Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 27, Pages 8260-8265Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1505405112
Keywords
diabetes; drug delivery; glucose-responsive; hypoxia-sensitive; microneedle
Categories
Funding
- State of North Carolina
- National Science Foundation
- American Diabetes Association [1-14-JF-29, 1-15-ACE-21]
- North Carolina Translational and Clinical Sciences Institute
- NIH Clinical and Translational Science Awards program (NIH) at the University of North Carolina at Chapel Hill [1UL1TR001111]
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A glucose-responsive closed-loop insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (smart insulin patch) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GO(x)) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
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