Novel 3D vascular disease models: Implications for the treatment of cardiovascular and renal diseases

Abstract

Cardiovascular and renal diseases are two of the world’s most pressing health challenges, contributing to millions of deaths annually. While advancements in clinical care have improved outcomes, existing lab and animal models often fail to reflect the complexity of human biology. This PhD research addresses that gap by developing advanced vascular avatars—lab-grown, living blood vessel models engineered to mimic how human arteries behave in health and disease. At the heart of this thesis is a dynamic vessel-on-a-chip system, constructed from human endothelial cells, smooth muscle cells, and immune cells. This model replicates early-stage events in atherosclerosis and aneurysms under flow conditions. It allows real-time visualization of immune cell infiltration, lipid accumulation, and vessel wall remodeling—key features of early atherosclerosis development. In a parallel adaptation, the same platform was used to model SMAD3-deficient aneurysms, reproducing features such as medial degeneration and inflammatory disruption. In addition to disease modeling, the research explores how physical forces like matrix stiffness and stretch influence vascular smooth muscle cells derived from human induced pluripotent stem cells (hiPSCs). These studies revealed that biomechanical stimuli promote a healthy, contractile cell state—an essential step toward creating realistic tissue-engineered blood vessels. Beyond the vasculature, this thesis investigates how small genetic variations—known as single nucleotide polymorphisms (SNPs)—linked to chronic kidney disease affect gene regulation. Functional assays demonstrated how these SNPs alter enhancer activity and gene expression, offering insight into inherited disease mechanisms. Together, these findings bridge the gap between mechanistic understanding and translational application. By combining microfluidic systems, stem cell biology, and genetic analysis, this research advances human-relevant disease models and supports the shift toward ethical, personalized, and regenerative approaches in medicine. As regulatory agencies increasingly support animal-free research, this work aligns with global efforts to improve both scientific accuracy and patient outcomes.