Abstract

The purpose of this Ph.D project was to study the mechanism of pH- and glucose-responsiveness and properties of polymeric composite membranes containing pH-sensitive poly(N-Isopropylacrylamide-co-metharcylic acid) hydrogel nanoparticles for controlled drug delivery, and to develop a closed-loop glucose-responsive insulin delivery device using these pH-sensitive hydrogel nanoparticles. The internal pH kinetics and spatial distribution of the membranes were studied using a ratiometric fluorescence dye pH mapping methodology. Approaches to improving the physicochemical and mechanical properties of the stimuli-responsive membranes were explored. Finally, a closed-loop glucose-responsive insulin delivery device regulating insulin delivery in response to changes in glucose concentration was developed and tested under in vitro conditions in this thesis.

The pH- and glucose-responsiveness for drug permeation through the membranes resulted from the dynamic internal pH changes in response to changes in external pH and glucose concentration. The faster and greater internal pH reduction was observed in response to the elevation of external glucose concentration. Glucose concentration-dependent internal pH gradients were observed in membranes during the glucose-enzyme reaction.

The mechanical and physicochemical properties and pH-responsive solute permeability of the membranes were significantly improved with the rational use of dibutyl sebacate. Further increase in dibutyl sebacate content (>10%) did not improve the mechanical and physicochemical properties of the plasticized membranes, and resulted in decreased pH-responsive solute permeability of the membranes. The hydrophobicity of the membranes increased with an increase in dibutyl sebacate content.

A novel closed-loop glucose-responsive insulin delivery device employing the pH-sensitive hydrogel nanoparticles to regulate insulin release in response to real-time changes in glucose concentration was successfully developed. The chemical and physical stability of insulin released from the insulin delivery device were preserved. These in vitro test results provided the potential to evaluate the in vivo hyperglycemic depression effects of the closed-loop insulin delivery device in future studies. This Ph.D project provides new insights into the rational design of a closed-loop glucose-responsive insulin delivery device simulating the physiological function of a healthy pancreas for use in improved diabetes treatment.