Injectable Acylhydrazone-Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation

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 degrees 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 degrees 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.