Thiol-ene photopolymerization offers a unique platform for the formation of peptide-functionalized poly(ethylene glycol) hydrogels and the encapsulation, culture and differentiation of cells. Specifically, this photoinitiated polymerization scheme occurs at neutral pH and can be controlled both spatially and temporally. Here, we have encapsulated human mesenchymal stem cells (hMSCs) in matrix metalloproteinase (MMP) degradable and cell-adhesive hydrogels using thiol-ene photopolymerization. We find that hMSCs survive equally well in this system, regardless of MMP-degradability. When hMSCs are encapsulated in these cell-degradable hydrogels, they survive and are able to proliferate. In classic hMSC differentiation medias, hMSCs locally remodel their microenvironment and take on characteristic morphologies; hMSCs cultured in growth or osteogenic differentiation media are less round, as measured by elliptical form factor, and are smaller than hMSCs cultured in chondrogenic or adipogenic differentiation media. In addition, hMSCs encapsulated in completely cell-degradable hydrogels and cultured in osteogenic, chondrogenic, or adipogenic differentiation media generally express increased levels of specific differentiation markers as compared to cells in hydrogels that are not cell-degradable. These studies demonstrate the ability to culture and differentiate hMSCs in MMP-degradable hydrogels polymerized via a thiol-ene reaction scheme and that increased cell-mediated hydrogel degradability facilitates directed differentiation of hMSCs.
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