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

UNS：用于创伤性脑损伤药物发现的脑芯片

• 批准号: 1512170
• 负责人: Martin Yarmush
• 金额: $ 42.27万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1512170&HistoricalAwards=false
• 关键词: UNS; Brain; chip; Traumatic; Injury

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.

PI：Yarmush，Martin L. 提案编号：1512170创伤性脑损伤（TBI）是美国每年残疾的主要原因，也是受伤平民和军人癫痫的主要危险因素。TBI极大地降低了受影响患者的生活质量，并且存在与TBI相关的显著的直接和间接成本。虽然一些药物TBI治疗方案正在进行临床审查，但尚未确定可以显著减缓导致神经损伤的事件的进展。改进的体外筛选方法对于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重现体内中枢神经系统细胞间的连接和反应。因此，本研究的目标是开发一种新型的高容量的“脑芯片”装置，该装置集成了成对的脑组织切片，并使用新型的微加工和光学成像工具，以确定可用于治疗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TBI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，以缓解TBI后神经元衰退。一个由科学和工程研究人员组成的跨学科小组将利用微制造技术开发一种“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，其中单个互连轴突在微通道上延伸。应变损伤将通过对微通道下方的空腔加压来引入。 在芯片上集成多电极阵列（MEA）将能够精确和在线识别响应于损伤的电生理变化。研究人员希望使用一种新的动态光学成像方法来评估各种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。通过使用微制造的“芯片上的大脑”阵列，研究人员将能够平行地筛选单个和组合的候选药物，比以前更有效。建立这样一个新的平台是重要的，因为它将加速控制损伤反应的分子实体的鉴定，并协同开发和筛选用于TBI和癫痫等复杂回路疾病的药物治疗。 教育计划包括高中、本科和研究生培训部分，重点是代表性不足的学生教育。此外，工业从业人员将参与生物工程课程，这是一个有效的方法，让学生接触到工业环境。