Research ArticleBIOMATERIALS

Self-propelled particles that transport cargo through flowing blood and halt hemorrhage

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Science Advances  02 Oct 2015:
Vol. 1, no. 9, e1500379
DOI: 10.1126/sciadv.1500379
  • Fig. 1 CaCO3 particles combined with an organic acid travel through aqueous solutions.

    (A) Schematic showing CaCO3 particles releasing CO2 and propelling themselves and their cargo when placed in water. (B) Schematic showing how particle movement was measured in buffer and whole blood. (C and D) Images of particles appearing at the surface of a buffered solution (C) and whole blood (D). Scale bars, 2 mm. (E) Schematic and images of a steel hull propelled by CaCO3 and TXA-NH3+. Scale bar, 2 mm. (F) Images of immobilized CaCO3 particles containing a fluorescently tagged cargo, FITC-dextran. Scale bars, 30 μm (green fluorescent particles) and 0.5 μm (scanning electron micrographs). (G) Schematic showing a mouse tail being amputated and treated with propelling CaCO3 particles. Red rectangle denotes the field of view in (H). (H) Histological section of a treated tail showing particles located 6 mm inside the tail, blood vessels, and caudal vertebrae (CV). Fluorescence staining shows actin (red), nuclei (blue), and CaCO3 particles (green). Scale bar, 200 μm.

  • Fig. 2 CaCO3 particles travel upstream and at high velocities through stagnant and flowing solutions.

    (A) Images of CaCO3 particles transporting upward through a stagnant acidic solution. (B) Particle velocity increased as a function of the volume of attached bubbles. The red line denotes the velocities of bubbles predicted by a model equating buoyant and drag forces. The black solid line denotes a one-half power regression of the data. Dashed lines denote the 99% confidence band (black) and 90% prediction band (gray) of regression. (C) Images of particles carried upward by CO2 bubbles. (D) Schematic showing how propulsion of particles with TXA-NH3+ through flowing water was measured. (E) The particles traveled against flow velocities of up to 3 mm/s. (Inset) Fraction of particles that accumulated for each flow velocity at 20 s. (F) Schematic showing how propulsion of particles through a channel of flowing whole blood was measured at three angles. (G) Maximum distances that particles traveled upstream through flowing and stagnant blood at various angles. Scale bars, 2 mm.

  • Fig. 3 Propelled thrombin clots flowing blood plasma and halts severe hemorrhage.

    (A and B) Schematic of clotting and occlusion of flowing blood plasma ex vivo in vertical (A) and horizontal (B) orientations. (C and D) Clotting of flowing human plasma ex vivo by thrombin-loaded particles at various flow rates in a vertical orientation (C) and at 0.13 mm/s in a horizontal orientation (D). n = 3. *P < 0.05. Error bars indicate SEM.

  • Fig. 4 Propelled thrombin is delivered deep into wounds and halts hemorrhage in vivo.

    (A) Bleeding times in vivo after the tails of mice were amputated. (B) Schematic showing a mouse liver punctured and treated with propelled thrombin. (C) Volume of blood loss in a separate cohort of mice after their livers were punctured and treated. (D and E) Histological sections of livers treated with propelled thrombin (D) or nonpropelled thrombin (E). Fluorescence staining shows actin (red), nuclei (blue), and CaCO3 particles (green). Scale bar, 200 μm. (F) Mass of CaCO3 delivered to sites of liver puncture. (G) Schematic showing a pig’s punctured femoral artery being treated with gauze impregnated with propelled thrombin. (H) Survival of pigs after treatment. n = 5. *P < 0.05, **P < 0.01. Error bars indicate SEM.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/1/9/e1500379/DC1

    Materials and Methods

    Fig. S1. Velocities of CaCO3 particulates and porous microparticles.

    Fig. S2. Imaging CaCO3 particulates in acidic solution.

    Fig. S3. Large carbonate particles propel horizontally but not upward.

    Fig. S4. Histological analysis of mouse tails treated with propelling CaCO3 microparticles.

    Fig. S5. Mice remain healthy after intravenous injection of particles.

    Fig. S6. Bubbles traveling upstream carry CaCO3 microparticles.

    Fig. S7. Measuring the maximum distance traveled by propelled particles through flowing whole blood.

    Fig. S8. Thrombin can be immobilized on CaCO3 particles and clot stagnant plasma.

    Fig. S9. Full apparatus used to detect occlusion of flowing blood plasma.

    Fig. S10. Alternative representations of data in Fig. 4.

    Fig. S11. Histological sections of two treated tails at different distances from the site of amputation.

    Fig. S12. Inguinal crease on a pig after treatment with propelled thrombin gauze.

    Fig. S13. Quantification of blood loss after mouse liver puncture.

    Fig. S14. Blood loss and MAP in a porcine model of lethal femoral artery hemorrhage.

    Movie S1. Transport of CaCO3 particulates in 1 M citric acid.

  • Supplementary Materials

    This PDF file includes:

    • Materials and Methods
      Fig. S1. Velocities of CaCO3 particulates and porous microparticles.
    • Fig. S2. Imaging CaCO3 particulates in acidic solution.
    • Fig. S3. Large carbonate particles propel horizontally but not upward.
    • Fig. S4. Histological analysis of mouse tails treated with propelling CaCO3 microparticles.
    • Fig. S5. Mice remain healthy after intravenous injection of particles.
    • Fig. S6. Bubbles traveling upstream carry CaCO3 microparticles.
    • Fig. S7. Measuring the maximum distance traveled by propelled particles through flowing whole blood.
    • Fig. S8. Thrombin can be immobilized on CaCO3 particles and clot stagnant plasma.
    • Fig. S9. Full apparatus used to detect occlusion of flowing blood plasma.
    • Fig. S10. Alternative representations of data in Fig. 4.
    • Fig. S11. Histological sections of two treated tails at different distances from the site of amputation.
    • Fig. S12. Inguinal crease on a pig after treatment with propelled thrombin gauze.
    • Fig. S13. Quantification of blood loss after mouse liver puncture.
    • Fig. S14. Blood loss and MAP in a porcine model of lethal femoral artery hemorrhage.
    • Legend for movie S1

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    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). Transport of CaCO3 particulates in 1 M citric acid.

    Files in this Data Supplement: