Research ArticleNANOROBOTS

A microrobotic system guided by photoacoustic computed tomography for targeted navigation in intestines in vivo

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Science Robotics  24 Jul 2019:
Vol. 4, Issue 32, eaax0613
DOI: 10.1126/scirobotics.aax0613
  • Fig. 1 Schematic of PAMR in vivo.

    (A) Schematic of the PAMR in the GI tract. The MCs are administered into the mouse. NIR illumination facilitates the real-time PA imaging of the MCs and subsequently triggers the propulsion of the micromotors in targeted areas of the GI tract. (B) Schematic of PACT of the MCs in the GI tract in vivo. The mouse was kept in the water tank surrounded by an elevationally focused ultrasound transducer array. NIR side illumination onto the mouse generated PA signals, which were subsequently received by the transducer array. (Inset) Enlarged view of the yellow dashed box region, illustrating the confocal design of light delivery and PA detection. US, ultrasound; CL, conical lens; DAQ, data acquisition system. (C) Enteric coating prevents the decomposition of MCs in the stomach. (D) External CW NIR irradiation induced the phase transition and subsequent collapse of the MCs on demand in the targeted areas and activated the movement of the micromotors upon unwrapping from the capsule. (E) Active propulsion of the micromotors promoted retention and cargo delivery efficiency in intestines.

  • Fig. 2 Characterization of the MCs.

    (A) SEM image of an ingestible micromotor. Scale bar, 10 μm. (B) Microscopic images of the MCs with different sizes. Scale bars, 50 μm. (C) PACT images of Mg particles, blood, and MCs in silicone rubber tubes with laser wavelengths at 720, 750, and 870 nm, respectively. Scale bar, 500 μm. (D) PACT spectra of MCs (red line), blood (blue line), and Mg particles (black line). (E and F) PACT images (E), the corresponding PA amplitude (F) of the MCs with different micromotor loading amounts, and the dependence of the PA amplitude on the fluence of NIR light illumination [inset in (F)]. Scale bar, 500 μm (E). (G) Dependence of PA amplitude of the MCs (red line) and blood (black line) on the depth of tissue and the normalized PA amplitude and fluorescence intensity of the MCs under tissues (inset). Norm., normalized; amp., amplitude; Fl., fluorescence; int., intensity. Error bars represent the SDs from five independent measurements.

  • Fig. 3 Characterization of the dynamics of the PAMR.

    (A and B) Schematic (A) and time-lapse PACT images in deep tissues (B) illustrating the migration of an MC in the model intestine. Scale bar, 500 μm. The thickness of the tissue above the MC is 10 mm. (C to E) Schematic (C) and time-lapse microscopic images (D and E) showing the stability of the MCs in gastric acid and intestinal fluid (D) without CW NIR irradiation and the use of CW NIR irradiation to trigger the collapse of an MC and the activation of the micromotors (E). Scale bars, 50 μm (D and E).

  • Fig. 4 PACT evaluation of the PAMR dynamics in vivo.

    (A) Time-lapse PACT images of the MCs in intestines for 7.5 hours. The MCs migrating in the intestine are shown in color; the mouse tissues are shown in gray. Scale bar, 2 mm. (B and C) Movement displacement caused by the migration of the MCs in the intestine (B) and by the respiration motion of the mouse (C). (D) Comparison of the speeds of the MC migration and the respiration-induced movement. Error bars represent the SDs from three independent measurements.

  • Fig. 5 Evaluation of the PAMR for targeted retention and delivery.

    (A) Schematic of the use of the PAMR for targeted delivery in intestines. (B) Time-lapse PACT images of the migration of an MC toward a model colon tumor. Scale bars, 500 μm. (C and D) PACT images (C) and overlaid time-lapse bright-field and fluorescence microscopic images (D) showing the retention of the micromotors in intestines via the NIR-activated propulsion of the micromotors. Scale bars, 200 μm (C) and 20 μm (D). (E) Microscopic images showing the in vivo retention of the control microparticles and the micromotors in intestines (left) and the quantitative analysis of the particle retention in intestines (right). Control 1 and Control 2 represent paraffin-coated passive Mg and passive Mg/Au microparticles, respectively. Scale bar, 100 μm. Error bars represent the SDs from five independent measurements. (F) Microscopic image displaying the change of pH of the surrounding environment upon the micromotors in PBS. (G) Schematic (left) and the experimental (right) diffusion profiles of control silica particles and ingestible micromotors in mucus after 1 hour. Error bars represent the SDs from five independent measurements. (H) Histology analysis for the duodenum, jejunum, and distal colon of the mice treated with the MCs or DI water as the control for 12 hours. Scale bar, 100 μm.

Supplementary Materials

  • robotics.sciencemag.org/cgi/content/full/4/32/eaax0613/DC1

    Text S1. Small-animal whole-body imaging modalities and PACT

    Fig. S1. The fabrication flow of the ingestible micromotors.

    Fig. S2. The preparation of the MCs.

    Fig. S3. Bright-field and fluorescence microscopic images of the micromotors confirming the successful drug loading in micromotors.

    Fig. S4. Bright-field and fluorescence microscopic images of the MCs confirming the successful drug loading in the MCs.

    Fig. S5. Dependence of the size of the MCs on the rotation speed of magnetic stirring.

    Fig. S6. Long-term stability of the PA signals of the MCs under the NIR illumination used in the PACT in vitro and in vivo.

    Fig. S7. Fluorescence imaging of the MCs in a silicone tube under tissues with different depths.

    Fig. S8. Long-term structure stability of the MCs in the gastric fluid and the intestinal fluid.

    Fig. S9. Velocities of Mg-based micromotors in the different media.

    Fig. S10. Velocities of bare Mg microparticles in the different media.

    Fig. S11. Quantification of MC migration speeds.

    Fig. S12. Characterization of Mg dissolution in micromotors 12 hours after administration.

    Fig. S13. Effects of cross-linking and DOX loading amount on the EE of the micromotors and dose per micromotor.

    Fig. S14. Profile of DOX release from MCs and micromotors as a function of time.

    Fig. S15. The weight changes of the mice after the oral administration of the MCs and the control (DI water).

    Movie S1. Animated illustration of the PAMR in vivo.

    Movie S2. PA imaging of the migration of a MC in model intestines.

    Movie S3. NIR-triggered destruction of the MC and activated autonomous propulsion of the ingestible micromotors.

    Movie S4. Propulsion of the micromotors in biofluids.

    Movie S5. PA imaging of the MCs in vivo for 7.5 hours.

    Movie S6. PA imaging of the migration of an MC toward a model colon tumor in intestines.

    References (5055)

  • Supplementary Materials

    The PDF file includes:

    • Text S1. Small-animal whole-body imaging modalities and PACT
    • Fig. S1. The fabrication flow of the ingestible micromotors.
    • Fig. S2. The preparation of the MCs.
    • Fig. S3. Bright-field and fluorescence microscopic images of the micromotors confirming the successful drug loading in micromotors.
    • Fig. S4. Bright-field and fluorescence microscopic images of the MCs confirming the successful drug loading in the MCs.
    • Fig. S5. Dependence of the size of the MCs on the rotation speed of magnetic stirring.
    • Fig. S6. Long-term stability of the PA signals of the MCs under the NIR illumination used in the PACT in vitro and in vivo.
    • Fig. S7. Fluorescence imaging of the MCs in a silicone tube under tissues with different depths.
    • Fig. S8. Long-term structure stability of the MCs in the gastric fluid and the intestinal fluid.
    • Fig. S9. Velocities of Mg-based micromotors in the different media.
    • Fig. S10. Velocities of bare Mg microparticles in the different media.
    • Fig. S11. Quantification of MC migration speeds.
    • Fig. S12. Characterization of Mg dissolution in micromotors 12 hours after administration.
    • Fig. S13. Effects of cross-linking and DOX loading amount on the EE of the micromotors and dose per micromotor.
    • Fig. S14. Profile of DOX release from MCs and micromotors as a function of time.
    • Fig. S15. The weight changes of the mice after the oral administration of the MCs and the control (DI water).
    • References (5055)

    Download PDF

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.avi format). Animated illustration of the PAMR in vivo.
    • Movie S2 (.avi format). PA imaging of the migration of a MC in model intestines.
    • Movie S3 (.avi format). NIR-triggered destruction of the MC and activated autonomous propulsion of the ingestible micromotors.
    • Movie S4 (.avi format). Propulsion of the micromotors in biofluids.
    • Movie S5 (.avi format). PA imaging of the MCs in vivo for 7.5 hours.
    • Movie S6 (.avi format). PA imaging of the migration of an MC toward a model colon tumor in intestines.

    Files in this Data Supplement:

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