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Biomedical Microdevices

, Volume 11, Issue 2, pp 517–527 | Cite as

Magnetic alginate microspheres: system for the position controlled delivery of nerve growth factor

  • Gianni Ciofani
  • Vittoria Raffa
  • Arianna Menciassi
  • Alfred Cuschieri
  • Silvestro Micera
Article

Abstract

The use of polymeric carriers containing dispersed magnetic nanocrystalline particles for targeted delivery of drugs in clinical practice has attracted the interest of the scientific community. In this paper a system comprised of alginate microparticles with a core of magnetite and carrying nerve growth factor (NGF) is described. The magnetic properties of these microspheres, typical of superparamagnetic materials, allow precise and controlled delivery to the intended tissue environment. Experiments carried out on PC12 cells with magnetic alginate microspheres loaded with NGF have confirmed the induction of cell differentiation which is strongly dependent on the distance from the microsphere cluster. In addition, finite element modelling (FEM) of the release profile from the microspheres in culture, indicated the possibility of creating defined and predictable NGF gradients from the loaded microspheres. These observations on the carriage and release of growth factors by the proposed microparticles open new therapeutic options for both neuronal regeneration and of the development of effective neuronal interfaces.

Keywords

Targeted drug delivery NGF Alginate Magnetic microparticles Neuronal outgrowth 

Notes

Acknowledgements

The work described in this paper was partially supported by the IIT (Italian Institute of Technology) Network and the NINIVE (Non Invasive Nanotransducer for In Vivo gene thErapy, STRP 033378) project, co-financed by the 6FP of the European Commission.

Authors gratefully thank Mr. Carlo Filippeschi for his kind support using the FIB microscope.

References

  1. M. Arruebo, R. Fernandez-Pacheco, M.R. Ibarra, J. Santamaria, Magnetic nanoparticles for drug delivery. Nano Today 2(3), 22–32 (2007). doi: 10.1016/S1748-0132(07)70084-1 CrossRefGoogle Scholar
  2. R.P. Batycky, J. Hanes, R. Langer, D.A. Edwards, A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J. Pharm. Sci. 86, 1464–1477 (1997). doi: 10.1021/js9604117 CrossRefGoogle Scholar
  3. P. Berger, N.B. Adelman, K.J. Beckman, D.J. Campbell, A.B. Ellis, G.C. Lisensky, Preparation and properties of an aqueous ferrofluid. J. Chem. Educ. 76(7), 943–948 (1999)CrossRefGoogle Scholar
  4. M.A. Burns, G.I. Kvesitadze, D.J. Graves, Dried calcium alginate/magnetite spheres: a new support for chromatographic separations and enzyme immobilization. Biotechnol. Bioeng. 27(2), 137–145 (1985). doi: 10.1002/bit.260270206 CrossRefGoogle Scholar
  5. G. Ciofani, V. Raffa, A. Menciassi, P. Dario, Alginate and chitosan particles as drug delivery system for cell therapy. Biomed. Microdevices 10(2), 131–140 (2008a). doi: 10.1007/s10544-007-9118-7 CrossRefGoogle Scholar
  6. G. Ciofani, V. Raffa, T. Pizzorusso, A. Menciassi, P. Dario, Characterization of an alginate based drug delivery system for neurological applications. Med. Eng. Phys. 30(7), 848–855 (2008b). doi: 10.1016/j.medengphy.2007.10.003 CrossRefGoogle Scholar
  7. G. Ciofani, V. Raffa, Y. Obata, A. Menciassi, P. Dario, S. Takeoka, Magnetic driven alginate nanoparticles for targeted drug delivery. Curr. Nanosci. 4(2), 212–218 (2008c). doi: 10.2174/157341308784340886 CrossRefGoogle Scholar
  8. P. Couvreur, C. Vauthier, Nanotechnology: intelligent design to treat complex disease. Pharm. Res. 23(7), 1417–1450 (2006). doi: 10.1007/s11095-006-0284-8 CrossRefGoogle Scholar
  9. P. Dario, P. Garzella, M. Toro, S. Micera, M. Alavi, J.U. Meyer, E. Valderrama, L. Sebastiani, B. Ghelarducci, P. Pastacaldi, A microfabricated interface for neural recording and stimulation. J. Micromech. Microeng. 7, 233–236 (1997). doi: 10.1088/0960-1317/7/3/041 CrossRefGoogle Scholar
  10. M. Ferrari, Nanovector therapeutics. Curr. Opin. Chem. Biol. 9, 343–346 (2006). doi: 10.1016/j.cbpa.2005.06.001 CrossRefGoogle Scholar
  11. G.F. Goya, V. Grazú, M.R. Ibarra, Magnetic nanoparticles for cancer therapy. Curr. Nanosci. 4(1), 1–16 (2008). doi: 10.2174/157341308783591861 CrossRefGoogle Scholar
  12. L.A. Greene, S.E. Farinelli, M.E. Cunningham, D.S. Park, in Culture and experimental use of the PC12 rat pheochromocytoma cell line, in: Culturing Nerve Cells 2, ed. by F. Banker, K. Goslin (MIT Press, Cambridge, 1998)Google Scholar
  13. U. Häfeli, Magnetically modulated therapeutic systems. Int. J. Pharm. 277, 19–24 (2004). doi: 10.1016/j.ijpharm.2003.03.002 CrossRefGoogle Scholar
  14. B.P. Hanley, L. Xing, R.H. Cheng, Variance in multiplex suspension array assays: microsphere size variation impact. Theoretical Biology and Medical Modelling 4(31), 8 (2007)Google Scholar
  15. R. Hergt, S. Dutz, Magnetic particle hyperthermia—biophysical limitations of a visionary tumour therapy. J. Magn. Magn. Mat. 311, 187–192 (2007)CrossRefGoogle Scholar
  16. R. Heumann, D. Lindholm, C. Bandtlow, M. Meyer, M.J. Radeke, T.P. Misko, E. Shooter, H. Thoenen, Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerve during development, degeneration, and regeneration: role of macrophages. Proc. Natl. Acad. Sci. USA 84, 8735–8739 (1987)CrossRefGoogle Scholar
  17. S.H. Hu, T.Y. Liu, C.H. Tsai, S.Y. Chen, Preparation and characterization of magnetic ferroscaffolds for tissue engineering. J. Magn. Magn. Mat. 310, 2871–2873 (2007)CrossRefGoogle Scholar
  18. L.L. Jones, M.H. Tuszynski, Chronic intrathecal infusions after spinal cord injury cause scarring and compression. Microsc. Res. Tech. 54, 317–324 (2001)CrossRefGoogle Scholar
  19. R. Langer, Drug delivery and targeting. Nature 392, 5–10 (1998)Google Scholar
  20. N. Lago, D. Ceballos, F. Rodriguez, T. Stieglitz, X. Navarro, Long term assessment of axonal regeneration through polyimide regenerative electrodes to interface the peripheral nerve. Biomaterials 26(14), 2021–2031 (2005)CrossRefGoogle Scholar
  21. S.L. Lewin, D.S. Utley, E.T. Cheng, A.N. Verity, D.J. Terris, Simultaneous treatment with BDNF and CNTF after peripheral nerve transaction and repair enhances rate of functional recovery compared with BDNF treatment alone. Laryngoscope 107, 992–999 (1997)CrossRefGoogle Scholar
  22. G. Lundborg, A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance. J. Hand Surg. [Am.] 25, 391–414 (2000)CrossRefGoogle Scholar
  23. S.M. Maskery, T. Shinbrot, Deterministic and stochastic elements of axonal guidance. Annu. Rev. Biomed. Eng. 7, 187–221 (2005)CrossRefGoogle Scholar
  24. D. Maysinger, A. Morinville, Drug delivery to the nervous system. Trends Biotechnol. 15, 410–418 (1997)CrossRefGoogle Scholar
  25. Y. Murakami, S. Furukawa, A. Nitta, Y. Furukawa, Accumulation of nerve growth factor protein at both rostral and caudal stumps in the transected rat spinal cord. J. Neurol. Sci. 198, 63–69 (2002)CrossRefGoogle Scholar
  26. X. Navarro, S. Calvet, C.A. Rodriguez, C. Blau, M. Buti, E. Valderrama, J.U. Meyer, T. Stieglitz, Stimulation and recording from regenerated peripheral nerves through polyimide sieve electrodes. J. Periph. Nerv. System 3, 91–101 (1998)Google Scholar
  27. X. Navarro, T. Lago, S. Micera, T. Stieglitz, P. Dario, A critical review of interfaces with the peripheral nervous system for the control of neuroprostheses and hybrid bionic systems. J. Periph. Nerv. System 10, 229–258 (2005)CrossRefGoogle Scholar
  28. V. Raffa, P. Castrataro, A. Menciassi, P. Dario, in In Applied scanning probe methods, vol. II, ed. by B. Bushan, H. Fuchs (Springer, Heidelberg, 2005)Google Scholar
  29. P.J. Robinson, P. Dunnill, M.D. Lilly, The properties of magnetic supports in relation to immobilized enzyme reactors. Biotechnol. Bioeng. 15(3), 603–606 (1973)CrossRefGoogle Scholar
  30. B.I. Rosner, R.A. Siegel, A. Grosberg, R.T. Tranquillo, Rational design of contact guiding, neurotrophic matrices for peripheral nerve regeneration. Ann. Biomed. Eng. 31, 1383–1401 (2003)CrossRefGoogle Scholar
  31. X. Santos, J. Rodrigo, B. Hontanilla, G. Bilbao, Evaluation of peripheral nerve regeneration by nerve growth factor locally administered with a novel system. J. Neurosci. Meth. 85, 119–127 (1998)CrossRefGoogle Scholar
  32. P. Sapra, T.M. Allen, Internalizing antibodies are necessary for improved therapeutic efficacy of antibody-targeted liposomal drugs. Cancer Res. 62(24), 7190–7194 (2002)Google Scholar
  33. C.E. Schmidt, L.B. Leach, Neural tissue engineering: strategies for repair and regeneration. Annu. Rev. Biomed. Eng. 5, 293–347 (2003)CrossRefGoogle Scholar
  34. M.D. Shultz, S. Calvin, P.P. Fatouros, S.A. Morrison, E.E. Carpenter, Enhanced ferrite nanoparticles as MRI contrast agents. J. Magn. Magn. Mat. 311, 464–468 (2007)CrossRefGoogle Scholar
  35. W. Schütt, C. Grüttner, U. Häfeli, M. Zborowski, J. Teller, H. Putzar, C. Schümichen, Applications of magnetic targeting in diagnosis and therapy—possibilities and limitations: a mini-review. Hybridoma 16(1), 109–117 (1997)CrossRefGoogle Scholar
  36. W.D. Snider, E.M. Johson, Neurotrophic molecules. Ann. Neurol. 26, 489–506 (1989)CrossRefGoogle Scholar
  37. C.M. Stoscheck, Quantitation of protein. Method. Enzymol. 182, 50–69 (1990)CrossRefGoogle Scholar
  38. S. Teotia, M.N. Gupta, Magnetite-alginate beads for purification of some starch degrading enzymes. Mol. Biotechnol. 20(3), 231–237 (2002)CrossRefGoogle Scholar
  39. M.H. Tuszynski, K. Gabriel, F.H. Gage, S. Suhr, S. Meyer, A. Rosetti, Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory, motor, and noradrenergic neurites after adult spinal cord injury. Exp. Neurol. 137, 157–173 (1996)CrossRefGoogle Scholar
  40. K.J. Widder, A.E. Senyei, D.G. Scarpelli, Magnetic microspheres: a model system for site specific drug delivery in vivo. Proc. Soc. Exp. Biol. Med. 158(2), 141–146 (1978)Google Scholar
  41. J.O. Winter, S.F. Cogan, J.F. Rizzo III, Neurotrophin-eluting hydrogel coatings for neural stimulating electrodes. J. Biomed. Mater. Res. Part B. Appl. Biomater. 81B, 551–563 (2007)CrossRefGoogle Scholar
  42. U. Zimmermann, G. Pilwat, Organ specific application of drugs by means of cellular capsule systems. J. Biosci. 31(11–12), 732–736 (1976)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Gianni Ciofani
    • 1
    • 4
  • Vittoria Raffa
    • 1
  • Arianna Menciassi
    • 1
    • 2
  • Alfred Cuschieri
    • 1
  • Silvestro Micera
    • 1
    • 3
  1. 1.Scuola Superiore Sant’AnnaPisaItaly
  2. 2.Italian Institute of Technology (IIT)GenovaItaly
  3. 3.Swiss Federal Institute of Technology (ETH)ZurichSwitzerland
  4. 4.CRIM & ARTS LabScuola Superiore Sant’AnnaPontederaItaly

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