title: Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery.
abstract: 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 (GOx) 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.
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695; Molecular Pharmaceutics Division and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Jicheng
authors.initials: J
authors.lastname: Yu
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695; Molecular Pharmaceutics Division and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695; Molecular Pharmaceutics Division and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695; Molecular Pharmaceutics Division and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Rocco
authors.initials: R
authors.lastname: DiSanto
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695; Molecular Pharmaceutics Division and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Wujin
authors.initials: W
authors.lastname: Sun
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695;
authors.forename: Davis
authors.initials: D
authors.lastname: Ranson
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695;
authors.forename: Frances S
authors.initials: FS
authors.lastname: Ligler
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27695; Molecular Pharmaceutics Division and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599 zgu@email.unc.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005947:Glucose / Q000378:metabolism; D005949:Glucose Oxidase / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry; D000860:Hypoxia / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D010084:Oxidation-Reduction; D015203:Reproducibility of Results
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D006820:Hyaluronic Acid; D005949:Glucose Oxidase; D005947:Glucose
keywords: diabetes; drug delivery; glucose-responsive; hypoxia-sensitive; microneedle