Matrix stiffness plays an important role in stem cell differentiation. This study reports the synthesis of methacrylated hyaluronan (MeHA) with different degrees of methacrylation, ranging from 15 to 140% per disaccharide unit, which corresponds to a matrix stiffness ranging from 1.5 to 8 KPa. The swelling ratio was inversely proportional to the matrix stiffness, but the water content remained constant at >97% of the hydrogel mass. A fibril-like surface morphology and larger pore size were observed in lyophilized MeHA hydrogel with a lower stiffness. The matrix stiffness also affected the degradability of the MeHA hydrogel, where softer MeHA hydrogels (MeHA and MeHA ) were completely degraded within 6 days and a stiffer MeHA hydrogel (MeHA ) was able to retain ∼25% of its initial mass after 30 days. Subsequently, the crosslinked MeHA hydrogel was used as a scaffold to encapsulate human adipose-derived stem cells (hADSCs). The embedded cells remained viable and expressed ∼11-fold higher levels of aggrecan and 42-fold higher levels of collagen type II in MeHA compared with ADSCs cultured in HA-coated wells. In addition, cells grown in MeHA exhibited the highest rates of glycosaminoglycan and collagen type II synthesis of ∼5 ng/DNA and 0.4 ng/DNA, respectively. Immunofluorescence staining showed an increase of collagen type II synthesis in MeHA , MeHA and MeHA . This study showed that the matrix stiffness of a hydrogel can be modulated by the degree of methacrylation, thus affecting the efficacy of chondrogenesis in hADSCs. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 808-816, 2018.

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