Characterization of glucose-mediated insulin release from implantable polymers.

We characterized a glucose-sensitive, controlled-release insulin delivery system. Insulin release rates increased when glucose was perfused in the release media surrounding the matrix. The system was composed of solid, particulate insulin, incorporated into an ethylene-vinyl acetate copolymer (EVAc) matrix. Feedback control was mediated by the glucose oxidase enzyme immobilized to Sepharose beads, which were incorporated along with insulin into the EVAc matrix. When glucose in solution entered the insulin delivery system, gluconic acid was produced, causing a drop in the microenvironmental pH of the matrix. This fall in pH resulted in a rise in insulin solubility and consequently a rise in the insulin release rate from the matrix. Insulin concentrations increased in vitro and in vivo in response to glucose infusion. The increased insulin release was shown to consist of a finite pulse of insulin that required an optimal recovery period of 1 h to achieve a maximal repeated response to a glucose stimulus. Repeated pulses were demonstrated over a 4 h period. An optimum enzyme ratio was also determined.