Unravelling coupling between multiscale tissue mechanics and heart valve calcification

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Despite a high global prevalence and an immense clinical burden, the fundamental mechanisms of pathological aortic valve calcification remain largely elusive, hindering the development of potent therapeutic agents. In recent years, there has been an increasing interest in the regulatory role of mechanical forces, yet the bidirectional and spatiotemporal coupling between heterogeneous tissue mechanics and calcification remain poorly understood. In MechanoCal, I will develop a novel experimental-computational platform to unravel this complex interplay, by integrating in vitro microtissue technology, multiscale finite element modelling, and state-of-the-art multimodal characterisation techniques. I will engineer valve-mimicking, calcifying microtissues, that will be subjected to dynamic, multi-axial loading, resulting in heterogenous stresses. To quantify the tissue mechanical state, I will create a calibrated, multiscale finite element model, capturing the whole-tissue behaviour and the complex stress state around microcalcifications. I will leverage the expertise and in-house facilities for multimodal characterisation of the host group, to spatiotemporally monitor calcification and pathological cell differentiation in the microtissues. Finally, I will establish correlative maps between all the multidimensional biological, biochemical and biomechanical datasets to uncover mechanistic understanding of the complex mechanics-calcification coupling. These novel insights could impact drug discovery, cardiac biophysics modelling, and the design of tissue engineered heart valves.