Dynamic Hydrogels with Independently Tunable Stress Relaxation for Stem Cell Fate Regulation and Regenerative Engineering
The extracellular matrix (ECM) is a viscoelastic material that dissipates energy through stress relaxation, a time-dependent mechanical property crucial for directing cellular processes such as spreading, migration, proliferation, and differentiation. Dynamic hydrogels with reversible cross-links mimic this viscoelasticity, offering a promising platform for 3D cell culture and regenerative medicine. However, independently controlling stress relaxation without altering stiffness remains a major challenge. This review summarizes strategies for designing dynamic hydrogels that decouple stress relaxation from elastic modulus, and examines the effects of stress relaxation on stem cell fate and organoid self-organization. Key approaches include adjusting cross-linker kinetics, using guest-host interactions, and incorporating hydrolytically degradable units. Studies show that faster stress relaxation enhances cell spreading, proliferation, and osteogenic differentiation, while slower relaxation supports chondrogenesis. These findings underscore the importance of viscoelastic cues in stem cell regulation and provide design principles for biomimetic matrices. The review also discusses challenges in translating these materials to clinical applications, such as scalability and long-term stability. Ultimately, dynamic hydrogels with tunable stress relaxation hold significant potential for advancing in vitro stem cell culture models and regenerative therapies.