Browsing by Subject "Heart valve"
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Item An integrated computational-experimental approach for the in situ estimation of valve interstitial cell biomechanical state(2016-05) Buchanan, Rachel Marie; Sacks, Michael S.; Baker, Aaron B; Stachowiak, Jeanne C; Moon, Tess J; Guilak, FarshidMechanical forces are known to regulate aortic valve interstitial cell (AVIC) functional state by modulating their biosynthetic activity, translating to differences in tissue composition and structure and, potentially, leading to aortic valve (AV) dysfunction. While advances have been made toward the understanding of AVIC behavior ex-situ, the AVIC biomechanical state in its native extracellular matrix (ECM) remains largely unknown. Consequently, changes in AVIC behaviors, such as stiffness and contractility, resulting from pathological cues in-situ remain unidentified. We hypothesize that improved descriptions of AVIC biomechanical state in-situ, obtained using an inverse modeling approach, will provide deeper insight into AVIC interactions with the surrounding ECM, revealing important changes resulting from pathological state, and possibly informing pharmaceutical therapies. To achieve this, a novel integrated numerical-experimental framework to estimate AVIC mechanobiological state in-situ was developed. Flexural deformation of intact AV leaflets was used to quantify the effects of AVIC stiffness and contraction at the tissue level. In addition to being a relevant deformation mode of the cardiac cycle, flexure is highly sensitive to layer-specific changes in AVIC biomechanics. As a first step, a tissue-level bilayer model that accurately captures the bidirectional flexural response of AV intact layers in a passive state was developed. Next, tissue micromorphology was incorporated in a macro-micro scale framework to simulate layer-specific AVIC-ECM interactions. The macro-micro AV model enables the estimation of changes in effective AVIC stiffness and contraction in-situ that are otherwise grossly inaccessible through experimental approaches alone. Finally, microindentation studies examining AVIC activation were run in parallel with in-situ studies to emphasize the necessity of an in-situ approach, and the advantage it affords over existing ex-situ methodology. In conclusion, the developed numerical-experimental methodology can be used to obtain AVIC properties in-situ. Most importantly, it can lead to further understanding of AVIC-ECM mechanical coupling under various pathophysiological conditions and the investigation of possible treatment strategies targeting the myofibroblast phenotype characteristic of early signs of sclerotic valvular disease.Item One cell as a mixture : simulation of the mechanical responses of valve interstitial cells(2016-08) Sakamoto, Yusuke; Sacks, Michael S.; Prudhomme, Serge; Gonzalez, Oscar; Ghattas, Omar; Rodin, Gregory J; Guilak, FarshidThe 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.Item Remodeling of the mitral valve : an integrated approach for predicting long-term outcomes in disease and repair(2019-12) Rego, Bruno Vale; Sacks, Michael S.; Baker, Aaron B; Yankeelov, Thomas E; Gorman, Robert CMitral regurgitation (MR) is the most prevalent valvular heart disease, afflicting 2.5% of the western-world population, and is becoming the next cardiac epidemic. MR is characterized by incomplete closure of the mitral valve (MV) caused by either primary (myxomatous degeneration and rheumatic fever) or secondary (ischemic left ventricular remodeling) etiologic factors. Ischemic MR (IMR) afflicts at least 300,000 Americans annually, an alarmingly high number that keeps rising as the population ages and grows. IMR is present in over 50% of patients with reduced left ventricular function induced by myocardial infarction. There are two major treatment strategies for IMR: valve replacement and valve repair. Although repair has long been embraced as the preferred treatment strategy, almost one third of patients experience recurrence of MR within a year of treatment. While new concepts and techniques for MV repair are continually emerging, these novel approaches must be developed with a profound understanding of MV tissue structure and mechanical behavior, which will depend on placing the MV in a larger context of overall left heart function. In addition, a detailed connection must be drawn between stress/strain at the tissue level and cellular deformation, as well as the remodeling pathways triggered via mechanotransduction in response to disease-induced alterations in geometric boundary conditions. In carrying out the research presented in this dissertation, I have aimed to address the questions of when, how, and to what extent the MV apparatus tissues physically remodel in the presence of both pathological (e.g., infarction) and non-pathological (e.g., pregnancy) perturbations to cardiac function. Additionally, I have built advanced computational finite element models to simulate the mechanical effects of disease on valvular function, and to relate disease progression to cellular and tissue-level remodeling phenomena. In parallel, I used state-of-the-art imaging and mechanical characterization tools to develop specialized structural constitutive models for valvular tissues that quantify the effects of microstructural and morphological heterogeneity on local tissue and cellular deformation, both of which play a large role in mediating valvular maintenance (in homeostasis) and remodeling (under non-homeostatic conditions such as disease). The ultimate goal of this work was to progress toward more generalized models of valvular remodeling following perturbations to cardiac function. This, in turn, will lay the groundwork for models that can better predict the outcomes of MV repair, and thus will facilitate the development of computational tools to design and optimize surgical repair strategies in silico