Dynamic freedom: substrate stress relaxation stimulates cell responses

Tissue engineers have explored a set of materials cues that can allow control of cell viability and guide cell fate and functions. Although the effect of substrate stiffness on cell fate has been extensively studied and established, the role of substrate stress relaxation, the ability of a substrate to dissipate cell-induced forces, is only emerging. Recently, several studies have demonstrated that substrate stress relaxation is an important mechanical cue for cell spreading, proliferation and differentiation in vitro. In this mini-review, we highlight the influence of substrate stress relaxation on cell behavior and function as well as provide future perspectives. Firstly, we describe the methods used for characterizing the stress relaxation/creep responses of hydrogels along with the molecular origin of viscoelastic properties. Then, we highlight the most recent studies elucidating the stress relaxation effect on cellular behavior using physically cross-linked hydrogels. Finally, we report on an emerging alternative design of tunable viscoelastic hydrogels: chemically cross-linked (reversible linkages) adaptable hydrogels that have been used as stable 3D cell culture platforms for a few years in the era of hydrogel systems.