Modeling early stage atherosclerosis in a primary human vascular microphysiological system

Abstract

Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. TEBVs maintain mechanical strength, vasoactivity, and nitric oxide (NO) production for at least 4 weeks. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Removing eLDL leads to recovery of vasoactivity, but not loss of foam cells or recovery of permeability, while pretreatment with lovastatin or the P2Y11 inhibitor NF157 reduces monocyte accumulation and blocks foam cell formation. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo.

The year in basic vascular biology research: from mechanoreceptors and neutrophil extracellular traps to smartphone data and omics

“…Moreover, analysis of the biomechanical integrity of the aorta has provided insight into optimal medical therapy for patients with a rare autosomal-dominant connective tissue disorder. 31 Novel engineering approaches were also used to generate endothelialized arteriole-scale blood vessels 32 and organoids 33 that might be used to test new therapeutics. Palikuqi and colleagues 33 achieved this by transient reactivation of E twenty-six (ETS) variant transcription factor 2 (ETV2), that is normally restricted to embryonic development of the vascular endothelium, in mature human endothelial cells.…”

Engineering Cardiovascular Tissue Chips for Disease Modeling and Drug Screening Applications

“…Tissue chips have also incorporated 3D culture to better mimic the spatial dimensionality of native tissues. For example, Zhang et al (2020) developed arteriole-sized tissue engineered vascular grafts in the shape of hollow conduits in the presence of physiological shear stress (Figure 1A). For over 4 weeks, the authors demonstrated that the vascular grafts possessed mechanical strength, vasoactivity, and nitric oxide production.…”

“…In addition, vascular chips are also useful for modeling aspects of atherosclerosis. Tissue engineered blood vessels (1 mm OD, 1 cm length) were fabricated in a perfusion system to model earlystage atherosclerosis (Figures 1A,B; Zhang et al, 2020). The size of the engineered blood vessel was significantly larger compared to microfluidic approaches, which allowed for assessment of macro-scale properties such as vasoconstriction.…”

Biofabrication of tissue engineering vascular systems

“…To fabricate a TEBV, smooth muscle cells are mixed with ECM gel (collagen, fibrin, etc.) 49 or cultured for a long period to form a dense cell sheet 50 and then shaped to a tubular structure as tunica media. To endothelialize TEBVs, the inner lumen of the tubular structure formed by SMCs is filled with EC suspension.…”