Emulating Early Atherosclerosis in a Vascular Microphysiological System Using Branched Tissue-Engineered Blood Vessels

Atherosclerosis begins with the accumulation of cholesterol-carrying lipoproteins on blood vessel walls and progresses to endothelial cell dysfunction, monocyte adhesion, and foam cell formation. Endothelialized tissue-engineered blood vessels (TEBVs) have previously been fabricated to recapitulate artery functionalities, including vasoconstriction, vasodilation, and endothelium activation. Here, the initiation of atherosclerosis is emulated by designing branched TEBVs (brTEBVs) of various geometries treated with enzyme-modified low-density-lipoprotein (eLDL) and TNF-α to induce endothelial cell dysfunction and adhesion of perfused human monocytes. Locations of monocyte adhesion under pulsatile flow are identified, and the hemodynamics in the brTEBVs are characterized using particle image velocimetry (PIV) and computational fluid dynamics (CFD). Monocyte adhesion is greater at the side outlets than at the main outlets or inlets, and is greatest at larger side outlet branching angles (60° or 80° vs 45°). In PIV experiments, the branched side outlets are identified as atherosclerosis-prone areas where fluorescent particles show a transient swirling motion following flow pulses; in CFD simulations, side outlets with larger branching angles show higher vorticity magnitude and greater flow disturbance than other areas. These results suggest that the branched TEBVs with eLDL/TNF-α treatment provide a physiologically relevant model of early atherosclerosis for preclinical studies.