Injectable and degradable, hydrophobically modified poly(oligoethylene glycol methacrylate) hydrogels with decoupled physicochemical and biological properties

Abstract

Event Abstract Back to Event Injectable and degradable, hydrophobically modified poly(oligoethylene glycol methacrylate) hydrogels with decoupled physicochemical and biological properties Emilia Bakaic1, Niels M. Smeets1, Spencer Imbrogno1 and Todd Hoare1 1 McMaster University, Department of Chemical Engineering, Canada 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. Small angle neutron scattering confirmed the presence of self-assembled nanodomains in OLA-containing hydrogels, and pyrene fluorescence assays confirmed their hydrophobicity. Hydrogels prepared using longer OLA monomers and/or higher OLA monomer concentrations exhibited stronger mechanics but faster degradation (Fig. 2), attributable to higher physical crosslink densities (via increased OLA self-association) effectively competing with hydrazone bond formation. This competitive cross-linking approach represents a new mechanism to decouple gel mechanics and degradability. The swelling behavior of the resulting hydrogels was not significantly affected by OLA comonomers (Fig. 3A), but bovine serum albumin (BSA) adsorption was significantly increased as more OLA (higher z) of longer chain lengths (higher m) was incorporated. Thermoresponsive PO10OLA gels further enhanced BSA uptake (Fig. 3B) while both significantly slowing release kinetics and reducing burst release (Fig 3C). Conclusions: POEGMA hydrogels hydrophobically modified via copolymerization with oligo(lactic acid methacrylate) offer significant potential to decouple otherwise correlated gel properties (for tissue engineering) and tune both the uptake and release of hydrophobic (or hydrophobic-binding) drug cargoes (for controlled release). NSERC CREATE-IDEM (Integrated Development of Extracellular Matrices) Training Program (funding); 20/20: NSERC Ophthalmic Materials Research Network (funding)