Key Takeaways & Executive Findings
- •• • 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.
Abstract
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.
1. Introduction
Commercial hydrogels for 3D cell culture have traditionally been designed with static, elastic properties, failing to recapitulate the dynamic viscoelastic nature of native extracellular matrix (ECM). This mechanical mismatch leads to altered cell behavior, limited tissue organization, and poor outcomes in regenerative applications. Despite advances in tuning stiffness, the independent control of stress relaxation—a key viscoelastic parameter—has remained a bottleneck, as most cross-linking strategies simultaneously affect both properties. This limitation has hindered systematic studies of how viscoelasticity alone influences stem cell fate and organoid development.
This review addresses this gap by presenting rational design strategies for dynamic hydrogels that allow independent modulation of stress relaxation without significantly altering elastic modulus. By leveraging reversible cross-links with tunable kinetics, these materials enable precise control over the mechanical microenvironment. The experimental findings demonstrate that stress relaxation rates dictate stem cell lineage commitment and organoid morphogenesis, offering a powerful tool for engineering biomimetic matrices. These insights not only advance fundamental understanding of mechanotransduction but also provide practical guidelines for developing next-generation hydrogels for regenerative medicine.
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Shi Songsong, Qiu Jiaqi, Fu Zexi, Qu Xue (2026). Dynamic Hydrogels with Independently Tunable Stress Relaxation for Stem Cell Fate Regulation and Regenerative Engineering. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3749-3
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Frequently Asked Questions
What are the specific chemical strategies to decouple stress relaxation from stiffness in dynamic hydrogels?
Common strategies include using cross-linkers with controlled bond exchange rates, such as hydrazone or imine bonds, which can be tuned by pH or catalyst concentration. Another approach is to incorporate guest-host interactions (e.g., adamantane-cyclodextrin) with adjustable association/dissociation kinetics. Additionally, hydrolytically degradable units can be introduced to create time-dependent cross-link cleavage. These methods allow relaxation half-times to be varied from minutes to hours while maintaining elastic modulus within a narrow range (e.g., 1-10 kPa), as demonstrated in cited studies.
How does stress relaxation affect stem cell differentiation, and what are the underlying mechanotransduction pathways?
Faster stress relaxation promotes osteogenic differentiation of MSCs, while slower relaxation favors chondrogenesis. This is attributed to enhanced cell spreading and focal adhesion formation in fast-relaxing matrices, which activate YAP/TAZ signaling. Conversely, slow-relaxing matrices limit cell spreading and promote a round morphology, supporting chondrogenic markers. These findings are supported by experiments showing increased alkaline phosphatase activity and collagen II expression, respectively.
What are the scalability challenges for producing dynamic hydrogels with independently tunable stress relaxation for clinical translation?
Scalability challenges include batch-to-batch reproducibility in cross-linker synthesis and functionalization, as well as maintaining precise control over relaxation kinetics in large-scale production. Additionally, sterilization methods may alter cross-link dynamics. For clinical use, materials must meet regulatory standards for biocompatibility and degradation. Current studies are mostly at the lab scale, and scale-up requires optimization of synthesis and processing conditions.
How do dynamic hydrogels with tunable stress relaxation compare to natural ECM in terms of mechanical properties and cell response?
Dynamic hydrogels can be engineered to match the viscoelastic properties of specific tissues, such as brain (soft, fast-relaxing) or cartilage (stiffer, slow-relaxing). Studies show that cells cultured in these hydrogels exhibit more native-like behaviors, including enhanced spreading, migration, and differentiation, compared to elastic hydrogels. However, achieving the full complexity of ECM, including biochemical cues, remains a challenge.
What are the limitations of current dynamic hydrogels in long-term cell culture and organoid formation?
Long-term stability can be compromised due to continuous cross-link turnover, leading to matrix remodeling and potential loss of mechanical integrity. Additionally, the degradation products may affect cell viability. For organoid culture, the optimal relaxation rate may vary with developmental stage, requiring dynamic tuning over time. Current systems often lack spatiotemporal control, but recent advances in phototunable hydrogels offer potential solutions.
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