Injectable hydrogel systems based on thermo-sensitive polymer for delivering bioactive agents

Abstract

Pluronic F127, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, is well known material for its thermally induced reversible sol-gel transition behavior above critical gelation concentration owing to micelle packing mechanism. Because of different low critical solution temperature of each block, the micelle structure is obtained above around 15 ℃ and more micelles are formed as temperature increases. This temperature sensitive property have attracted a lot of interests in biomedical field especially for therapeutic agent delivery carriers due to high water contents and soft texture similar with extracellular matrix, but its low mechanical strength limits clinical applications. The micelle packing behaviors in Pluronic F127 hydrogel can be controlled by simple end group modification, resulting to drastic changes in gelation behavior. In chapter 2, the micelle packing abilities were compared by observing gelation behaviors with different interactions. After the adamantane groups were conjugated to the terminal end of Pluronic F127, the critical gelation concentration was increased, suggesting hindered micelle packing. The introduction of β-cyclodextrin polymer, however, significantly facilitated hydrogel formation owing to host-guest interactions between β-cyclodextrin and adamantane groups. The interactions between micelles are considered as a key factor to determine overall gelation behavior of Pluronic F127 hydrogel. From the understandings of Pluronic F127 hydrogel, the possibility of delivery carriers was evaluated. In chapter 3, Pluronic F127 multiblock copolymers were conjugated to several functional proteins for delivering bioactive agents including proteins and cells. Gelatin was utilized for cell delivery carrier due to its abundant Arg-Gly-Asp sequences which can provide cell adhesion site and albumin and lysozyme were introduced into the hydrogel matrix for charge interaction mediated sustained protein release behavior. To overcome the viscosity problem cause by high molecular weight of Pluronic F127 multiblock copolymer, differently modified Pluronic F127 blend system was designed in chapter 4. The resultant hydrogel showed highly increased stability in physiological environment and used for islet cell delivery system. From in vivo experiments, the high glucose level of mice with diabetes was controlled around 200 mg/dl for 2 weeks. Overall, the hydrogels are thought to be a promising delivery carrier for proteins and cells.