The role of non-linear viscoelastic hydrogel mechanics in cell culture and transduction

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

The mechanical complexity of the extracellular matrix (ECM) is central to how cells sense and respond to their environment, yet hydrogel design has often focused narrowly on stiffness. Emerging evidence highlights the importance of viscoelastic stress relaxation and plasticity in cell mechanotransduction. However, a key aspect remains underexplored: non-linear viscoelasticity, where stress relaxation and plasticity depend on the magnitude of applied stress or strain. In this perspective, we examine how such non-linear mechanical behaviors manifest in widely used hydrogels and discuss their biological relevance. We present experimental approaches, including oscillatory shear rheology, to detect non-linear viscoelastic effects, and introduce mathematical modeling approaches to interpret these behaviors. We find evidence in literature that several hydrogels commonly used in cell culture exhibit non-linear viscoelasticity occurring at stress and strain levels relevant to cell-generated forces. Specifically, both softening and stiffening hydrogels were found to exhibit accelerated stress relaxation or increased plasticity due to nonlinear viscoelasticity. By viewing non-linearity as a tunable design parameter, future hydrogel systems may better recapitulate the dynamic mechanical feedback loops cells experience in native tissues. This perspective encourages a paradigm shift in bioma

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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