Mind the Viscous Modulus: The Mechanotransductive Response to the Viscous Nature of Isoelastic Matrices Regulates Stem Cell Chondrogenesis.

The design of hydrogels as mimetics of tissues' matrices typically disregards the viscous nature of native tissues and focuses only on their elastic properties. In the case of stem cell chondrogenesis, this has led to contradictory results, likely due to unreported changes in the matrices' viscous modulus. Here, by employing isoelastic matrices with Young's modulus of ≈12 kPa, variations in viscous properties alone (i.e., loss tangent between 0.1 and 0.25) are demonstrated to be sufficient to drive efficient growth factor-free chondrogenesis of human mesenchymal stem cells, both in 2D and 3D cultures. The increase of the viscous component of RGD-functionalized polyacrylamide or polyethylene glycol maleimide hydrogels promotes a phenotype with reduced adhesion, alters mechanosensitive signaling, and boosts cell-cell contacts. In turn, this upregulates the chondrogenic transcription factor SOX9 and supports neocartilage formation, demonstrating that the mechanotransductive response to the viscous nature of the matrix can be harnessed to direct cell fate.

ChondroGELesis: Hydrogels to harness the chondrogenic potential of stem cells.

The extracellular matrix is a highly complex microenvironment, whose various components converge to regulate cell fate. Hydrogels, as water-swollen polymer networks composed by synthetic or natural materials, are ideal candidates to create biologically active substrates that mimic these matrices and target cell behaviour for a desired tissue engineering application. Indeed, the ability to tune their mechanical, structural, and biochemical properties provides a framework to recapitulate native tissues. This review explores how hydrogels have been engineered to harness the chondrogenic response of stem cells for the repair of damaged cartilage tissue. The signalling processes involved in hydrogel-driven chondrogenesis are also discussed, identifying critical pathways that should be taken into account during hydrogel design.