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Improving smooth muscle cell exposure to drugs from drug-eluting stents at early time points: a variable compression approach

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Abstract

The emergence of drug-eluting stents (DES) as a viable replacement for bare metal stenting has led to a significant decrease in the incidence of clinical restenosis. This is due to the transport of anti-restenotic drugs from within the polymer coating of a DES into the artery wall which arrests the cell cycle before restenosis can occur. The efficacy of DES is still under close scrutiny in the medical field as many issues regarding the effectiveness of DES drug transport in vivo still exist. One such issue, that has received less attention, is the limiting effect that stent strut compression has on the transport of drug species in the artery wall. Once the artery wall is compressed, the stents ability to transfer drug species into the arterial wall can be reduced. This leads to a reduction in the spatial therapeutic transfer of drug species to binding sites within the arterial wall. This paper investigates the concept of idealised variable compression as a means of demonstrating how such a stent design approach could improve the spatial delivery of drug species in the arterial wall. The study focused on assessing how the trends in concentration levels changed as a result of artery wall compression. Five idealised stent designs were created with a combination of thick struts that provide the necessary compression to restore luminal patency and thin uncompressive struts that improve the transport of drugs therein. By conducting numerical simulations of diffusive mass transport, this study found that the use of uncompressive struts results in a more uniform spatial distribution of drug species in the arterial wall.

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References

  • Ai L, Vafai K (2006) A coupling model for macromolecule transport in a stenosed arterial wall. Int J Heat Mass Transf 49(910):1568–1591

    Article  MATH  Google Scholar 

  • Axel DI, Kunert W, Gggelmann C, Oberhoff M, Herdeg C, Kttner A, Wild DH, Brehm BR, Riessen R, Kveker G, Karsch KR (1997) Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 96(2):636–645

    Article  Google Scholar 

  • Balakrishnan B, Dooley JF, Kopia G, Edelman ER (2007) Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution. J Controlled Release 123(2):100–108

    Article  Google Scholar 

  • Balakrishnan B, Dooley J, Kopia G, Edelman ER (2008) Thrombus causes fluctuations in arterial drug delivery from intravascular stents. J Controlled Release 131(3):173–180

    Article  Google Scholar 

  • Cho HJ, Kim TY, Cho HJ, Park KW, Zhang SY, Kim JH, Kim SH, Hahn JY, Kang HJ, Park YB, Kim HS (2006) The effect of stem cell mobilization by granulocyte-colony stimulating factor on neointimal hyperplasia and endothelial healing after vascular injury with bare-metal versus paclitaxel-eluting stents. J Am Coll Cardiol 48(2):366–374

    Article  Google Scholar 

  • Creel CJ, Lovich MA, Edelman ER (2000) Arterial paclitaxel distribution and deposition. Circ Res 86(8):879–884

    Article  Google Scholar 

  • Cremers B, Speck U, Kaufels N, Mahnkopf D, Khler M, Bhm M, Scheller B (2009) Drug-eluting balloon: very short-term exposure and overlapping. Thromb Haemost 101(1):201–206

    Google Scholar 

  • Cremers B, Milewski K, Clever YP, Aboodi MS, Biedermann M, Thim T, Kelsch B, Kaluza GL, Scheller B, Granada JF (2012) Long-term effects on vascular healing of bare metal stents delivered via paclitaxel-coated balloons in the porcine model of restenosis. Catheter Cardiovasc Interv 80(4):603–610

    Article  Google Scholar 

  • D’Angelo C, Zunino P, Porpora A, Morlacchi S, Migliavacca F (2011) Model reduction strategies enable computational analysis of controlled drug release from cardiovascular stents. SIAM J Appl Math 71(6):2312–2333. doi:10.1137/10081695X

    Article  MATH  MathSciNet  Google Scholar 

  • Denny W, OConnell B, Milroy J, Walsh M (2013) An analysis of three dimensional diffusion in a representative arterial wall mass transport model. Ann Biomed Eng 41(5):1062–1073

    Google Scholar 

  • Dogu G, Smith JM (1975) A dynamic method for catalyst diffusivities. AIChE J 21(1):58–61

    Article  Google Scholar 

  • Finkelstein A, McClean D, Kar S, Takizawa K, Varghese K, Baek N, Park K, Fishbein MC, Makkar R, Litvack F, Eigler NL (2003) Local drug delivery via a coronary stent with programmable release pharmacokinetics. Circulation 107(5):777–784

    Article  Google Scholar 

  • Friedman MH (2008) Principles and models of biological transport. Springer Science+Business Media, Berlin

  • Horner M, Joshi S, Dhruva V, Sett S, Stewart S (2010) A two-species drug delivery model is required to predict deposition from drug-eluting stents. Cardiovasc Eng Technol 1(3):225–234

    Google Scholar 

  • Hose D, Narracott A, Griffiths B, Mahmood S, Gunn J, Sweeney D, Lawford P (2004) A thermal analogy for modelling drug elution from cardiovascular stents. Comput Methods Biomech Biomed Eng 7(5):257–264

    Article  Google Scholar 

  • Huang ZJ, Tarbell JM (1997) Numerical simulation of mass transfer in porous media of blood vessel walls. Am J Physiol Heart Circ Physiol 273(1):464–477

    Google Scholar 

  • Hwang CW, Edelman ER (2002) Arterial ultrastructure influences transport of locally delivered drugs. Circ Res 90(7):826–832

    Article  Google Scholar 

  • Jensen LO, Maeng M, Kaltoft A, Thayssen P, Hansen HHT, Bottcher M, Lassen JF, Krussel LR, Rasmussen K, Hansen KN, Pedersen L, Johnsen SP, Soerensen HT, Thuesen L (2007) Stent thrombosis, myocardial infarction, and death after drug-eluting and bare-metal stent coronary interventions. J Am Coll Cardiol 50(5):463–470

    Article  Google Scholar 

  • Kastrati A, Dibra A, Spaulding C, Laarman GJ, Menichelli M, Valgimigli M, Di Lorenzo E, Kaiser C, Tierala I, Mehilli J, Seyfarth M, Varenne O, Dirksen MT, Percoco G, Varricchio A, Pittl U, Syvnne M, Suttorp MJ, Violini R, Schmig A (2007) Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J 28(22):2706–2713

    Article  Google Scholar 

  • Khakpour M, Vafai K (2008) A comprehensive analytical solution of macromolecular transport within an artery. Int J Heat Mass Transf 51(1112):2905–2913

    Article  MATH  Google Scholar 

  • Kolachalama VB, Levine EG, Edelman ER (2009) Luminal Flow Amplifies Stent-Based Drug Deposition in Arterial Bifurcations. PLoS ONE 4(12): e8105. doi:10.1371/journal.pone.0008105

  • Laarman GJ, Suttorp MJ, Dirksen MT, van Heerebeek L, Kiemeneij F, Slagboom T, van der Wieken LR, Tijssen JG, Rensing BJ, Patterson M (2006) Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention. N Engl J Med 355(11):1105– 1113

    Article  Google Scholar 

  • Levin AD, Vukmirovic N, Hwang CW, Edelman ER (2004) Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel. Proc Natl Acad Sci USA 101(25):9463–9467

    Article  Google Scholar 

  • Lovich M, Edelman E (1996) Tissue average binding and equilibrium distribution: an example with heparin in arterial tissues. Biophys J 70(3):1553–1559

    Article  Google Scholar 

  • Lovich MA, Creel C, Hong K, Hwang CW, Edelman ER (2001) Carrier proteins determine local pharmacokinetics and arterial distribution of paclitaxel. J Pharm Sci 90(9):1324–1335

    Article  Google Scholar 

  • McMahan CA, Gidding SS (2008) Coronary heart disease risk factors and atherosclerosis in young people. J Clin Lipidol 2(3):118–126

    Article  Google Scholar 

  • Members WG, Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, Zheng ZJ, Flegal K, O’Donnell C, Kittner S, Lloyd-Jones D, Goff DC, Hong Y, of the Statistics Committee M, Subcommittee SS, Adams R, Friday G, Furie K, Gorelick P, Kissela B, Marler J, Meigs J, Roger V, Sidney S, Sorlie P, Steinberger J, Wasserthiel-Smoller S, Wilson M, Wolf P (2006) Heart disease and stroke statistics 2006 update. Circulation 113(6):85–151

    Google Scholar 

  • Mongrain Leask, Brunette Faik, Bulman-Feleming TN (2005) Numerical modeling of coronary drug eluting stents. Stud Health Technol Inform 113:443–458

    Google Scholar 

  • Mongrain R, Faik I, Leask R, Rods-Cabau J, Larose E, Bertrand O (2007) Effects of diffusion coefficients and struts apposition using numerical simulations for drug eluting coronary stents. J Biomech Eng 129(5):733–742

    Article  Google Scholar 

  • Mota M, Yelshin A, Fidaleo M, Flickinger MC (2007) Modelling diffusivity in porous polymeric membranes with an intermediate layer containing microbial cells. Biochem Eng J 37(3):285–293

    Article  Google Scholar 

  • O’Connell B, Walsh M (2010) Demonstrating the influence of compression on artery wall mass transport. Ann Biomed Eng 38(4):1354–1366

    Article  Google Scholar 

  • Pan CJ, Tang JJ, Weng YJ, Wang J, Huang N (2009) Preparation and in vitro release profiles of drug-eluting controlled biodegradable polymer coating stents. Colloids Surf B Biointerfaces 73(2):199– 206

    Article  Google Scholar 

  • Pontrelli G, de Monte F (2007) Mass diffusion through two-layer porous media: an application to the drug-eluting stent. Int J Heat Mass Transf 50(1718):3658–3669

    Article  MATH  Google Scholar 

  • Prosi M, Zunino P, Perktold K, Quarteroni A (2005) Mathematical and numerical models for transfer of low-density lipoproteins through the arterial walls: a new methodology for the model set up with applications to the study of disturbed lumenal flow. J Biomech 38(4):903–917

    Article  Google Scholar 

  • Report NVS (2002) National vital statistics report

  • Spaulding C, Henry P, Teiger E, Beatt K, Bramucci E, Carri D, Slama MS, Merkely B, Erglis A, Margheri M, Varenne O, Cebrian A, Stoll HP, Snead DB, Bode C (2006) Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 355(11):1093–1104

    Article  Google Scholar 

  • Sternberg K, Kramer S, Nischan C, Grabow N, Langer T, Hennighausen G, Schmitz KP (2007) 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 18(7):1423–1432

    Article  Google Scholar 

  • Sun N, Wood N, Hughes A, Thom S, Xu X (2006) Fluid-wall modelling of mass transfer in an axisymmetric stenosis: effects of shear-dependent transport properties. Ann Biomed Eng 34(7):1119– 1128

    Article  Google Scholar 

  • Sun N, Wood NB, Hughes AD, Thom SAM, Yun XuX (2007) Effects of transmural pressure and wall shear stress on ldl accumulation in the arterial wall: a numerical study using a multilayered model. Am J Physiol Heart Circ Physiol 292(6):3148–3157

    Article  Google Scholar 

  • Trudnowski R (1974) Specific gravity of blood and plasma at 4 and 37 degrees c. Clinical Chemistry 20(0009–9147 (Linking)):615–616

    Google Scholar 

  • van der Hoeven BL, Pires NM, Warda HM, Oemrawsingh PV, van Vlijmen BJ, Quax PH, Schalij MJ, van der Wall EE, Jukema J (2005) Drug-eluting stents: results, promises and problems. Int J Cardiol 99(1):9–17

    Article  Google Scholar 

  • Waksman R (2002) Drug-eluting stents: from bench to bed. Cardiovasc Radiat Med 3(34):226–241

    Article  Google Scholar 

  • Weiler JM, Sparrow EM, Ramazani R (2012) Mass transfer by advection and diffusion from a drug-eluting stent. Int J Heat Mass Transf 55(13):1–7

    MATH  Google Scholar 

  • Wootton DM, Ku DN (1999) Fluid mechanics of vascular systems, diseases, and thrombosis. Annu Rev Biomed Eng 1(1):299–329

    Article  Google Scholar 

  • Yang C, Burt HM (2006) Drug-eluting stents: factors governing local pharmacokinetics. Adv Drug Deliv Revi 58(3):402–411

    Article  Google Scholar 

  • Yang N, Vafai K (2006) Modeling of low-density lipoprotein (ldl) transport in the artery effects of hypertension. Int J Heat Mass Transf 49(56):850–867

    Article  MATH  Google Scholar 

  • Zhu X, Pack DW, Braatz RD (2012) Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution. Comput Methods Biomech Biomed Eng iFirst:1–12. doi:10.1080/10255842.2012.672815

  • Zunino Paolo (2004) Multidimensional pharmacokinetic models applied to the design of drug-eluting stents. Cardiovasc Eng 4:181–191

    Google Scholar 

  • Zunino P, D’Angelo C, Petrini L, Vergara C, Capelli C, Migliavacca F (2009) Numerical simulation of drug eluting coronary stents: mechanics, fluid dynamics and drug release. Comput Methods Appl Mech Eng 198(4546):3633–3644

    Article  MATH  MathSciNet  Google Scholar 

Download references

Acknowledgments

Irish Research Council for funding under the EMBARK Initiative and the Irish Government under the Programme for Research in Third Level Institutions (PRTLI) Cycle 5 and co-funded under the European Regional Development Fund.

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Authors and Affiliations

  1. Centre for Applied Biomedical Engineering (CABER), Department of Mechanical, Aeronautical and Biomedical Engineering and The Materials and Surface Science Institute, University of Limerick, Limerick, Ireland

    Barry M. O’Connell, Eoghan M. Cunnane, William J. Denny, Grainne T. Carroll & Michael T. Walsh

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  1. Barry M. O’Connell
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  2. Eoghan M. Cunnane
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  3. William J. Denny
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  4. Grainne T. Carroll
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  5. Michael T. Walsh
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Correspondence to Michael T. Walsh.

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O’Connell, B.M., Cunnane, E.M., Denny, W.J. et al. Improving smooth muscle cell exposure to drugs from drug-eluting stents at early time points: a variable compression approach. Biomech Model Mechanobiol 13, 771–781 (2014). https://doi.org/10.1007/s10237-013-0533-9

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