Development of a novel aorta-on-a-chip (AoC) model for thoracic aortic aneurysm research

Abstract Thoracic aortic aneurysm (TAA) is a life-threatening vascular condition marked by progressive dilation of the aorta, predisposing patients to dissection or rupture. Current understanding of TAA pathogenesis relies heavily on murine models, as obtaining native aortic samples of -early disease state- patients and especially control individuals remains challenging. However, these in vivo models present translational limitations and inconsistencies in drug responses. Thus, there is a critical need for humanized platforms that reflect more accurately disease mechanisms and support therapeutic development. Stem cell-based modeling offers a powerful alternative to overcome these limitations. Within our lab, we use induced pluripotent stem cells (iPSC) derived from TAA patients and their CRISPR-Cas9-corrected isogenic controls to generate vascular cells: endothelial cells (EC) and vascular smooth muscle cells (VSMC) of neural crest or lateral mesoderm origin. Although these iPSC-VSMC express early VSMC markers, they exhibit limited maturation in conventional 2D settings. Efforts to enhance maturation via biochemical (Heparin) or mechanical (cyclic stretching) stimuli have yielded modest improvement. To address this, we are developing the first TAA-specific iPSC-based aorta-on-a-chip (AoC) platform. Within custom-fabricated microfluidic chips, 3D cell seeding via viscous finger patterning (VFP) has demonstrated a high success rate and yields highly consistent circumferential (chip-to-chip) lumen widths, underscoring the reproducibility of the approach. However, achieving uniform lumen width along the longitudinal axis still requires fine-tuning. These VFP-generated aortic constructs will be subsequently exposed to controlled mechanical cues (pressure and shear stress) to recapitulate the native aortic microenvironment. By mimicking (patho)physiological conditions, the AoC aims to promote cell maturity and enable precise evaluation of disease mechanisms and drug responses. Ultimately, this iPSC-based AoC represents a next-generation tool for TAA disease modeling, aligning with the 3R principle (Reduce, Replace and Refine) and advancing personalized translational research and drug discovery.3D iPSC-derived aorta-on-a-chip modelFor image description, please refer to the figure legend and surrounding text.