In Vivo Performance and Biocompatibility of a Subcutaneous Implant for Real-Time Glucose-Responsive Insulin Delivery

An implantable, glucose-responsive insulin delivery microdevice was reported previously by our group, providing rapid insulin release in response to hyperglycemic events and efficacy in vivo over a 1-week period when implanted intraperitoneally in rats with diabetes. Herein, we focused on the improvement of the microdevice prototype for long-term glycemic control by subcutaneous (SC) implantation, which allows for easy retrieval and replacement as needed. To surmount the strong immune response to the SC implant system, the microdevice was treated by surface modification with high-molecular-weight polyethylene glycol (PEG). In vitro glucose-responsive insulin release, in vivo efficacy, and biocompatibility of the microdevice were studied. Modification with 20-kDa PEG chains greatly reduced the immune response without a significant change in glucose-responsive insulin release in vitro. The fibrous capsule thickness was reduced from approximately 1,000 mu m for the untreated devices to 30-300 mu m for 2-kDa PEG-treated and to 30-50 mu m for 20-kDa PEG-treated devices after 30 days of implantation. The integrity of the glucose-responsive bioinorganic membrane and the resistance to acute and chronic immune response were improved with the long-chain 20-kDa PEG brush layer. The 20-kDa PEG-treated microdevice provided long-term maintenance of euglycemia in a rat model of diabetes for up to 18 days. Moreover, a consistent rapid response to short-term glucose challenge was demonstrated in multiple-day tests for the first time on rats with diabetes in which the devices were implanted. The improvement of the microdevice is a promising step toward a long-acting insulin implant system for a true, closed-loop treatment of diabetes.