Advertisement

Journal of Materials Science: Materials in Medicine

, Volume 23, Issue 9, pp 2151–2162 | Cite as

Development of a specially tailored local drug delivery system for the prevention of fibrosis after insertion of cochlear implants into the inner ear

  • Anne Bohl
  • Henning W. Rohm
  • Piera Ceschi
  • Gerrit Paasche
  • Anne Hahn
  • Stephan Barcikowski
  • Thomas Lenarz
  • Timo Stöver
  • Hans-Wilhelm Pau
  • Klaus-Peter Schmitz
  • Katrin Sternberg
Article

Abstract

A cochlear implant (CI)-associated local drug delivery system based on dexamethasone (DMS) was developed with the purpose to inhibit the growth of fibrotic tissue which influences the signal transmission from the CI to the neurons of the inner ear. For the realization of a targeted DMS delivery the following concepts were combined: modification of the silicone-based electrode carrier by incorporation of DMS and a DMS-containing polymeric coating chemically attached on the surface of the electrode carrier. It was demonstrated that the coated CI showed a high coating stability in a simulated implantation procedure. The in vitro drug release studies in a quasi-stationary model revealed a faster DMS release in the initial phase originating from the DMS-containing coatings and then a lower and sustained DMS release originating from the DMS-loaded silicone carrier. The performed in vitro biocompatibility study confirmed that the released DMS was non-toxic for cultured spiral ganglion cells.

Keywords

High Performance Liquid Chromatography PLLA Cochlear Implant Environmental Scan Electron Microscopy Silicone Sample 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank Peter Littwin, Martina Schröder and Andrea Rohde for their technical assistance as well as Thilo Storm and Katharina Wulf for their helpful notes and suggestions. Furthermore, the Tepha, Inc. (Lexington, MA, USA) and the Bayer MaterialScience AG (Leverkusen, Germany) are acknowledged for the supply of the polymeric biomaterials P(4HB) and PUR, respectively. This work was funded by the Deutsche Forschungsgemeinschaft (DFG) within SFB Transregio 37 “Mikro- und Nanosysteme in der Medizin–Rekonstruktion biologischer Funktionen” (GZ: TRR 37) and the Bundesministerium für Bildung und Forschung (BMBF) within REMEDIS “Höhere Lebensqualität durch neuartige Mikroimplantate” (FKZ: 03IS2081).

References

  1. 1.
    Van de Water TR, Dinh CT, Vivero R, Hoosien G, Eshraghi AA, Balkany TJ. Mechanism of hearing loss from trauma and inflammation: otoprotective therapies from the laboratory to the clinic. Acta Otolaryngol. 2010;130(3):308–11.CrossRefGoogle Scholar
  2. 2.
    Furze A, Kralick D, Vakharia A, Jaben K, Graves R, Adil E, Eshraghi AA, Balkany TJ, Van de Water TR. Dexamethasone and methylprednisolone do not inhibit neuritic outgrowth while inhibiting outgrowth of fibroblasts from spiral ganglion explants. Acta Otolaryngol. 2008;128:122–7.CrossRefGoogle Scholar
  3. 3.
    Paasche G, Bockel F, Tasche C, Lesinski-Schiedat A, Lenarz T. Changes of postoperative impedances in cochlear implant patients: the short-term effects of modified electrode surfaces and intracochlear corticosteroids. Otol Neurotol. 2006;27:639–47.CrossRefGoogle Scholar
  4. 4.
    Hargunani CA, Kempton JB, DeGagne JM, Trune DR. Intratympanic injection of dexamethasone: time course of inner ear distribution and conversion to its active form. Otol Neurotol. 2006;27:564–9.CrossRefGoogle Scholar
  5. 5.
    Bird PA, Murray DP, Zhang M, Begg EJ. Intratympanic versus intravenous delivery of dexamethasone and dexamethasone sodium phosphate to cochlear perilymph. Otol Neurotol. 2011;32:933–6.CrossRefGoogle Scholar
  6. 6.
    Braun S, Ye Q, Radeloff A, Kiefer J, Gstoettner W, Tillein J. Protection of inner ear function after cochlear implantation: compound action potential measurements after local application of glucocorticoids in the guinea pig cochlea. ORL J Otorhinolaryngol Relat Spec. 2011;73:219–28.CrossRefGoogle Scholar
  7. 7.
    Rajan G, Kuthubutheen J, Hedne N, Krishnaswamy J. The role of preoperative, intratympanic glucocorticoids for hearing preservation in cochlear implantation: a prospective clinical study. Laryngoscope. 2012;122:190–5.CrossRefGoogle Scholar
  8. 8.
    Borden RC, Saunders JE, Berryhill WE, Krempl GA, Thompson DM, Queimado L. Hyaluronic acid hydrogel sustains the delivery of dexamethasone across the round window membrane. Audiol Neurootol. 2011;16:1–11.Google Scholar
  9. 9.
    Eastwood H, Chang A, Kel G, Sly D, Richardson R, O’Leary SJ. Round window delivery of dexamethasone ameliorates local and remote hearing loss produced by cochlear implantation into the second turn of the guinea pig cochlea. Hear Res. 2010;265:25–9.CrossRefGoogle Scholar
  10. 10.
    Salt AN, Plontke SK. Local inner-ear drug delivery and pharmacokinetics. Drug Discov Today. 2005;10:1299–306.CrossRefGoogle Scholar
  11. 11.
    Maini S, Lisnichuk H, Eastwood H, Pinder D, James D, Richardson RT, Chang A, Connolly T, Sly D, Kel G, O’Leary SJ. Targeted therapy of the inner ear. Audiol Neurootol. 2009;14:402–10.CrossRefGoogle Scholar
  12. 12.
    Souter M, Eastwood H, Marovic P, Kel G, Wongprasartsuk S, Ryan AF, O’Leary SJ. Systemic immunity influences hearing preservation in cochlear implantation. Otol Neurotol. 2012;33(4):532–8.CrossRefGoogle Scholar
  13. 13.
    Arnold W, Senn P, Hennig M, Michaelis C, Deingruber K, Scheler R, Steinhoff HJ, Riphagen F, Lamm K. Novel slow- and fast-type drug release round-window microimplants for local drug application to the cochlea: an experimental study in guinea pigs. Audiol Neurootol. 2005;10:53–63.CrossRefGoogle Scholar
  14. 14.
    Praetorius M, Limberger A, Müller M, Lehner R, Schick B, Zenner HP, Plinkert P, Knipper M. A novel microperfusion system for the long-term local supply of drugs to the inner ear: implantation and function in the rat model. Audiol Neurootol. 2001;6:250–8.CrossRefGoogle Scholar
  15. 15.
    Paasche G, Gibson P, Averbeck T, Becker H, Lenarz T, Stöver T. Technical report: modification of a cochlear implant electrode for drug delivery to the inner ear. Otol Neurotol. 2003;24:222–7.CrossRefGoogle Scholar
  16. 16.
    Jolly C, MedEl. Implantable neuro-stimulation electrode with drug elution material. Patent US 2008/0033520 A1, 2008.Google Scholar
  17. 17.
    Dittrich B, Hammann D, Wenzel G, Möller M, Klee D. Dexamethasone releasing cylindrical polydimethyldisiloxane matrices. Biomaterialien (München). 2009;10:61.Google Scholar
  18. 18.
    Farahmand Ghavi F, Mirzadeh H, Imani M, Jolly C, Farhadi M. Corticosteroid-releasing cochlear implant: a novel hybrid of biomaterial and drug delivery system. J Biomed Mater Res B Appl Biomater. 2010;94:388–98.Google Scholar
  19. 19.
    Jolly C, Garnham C, Mirzadeh H, Truy E, Martini A, Kiefer J, Braun S. Electrode features for hearing preservation and drug delivery strategies. Adv Otorhinolaryngol. 2010;67:28–42.Google Scholar
  20. 20.
    Mohammad F, Maryam J, Pirooz S, Farahmand GF, Hesamedin E, Hamid M, Mohammad I, Jolly C. Dexamethasone eluting cochlear implant: Histological study in animal model. Cochlear Implants Int. 2012. doi: 10.1179/17547628MY.0000000024.
  21. 21.
    Sternberg K, Kramer S, Nischan C, Grabow N, Langer T, Hennighausen G, Schmitz KP. In vitro study of drug-eluting stent coatings based on poly(l-lactide) incorporating cyclosporine A: drug release, polymer degradation and mechanical integrity. J Mater Sci Mater Med. 2007;18:1423–32.CrossRefGoogle Scholar
  22. 22.
    Wadhwa R, Lagenaur CF, Cui XT. Electrochemically controlled release of dexamethasone from conducting polymer polypyrrole coated electrode. J Control Release. 2006;110:531–41.CrossRefGoogle Scholar
  23. 23.
    Radeloff A, Unkelbach MH, Mack MG, Settevendemie C, Helbig S, Mueller J, Hagen R, Mlynski R. A coated electrode carrier for cochlear implantation reduces insertion forces. Laryngoscope. 2009;119:959–63.CrossRefGoogle Scholar
  24. 24.
    Wefstaedt P, Scheper V, Lenarz T, Stöver T. Brain-derived neurotrophic factor/glial cell line-derived neurotrophic factor survival effects on auditory neurons are not limited by dexamethasone. NeuroReport. 2005;16:2011–4.CrossRefGoogle Scholar
  25. 25.
    Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, Davidson CJ, McKoy JM, Raisch DW, Whisenant BK, Yarnold PR, Belknap SM, West DP, Gage JE, Morse RE, Gligoric G, Davidson L, Feldman MD. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol. 2006;47(1):175–81.CrossRefGoogle Scholar
  26. 26.
    Lanzer P, Sternberg K, Schmitz KP, Kolodgie F, Nakazawa G, Virmani R. Drug-eluting coronary stent very late thrombosis revisited. Herz. 2008;33:334–42.CrossRefGoogle Scholar
  27. 27.
    Kukreja N, Onuma Y, Daemen J, Serruys PW. The future of drug-eluting stents. Pharmacol Res. 2008;57:171–80.CrossRefGoogle Scholar
  28. 28.
    Martin DP, Williams SF. Medical applications of poly-4-hydroxybutyrate: a strong flexible absorbable biomaterial. Biochem Eng J. 2003;16:97–105.CrossRefGoogle Scholar
  29. 29.
    Dexamethason. Arzneistoff-Profile, Basisinformation über arzneiliche Wirkstoffe. Frankfurt am Main: GOVI-Verlag, Pharmazeutischer Verlag; 2009.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Anne Bohl
    • 1
  • Henning W. Rohm
    • 1
  • Piera Ceschi
    • 2
  • Gerrit Paasche
    • 2
  • Anne Hahn
    • 3
  • Stephan Barcikowski
    • 3
  • Thomas Lenarz
    • 2
  • Timo Stöver
    • 4
  • Hans-Wilhelm Pau
    • 5
  • Klaus-Peter Schmitz
    • 1
  • Katrin Sternberg
    • 1
  1. 1.Institute for Biomedical EngineeringUniversity of RostockRostockGermany
  2. 2.Department of OtolaryngologyHannover Medical SchoolHannoverGermany
  3. 3.Laser Zentrum Hannover e. V.HannoverGermany
  4. 4.Department of OtolaryngologyJohann Wolfgang Goethe UniversityFrankfurt am MainGermany
  5. 5.Department of Otorhinolaryngology, Head and Neck SurgeryUniversity of RostockRostockGermany

Personalised recommendations