The Role of Single and Repeated Traumatic Injury on the Blood-brain Endothelial Barrier Function

最近的研究表明，中度、严重和更关键的重复性创伤性脑损伤可以导致血脑屏障的破坏。血流内容物和大脑其他部分之间的这一关键保护性屏障的失效可能会导致短期和长期的问题，因为致病因子对大脑的入侵增加。血脑屏障破裂的原因，以及反复损伤更严重地降解血脑屏障的可能性，目前还知之甚少。很少有非动物实验室模型可以复制血脑屏障的机械、结构和功能的复杂性，可以用来研究创伤性脑损伤。这个项目将使用一种新的非动物(台式)血脑屏障模型来研究反复创伤后血脑屏障的破坏。该项目将通过确定创伤后大脑屏障功能降低的生物和结构原因来促进健康。该项目的教育和推广工作的重点是吸引高中生，他们将在为期一周的夏令营中使用最新的生物医学制造和创新技术。这个项目将促进血脑屏障机械生物学领域的基本见解，特别是对应变、减速和反复损伤在导致血脑屏障和整个神经血管单位的结构和功能改变中的作用的理解。将设计和制造包含神经和微血管细胞类型以及毛细血管流动的血脑屏障神经血管单元(器官芯片)的三维体外模型。这些器官芯片结构将在定制设计的生物反应器中遭受单一或多个创伤，以量化和模拟血脑屏障破裂的时间演变，作为损伤程度、撞击次数和撞击间隔时间的函数。因此，该项目将为血脑屏障细胞表型、新陈代谢和功能的机制调控提供重要的见解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Recent studies have shown that moderate, severe, and more crucially, repetitive traumatic brain injury can cause the breakdown of the blood-brain barrier. Failure of this critical protective barrier between the contents of the bloodstream and rest of the brain can cause both short- and long-term problems because of increased invasion of the brain by disease causing agents. The causes of breakdown of the blood-brain barrier, as well as the potential of repetitive injury to more severely degrade the blood-brain barrier is poorly understood. There are very few non-animal laboratory models that copy the mechanical, structural and functional complexities of the blood-brain barrier that can be used to study traumatic brain injury. This project will use a new non-animal (benchtop) model of the blood-brain barrier to study its breakdown after repetitive traumatic injury. The project will advance health by determining the biological and structural causes for reduced barrier function in the brain following traumatic injury. The educational and outreach work in the project is centered on engaging high-school students who will use the latest technologies of Biomedical Manufacturing and Innovation in a week-long summer camp. This project will advance fundamental insights within the field of blood-brain barrier mechanobiology, specifically the understanding of the role of strain, deceleration and repeated injury, in causing altered structure and dysfunction of the blood brain barrier and the overall neurovascular unit. Three-dimensional in vitro models of the blood-brain barrier neurovascular unit (organ-chips) incorporating neural and microvascular cell types, and capillary fluid flow will be designed and engineered. These organ-chip constructs will be subject to single or multiple traumatic injuries in custom-designed bioreactors to quantify and model the temporal evolution of blood-brain barrier breakdown as a function of injury magnitude, number of impacts and time between impacts. This project will thus provide important insights into the mechanoregulation of blood-brain barrier cellular phenotype, metabolism and function.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.