Extracellular matrix compliance influences cellular adhesion and migration, proliferation and apoptosis,
and differentiation. Much of our current knowledge of the effects of substrate stiffness on cellular behavior is based on elastic substrates, in particular cross‐linked polyacrylamide hydrogels. Biological tissues, however, are viscoelastic and exhibit stress relaxation and energy dissipation on physiologically relevant timescales. While emerging evidence suggests that these physical properties also influence cellular behavior, materials in which viscoelasticity can be precisely engineered are currently lacking. Here, we describe programmable hydrogel matrices assembled from artificial recombinant proteins designed to be cross‐linked by covalent bonds involving cysteine residues, by association of helical domains as coiled coils, or by both mechanisms. Using these proteins, we construct chemical, physical, and chemical‐physical hydrogel networks that deform elastically or viscoelastically depending on the type of cross‐linking (Dooling et al., Adv. Mater., 2016, 28, 4651–4657). In viscoelastic networks, the amount of stress relaxation is tuned by controlling the ratio of physical cross‐linking to chemical crosslinking, and the timescale for stress relaxation is tuned over five orders of magnitude by single point mutations to the coiled‐coil physical cross‐linking domain (Dooling and Tirrell, ACS Cent. Sci., 2016, 2,
812–819). The genetic engineering approach also allows biological activity to be encoded directly within
the protein sequence in the form of cell‐adhesive domains and proteolytic cleavage sites. The capacity to program the viscoelasticity and biological activity of hydrogel matrices is anticipated to have applications in studying and engineering cell‐matrix interactions
