Structure–reactivity based control of radical-mediated degradation in thiol–Michael hydrogels

Thiol-Michael addition reactions are widely used for forming cytocompatible and well-defined hydrogels. Numerous types of Michael acceptors have been implemented in these reactions; while maleimides enable rapid crosslinking under physiological conditions and are commonly used for their simplicity, slower-reacting electrophiles such as vinyl sulfones and acrylates offer distinct advantages including improved network homogeneity and ease of handling because of the slower reaction rates. Additionally, thiol-acrylate adducts are hydrolytically labile, whereas thiol-vinyl sulfone adducts are comparably more stable in aqueous environments. Building on our previous work demonstrating radical-mediated degradation of thiol-maleimide hydrogels, we sought to determine whether other thiol-Michael adducts are similarly susceptible to cleavage by radical species. Using both linear and network-forming polymer systems, we found that both Michael-adduct types undergo radical-mediated degradation to varying extents. Furthermore, acrylates are far more prone to radical homopolymerization, enabling semi-orthogonal degradation modes in hydrogels, wherein hydrolytic and radical responses are independently programmed according to the chemical structure and stoichiometric excess of the Michael acceptor. Extending the results of these findings in networks synthesized <i>via</i> thiol-Michael addition, we also observed similar radical-mediated degradation behavior in thiol-norbornene networks formed <i>via</i> thiol-ene photopolymerization, suggesting that even electron-rich thioethers are degradable under sufficiently aggressive initiation conditions where the concentration of radicals exceeds that of the crosslinks. Together, these results extend the chemical space for engineering hydrogels with variable degradation profiles and illustrate design principles for tuning material responses to multiple chemical stimuli.