Nat Mater. 2015 Nov 30. doi: 10.1038/nmat4489. [Epub ahead of print]

Hydrogels with tunable stress relaxation regulate stem cell fate and activity.

Chaudhuri O^1,2,3, Gu L^1,2, Klumpers D^1,2,4, Darnell M^1,2, Bencherif SA^1,2, Weaver JC², Huebsch N^1,5, Lee HP³, Lippens E^2,6, Duda GN⁶, Mooney DJ^1,2.

Abstract

Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel's initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.