Research ArticleDrug Delivery

Snake fang–inspired stamping patch for transdermal delivery of liquid formulations

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Science Translational Medicine  31 Jul 2019:
Vol. 11, Issue 503, eaaw3329
DOI: 10.1126/scitranslmed.aaw3329
  • Fig. 1 Design of the snake fang–inspired stamping patch.

    (A) Illustrations of the venom delivery system of the rear-fanged snake. Venom from the Duvernoy’s gland runs along the grooved fang and rapidly flows, under capillary action, into the tissue of the prey. (B) Photograph of the snake fang–inspired MN array. The inset shows a scanning electron microscopy image of the MG-MN, which has two distinct parts: a nongrooved tip and a grooved wing. After the nongrooved tip pierces the skin, the grooved wing forms a conduit with the wall of the incised skin. (C) Photograph of the integrated MN patch held on a human fingertip. The patch consists of an MN array and a PDMS chamber. The inset shows an MN formed over a thin PEG-DA film that has microholes (diameter, 20 μm) through which liquid formulations can trickle out of the chamber (drug outlet). (D) Conceptual diagrams of the patch. Liquid drugs are loaded into the chamber through the inlet of the reservoir before use. When the patch is applied over the skin with gentle pressure from a thumb, liquid drugs loaded in the reservoir roll down the grooves (yellow arrows) and enter the skin by capillary action. (E) OCT image of a cross section of the dorsal skin from a mouse that was injected with the MN array. The image indicates uniform penetration of the array into the skin through the SC. (F) Bright-field, fluorescence and merged micrographs (from left) of a histological section of mouse skin after insertion and removal of an MN patch loaded with FITC-BSA. Scale bars, 300 μm (B); 100 μm (B, inset); 5 mm (C); 100 μm (C, inset); 300 μm (E); and 300 μm (F).

  • Fig. 2 Rational design of MG-MNs for the transdermal delivery of liquid drugs.

    (A and B) Scanning electron microscopy images of the top (A) and side (B) views of (i) tri-grooved, (ii) tetra-grooved, (iii) penta-grooved, and (iv) hexa-grooved MNs. (C) 3D reconstruction images of confocal micrographs of MG-MNs. Top row shows top view; bottom row shows side view. (D) Top views of OCM micrographs showing the different types of holes created in mouse skin by MNs with different numbers of grooves. (E to H) Top views (E), side views (F and G), and cross-sectional views (H) of confocal micrographs showing the penetration of MNs (red) with different numbers of grooves loaded with FITC-BSA (green) into the dorsal skin of mice across the SC (blue). The SC is removed in (G) to better visualize the delivery of FITC-BSA into the skin. Scale bars, 100 μm (A to H).

  • Fig. 3 Skin-penetration performance of MG-MNs.

    (A) Total height and groove height of various MG-MNs. (B and C) Pierced depth (B) and hole diameter (C) in mouse skin for different types of MG-MNs. (D) Fracture forces of MNs with different numbers of grooves. Data represent means ± SD (n = 5).

  • Fig. 4 Simulation of hydrodynamics of liquid drug delivery in MG-MNs.

    (A) Schematic illustration of MG-MNs having upper wide and lower narrow channels through which a liquid droplet is delivered. (B) Schematic of the simulation model of the drug delivery process in a single groove of MG-MNs inserted into the skin. (C) Time-lapse simulation results of a water droplet that initially moves slowly and then rapidly passes through the channel enclosed by an MN wall and skin tissue. (D) Calculated moving velocities of droplets with different fluid properties during the drug delivery process.

  • Fig. 5 In vivo transdermal delivery of FITC-BSA and lidocaine into mice using MG-MN patches.

    (A) In vivo fluorescence images taken after applying an MG-MN patch loaded with FITC-BSA onto the dorsal skin of mice for different MN insertion times. (B) Merged (bright field + fluorescence, top row) and fluorescence (bottom row) micrographs of histological sections of the pierced murine skin for different insertion times. The images were taken after removal of the MN. FITC-BSA is indicated in green. (C and D) Quantitative analysis of fluorescence intensity of FITC-BSA in the in vivo test (C) and the diffusion area of FITC-BSA during the test (D). (E and F) In vivo fluorescence images before (E) and after (F) removal of the FITC-BSA–loaded patch. The MN insertion time was 15 s in this experiment. (G) Quantitative analysis of fluorescence intensity of FITC-BSA in the in vivo test (F). (H) The amounts of lidocaine delivered into the skin for different insertion times, quantified using HPLC. Scale bars, 100 μm (B). Data represent means ± SD (n = 5).

  • Fig. 6 Vaccination using MG-MN patches.

    (A) Anti–OVA-specific IgG titers from guinea pigs, analyzed using ELISA, 14 and 28 days after immunization. MN patches loaded with 2 μl of OVA were applied to the dorsal skin of guinea pigs (n = 10) for two different insertion times: 5 and 15 s. The same dose of the OVA was administered to guinea pigs via intramuscular (IM) injection for comparison. A 2-μl dose of PBS was injected with the patch as a control. (B) HI titers of mice (n = 10) after administration of pH1N1 via MN or intramuscular injection. (C and D) Survival rate and change in body weight of mice after a lethal exposure to the pH1N1 4 weeks after vaccination. The means and SEM (n = 10; *P < 0.05, **P < 0.01, and ***P < 0.001) are shown in all panels (Welch’s ANOVA).

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/503/eaaw3329/DC1

    Materials and Methods

    Fig. S1. Fabrication of the snake fang–inspired MN patch.

    Fig. S2. Optimization of UV exposure conditions for the fabrication of MNs with robust structures and sharp tips.

    Fig. S3. Penetration of MG-MNs into the human and porcine skin.

    Fig. S4. Fabrication of MG-MNs.

    Fig. S5. Automated skin penetration test.

    Fig. S6. Schematic of the spectral domain OCT system.

    Fig. S7. Schematic of the OCM system.

    Fig. S8. Mechanical property test of MN arrays.

    Data file S1. Primary data.

    Movie S1. 3D confocal reconstruction of the hexa-grooved MN.

    Movie S2. 3D reconstruction showing the penetration of the hexa-grooved MN (red) loaded with FITC-BSA (green) into the dorsal skin of mice across the SC (blue).

    Movie S3. Simulation of liquid drug delivery in a single groove of MG-MN.

  • The PDF file includes:

    • Materials and Methods
    • Fig. S1. Fabrication of the snake fang–inspired MN patch.
    • Fig. S2. Optimization of UV exposure conditions for the fabrication of MNs with robust structures and sharp tips.
    • Fig. S3. Penetration of MG-MNs into the human and porcine skin.
    • Fig. S4. Fabrication of MG-MNs.
    • Fig. S5. Automated skin penetration test.
    • Fig. S6. Schematic of the spectral domain OCT system.
    • Fig. S7. Schematic of the OCM system.
    • Fig. S8. Mechanical property test of MN arrays.
    • Legends for movies S1 to S3

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Data file S1 (Microsoft Excel format). Primary data.
    • Movie S1 (.avi format). 3D confocal reconstruction of the hexa-grooved MN.
    • Movie S2 (.avi format). 3D reconstruction showing the penetration of the hexa-grooved MN (red) loaded with FITC-BSA (green) into the dorsal skin of mice across the SC (blue).
    • Movie S3 (.avi format). Simulation of liquid drug delivery in a single groove of MG-MN.

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