A Four-Channel Microfluidic Vascular-Wall Chip for Modeling Early Atherosclerosis-Related Endothelial Dysfunction and Evaluating Combined Anti-Inflammatory Treatment

Atherosclerosis begins with endothelial dysfunction, inflammatory activation, and immune-cell recruitment within a spatially organized vascular wall. Conventional static cultures and Transwell systems are advantageous for isolated readouts, but they fail to effectively recapitulate multicellular compartmentalization, extracellular matrix support, and dynamic perfusion within a singular platform. Here, we present a four-channel microfluidic vascular-wall chip designed to reconstitute an endothelial cell-extracellular matrix-smooth muscle cell arrangement and to model early atherosclerosis-related inflammatory endothelial dysfunction. The device comprises a perfusable endothelial channel, a collagen I hydrogel region embedded with human aortic smooth muscle cells, a cell-free matrix region, and a culture-medium supply channel. Under physiological conditions, HUVECs formed a ZO-1-positive endothelial barrier and maintained high cellular viability. Stimulation with TNF-α and IL-1β (10 ng/mL each) elevated IL-6 secretion, promoted the recruitment of THP-1-derived M0-like macrophages, disrupted ZO-1 continuity, and increased FITC-dextran permeability without causing extensive cell death. The chip was subsequently utilized to evaluate metformin and atorvastatin therapies. The combinational treatment produced a more pronounced attenuation of MCP-1 secretion than either monotherapy under the inflammatory background. While this platform does not recapitulate advanced plaque formation, lipid deposition, foam-cell formation, or disturbed arterial shear, it successfully provides a microfluidic model of early inflammatory endothelial dysfunction to facilitate mechanistic studies and preliminary anti-inflammatory drug evaluation.