Phase-reversible glucose -sensitive hydrogels for modulated insulin delivery

It is highly desirable to develop a simple, continuous, and non-invasive insulin delivery system mimicking physiological insulin release for the control of hyperglycemia and prevention of the resulting complications. While various techniques for insulin delivery have been developed, chemically self-regulated insulin delivery systems have attracted a growing interest due to the presence of both glucose sensor and insulin delivery functions. An ideal insulin delivery system would have the capability to sense the glucose level in the blood and release insulin at an appropriate rate corresponding to the glucose level. The main goal of this study was to prepare and characterize hydrogels which undergo reversible gel-sol phase transition in response to the changes of glucose concentration. Glucose-containing polymers were prepared and characterized for allyl glucose content monomer reactivity ratio, and molecular weight. Con A conjugated with monomethoxy poly(ethylene glycol) showed increased solubility and stability in aqueous solution. Modified Con A could form hydrogels with glucose-containing polymers due to retained saccharide-binding activity. The phase diagrams for the gel formation between Con A or modified Con A and glucose-containing polymers were constructed. The mixture solutions containing modified Con A resulted in a clear gel and a sol, while Con A solutions with the copolymers resulted in various phases such as a clear gel, a turbid gel, precipitates, and a sol. The hydrogels composed of modified Con A underwent phase transition to sol in the presence of free glucose in the surrounding environment. Viscosity of the hydrogels significantly decreased by the addition of glucose to the hydrogels. The reversible phase transition between a gel and a sol was verified in response to the changes of glucose concentration over 30 days at room temperature. Insulin release study was performed using three kinds of insulin delivery systems such as membrane, matrix, and erodible matrix system. The glucose-sensitive hydrogels controlled the release rate of insulin as a function of glucose concentration. For the ideal preparations of phase-reversible glucose-sensitive hydrogels, Con A was intended to immobilize into a glucose-containing polymer. The reactive polymers were synthesized and characterized for the number of active ester groups per polymer chain.