RR&D Research Career Scientist Award Application

基本信息

批准号：
10533265
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：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533265
关键词：
Activities of Daily Living Affect American Amputees Amyotrophic Lateral Sclerosis Animal Model Animals Anti-Inflammatory Agents Antioxidants Architecture Area Attenuated Award Bathing Behavior Biocompatible Materials Biological Biomimetics Brain Caregivers Cells Central Nervous System Cervical Cervical spinal cord injury Chemistry Chronic Clinical Computers Corrosives Coupled Dedications Deep Brain Stimulation Department of Defense Detection Devices Disabled Persons Disease Electrodes Endotoxins Engineering Enzymes Failure Geometry Goals Healthcare Immobilization Immunity Implant Individual Infiltration Inflammation Inflammatory Inflammatory Infiltrate Injury Investigation Journals Laboratories Life Expectancy Limb Prosthesis Literature Longevity Lower Extremity Macrophage Manuscripts Mechanics Mediating Methods Microelectrodes Microglia Military Personnel Mission Modeling Modulus Motion Movement Muscle Myeloid Cells Names Nanotechnology Natural Immunity Nature Nerve Degeneration Neurons Neurosciences Osmosis Outcome Oxidative Stress Paralysed Pathway interactions Patients Peer Review Performance Persons Pharmaceutical Preparations Play Polymers Privatization Process Publishing Quadriplegia Quality of life Recovery Rehabilitation therapy Reporting Research Research Personnel Resolution Robotics Role Science Scientist Seizures Self-Help Devices Seminal Services Shunt Device Signal Transduction Source Specificity Spinal cord injury Spinal cord injury patients Sterility Stroke Structure Surface System Technology Therapeutic Thinking Time Tissues Toll-Like Receptor Pathway Treatment Protocols United States National Institutes of Health Upper Extremity Ventricular Veterans Work antioxidant therapy arm arm movement biomacromolecule blood-brain barrier permeabilization brain machine interface career clinical application communication device disability experience falls feeding functional electrical stimulation implantable device implantation improved indexing injured interest limb loss materials science mechanical device metallicity mimetics nanocomposite nanopolymer nervous system disorder neural neuroinflammation neuroprotection neurotransmission novel receptor response restoration

项目摘要

Overall goals: My laboratory is dedicated to understanding and mitigating the neuroinflammatory response to implanted devices within the central nervous system. Such devices range from ventricular shunts to various types of stimulating and recording electrodes. Neural devices range in material type, size, architecture, function, and placement. Regardless of any of these variables, the neuroinflammatory response to the implant plays a significant role on the integrity of the healthy tissue and the longevity of device performance. A progressive decline in recordings quality after implantation has been known for over 40 years. Unfortunately, recording instability is still a commonly documented problem. A major portion of my work has focused on studying various aspects of intracortical microelectrode performance, and pursuing both materials-based and therapeutic-based methods to mitigate the inflammatory-mediated intracortical microelectrode failure mechanisms. Areas include: 1) Role of tissue/device mechanical mismatch on microelectrode failure. I have developed biologically- inspired, mechanically-dynamic intracortical microelectrodes based on their polymer nanocomposite material. Enabled by the novel material system, I am able to independently examine and manipulate device modulus, geometry, and drug-eluting capabilities. Over the past ten years, my team has successfully demonstrated that mechanically-dynamic polymer-based intracortical microelectrodes are stiff enough to be inserted into the brain, become compliant to reduce micro-motion and inhibit late-stage neuroinflammatory responses, and can be fabricated into functional intracortical microelectrodes capable of recording from neural structures in live animals. We have also recently demonstrated that mechanically-dynamic polymer-based intracortical microelectrodes can be utilized to deliver anti-inflammatory therapeutics to further mitigate implant-associated inflammation. As part of our ongoing Department of Defense CDMRP award, we are collaboratively working to characterize the relationship between microelectrode-induced tissue strain and recording performance. 2) Role of oxidative stress on microelectrode failure. Oxidative pathways have been implicated in both neurodegeneration and corrosive damage to both the metallic and insulating materials of current intracortical microelectrode technologies. Thus, approaches to mitigate or attenuate the deleterious effects of oxidative inflammatory products are of significant importance. We have demonstrated that several antioxidants can be delivered systemically or locally to temporally mitigate neuronal damage and loss, and that bioactive coatings with mimetic anti-oxidative enzymes can prolong neuroprotection. Further, unpublished results have also established a correlation between osmotically delivered antioxidant therapy within the brain and improved intracortical microelectrode recording performance. Over the next four years, my new VA Merit Review will explore the connection between surface-immobilize biomimetic antioxidative therapies and intracortical microelectrode recording performance. 3) Role of specific immunity pathways microelectrode failure. Few direct connections have been demonstrated between the neuroinflammatory response to intracortical microelectrodes and device performance. We have identified a possible connection between each of these studies to be in large part due to innate immunity-specific toll-like receptor pathways of resident microglia or infiltrating macrophages. Further, we have established that inhibiting the innate immunity co-receptor cluster of differentiation 14 on myeloid cells and not resident microglia reduced blood-brain barrier permeability and increased neuroprotection and intracortical microelectrode recording performance. My laboratory has identified a precise pathway that facilitates stability of the microelectrode-tissue interface, which may lead to new treatment regimens to enable long-term performance. Ongoing work is supported by the NIH, with interest from private corporate sources.

总体目标：我的实验室致力于了解和减轻神经炎症反应中枢神经系统内的植入装置。此类装置的范围从心室分流器到各种刺激和记录电极的类型。神经设备的材料类型、尺寸、架构、功能、和安置。无论这些变量如何，对植入物的神经炎症反应都起着重要作用对健康组织的完整性和设备性能的寿命具有重要作用。一个进步的 40 多年来，人们都知道植入后录音质量会下降。不幸的是，录音不稳定仍然是一个普遍记录的问题。我工作的主要部分集中在研究各种皮质内微电极性能方面，并追求基于材料和基于治疗的减轻炎症介导的皮质内微电极失效机制的方法。领域包括： 1）组织/装置机械失配对微电极故障的作用。我已经在生物学上发展了- 基于聚合物纳米复合材料的受启发的机械动态皮质内微电极。在新颖的材料系统的支持下，我能够独立检查和操纵设备模量，几何形状和药物洗脱能力。在过去的十年里，我的团队成功地证明了：基于机械动力聚合物的皮质内微电极足够坚硬，可以插入大脑，变得顺从以减少微运动并抑制晚期神经炎症反应，并且可以制成功能性皮质内微电极，能够记录活体动物的神经结构。我们最近还证明了基于机械动态聚合物的皮质内微电极可用于提供抗炎治疗，以进一步减轻与植入物相关的炎症。作为作为我们正在进行的国防部 CDMRP 奖励的一部分，我们正在合作努力描述微电极引起的组织应变与记录性能之间的关系。 2）氧化应激对微电极失效的作用。氧化途径与这两种情况有关当前皮质内金属和绝缘材料的神经退行性变和腐蚀损伤微电极技术。因此，减轻或减弱氧化的有害影响的方法炎症产物具有重要意义。我们已经证明，几种抗氧化剂可以全身或局部递送以暂时减轻神经元损伤和损失，并且生物活性涂层具有模拟抗氧化酶可以延长神经保护作用。此外，未发表的结果还建立了大脑内渗透性抗氧化疗法与改善的抗氧化疗法之间的相关性皮质内微电极记录性能。在接下来的四年里，我的新退伍军人事务部绩效审查将探索表面固定仿生抗氧化疗法与皮质内疗法之间的联系微电极记录性能。 3）特异性免疫途径微电极失效的作用。直接联系很少证明了皮质内微电极和装置的神经炎症反应之间的关系表现。我们已经确定了每项研究之间可能存在的联系，这在很大程度上是由于常驻小胶质细胞或浸润巨噬细胞的先天免疫特异性 Toll 样受体途径。此外，我们已经确定抑制骨髓细胞上分化 14 的先天免疫辅助受体簇非驻留小胶质细胞降低了血脑屏障的通透性并增加了神经保护和皮质内微电极记录性能。我的实验室已经确定了一条促进稳定性的精确途径微电极-组织界面，这可能会导致新的治疗方案以实现长期性能。正在进行的工作得到了美国国立卫生研究院的支持，私营企业也对此感兴趣。