Key considerations for modeling calcific aortic valve disease on a chip

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in aging populations and is characterized by progressive thickening, fibrosis, and mineralization of the aortic valve leaflets. Currently, no pharmacological therapies are available to prevent or slow disease progression, leaving surgical or transcatheter aortic valve replacement as the only treatment option. CAVD is an active, inflammatory pathology driven by complex interactions among extracellular matrix (ECM) remodeling, hemodynamic forces, inflammatory signaling, endothelial dysfunction, and osteogenic differentiation. The native aortic valve microenvironment is highly organized, consisting of a three-layered ECM integrated with valve interstitial cells and covered by a monolayer of valve endothelial cells. Heart valves are dynamic tissues that experience various mechanical forces during each cardiac cycle, including shear stress, tensile forces, and compressive forces. Currently, there is no clinical model that can truly mimic the progressive remodeling of the valve during CAVD, which is impeding our ability to identify disease-preventing pharmacotherapies. Recent advances in microphysiological technologies offer a promising avenue for developing human-relevant CAVD platforms that integrate controlled fluid flow, cyclic mechanical stimulation, physiologically relevant ECM environments, and compartmentalized multicellular architectures. However, the field remains in its infancy. In this review, we discuss the key structural, biomechanical, cellular, extracellular matrix, and sex-specific considerations required to engineer physiologically relevant CAVD-on-a-Chip models. We further highlight the advantages of these microphysiological systems over conventional animal models and discuss their potential to advance mechanistic discovery, therapeutic screening, and precision medicine approaches for CAVD.