One cell as a mixture : simulation of the mechanical responses of valve interstitial cells

The function of the heart valve interstitial cells (VICs) are intimately connected to heart valve tissue remodeling and repair as well as initiation of pathological processes. It is known that excessive and persisting environmental changes cause the improper regulations of VICs, and a clinically significant valve pathology may result. Much of VIC function is modulated through changes in stress fiber activation, resulting in part from changes in external loading by the surrounding extracellular matrix (ECM) and cytokines. Thus, current research challenges aim at characterizing the mechanisms that activate VIC contractility, and at modeling the mechanical interactions of contractile VICs with the surrounding valve matrix. Especially, many questions remain as how stress fibers develop active contractile forces under varying normal and pathological conditions. The main objective of this dissertation is to develop a novel computational model of a VIC capable of describing its mechanical response under different external stimuli and activation states. To this end, solid mixture model framework of a VIC is developed, where the VIC cytoplasm is treated as a solid mixture of two phases: isotropic cytoskeleton and stress fibers with some orientations. The stress fiber model is then incrementally extended to capture more and more complex mechanical responses of VICs. The finite element simulations are performed with the aid of experimental data to investigate how the internal mechanics of VICs, such as solid cytoskeletal network, contracting stress fibers, and cell nucleus, affect the mechanical responses of VICs within a native tissue. The development of the computational model of a VIC as well as its numerical implementation are critical to study the heart valve disease in cellular level because of the complexity of the mechanisms and difficulty of directly analyzing the subcellular mechanics. The computational model in conjunction with experimental data provide insight into how the VICs respond within the native valve tissue, and how the heart valve disease may initiate. This dissertation is the first step towards developing prevention mechanisms and cure for the heart valve disease from cellular and subcellular levels.