In vitro study of drug-eluting stent coatings based on poly(l-lactide) incorporating cyclosporine A – drug release, polymer degradation and mechanical integrity

  • Katrin Sternberg
  • Sven Kramer
  • Claudia Nischan
  • Niels Grabow
  • Thomas Langer
  • Gerhard Hennighausen
  • Klaus-Peter Schmitz
Original Paper

Abstract

In this study, absorbable polymer stent coatings for localized drug delivery based on poly(l-lactide) (PLLA) and cyclosporine A (CsA) were developed and tested in vitro. Metallic stents were coated with different compositions of PLLA/CsA (70/30, 60/40, 50/50% w/w) and β-sterilized. The specimens were used to assess the drug release kinetics with HPLC. Sterilization influenced polymer degradation was measured with GPC. Mechanical integrity of the stent coatings was studied with SEM. The interconnection of the coated stents with a balloon-catheter was characterized by the measurement of stent dislodgment force. A migration assay was used to determine the inhibitory effect of the model drug CsA on smooth muscle cell (SMC) migration. The release of CsA was established over time periods up to 24 days in sodium chloride solution and in porcine blood plasma. An inhibition of SMC migration (max. 26–33%) was found for CsA concentrations of 4 × 10−5 to 4 × 10−7 mol/l. Marked molecular weight reduction (70–80%) of the PLLA matrix occurred after β-sterilization. We also observed a substantial decrease of in vitro degradation time. The maintenance of the mechanical integrity of the polymer coating during crimping and dilation of the specimens could be verified, and a sufficient stent dislodgment force of 0.8–0.9 N was measured.

References

  1. 1.
    P. J. De FEYTER, J. VOS and B. J. RENSING, Curr. Interv. Cardiol. Rev. 2 (2000) 326Google Scholar
  2. 2.
    G. S. MINTZ, J. J. POPMA, A. D. PICHARD, K. M. KENT, L. F. SATLER, S. C. WONG, M. K. HONG, J. A. KOVACH and M. B. LEON, Circulation 94 (1996) 35Google Scholar
  3. 3.
    R. HOFFMAN, G. S. MINTZ, G. R. DUSSAILLANT, J. J. PAOPMA, A. D. PICHARD, L. F. SATLER, K. M. KENT, J. GRIFFIN and M. B. LEON, Circulation 94 (1996) 1247Google Scholar
  4. 4.
    R. FATTORI and T. PIVA, Lancet North Am. Ed. 361 (2003) 247Google Scholar
  5. 5.
    J. E. SOUSA, P. W. SERRUYS and M. A. COSTA, Circulation 107 (2003) 2274 (Part I), 2283 (Part II)Google Scholar
  6. 6.
    K. J. SALU, J. M. BOSMANS, H. BULT and C. J. VRINTS, Acta Cardiol. 59 (2004) 51CrossRefGoogle Scholar
  7. 7.
    R. S. SCHWARTZ, E. EDELMAN, A. CARTER, N. CHRONOS, C. ROGERS, K. A. ROBINSON, R. WAKSMAN, J. WEINBERGER, R. L. WILENSKY, D. N. JENSEN, B. D. ZUCKERMAN and R. VIRMANI, Circulation 106 (2002) 1867CrossRefGoogle Scholar
  8. 8.
    T. TSUJI, H. TAMAI, K. IGAKI, E. KYO, K. KOSUGA, T. HATA, M. OKADA, T. NAKAMURA, S. FUJITA, S. TAKEDA, S. MOTOHARA and H. UEHATA, Int. J. Cardiovasc. Intervent. 5 (2003) 13CrossRefGoogle Scholar
  9. 9.
    F. VOGT, A. STEIN, G. RETTEMEIER, N. KROTT, R. HOFFMANN, J. vom DAHL, A. K. BOSSERHOFF, W. MICHAELI, P. HANRATH, C. WEBER and R. BLINDT, Eur. Heart. J. 25 (2004) 1330CrossRefGoogle Scholar
  10. 10.
    K. J. SALU, J. M. BOSMANS, H. BULT and C. J. VRINTS, Acta Cardiol. 59 (2004) 165CrossRefGoogle Scholar
  11. 11.
    E. REGAR, G. SIANOS and P. W. SERRUYS, Brit. Med. Bull. 59 (2001) 227CrossRefGoogle Scholar
  12. 12.
    S. V. RANADE, K. M. MILLER, R. E. RICHARD, A. K. CHAN, M. J. ALLEN.and M. N. HELMUS, J. Biomed. Mater. Res. 71 (2004) 625CrossRefGoogle Scholar
  13. 13.
    P. J. MOHACSI, D. TÜLLER, B. HULLIGER and P. L. J. WIJNGAARD, J. Heart Lung Transplant. 16 (1997) 484Google Scholar
  14. 14.
    J. I. MOON, Y. S. KIM, M. S. KIM, E. H. KIM, H. J. KIM, S. I. KIM and K. Park, Transplant. Proc. 32 (2000) 2026CrossRefGoogle Scholar
  15. 15.
    B. M. MEISER, M. E. BILLINGHAM and R. E. MORRIS, Lancet 338 (1991) 1297CrossRefGoogle Scholar
  16. 16.
    R. L. STOLTENBERG, J. GERAGHTY, D. M. STEELE, E. KENNEDY, D. A. HULLETT and H. W. SOLLINGER, Transplantation 60 (1995) 993CrossRefGoogle Scholar
  17. 17.
    T. SAITO, A. IGUCHI, M. SAKURAI and K. TABAYASHI, Ann. Thorac. Surg. 77 (2004) 684CrossRefGoogle Scholar
  18. 18.
    T. W. TALBERT, J. R. GREEN, D. P. MUKHERJEE, A. L. OGDEN, R. H. MAYEUX, J. Long Term Eff. Med. Implants 13 (2003) 319CrossRefGoogle Scholar
  19. 19.
    A. P. TESTA PEZZIN, T. P. CARDOSO, M. do CARMO ALBERTO RINCON, C. A. de CARVALHO ZAVAGLIA, E. A. de REZENDE DUEK, Artif. Organs. 27 (2003) 428CrossRefGoogle Scholar
  20. 20.
    P. MAKELA, T. POHJONEN, P. TORMALA, T. WARIS and N. ASHAMMAKHI, Biomaterials 23 (2002) 2587CrossRefGoogle Scholar
  21. 21.
    A. K. CHEPUROV, G. G. KRIVOBORODOV, A. V. ZUBAREV , N. V. ZAITSEV and N. I. MARKINA, Urologiia 3 (2003) 44Google Scholar
  22. 22.
    T. ISOTALO, M. TALJA, T. VALIMAA, P. TORMALA and T. L. TAMMELA, J. Endourol. 16 (2002) 759CrossRefGoogle Scholar
  23. 23.
    M. MULTANEN, T. L. TAMMELA, M. LAURILA, J. SEPPALA, T. VALIMAA, P. TORMALA and M. TALJA, Urol. Res. 30 (2002) 227CrossRefGoogle Scholar
  24. 24.
    T. TSUJI, H. TAMAI, K. IGAKI, E. KYO, K. KOSUGA, M. OKADA, T. NAKAMURA, S. FUJITA, S. TAKEDA, S. MOTOHARA and H. UEHATA, Circulation 106 II (2002) 356Google Scholar
  25. 25.
    N. GRABOW, H. MARTIN and K.-P. SCHMITZ, Biomed. Tech. (Berlin) 47 Suppl 1 (2002) 503CrossRefGoogle Scholar
  26. 26.
    M. SCHLUN, K. STERNBERG, N. GRABOW, N. HAKANßON, S. KRAMER and K.-P. SCHMITZ, Biomed. Tech. (Berlin) 48 Suppl 1 (2003) 390Google Scholar
  27. 27.
    G. RAJASUBRAMANIAN, R. S. MEIDELL, C. LANDAU, M. L. DOLLAR, D. B. HOLT, J. E. WILLARD, M. D. PRAGER, R. C. EBERHART, ASAIO J. 40 (1994) M584CrossRefGoogle Scholar
  28. 28.
    C. M. AGRAWAL, K. F. HAAS, D. A. LEOPOLD and H. CLARK, Biomaterials 13 (1992) 176CrossRefGoogle Scholar
  29. 29.
    K. J. ZHU, J. X. ZHANG, C. WANG, H. YASUDA, A. ICHIMARU and K. YAMAMOTO, J. Microencapsul. 20 (2003) 731CrossRefGoogle Scholar
  30. 30.
    K. T. NGUYEN, S. H. SU, A. SHENG, D. WAWRO, N. D. SCHWADE, C. F. BROUSE, P. E. GREILICH, L. TANG and R. C. EBERHART, Biomaterials 24 (2003) 5191CrossRefGoogle Scholar
  31. 31.
    M. ZILBERMAN, R. C. EBERHART and N. D. SCHWADE, J. Biomater. Sci. Polym. Ed. 13 (2002) 1221CrossRefGoogle Scholar
  32. 32.
    M. LABINAZ, J. P. ZIDAR, R. S. STACK and H. R. PHILLIPS, J. Interv. Cardiol. 8 (1995) 395CrossRefGoogle Scholar
  33. 33.
    H. TAMAI, K. IGAKI, E. KYO, K. KOSUGA, A. KAWASHIMA, S. MATSUI, H. KOM, T. TSUJI, S. MOTOHARA and H. UEHATA, Circulation 102 (2000) 399Google Scholar
  34. 34.
    H. BARDELMEIJER, M. OUWEHAND, J. H. BEIJNEN, J. H. M. SCHELLENS and O. van TELLINGEN, J. Chromatogr. B. Biomed. Appl. 763 (2001) 201CrossRefGoogle Scholar
  35. 35.
    E. W. FISCHER, H. J. STERZEL and G. WEGNER, Kolloid-Z. u. Z. Polymere 251 (1973) 980CrossRefGoogle Scholar
  36. 36.
    B. KALB and A. J. PENNINGS, Polymer 21 (1980) 607CrossRefGoogle Scholar
  37. 37.
    D.H. LEWIS, in Biodegradable Polymers as Drug Delivery Systems, edited by M. Chasin and R. Langer (New York: Marcel Dekker, 1990) pp. 8, 24Google Scholar
  38. 38.
    Arzneistoff-Profile, Basisinformation über arzneiliche Wirkstoffe, Govi-Verlag GmbH, Pharmazeutischer Verlag, Frankfurt am Main, ASP-7. Erg.-Lieferung (1990) 1–8Google Scholar
  39. 39.
    P. NUGROHO, H. MITOMO, F. YOSHII and T. KUME, Polym. Degrad. Stab. 72 (2001) 337CrossRefGoogle Scholar
  40. 40.
    J. P. NUUTINEN, C. CLERC, T. VIRTA and P. TÖRMÄLÄ, J. Biomater. Sci. Polym. Edn. 13 (2002) 1325CrossRefGoogle Scholar
  41. 41.
    N. GRABOW, M. SCHLUN, K. STERNBERG, N. HAKANßON, S. KRAMER, and K.-P. SCHMITZ, J. Biomech. Eng. 127 (2005) 25CrossRefGoogle Scholar
  42. 42.
    P. MAINIL-VARLET, R. CURTIS and S. GOGOLEWSKI, J. Biomed. Mater. Res. 36 (1997) 360CrossRefGoogle Scholar
  43. 43.
    S. LI, H. GARREAU and M. VERT, J. Mater. Sci. Mater. Med. 1 (1990) 198CrossRefGoogle Scholar
  44. 44.
    R. SUURONEN, T. POHJONEN, J. HIETANEN and C. LINDQUIST, J. Oral. Maxillofac. Surg. 56 (1998) 604CrossRefGoogle Scholar
  45. 45.
    S. IANNACE, A. MAFFEZZOLI, G. LEO and L. NICOLAIS, Polymer 42 (2001) 3799CrossRefGoogle Scholar
  46. 46.
    M. ZILBERMAN, N. D. SCHWADE, R. S. MEIDELL and R. C. EBERHART, J Biomater. Sci. Polym. Ed. 12 (2001) 875CrossRefGoogle Scholar
  47. 47.
    S. GOGOLEWSKI, M. JOVANOVIC, S. M. PERREN, J. G. DILLON and M. K. HUGHES, J. Biomed. Mater. Res. 27 (1993) 1135CrossRefGoogle Scholar
  48. 48.
    A. M. LINCOFF, J. G. FURST, S. G. ELLIS, R. J. TUCH, E. J. TOPOL, J. Am. Coll. Cardiol. 29 (1997) 808CrossRefGoogle Scholar
  49. 49.
    H. PISTNER, Osteosynthese mit bioresorbierbaren Materialien, Einhorn-Presse Verlag, Reinbek (1999) 66–86Google Scholar
  50. 50.
    T. FREIER, C. KUNZE, C. NISCHAN, S. KRAMER, K. STERNBERG, M. SAß, U. T. HOPT, K. -P. SCHMITZ, Biomaterials 23 (2002) 2649CrossRefGoogle Scholar
  51. 51.
    S. J. HU R. FERNANDEZ, J. W. JONES Jr., Transplant. Proc. 31 (1999) 663CrossRefGoogle Scholar
  52. 52.
    M. S. KIM H. HA, Y. S. KIM, J. PARK, H. KIM, J. SEO, J. H. LEE and K. PARK, Transplant. Proc. 35 (2003) 189CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Katrin Sternberg
    • 1
  • Sven Kramer
    • 1
  • Claudia Nischan
    • 1
  • Niels Grabow
    • 1
  • Thomas Langer
    • 1
  • Gerhard Hennighausen
    • 2
  • Klaus-Peter Schmitz
    • 1
  1. 1.Institute for Biomedical Engineering University of RostockRostockGermany
  2. 2.Institute for Experimental PharmacologyUniversity of RostockRostockGermany

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