(775a) Adaptable Elastin-like Protein – Hyaluronic Acid (ELP – HA) Hybrid Hydrogels with Tunable Stress Relaxation Rates for Cell-Matrix Interaction Studies

Synthetic hydrogels have been widely used as in vitro models to study cell-matrix interactions and elucidate signal transduction mechanisms in biomaterials science. However, these hydrogels are typically elastic with minimal viscous dissipation, whereas native extracellular matrices (ECMs) are viscoelastic with stress relaxation characteristics. Thus, to better mimic the native cellular microenvironment and to understand the role of stress relaxation in guiding cell behaviors, we designed a viscoelastic hybrid hydrogel system consisting of protein-engineered, elastin-like protein (ELP) and chemically modified hyaluronic acid (HA). This family of adaptable ELP-HA hydrogels was formed via dynamic covalent hydrazone linkages through the reactions between hydrazine groups on ELP and aldehyde or benzaldehyde groups on HA. By combining the precise sequence control of protein-engineered materials and the kinetic features of dynamic covalent chemistry, we were able to independently tune the stress relaxation rate without causing changes to several other important matrix parameters, including polymer concentration, initial stiffness, and cell-adhesive ligand density. Human intestinal organoids were encapsulated within this family of ELP-HA hydrogels to evaluate their potential as in vitro biomimetic scaffolds for cell-matrix interaction studies. While all cultures remained highly viable, matrix stress relaxation rate appeared to influence cell proliferation rate and the ability of the cells to properly polarize and organize into an organoid-like tissue with an epithelial-coated internal lumen.