Improved treatment of diabetics with glucose regulated delivery of insulin is the long term goal of this project. Glucose sensitive polymeric membranes (containing amine groups and glucose oxidase) that swell and become more permeable to insulin have been prepared. An internal pH decrease caused by gluconic acid formation in the membrane protonates the amine groups, causing electrostatic charge repulsion, consequent swelling, and enhanced insulin permeation. The preparation and characterization of new glucose sensitive membranes with improved sensitivity and extended range of operation, and the design and fabrication of delivery devices incorporating these membranes that can control the delivery of insulin under physiological conditions, are the immediate goals of the proposed research. A sequential, segmented research program will be conducted, allowing concentration of our efforts on the critical problems one at a time, in their order of importance. To enhance sensitivity, preparation and analysis of """"""""phase transition"""""""" polymers that undergo large changes in swelling over narrow pH intervals will be done in year 1. In year 2, we will develop configurations that provide higher oxygen concentration to the membrane to extend the range of sensitivity to glucose. Two design concepts to achieve this will be applied and specific embodiments of each concept will be analyzed with respect to expected performance: 1) The """"""""drum"""""""" concept: a silicon rubber air sac,, replenishable from adjacent tissue, is created in intimate contact with the glucose sensitive membrane. 2) The two-dimensional 02 delivery concept: a silicone rubber tube with a glucose sensitive membrane as a barrier to insulin delivery will permit radial 02 transport through the walls of the tube. In year three, devices incorporating the most sensitive phase transition polymer in a configuration allowing sufficient oxygen permeation will be made and experimentally evaluated by measuring in vitro insulin release rates at a series of physiological glucose concentrations. The silicone rubber tube/glucose sensitive membrane designs are intended for use in two possible modes: 1) as short term implants that are replaced frequently; and, 2) as the tip of a catheter connected to a gas pressurized reservoir and the body. Both of these device configurations are specifically proposed as methods to overcome potential limitations (due to enzyme stability and biocompatibility) of previous monolithic, long term implant designs.
