Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs

Jicheng Yu; Jinqiang Wang; Yuqi Zhang; Guojun Chen; Weiwei Mao; Yanqi Ye; Anna R Kahkoska; John B Buse; Robert Langer; Zhen Gu

doi:10.1038/s41551-019-0508-y

Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs

Nat Biomed Eng. 2020 May;4(5):499-506. doi: 10.1038/s41551-019-0508-y. Epub 2020 Feb 3.

Authors

Jicheng Yu^{1

2}, Jinqiang Wang^{1

3

4}, Yuqi Zhang^{1

2}, Guojun Chen^{1

3

4}, Weiwei Mao², Yanqi Ye^{1

2}, Anna R Kahkoska⁵, John B Buse⁵, Robert Langer^{6

7

8

9

10}, Zhen Gu^{11

12

13

14

15}

Affiliations

¹ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.
² Zenomics Inc., Los Angeles, CA, USA.
³ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
⁶ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Anesthesiology, Boston Children's Hospital, Boston, MA, USA.
⁹ Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA. guzhen@ucla.edu.
¹² Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA. guzhen@ucla.edu.
¹³ California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA. guzhen@ucla.edu.
¹⁴ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. guzhen@ucla.edu.
¹⁵ Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, CA, USA. guzhen@ucla.edu.

Abstract

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm²). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Blood Glucose / metabolism*
Diabetes Mellitus, Experimental / blood
Disease Models, Animal
Drug Delivery Systems
Humans
Insulin / pharmacology*
Insulin Secretion / drug effects
Male
Mice, Inbred C57BL
Needles
Swine
Swine, Miniature
Transdermal Patch*

Substances

Blood Glucose
Insulin

Grants and funding

F30 DK113728/DK/NIDDK NIH HHS/United States