Annals of Biomedical Engineering

, Volume 42, Issue 5, pp 929–939 | Cite as

Therapeutic Magnetic Microcarriers Guided by Magnetic Resonance Navigation for Enhanced Liver Chemoembilization: A Design Review

  • Pierre Pouponneau
  • Gaël Bringout
  • Sylvain Martel


This review paper describes the past, present and future design of therapeutic magnetic carriers (TMMC) being guided in the vascular network using a novel technique known as magnetic resonance navigation (MRN). This targeting method is an extension of magnetic resonance imaging (MRI) technologies. MRN, based on magnetic gradient variation, aims to navigate carriers in real-time along a pre-planned trajectory from their injection site to a targeted area. As such, this approach should minimize systemic distribution of toxic agents loaded into the carriers and improve therapeutic efficacy by delivering a larger proportion of the drug injected. MRN-compatible carriers (shape, material, size, magnetic properties, biocompatibility) have to be designed by taking into consideration the constraints of the medical task and MRN. In the past, as a proof of concept of MRN feasibility, a 1.5-mm ferromagnetic bead was guided in the artery of a living swine with a clinical MRI system. Present day, to aim at medical applications, TMMC have been designed for targeted liver chemoembolization by MRN. TMMC are 50-μm biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin as an antitumor drug. TMMC were selectively guided to the right or left liver lobes in a rabbit model with a clinical MRI scanner upgraded with steering coils. To treat human liver tumor, according to the theoretical MRN model, future TMMC design should take into consideration magnetic nanoparticle properties (nature and loading), MRN platform performances (gradient amplitude and rise time) and vascular hepatic network properties (blood flow velocity and geometry) to optimize the carrier diameter for efficient chemoembolization.


Magnetic tumor targeting Magnetic resonance imaging (MRI) Magnetic nanoparticles Microparticles Drug delivery 



This work was supported by the Canadian Institutes for Health Research (CIHR), the Canada Research Chair program, the Canada Foundation for Innovation (CFI), the Natural Sciences and Engineering Research Council of Canada (NSERC), and Fonds Québécois de la Recherche sur la Nature et les Technologies (FQRNT).


  1. 1.
    Abbott, J. J., K. E. Peyer, M. C. Lagomarsino, Z. Li, D. Lixin, I. K. Kaliakatsos, and B. J. Nelson. How should microrobots swim? Int. J. Robot. Res. 28:1434–1447, 2009.CrossRefGoogle Scholar
  2. 2.
    Amesur, N. B., A. B. Zajko, and B. I. Carr. Chemo-embolization for unresectable hepatocellular carcinoma with different sizes of embolization particles. Dig. Dis. Sci. 53:1400–1404, 2008.PubMedCrossRefGoogle Scholar
  3. 3.
    Amirfazli, A. Nanomedicine: magnetic nanoparticles hit the target. Nat. Nanotechnol. 2:467–468, 2007.PubMedCrossRefGoogle Scholar
  4. 4.
    Arcese, L., M. Fruchard, and A. Ferreira. Endovascular magnetically guided robots: navigation modeling and optimization. IEEE Trans. Biomed. Eng. 59:977–987, 2012.PubMedCrossRefGoogle Scholar
  5. 5.
    Basciano, C. A., C. Kleinstreuer, A. S. Kennedy, W. A. Dezarn, and E. Childress. Computer modeling of controlled microsphere release and targeting in a representative hepatic artery system. Ann. Biomed. Eng. 38:1862–1879, 2010.PubMedCrossRefGoogle Scholar
  6. 6.
    Bruix, J., and J. M. Llovet. Major achievements in hepatocellular carcinoma. Lancet 373:614–616, 2009.PubMedCrossRefGoogle Scholar
  7. 7.
    Carlisle, K. M., M. Halliwell, A. E. Read, and P. N. Wells. Estimation of total hepatic blood flow by duplex ultrasound. Gut 33:92–97, 1992.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Chanu, A., O. Felfoul, G. Beaudoin, and S. Martel. Adapting the clinical MRI software environment for real-time navigation of an endovascular untethered ferromagnetic bead for future endovascular interventions. Magn. Reson. Med. 59:1287–1297, 2008.PubMedCrossRefGoogle Scholar
  9. 9.
    Chorny, M., I. Fishbein, B. B. Yellen, I. S. Alferiev, M. Bakay, S. Ganta, R. Adamo, M. Amiji, G. Friedman, and R. J. Levy. Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields. Proc. Natl Acad. Sci. U.S.A. 107:8346–8351, 2010.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Dames, P., B. Gleich, A. Flemmer, K. Hajek, N. Seidl, F. Wiekhorst, D. Eberbeck, I. Bittmann, C. Bergemann, T. Weyh, L. Trahms, J. Rosenecker, and C. Rudolph. Targeted delivery of magnetic aerosol droplets to the lung. Nat. Nanotechnol. 2:495–499, 2007.PubMedCrossRefGoogle Scholar
  11. 11.
    Darton, N. J., A. J. Sederman, A. Ionescu, C. Ducati, R. C. Darton, L. F. Gladden, and N. K. H. Slater. Manipulation and tracking of superparamagnetic nanoparticles using MRI. Nanotechnology 19:395102, 2008.PubMedCrossRefGoogle Scholar
  12. 12.
    Di Bisceglie, A. M. Epidemiology and clinical presentation of hepatocellular carcinoma. J. Vasc. Interv. Radiol. 13:S169–S171, 2002.PubMedCrossRefGoogle Scholar
  13. 13.
    Dobson, J. Cancer therapy: a twist on tumour targeting. Nat. Mater. 9:95–96, 2010.PubMedCrossRefGoogle Scholar
  14. 14.
    Felfoul, O., J. B. Mathieu, G. Beaudoin, and S. Martel. In vivo MR-tracking based on magnetic signature selective excitation. IEEE Trans. Med. Imaging 27:28–35, 2008.PubMedCrossRefGoogle Scholar
  15. 15.
    Frutiger, D. R., K. Vollmers, B. E. Kratochvil, and B. J. Nelson. Small, fast, and under control: wireless resonant magnetic micro-agents. Int. J. Robot. Res. 29:613–636, 2010.CrossRefGoogle Scholar
  16. 16.
    Gosselin, F. P., V. Lalande, and S. Martel. Characterization of the deflections of a catheter steered using a magnetic resonance imaging system. Med. Phys. 38:4994–5002, 2011.PubMedCrossRefGoogle Scholar
  17. 17.
    Jakab, F., Z. Rath, F. Schmal, P. Nagy, and J. Faller. Changes in hepatic hemodynamics due to primary liver tumours. HPB Surg. 9:245–248, 1996.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Jakab, F., Z. Rath, F. Schmal, P. Nagy, and J. Faller. A new method to measure portal venous and hepatic arterial blood flow in patients intraoperatively. HPB Surg. 9:239–243, 1996.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Konya, A., K. C. Wright, I. A. Szwarc, and R. D. Collins. Technical aspects of catheter-related interventions in the liver of the rabbit. Acta Radiol. 38:332–334, 1997.PubMedCrossRefGoogle Scholar
  20. 20.
    Kósa, G., P. Jakab, G. Székely, and N. Hata. MRI driven magnetic microswimmers. Biomed. Microdevices 14:165–178, 2012.PubMedCrossRefGoogle Scholar
  21. 21.
    Lencioni, R., T. de Baere, M. Burrel, J. G. Caridi, J. Lammer, K. Malagari, R. C. Martin, E. O’Grady, M. I. Real, T. J. Vogl, A. Watkinson, and J. F. Geschwind. Transcatheter treatment of hepatocellular carcinoma with doxorubicin-loaded DC bead (DEBDOX): technical recommendations. Cardiovasc. Interv. Radiol. 35:980–985, 2011.CrossRefGoogle Scholar
  22. 22.
    Liapi, E., and J. F. Geschwind. Transcatheter and ablative therapeutic approaches for solid malignancies. J. Clin. Oncol. 25:978–986, 2007.PubMedCrossRefGoogle Scholar
  23. 23.
    Lin, R., L. Shi Ng, and C. H. Wang. In vitro study of anticancer drug doxorubicin in PLGA-based microparticles. Biomaterials 26:4476–4485, 2005.PubMedCrossRefGoogle Scholar
  24. 24.
    Lubbe, A. S., C. Bergemann, H. Riess, F. Schriever, P. Reichardt, K. Possinger, M. Matthias, B. Dorken, F. Herrmann, R. Gurtler, P. Hohenberger, N. Haas, R. Sohr, B. Sander, A. J. Lemke, D. Ohlendorf, W. Huhnt, and D. Huhn. Clinical experiences with magnetic drug targeting: a phase I study with 4′-epidoxorubicin in 14 patients with advanced solid tumors. Cancer Res. 56:4686–4693, 1996.PubMedGoogle Scholar
  25. 25.
    Martel, S. Combining pulsed and DC gradients in a clinical MRI-based microrobotic platform to guide therapeutic magnetic agents in the vascular network. Int. J. Robot. Res. 10:7, 2012.Google Scholar
  26. 26.
    Martel, S., O. Felfoul, J. B. Mathieu, A. Chanu, S. Tamaz, M. Mohammadi, M. Mankiewicz, and N. Tabatabaei. MRI-based medical nanorobotic platform for the control of magnetic nanoparticles and flagellated bacteria for target interventions in human capillaries. Int. J. Robot. Res. 28:1169–1182, 2009.CrossRefGoogle Scholar
  27. 27.
    Martel, S., J. B. Mathieu, O. Felfoul, A. Chanu, E. Aboussouan, S. Tamaz, P. Pouponneau, L. Yahia, G. Beaudoin, G. Soulez, and M. Mankiewicz. Automatic navigation of an untethered device in the artery of a living animal using a conventional clinical magnetic resonance imaging system. Appl. Phys. Lett. 90:114105, 2007.CrossRefGoogle Scholar
  28. 28.
    Martel, S., J. B. Mathieu, O. Felfoul, A. Chanu, E. Aboussouan, S. Tamaz, P. Pouponneau, L. Yahia, G. Beaudoin, G. Soulez, and M. Mankiewicz. A computer-assisted protocol for endovascular target interventions using a clinical MRI system for controlling untethered microdevices and future nanorobots. Comput. Aided Surg. 13:340–352, 2008.PubMedCrossRefGoogle Scholar
  29. 29.
    Mathieu, J. B., and S. Martel. Steering of aggregating magnetic microparticles using propulsion gradients coils in an MRI Scanner. Magn. Reson. Med. 63:1336–1345, 2010.PubMedCrossRefGoogle Scholar
  30. 30.
    Nacev, A., A. Komaee, A. Sarwar, R. Probst, S. H. Kim, M. Emmert-Buck, and B. Shapiro. Towards control of magnetic fluids in patients: directing therapeutic nanoparticles to disease locations. IEEE Contr. Syst. Mag. 32:43, 2012.CrossRefGoogle Scholar
  31. 31.
    Namiki, Y., T. Namiki, H. Yoshida, Y. Ishii, A. Tsubota, S. Koido, K. Nariai, M. Mitsunaga, S. Yanagisawa, H. Kashiwagi, Y. Mabashi, Y. Yumoto, S. Hoshina, K. Fujise, and N. Tada. A novel magnetic crystal-lipid nanostructure for magnetically guided in vivo gene delivery. Nat. Nanotechnol. 4:598–606, 2009.PubMedCrossRefGoogle Scholar
  32. 32.
    Namur, J., M. Wassef, J. M. Millot, A. L. Lewis, M. Manfait, and A. Laurent. Drug-eluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model. J. Vasc. Interv. Radiol. 21:259–267, 2010.PubMedCrossRefGoogle Scholar
  33. 33.
    Nelson, B. J., I. K. Kaliakatsos, and J. J. Abbott. Microrobots for minimally invasive medicine. Annu. Rev. Biomed. Eng. 12:55–85, 2010.PubMedCrossRefGoogle Scholar
  34. 34.
    Noar, J. H., R. D. Evans, D. Wilson, J. Costello, E. Ioannou, A. Ayeni, N. J. Mordan, M. Wilson, and J. Pratten. An in vitro study into the corrosion of intra-oral magnets in the presence of dental amalgam. Eur. J. Orthod. 25:615–619, 2003.PubMedCrossRefGoogle Scholar
  35. 35.
    Park, S., K. Cha, and J. Park. Development of biomedical microrobot for intravascular therapy. Int. J. Robot. Res. 7:97–98, 2010.Google Scholar
  36. 36.
    Plank, C. Nanomedicine: silence the target. Nat. Nanotechnol. 4:544–545, 2009.PubMedCrossRefGoogle Scholar
  37. 37.
    Polyak, B., I. Fishbein, M. Chorny, I. Alferiev, D. Williams, B. Yellen, G. Friedman, and R. J. Levy. High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents. Proc. Natl Acad. Sci. U.S.A. 105:698–703, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Pouponneau, P., J. C. Leroux, and S. Martel. Magnetic nanoparticles encapsulated into biodegradable microparticles steered with an upgraded magnetic resonance imaging system for tumor chemoembolization. Biomaterials 30:6327–6332, 2009.PubMedCrossRefGoogle Scholar
  39. 39.
    Pouponneau, P., J. C. Leroux, G. Soulez, L. Gaboury, and S. Martel. Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation. Biomaterials 32:3481–3486, 2011.PubMedCrossRefGoogle Scholar
  40. 40.
    Pouponneau, P., O. Savadogo, T. Napporn, L. Yahia, and S. Martel. Corrosion study of iron-cobalt alloys for MRI-based propulsion embedded in untethered microdevices operating in the vascular network. J. Biomed. Mater. Res. B 93:203–211, 2010.Google Scholar
  41. 41.
    Pouponneau, P., O. Savadogo, T. Napporn, L. Yahia, and S. Martel. Corrosion study of single crystal Ni-Mn-Ga alloy and Tb0.27Dy0.73Fe1.95 alloy for the design of new medical microdevices. J. Mater. Sci. Mater. Med. 22:237–245, 2011.PubMedCrossRefGoogle Scholar
  42. 42.
    Pouponneau, P., V. Segura, O. Savadogo, J.-C. Leroux, and S. Martel. Annealing of magnetic nanoparticles for their encapsulation into microcarriers guided by vascular magnetic resonance navigation. J. Nanopart. Res. 14:1–13, 2012.CrossRefGoogle Scholar
  43. 43.
    Pouponneau, P., G. Soulez, G. Beaudoin, J. C. Leroux, and S. Martel. MR imaging of therapeutic magnetic microcarriers guided by magnetic resonance navigation for targeted liver chemoembolization. Cardiovasc. Interv. Radiol. DOI: 10.1007/s00270-013-0770-4, 2013.
  44. 44.
    Reyes, D. K., J. A. Vossen, I. R. Kamel, N. S. Azad, T. A. Wahlin, Torbenson, MS, M. A. Choti, and J. F. Geschwind. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J. 15:526–532, 2009.PubMedCrossRefGoogle Scholar
  45. 45.
    Riegler, J., J. A. Wells, P. G. Kyrtatos, A. N. Price, Q. A. Pankhurst, and M. F. Lythgoe. Targeted magnetic delivery and tracking of cells using a magnetic resonance imaging system. Biomaterials 31:5366–5371, 2010.PubMedCrossRefGoogle Scholar
  46. 46.
    Silveira, L. A., F. B. Silveira, and V. P. Fazan. Arterial diameter of the celiac trunk and its branches. Anatomical study. Acta Cir. Bras. 24:43–47, 2009.PubMedCrossRefGoogle Scholar
  47. 47.
    Tamaz, S., R. Gourdeau, A. Chanu, J. B. Mathieu, and S. Martel. Real-time MRI-based control of a ferromagnetic core for endovascular navigation. IEEE Trans. Biomed. Eng. 55:1854–1863, 2008.PubMedCrossRefGoogle Scholar
  48. 48.
    Vartholomeos, P., and C. Mavroidis. In silico studies of magnetic microparticle aggregations in fluid environments for MRI-guided drug delivery. IEEE Trans. Biomed. Eng. 59:3028–3038, 2012.PubMedCrossRefGoogle Scholar
  49. 49.
    Yesin, K. B., K. Vollmers, and B. J. Nelson. Modeling and control of untethered biomicrorobots in a fluidic environment using electromagnetic fields. Int. J. Robot. Res. 25:527–536, 2006.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2014

Authors and Affiliations

  • Pierre Pouponneau
    • 1
  • Gaël Bringout
    • 1
  • Sylvain Martel
    • 1
  1. 1.NanoRobotics Laboratory, Department of Computer and Software Engineering and Institute of Biomedical EngineeringEcole Polytechnique de Montréal (EPM)MontrealCanada

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