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A Microphysiological System to Study Leukocyte-Endothelial Cell Interaction during Inflammation
Published on: December 9, 2021
An intimal-lumen model in a microfluidic device: potential platform for atherosclerosis-related studies
Fahima Akther1,2, Dimple Sajin1,3, Shehzahdi S Moonshi1,3
1Queensland Micro- and Nanotechnology, Griffith University, Nathan, Queensland 4111, Australia. h.ta@griffith.edu.au.
Insights
Researchers developed a novel microfluidic model simulating atherosclerosis by mimicking arterial blood flow. This tool effectively studies monocyte transmigration and foam cell formation, aiding in drug discovery for this vascular disease.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Microfluidics
Background:
- Atherosclerosis is a major global cause of death, characterized by chronic inflammation and vascular dysfunction.
- Current *in vitro* models lack physiologically relevant hemodynamic microenvironments and exhibit interspecies differences *in vivo*.
- Studying early atherosclerosis requires models that accurately replicate the arterial shear rate and cellular interactions.
Purpose of the Study:
- To develop a robust microfluidic intimal-lumen model for studying early atherosclerosis.
- To create a physiologically relevant microenvironment under arterial shear rate for observing monocyte transmigration and foam cell formation.
- To validate the model's utility for drug testing, specifically examining aspirin's inhibitory effects.
Main Methods:
- A microfluidic device with interconnected dual channels was designed to mimic the vascular lumen and intimal layer.
- Murine endothelial cells formed the vascular lumen, while collagen-embedded murine smooth muscle cells formed the intimal layer.
- Endothelial dysfunction was induced by TNF-α stimulation, and native low-density lipoprotein (LDL) was used to promote lipid accumulation.
Main Results:
- The model successfully induced endothelial dysfunction, monocyte adhesion, and transmigration under arterial shear rates.
- Subendothelial foam cell formation was observed under flow conditions, mimicking early atherosclerosis.
- Aspirin demonstrated a significant, dose-dependent inhibitory effect on monocyte adhesion and transmigration.
Conclusions:
- The developed microfluidic intimal-lumen model provides a physiologically relevant platform for studying early atherosclerosis.
- This model accurately replicates key pathological processes like monocyte transmigration and foam cell formation under arterial shear.
- The model serves as a valuable tool for pre-clinical drug screening and testing, as demonstrated by aspirin's efficacy.
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.
