Research ArticleAPPLIED SCIENCES AND ENGINEERING

Temporal pressure enhanced topical drug delivery through micropore formation

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Science Advances  29 May 2020:
Vol. 6, no. 22, eaaz6919
DOI: 10.1126/sciadv.aaz6919
  • Fig. 1 Temporal pressure enhanced transdermal delivery.

    (A) Schematic diagram demonstrating the effect of temporal pressure application leading to the occurrence of microphysiological changes, allowing the delivery of drugs across the skin barrier. (B) Representative images of mice with topically applied fluorescent nanoparticles (NPs) after the pressure and MN treatment. (C) Quantification of the fluorescent signal in (A). (D) Quantification of NPs in the dermis. (E) Fluorescence imaging [blue, 4′,6-diamidino-2-phenylindole (DAPI); red, NPs] of histological skin samples in (A). (F) Left: H&E staining of skin samples. Right: The appearance of mouse skin with or without the pressure treatment and MN. Scale bars, 100 μm. n = 3, all data are means ± SD, *P < 0.05. Photo credit: Daniel Chin Shiuan Lio, School of Chemical and Biomedical Engineering, Nanyang Technological University.

  • Fig. 2 Optimization of temporal pressure application.

    (A) Overview of the procedure performed to optimize pressure and application time. (B) Representative IVIS images of the mice treated with 0.28 MPa for different application times. (C) Quantification of fluorescent signal in IVIS imaging of mice treated with different pressures (0.14, 0.28, and 0.4 MPa). (D) Quantification of the fluorescent signal in IVIS imaging of mice treated with the same pressure (0.28 MPa) but with different duration (1 min, 5 min, 0.5 hours, and 1.5 hours). (E) Quantification of the fluorescent signal in the dermis of mouse skin treated with different pressures (0.14, 0.28, and 0.4 MPa). ns, not significant. (F) Quantification of fluorescent signal in the dermis of mouse skin treated with the same pressure (0.28 MPa) but with different durations (1 min, 5 min, 0.5 hours, and 1.5 hours). (G) Fluorescence imaging (blue, DAPI; red, NPs) and H&E staining of mouse skin treated with the same pressure (0.28 MPa) but with different durations (1 min, 5 min, 0.5 hours, and 1.5 hours). Scale bars, 100 μm. n = 3, *P < 0.05 and **P < 0.01. Photo credit: Daniel Chin Shiuan Lio, School of Chemical and Biomedical Engineering, Nanyang Technological University.

  • Fig. 3 Topical delivery of dextran molecules after pressure treatment.

    (A) Schematic of experiments. (B) IVIS image of mice after topical delivery of dextran molecules after the pressure treatment (C → no pressure, 1 → 1 min pressure treatment, 5 → 5 min pressure treatment). (C) Normalized quantification of dextran in treated skin in (B). (D) Fluorescence imaging (blue, DAPI; red, NPs) of histological skin samples in (B). Scale bars, 100 μm. n = 3, all data are means ± SD, *P < 0.05 and **P < 0.01. Photo credit: Daniel Chin Shiuan Lio, School of Chemical and Biomedical Engineering, Nanyang Technological University.

  • Fig. 4 Transdermal delivery of NPs in rabbit skin with the temporal pressure treatment.

    (A) IVIS fluorescence imaging of excised rabbit skin after pressure treatment and application of NPs. Circled areas represent the area of interest. (B) Fluorescence imaging (blue, DAPI; red, NPs) and H&E staining of rabbit skin after the treatment. (C) Quantification of NP fluorescence signal in (A). Scale bars, 100 μm. n = 3, all data are means ± SD, *P < 0.05. Photo credits: Daniel Chin Shiuan Lio, School of Chemical and Biomedical Engineering, Nanyang Technological University.

  • Fig. 5 Micropore formation and altered junction protein expression in pressure-treated mouse skin.

    (A) H&E staining of the mouse skin after the pressure treatment. The staining was performed 12 hours after the pressure treatment. Confocal images of pressure treated skin stained with DAPI (blue) and Cx43 (red) antibodies (B) and occludin (C). ImageJ quantification of Cx43 (D) and occludin (E) expression in the epidermis layer. Scale bars, 50 μm. n = 3, all data are means ± SD, *P < 0.05.

  • Fig. 6 Blood glucose control in normal mice with topically delivered insulin after the pressure treatment.

    (A) The change of blood glucose in the mouse circulation with topically delivered insulin after the pressure treatment, no pressure, and insulin injection over a period of 5 hours. (B) Quantification of insulin in the blood circulation after the pressure treatment and topical delivery of insulin over a period of 5 hours. n = 3, all data are means ± SD, *P < 0.05 and **P < 0.01.

  • Fig. 7 Assessing temporal pressure as a method to topically administer insulin, daily, for 5 days.

    Blood glucose control in diabetic mice for a period of 5 days with (A) control, (B) subcutaneous injection of insulin, (C) topical application of insulin, (D) topical application of insulin after MN treatment, (E) transdermal delivery of insulin with dissolvable MNs, and (F) topical application of insulin after pressure treatment. n = 3, all data are means ± SD.

Supplementary Materials

  • Supplementary Materials

    Temporal pressure enhanced topical drug delivery through micropore formation

    Daniel Chin Shiuan Lio, Rui Ning Chia, Milton Sheng Yi Kwek, Christian Wiraja, Leigh Edward Madden, Hao Chang, S. Mohideen Abdul Khadir, Xiaomeng Wang, David L. Becker, Chenjie Xu

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