Artery‐on‐Chip Demonstrates Mechanical and Functional Features of Healthy and Diseased Living Smooth Muscle Tissue

ABSTRACT Arterial diseases alter blood vessel function through complex mechanisms, requiring microphysiological systems that mimic human arteries. We established an artery‐on‐chip (ARTOC) using vascular derivatives of human induced pluripotent stem cells (iPSCs) cultured with pulsatile flow on an electrospun fibrin hydrogel. ARTOCs possessed mature, multilayered smooth muscle expressing robust extracellular matrix and contractile proteins, exhibiting stimuli‐induced contractility and achieving material properties comparable to those of native arteries. Using real‐time monitoring of circumferential strain and luminal pressure to inform computational fluid dynamics modeling, we successfully tuned biomechanical cues to promote the function of both endothelial and smooth muscle cells simultaneously in the ARTOC. Multiplexed protein and transcriptomic expression analysis of ARTOCs revealed a dynamic response to pulsatile flow over time. For disease modeling, we used iPSCs from a polycythemia patient, finding aberrant cytoskeletal protein expression and increased vessel wall stiffness in diseased ARTOCs compared to controls. We then characterized a novel isogenic disease model using iPSCs CRISPR‐edited with the LMNA Hutchinson‐Guilford Progeria Syndrome mutation. LMNA HGPS ARTOCs showed excessive extracellular matrix accumulation, medial layer loss, premature senescence, and reduced tissue elasticity. The tunable material‐based ARTOC platform accurately models healthy and diseased arteries, representing a significant step toward translational research.