3D Models of the Blood-Brain Barrier for Studying Trauma-Induced Cerebral and Systemic Injuries

创伤性脑损伤（TBI）是全球死亡和残疾的主要原因，影响年轻人， 越来越多的老年患者。TBI患者遭受两种不同但密切相关的损伤。主要损伤是 由破坏撞击部位大脑和脉管系统结构完整性的物理力引起， 而继发性损伤是局部缺血性的和炎性的，其扩散到大脑的大部分， 其他器官如肺和心脏。从原发性损伤到继发性损伤的转变是通过介导的 通过血脑屏障（BBB）。血脑屏障是微血管系统的高度选择性半渗透屏障， 将循环血液与脑实质和中枢神经系统中的细胞外液分离。 它不仅由内皮细胞和内皮下基质组成，而且还包括其他血管周围细胞，即内皮细胞。 胶质细胞和星形胶质细胞，它们共同形成神经血管单位。破坏损伤部位的血脑屏障， 血液和脑成分之间的交换，导致脑内和颅内出血，以及 全身性炎症和凝血病。尽管对TBI诱导的脑和全身损伤进行了广泛的研究， 在过去的几年中，局部TBI如何传播继发性损伤仍然知之甚少，主要是由于 缺乏生理相关的3D模型系统。在这份提案中，我们组建了一个跨学科的 具有微血管工程和血管生物学、血液学和止血、TBI和 细胞信号转导以重建人血脑屏障。这种体外重建的血脑屏障将1）在其微血管阿尔奇中是3D的， tect包含BBB细胞和基质成分，2）允许血液或其成分的动态流动， 在动脉和静脉血流中发现的确定的模式和剪切应力，以及3）允许在生物- 化学（细胞内信号）和细胞水平（光学和电子显微镜）。我们将使用该模型系统- 目的是利用血液衍生因子在维持和破坏BBB完整性和功能中的作用， 确定有助于BBB破坏的细胞内信号通路（激酶抑制剂回归分析） 以及使用系统生物学方法对其进行修复，并在现场或床边开发评估 BBB完整性状态（新生物标志物开发），并有助于开发TBI的新治疗靶点。找到- 这项研究的结果将对未来的神经血管工程方法产生许多影响 和治疗发展。

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, affecting young adults and increasingly aging patients. Patients with TBI suffer two distinct but closely related injuries. The primary injury is caused by physical forces that disrupt the structural integrity of the brain and vasculature at the site of impact, whereas the secondary injury is ischemic and inflammatory that disseminates to the most parts of the brain and other organs such as the lungs and the heart. The transition from the primary to the secondary injury is mediated through the blood brain barrier (BBB). BBB is a highly selective semipermeable barrier of microvasculature that separates the circulating blood from the brain parenchyma and extracellular fluid in the central nervous system. It consists of not only endothelial cells and the subendothelial matrix but also other perivascular cells, i.e. peri- cytes and astrocytes, that together form the neurovascular unit. Disrupting BBB at the site of injury permits direct exchange between blood and cerebral components, leading to intracerebral and intracranial hemorrhage, and systemic inflammation and coagulopathy. Despite extensive efforts on TBI-induced cerebral and systemic inju- ries in the past, how local TBI disseminates the secondary injury remains poorly understood, largely due to the lack of a physiologically relevant 3D-model system. In this proposal, we have assembled an interdisciplinary team with expertise in microvascular engineering and vascular biology, hematology and hemostasis, TBI, and cell signaling to reconstruct human BBB. This in vitro reconstructed BBB will 1) be 3D in its microvascular archi- tect to contain cellular and matrix components of BBB, 2) allow for dynamic flow of blood or its components with defined patterns and shear stresses found in arterial and venous blood flow, and 3) permit manipulation at bio- chemical (intracellular signaling) and cellular levels (light and electron microscopy). We will use this model sys- tem to exploit roles of blood derived factors in maintaining and disrupting the BBB integrity and function, to identify intracellular signal pathways (the kinase inhibitor regression analysis) that contribute to BBB breakdown and its repairs using a systems biology approach, and to develop in field or bedside devices that evaluate the state of BBB integrity (new biomarker development) and help developing new therapeutic targets for TBI. Find- ings from this proposed study will have numerous implications in future neurovascular engineering approaches and therapeutic development.