Coronary Stent Design- Part B

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Drug Eluting Stents
Stent Structure
Engineering requirements

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Coronary Stent Design- Part B

  1. 1. Coronary Stent Design Part B - Drug Eluting Stents Dr. Amir KraitzerThe contents of materials available on this presentation are reserved. Content may not be reproduced,published, or transferred except with the prior written permission of Dr. Amir Kraitzer
  2. 2. Outline Contemporary DES design Platform  Materials  Design Drug Drug Eluting Matrix Fabrication techniques DES Risks
  3. 3. Contemporary DES design Platform Drug DES Coating
  4. 4. Outline Contemporary DES design Platform  Design  Materials Drug Drug Eluting Matrix Fabrication techniques DES Risks
  5. 5. Platform DesignConsiderations Strength and fatigue Deliverability Arterial wall interaction Hemodynamic factorsMay be controlled by Structure design  Open cell  Closed cell Surface Area Struts
  6. 6. Structure design Tubular Slotted (Closed cell) Coiled (Open cell) Modular design  Crown  Bar arms  Links
  7. 7. Arterial wall interaction a) NIR stent, (b) S7) FE analysis of the NIR (Boston Scientific) stent and the S7 (Medtronic AVE) the slotted tube NIR design cause higher arterial stress compared to S7 Clinical restenosis rates show higher restenosis rates in the NIR compared with S7(C. Lally et al. / Journal of Biomechanics 38 (2005
  8. 8. Impact of strut thickness Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial, Journal of the American College of Cardiology, Volume 41, Issue 8, Pages 1283-1288
  9. 9. Number of Struts α=0 α=1 As struts become more numerous and evenly distributed, neointimal area fell in a predictable mannerGarasic et al , Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial InjuryCirculation 2000
  10. 10. Hemodynamic factors IH thickness is inversely proportional to wall shear stress (WSS). High WSS is desired Local endothelial shear stress (ESS) is sensed by luminal endothelial mechanoreceptors Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior, Chatzizisis et al. J. Am. Coll. Cardiol. 2007;49;2379-2393
  11. 11. Hemodynamic factors – cont. The pulsatile blood flow in combination with the complex geometric configuration of the coronaries determines the ESS patterns In geometrically irregular regions, disturbed laminar flow occurs. Thus, pulsatile flow generates low and/or oscillatory ESS Role of Endothelial Shear Stress in the Natural History of Coronary Atherosclerosis and Vascular Remodeling: Molecular, Cellular, and Vascular Behavior, Chatzizisis et al. J. Am. Coll. Cardiol. 2007;49;2379-2393
  12. 12. .Hemodynamic factors – cont Presence of a stent induces flow separation downstream of the stent Regions of decreased and increased WSS occur near the edges of a stent High WSS obtained with reduction in the number of struts and the strut thickness, large strut spacing, and flexible stents Materials, Fluid Dynamics, and Solid Mechanics Aspects of Coronary Artery Stents: A State-of-the-Art Review, Gladius Lewis, J Biomed Mater Res Part B: Appl Biomater 86B: 569–590, 2008
  13. 13. Outline Contemporary DES design Platform  Design  Materials Drug Drug Eluting Matrix Fabrication techniques DES Risks
  14. 14. Platform - MaterialConsiderations Mechanical properties Biocompatibility Radiopacity Expansion propertiesCurrent materials Trimaxx Stent (Stainless Steel – Stainless steel 316L Tantalum – Stainless Steel) Cobalt chromium A thin 3-layer tantalum sandwich between two layers of stainless Tantalum steel for enhanced fluoroscopic Platinum-Iridium radiopacity Nitinol
  15. 15. Cobalt Chrome
  16. 16. Outline Contemporary DES design Platform  Design  Materials Drug Drug Eluting Matrix Fabrication techniques DES Risks
  17. 17. The Drug Anti-Proliferative Immunosupressives Migration Inhibitors Enhanced Healing Factors(Taxol (paclitaxel Sirolimus Batimistat BCP671Actinomycin Tacrolimus Prolyl Hydrosylase VEGF InhibitorsMethotraxate Everolimus Halofunginone EstradiolsAngiopeptin Leflunomide C-preteinase NO Donor Inhibitors CompoundsVincristine M-Prednisolone Probucol EPC antibodiesMitmycine DexamethasoneStatins CyclosporineC MYC antisense Mycophenolic AcidAbbott ABT-578 MizoribineRestenASE Interferon ?-1bcholoro--2 Tranilast deoxyadenosinePCNA Ribozyme
  18. 18. The DrugOptimal drug:  Prevents smooth muscle cell proliferation  Preserves vascular endothelial healing  Has wide therapeutic to toxic ratioSirolimus  Originally used as immunosuppressive drug for transplant rejection  mTOR binding blocking cell proliferation  CytostaticPaclitaxel  Originally used for cancer treatment  Inhibits mitosis in dividing by binding to microtubules  Extremely hydrophobic  Low therapeutic to toxic ratio  Cytotoxic
  19. 19. The drug Pimecrolimus Tacrolimus Everolimus Zotarolimus Sirolimus BiolimusAnti-inflammatory mTor binding
  20. 20. Targeted drugs Farnesylthiosalicylate (FTS, Salirasib)  Originally developed for cancer treatment  Currently under clinical investigation (phase II)  Cytostatic and nontoxic drug  Specifically targeted  Inhibited intimal thickening without interfering endothelial proliferation in rats  Hydrophobic
  21. 21. Outline Contemporary DES design Platform  Design  Materials Drug Drug Eluting Matrix Fabrication techniques DES Risks
  22. 22. DES Coating - generalConsiderationsControlled drug release is important for: Mechanical properties2. Obtaining appropriate kinetics to eventually Drug release kinetics eliminate restenosis Biocompatibility3. Maintaining a confluent endothelial coverage in order to suppress thrombosisRelease mechanisms Dip coated Durable polymer Degradable polymer Porous ceramic coating
  23. 23. CypherJohnson & Johnson (Cordis)316L platformDrug – SirolimusCopolymer of ethylene and vinyl acetateand poly butyl methacrylate(PEVAC:PBMA ) + Parylene coating100% drug released in within ~1month
  24. 24. Taxus Boston Scientific 316L platform Drug –paclitaxel Triblock copolymer poly (styrene- isobutylene-styrene)] (SIBS) – Translute™ Slow Release (SR) version  7.5% drug is release in the 1st month  92.5% of the drug remains in the matrix for a long period
  25. 25. Taxus– SIBSBare metal stent SIBS-coated stent 180 days post implantation 0.6ug/mm2 1ug/mm2 2ug/mm2 4ug/mm2
  26. 26. Defects in Polymer CoatingsTaxusCypherScanning Electron Microscopic Analysis of Defects in Polymer Coatings of ThreeCommercially Available Stents, Otsuka et al, JOURNAL OF INVASIVE CARDIOLOGY, 2007
  27. 27. EndeavorMedtronicCobalt Chrome alloy platformDrug - Zotarolimus (ABT-578)Phosphorylcholine coatingMinimal late thrombosis between1 and 9 months PC Coated Uncoated stent
  28. 28. Coating - Biodegradable Biomatrix  Biolimus/ Poly (Lactic Acid) 50:50 mix  10 microns coating thickness  Degrades in 9 months
  29. 29. Coating - Biodegradable Conor/Cordis Eluting Stent System  Controlled drug release from adjacent reservoirs  Dual drug release
  30. 30. Outline Contemporary DES design Platform  Design  Materials Drug Drug Eluting Matrix Fabrication techniques DES Risks
  31. 31. Drug Eluting Stent fabrication Blank Laser Cutting Laser-cut base stent Unfinished Electropolish and surface Expanded Metal Stent treatment as needed Finishing Drug loading Finished Expanded Metal Stent loaded on delivery Stent catheter Coating Process Coated Expanded Crimping Stent Sterilization & packaging Crimping Catheter/Ballon Catheter Assembled Stent System
  32. 32. Fabrication: Crimping Stents are typically produced in their expanded form Crimping collapses the stent Reference: Machine Solutions, Inc.
  33. 33. Outline Contemporary DES design Platform  Design  Materials Drug Drug Eluting Matrix Fabrication techniques DES Risks
  34. 34. DES Risks Material/ drug hypersensitivity Adverse effects of stent after complete drug elution Thrombosis and late incomplete stent apposition Restenosis
  35. 35. DES Risks – FDA update
  36. 36. Cypher Risks– Case Study Images I, II show uncovered stent struts with extensive A 34-year-old woman underlying fibrin deposition underwent placement of (gray arrow-head), luminal Cypher in the proximal left circumflex artery for acute platelet-rich thrombus (Thr) myocardial infarction 2 Image II present lack of years antemortem. endothelialization (black arrow- At the site of thrombus head) formation (sections 5 and 6), neointimal thickness is minimal, and the number of uncovered stent struts is maximalPathological Correlates of Late Drug-Eluting StentThrombosis, Finn et al, Circulation. 2007
  37. 37. References Amir Kraitzer, Yoel Kloog, Meital Zilberman, Approaches for Prevention of Restenosis, J Biomed Mater Res Part B: Appl Biomater 85B: 583–603, 2008 Gladius Lewis, Review: Materials, Fluid Dynamics, and Solid Mechanics Aspects of Coronary Artery Stents: A State-of-the-Art Review, Biomed Mater Res Part B: Appl Biomater 86B: 569–590, 2008 Meital Zilberman, Amir Kraitzer, Orly Grinberg and Jonathan J. Elsner, Drug-Eluting Medical Implants, In : Handbook of European Pharmacology, 2008 Subbu Venkatraman, Freddy Boey, Release profiles in drug-eluting stents: Issues and uncertainties, Journal of Controlled Release 120 (2007) 149–160

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