Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder that results in premature and accelerated aging, while accumulation of progerin also occurs during physiological aging. Notably, one of the major targets of HGPS is the cardiovascular system, which are mechanically active tissues. Typical symptoms include hypertension, myocardial infarction, congestive heart failure, calcific aortic stenosis, and peripheral atherosclerosis. For example, autopsy findings have illustrated profound loss of vascular smooth muscle cells (SMCs) in the medial layer of large arteries, such as the aorta and carotid arteries, with replacement by collagen and extracellular matrix. Vascular wall echodensity is also increased in HGPS patients associated with exaggerated fibrotic adventitia formation. The overarching goal of this proposal is to optimize a biomimetic HGPS-on-a-chip system generated with patient-derived fibroblasts (FBs), SMCs, and endothelial cells (ECs) that allow application of relevant cyclic stretch for performing ‘clinical trials’ or informing clinical trial designs for HGPS patients. In particular, we will generate a whole-thermoplastic microfluidic system with a dual-layer blood vessel-mimicking structure. Based on our preliminary device previously already reported, the proposed system will be whole-thermoplastic consisting of two channels separated by a thin thermoplastic polyurethane (TPU) membrane. On top, layers will include a collagen hydrogel encapsulating FBs (adventitia) and an elastin hydrogel embedded with SMCs (media), post-seeded again with a monolayer of ECs. This methodology recreates the in vivo microenvironment of blood vessels to faithfully model pathological changes in HGPS.