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Abstract The biochemical and biophysical properties of the extracellular matrix (ECM) play a pivotal role in regulating cellular behaviors such as proliferation, migration, and differentiation. Engineered protein‐based hydrogels, with highly tunable multifunctional properties, have the potential to replicate key features of the native ECM. Formed by self‐assembly or crosslinking, engineered protein‐based hydrogels can induce a range of cell behaviors through bioactive and functional domains incorporated into the polymer backbone. Using recombinant techniques, the amino acid sequence of the protein backbone can be designed with precise control over the chain‐length, folded structure, and cell‐interaction sites. In this review, the modular design of engineered protein‐based hydrogels from both a molecular‐ and network‐level perspective are discussed, and summarize recent progress and case studies to highlight the diverse strategies used to construct biomimetic scaffolds. This review focuses on amino acid sequences that form structural blocks, bioactive blocks, and stimuli‐responsive blocks designed into the protein backbone for highly precise and tunable control of scaffold properties. Both physical and chemical methods to stabilize dynamic protein networks with defined structure and bioactivity for cell culture applications are discussed. Finally, a discussion of future directions of engineered protein‐based hydrogels as biomimetic cellular scaffolds is concluded. 

Abstract Dynamic covalent chemistry (DCC) crosslinks can form hydrogels with tunable mechanical properties permissive to injectability and self‐healing. However, not all hydrogels with transient crosslinks are easily extrudable. For this reason, two additional design parameters must be considered when formulating DCC‐crosslinked hydrogels: 1) degree of functionalization (DoF) and 2) polymer molecular weight (MW). To investigate these parameters, hydrogels comprised of two recombinant biopolymers: 1) a hyaluronic acid (HA) modified with benzaldehyde and 2) an elastin‐like protein (ELP) modified with hydrazine (ELP‐HYD), are formulated. Several hydrogel families are synthesized with distinct HA MW and DoF while keeping the ELP‐HYD component constant. The resulting hydrogels have a range of stiffnesses,G′ ≈ 10–1000 Pa, and extrudability, which is attributed to the combined effects of DCC crosslinks and polymer entanglements. In general, lower MW formulations require lower forces for injectability, regardless of stiffness. Higher DoF formulations exhibit more rapid self‐healing. Gel extrusion through a cannula (2 m length, 0.25 mm diameter) demonstrates the potential for minimally invasive delivery for future biomedical applications. In summary, this work highlights additional parameters that influence the injectability and network formation of DCC‐crosslinked hydrogels and aims to guide future design of injectable hydrogels.