Research ArticleMEDICAL ROBOTS

Magnetically actuated microrobots as a platform for stem cell transplantation

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Science Robotics  29 May 2019:
Vol. 4, Issue 30, eaav4317
DOI: 10.1126/scirobotics.aav4317
  • Fig. 1 Fabrication and magnetic actuation of the microrobots.

    (A) Schematic of the microrobots. (B) Overall fabrication process of the microrobots. (C) CAD layouts for cylindrical, hexahedral, helical, and spherical scaffold-type microrobots. (D) SEM images of the fabricated cylindrical, hexahedral, helical, and spherical microrobots. Scale bars, 40 μm. (E) The three propulsion mechanisms of the microrobots. (F) Cylindrical and hexahedral microrobots pulled by a magnetic field gradient. Helical and spherical microrobots manipulated by a rotating magnetic field. Scale bars, 500 μm. (G) Writing of BMR trajectories using helical and spherical microrobots. Scale bars, 1 mm.

  • Fig. 2 Immunofluorescence and SEM images of hippocampal NSCs on microrobots.

    Immunofluorescence images showing the hippocampal NSCs after 72 hours of culture; differentiated astrocytes, oligodendrocytes, and neurons after 72 hours of differentiation; and the numbers of hippocampal NSCs after 24 and 72 hours of culture and of differentiated astrocytes, oligodendrocytes, and neurons after 72 hours of differentiation. SEM images of differentiated neurons on a substrate and on a microrobot with entangled neurites. Staining for markers of different cell types (nestin for NSCs, GFAP for astrocytes, GalC for oligodendrocytes, and Tubb3 for neurons); Hoechst 33342 counterstaining was performed to visualize the nuclei (two types of microrobots were used in each experiment, and each experiment was repeated two times).

  • Fig. 3 Targeted cell delivery using a microrobot in a BoC.

    Targeted HCT116 cell delivery using a microrobot in an in vitro liver-tumor network by bright-field (BF) and Calcein AM–stained green fluorescence (GF) images. (A) Configuration of a cell-loaded microrobot, liver, and tumor microorgans in the microfluidic BoC. (B) Microrobot with attached HCT116 cells placed in a chamber (scale bars, 50 μm). (C) Movement of a microrobot to the target tumor MT, passing four liver MTs (scale bar, 500 μm). (D) Arrival of the microrobot at the target tumor MT (scale bars, 50 μm). Liver and tumor MTs with a cell-loaded microrobot before (E) and after (F) cultivation for 42 hours (scale bars, 200 μm).

  • Fig. 4 Magnetic actuation of the microrobots in the brain ex vivo.

    (A) Ex vivo model of a brain blood vessel and the magnetic field control system. (B) Experimental setup for magnetic manipulation and a fixed rat brain with transparent blood vessels. Scale bar, 2 mm. (C and D) Snapshots of helical and spherical microrobots in a transparent brain blood vessel during magnetic manipulation (ICA, ACA, and MCA). Scale bars, 200 μm. (E) Positional control of the spherical and helical microrobots from the surface of a brain slice to a ventricle. Scale bars, 500 μm.

  • Fig. 5 In vivo MSC transportation using magnetically actuated microrobots.

    (A) SEM images of hTMSCs attached to a spherical microrobot. Scale bars, 10 μm; insets, 100 μm. (B) Viability of hTMSCs on a microrobot after 3 days (green, live cells; red, dead cells). Scale bars, 20 μm. (C) In vivo transportation of microrobots carrying hTMSCs using an external magnetic field: (a) and (b) after injection, (c) and (d) after magnetic actuation rightward (red arrow), (e) and (f) merged images at 0 and 9 min. The distance moved was 1.9 mm, which is 24-fold the length of a microrobot and 120-fold the diameter of an hTMSC. Scale bars, 10 mm [(a), (c), and (e)] and 1 mm [(b), (d), and (f)].

Supplementary Materials

  • robotics.sciencemag.org/cgi/content/full/4/30/eaav4317/DC1

    Fig. S1. The velocities of microrobots under external magnetic fields with various rotating frequencies.

    Fig. S2. Manipulation of the helical microrobot in a horizontal microfluidic channel and the spherical microrobot in a vertical microfluidic channel.

    Fig. S3. Three-dimensional images of hippocampal NSCs distributed on helical and spherical microrobots.

    Fig. S4. The number of proliferated stem cells on the microrobots and the numbers of cells on the microrobots after differentiation into astrocytes, oligodendrocytes, and neurons.

    Fig. S5. Targeted HCT116 cell delivery and transplantation using a microrobot in BoC.

    Fig. S6. Fluorescence imaging of the cells attached to the microrobot, ATP content in the cells for quantitative analysis of the cell viability of the treatment group, and reconstructed confocal image of the immunofluorescence staining of the HCT116 cells attached to the helical microrobot.

    Fig. S7. The process of hanging drop cell culture with a spherical microrobot.

    Fig. S8. Measured magnetic field intensity and gradient used for the in vivo experiment.

    Table S1. Design parameters for each microrobot.

    Movie S1. Magnetic manipulation of the helical and spherical microrobots using a rotating magnetic field.

    Movie S2. Three-dimensional animation of the confocal microscopic images of the differentiation of astrocytes, oligodendrocytes, and neurons on the helical and spherical microrobots.

    Movie S3. Magnetic manipulation of the helical and spherical microrobots after hippocampal NSC attachment.

    Movie S4. Targeted cell delivery in in vitro microorgan network using a magnetically actuated microrobot.

    Movie S5. Microtissue cultivation after targeted cell delivery using a microrobot in the BoC.

    Movie S6. Manipulation of the helical and spherical microrobots in a rat brain blood vessel for an ex vivo test.

    Movie S7. Manipulation of the helical and spherical microrobots in a ventricle of a sagittal brain slice to mimic an in vivo environment.

    Movie S8. Magnetic manipulation of the spherical microrobot with attached hTMSCs.

    References (5574)

  • Supplementary Materials

    The PDF file includes:

    • Fig. S1. The velocities of microrobots under external magnetic fields with various rotating frequencies.
    • Fig. S2. Manipulation of the helical microrobot in a horizontal microfluidic channel and the spherical microrobot in a vertical microfluidic channel.
    • Fig. S3. Three-dimensional images of hippocampal NSCs distributed on helical and spherical microrobots.
    • Fig. S4. The number of proliferated stem cells on the microrobots and the numbers of cells on the microrobots after differentiation into astrocytes, oligodendrocytes, and neurons.
    • Fig. S5. Targeted HCT116 cell delivery and transplantation using a microrobot in BoC.
    • Fig. S6. Fluorescence imaging of the cells attached to the microrobot, ATP content in the cells for quantitative analysis of the cell viability of the treatment group, and reconstructed confocal image of the immunofluorescence staining of the HCT116 cells attached to the helical microrobot.
    • Fig. S7. The process of hanging drop cell culture with a spherical microrobot.
    • Fig. S8. Measured magnetic field intensity and gradient used for the in vivo experiment.
    • Table S1. Design parameters for each microrobot.
    • Legends for movies S1 to S8
    • References (5574)

    Download PDF

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). Magnetic manipulation of the helical and spherical microrobots using a rotating magnetic field.
    • Movie S2 (.mp4 format). Three-dimensional animation of the confocal microscopic images of the differentiation of astrocytes, oligodendrocytes, and neurons on the helical and spherical microrobots.
    • Movie S3 (.mp4 format). Magnetic manipulation of the helical and spherical microrobots after hippocampal NSC attachment.
    • Movie S4 (.mp4 format). Targeted cell delivery in in vitro microorgan network using a magnetically actuated microrobot.
    • Movie S5 (.mp4 format). Microtissue cultivation after targeted cell delivery using a microrobot in the BoC.
    • Movie S6 (.mp4 format). Manipulation of the helical and spherical microrobots in a rat brain blood vessel for an ex vivo test.
    • Movie S7 (.mp4 format). Manipulation of the helical and spherical microrobots in a ventricle of a sagittal brain slice to mimic an in vivo environment.
    • Movie S8 (.mp4 format). Magnetic manipulation of the spherical microrobot with attached hTMSCs.

    Files in this Data Supplement:

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