Journal of Materials Science: Materials in Medicine

, Volume 24, Issue 11, pp 2589–2600 | Cite as

In vitro study of dual drug-eluting stents with locally focused sirolimus and atorvastatin release

  • Svea PetersenEmail author
  • Janine Hussner
  • Thomas Reske
  • Niels Grabow
  • Volkmar Senz
  • Robert Begunk
  • Daniela Arbeiter
  • Heyo K. Kroemer
  • Klaus-Peter Schmitz
  • Henriette E. Meyer zu Schwabedissen
  • Katrin Sternberg


Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(l-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70 % respectively 90 % of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal–luminal than luminal–abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.


Drug Release PLLA Release Phase Triflusal Rigid Amorphous Fraction 
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.



The authors thank Dalibor Bajer, Peter Littwin, Martin Radtke and Andrea Rohde for expert technical assistance in stent coating, Ramona Krey, Inge Rühl, Janine Schmidt and Martina Schröder for support with stent characterization regarding morphology and layer thickness and the Biotronik SE & Co. KG for the generous supply of metallic stents and balloon catheter. Additionally, Professor Gerhard Hennighausen is acknowledged for his helpful notes and suggestions. Furthermore, financial support by the Bundesministerium für Bildung und Forschung (BMBF) within REMEDIS “Höhere Lebensqualität durch neuartige Mikroimplantate” (FKZ: 03IS2081) is gratefully acknowledged.

Supplementary material

10856_2013_5001_MOESM1_ESM.doc (1.1 mb)
Supplementary material 1 (DOC 1091 kb)


  1. 1.
    Farb A, Burke AP, Kolodgie FD, Virmani R. Circulation. 2003;108:1701–6.CrossRefGoogle Scholar
  2. 2.
    Lanzer P, Sternberg K, Schmitz K-P, Kolodgie F, Nakazawa G, Virmani R. Herz. 2008;33:334–42.CrossRefGoogle Scholar
  3. 3.
    Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani RJ. J Am Coll Cardiol. 2006;48:193–202.CrossRefGoogle Scholar
  4. 4.
    Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R. Circulation. 2007;115:1051–8.CrossRefGoogle Scholar
  5. 5.
    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 MDJ. J Am Coll Cardiol. 2006;47:175–81.CrossRefGoogle Scholar
  6. 6.
    Sternberg K, Kramer S, Nischan C, Grabow N, Langer T, Hennighausen G, Schmitz K-PJ. J Mater Sci Mater Med. 2007;18:1423–32.CrossRefGoogle Scholar
  7. 7.
    Ge J, Qian J, Wang X, Wang Q, Yan W, Yan Y, Fan B, Ge L, Liu X. Catheter Cardiovasc Interv. 2007;69:198–202.CrossRefGoogle Scholar
  8. 8.
    Pan CJ, Tang JJ, Weng YJ, Wang J, Huang NJ. J Mater Sci Mater Med. 2007;18:2193–8.CrossRefGoogle Scholar
  9. 9.
    Kandzari DE, Leon MB, Popma JJ, Fitzgerald PJ, O’Shaughnessy C, Ball MW, Turco M, Applegate RJ, Gurbel PA, Midei MG, Badre SS, Mauri L, Thompson KP, LeNarz LA, Kuntz REJ. J Am Coll Cardiol. 2006;48:2440–7.CrossRefGoogle Scholar
  10. 10.
    Fajadet J, Wijns W, Laarman G-J, Kuck K-H, Ormiston J, Münzel T, Popma JJ, Fitzgerald PJ, Bonan R, Kuntz RE. Circulation. 2006;114:798–806.CrossRefGoogle Scholar
  11. 11.
    Miyazawa A, Ako J, Hongo Y, Hur S-H, Tsujino I, Courtney BK, Hassan AHM, Kandzari DE, Honda Y, Fitzgerald PJ. Am Heart J. 2008;155:108–13.CrossRefGoogle Scholar
  12. 12.
    Grube E, Sonoda S, Ikeno F, Honda Y, Kar S, Chan C, Gerckens U, Lansky AJ, Fitzgerald PJ. Circulation. 2004;109:2168–71.CrossRefGoogle Scholar
  13. 13.
    Serruys PW, Ong ATL, Piek JJ, Neumann F-J, Van der Giessen WJ, Wiemer M, Zeiher A, Grube E, Haase J, Thuesen L, Hamm C, Otto-Terlouw PC. EuroIntervention. 2005;1:58–65.Google Scholar
  14. 14.
    Grube E, Buellesfeld L. Expert Rev Med Devices. 2006;3:731–41.CrossRefGoogle Scholar
  15. 15.
    Kukreja N, Onuma Y, Daemen J, Serruys PW. Pharmacol Res. 2008;57:171–80.CrossRefGoogle Scholar
  16. 16.
    Huang Y, Venkatraman SS, Boey FYC, Lahti EM, Umashankar PR, Mohanty M, Arumugam S, Khanolkar L, Vaishnav S. Biomaterials. 2010;31:4382–91.CrossRefGoogle Scholar
  17. 17.
    Asahara T, Murohara T, Sullivan A, Silver M, Van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Science. 1997;275:964–6.CrossRefGoogle Scholar
  18. 18.
    Hristov M, Erl W, Weber PC. Arterioscler Thromb Vasc Biol. 2003;23:1185–9.CrossRefGoogle Scholar
  19. 19.
    Chevalier B, Silber S, Park S-J, Garcia E, Schuler G, Suryapranata H, Koolen J, Hauptmann KE, Wijns W, Morice M-C, Carrie D, Van Es G-A, Nagai H, Detiege D, Paunovic D, Serruys PW. Circ Cardiovasc Interv. 2009;2:188–95.CrossRefGoogle Scholar
  20. 20.
    Wang T, Yang Y-J, Xu BJ. J Am Coll Cardiol. 2012;59:E1395.CrossRefGoogle Scholar
  21. 21.
    Eindhoven JA, Onuma Y, Oemrawsingh RM, Daemen J, Van Nierop JWI, De Jaegere PPT, Boersma E, Serruys PW, Van Domburg RT. EuroIntervention. 2012;7:1420–7.CrossRefGoogle Scholar
  22. 22.
    Libby P, Schoenbeck U, Mach F, Selwyn AP, Ganz P. Am J Med. 1998;104:14S–8S.CrossRefGoogle Scholar
  23. 23.
    Ii M, Losordo DW. Vascul Pharmacol. 2007;46:1–9.CrossRefGoogle Scholar
  24. 24.
    Gallagher KM, Corrigan OIJ. J Control Release. 2000;69:261–72.CrossRefGoogle Scholar
  25. 25.
    Sternberg K, Kroemer HK, Schmitz K-P, Weitschies W, Grabow N, Harder C, Littwin P, Bajer D. Device for Coating a Stent and associated Coating Method and Stent Produced According to the Method.Google Scholar
  26. 26.
    Hamon M, Niculescu R, Deleanu D, Waksman R, Weissmann N. EuroIntervention. 2011;7:M187.CrossRefGoogle Scholar
  27. 27.
    Kalb B, Pennings AJ. Polymer. 1980;21:607–12.CrossRefGoogle Scholar
  28. 28.
    Parry TJ, Brosius R, Thyagarajan R, Carter D, Argentieri D, Falotico R, Siekierka J. Eur J Pharmacol. 2005;524:19–29.CrossRefGoogle Scholar
  29. 29.
    Matter CM, Rozenberg I, Jaschko A, Greutert H, Kurz DJ, Wnendt S, Kuttler B, Joch H, Grünenfelder J, Zünd G, Tanner FC, Lüscher TFJ. Cardiovasc Pharmacol. 2006;48:286–92.CrossRefGoogle Scholar
  30. 30.
    Vecerina I, Pham V. Automated Coating Apparatus and Method. 2009; US patent WO/2009/065087.Google Scholar
  31. 31.
    Tochterman AJ, Fox WJ, Harold N. Selectively coating luminal surfaces of stents. 2011; US patent US 7,867,547 B2.Google Scholar
  32. 32.
    Hooper KA, Cox JD, Kohn JJ. Appl Polym Sci. 1997;63:1499–510.CrossRefGoogle Scholar
  33. 33.
    Alexis F. Polym Int. 2005;54:36–46.CrossRefGoogle Scholar
  34. 34.
    Lu SX, Cebe P. Polymer. 1996;37:4857–63.CrossRefGoogle Scholar
  35. 35.
    Delpouve N, Saiter A, Mano JF, Dargent E. Polymer. 2008;49:3130–5.CrossRefGoogle Scholar
  36. 36.
    Hurrell S, Cameron RE. Biomaterials. 2002;23:2401–9.CrossRefGoogle Scholar
  37. 37.
    Pan C-J, Tang J–J, Weng Y-J, Wang J, Huang N. Colloids Surf B. 2009;73:199–206.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Svea Petersen
    • 1
    Email author
  • Janine Hussner
    • 2
  • Thomas Reske
    • 1
  • Niels Grabow
    • 1
  • Volkmar Senz
    • 1
  • Robert Begunk
    • 2
  • Daniela Arbeiter
    • 1
  • Heyo K. Kroemer
    • 2
  • Klaus-Peter Schmitz
    • 1
  • Henriette E. Meyer zu Schwabedissen
    • 2
  • Katrin Sternberg
    • 1
  1. 1.Institute for Biomedical EngineeringUniversity of RostockRostockGermany
  2. 2.Institute of PharmacologyErnst-Moritz-Arndt UniversityGreifswaldGermany

Personalised recommendations