Abstract Proteolytically degradable hydrogels are widely used as delivery carriers in regenerative medicine. However, the in vivo degradation rate of these materials is difficult to control because of site‐specific enzymatic activity, implant design, and disease state, impairing tissue regeneration. Hydrogels with crosslinks that degrade hydrolytically offer an alternate route to tune in vivo degradation profile. In this study, a synthetic 4‐arm maleimide‐terminated poly(ethylene glycol) (PEG‐4MAL) hydrogel system that combines hydrolytic ester‐linked PEG‐4MAL (PEG‐4eMAL) macromer with nondegradable amide‐linked PEG‐4MAL (PEG‐4aMAL) macromer in various stoichiometric ratios to tune the degradability rate is engineered. The macromers are crosslinked with dithiothreitol (DTT) via thiol‐maleimide click reaction. Rheological analysis shows that a family of PEG‐4eMAL/PEG‐4aMAL hydrogels has equivalent mechanical properties, but increasing the PEG‐4eMAL content increases the rate of degradation in vitro and in vivo. PEG‐4eMAL/PEG‐4aMAL hydrogels support high viability of encapsulated human cells. Notably, the ratio of PEG‐4eMAL/PEG‐4aMAL modulates local immune cell recruitment when implanted in the subcutaneous space. These results establish the use of PEG‐4eMAL/PEG‐4aMAL hydrogels as a hydrolytically degradable platform to tune in vivo degradation and immune responses.
Hunckler et al. (2025) studied this question.