Mechanical Analysis of Single Myocyte Contraction in a 3D Viscoelastic Gel

Abstract

Objective: Under congenital or acquired pathological conditions, excessive mechanical stress in myocardium leads to arrhythmias and heart failure, yet mechano-chemo-transduction (MCT) mechanisms are poorly understood at the single cell level during heart disease development. We recently developed a novel Cell-in-Gel system, embedding isolated live myocytes in a constraining hydrogel, to study MCT mechanisms under various mechanical scenarios.Methods: A mechanical model is used to calculate time-varying displacement, strain, and stress fields present during ongoing Cell-in-Gel experiments. Our previous 3D analytical solution of a single contracting myocyte embedded in an infinite elastic matrix (based on the Eshelby Inclusion problem) is extended to include the effects of Gel (matrix) viscosity. The model is calibrated by viscoelastic characterization of the Gel of various cross-linker densities using a dynamic rotary rheometer.Results: The analytical model enables quick parametric studies to establish trends with Gel stiffness and viscosity. As previously found for a purely elastic matrix, the stress state within the cell is multi-axial and uniform, yet cell surface tractions are quite non-uniform, and a typical cardiomyocyte in a gel of similar stiffness can contract only 20% of its load-free fractional shortening. The presence of Gel viscosity, however, adds a time lag between strains and stresses in both the cell and Gel and causes an increase in energy and mechanical power requirements for cell contraction.Conclusions: The mechanical model provides a baseline prediction (without up-regulation of Ca2+ transients) of the response of the myocyte during contraction in-gel. With preload or afterload, Cell-in-Gel data show stronger fractional shortening than predicted, so the model effectively quantifies this contractility enhancement (related to the Anrep effect). Thus, our analysis method can be used to quantitatively inform ongoing MCT studies that link mechanical stress to cardiac function and remodeling.