Cell Activities on Viscoelastic Substrates Show an Elastic Energy Threshold and Correlate with the Linear Elastic Energy Loss in the Strain‐Softening Region

Abstract Energy‐sensing in viscoelastic substrates has recently been shown to be an important regulator of cellular activities, modulating mechanical transmission and transduction processes. Here, this study fine‐tunes the elastic energy of viscoelastic hydrogels with different physical and chemical compositions and shows that this has an impact on cell response in 2D cell cultures. This study shows that there is a threshold value for elastic energy (≈0.15 J m −3 ) above which cell adhesion is impaired. When hydrogels leave the linear stress–strain range, they show softening (plastic) behavior typical of soft tissues. This study identifies a correlation between the theoretical linear elastic energy loss in the strain‐softening region and the number of cells adhering to the substrate. This also has implications for the formation of vinculin‐rich anchorage points and the ability of cells to remodel the substrate through traction forces. Overall, the results reported in this study support that the relationship between cell activities and energy‐sensing in viscoelastic substrates is an important aspect to consider in the development of reliable ex vivo models of human tissues that mimic both normal and pathological conditions.