Unravelling coupling between multiscale tissue mechanics and heart valve calcification

尽管病理性主动脉瓣钙化的全球患病率高，临床负担沉重，但其基本机制仍在很大程度上难以捉摸，阻碍了有效治疗药物的发展。近年来，人们对机械力的调节作用越来越感兴趣，但异质组织力学与钙化之间的双向和时空耦合仍然知之甚少。在MechanoCal，我将开发一个新的实验计算平台，通过整合体外显微组织技术，多尺度有限元建模和最先进的多模态表征技术来解开这种复杂的相互作用。我将设计模拟阀门的，钙化的微组织，使其承受动态的，多轴载荷，产生非均质应力。为了量化组织力学状态，我将创建一个校准的多尺度有限元模型，捕捉整个组织的行为和微钙化周围的复杂应力状态。我将利用专业知识和内部设备对宿主群体进行多模式表征，以时空监测显微组织中的钙化和病理细胞分化。最后，我将建立所有多维生物、生化和生物力学数据集之间的相关图，以揭示复杂力学-钙化耦合的机制理解。这些新的见解可能会影响药物发现、心脏生物物理建模和组织工程心脏瓣膜的设计。

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.