Hydrolytic degradation of PEG-based thiol–norbornene hydrogels enables multi-modal controlled release

Poly(ethylene glycol) (PEG) hydrogels crosslinked by orthogonal thiol-norbornene click chemistry have emerged as an ideal platform for tissue engineering and drug delivery applications due to their rapid crosslinking kinetics and excellent biocompatibility. Norbornene-functionalized PEG (PEGNB) is routinely synthesized through the Steglich esterification of 5-norbornene-2-carboxylic acid with hydroxyl-terminated PEG. When crosslinked with thiol-bearing macromers, PEGNB hydrogels undergo slow hydrolytic degradation due to hydrolysis of ester bonds connecting a PEG backbone and a NB moiety. In prior work, we replaced the pungent and nauseous 5-norbornene-2-carboxylic acid with odorless carbic anhydride (CA) for synthesizing PEG-norbornene-carboxylate (PEGNB_CA), a new macromer that could be readily photo-crosslinked into thiol-norbornene hydrogels with faster hydrolytic degradation than the PEGNB counterparts. In this contribution, we employed a modular approach to tune the hydrolytic degradation of PEGNB_CA hydrogels over days to months. We first demonstrated the diverse crosslinking of PEGNB_CA hydrogels using either photopolymerization or enzymatic crosslinking. We characterized the hydrolytic degradation of these hydrogels under different solution pH values and temperatures. <i>Via</i> adjusting crosslinker functionality and the ratio of fast-degrading PEGNB_CA to slow-degrading PEGNB, tunable hydrolytic degradation of PEGNB_CA hydrogels was achieved from under 2 days to over 3 months. Finally, we designed the highly tunable PEGNB_CA hydrogels with varying mesh sizes, degradation rates, and covalent tethering of degradable linkers to afford long-term controlled release of model drugs.