DEVELOPMENT OF 3D MICROFLUIDICS ORGAN-ON-CHIP MODEL TO MIMIC THE INTRAPLAQUE MICROVASCULATURE

Abstract

Coronary artery disease is the leading cause of mortality and morbidity in Qatar and around the world. The build-up of atherosclerotic plaque in coronary arteries is the underlying cause of coronary artery disease. It results from the chronic accumulation of lipids, inflammatory cells, and smooth muscle cells in the arterial wall. In advanced atherosclerotic plaque, new microvessels grow from the vasa vasorum of the adventitia into the plaques, a process known as intraplaque angiogenesis. Clinical evidence shows a strong link between the extent of intraplaque angiogenesis and the vulnerability of plaques to adverse events. Given the critical role of intraplaque microvasculature in plaque vulnerability, cell-based assays mimic the biological processes mediated by intraplaque angiogenesis, allowing us to understand the pathophysiology of this phenomenon better. However, no cell model has previously addressed the biology of capillary microcirculation in the human advanced atherosclerotic plaque. In our study, we aimed to establish a new in vitro model to investigate the microvessels and their interactions with various cellular components of the plaque, specifically under experimental conditions similar to those found in the necrotic core of atherosclerotic plaques: inflammation and modified lipids. We optimized a 3D microfluidics organ on- chip platform incorporating a perfused microvessel and extracellular matrix (ECM) gel, representing the plaque space. Fluorescent-labeled THP-1 monocytes were perfused to observe cell extravasation and recruitment in ECM gel. Vascular smooth muscle cells (SMC) and modified low-density lipoprotein (LDL) were also incorporated into the model. Our findings revealed that the combination of collagen and Matrigel® ECM gel stimulated monocyte transmigration while limiting the over-invasion of SMC into the ECM, thereby recapitulating the microenvironment of atherosclerotic plaque. Although the integration of oxidized LDL did not have an additive effect on inflammatory- mediated monocyte adhesion and transmigration, we found that it significantly reduced the SMC migration into the ECM gel. The co-culture of polarized M2 macrophages or macrophages treated with hypoxia-inducible factor-prolyl hydroxylase inhibitors, which activate intracellular HIF levels, demonstrated sprouting angiogenesis of the perfused microvessels into the ECM gel. In conclusion, we have established a novel 3D microfluidics organ-on-chip model that simulates the growth of intraplaque microvessels, providing a valuable tool for research in the field of atherosclerosis.

Date of Award	2024
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences