title: Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery.
abstract: A glucose-responsive closed-loop insulin delivery system represents the ideal treatment of type 1 diabetes mellitus. In this study, we develop uniform injectable microgels for controlled glucose-responsive release of insulin. Monodisperse microgels (256 ± 18 μm), consisting of a pH-responsive chitosan matrix, enzyme nanocapsules, and recombinant human insulin, were fabricated through a one-step electrospray procedure. Glucose-specific enzymes were covalently encapsulated into the nanocapsules to improve enzymatic stability by protecting from denaturation and immunogenicity as well as to minimize loss due to diffusion from the matrix. The microgel system swelled when subjected to hyperglycemic conditions, as a result of the enzymatic conversion of glucose into gluconic acid and protonation of the chitosan network. Acting as a self-regulating valve system, microgels were adjusted to release insulin at basal release rates under normoglycemic conditions and at higher rates under hyperglycemic conditions. Finally, we demonstrated that these microgels with enzyme nanocapsules facilitate insulin release and result in a reduction of blood glucose levels in a mouse model of type 1 diabetes.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
authors.forename: Tram T
authors.initials: TT
authors.lastname: Dang
authors.forename: Minglin
authors.initials: M
authors.lastname: Ma
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Tang
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Dong
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002384:Catalysis; D048271:Chitosan / Q000737:chemistry; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004798:Enzymes / Q000737:chemistry*; D005782:Gels; D005942:Gluconates / Q000737:chemistry; D005947:Glucose / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000188:drug therapy; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D046529:Microscopy, Electron, Transmission; D053769:Nanocapsules / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D004337:Drug Carriers; D004798:Enzymes; D005782:Gels; D005942:Gluconates; D007328:Insulin; D053769:Nanocapsules; D011994:Recombinant Proteins; D048271:Chitosan; D005947:Glucose; C030691:gluconic acid