UNS: Brain-on-a-chip for Traumatic Brain Injury Drug Discovery

PI: Yarmush, Martin L.提案号：1512170创伤性脑损伤（TBI）是美国每年致残的主要原因，也是受伤平民和军人中癫痫的主要危险因素。创伤性脑损伤显著降低患者的生活质量，与创伤性脑损伤相关的直接和间接成本显著。虽然一些药物TBI治疗方案正在临床审查中，但尚未发现能够显著减轻导致神经损伤的事件进展的药物。改进体外筛选方法对加快药物鉴定和开发至关重要。动物研究既昂贵又耗时，但大多数体外方法无法概括体内中枢神经系统细胞间的联系和反应。因此，本研究的目标是开发一种新型的高含量“脑芯片”设备，该设备集成了成对的脑组织切片，并使用新型微加工和光学成像工具，以识别可用于治疗TBI的候选药物。最近的许多研究表明，线粒体功能障碍有助于继发性脑损伤的严重程度和相关的轴突功能障碍。因此，研究人员的目标是开发一种高含量的方法来筛选线粒体药物，以减轻脑损伤后的神经元衰退。一个由科学和工程研究人员组成的跨学科团队将利用微加工技术开发一种“芯片上的大脑”设备，该设备将用于培养成对的大脑器官型组织切片，这些组织切片具有在微通道上延伸的单个相互连接的轴突。通过对微通道下方的空腔加压，将会造成应变损伤。集成在芯片上的多电极阵列（MEA）将能够精确和在线地识别损伤后的电生理变化。研究人员希望利用一种新的动态光学成像方法来评估不同的应变损伤如何影响两个器官型切片之间的电生理和生化反应。通过使用微型制造的“大脑芯片”阵列，研究人员将能够并行地筛选候选药物，无论是单独的还是联合的，比以前更有效。建立这样一个新平台意义重大，因为它将加速识别控制损伤反应的分子实体，并协同开发和筛选治疗复杂电路障碍（如TBI和癫痫）的药物治疗。该教育计划包括高中、本科和研究生培训部分，重点关注代表性不足的学生教育。此外，工业从业者将参与生物工程课程，这是一个有效的途径，让学生接触到工业环境。

PI: Yarmush, Martin L. Proposal Number: 1512170Traumatic brain injuries (TBI) are the leading cause of disability each year in the US and are also a major risk factor for epilepsy in both injured civilian and military populations. TBI dramatically reduces quality of life in affected patients and there are significant direct and indirect costs associated with TBI. While some drug TBI treatment protocols are under clinical review, none has been identified which can significantly attenuate the progression of events leading to neurological impairment. Improved in vitro screening methods are critical to expedite drug identification and development. Animal studies are both expensive and time consuming, but most in vitro approaches fail to recapitulate in vivo central nervous system inter-cellular connections and responses. Therefore, the goal of the proposed studies is to develop a novel high content "Brain-on-a-Chip" device, which integrates pairs of brain tissue slices and uses novel microfabrication and optical imaging tools, to identify drug candidates that can be used to treat TBI.Many recent studies indicate that mitochondrial dysfunction contributes to secondary TBI severity and associated axonal dysfunction. As such, the investigators aim to develop a high-content approach to screen mitochondrial drugs to alleviate post-TBI neuronal decay. An interdisciplinary team of science and engineering investigators will utilize microfabrication techniques to develop a "Brain-on-a-Chip" device which will be used to culture paired brain organotypic tissue slices with individual interconnecting axons that extend over microchannels. Strain injury will be introduced by pressurizing a cavity beneath the microchannels. Integrating a multi-electrode array (MEA) on-chip will enable precise and on-line identification of electrophysiological changes in response to injury. The investigators expect to assess how various strain injuries affect electrophysiological and biochemical responses between two organotypic slices using a novel dynamic optical imaging approach. By using microfabricated "Brain-on-a-Chip" arrays, the investigators will be able to screen, in parallel, drug candidates both individually and in combination, more efficiently than has been previously possible. Establishment of such a novel platform is significant, because it would accelerate the identification of molecular entities which control the injury response and, in concert, the development and screening of drug treatments for complex circuit disorders like TBI and epilepsy. The education plan includes high school, undergraduate, and graduate training components with a focus on underrepresented student education. Furthermore, industrial practitioners will be involved in bioengineering courses, which is an effective approach allowing student exposure to the industrial environment.