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

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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.