Date Approved

2-10-2021

Embargo Period

2-11-2021

Document Type

Dissertation

Degree Name

PhD Doctor of Philosophy

Department

Biomedical Engineering

College

Henry M. Rowan College of Engineering

First Advisor

Galie, Peter

Second Advisor

Alpaugh, Mary

Third Advisor

Hecht, Gregory

Subject(s)

Blood-brain barrier; Central nervous system--Diseases

Disciplines

Biomedical Engineering and Bioengineering | Medicine and Health Sciences

Abstract

The effect of disturbed flow profiles on the endothelium have been studied extensively in systemic vasculature, but less is known about the response of the blood-brain barrier (BBB) to these flow regimes. Here we investigate the effect of steady and pulsatile disturbed flow on the integrity of the BBB using a three-dimensional, perfusable bifurcation model consisting of a co-culture of endothelial cells with mural and glial cells. Experimental flow patterns predicted by computational fluid dynamics mimic in vivo flow regimes, specifically the presence of a recirculation zone immediately downstream of the bifurcation reveal periodic changes in the instantaneous shear stress along the channel wall. Dextran permeability assays and immunostaining with markers for tight junctions show that barrier disruption is significantly greater in areas of disturbed flow compared to fully developed regions downstream of the bifurcation. RNA sequencing found differences in gene expression between the disturbed and fully developed regions, and lumican which has been implicated in ECM organization and collagen fibrillogenisis was shown to be significantly upregulated in the fully developed region. Furthermore, the downregulation of the protein is associated with barrier breakdown. Overall, disturbed flow-induced disruption of the blood-brain barrier suggests that flow-mediated mechanisms may contribute to vascular pathologies in the central nervous system.

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