Hydrogels cross-linked by inverse electron demand Diels–Alder
(iEDDA) click chemistry are increasingly used in biomedical applications.
With a few exceptions in naturally derived and chemically modified
macromers, iEDDA click hydrogels exhibit long-term hydrolytic stability,
and no synthetic iEDDA click hydrogels can undergo accelerated and
tunable hydrolytic degradation. We have previously reported a novel
method for synthesizing norbornene (NB)-functionalized multiarm poly(ethylene
glycol) (PEG), where carbic anhydride (CA) was used to replace 5-norbornene-2-carboxylic
acid. The new PEGNBCA-based thiol-norbornene hydrogels
exhibited unexpected fast yet highly tunable hydrolytic degradation.
In this contribution, we leveraged the new PEGNBCA macromer
for forming iEDDA click hydrogels with [methyl]tetrazine ([m]Tz)-modified
macromers, leading to the first group of synthetic iEDDA click hydrogels
with highly tunable hydrolytic degradation kinetics. We further exploited
Tz and mTz dual conjugation to achieve tunable hydrolytic degradation
with an in vitro degradation time ranging from 2 weeks to 3 months.
Finally, we demonstrated the excellent in vitro cytocompatibility
and in vivo biocompatibility of the new injectable PEGNBCA-based iEDDA click cross-linked hydrogels.
A new class of temperature responsive polymer, termed PADO, is synthesized by reversible addition-fragmentation chain-transfer polymerization. Synthesized from copolymerization of diacetone acrylamide (DAAM), di(ethylene glycol) ethyl ether acrylate, and oligo(ethylene glycol) methyl ether acrylate, PADO polymer phase separates at temperature above its lower critical solution temperature (36-42 °C) due to enhanced hydrophobic interactions between the short ethylene glycol side chains. Solution of PADO polymers exhibit injectable shear-thinning properties and reach sol-gel transition rapidly (<5 min) at 37 °C. When the ketone moieties on DAAM are linked by adipic acid dihydrazdie, PADO polymers form crosslinked and injectable acylhydrazone hydrogels, which are hydrolytically degradable at a mild acidic environment owing to the pH sensitive acylhydrazone bonds. The pH-responsive degradation kinetics can be controlled by tuning polymer contents and ketone/hydrazide ratio. Importantly, the injectable PADO hydrogels are highly cytocompatible and can be easily formulated for pH-responsive sustained protein delivery.
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