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An ingestible self-orienting system for oral delivery of macromolecules

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Science  08 Feb 2019:
Vol. 363, Issue 6427, pp. 611-615
DOI: 10.1126/science.aau2277
  • Fig. 1 Mechanical API localization and injection for oral gastric delivery.

    (A) The SOMA localizes to the stomach lining, orients its injection mechanism toward the tissue wall, and injects a drug payload through the mucosa. The drug dissolves and the rest of the device passes out of the body. (B) A fabricated SOMA. (C) A comparison between the shape of the leopard tortoise (S. pardalis) and that of the SOMA. The SOMA quickly orients and remains stable in the stomach environment after reaching its preferred orientation. [Photo: M. M. Karim/Wikimedia Commons, CC-BY-SA 2.5] (D) The SOMA uses a compressed spring fixed in caramelized sucrose (brown) to provide a force for drug-loaded millipost (blue) insertion. After actuation, the spring remains encapsulated within the device.

  • Fig. 2 The SOMA self-orients quickly from any position and remains stable once oriented.

    (A) Imaging at 1000 frames per second reveals that the SOMA, made from a mixture of PCL and stainless steel, self-orients. (B) Simulation-predicted and (C) experimentally measured (n = 15) orientation times from a given initial angle, θ1, of ellipsoids, spheres, and SOMAs made from the same mass of PCL and stainless steel. The SOMA self-orients most quickly in the shaded regions between 0° and 45° and between 100° and 180°. The corner on the SOMA lengthens orientation times in the region of 45° to 100°, but (D) the corner also stabilizes the preferred orientation. The experimentally determined maximum tilting angle, θ2, when exposed to a rocking motion of 15° at 0.5 rad/s (n = 10), is effectively 0° for the SOMA. This prevents the drug from misfiring into the lumen rather than the tissue. (E) Experimentally measured orientation times in fluids with varying viscosities from a 90° starting angle (n = 6). (F) SOMAs with weighted metal bottoms self-orient in vivo, whereas (G) PCL-only SOMAs fail to orient appropriately. Error bars indicate SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

  • Fig. 3 Millipost fabrication and insertion-force characterization.

    (A) (I) Millipost stainless steel mold. (II) API mixture screen-printed into tip section. (III) Vibrations ensure powder fills cavity. (IV) Top section filled with biodegradable polymer. (V) Material compressed at 550 MPa. (B) 7-mm-long insulin millipost. (C) In vivo insertion force profile of insulin milliposts propelled at 0.2 mm/s in swine stomach (n = 2 stomachs, n = 8 insertions). Error bars indicate SD. (D) Micro-CT imaging of SOMA delivering a barium sulfate millipost into swine stomach tissue. Bottom is larger to ensure millipost stability during imaging. (E) Swine stomach hematoxylin and eosin–stained histology of dye injected by Carr-Locke needle in vivo to demonstrate penetration depth, (F) insulin millipost injected via a 5-N spring in the SOMA in situ, and (G) steel millipost inserted with a 9-N spring ex vivo. (H and I) Immunohistochemistry histology stained against α–smooth muscle actin of events in (F) and (G). M, mucosa; MM, muscularis mucosa; SM, submucosa; OM, outer muscularis.

  • Fig. 4 In vivo API millipost delivery and device evaluation.

    (A and B) Blood plasma levels for human insulin (H.I.) recorded in swine after manual subcutaneous millipost injection (S.C.) (n = 5), intragastric (I.G.) surgical millipost placement (n = 5), or I.G. millipost placement via a SOMA (n = 3). These swine are compared with animals dosed with SOMAs designed to localize the millipost to the tissue wall without injection (I.G. no inj.) (n = 5). 300 μg of human insulin was submerged underneath the tissue for each injection trial. Manually placed milliposts contain 80% human insulin and 20% PEO 200k. (C and D) All swine administered with an insulin injection demonstrated hypoglycemia, and many were rescued with dextrose. The SOMA datasets only include swine with successful fasting without residual food or measurable gastric fluid. Error bars indicate SD. N.D., no statistically significant difference.

Supplementary Materials

  • An ingestible self-orienting system for oral delivery of macromolecules

    Alex Abramson, Ester Caffarel-Salvador, Minsoo Khang, David Dellal, David Silverstein, Yuan Gao, Morten Revsgaard Frederiksen, Andreas Vegge, František Hubálek, Jorrit J. Water, Anders V. Friderichsen, Johannes Fels, Rikke Kaae Kirk, Cody Cleveland, Joy Collins, Siddartha Tamang, Alison Hayward, Tomas Landh, Stephen T. Buckley, Niclas Roxhed, Ulrik Rahbek, Robert Langer, Giovanni Traverso

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Supplementary Text
    • Figs. S1 to S16
    • Tables S1 to S3
    • Caption for Movie S1
    • References

    Images, Video, and Other Media

    Movie S1
    Video of SOMA prototype self-orienting.

    Additional Data

    MATLAB Code

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