Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第14836号 / 工博第3133号 / 新制||工||1469(附属図書館) / 27242 / UT51-2009-F478 / 京都大学大学院工学研究科マイクロエンジニアリング専攻 / (主査)教授 小寺 秀俊, 教授 北條 正樹, 教授 田畑 修 / 学位規則第4条第1項該当

The applications of elastic membrane range from determining the mechanical properties of biological cells by indentation tests to predicting the deformed shape of a large commercial tent structure. In this work, direct membrane theory and a particular Varga strain energy function are used to model the indentation and puncturing of an isotropic spherical elastic membrane containing a fluid with a rigid indenter. The balance laws are applied to obtain the governing differential equations and numerical shooting method is used to solve them. Furthermore, a global mode of failure is established by computing the energy stored at the punctured membrane and this value determines a critical value for the energy of the membrane beyond which the punctured state of the membrane is energetically preferred. An additional mode of failure is identified in which the membrane loses local convexity requirements and it corresponds to the local loss of elastic behavior of the membrane. / Graduate / 0548 / deris@Uvic.ca

In the classic Hill model for muscle contraction, the split between the muscle and tendon is arbitrary and the problem lacks a unique solution. Instead of reformulating the problem to a differential-algebraic equation and solving for a set of initial conditions, a constant tendon length is commonly assumed in musculoskeletal simulation tools. This assumption has not been thoroughly tested and introduces errors of unknown magnitude to the simulations. In this thesis, the contractile element of the Hill model is modelled as a friction clutch in parallel to a viscous damper. This provides an evolution law for the muscle length by which the muscle speed is numerically calculated taking into account a non-zero tendon speed. A simple biceps curl is simulated with the friction clutch model and compared to corresponding commercial musculoskeletal simulations. Overall, the results are similar, in particular for the muscle lengths which are almost identical in every simulation (0.00-0.42% difference). The difference in tendon speed is 0.00-3.26%, with upwards tendencies. In general, the error percentage of the tendon speed appears to decrease by the same amount that the contraction speed is reduced. Conclusively, it can be said that the introduced friction clutch model delivers comparative outcomes to a commercial musculoskeletal simulation software, while not assuming a constant tendon length. However, while presenting a relatively simple solution, an increased computation time is to be expected due to the need of a differential equation solver. Further investigation regarding implementation and computing times in more complex simulations may provide an alternative approach to conventional musculoskeletal simulations.

Calcific aortic valve disease (CAVD) is one of the most common causes of cardiovascular disease in North America. Mechanical factors have been closely linked to the pathogenesis of CAVD and may contribute to the disease by actively regulating the mechanobiology of valve interstitial cells (VICs). Mechanical forces affect VIC function through interactions between the VIC and the extracellular matrix (ECM). Studies have shown that the transfer of mechanical stimulus during cell-ECM interaction depends on the local material properties at hierarchical length scales encompassing tissue, cell and cytoskeleton. In this thesis, biomechanical tools were developed and applied to investigate hierarchical cell-ECM interactions, using VICs and valve tissue as a model system. Four topics of critical importance to understanding VIC-ECM interactions were studied: focal biomechanical material properties of aortic valve tissue; viscoelastic properties of VICs; transduction of mechanical deformation from the ECM to the cytoskeletal network; and the impact of altered cell-ECM interactions on VIC survival. To measure focal valve tissue properties, a micropipette aspiration (MA) method was implemented and validated. It was found that nonlinear elastic properties of the top layer of a multilayered biomaterial can be estimated by MA by using a pipette with a diameter smaller than the top layer thickness. Using this approach, it was shown that the effective stiffness of the fibrosa layer is greater than that of the ventricularis layer in intact aortic valve leaflets (p<0.01). To characterize the viscoelastic properties of VICs, an inverse FE method of single cell MA was developed and compared with the analytical half-space model. It was found that inherent differences in the half-space and FE models of single cell MA yield different cell viscoelastic material parameters. However, under particular experimental conditions, the parameters estimated by the half-space model are statistically indistinguishable from those predicted by the FE model. To study strain transduction from the ECM to cytoskeleton, an improved texture correlation algorithm and a uniaxial tension release device were developed. It was found that substrate strain fully transfers to the cytoskeletal network via focal adhesions in live VICs under large strain tension release. To study the effects of cell-ECM interactions on VIC survival, two mechanical stimulus systems that can simulate the separate effects of cell contraction and cell monolayer detachment were developed. It was found that cell sheet detachment and disrupted cell-ECM signaling is likely responsible for the apoptosis of VICs grown in culture on thin collagen matrices, leading to calcification. The studies presented in this thesis refine existing biomechanical tools and provide new experimental and analytical tools with which to study cell-ECM interactions. Their application resulted in an improved understanding of hierarchical valve biomechanics, mechanotransduction, and mechanobiology.

Calcific aortic valve disease (CAVD) is one of the most common causes of cardiovascular disease in North America. Mechanical factors have been closely linked to the pathogenesis of CAVD and may contribute to the disease by actively regulating the mechanobiology of valve interstitial cells (VICs). Mechanical forces affect VIC function through interactions between the VIC and the extracellular matrix (ECM). Studies have shown that the transfer of mechanical stimulus during cell-ECM interaction depends on the local material properties at hierarchical length scales encompassing tissue, cell and cytoskeleton. In this thesis, biomechanical tools were developed and applied to investigate hierarchical cell-ECM interactions, using VICs and valve tissue as a model system. Four topics of critical importance to understanding VIC-ECM interactions were studied: focal biomechanical material properties of aortic valve tissue; viscoelastic properties of VICs; transduction of mechanical deformation from the ECM to the cytoskeletal network; and the impact of altered cell-ECM interactions on VIC survival. To measure focal valve tissue properties, a micropipette aspiration (MA) method was implemented and validated. It was found that nonlinear elastic properties of the top layer of a multilayered biomaterial can be estimated by MA by using a pipette with a diameter smaller than the top layer thickness. Using this approach, it was shown that the effective stiffness of the fibrosa layer is greater than that of the ventricularis layer in intact aortic valve leaflets (p<0.01). To characterize the viscoelastic properties of VICs, an inverse FE method of single cell MA was developed and compared with the analytical half-space model. It was found that inherent differences in the half-space and FE models of single cell MA yield different cell viscoelastic material parameters. However, under particular experimental conditions, the parameters estimated by the half-space model are statistically indistinguishable from those predicted by the FE model. To study strain transduction from the ECM to cytoskeleton, an improved texture correlation algorithm and a uniaxial tension release device were developed. It was found that substrate strain fully transfers to the cytoskeletal network via focal adhesions in live VICs under large strain tension release. To study the effects of cell-ECM interactions on VIC survival, two mechanical stimulus systems that can simulate the separate effects of cell contraction and cell monolayer detachment were developed. It was found that cell sheet detachment and disrupted cell-ECM signaling is likely responsible for the apoptosis of VICs grown in culture on thin collagen matrices, leading to calcification. The studies presented in this thesis refine existing biomechanical tools and provide new experimental and analytical tools with which to study cell-ECM interactions. Their application resulted in an improved understanding of hierarchical valve biomechanics, mechanotransduction, and mechanobiology.