Role of Fiber Orientations in the Mechanobiology of Cells under Stretch

Abstract

Fiber reinforcement plays an important role in the structure and function of biological materials. Soft connective tissues in human body like artery, heart tissues, skin etc. exhibit anisotropic material responses due to the orientation of fibers along specific directions. At a cellular level, stress fibers in the cytoskeleton play an important role in maintaining cellular shape and influence cell adhesion, migration, and contractility. Cells respond to changes in their mechanical milieu and drive biochemical processes which induce growth and remodeling of the underlying material properties. This results in non-uniform changes to the structural form and function over time. Continuum mechanics-based approaches to address biological growth and remodeling demonstrate an intimate relationship between the cellular level mechanobiology and the underlying tissue properties. How does orientation of fibers affect mechanical response of tissues? How do mechanosensing processes influence cellular growth and remodeling under stretch? I have combined experimental techniques and analytical models, to quantify structure-property correlations in cells and biomimetic materials under stretch.

In the first study, we investigated the role of fiber orientations in the mechanics of bioinspired fiber reinforced elastomers (FRE) fabricated to mimic tissue architectures. We fabricated FRE materials in transversely isotropic layouts and characterized the nonlinear stress-strain relationships using uniaxial and equibiaxial experiments. We used these data within a continuum mechanical framework to propose a novel constitutive model for incompressible FRE materials with embedded extensible fibers. The model shows that the interaction between the fiber and matrix along with individual contributions from the matrix and fibers were crucial in capturing the stress-strain responses in the FRE composites. The deviatoric stress components show inversion at fiber orientation angles near the magic angle (54.7°) in the FRE composites. These results are useful in soft robotic applications and in the biomechanics of fiber reinforced tissues.

Secondly, we apply these formulations at a cellular level to quantify the role of stress fiber elongation and realignment to changes in cellular morphomechanics under uniaxial cyclic stretch. Cyclic uniaxial stretching results in cellular reorientation orthogonal to the applied stretch direction via a strain avoidance reaction. We show that uniaxial cyclic stretch induces stress fiber lengthening, realignment and increase in cortical actin in fibroblasts stretched over varied amplitudes and durations. Higher amounts of actin and realignment of stress fibers were accompanied with an increase in the effective elastic modulus of cells. We modelled stress fiber growth and reorientation dynamics using a nonlinear, orthotropic, fiber-reinforced continuum representation of the cell. The model predictions match the observed increased cellular stiffness under uniaxial cyclic stretch. As a final study, we have designed and fabricated a microscope mountable cell-stretching device and used it to quantify stretch-induced changes in cellular contractility by measuring the changes cellular traction forces. Our results show a significant 2 increase in cellular traction forces when subjected to prolonged duration of cyclic stretch. Together, these studies demonstrate the importance of uniaxial stretching in mechanotransduction processes which are essential in understanding growth processes and in disease models of fibrosis.