Senior Research Career Scientist

高级研究职业科学家

• 批准号: 10749218
• 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 2030-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749218
• 关键词: Activities of Daily Living; Affect; American; Amputees; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Antioxidants; Area; Attenuated; Basic Science; Bathing; Behavior; Belief; Biocompatible Materials; Biological; Blood; Brain; Caregivers; Cells; Cellular immunotherapy; Central Nervous System; Cervical; Cervical spinal cord injury; Chemistry; Chronic; Clinical; Computers; Corrosives; Dedications; Deep Brain Stimulation; Detection; Devices; Disabled Persons; Disease; Electrodes; Engineering; Enzymes; Failure; Feces; Genes; Geometry; Goals; Government; Healthcare; Immunity; Implant; Individual; Infiltration; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Innate Immune System; Institution; Investigation; Journals; Laboratories; Life Expectancy; Limb Prosthesis; Liquid substance; Literature; Longevity; Lower Extremity; Manuscripts; Mechanics; Mediating; Methods; Microelectrodes; Military Personnel; Mission; Modeling; Modulus; Molecular; Motion; Movement; Muscle; Names; Nanotechnology; Natural Immunity; Nature; Nerve Degeneration; Neurons; Neurosciences; Outcome; Oxidative Stress; Paralysed; Pathologic; Pathway interactions; Patients; Peer Review; Performance; Persons; Pharmaceutical Preparations; Polymers; Privatization; Process; Proteins; Publishing; Quadriplegia; Quality of life; Recovery; Rehabilitation therapy; Reporting; Research; Research Personnel; Resolution; Ribosomal RNA; Robotics; Role; Science; Scientist; Seizures; Self-Help Devices; Seminal; Services; Shunt Device; Signal Transduction; Specificity; Spinal cord injury; Spinal cord injury patients; Sterility; Stream; Stroke; System; Technology; Therapeutic; Thinking; Time; Tissues; Translating; Upper Extremity; Ventricular; Veterans; Work; arm; biomacromolecule; blood-brain barrier crossing; brain computer interface; brain health; brain machine interface; brain tissue; career; clinical application; communication device; disability; experience; falls; feeding; gene therapy; gut microbiome; implantable device; implantation; improved; indexing; injured; interest; limb loss; materials science; mechanical device; metallicity; microbiome; mimetics; multidisciplinary; nervous system disorder; neural; neuroinflammation; neuroprotection; neurotransmission; pre-clinical; response; spatiotemporal

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.

总体目标：我的实验室致力于了解和促进所有植入的神经炎症反应。 中枢神经系统内的装置。这种装置的范围从心室分流器到各种类型的分流器。 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， 由于它们在研究中的重要性，以了解大脑和大脑的康复应用中的作用， 计算机接口，这是退伍军人管理局特别感兴趣的。通过了解失败的机制，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/器械机械不匹配在微电极失效中的作用。我们从生物学的角度 用于皮质内微电极的材料，以独立地检查和操纵装置的模量，几何形状， 和药物洗脱能力。我们已经证明，机械动态皮质内微电极 足够坚硬以插入大脑，变得顺应以减少微运动并抑制晚期 神经炎症反应，可以制成功能性皮质内微电极，并可以利用 以从装置基底或与微流体装置组合递送抗炎治疗剂。 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， 与模拟抗氧化酶一起使用可以延长神经保护并改善记录性能。 3)特异性免疫途径在微电极失效中的作用。病理学评估 对皮质内微电极的神经炎症反应仅限于十几种已知的 神经炎性蛋白我们正在使用空间分辨组学来开发一个最全面的 分析微电极/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)肠道微生物组在微电极失效中的作用。微生物组可能在调节中发挥作用 神经炎症肠道微生物组的成分可以直接渗入大脑， 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16 S rRNA分析表明，肠道居民的组成， 微电极植入后粪便和脑组织中的微生物组发生变化， 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 从临床前到临床治疗，以改善微电极性能。

项目成果

Mechanically Adaptive Implants Fabricated with poly(2-hydroxy-ethyl methacrylate-) based negative photoresists

使用聚（甲基丙烯酸 2-羟乙酯）基负光刻胶制造的机械自适应植入物

• DOI: 10.1039/d0tb00980f
• 发表时间: 2020
• 期刊: Journal of materials chemistry
• 作者: Monney, B.

Neuron-like neural probes.

类似神经元的神经探针。

• DOI: 10.1038/s41563-019-0312-9
• 发表时间: 2019
• 期刊: Nature materials
• 影响因子: 41.2
• 作者: Capadona,JeffreyR;Shoffstall,AndrewJ;Pancrazio,JosephJ
• 通讯作者: Pancrazio,JosephJ

Tools for Surface Treatment of Silicon Planar Intracortical Microelectrodes.

用于硅平面皮质内微电极表面处理的工具。

• DOI: 10.3791/63500
• 发表时间: 2022
• 期刊: Journal of visualized experiments : JoVE
• 作者: Krebs,OliviaK;Mittal,Gaurav;Ramani,Shreya;Zhang,Jichu;Shoffstall,AndrewJ;Cogan,StuartF;Pancrazio,JosephJ;Capadona,JeffreyR
• 通讯作者: Capadona,JeffreyR