Research ArticleHEALTH AND MEDICINE

Long-acting reversible contraception by effervescent microneedle patch

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Science Advances  06 Nov 2019:
Vol. 5, no. 11, eaaw8145
DOI: 10.1126/sciadv.aaw8145
  • Fig. 1 Design and fabrication of effervescent MN patches.

    Schematic illustration of the design of an MN patch with effervescent backing and of the process of MN patch application to skin to rapidly deliver MNs into the skin by fast dissolution of the effervescent backing. Photo credit: Wei Li, Georgia Tech.

  • Fig. 2 Characterization of effervescent MN patches.

    (A) Representative bright-field microscopy images of an MN patch with effervescent backing. The yellow arrows indicate the interface of the MN and backing. Scale bars, 1 mm (top) and 500 μm (bottom). (B) Scanning electron micrograph of MN array. Scale bar, 500 μm. (C) Mechanical behavior of the effervescent MN patch. (D) Scanning electron micrograph of LNG crystals extracted from MNs. Scale bar, 20 μm. (E) Size distribution of LNG crystals.

  • Fig. 3 Detachment of MNs from effervescent MN patches.

    (A) Schematic illustration of the experimental setup for the detachment test of effervescent MN patches. (B) Representative bright-field microscopy images of MN patches before (left) and immediately after (right) placement in PBS solution. The yellow arrows indicate gas bubbles generated in the effervescent backing. Scale bar, 500 μm. (C) Dissolution of the effervescent backing and detachment of MNs in PBS over time. Scale bar, 500 μm. (D) Fluorescent images of MNs separated from the patch with effervescent backing in PBS solution. Scale bars, 500 μm (left) and 200 μm (right). (E) Quantification of detachment time of 100% of MNs from patches with effervescent backing, PVA/sucrose backing, or PVP backing in PBS buffer. Each point represents mean ± SD (n = 3), **P < 0.01.

  • Fig. 4 Application of effervescent MN patches to porcine skin ex vivo.

    (A) Representative bright-field (above) and fluorescence (below) microscopy images of an effervescent MN patch with MNs containing red fluorescent dye (Nile red). Scale bars, 500 μm. (B) Representative bright-field (above) and fluorescence (below) microscopy images of porcine skin after MN patch insertion and MN detachment in porcine skin ex vivo. Scale bar, 2 mm. (C) Representative bright-field microscopy images of a residual patch after application to porcine skin. Black arrows indicate the dissolved PVP polymer in the backing at the sites of MN separation. Scale bars, 500 μm (left) and 200 μm (right). (D) Representative image of a histological section of porcine skin after MN patch insertion and separation of MNs imaged by bright-field microscopy. Scale bar, 200 μm. (E) Quantification of the efficiency of MN detachment and delivery of Nile red dye from MN patches with effervescent backing, PVA/sucrose backing, and PVP backing. Each point represents mean ± SD (n = 5), *P < 0.05. (F) Cumulative LNG release in vitro from LNG-loaded MN patches in PBST solution containing ethanol at different concentrations at 37°C, shown as a function of time. Each point represents mean ± SD (n = 3).

  • Fig. 5 LNG pharmacokinetics from effervescent MN patches in vivo.

    (A) Representative images of rat skin in vivo after MN patch application and removal showing MNs embedded in the skin by bright-field (top) and fluorescence (bottom) microscopy. Scale bar, 500 μm. (B) Representative histological section of rat skin imaged by bright-field (top) and fluorescence (bottom) microscopy, showing MNs embedded in skin after application of effervescent MN patch in vivo. Scale bar, 200 μm. (C) Representative images of rat skin are shown immediately or 1 day after application of an effervescent MN patch in vivo. Yellow arrows indicate the MN patch application site. Scale bar, 1 cm. (D) Rat plasma concentrations of LNG after administration of LNG-loaded effervescent MN patches. The therapeutic LNG level in humans is indicated by the blue dashed line. Each point represents mean ± SD (n = 10). (E) Cumulative LNG absorbed in vivo after administration of LNG-loaded effervescent MN patches as a function of time as determined by pharmacokinetic modeling of the data shown in (D). Each point represents mean ± SD (n = 10). Photo credit: Wei Li, Georgia Tech.

  • Fig. 6 Application of effervescent MN patches to human participants.

    (A) Representative bright-field microscopy images of a section of an effervescent MN patch before (top) and after (bottom) application to human skin. Scale bar, 500 μm. (B) Representative images of the site of effervescent MN patch application (yellow arrows) to the skin of a human participant over time. Inset shows magnified images of the skin application site. These images are all from the same participant. (C) Representative photographic image of skin on a human participant stained to show where a 10 × 10 array of MNs punctured into skin. Scale bar, 2 mm. (D) The efficiency of penetration and detachment of effervescent MN patches in skin of human participants. Each point represents mean ± SD (n = 3). (E) Normalized erythema intensity of human skin over time at the site of effervescent MN patch application. Each point represents mean ± SD (n = 10). (F) Preference of human participants for monthly application of effervescent MN patch compared to monthly hypodermic injection for delivery of contraceptive (n = 10). (G) Preference of human participants for monthly application of effervescent MN patch compared to daily oral administration by pill for delivery of contraceptive (n = 10). Photo credit: Wei Li, Georgia Tech.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/11/eaaw8145/DC1

    Fig. S1. Representative images of the slow dissolution of an MN patch with PVA/sucrose backing (i.e., noneffervescent) in PBS over time.

    Fig. S2. Local effects of an effervescent MN patch for LNG delivery on rat skin in vivo.

    Fig. S3. Assessment of reported pain during MN patch administration scored by participants on a visual analog scale of 0 (no pain) to 10 (pain of a hypodermic injection).

    Fig. S4. Percentage of participants showing preference for self-administration or doctor administration for future application of an effervescent MN patch for long-acting contraception.

    Table S1. Pharmacokinetic parameters of LNG following administration of effervescent MN patch containing LNG.

    Table S2. Summary of the prevalence of skin reactions at different time points after the application of effervescent MN patches to human participants.

    Movie S1. Separation of MNs from effervescence backing in PBS solution.

    Movie S2. Separation of MNs from noneffervescence backing in PBS solution.

  • Supplementary Materials

    The PDFset includes:

    • Fig. S1. Representative images of the slow dissolution of an MN patch with PVA/sucrose backing (i.e., noneffervescent) in PBS over time.
    • Fig. S2. Local effects of an effervescent MN patch for LNG delivery on rat skin in vivo.
    • Fig. S3. Assessment of reported pain during MN patch administration scored by participants on a visual analog scale of 0 (no pain) to 10 (pain of a hypodermic injection).
    • Fig. S4. Percentage of participants showing preference for self-administration or doctor administration for future application of an effervescent MN patch for long-acting contraception.
    • Table S1. Pharmacokinetic parameters of LNG following administration of effervescent MN patch containing LNG.
    • Table S2. Summary of the prevalence of skin reactions at different time points after the application of effervescent MN patches to human participants.

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    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.avi format). Separation of MNs from effervescence backing in PBS solution.
    • Movie S2 (.avi format). Separation of MNs from noneffervescence backing in PBS solution.

    Files in this Data Supplement:

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