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RR&D Research Career Scientist Award Application

基本信息

批准号：
10311087
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/10311087
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 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 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

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：我的实验室致力于理解和减轻神经炎症反应