Senior Research Career Scientist

总体目标：我的实验室努力了解和促进所有植入的神经炎性反应 中枢神经系统内的装置。这类装置的范围从脑室分流到各种类型的 刺激和记录电极。然而，我的大部分努力都是在皮质内微电极上进行的 由于它们在了解大脑的研究中的意义以及大脑在康复应用中的作用 计算机接口，这是退伍军人管理局特别感兴趣的。通过对失效机理的了解，我们可以 寻求基于材料和基于治疗的方法来减轻炎症介导的失败。 1)组织/装置机械失配在微电极失效中的作用。我们开发了生物灵感 用于皮质内微电极的材料，用于独立检查和操纵设备的模数、几何形状、 以及药物洗脱能力。我们已经证明了机械动态皮质内微电极 僵硬到足以插入大脑，变得顺从，减少微运动并抑制晚期 神经炎性反应，可以制造成功能性皮质内微电极，并可用于 从装置衬底或结合微流体装置输送抗炎治疗药物。 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，提高录音性能。 3)特异性免疫通路在微电极失效中的作用。肾小球滤过性病变的病理评估 已知的皮质内微电极的神经炎性反应仅限于十几种。 神经炎性蛋白。我们正在利用空间分辨组学开发出最全面的 分析了微电极/组织界面的日期。通过识别感兴趣的基因和蛋白质，我们就可以 探索关于特定先天免疫系统的假说，或开发免疫细胞沉默的基因疗法。 4)肠道微生物群在微电极失效中的作用。微生物组可能在调控中发挥作用 神经炎。肠道微生物群的成分可以直接渗透到大脑中，导致局部 炎症反应，或通过进入血流的代谢物或炎症因子间接起作用 穿过血脑屏障。我们利用16S rRNA分析表明，肠道滞留的组成 微电极植入后粪便和脑组织中微生物群的变化及其调控 通过治疗来影响慢性皮质内记录的质量。我们试图将这些发现转化为 从临床前治疗到临床治疗，以改善微电极的性能。

Overall goals: My laboratory strives to understand and facilitate the neuroinflammatory response to all implanted devices within the central nervous system. Such devices range from ventricular shunts to various types of stimulating and recording electrodes. However, most of my efforts have been on intracortical microelectrodes due to their significance in research to understand the brain and the role in rehabilitative applications of Brain Computer Interfacing, which is of particular interest to the VA. By understanding mechanism of failure, we can pursue both materials-based and therapeutic-based methods to mitigate the inflammatory-mediated failure. 1) Role of tissue/device mechanical mismatch in microelectrode failure. We developed biologically inspired materials for intracortical microelectrodes to independently examine and manipulate device modulus, geometry, and drug-eluting capabilities. We have demonstrated that mechanically dynamic intracortical microelectrodes are stiff enough to be inserted into the brain, become compliant to reduce micro-motion and inhibit late-stage neuroinflammatory responses, can be fabricated into functional intracortical microelectrodes, and can be utilized to deliver anti-inflammatory therapeutics from the device substrate or in combination with microfluid devices. 2) Role of oxidative stress in 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 and improve recording performance. 3) Role of specific immunity pathways in microelectrode failure. Pathological assessment of the neuroinflammatory response to intracortical microelectrodes has been limited to a dozen or so known neuroinflammatory proteins. We are using spatially resolved omics to developed one of the most comprehensive analyses to date the microelectrode/tissue interface. By identifying genes and proteins of interest, we can then explore hypotheses about specific innate immune systems or develop gene therapies for immune cell silencing. 4) Role of gut microbiome in microelectrode failure. Microbiome may play a role in modulating neuroinflammation. Constituents of the gut microbiome can directly infiltrate the brain causing a local inflammatory response, or act indirectly via metabolites or inflammatory factors that enter the blood stream and cross the blood brain barrier. We utilized 16S rRNA analysis to show that the composition of gut-resident microbiome in feces and brain tissue changes following microelectrode implantation and can be modulated through treatment to impact the quality of chronic intracortical recordings. We seek to translate these findings from preclinical to clinical therapies to improve microelectrode performance.