PROJECT SUMMARY Cerebral atrophy is commonly encountered in penetrating severe Traumatic Brain Injury (sTBI) survivors. Brain infiltration of blood-borne cytotoxic proteins and immune cells due to cerebrovascular dysfunction is an important factor contributing to progressive cerebral atrophy and onset of Alzheimer’s Disease dementia in sTBI patients. However, there have been no efforts to develop interventional therapies that can prevent cerebrovascular dysfunction and infiltration of peripheral immune cells into the brain in penetrating sTBI. Our central hypothesis is that acutely implanted engineered Chondroitin Sulfate (eCS) 3D matrices will accelerate cerebrovascular repair and prevent cerebral atrophy and loss of function in sTBI rats. We propose to test our hypothesis using a novel preclinical rat model of penetrating sTBI in the following two specific aims: Aim-1. Characterize cerebrovascular permeability and immune cell composition in sTBI. Aim-2. Determine the effectiveness of eCS matrix implants in mediating cerebrovascular repair and functional recovery. The proposed studies are expected to provide novel insight into the role of cerebrovascular dysfunction in progressive neurodegeneration and cerebral atrophy in sTBI. Collectively, these studies will inform the development of tissue engineered brain implants that can accelerate cerebrovascular repair and prevent brain volume loss and functional deficits in sTBI patients.