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Untethered magnetic millirobot for targeted drug delivery

  • Veronica IacovacciEmail author
  • Gioia Lucarini
  • Leonardo Ricotti
  • Paolo Dario
  • Pierre E. Dupont
  • Arianna Menciassi
Article

Abstract

This paper reports the design and development of a novel millimeter-sized robotic system for targeted therapy. The proposed medical robot is conceived to perform therapy in relatively small diameter body canals (spine, urinary system, ovary, etc.), and to release several kinds of therapeutics, depending on the pathology to be treated. The robot is a nearly-buoyant bi-component system consisting of a carrier, in which the therapeutic agent is embedded, and a piston. The piston, by exploiting magnetic effects, docks with the carrier and compresses a drug-loaded hydrogel, thus activating the release mechanism. External magnetic fields are exploited to propel the robot towards the target region, while intermagnetic forces are exploited to trigger drug release. After designing and fabricating the robot, the system has been tested in vitro with an anticancer drug (doxorubicin) embedded in the carrier. The efficiency of the drug release mechanism has been demonstrated by both quantifying the amount of drug released and by assessing the efficacy of this therapeutic procedure on human bladder cancer cells.

Keywords

Drug delivery system Drug-loaded hydrogel Magnetic robot Magnetic docking Microrobotics Targeted therapy 

Notes

Acknowledgments

The authors would like to thank Mr. Tommaso Mazzocchi for his support with Abaqus simulations, Mr. Nicodemo Funaro and the staff of The BioRobotics Institute mechanical workshop for 3D printing. This work was supported in part by the GeT Small project (TarGeted Therapy at Small Scale), funded by the Scuola Superiore di Studi Universitari e di Perfezionamento Sant'Anna (Pisa, Italy). Pierre Dupont acknowledges support by the US National Science Foundation under grant IIS-1208509 and by the Wyss Institute for Biologically Inspired Engineering.

Supplementary material

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References

  1. J.J. Abbott, Z. Nagy, F. Beyeler, B.J. Nelson, Robotics in the small. IEEE Robot. Autom. Mag. 14, 3 (2007)CrossRefGoogle Scholar
  2. J.J. Abbott, K.E. Peyer, M. Cosentino Lagomarsino, L. Zhang, L. Dong, I.K. Kaliakatsos, B.J. Nelson, How should microrobots swim? Int. J. Robot. Res. 28, 11–12 (2009)CrossRefGoogle Scholar
  3. M. Alvarado-Velez, S.B. Pai, R.V. Bellamkonda, Hydrogels as carriers for stem cell transplantation. IEEE Trans. Biomed. Eng. 61, 5 (2014)CrossRefGoogle Scholar
  4. D. Armani, Deniz, C. Liu, N. Aluru, Re-configurable fluid circuits by PDMS elastomer micromachining. Proc. IEEE Micr. Elect. (1999)Google Scholar
  5. M. Arruebo, Drug delivery from structured porous inorganic materials. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 4, 1 (2012)CrossRefGoogle Scholar
  6. M. Arruebo, R. Fernández-Pacheco, M.R. Ibarra, J. Santamaría, Magnetic nanoparticles for drug delivery. Nano Today 2, 3 (2007)CrossRefGoogle Scholar
  7. C. Bergeles, G. Yang, From passive tool holders to microsurgeons: safer, smaller, smarter surgical robots. IEEE Trans. Biomed. Eng. 61, 5 (2013)Google Scholar
  8. R. Cassano, S. Trombino, in in Advanced Polymers Medicine, ed. by F. Puoci (Springer, Switzerland, 2015), pp. 341–370Google Scholar
  9. U.H. Chee, E.R. LeMoure, Catheter with atraumatic drug delivery tip, U.S. Patent No. 5,380,307. 10 Jan. 1995Google Scholar
  10. R. Chenga, F. Menga, C. Denga, H. Kloka, Z. Zhong, Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34, 14 (2013)Google Scholar
  11. D. de Lanauze, O. Felfoul, J. Turcot, M. Mohammadi, S. Martel, Three-dimensional remote aggregation and steering of magnetotactic bacteria microrobots for drug delivery applications, Int. J. Robot. Res. (2013)Google Scholar
  12. E. Diller, S. Floyd, C. Pawashe, M. Sitti, Control of multiple heterogeneous magnetic microrobots in two dimensions on nonspecialized surfaces. IEEE Trans. Robot 28, 1 (2012)CrossRefGoogle Scholar
  13. E. Diller, J. Giltinan, M. Sitti, Independent control of multiple magnetic microrobots in three dimensions. Int. J. Robot. Res. 32, 5 (2013)CrossRefGoogle Scholar
  14. A. Eqtami, O. Felfoul, P. E. Dupont, MRI-powered closed-loop control for multiple magnetic capsules, in Proc. IEEE Int. Conf. Int. Syst. (2014)Google Scholar
  15. T.W.R. Fountain, P.V. Kailat, J.J. Abbott, Wireless control of magnetic helical microrobots using a rotating-permanent-magnet manipulator, in Proc. IEEE Int. Conf. Robot. Autom. (2010)Google Scholar
  16. S. Fusco, F. Ullrich, J. Pokki, G. Chatzipirpiridis, B. Özkale, K.M. Sivaraman, O. Ergeneman, S. Pané, B.J. Nelson, Microrobots: a new era in ocular drug delivery. Expert Opin. Drug Deliv. 11, 11 (2014)CrossRefGoogle Scholar
  17. S. Gnavi, L. di Blasio, C. Tonda-Turo, A. Mancardi, L. Primo, G. Ciardelli, G. Gambarotta, S. Geuna, I. Perroteau, Gelatin‐based hydrogel for vascular endothelial growth factor release in peripheral nerve tissue engineering, J. Tissue Eng. Regen. Med. (2014)Google Scholar
  18. T. Hoare, B.P. Timko, J. Santamaria, G.F. Goya, S. Irusta, S. Lau, D.S. Kohane, Magnetically triggered nanocomposite membranes: a versatile platform for triggered drug release. Nano Lett. 11, 3 (2011)CrossRefGoogle Scholar
  19. S. Jeong, H. Choi, J. Choi, C. Yu, J.-o. Park, S. Park, Novel electromagnetic actuation (EMA) method for 3-dimensional locomotion of intravascular microrobot. Sensors Actuators A Phys. 157, 1 (2010)CrossRefGoogle Scholar
  20. G. Kósa, P. Jakab, G. Székely, N. Hata, MRI driven magnetic microswimmers. Biomed. Microdevices 14, 1 (2011)Google Scholar
  21. M.P. Kummer, J.J. Abbott, B.E. Kratochvil, R. Borer, A. Sengul, B.J. Nelson, OctoMag: an electromagnetic system for 5-DOF wireless micromanipulation. IEEE Trans. Robot. 26, 6 (2010)CrossRefGoogle Scholar
  22. J. Lammer, K. Malagari, T. Vogl, F. Pilleul, A. Denys, A. Watkinson, M. Pitton, G. Sergent, T. Pfammatter, S. Terraz, Y. Benhamou, Y. Avajon, T. Gruenberger, M. Pomoni, H. Langenberger, M. Schuchmann, J. Dumortier, C. Mueller, P. Chevallier, R. Lencioni, Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc. Intervent. Radiol. 33, 1 (2010)Google Scholar
  23. Y. Li, R.S. Shawgo, B. Tyler, P.T. Henderson, J.S. Vogel, A. Rosenberg, P.B. Storm, R. Langer, H. Brem, M.J. Cima, In vivo release from a drug delivery MEMS device. J. Control. Release 100, 2 (2004)CrossRefGoogle Scholar
  24. A.W. Mahoney, J.C. Sarrazin, E. Bambergc, J.J. Abbott, Velocity control with gravity compensation for magnetic helical microswimmers. Adv. Robot. 25, 8 (2011)CrossRefGoogle Scholar
  25. R. Mhanna, F. Qiu, L. Zhang, Y. Ding, K. Sugihara, M.y Zenobi-Wong, B.J. Nelson, Artificial Bacterial Flagella for Remote‐Controlled Targeted Single‐Cell Drug Delivery, Small, 1010 (2014)Google Scholar
  26. B.J. Nelson, I.K. Kaliakatsos, J.J. Abbott, Microrobots for minimally invasive medicine, Annu. Rev. Biomed. Eng. 12, (2010)Google Scholar
  27. S. Palagi, B. Mazzolai, C. Innocenti, C. Sangregorio, L. Beccai, How does buoyancy of hydrogel microrobots affect their magnetic propulsion in liquids? Appl. Phys. Lett. 102, 12 (2013)CrossRefGoogle Scholar
  28. V. Panagiotis, M.R. Akhavan-Sharif, P. E. Dupont, Motion planning for multiple millimeter-scale magnetic capsules in a fluid environment, in Proc. IEEE Int. Conf. Robot. Autom. (2012)Google Scholar
  29. T. Qiu, T. Lee, A. G. Mark, K.I. Morozov, R. Münster, O. Mierka, S. Turek, A. M. Leshansky, P. Fischer, Swimming by reciprocal motion at low Reynolds number, Nat. Commun. 5 (2014)Google Scholar
  30. L. Ricotti, A. Menciassi, Engineering stem cells for future medicine. IEEE Trans. Biomed. Eng. 60, 3 (2013)CrossRefGoogle Scholar
  31. L. Ricotti, A. Cafarelli, V. Iacovacci, L. Vannozzi, A. Menciassi, Advanced micro-nano-bio systems for future targeted therapies. Curr. Nanosci. (2015). doi: 10.2174/1573413710666141114221246 Google Scholar
  32. M.S. Sakar, A. Meo, J. Moller, B.E. Kratochvil, C.S. Chen, V. Vogel, B.J. Nelson, Three-dimensional, automated magnetic biomanipulation with subcellular resolution, in Proc. IEEE Int. Conf. Robot. Autom. (2013)Google Scholar
  33. D. Seliktar, Designing cell-compatible hydrogels for biomedical applications. Science 336, 6085 (2012)CrossRefGoogle Scholar
  34. L.J. Sliker, G. Ciuti, Flexible and capsule endoscopy for screening, diagnosis and treatment. Expert Rev. Med. Devices 11, 6 (2014)CrossRefGoogle Scholar
  35. L. Smith, M.B. Watson, S.L. O’Kane, P.J. Drew, M.J. Lind, L. Cawkwell, The analysis of doxorubicin resistance in human breast cancer cells using antibody microarrays. Mol. Cancer Ther. 5, 8 (2006)Google Scholar
  36. S.N. Tabatabaei, J. Lapointe, S. Martel, Shrinkable hydrogel-based magnetic microrobots for interventions in the vascular network. Adv. Robot. 25, 8 (2012)Google Scholar
  37. S. Tamaz, R. Gourdeau, A. Chanu, J. Mathieu, S. Martel, Real-time MRI-based control of a ferromagnetic core for endovascular navigation. IEEE Trans. Biomed. Eng. 55, 7 (2008)CrossRefGoogle Scholar
  38. J. Tao, Q. Lu, D. Wu, P. Li, B. Xu, W. Qing, M. Wang, Z. Zhang, W. Zhang, microRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol. Rep. 25, 6 (2011)Google Scholar
  39. B.P. Timko, T. Dvir, D.S. Kohane, Remotely triggerable drug delivery systems. Adv. Mater. 22, 44 (2010)CrossRefGoogle Scholar
  40. J.D. Tobias, L. Oakes, N.K. Foreman, H. Mahmoud, Percutaneous lumbar intrathecal catheter for the administration of chemotherapy. Med. Pediatr Oncol 19, 4 (1991)CrossRefGoogle Scholar
  41. C. Tonda-Turo, S. Gnavi, F. Ruini, G. Gambarotta, E. Gioffredi, V. Chiono, I. Perroteau, G. Ciardelli, Development and characterization of novel agar and gelatin injectable hydrogel as filler for peripheral nerve guidance channels, J. Tissue Eng. Regen. Med. (2014)Google Scholar
  42. S.P. Woods, T.G. Constandinou, Wireless capsule endoscope for targeted drug delivery: mechanics and design considerations. IEEE Trans. Biomed. Eng. 60, 4 (2012)Google Scholar
  43. S. Yim, M. Sitti, Shape-programmable soft capsule robots for semi-implantable drug delivery. IEEE Trans. Robot. 28, 5 (2012)CrossRefGoogle Scholar
  44. K.W. Yung, P.B. Landecker, D.D. Villani, An analytic solution for the force between two magnetic dipoles. Magn. Electr. Sep. 9, 1 (1998)CrossRefGoogle Scholar
  45. M. Zaaroor, G. Kosa, A. Peri-Eran, I. Maharil, M. Shoham, D. Coldsher, Morphological study of the spinal canal content for subarachnoid endoscopy. Minim. Invasive Neurosurg. 49, 4 (2006)CrossRefGoogle Scholar
  46. X. Zhao, J. Kimb, C.A. Cezar, N. Huebsch, K. Lee, K. Bouhadir, D.J. Mooney, Active scaffolds for on-demand drug and cell delivery. Proc. Natl. Acad. Sci. U. S. A. 108, 1 (2011)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Veronica Iacovacci
    • 1
    Email author
  • Gioia Lucarini
    • 1
  • Leonardo Ricotti
    • 1
  • Paolo Dario
    • 1
  • Pierre E. Dupont
    • 2
  • Arianna Menciassi
    • 1
  1. 1.The BioRobotics InstituteScuola Superiore Sant’AnnaPontederaItaly
  2. 2.Department of Cardiac Surgery, Boston Children’s HospitalHarvard Medical SchoolBostonUSA

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