• • Stress relaxation in hydrogels can be independently tuned by adjusting the kinetics of reversible cross-links, such as hydrazone bonds, without significantly altering elastic modulus; for example, hydrogels with relaxation half-times ranging from minutes to hours were achieved while maintaining stiffness within a narrow range (e.g., 1-10 kPa). This decoupling is critical for dissecting the individual roles of viscoelasticity in cell behavior, enabling precise design of ECM mimics for tissue engineering.
• • Faster stress relaxation (relaxation half-time < 1 h) promotes mesenchymal stem cell (MSC) spreading and osteogenic differentiation, as evidenced by increased alkaline phosphatase activity and mineral deposition, compared to slower relaxing gels (half-time > 10 h). This finding guides the design of hydrogels for bone regeneration, where rapid stress dissipation facilitates cell-mediated matrix remodeling.
• • Slower stress relaxation (half-time > 10 h) supports chondrogenic differentiation of MSCs, with higher expression of collagen II and aggrecan, suggesting that viscoelasticity can be tailored to direct lineage commitment. This is clinically relevant for cartilage repair, where a stable, slow-relaxing matrix may better mimic native tissue.
• • Dynamic hydrogels with independently tunable stress relaxation have been used to culture organoids with improved self-organization and function; for instance, intestinal organoids exhibited enhanced budding efficiency (e.g., 2-fold increase) when cultured in fast-relaxing matrices compared to stiff, elastic gels. This demonstrates the potential of viscoelastic hydrogels to recapitulate developmental processes in vitro, advancing organoid technology for drug screening and regenerative medicine.