Injectable and degradable Poly(oligoethylene glycol methacrylate)-based hydrogels-synthetic versatility for improved biomaterial design

Introduction: Poly(ethylene glycol) (PEG)-based hydrogels are attractive biomaterials due to their hydrophilic, non-cytotoxic and non-immunogenic properties[1]. We recently reported on in situ-gelling PEG-analogue hydrogels based on poly(oligoethylene glycol methacrylate) (POEGMA) formed via rapid gelation of hydrazide and aldehyde-functionalized POEGMA oligomers upon mixing that overcome many of the limitations of conventional PEG-based hydrogels while maintaining their favorable properties[2]. By tuning the length of the oligo(ethylene glycol) side chains[3], both PEG-mimetic and thermoresponsive hydrogels can be formed[4]. However, such materials suffer from two main drawbacks: (1) their highly hydrophilic nature limits their potential for hydrophobic drug delivery and (2) their cross-link density and degradation time cannot be decoupled. Herein we report on hydrogels generated based on hydrazide and aldehyde-functionalized copolymers of OEGMA and self-associating oligo(lactic acid) methacrylate (OLA) that address this challenge. Materials and Methods: Hydrazide-functionalized poly(OEGMA-OLA) copolymers (POxOLAm-z) were prepared by free radical copolymerization of OEGMA, OLA, and acrylic acid followed by carbodiimide-mediated coupling of an excess of adipic acid dihydrazide. OEGMA monomer mixtures of 10% n=2 / 90% n=8-9 (PO10) or 100% n=8-9 (PO100) were used, where n is the number of ethylene glycol repeat units in the OEGMA monomers; the former is thermoresponsive while the latter has no phase transition temperature. OLA monomers containing m=4, 8, or 16 lactic acid repeat units were copolymerized at z=0-20 mol% to vary the hydrophobic driving force for OLA self-assembly. Cross-linking was performed using aldehyde-functionalized POEGMA polymers with the same OEGMA monomer ratio (Fig. 1). Results and Discussion: Gelation of OLA-containing oligomers was significantly faster than OEGMA-only oligomers due to the presence of the hydrophobic intrachain interactions.