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

创伤性脑损伤(TBI)是全世界死亡和残疾的主要原因，影响年轻人和 日益老龄化的患者。脑外伤患者遭受两种截然不同但密切相关的损伤。原发伤者是 由物理力量引起的，破坏了撞击地点大脑和血管系统的结构完整性， 而继发性损伤是缺血性和炎症性的，扩散到大脑的大部分和 其他器官，如肺和心脏。从原发损伤到继发损伤的转变是中介的 通过血脑屏障(BBB)。血脑屏障是一种高度选择性的微血管半透屏障， 将循环血液从脑实质和中枢神经系统的细胞外液中分离出来。 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，即血管周围细胞。 细胞和星形胶质细胞共同构成神经血管单位。直接破坏受伤现场的血脑屏障 血液和脑成分之间的交换，导致脑和颅内出血，以及 全身炎症和凝血障碍。尽管对颅脑损伤所致的脑损伤和全身损伤进行了广泛的研究。 在过去，局部脑外伤如何传播继发性损伤仍然知之甚少，这主要是由于 缺乏生理上相关的3D模型系统。在这项提案中，我们汇集了一个跨学科的 拥有微血管工程和血管生物学、血液学和止血、脑外伤和 重建人血脑屏障的细胞信号。这个体外重建的血脑屏障将1)在其微血管构筑中是3D的。 包含血脑屏障的细胞和基质成分，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定义的模式和剪切力，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)。我们将使用这种型号的sys- 利用血源性因子在维持和破坏血脑屏障完整性和功能方面的作用，以 确定导致血脑屏障破坏的细胞内信号通路(激酶抑制回归分析) 以及使用系统生物学方法进行修复，并在现场或床边开发评估 血脑屏障完整性状态(新的生物标记物开发)，并帮助开发新的脑损伤治疗靶点。找到- 来自这项拟议研究的Ings将在未来的神经血管工程方法中有许多意义 和治疗的发展。

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.