Calcific aortic valve disease (CAVD) is a common cause of mortality and morbidity in the elderly population. Due to an inadequate understanding of the mechanisms that drive the progression of aortic stenosis, there is no effective treatment for CAVD other than surgical or transcatheter valve replacement.
Although histological assessment of heart valves provides a snapshot of CAVD features, it does not reveal the complex mechanisms underlying the development of this disease. Furthermore, there are no animal models of CAVD that truly reflect human aortic disease. Our limited knowledge of the sequence of events that occur during the CAVD pathogenesis provides a major obstacle in developing medical treatments for this disease. Engineered models of valvular disease can serve a critical role in unlocking the complex pathology of CAVD, as they enable a controlled manipulation of causative connections.
This project utilises an engineered aortic valve model that mimics features found in the early and late stages of CAVD for the systematic study of CAVD pathogenesis. It utilises 3D printing and soft lithography techniques to create a CAVD model incorporating moving valves, which can be opened and closed in response to pulsatile pressure. The valves will be coated with extracellular matrix, valvular interstitial cells, and valvular endothelial cells to mimic the 3D microenvironment of the valve tissue. The model allows the stiffness, extracellular matrix thickness and composition, and stenosis level of the valves to be tuned. Using this model, we will characterise the response of valvular interstitial and endothelial cells as well as circulating immune cells and platelets to changes in hemodynamics during moderate and severe stages of CAVD in a systematic manner.
This project will provide a better understanding of the mechanisms driving CAVD progression and a platform for screening drug targets, and ultimately, the development of long sought-after medical therapy for CAVD.