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. Via 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.