Engineering Synthetic Insulin-Secreting Cells Using Hyaluronic Acid Microgels Integrated with Glucose-Responsive Nanoparticles

Abstract

Diabetes is a major public health problem currently affecting 382 million people across the world. A synthetic insulin delivery system that mimics the function of insulin-secreting cells and continuously releases insulin in response to blood glucose level changes holds great promise in improving the quality of life for diabetics. Here we report a new glucose-responsive formulation for self-regulated delivery of insulin using injectable hyaluronic acid (HA) microgels (µHA, average diameter: 5.9 ± 2.3 µm) integrated with acid-degradable ketal-modified dextran-based glucose responsive nanoparticles (GRN, average diameter: 226.9 ± 20.6 nm). Packed with insulin and a glucose-specific enzyme (glucose oxidase, GOx) by a double-emulsion method, the dextran nanoparticles can be dissolved and subsequently release insulin in a hyperglycemic state, triggered by the enzymatic conversion of glucose into gluconic acid. To further avoid the burst release, reduce loss of enzymes, and facilitate administration, we integrated nanoparticles into HA microgels, crosslinked through an emulsion procedure. In vitro studies demonstrated that the insulin release rate associated with HA microgels was effectively regulated by changes in the glucose concentration. In vivo studies, in which chemically-induced type 1 diabetic mice were subcutaneously injected with the microgels, validated that a single injection of the developed formulation stabilized the blood glucose levels in the normoglycemic state (<200 mg/dL) for over 1 week.