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

Nature Biomedical Engineering volume 4, pages 499–506 (2020)Cite this article

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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.

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Fig. 1: Schematic of the glucose-responsive insulin delivery system using microneedle-array patches with glucose-responsive matrix.
Fig. 2: Characterization of the GR-MN.
Fig. 3: In vivo evaluation of the GR-MN patch in an STZ-induced diabetic mouse model.
Fig. 4: In vivo evaluation of GR-MN in an STZ-induced diabetic minipig model.

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Data availability

The authors declare that all of the data supporting the findings of this study are available within the paper and the Supplementary Information.

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Acknowledgements

This work was supported by grants from Zenomics Inc. and a start-up package from University of California, Los Angeles. We acknowledge the use of the Analytical Instrumentation Facility at North Carolina State, which is supported by the State of North Carolina and National Science Foundation. A.R.K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (grant no. F30DK113728). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA

    Jicheng Yu, Jinqiang Wang, Yuqi Zhang, Guojun Chen, Yanqi Ye & Zhen Gu

  2. Zenomics Inc., Los Angeles, CA, USA

    Jicheng Yu, Yuqi Zhang, Weiwei Mao & Yanqi Ye

  3. Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA

    Jinqiang Wang, Guojun Chen & Zhen Gu

  4. California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA

    Jinqiang Wang, Guojun Chen & Zhen Gu

  5. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Anna R. Kahkoska & John B. Buse

  6. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  7. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  8. Department of Anesthesiology, Boston Children’s Hospital, Boston, MA, USA

    Robert Langer

  9. Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  10. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer

  11. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA

    Zhen Gu

  12. Center for Minimally Invasive Therapeutics, University of California, Los Angeles, Los Angeles, CA, USA

    Zhen Gu

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  1. Jicheng Yu
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Contributions

J.Y. and Z.G. conceived the study idea. J.Y., A.R.K., J.B.B., R.L. and Z.G. designed the experiments. J.Y., J.W., Y.Z., G.C., W.M. and Y.Y. performed the experiments. All authors contributed to writing the manuscript, discussing the results and implications and editing the manuscript at all stages.

Corresponding author

Correspondence to Zhen Gu.

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Competing interests

Z.G., J.Y. and G.C. have applied for patents related to this study. Z.G. is a scientific co-founder of Zenomics Inc. R.L. and J.B.B. are Scientific Advisory Board members of Zenomics Inc. J.Y., Y.Z., W.M. and Y.Y. are full-time employees of Zenomics Inc. R.L. discloses potential competing interests due to his affiliation with Zenomics Inc. For a list of entities with which R.L. is involved, compensated or uncompensated, see https://tinyurl.com/RLCOINBME. The remaining authors declare no competing interests.

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Yu, J., Wang, J., Zhang, Y. et al. Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs. Nat Biomed Eng 4, 499–506 (2020). https://doi.org/10.1038/s41551-019-0508-y

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