Abstract
Atherosclerosis, a chronic inflammatory disorder characterized by endothelial dysfunction and blood vessel narrowing, is the leading cause of cardiovascular diseases including heart attack and stroke. Herein, we present a novel tunable microfluidic atherosclerosis model to study vascular inflammation and leukocyte-endothelial interactions in 3D vessel stenosis. Flow and shear stress profiles were characterized in pneumatic-controlled stenosis conditions (0%, 50% and 80% constriction) using fluid simulation and experimental beads perfusion. Due to non-uniform fluid flow at the 3D stenosis, distinct monocyte (THP-1) adhesion patterns on inflamed [tumor necrosis factor-α (TNF-α) treated] endothelium were observed, and there was a differential endothelial expression of intercellular adhesion molecule-1 (ICAM-1) at the constriction region. Whole blood perfusion studies also showed increased leukocyte interactions (cell rolling and adherence) at the stenosis of healthy and inflamed endothelium, clearly highlighting the importance of vascular inflammation, flow disturbance, and vessel geometry in recapitulating atherogenic microenvironment. To demonstrate inflammatory risk assessment using leukocytes as functional biomarkers, we perfused whole blood samples into the developed microdevices (80% constriction) and observed significant dose-dependent effects of leukocyte adhesion in healthy and inflamed (TNF-α treated) blood samples. Taken together, the 3D stenosis chip facilitates quantitative study of hemodynamics and leukocyte-endothelial interactions, and can be further developed into a point-of-care blood profiling device for atherosclerosis and other vascular diseases.
Highlights
By accumulation of cholesterol-containing low-density lipoproteins in the sub-endothelial space, due to a complex interplay between activated leukocytes and the inflamed endothelium
Atherosclerosis, a chronic inflammatory disorder characterized by endothelial dysfunction and blood vessel narrowing, is the leading cause of cardiovascular diseases including heart attack and stroke
Flow and shear stress profiles were characterized in pneumatic-controlled stenosis conditions (0%, 50% and 80% constriction) using fluid simulation and experimental beads perfusion
Summary
By accumulation of cholesterol-containing low-density lipoproteins in the sub-endothelial space (intima), due to a complex interplay between activated leukocytes (monocytes, macrophages, and T cells) and the inflamed endothelium. Atherosclerosis is a geometrically focal disease that preferentially affects vessel bifurcations, characterized by disturbed blood flow and low shear stresses (1–4 dyn/cm2).[2] Several in vitro models have been developed to study lesion formation and disease progression, but these two-dimensional (2D) or three-dimensional (3D) coculture models[3,4] and cone-and-plate flow chambers,[5] do not incorporate atherogenic vascular geometries and the associated complex flow profiles. To understand the effects of flow disturbance in monocyte recruitment, THP-1 cells (monocytic cell line) were perfused over inflamed human umbilical vein endothelial cells (HUVECs) monolayer at different channel constrictions (50% and 80%) and wall shear stresses (1 and 10 dyn/cm[2]). We characterized vascular inflammation in a perfusion culture, and our results indicated active endothelial cell alignment and differential flow-based inflammatory responses (ICAM-1) at the 3D bump in 80% channel constriction. To demonstrate the potential of our 3D stenosis chip for inflammatory profiling, we perfused healthy and tumor necrosis factor-a (TNF-a) treated whole blood in 80% stenosis
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