Designing Biomimetic Strain-Stiffening into Synthetic Hydrogels

Biological tissues are mechanoresponsive; that is, their properties dynamically change in response to mechanical stimuli. For example, in response to shear or elongational strain, collagen, fibrin, actin, and other filamentous biomaterials undergo dramatic strain-stiffening. Above a critical strain, their stiffness increases over orders of magnitude. While it is widely accepted that the stiffness of biological tissues impacts cell phenotype and several diseases, the biological impact of strain-stiffening remains understudied. Synthetic hydrogels that mimic the mechanoresponsive nature of biological tissues could serve as an in vitro platform for these studies. This review highlights recent efforts to mimic the strain-stiffening behavior of biological materials in synthetic hydrogels. We discuss the design principles for imparting synthetic hydrogels with biomimetic strain-stiffening, critically compare designs of strain-stiffening hydrogels that have been reported thus far, and discuss their use as in vitro platforms to probe how strain-stiffening impacts cell behavior, diseases, and other biological processes.