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.
