An intimal-lumen model in a microfluidic device: potential platform for atherosclerosis-related studies

Abstract

Atherosclerosis is a chronic inflammatory vascular disorder driven by factors such as endothelial dysfunction, hypertension, hyperlipidemia, and arterial calcification, and is considered a leading global cause of death. Existing atherosclerosis models have limitations due to the absence of an appropriate hemodynamic microenvironment in vitro and interspecies differences in vivo. Here, we develop a simple but robust microfluidic intimal-lumen model of early atherosclerosis using interconnected dual channels for studying monocyte transmigration and foam cell formation at an arterial shear rate. To the best of our knowledge, this is the first study that creates a physiologically relevant microenvironment under an arterial shear rate to modulate lipid-laden foam cells on a microfluidic platform. As a proof of concept, we use murine endothelial cells to develop a vascular lumen in one channel and collagen-embedded murine smooth muscle cells to mimic the subendothelial intimal layer in another channel. The model successfully triggers endothelial dysfunction upon TNF-α stimulation, initiating monocyte adhesion to the endothelial monolayer under the arterial shear rate. Unlike existing in vitro models, native low-density lipoprotein (LDL) is added in the culture media instead of ox-LDL to stimulate subendothelial lipid accumulation, thereby mimicking more accurate physiology. The subendothelial transmigration of adherent monocytes and subsequent foam cell formation is also achieved under flow conditions in the model. The model also investigates the inhibitory effect of aspirin in monocyte adhesion and transmigration. The model exhibits a significant dose-dependent reduction in monocyte adhesion and transmigration upon aspirin treatment, making it an excellent tool for drug testing.