Bioengineering Approaches to Control Micromechanics for Analysis of Cardiomyocyte Contractility

Bioengineering techniques, including use of biological microelectromechanical systems (BioMEMS), advanced imaging methods, and biomechanical theory and modeling provides a means to study cardiomyocyte contractility. By fabricating BioMEMS devices, cardiomyocytes are plated on substrates under more realistic physiological conditions including mimicking of a three-dimensional (3D) system and modification to substrate stiffness. Initial studies relate to remodeling characteristics of neonatal rat ventricular myocytes in 3D with such microtopography surfaces of different stiffness with respect to time. These four-dimensional (3D + time) studies are then furthered in regard to cardiomyocyte contractility, including maximum shortening, shortening velocity, and force generation, expressed as surface stress and surface tension. These studies provided a greater understanding of how cardiomyocyte structure affects contractility in the localized microenvironment. The use of bioengineering techniques to characterize the cardiomyocyte form-function relationship was then extended towards a clinical application. By utilizing human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), modeling of human disease and therapeutic treatments is available. In these studies, iPSC-CMs were derived from family members that either did or did not possess a cardiac troponin T point mutation. This mutation causes a desensitized thin filament to calcium, leading to a dilated cardiomyopathy. Initial studies focused on the differences of sarcomere development (alpha-actinin expression) and function (maximum shortening, shortening velocity) of the normal and mutation iPSC-CMs over time when plated on relatively soft substrates. Studies then focused on a means to rescue the mutation cells through use of a myosin activator, Omecamtiv Mecarbil, for development of a therapeutic treatment in clinical conditions. Mutation iPSC-CMs, when continuously treated with Omecamtiv Mecarbil, were found to assist in restoring the thin filament sensitivity to calcium at a more physiological range and functional equivalent to normal iPSC-CMs. These studies demonstrate the value of using bioengineering techniques for both basic science and clinical applications.