Neural Recording

用于共定位可调谐药物输送和神经记录的微电极

• 批准号: 10538836
• 负责人: Allison Hess Dunning
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538836
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Animals; Anti-Inflammatory Agents; Area; Attenuated; Autopsy; Biological; Brain; Caring; Chemicals; Chronic; Clinical; Communication; Complex; Computers; Data; Devices; Dexamethasone; Diffuse; Disease; Drug Delivery Systems; Environment; Geometry; Harvest; Implant; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Kinetics; Label; Life; Limb structure; Liquid substance; Location; Mechanics; Methods; Microelectrodes; Motor; Motor Cortex; Muscle; Nanotubes; Nervous System Trauma; Nervous system structure; Neurons; Neurosciences; Occupations; Performance; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Polymers; Process; Property; Psychological reinforcement; Pump; Robotics; Self Care; Signal Transduction; Silicon; Site; Social Interaction; Specificity; Spinal cord injury; Structure; Sucrose; Surface; System; Technology; Testing; Therapeutic; Time; Tissues; Titania; Translations; Transportation; United States Department of Veterans Affairs; Veterans; Volition; Wild Type Mouse; arm; astrogliosis; base; biological systems; brain machine interface; brain tissue; cell type; clinical application; clinical translation; disability; electric impedance; electrical property; experience; experimental group; flexibility; functional electrical stimulation; functional independence; improved; in vivo; inflammatory marker; injured; innovation; interfacial; loved ones; mechanical properties; motor behavior; motor deficit; motor disorder; nanocomposite; nervous system disorder; neural implant; neuroinflammation; neurotransmission; novel; prevent; relating to nervous system; response

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.

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后果。皮质内 脑机接口(IBMI)为恢复计算机的意志控制提供了一个引人注目的解决方案 光标、机械臂和功能性电刺激控制的肢体。但是，iBMI功能是 依靠我们在留置微电极上检测神经元信号的能力 几十年。这一要求受到了植入物的生物反应的挑战，这阻碍了 健康神经元和植入的微电极之间的通讯。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， 这会导致慢性组织损伤，从而加剧生物反应。一些团体已经发展起来 灵活的基于聚合物的装置，尽管这些装置通常需要加固以防止在 插入。局部药物传递也可以用来控制组织反应，尽管通常是 要么是因为载药涂层耗尽而寿命很短，要么是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，提供了双管齐下的 无需复杂的流体输送系统即可减轻炎症组织反应的方法。 一种机械适应性聚合物纳米复合材料(NC)提供了一种足够坚硬的结构材料 插入皮质，但在插入后几分钟内显著软化，以最大限度地减少慢性差异 组织拉伤。高度有序、垂直取向的二氧化钛纳米管阵列(TNA)将执行两种药物- 释放皮质内微电极记录部位。TNA是高度可调的材料，可以高效地 储存药剂，在几周到几个月内缓慢扩散到组织中，并控制释放情况 通过纳米管的几何形状。化学掺杂工艺提高TNA的导电性以促进传感 神经元活动。我们假设将柔软的结构材料与持续消炎相结合 药物释放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与炎症反应的关系。 回应。设备包括集成到NC中的TNA微段。地塞米松，具有代表性的抗肿瘤药物 炎性皮质类固醇，将被加载到NC或TNAS中，以提供快速和持续的 (&gt；8周)发布配置文件。设备将被植入野生型小鼠体内，最长可达1，2，4或8只 几周。在每个时间点，组织中的局部炎症标志物将被评估为两个实验 不释放组和不释放蔗糖对照组。这项研究将用于评估时间进程 研究两种不同释药模式的炎症反应，并评估TNAS体内地塞米松的释放量。 在第二项研究中，我们将利用TNAs的药物输送和电学特性。 我们将使用TNAS作为记录地点来制造具有记录功能的基于NC的神经探针，请参见 被检测到的神经活动。将把探针植入野生型小鼠的初级运动皮质 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，随后将对细胞类型进行尸检量化。我们将评估 软性材料、局部药物干预和微电极记录部位材料的贡献。 我们预计，直接从记录地点进行的持续(8周)药物释放将导致 神经记录稳定性的实质性改善将有助于将iBMI技术推向安全 临床使用具有长期可靠性。