Modulation of Thiol–Ene Coupling by the Molecular Environment of Polymer Backbones for Hydrogel Formation and Cell Encapsulation

Thiol–ene radical coupling is increasingly used for the biofunctionalization of biomaterials and the formation of 3D hydrogels enabling cell encapsulation. Indeed, thiol–ene chemistry presents interesting features that are particularly attractive for platforms requiring specific reactions of peptides or proteins, in particular in situ, during cell culture or encapsulation: thiol–ene coupling occurs specifically between a thiol and a nonactivated alkene (unlike Michael addition); it is relatively tolerant to the presence of oxygen; and it can be triggered by light. Despite such interest, little is known about the factors impacting polymer thiol–ene chemistry in situ. Here, we explore some of the molecular parameters controlling photoinitiated thiol–ene coupling (with UV and visible-light irradiation), with a series of alkene-functionalized polymer backbones. 1H NMR spectroscopy is used to quantify the efficiency of couplings, whereas photorheology allows correlation to gelation and mechanical properties of the resulting materials. We identify the impact of weak electrolytes in regulating coupling efficiency, presumably via thiol deprotonation and regulation of local diffusion. The conformation of associated polymer chains, regulated by the pH, is also proposed to play an important role in the modulation of both thiol–ene coupling and cross-linking efficiencies. Ultimately, suitable conditions for cell encapsulations are identified for a range of polymer backbones and their impact on cytocompatibility is investigated for cell encapsulation and tissue engineering applications. Overall, our work demonstrates the importance of polymer backbone design to regulate thiol–ene coupling and in situ hydrogel formation.