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: 10701820
• 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/10701820
• 关键词: Acceleration; Acute; Adrenal Cortex Hormones; Affect; Animals; Anti-Inflammatory Agents; Area; Attenuated; Autopsy; Biological; Brain; Bypass; 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; Location; Mechanics; Methods; Microelectrodes; Motor; Motor Cortex; Muscle; Nanotubes; Nervous System; Nervous System Trauma; Neurons; Neurosciences; Occupations; Performance; Peripheral; Pharmaceutical Preparations; 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; 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; functional restoration; improved; in vivo; inflammatory marker; injured; innovation; interfacial; loved ones; mechanical properties; meter; motor behavior; motor deficit; motor disorder; nanocomposite; nanopolymer; nervous system disorder; neural; neural implant; neuroinflammation; neurotransmission; novel; pharmacologic; prevent; response; technology platform

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遭受神经系统损伤或疾病，导致严重运动 功能障碍，对受影响的个人及其亲人造成毁灭性后果。心脏内 脑机界面（IBMI）提供了一种令人信服的解决方案，用于恢复计算机的自愿控制 光标，机器人臂和功能性电刺激控制的肢体。但是，IBMI功能是 依靠我们检测到留置微电极上神经元信号多年的能力 几十年。这种要求受到对植入物的生物反应的挑战，这阻碍了 健康神经元与植入的微电极之间的通信。成功的IBMI临床 翻译，以及用户的功能独立性增长，取决于提高质量 和生物生物界面的稳定性。 用于皮质内微电极设备的标准材料是刚性材料，例如硅， 这会导致慢性组织损伤加剧生物学反应。一些小组已经发展 柔性聚合物的设备，尽管这些设备通常需要加固以防止在 插入。局部药理输送也可以用于控制组织反应，尽管通常是 短暂的作为吸毒涂料的短暂寿命会耗尽，或者需要复杂而侵入性的流体系统。 我们的方法结合了先进的结构和微电极材料，以提供两管 减轻炎症组织反应的方法，而无需复杂的流体递送系统。 机械自适应的聚合物纳米复合材料（NC）提供了足够硬的结构材料 插入皮质中，但在插入后几分钟内会大大变软，以最大程度地减少慢性差异 组织应变。高度排序的，垂直面向的钛纳米管阵列（TNA）将执行这两种药物 释放皮质内微电极记录位点。 TNA是高度可调的材料，可以有效 储存药理学剂，这些药理学剂在数周到几个月内缓慢扩散到组织中，释放曲线受控制 由纳米管几何形状。化学掺杂过程提高了TNA电导率以促进感应 神经元活性。我们假设将软结构材料与持续的抗炎作用相结合 药物输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与炎症之间的关系 回复。设备包含集成到NC中的TNA微膜片。地塞米松，代表性抗 炎性皮质类固醇将被加载到NC或TNA中，以提供快速持续的 （> 8周）分别释放轮廓。设备将植入最多1、2、4或8的野生型小鼠 几周。在每个时间点，将评估组织中局部炎症标志物的两个实验 组以及非释放和释放蔗糖的控制。这项研究将用于评估时间课程 对两个不同释放曲线的炎症反应，并评估从TNA中释放的体内DEX。 在第二项研究中，我们将利用TNA的药物输送和电性能。 我们将使用TNA作为记录功能作为记录位点的记录功能制造基于NC的神经探针 检测到哪些神经活动。探针将植入野生型小鼠的主要运动皮层中 16周。在整个植入期，神经活动，电化学阻抗和精细运动行为 将评估，随后是细胞类型的验尸定量。我们将评估 软材料，局部药理干预和微电极记录现场材料的贡献。 我们预计直接从记录站点释放（> 8周）的药理学释放将导致 神经记录稳定性的实质改善将有助于将IBMI技术推向安全 具有长期可靠性的临床用途。