Human coronary artery tri-culture organ-chip recapitulates anti-inflammatory effect of pulsatile wall strain

Inflammation is a precursor to vascular diseases, including atherosclerosis, and is modulated by the local biomechanical environment. There is an urgent need for improved in vitro models, to advance understanding, and to test new therapeutic approaches.. This study describes the development and characterization of a human coronary artery organ-chip model of vascular inflammation, with physiological biomechanical stimulation. Human coronary artery endothelial cells and smooth muscle cells were cultured on appropriate extracellular matrices in the two adjoining channels of the Chip-S1(R) from Emulate Inc. Both endothelial and smooth muscle cells demonstrated characteristic phenotypic identity, shown by expression of CD31 and -SMA respectively. Application of physiological pulsatile tensile strain induced alignment of both cell types, perpendicular to strain direction, as seen in vivo. Addition of TNF- to the vascular channel drove an inflammatory response in both cell types, shown by upregulation of ICAM-1 and P65, and attachment and invasion of circulating THP-1 monocytes. Strain field analysis revealed pressure-dependent spatial variation with 12% strain in the center of the chip, and 5% towards the ends. Pulsatile tensile strain reduced the inflammatory response to TNF- with a greater localized inflammatory response in areas of lower strain, further replicating in vivo behavior. In conclusion, we present a fully characterized, tri-culture model of the human coronary artery which recapitulates the physiological effects of pulsatile vessel dilation on morphology and localized inflammatory susceptibility. Our model was developed upon a commercially-available, organ-chip platform, allowing for rapid adoption for therapeutic testing, and fundamental discovery science.