Therapy of traumatic injuries of the spinal cord by magnetic nanoparticles: experimental aspects of promising technology

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Abstract

In this analytical review an attempt to sum up the available data in magnetite nanoparticle-marked stem cells utilization is made. Now this question remains on the experimental study level. Available data is diversified and needs an integral look to be taken. It is found that magnetite nanoparticles are non-toxic for the cells and do not interrupt physiological metabolic pathways. They can also be captured by cell using different transporters. Cells containing the magnetite nanoparticles can migrate along the magnetic flux lines. Animals with traumatic spinal cord lesions that got the nanoparticles-containing cell therapy showed the neurological status improvement. There is very little data in usage of this method in clinical practice; the solution of this problem requires more clinical trials.

 

About the authors

S. V. Kolesov

N.N. Priorov National Medical Research Center of Traumatology and Orthopaedics

Author for correspondence.
Email: dr-kolesov@yandex.ru
Russian Federation, Moscow

V. V. Shvets

N.N. Priorov National Medical Research Center of Traumatology and Orthopaedics

Email: dr-kolesov@yandex.ru
Russian Federation, Moscow

M. L. Sazhnev

N.N. Priorov National Medical Research Center of Traumatology and Orthopaedics

Email: dr-kolesov@yandex.ru
Russian Federation, Moscow

A. A. Panteleev

N.N. Priorov National Medical Research Center of Traumatology and Orthopaedics

Email: dr-kolesov@yandex.ru
Russian Federation, Moscow

D. S. Gorbatyuk

N.N. Priorov National Medical Research Center of Traumatology and Orthopaedics

Email: dr-kolesov@yandex.ru
Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. Spatial distribution of cells in a magnetic field (by V. Vaněček et al. [32]). The white rectangle is the border of the magnet. a-cells with the imposition of an external magnetic field; b-cells without the imposition of the field; C and d-increased area of white squares in the center of a and b, respectively. Scale: a, b — horizontal line 5000 microns; C and g-50 microns. Color: a, b — green fluorescent protein (green fluorescent protein-GFP), b, g — Prussian blue (Prussian blue)

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3. Fig. 2. Cells of the MSC line after «sowing» on the surface with square magnets (100×100 microns). a — 4 h from the moment of sowing, b — 3 days from the moment of sowing. Macheadquarters: the horizontal line in Fig. a — 100 microns, b —50 microns. Coloration-GFP (by Zablotskii et al. [29]).

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4. Fig. 3. Basic principles of cell distribution relative to magnetic field lines. Z and X are the coordinate axes. F1, F2-examples of magnetic forces that shift the cell to the corner of the magnet, where is its pole and the density of the field lines is maximal. The blue lines in the lower figure — the magnetic forces, red-the direction of proliferation away from the» anchor « cell (by V. Zablotskii et al. [29].)

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5. Fig. 4. Features of capture of different types of magnetic nanoparticles (by M. Marcus et al. [30]). Top row: uncoated magnetite particles; 2nd row: magnetite with starch coating; 3rd row: dextran coated magnetite; 4th row: uncoated maghemite. Confocal fluorescence microscopy on the left and center, electron microscopy on the right. Scale: horizontal line-50 nm.

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6. Fig. 5. Survival of RS-12 cells after administration.in the environment of the magnetic particles. 1st row: results for uncoated magnetite particles; 2nd row: starch-coated magnetite particles; 3rd row: dextran-coated magnetite particles; 4th row: uncoated maghemite particles.Note. * — p<0.05; * * — p<0.01 (according to M. Marcus et al. [30]).

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7. Fig. 6. Images obtained by confocal microscopy of RS-12 cells after 24 h incubation with uncoated maghemite nanoparticles. The particles are labeled rhodamine (rhodamine). a — phase-contrast image; b — fluorescence microscopy; c — combined image (by M. Marcus et al. [30]).

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8. Fig. 7. Protective effect of magnetic nanoparticles on stem cells transplanted for the treatment of traumatic spinal cord injuries. Row a —percentage of cells that survived incubation with different concentrations of magnetic nanoparticles. Row b — the result of cell incubation with the addition of hydrogen peroxide (10 mmol/ml), magnetic nanoparticles (25 μg/ml) or a combination thereof (according to A. Pal et al. [31]).

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9. Fig. 8. Mechanism of cytoprotective action of magnetic nanoparticles (by A. Pal et al. [31]).

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10. Fig. 9. Morphological data of RS-12 cells and peculiarities of their branching. The data were obtained 1, 3 and 5 days after the introduction of magnetic nanoparticles (uncoated maghemite, 0.25 mg/ml) into the medium; gray columns — the control group, red — cells with the introduction of nanoparticles.a — the length of the processes in micrometers; b — the number of branching points; c — the number of processes localized on the cell body; g — fluorescence microscopic picture of cells (5 days after the introduction of magnetic particles). On the left-the glow of antibodies to alphatubulin; in the center-the fluorescent glow of captured magnetic particles; on the right — the combined image. The horizontal line is 50 microns.Note. * — p<0.05 (according To M. Marcus et al. [30])

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11. Fig. 10. The ability of cells to form action potentials.a — confocal microscopic images of cells of the sh-SY5Y line after 24 h incubation with magnetic particles (maghemite without coating); b — image of the primary leech neuron (primary leech neuron), confocal microscopy, after 24 h incubation with magnetic particles; c — data of electrophysiological measurements of primary leech neurons (M. Marcus et al. [30]).

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12. Fig. 11. Clusters of cells have a pronounced hypointensive signal (a), in contrast to the results of the control group (d); b, c — histological sections (color Prussian blue); d, e — similar studies in the control group. Scale: horizontal line-100 microns (by V. Vanecek et al. [32]).

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13. Fig. 12. Functional recovery data (by T. Amemori et al. [27])Note. * p<0.05. Tx — time of cell transplantation

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14. Fig. 13. Functional test results. TRM — control group (injury); LF nanoparticle; MP — applying a magnetic field; m+LF combination of factors (for A. Pal et al. [31])

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15. Fig. 14. Spatial arrangement of cells according to the course of the magnetic field lines when using magnets of different shapes. a — flat magnet; b — «stepped» magnet. Places of the greatest intensity of the magnetic field are marked with red, orange and green dots; cells are schematically marked with blue circles. Visible the heterogeneity of their distribution: the flat magnet — the edges, the speedin the center (V. Vaněček et al. [32]).

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16. Fig. 15. The dependence of the number of cells in the lesion on time. Left: black line — the concentration of cells when using a magnet, graywithout the use of a magnet. Right: comparison of mathematically calculated and experimentally observed results (by V. Vaněček et al. [32]).2]).

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17. Fig. 16. Experimentally recorded results of quantitative distribution of cells throughout the area of the damaged rat spinal cord (18 cm), including but not limited to the area of damage. The dotted line indicates the mathematically calculated magnetic field strength of a flat magnet depending on the position of a certain point on the cranial-caudal «axis». The greater number of cells in the caudal Department compared to the cranial Department due to technical reasons, namely — the introduction of cells by lumbar puncture (V. Vaněček et al. [32])

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18. Fig. 17. MRI image of a patient with spinal cord injury (33 years) in the cervical spine, obtained 1 day after the introduction of magnetic nanoparticle-labeled cells by lumbar puncture. Sagittal T2-weighted images of the spine as a whole (a) and a fragment of the lumbar spine (b); C — axial image of the vertebra LIV. White arrows on all images indicate the accumulation of magnetic nanoparticle-labeled cells. In the cervical spinal cord cells were not found (for A. Chotivichit et al. [33]).

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19. Fig. 18. MRI images of the segment CI of the spinal cord obtained at different times after surgery: a — state before surgery; b —2 days after surgery; b —2 weeks; g —1 month, d —7 months. The arrow shows the «hearth» of the accumulation of magnetic particles labeled stem cells, which later on Mr-tomograms is not defined (for Chotivichit A. et al. [33])

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