Independently Tunable Viscoelasticity in Hydrogels as a Mechanical Cue for Tissue Engineering.

Abstract

The mechanical properties of the extracellular matrix (ECM) play a critical role in regulating cellular behavior and fate. In the design and application of tissue engineering materials, previous studies have primarily focused on the role of material stiffness (elastic modulus) in modulating cellular events. However, biological tissues and the ECM exhibit more complex mechanical behaviors, such as viscoelasticity, highlighting the importance of considering viscoelasticity as a design parameter for biomaterials. Current biomimetic strategies might place less emphasis on the dynamic mechanical microenvironment of viscoelastic ECMs. Emerging evidence suggests that independently tuning the viscoelasticity of matrices can influence cellular biological processes and enhance tissue regeneration outcomes. This review highlights the emerging focus on independently tunable viscoelastic hydrogels and their potential applications in tissue engineering. In this article, we review the design of hydrogels with adjustable viscoelasticity aimed at guiding cellular and tissue behavior, advancing the development of in vitro cell culture models and in vivo regenerative therapies. This review introduces the concept of viscoelasticity, elaborates on the viscoelastic properties of biological tissues, and summarizes commonly used evaluation metrics and characterization techniques for viscoelasticity. Next, it highlights the strategies for constructing hydrogels with tunable viscoelasticity and discusses the regulatory effects of viscoelasticity on cellular behaviors, along with the associated mechanobiological mechanisms and signaling pathways. Finally, the review provides an overview of the current applications of viscoelastic hydrogels in tissue engineering and offers perspectives on future research directions.Impact StatementViscoelasticity is an essential but often overlooked mechanical property that governs cellular behaviors and tissue remodeling. Recent advances reveal that cells actively sense and respond to viscoelastic cues, influencing adhesion, migration, differentiation, and proliferation. By examining emerging hydrogel designs with independently tunable viscoelasticity, we highlight their potential to enhance cell-instructive biomaterials, improve organoid models, and enable personalized regenerative therapies. This review provides a comprehensive perspective on viscoelasticity-driven cell regulation and offers insights into future directions for designing biomaterials that better mimic native tissue mechanics.