Project Grant R61HL159947

LASTING IMPACTS: DYNAMIC, FULLY NATURAL BIOPRINTED 3D HUMAN NEUROVASCULAR BIOMIMETIC MODEL TO STUDY TRAUMATIC BRAIN INJURY PATHOPHYSIOLOGY - ABSTRACT LASTING IMPACTS: DYNAMIC, FULLY NATURAL BIOPRINTED 3D HUMAN NEUROVASCULAR BIOMIMETIC TO STUDY TRAUMATIC BRAIN INJURY PATHOPHYSIOLOGY EVERY YEAR AN ESTIMATED 2.5 MILLION PEOPLE SUSTAIN A TRAUMATIC BRAIN INJURY (TBI), AND MANY SURVIVORS EXPERIENCE SUBSEQUENT LONG-TERM COGNITIVE DEFICITS, SENSORIMOTOR IMPAIRMENTS, AND NEUROPSYCHIATRIC DISABILITY THAT RESULT IN PROFOUND PSYCHOSOCIAL AND ECONOMIC CONSEQUENCES FOR AFFECTED INDIVIDUALS. ACUTE AND CHRONIC EFFECTS OF NEUROTRAUMA REPRESENT LEADING CAUSES OF MORTALITY, MORBIDITY, AND LONG-TERM DISABILITY IN THE US AND AROUND THE WORLD. ALTHOUGH TBI IS CLEARLY DEFINED NEUROPATHOLOGICALLY, LESS WELL-DEFINED IS THE RELATIONSHIP BETWEEN THE INITIAL IMPACT AND THE RESULTING PROGRESSION OF TRAUMA-RELATED NEUROVASCULAR PATHOLOGY. THIS MULTIDISCIPLINARY MULTI-PI PROPOSAL IS RESPONSIVE TO THE TRANS-AGENCY BLOOD-BRAIN INTERFACE PROGRAM (RFA-HL-20-021, R61/R33) AND BUILDS ON A LONGSTANDING COLLABORATION BETWEEN LAWRENCE LIVERMORE NATIONAL LABORATORY, BOSTON UNIVERSITY SCHOOL OF MEDICINE, AND THE NIH/NIA-FUNDED BOSTON UNIVERSITY ALZHEIMER'S DISEASE CENTER TO ADDRESS FUNDAMENTAL MECHANISMS UNDERPINNING ACUTE AND CHRONIC EFFECTS OF NEUROTRAUMA, INCLUDING TRAUMA-INDUCED MICROVASCULAR INJURY AND LATENT TAU PROTEIN NEURODEGENERATIVE PATHOLOGIES ASSOCIATED WITH CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE). THIS PROJECT WILL DEVELOP AND CHARACTERIZE A HUMAN IN VITRO PERFUSABLE NEUROVASCULAR UNIT (NVU) MODEL WITH THE OVERARCHING GOAL OF IDENTIFYING BIOMECHANICAL TRIGGERS AND MOLECULAR-CELLULAR RESPONSES TO BRAIN INJURY THAT DETERMINE THE LOCATION, SEVERITY, AND PROGRESSION OF TRAUMATIC MICROVASCULAR INJURY (TMI), BLOOD- BRAIN BARRIER (BBB) DISRUPTION, AND PHOSPHORYLATED TAU PROTEINOPATHY. TO ACCOMPLISH THIS OBJECTIVE, THIS WORK WILL LEVERAGE AN EXISTING BBB PLATFORM TO BIOFABRICATE A 3D MULTI-CELLULAR DYNAMIC HUMAN NVU BIOMIMETIC WITH PERFUSABLE ENDOTHELIALIZED VASCULATURE. THE RESULTING OPTICALLY CLEAR NVU PLATFORM WILL ENABLE SYSTEMATIC INTERROGATION OF THE HUMAN CEREBROVASCULATURE, INCLUDING ALL HUMAN NVU CELL TYPES, WITH SPATIOTEMPORAL CONTROL AND STRUCTURE-FUNCTION MEASUREMENTS IN REAL-TIME. IN THE R61 PHASE, WE WILL MODIFY OUR EXISTING 3D-PRINTED BBB MODEL TO INCLUDE CULTURE OF HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED ENDOTHELIA, PERICYTES, ASTROCYTES, AND NEURONS. EFFECTS OF CELLULAR COMPOSITION, STRUCTURE-FUNCTION RELATIONS, FLUID FLOW DYNAMICS (INTRAVASCULAR, INTERSTITIAL), AND CULTURE INCUBATION CONDITIONS ON IPSC MATURATION WILL BE INVESTIGATED. IN THE R61 PHASE, WE WILL DEVELOP A PLATFORM-COMPATIBLE INJURY INSTRUMENT INFORMED BY COMPUTATIONAL SIMULATIONS TO MATCH LOADS USED IN IN VIVO ANIMAL STUDIES. EMBEDDED MARKERS IN THE 3D-PRINTED MODEL WILL ENABLE DIRECT MEASUREMENT AND VISUALIZATION OF TIME-VARYING STRAIN DURING IMPACT AS A FUNCTION OF VASCULAR, GLIAL, AND NEURONAL PATHOLOGY AND COMPROMISED FUNCTION (R33 PHASE). IN ADDITION, WE WILL INVESTIGATE MOLECULAR, CELLULAR, AND FUNCTIONAL EFFECTS OF SECONDARY DAMAGE POST-TBI INJURY. RESULTS WILL BE INFORMED BY COMPANION STUDIES IN EXPERIMENTAL ANIMALS AND CLINICOPATHOLOGICAL CORRELATION WITH UNIQUE HUMAN BRAIN SPECIMENS. THIS PROJECT WILL CONTRIBUTE TO FUNDAMENTAL UNDERSTANDING OF BRAIN INJURY BIOMECHANICS AND RELATIONSHIP TO ACUTE AND CHRONIC EFFECTS OF NEUROTRAUMA IN THE HUMAN BRAIN.