Natural tissues and extracellular matrices (ECMs) are not purely elastic materials but exhibit dissipative properties. Although it has recently emerged as a novel regulator of cellular responses, the contribution of material dissipation to guiding cell-fate decisions is still in its infancy. Here, a strategy for tuning the dissipation rate of viscoplastic substrates while precisely regulating linear elasticity is reported. Semi-interpenetrating substrates consisting of a rigid hydrogel network intertwined with a branched biopolymer are described. The release of these weak physical entanglements under loading dissipates the applied stress and leads to the extension of the linear elasticity. These results reveal a crucial link between this material property and cell response in 2D cultures, impacting cell migration mode and speed, vinculin-dependent focal adhesion geometry and size, F-actin organization, the transmission of forces, and Yes-associated protein nuclear translocation. It is shown that cells require joint actomyosin contractility and microtubule tension to probe the substrate and decide whether or not to adhere, revealing a clear correlation between force transmission, substrate dissipation rate, and amount of anchoring points. Overall, these findings introduce linear elasticity as a novel design parameter for assembling tunable dissipative materials to study cell mechanosensing in 2D and possibly also in 3D cultures.
