RR&D Research Career Scientist Award Application

RR

• 批准号: 10060750
• 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
• 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/10060750
• 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; Cervical; Cervical spinal cord injury; Chemistry; Chronic; Clinical; Computers; Corrosives; Coupled; Deep Brain Stimulation; Department of Defense; Detection; Devices; Disabled Persons; Disease; Electrodes; Endotoxins; Engineering; Enzymes; Failure; Geometry; Goals; Healthcare; Immobilization; Immunity; Implant; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Institution; Investigation; Journals; Laboratories; Lead; Life Expectancy; Limb Prosthesis; Literature; Longevity; Lower Extremity; Manuscripts; Mechanics; Mediating; Methods; Microelectrodes; Microglia; Military Personnel; Mission; Modeling; Modulus; Motion; Movement; Muscle; Myeloid Cells; Names; Nanotechnology; Natural Immunity; Nature; Nerve Degeneration; Neuraxis; Neurons; Neurosciences; Outcome; Oxidative Stress; Paralysed; Pathway interactions; Patients; Peer Review; Performance; 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; Volition; Work; antioxidant therapy; arm; arm movement; base; 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; macrophage; materials science; mechanical device; metallicity; mimetics; nanocomposite; nervous system disorder; neuroinflammation; neuroprotection; neurotransmission; novel; receptor; relating to nervous system; response; restoration

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。这种装置的范围从心室分流器到各种 刺激和记录电极的类型。神经装置的材料类型，大小，结构，功能， 和安置。不管这些变量中的任何一个，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器械性能的寿命具有重要作用。渐进 植入后记录质量的下降已经被知道超过40年了。不幸的是， 不稳定性仍然是一个普遍记录在案的问题。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。这些领域包括： 1)组织/器械机械不匹配对微电极失效的作用。我从生物学角度- 基于其聚合物纳米复合材料的受启发的机械动态皮质内微电极。 通过新的材料系统，我能够独立检查和操作设备模量， 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， 基于机械动力学聚合物的皮质内微电极足够硬以插入脑中， 变得顺应以减少微运动并抑制晚期神经炎症反应，并且可以 制造成能够记录活体动物神经结构的功能性皮质内微电极。 我们最近还证明，机械动态聚合物为基础的皮质内微电极， 可用于递送抗炎治疗剂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奖的一部分，我们正在合作， 微电极诱导的组织应变与记录性能之间的关系。 2)氧化应激在微电极失效中的作用。氧化途径与这两种疾病都有关系。 神经变性和腐蚀性损伤的金属和绝缘材料的电流皮质内 微电极技术因此，减轻或减弱氧化应激的有害影响的方法是可行的。 炎性产物是非常重要的。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， 模拟抗氧化酶可以延长神经保护作用。此外，未发表的结果也 建立了脑内抗氧化剂治疗与改善 皮质内微电极记录性能。在接下来的四年里，我的新退伍军人管理局功绩评估将 探索表面仿生抗氧化疗法与皮质内 微电极记录性能。 3)特定免疫通路的作用微电极失效。很少有直接联系 证实了对皮质内微电极和器械的神经炎症反应之间的差异 性能我们已经确定了这些研究之间的可能联系，这在很大程度上是由于 固有免疫特异性Toll样受体途径的常驻小胶质细胞或浸润巨噬细胞。我们还 已经确定，抑制骨髓细胞上的先天免疫共受体分化簇14和 非常驻小胶质细胞降低血脑屏障通透性，增加神经保护和皮质内 微电极记录性能。我的实验室已经确定了一种精确的途径， 微电极-组织界面，这可能导致新的治疗方案，使长期性能。 正在进行的工作得到了美国国立卫生研究院的支持，私营公司也对此感兴趣。