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Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell–matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell–cell and cell–matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell–matrix interaction, and cell–cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration.

Controlling hydrogel structures by combination of physical and chemical cross-links provides a novel system to regulate (stem) cell fate. In this study, we designed a polyethylene glycol (PEG)-based hydrogel where the polymer chains contain both physical and chemical cross-linking units in the same chain with self-assembling L-tyrosine-based dipeptides and photopolymerizable polyacrylate groups, respectively. It is shown that hydrogel architectures derived from this polymer are correlated to the cross-linking mechanisms. Combination of these cross-links controls three-dimensional gel architecture to regulate stem cell behavior in these hydrogels. Particularly, interaction of mesenchymal stem cells with the hydrogel enabled cellular aggregation to enhance chondrogenic differentiation as observed from the deposition of chondrogenic matrix. Increased chondrogenesis was due to enhanced cell-cell adhesion, which was mediated by gel morphology. This study shows the interplay of physical and chemical cross-links in hydrogels to regulate stem cell function and provides a novel molecular engineering tool for controlling hydrogel properties.

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Front Cover: http://doi.wiley.com/10.1002/mabi.201400535, G. Rajesh Krishnan, C. Cheah, and D. Sarkar show that physicochemical and mechanomorphological character of polyethylene glycol (PEG) hydrogel are modulated by a hybrid crosslinking mechanism where physical crosslinks are induced by hydrophobic selfassembling domains and chemical crosslinks are formed through photopolymerization. These hydrogels enable aggregation and organization of mesenchymal stem cells to control their functional state in 3D microenvironment. Enhanced aggregation of stem cells induced chondrogenesis by promoting deposition of chondrogenic matrix. Thus, cross‐linking engineering of PEG hydrogel provides an effective tool to control stem cell fate.