Research ArticleBioengineering

Ultrasound-mediated gastrointestinal drug delivery

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Science Translational Medicine  21 Oct 2015:
Vol. 7, Issue 310, pp. 310ra168
DOI: 10.1126/scitranslmed.aaa5937
  • Fig. 1. Ex vivo characterization of UMGID.

    (A) Ex vivo experimental setup, the Franz diffusion cell. A section of fresh GI tissue is shown positioned between a donor and receiver chamber. US, ultrasound. (B) Comparison of the amount of glucose delivered to various tissues of the GI tract with 20-kHz ultrasound at 7.5 W/cm2 and without ultrasound (control) for 2 min with the horn set to pulse (50% duty cycle of 5-s on and 5-s off, resulting in 1 min of ultrasound exposure). (C to E) Survey of glucose (C), inulin (5 kD) (D), hydrocortisone (E), and mesalamine (E) delivery—all at 1 mg/ml—to porcine intestine and colon ex vivo using 20- and 40-kHz ultrasound at the lowest intensity considered for each frequency. Treatment duration was 1 min of ultrasound at a 50% duty cycle, as described in (B). (F) Multiphoton microscopy of cross sections of colonic tissue exposed to dextrans labeled with Texas red with and without 20-kHz ultrasound. The red channel and second harmonic (to show structural elements of the tissue) are shown. Scale bars, 500 μm. Data in (B) to (E) are averages ± 1 SD. Sample sizes indicated are biological replicates. Each experiment was performed once. Because not all experiments could be performed from one organ, controls were run for each additional organ procured to account for potential intertissue variability. P values in (C) to (E) were determined by two-tailed Student’s t tests.

  • Fig. 2. Ex vivo and in vivo investigation of the mechanism of drug delivery enhancement with ultrasound.

    (A) Relative enhancement in glucose delivery to small intestine as a result of 40°C heating for 2 or 5 min or 20-kHz ultrasound at 7.5 W/cm2 at a duty cycle of 50% for 2 min total. (B) Relative enhancement in glucose delivery to small intestine as a result of treatment with 1-MHz ultrasound set to 2 W/cm2 (5.22 W actual) for 3.4 min, stirring of the donor chamber, or 40-kHz ultrasound set to an intensity of 13.4 W/cm2. (C) Number of pits generated in aluminum foil after treatment with 20-, 40-, 60-kHz, or 1-MHz ultrasound for 2 s at the highest intensity considered for each frequency. In (A) to (C), data are averages ± 1 SD; P values were determined by one-way analysis of variance (ANOVA) with multiple comparisons. (D) Representative images of pitted aluminum foil samples treated with either 20-, 40-, or 60-kHz ultrasound. Scale bar, 3 mm. (E and F) Averaged Gaussian filtered amplitude spectrum of six fast Fourier transforms (FFTs) taken on in situ acoustic data collected externally in vivo in pigs during f = 20 kHz UMGID along with a representative amplitude spectrum for each repeat (E) and a control when ultrasound was not on (F). (G) Estimation of pore size radii created in porcine small intestine tissue and permeability (averages ± 1 SD) of glucose and inulin as a result of ultrasound exposure using the aqueous porous pathway model.

  • Fig. 3. In vivo axial UMGID in pigs.

    (A) Experimental setup showing placement of a medicated enema and insertion of the 20-kHz ultrasound probe in the rectum of a pig. (B) Representative macroscopic (top) and histological (bottom) views of the rectum not treated with ultrasound (control) or a single administration of 20-kHz ultrasound. The outlined area indicates minor localized saponification of the muscularis in <5% of the treated area examined. Scale bars, 100 μm. (C) Mesalamine drug content in colon tissue biopsies normalized by the mass of the tissue biopsy without (control) and with (treated) a single administration of 20-kHz ultrasound. Each point represents one biological replicate. P value determined by two-tailed Student’s t test. (D) Animals’ blood glucose normalized to its initial value as a result of the placement of an enema containing 100 U of insulin without (left) or with (right) a single administration of 20-kHz ultrasound. Each individual curve is a biological repeat.

  • Fig. 4. Effect of rectal ultrasound on blood markers, histology, fecal score, and cytokine expression.

    (A) Daily ultrasound treatment schedule in healthy pigs in the absence of colitis. (B) The custom-designed ultrasound probe tip with a shaft diameter of 2 mm. The two bumps shown have a diameter of 3 mm and enhance radial ultrasound emission. (C) Hematocrit and hemoglobin normalized to day 1 for healthy animals (control), healthy animals receiving daily probe insertion (probe insertion), and healthy animals receiving daily 40-kHz ultrasound treatment (US). Although five animals were used in each group, some blood samples from days 1 and 14 clotted, resulting in fewer than five values for some groups. (D) Histology scores of tissue sections at day 14. The median, 25th, and 75th percentiles are shown. The whiskers indicate the most extreme data points. (E) Total fecal score for all three groups over the 14-day period. (F) Cytokine mRNA levels in colonic tissue samples (n = 4 biological repeats for all groups). Counts were assessed using the Mouse Inflammatory Panel (NanoString Technologies). Data are normalized across samples using internal positive spike-in controls. Data in (C), (E), and (F) are averages ± 1 SD. Sample sizes indicated are biological replicates.

  • Fig. 5. In vivo radial UMGID of mesalamine in a rodent colitis model.

    (A) Colitis induction and treatment schedule. DSS was given daily for 7 days to induce acute colitis in mice. Starting on day 2, animals receiving treatment were administered either a mesalamine enema daily (QD), mesalamine with 40-kHz ultrasound QD, or mesalamine with 40-kHz ultrasound every other day (QOD) for 2 weeks. (B) Total fecal score for healthy animals (control) and animals with DSS-induced colitis: receiving no treatment (disease), receiving mesalamine enema daily (drug enema QD), receiving mesalamine enema with ultrasound treatment daily (US treatment QD), and receiving mesalamine enema with ultrasound treatment every other day (US treatment QOD). Data are averages ± 1 SD (n = 5 animals). P values given are for the indicated group receiving ultrasound compared to the disease and drug enema groups (one-way ANOVA with multiple comparisons). (C) Histology scores of colonic tissue sections on day 14 (n = 5 animals per treatment group). The median, 25th, and 75th percentiles are shown. The whiskers indicate the most extreme data points. The P value is for US treatment QD compared to all other disease groups (determined by one-way ANOVA with multiple comparisons). (D) Histological images of colonic tissue at day 14. Representative images of tissue scored 0 (healthy) to 4.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/310/310ra168/DC1

    Supplementary Methods

    Fig. S1. Glucose, inulin, and hydrocortisone uptake in GI tissues ex vivo.

    Fig. S2. Distribution of permeants between porcine colonic tissue and the receiver chamber ex vivo.

    Fig. S3. Permeability of the porcine small intestine to glucose and inulin.

    Fig. S4. Tolerability of rectal ultrasound in healthy mouse and pig models.

    Fig. S5. Representative NMR spectra of mesalamine and hydrocortisone before and after sonication.

    Fig. S6. Impact of sonication on insulin activity.

    Table S1. Sample size, regression slope, and R2 values for tissue permeability tests.

    References (3340)

  • Supplementary Material for:

    Ultrasound-mediated gastrointestinal drug delivery

    Carl M. Schoellhammer, Avi Schroeder, Ruby Maa, Gregory Yves Lauwers, Albert Swiston, Michael Zervas, Ross Barman, Angela M. DiCiccio, William R. Brugge, Daniel G. Anderson, Daniel Blankschtein,* Robert Langer,* Giovanni Traverso*

    *Corresponding author. E-mail: dblank{at}mit.edu (D.B.); rlanger{at}mit.edu (R.L.); ctraverso{at}partners.org (G.T.)

    Published 21 October 2015, Sci. Transl. Med. 7, 310ra168 (2015)
    DOI: 10.1126/scitranslmed.aaa5937

    This PDF file includes:

    • Supplementary Methods
    • Fig. S1. Glucose, inulin, and hydrocortisone uptake in GI tissues ex vivo.
    • Fig. S2. Distribution of permeants between porcine colonic tissue and the receiver chamber ex vivo.
    • Fig. S3. Permeability of the porcine small intestine to glucose and inulin.
    • Fig. S4. Tolerability of rectal ultrasound in healthy mouse and pig models.
    • Fig. S5. Representative NMR spectra of mesalamine and hydrocortisone before and after sonication.
    • Fig. S6. Impact of sonication on insulin activity.
    • Table S1. Sample size, regression slope, and R2 values for tissue permeability tests.
    • References (3340)

    [Download PDF]

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