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Engineering Synthetic Insulin-Secreting Cells Using Hyaluronic Acid Microgels Integrated with Glucose-Responsive Nanoparticles

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Abstract

Diabetes is a major public health problem currently affecting 382 million people across the world. A synthetic insulin delivery system that mimics the function of insulin-secreting cells and continuously releases insulin in response to blood glucose level changes holds great promise in improving the quality of life for diabetics. Here we report a new glucose-responsive formulation for self-regulated delivery of insulin using injectable hyaluronic acid (HA) microgels (µHA, average diameter: 5.9 ± 2.3 µm) integrated with acid-degradable ketal-modified dextran-based glucose responsive nanoparticles (GRN, average diameter: 226.9 ± 20.6 nm). Packed with insulin and a glucose-specific enzyme (glucose oxidase, GOx) by a double-emulsion method, the dextran nanoparticles can be dissolved and subsequently release insulin in a hyperglycemic state, triggered by the enzymatic conversion of glucose into gluconic acid. To further avoid the burst release, reduce loss of enzymes, and facilitate administration, we integrated nanoparticles into HA microgels, crosslinked through an emulsion procedure. In vitro studies demonstrated that the insulin release rate associated with HA microgels was effectively regulated by changes in the glucose concentration. In vivo studies, in which chemically-induced type 1 diabetic mice were subcutaneously injected with the microgels, validated that a single injection of the developed formulation stabilized the blood glucose levels in the normoglycemic state (<200 mg/dL) for over 1 week.

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Acknowledgments

This work was supported by the grants from the American Diabetes Association (ADA) to Z.G. (1-14-JF-29 and 1-15-ACE-21) and the grant from NC TraCS, NIH’s Clinical and Translational Science Awards (CTSA, NIH grant 1UL1TR001111) at UNC-CH.

Conflict of interest

Jin Di, Jicheng Yu, Yanqi Ye, Davis Ranson, Abhilasha Jindal and Zhen Gu declare that they have no conflicts of interest.

Ethical Standards

No human studies were carried out by the authors for this article. All animal studies were carried out in accordance with institutional, national, international guidelines and approved by the Institutional Animal Care and Use Committee at North Carolina State University and University of North Carolina at Chapel Hill.

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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, 27695, USA

      Jin Di, Jicheng Yu, Yanqi Ye, Davis Ranson, Abhilasha Jindal & Zhen Gu

    2. Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

      Jin Di, Jicheng Yu, Yanqi Ye & Zhen Gu

    3. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

      Zhen Gu

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    1. Jin Di
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    2. Jicheng Yu
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    Correspondence to Zhen Gu.

    Additional information

    Associate Editor Nicholas Peppas oversaw the review of this article.

    This article is part of the 2015 Young Innovators Issue.

    Zhen Gu received his B.S. degree in Chemistry and M.S. degrees in Polymer Chemistry and Physics from Nanjing University. In 2010, he obtained Ph.D. degree at the University of California, Los Angeles, under the guidance of Prof. Yi Tang in the Department of Chemical and Biomolecular Engineering. He was a postdoctoral associate working with Prof. Robert Langer at Massachusetts Institute of Technology and Harvard Medical School during 2010 to 2012. He is currently an Assistant Professor in the Joint Department of Biomedical Engineering at the University of North Carolina at Chapel Hill and North Carolina State University. He also holds joint positions in the Molecular Pharmaceutics Division in the UNC Eshelman School of Pharmacy and Endocrinology and Metabolism Division in the Department of Medicine. His group studies controlled drug delivery, bio-inspired materials and nanobiotechnology. He has published over 50 research papers and applied 20 patents. He is the recipient of the Pathway Award and Junior Faculty Award of the American Diabetes Association and the Sigma Xi Young Faculty Research Award.

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    Jin Di and Jicheng Yu have contributed equally to the study.

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    Di, J., Yu, J., Ye, Y. et al. Engineering Synthetic Insulin-Secreting Cells Using Hyaluronic Acid Microgels Integrated with Glucose-Responsive Nanoparticles. Cel. Mol. Bioeng. 8, 445–454 (2015). https://doi.org/10.1007/s12195-015-0390-y

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    • DOI: https://doi.org/10.1007/s12195-015-0390-y

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