RR&D Research Career Scientist Award Application

总体目标：我的实验室致力于了解和减轻神经炎性反应 在中枢神经系统内植入装置。这种装置的范围从脑室分流到各种 刺激电极和记录电极的类型。神经设备在材料类型、大小、结构、功能、 和位置。不管这些变量中的任何一个，对植入物的神经炎性反应起到了 对健康组织的完整性和设备性能的长寿具有重要作用。进步者 植入后录音质量下降已有40多年的历史了。不幸的是，录制 不稳定仍然是一个常见的记录在案的问题。我的大部分工作都集中在研究各种 皮质内微电极性能的方面，并追求基于材料和基于治疗的 方法减轻炎症介导的皮质内微电极失效机制。这些领域包括： 1)组织/装置机械失配在微电极失效中的作用。我在生物学上发展了- 基于其聚合物纳米复合材料的激励、机械动态皮质内微电极。 在新型材料系统的支持下，我能够独立地检查和操纵器件的模数， 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 基于机械动态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性反应，并且可以 制成功能性皮质内微电极，能够从活体动物的神经结构中进行记录。 我们最近还展示了基于机械动力学聚合物的皮质内微电极 可用于提供抗炎治疗药物，以进一步减轻种植体相关的炎症。AS 作为我们正在进行的国防部CDMRP奖的一部分，我们正在协作工作，以确定 微电极诱发的组织应变与记录性能的关系。 2)氧化应激在微电极失效中的作用。氧化途径被认为与这两个事件有关 电流皮质内金属和绝缘材料的神经退变和腐蚀损伤 微电极技术。因此，减轻或减弱氧化有害影响的方法 炎症性产品具有重要意义。我们已经证明了几种抗氧化剂可以 系统地或局部地输送以暂时减轻神经元损伤和丢失，且生物活性涂层 具有模拟抗氧化酶，可延长神经保护。此外，未发表的结果也 建立了大脑内渗透传递的抗氧化剂疗法与改善的 皮质内微电极记录性能。在接下来的四年里，我的新退伍军人功绩评估将 探索表面固定化仿生抗氧化疗法与皮质内的联系 微电极记录性能。 3)特异性免疫通路在微电极失效中的作用。很少有直接连接是 皮层内微电极的神经炎性反应与装置之间的关系 性能。我们已经确定了这些研究之间可能的联系，这在很大程度上是因为 固有免疫-常驻小胶质细胞或浸润性巨噬细胞的Toll样受体通路。此外，我们 已经确定抑制髓系细胞上的天然免疫共受体分化簇14和 非常驻小胶质细胞降低血脑屏障通透性，增强神经保护和皮质内 微电极记录性能。我的实验室已经确定了一条精确的途径，有助于稳定 微电极-组织界面，这可能导致新的治疗方案，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，私营企业对此感兴趣。

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.