The further development of glucose sensitive membranes to control insulin delivery at rates which vary with glucose concentration is the goal of the proposed research. The original concept of producing polymers which swell in response to elevated glucose concentrations and allow greater transport of insulin from a reservoir has been demonstrated. The utility of these membranes under conditions approximating their eventual use in an insulin delivery device will be determined in the proposed studies.
The aims of the new investigations are to measure insulin transport through glucose sensitive membranes of the present as well as improved design under conditions which test the ability of the membranes to control insulin delivery in a physiologically useful way. Specifically, the following parameters will be measured: insulin permeation rates in the absence of glucose and in the presence of a series of constant, physio-logically-relevant glucose concentrations; the kinetics of changes in permeability induced by controlled increases and decreases in glucose level; the reproducibility of the glucose response; and finally, the long-term stability of the membrane's capability for glucose response. Insulin transport studies will be performed with iodide free 125I insulin prepared with a new procedure developed in our lab and verified with an independent method (immunoassay or colorimetrically). A specially designed transport cell permitting glucose solutions to be pumped through the downstream compartment will be used. The radiation induced polymerization of frozen monomer solutions used successfully to date will continue to be used for membrane preparation. The optimization of the insulin transport properties of the present glucose sensitive membranes will be carried out by designing, preparing and characterizing new membranes formulated with differing ratios of each of the chemical constituents of the membranes. Preparation of membranes with improved swelling and mechanical properties will be done with new monomers. The achievement of improved response time by formulation of the membrane as a very thin """"""""skin"""""""" membrane bonded to another, highly porous membrane will also be performed. The response of the optimized membranes to glucose will be evaluated after contact with blood and with soft tissue. The tissue response to the optimized membranes implanted subcutaneously and intraperitoneally will be evaluated. A second generation implantable delivery device employing optimized glucose sensitive membranes will be developed and tested by implantation in mice.
