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

doi:10.1038/s41551-019-0508-y

. 2020 May;4(5):499-506.

doi: 10.1038/s41551-019-0508-y. Epub 2020 Feb 3.

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

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.

PMID: 32015407
PMCID: PMC7231631
DOI: 10.1038/s41551-019-0508-y

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

Jicheng Yu et al. Nat Biomed Eng. 2020 May.

. 2020 May;4(5):499-506.

doi: 10.1038/s41551-019-0508-y. Epub 2020 Feb 3.

Authors

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.

PMID: 32015407
PMCID: PMC7231631
DOI: 10.1038/s41551-019-0508-y

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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Conflict of interest statement

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.

Figures

**Fig. 1 |. Schematic of the glucose-responsive insulin delivery system using microneedle-array patches with glucose-responsive matrix.**
a, Schematic of the fabrication process of a glucose-responsive insulin patch from a silicone mould using an in situ photopolymerization strategy. b, Mechanism of glucose-triggered insulin release from GR-MNs. Upon exposure to a hyperglycaemic state, the increased negative charges resulting from the formation of the glucose-boronate complexes can weaken the electrostatic interaction between negatively charged insulin and polymers and induce the volume variation of polymeric matrix, promoting the quick release of insulin from the microneedles. Glucose levels of diabetic pigs can be effectively regulated by the administration of a glucose-responsive insulin patch. c, Characterization of the GR-MN. (i) Photograph of the GR-MN patch. (ii) Scanning electron microscopy image of the microneedle array. Scale bar, 500 μm. (iii) Microscopy (top) and fluorescence microscopy (bottom) images of the rhodamine B-labelled insulin (red)-loaded microneedle patch. Scale bar, 500μm.

**Fig. 2 |. Characterization of the GR-MN.**
a, Mechanical behaviour of the GR-MNs. b, Glucose-lowering activity of the insulin extracted from the freshly prepared patch in diabetic mice (n = 5). Initial glucose levels were compared with glucose levels at 60 min post-injection of insulin solution. c, Glucose-lowering activity of the insulin extracted from the patches stored at room temperature in diabetic mice (n = 5). d, Glucose concentration-dependent glucose-binding capability of the glucose-responsive polymeric matrix (n = 3). e, In vitro accumulated insulin release of the glucose-responsive polymeric matrix (n = 3) in several glucose concentrations at 37°C. f, Pulsatile release profile showing the rate of insulin release from the glucose-responsive polymeric matrix (n = 3) as a function of the glucose concentration (blue: 100 mgdl⁻¹; red: 400 mgdl⁻¹). Inb-f, data are presented as mean ± s.d.

**Fig. 3 |. In vivo evaluation of the GR-MN patch in an STZ-induced diabetic mouse model.**
a, Mouse dorsum skin (the area within the blue dashed line) transcutaneously treated with a microneedle patch. b,c, PGLs (b) and plasma human insulin concentrations (c) in STZ-induced diabetic mice (n = 5) after treatment with PBS, subcutaneous insulin solution (insulin dose: 0.05 mg), the CR-MN patch (insulin dose: 0.5 mg) or the GR-MN patch (insulin dose: 0.5 mg). SC, subcutaneous. Statistical significance for comparison of the GR-MN and CR-MN groups was determined by two-tailed Student’s f-test (from left to right in b: ***P = 2.94×10⁻⁴ at 4h; ***P = 1.29×10⁻⁵ at 6 h; ***P = 1.16×10⁻⁵ at 8 h; ***P = 1.09×10⁻⁵ at 10 h; *P = 0.0478 at 12 h; from left to right in c: **P = 6.42×10⁻³ at 4h; ***P = 1.21×10⁻⁴ at 6h; ***P= 9.45×10⁻⁴ at 8h; **P= 2.14×10⁻³ at 12h). d, In vivo intraperitoneal glucose tolerance test in diabetic mice (n = 5) at 4h post-administration of GR-MN or CR-MN compared with healthy control mice. Glucose dose: 1.5gkg⁻¹. Statistical significance for comparison of the GR-MN and CR-MN groups was determined by two-tailed Student’s f-test (**P= 2.13 ×10⁻³ at 20 min; ***P = 5.76 × 10⁻⁵ at 30 min; ***P = 8.89×10⁻⁶ at 40 min; ***P = 1.64×10⁻⁶ at 50 min; ***P = 1.18 × 10⁻⁶ at 60 min; ***P = 5.06 × 10⁻⁸ at 80 min; ***P = 1.96 × 10⁻⁸ at 100 min; ***P = 1.02 × 10⁻⁷ at 120min).e, Responsiveness in diabetic mice (n = 5) was calculated based on the area under the curve (AUC) from 0–120min, with the baseline set at the 0-min plasma glucose reading. Statistical significance was determined by two-tailed Student’s f-test (***P = 6.26 ×10⁻⁹). f, In vivo glucose-responsive insulin release promoted by intraperitoneal glucose challenge at 4h post-administration of GR-MN in diabetic mice (n = 5). Glucose dose: 3gkg⁻¹. In b,c, the blue arrows indicate the time points of microneedle administration. In d,f, the red arrows indicate the time points of glucose administration. In b-f, data are presented as mean ± s.d.

**Fig. 4 |. in vivo evaluation of GR-MN in an STZ-induced diabetic minipig model.**
a, Top: schematic of a minipig treated with GR-MN at the leg site and monitored with a CGMS. Bottom left: photograph of a GR-MN patch applied on a minipig’s leg. Bottom right: haematoxylin and eosin-stained section of minipig skin penetrated by one microneedle. Scale bar, 200 μm. b,c, PGLs in STZ-induced diabetic minipigs (n = 3) after treatment with GR-MN (b) and CR-MN (c). Insulin dose: 7 mg. d, In vivo oral glucose tolerance test in diabetic minipigs (n = 3) at 4h post-administration of GR-MN or CR-MN. Glucose dose: 1 gkg⁻¹. e, Responsiveness in diabetic minipigs (n = 3) was calculated based on the AUC from 0–150 min, with the baseline set at the 0-min plasma glucose reading. Statistical significance was determined by two-tailed Student’s f-test (**P = 1.27 ×10⁻³). OGTT, oral glucose tolerance test. f, In vivo glucose-responsive insulin release promoted by intravenous glucose challenge at 4h post-administration of the GR-MN patches in diabetic minipigs (n = 3). Glucose dose: 0.7g kg⁻¹. The detection range of CGMS was 40–400 mgdl⁻¹. In b,c, the blue arrows indicate the time points of microneedle administration and the pink arrows indicate the time points of feeding. In d,f, the red arrows indicate the time points of glucose administration. In d-f, data are presented as mean ± s.d.

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References

1. Veiseh O, Tang BC, Whitehead KA, Anderson DG & Langer R Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug Discov 14, 45–57 (2015). - PMC - PubMed
1. Ohkubo Y et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract 28, 103–117 (1995). - PubMed
1. Owens DR, Zinman B & Bolli GB Insulins today and beyond. Lancet 358, 739–746 (2001). - PubMed
1. Bakh NA et al. Glucose-responsive insulin by molecular and physical design. Nat. Chem 9, 937–943 (2017). - PubMed
1. Yu J, Zhang Y, Bomba H & Gu Z Stimuli-responsive delivery of therapeutics for diabetes treatment. Bioeng. Transl. Med 1, 323–337 (2016). - PMC - PubMed

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[1] Veiseh O, Tang BC, Whitehead KA, Anderson DG & Langer R Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug Discov 14, 45–57 (2015). - PMC - PubMed

[2] Veiseh O, Tang BC, Whitehead KA, Anderson DG & Langer R Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug Discov 14, 45–57 (2015). - PMC - PubMed

[3] Ohkubo Y et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract 28, 103–117 (1995). - PubMed

[4] Ohkubo Y et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract 28, 103–117 (1995). - PubMed

[5] Owens DR, Zinman B & Bolli GB Insulins today and beyond. Lancet 358, 739–746 (2001). - PubMed

[6] Owens DR, Zinman B & Bolli GB Insulins today and beyond. Lancet 358, 739–746 (2001). - PubMed

[7] Bakh NA et al. Glucose-responsive insulin by molecular and physical design. Nat. Chem 9, 937–943 (2017). - PubMed

[8] Bakh NA et al. Glucose-responsive insulin by molecular and physical design. Nat. Chem 9, 937–943 (2017). - PubMed

[9] Yu J, Zhang Y, Bomba H & Gu Z Stimuli-responsive delivery of therapeutics for diabetes treatment. Bioeng. Transl. Med 1, 323–337 (2016). - PMC - PubMed

[10] Yu J, Zhang Y, Bomba H & Gu Z Stimuli-responsive delivery of therapeutics for diabetes treatment. Bioeng. Transl. Med 1, 323–337 (2016). - PMC - PubMed

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

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

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