100th Anniversary of Macromolecular Science Viewpoint: Synthetic Protein Hydrogels.

Our bodies are composed of soft tissues made of various proteins. In contrast, most hydrogels designed for biological applications are made of synthetic polymers. Recently, it is increasingly recognized that genetically synthesized proteins can be tailored as building blocks of hydrogels with biological, chemical, and mechanical properties similar to native soft tissues. In this Viewpoint, we summarize recent progress in synthetic protein hydrogels. We compare the structural and mechanical properties of different protein building blocks. We discuss various biocompatible cross-linking strategies based on covalent chemical reactions and noncovalent physical interactions. We introduce how stimulus-responsive conformational changes or intermolecular interactions at the molecular level can be used to engineer responsive hydrogels. We highlight that hydrogel network structures are as important as the protein sequences for the properties and functions of protein hydrogels and should be carefully designed. Despite great progress and potentials of synthetic protein hydrogels, there are still quite a few unsettled challenges and unexploited opportunities, providing abundant room for future investigation and development, particularly as this field is quickly expanding beyond its initial stage. We discuss a number of possible directions, including optimizing protein production and reducing cost, engineering anisotropic hydrogels to better mimic native tissues, rationally designing hydrogel mechanical properties, investigating interplays of hydrogels and residing cells for 3D cell culture and organoid construction, and evaluating long-term cytotoxicity and immune response.