Modeling Foam Cell Formation in A Hydrogel-Based 3D-Intimal Model: A Study of The Role of Multi-Diseases During Early Atherosclerosis

Monocyte recruitment and transmigration are crucial in atherosclerotic plaque development. The multi-disease complexities aggravate the situation and continue to be a constant concern for understanding atherosclerosis plaque development. Herein, a 3D hydrogel-based model that integrates disease-induced microenvironments is sought to be designed, allowing us to explore the early stages of atherosclerosis, specifically examining monocyte fate in multi-disease complexities. As a proof-of-concept study, murine cells are employed to develop the model. The model is constructed with collagen embedded with murine aortic smooth muscle cells and a murine endothelial monolayer lining. The model achieves in vitro disease complexities using external stimuli such as glucose and lipopolysaccharide (LPS). Hyperglycemia exhibits a significant increase in monocyte adhesion but no enhancement in monocyte transmigration and foam cell conversion compared to euglycemia. Chronic infection achieved by LPS stimulation results in a remarkable augment in initial monocyte attachment and a significant increment in monocyte transmigration and foam cells in all concentrations. Moreover, the model exhibits synergistic sensitivity under multi-disease conditions such as hyperglycemia and infection, enhancing initial monocyte attachment, cell transmigration, and foam cell formation. Additionally, western blot data prove the enhanced levels of inflammatory biomarkers, indicating the model's capability to mimic disease-induced complexities during early atherosclerosis progression. The presented 3D-atherosclerosis intimal model mimics atherosclerosis pathogenesis in muti-disease complexities. Factors such as hyperglycemia and infection induce early atherosclerosis pathogenicity. The addition of external stimuli in the model initiates endothelial dysfunction that facilitates monocyte transmigration and subendothelial lipid diffusion, subsequently triggering the conversion of monocytes into foam cells upon lipid accumulation.image