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<p>The extracellular matrix (ECM), a fundamental prerequisite for cellular viability, inherently possesses viscoelasticity—a dynamic and time-dependent mechanical property, characterized by stress relaxation, to dissipate energy that induces matrix deformation. Importantly, viscoelasticity has been demonstrated to play an irreplaceable role in directing fundamental cellular processes, including spreading, migration, proliferation, phenotype transition, and tissue organization. In the field of tissue repair and regenerative medicine, viscoelastic/dynamic hydrogels are increasingly becoming the ideal ECM-mimicking matrix for three-dimensional (3D) <i>in vitro</i> cell culture. The reversible cross-linking of dynamic hydrogels enables dynamic and continuous dissociation and recombination, thereby creating a mechanical microenvironment for cells similar to the natural viscoelasticity of ECM. However, given that matrix stiffness and stress relaxation frequently act in concert to modulate cellular behavior, the analytical scope regarding the regulatory mechanisms of individual mechanical cues remains constrained. Although progress has been made in the design of dynamic hydrogels, how to independently regulate stress relaxation without significantly altering matrix stiffness remains a key bottleneck. Here, we briefly review the viscoelastic nature of tissues and ECM, and summarize the critical strategies for the rational design of dynamic hydrogel matrices, which allow independent modulation of stress relaxation without significantly altering stiffness (elastic modulus). We then reviewed the effects of stress relaxation on organoid self-organization and cell behavior, and discussed the prospects and challenges of dynamic hydrogel matrices in controlling stem cell fate <i>in vitro</i>. Collectively, these studies not only reveal the fundamental principles of stress relaxation in regulating stem cell behavior but also provide design principles for developing biomimetic materials that match the mechanical properties of tissues and ECM, thereby advancing the precise construction of <i>in vitro</i> stem cell culture models in regenerative medicine.</p>

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Dynamic hydrogels with independently tunable stress relaxation for stem cell fate regulation and regenerative engineering

  • 期刊论文

  • 发表日期：

    2026年1月29日

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  • Songsong Shi,
  • Jiaqi Qiu,
  • Zexi Fu,
  • Xue Qu

摘要

The extracellular matrix (ECM), a fundamental prerequisite for cellular viability, inherently possesses viscoelasticity—a dynamic and time-dependent mechanical property, characterized by stress relaxation, to dissipate energy that induces matrix deformation. Importantly, viscoelasticity has been demonstrated to play an irreplaceable role in directing fundamental cellular processes, including spreading, migration, proliferation, phenotype transition, and tissue organization. In the field of tissue repair and regenerative medicine, viscoelastic/dynamic hydrogels are increasingly becoming the ideal ECM-mimicking matrix for three-dimensional (3D) in vitro cell culture. The reversible cross-linking of dynamic hydrogels enables dynamic and continuous dissociation and recombination, thereby creating a mechanical microenvironment for cells similar to the natural viscoelasticity of ECM. However, given that matrix stiffness and stress relaxation frequently act in concert to modulate cellular behavior, the analytical scope regarding the regulatory mechanisms of individual mechanical cues remains constrained. Although progress has been made in the design of dynamic hydrogels, how to independently regulate stress relaxation without significantly altering matrix stiffness remains a key bottleneck. Here, we briefly review the viscoelastic nature of tissues and ECM, and summarize the critical strategies for the rational design of dynamic hydrogel matrices, which allow independent modulation of stress relaxation without significantly altering stiffness (elastic modulus). We then reviewed the effects of stress relaxation on organoid self-organization and cell behavior, and discussed the prospects and challenges of dynamic hydrogel matrices in controlling stem cell fate in vitro. Collectively, these studies not only reveal the fundamental principles of stress relaxation in regulating stem cell behavior but also provide design principles for developing biomimetic materials that match the mechanical properties of tissues and ECM, thereby advancing the precise construction of in vitro stem cell culture models in regenerative medicine.