How Matrix Viscoelasticity Affects Cell Fate

Team Dynamic Matrices | 21 August 2025

Living tissue is viscoelastic. Push on it and hold, and the resistance fades over seconds to minutes as the matrix rearranges. Most synthetic culture gels are not; they push back like a spring for as long as you hold. That difference turns out to be one of the strongest mechanical cues a cell reads, and for a long time it was invisible because the materials used to study mechanobiology could not vary it. This post walks through the experiments that changed that, in enough detail to be useful.

The distinction in one paragraph

An elastic gel stores all the energy a cell puts into it and returns it. A viscoelastic gel dissipates some of that energy through stress relaxation, and a plastic one keeps some of the deformation permanently. Covalent PEG and polyacrylamide gels are close to purely elastic. Collagen, fibrin, basement membrane and reversibly crosslinked synthetic gels are viscoelastic. A cell in a viscoelastic gel can pull ligands together, cluster integrins, and remodel its local environment in ways an elastic gel forbids. That is the mechanism (Chaudhuri et al., Nature, 2020).

The experiments

MSC lineage, Chaudhuri et al., Nature Materials, 2016. Alginate hydrogels with the same initial stiffness (about 17 kPa) but relaxation half-times from roughly one minute to over an hour. In fast-relaxing gels, MSCs spread more, proliferated more, and differentiated toward bone; in slow-relaxing gels, toward fat. The effect depended on integrin clustering and actomyosin contractility. At 9 kPa, a softer stiffness, faster relaxation still pushed osteogenesis. Stiffness was held constant; fate changed with relaxation alone.

Cell spreading and migration, Chaudhuri et al., Nature Communications, 2015. Fast relaxation increased spreading and YAP nuclear localisation in 2D and 3D, and enabled filopodia-driven migration in confining gels that elastic gels of the same stiffness blocked.

Neural progenitors, Madl et al., Nature Materials, 2017. Neural progenitor cell stemness in 3D depended on matrix remodelability rather than stiffness. Cells in non-degradable, elastic gels lost stemness; cells that could remodel their surroundings, whether by degradation or by matrix viscoelasticity, kept it. Relaxation and remodelling rivalled stiffness in deciding astrocytic versus neuronal outcomes.

Pluripotent stem cells, Indana et al., Advanced Materials, 2021. Human iPSCs formed lumen-containing cysts in viscoelastic gels but not in elastic ones of the same stiffness. The combination of viscoelasticity and adhesion signalling controlled 3D morphogenesis.

Intestinal organoids, Gjorevski et al., Nature, 2016. Stem cells expanded in stiffer PEG gels but needed a softening, remodelable environment to form crypts. Elshazly et al. and later work from the Lutolf lab extended this to showing that gel viscoelasticity influences organoid symmetry breaking.

Developing tissue, Elosegui-Artola et al., Nature Materials, 2023. In an engineered model of tissue morphogenesis, matrix viscoelasticity controlled the spatiotemporal pattern of branching, with the ratio of tissue to matrix relaxation timescales setting the outcome.

The 2020 Nature review by Chaudhuri, Cooper-White, Janmey, Mooney and Shenoy pulled these threads together: viscoelasticity is a fundamental regulator of cell behaviour, equal in standing to stiffness.

What it means for culture systems

Two consequences follow. First, a purely elastic gel presents a mechanical environment that does not occur in vivo, so results in it need to be interpreted with that in mind. Second, if you want to study relaxation, or simply to give organoids the remodelable environment they need, you need a matrix in which relaxation can be set deliberately and ideally independently of stiffness. Matrigel and older synthetic gels cannot do that.

How we designed DyNAtrix around this

DyNAtrix is a synthetic hydrogel crosslinked by short DNA duplexes. The force at which a duplex ruptures depends on its sequence and length, so the relaxation time of the gel is written into the crosslinker design. Across our crosslinker library, relaxation spans about five orders of magnitude, from sub-second to hours, from the same polymer backbone. Stiffness is set separately by polymer content. In the Nature Nanotechnology paper we used this to show that human MSCs, iPSCs, trophoblast organoids and MDCK cysts respond to relaxation at fixed stiffness, and that the right relaxation window differs by cell type (Peng et al., 2024). Viscoelasticity goes from an uncontrolled property to a designed parameter.