Glucose-sensitive hydrogels from covalently modified carboxylated pullulan and concanavalin A for smart controlled release of insulin

Pullulan, which is a linear glucan with non-toxicity, good biocompatibility and biodegradability, was carboxylated with succinic anhydride to yield a pullulan derivative bearing COOH groups (CPUL). The CPUL structure was determined by Fourier-transform infrared (FTIR) and 1H nuclear magnetic resonance (NMR) spectroscopies. 1H NMR integration showed that the degree of substitution of COOH residues was 0.2. A covalently modified concanavalin A (ConA)-CPUL hydrogel with glucose sensitivity was prepared by an amidization reaction between the COOH group of CPUL and the NH2 group of ConA via a safe and mild 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide activation method. Insulin-loaded CPUL-ConA (insulin/CPUL-ConA) hydrogels were prepared by absorption of insulin in situ. Analysis of the release profiles in vitro confirmed that smart controlled release of insulin from the insulin/CPUL-ConA hydrogels could be achieved because of specific ConA-glucose binding. The insulin/CPUL-ConA hydrogels showed the characteristic viscoelasticity and shear thinning properties of covalently modified hydrogels. Scanning electron microscopy showed that the hydrogels had crosslinked network structures containing uniform pores and insulin particles. This work provides a pullulan-based glucose-sensitive hydrogel that enables smart controlled release of insulin in response to changes in glucose concentration. Such hydrogels could be used in closed-loop systems for diabetes therapy.