Distortion Energy Drives Cellular and Mechanical Changes in Fibroblast-Seeded Collagen Scaffolds Under Cyclic Loading

Fibroblast activity in soft tissues is highly regulated by the mechanical environment of the extracellular matrix. Physical thresholds that regulate fibroblast-mediated remodeling have been previously identified using stress or strain invariants, but these thresholds depend on loading configuration, precluding the formulation of a unifying theory to predict cell response across loading environments. An alternative approach for predicting matrix remodeling is to use distortion energy, a scalar measure of deformation that accounts for both stress and strain. Here we explore whether distortion energy can predict cellular and mechanical changes across three cyclic loading configurations: uniaxial tension, uniaxial compression, and biaxial tension-compression. Collagen scaffolds were seeded with murine fibroblasts and mechano-stimulated for 7 days with a multi-axial bioreactor that cyclically applied approximately 40 J/m3 of strain energy for all loading types (error < 1%). We measured the mechanical properties of the cell-seeded constructs, before and after stimulation, and quantified cell density and fiber alignment using confocal microscopy. Multiple regression analysis revealed that changes in cell density across loading configurations had the greatest correlation with distortion energy (partial r = 0.85, p = 0.001), rather than traditional stress and strain invariants (e.g., first principal, von Mises). Distortion energy also had strong positive correlations with tensile stiffness, but not compressive properties. Overall, this study found distortion energy to be the best predictor of cellular and mechanical changes across simple and complex loads, suggesting that distortion energy may be a key physical driver for fibroblast activity and matrix remodeling.