Tuning Viscoelasticity of Dynamic Covalent Hydrogels for Human Tissue Modeling

ABSTRACT The development of three‐dimensional (3D) in vitro tissue culture models is critical for biomedical research. Hydrogel‐based systems have become preferred scaffolds for 3D models, as they have tunable viscoelastic properties, which are well‐known to influence cell morphology and function. Particularly, reversible hydrogel crosslinks formed through dynamic covalent chemistry (DCC) can introduce viscoelastic behavior including stress relaxation. However, traditional strategies to increase relaxation rates in DCC gels rely on faster bond kinetics, resulting in faster erosion rates that prevent their use for long‐term 3D culture. As an alternative strategy, we explore the use of molecular parameters (specifically molecular weight and degree of functionalization) to carefully control hydrogel stiffness and stress relaxation behavior, creating different combinations of mechanics, while preventing rapid erosion. To aid in interpreting our measurements, we develop and validate a modified theoretical model of gel viscoelasticity to account for additional relaxation process, applying it to a two‐component DCC gel composed of modified hyaluronic acid and elastin‐like protein. Finally, we utilize this tunable gel platform to explore the impact of scaffold viscoelasticity on encapsulated human neural progenitor cells. In summary, this work expands the molecular design space of DCC hydrogels to achieve tunable viscoelastic properties for 3D in vitro models.