coronary stent design- part b
DESCRIPTION
Drug Eluting Stents Stent Structure Engineering requirementsTRANSCRIPT
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Coronary Stent Design Part B - Drug Eluting Stents
Dr. Amir Kraitzer
The 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
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Outline Contemporary DES design Platform
Materials Design
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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Contemporary DES design
DESPlatform DrugDrug
Coating
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Outline
Contemporary DES design Platform
Design Materials
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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Platform DesignConsiderations Strength and fatigue Deliverability Arterial wall interaction Hemodynamic factors
May be controlled by Structure design
Open cell Closed cell
Surface Area Struts
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Structure design
Tubular Slotted (Closed cell) Coiled (Open cell) Modular design
Crown Bar arms Links
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Arterial wall interaction
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)
)a (NIR stent, (b) S7
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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
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Number of Struts
Garasic et al , Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury Circulation 2000
As struts become more numerous and evenly distributed, neointimal area fell in a predictable manner
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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
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Hemodynamic factors – cont.
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
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
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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
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Outline
Contemporary DES design Platform
Design Materials
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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Platform - Material
Considerations Mechanical properties Biocompatibility Radiopacity Expansion properties
Current materials
Stainless steel 316L Cobalt chromium Tantalum Platinum-Iridium Nitinol
Trimaxx Stent (Stainless Steel – Tantalum – Stainless Steel)
A thin 3-layer tantalum sandwich between two layers of stainless steel for enhanced fluoroscopic radiopacity
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Cobalt Chrome
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Outline
Contemporary DES design Platform
Design Materials
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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The DrugAnti-Proliferative Immunosupressives Migration Inhibitors
Enhanced Healing
Factors Taxol (paclitaxel)Sirolimus Batimistat BCP671
Actinomycin Tacrolimus Prolyl Hydrosylase Inhibitors
VEGF
Methotraxate Everolimus Halofunginone Estradiols
Angiopeptin Leflunomide C-preteinase Inhibitors
NO Donor Compounds
Vincristine M-Prednisolone Probucol EPC antibodies
Mitmycine Dexamethasone
Statins Cyclosporine
C MYC antisense Mycophenolic Acid
Abbott ABT-578 Mizoribine
RestenASE Interferon ?-1b
2-choloro-deoxyadenosine
Tranilast
PCNA Ribozyme
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The DrugOptimal drug:
Prevents smooth muscle cell proliferation Preserves vascular endothelial healing Has wide therapeutic to toxic ratio
Sirolimus Originally used as immunosuppressive
drug for transplant rejection mTOR binding blocking cell proliferation Cytostatic
Paclitaxel Originally used for cancer treatment Inhibits mitosis in dividing by binding to
microtubules Extremely hydrophobic Low therapeutic to toxic ratio Cytotoxic
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The drug
mTor binding
Pimecrolimus Tacrolimus Everolimus Zotarolimus SirolimusBiolimus
Anti-inflammatory
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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
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Outline
Contemporary DES design Platform
Design Materials
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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DES Coating - general
Considerations Mechanical properties Drug release kinetics Biocompatibility
Release mechanisms Dip coated Durable polymer Degradable polymer Porous ceramic coating
Controlled drug release is important for:
1.Obtaining appropriate kinetics to eventually eliminate restenosis
2.Maintaining a confluent endothelial coverage in order to suppress thrombosis
Controlled drug release is important for:
1.Obtaining appropriate kinetics to eventually eliminate restenosis
2.Maintaining a confluent endothelial coverage in order to suppress thrombosis
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CypherJohnson & Johnson (Cordis)316L platformDrug – Sirolimus Copolymer of ethylene and vinyl acetate and poly butyl methacrylate(PEVAC:PBMA ) + Parylene coating100% drug released in within ~1month
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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
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Taxus – SIBSBare metal stent SIBS-coated stent
1ug/mm2 0.6ug/mm2
2ug/mm2 4ug/mm2
180 days post implantation
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Defects in Polymer Coatings
Scanning Electron Microscopic Analysis of Defects in Polymer Coatings of Three Commercially Available Stents, Otsuka et al, JOURNAL OF INVASIVE CARDIOLOGY, 2007
Taxus
Cypher
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EndeavorMedtronic
Cobalt Chrome alloy platform
Drug - Zotarolimus (ABT-578) Phosphorylcholine coatingMinimal late thrombosis between 1 and 9 months
Uncoated stentPC Coated
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Coating - Biodegradable Biomatrix
Biolimus/ Poly (Lactic Acid) 50:50 mix 10 microns coating thickness Degrades in 9 months
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Coating - Biodegradable
Conor/Cordis Eluting Stent System Controlled drug release from adjacent reservoirs Dual drug release
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Outline
Contemporary DES design Platform
Design Materials
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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Drug Eluting Stent fabrication Laser-cut base stent Electropolish and surface
treatment as needed Drug loading Stent loaded on delivery
catheter Crimping Sterilization & packaging
Blank
Laser Cutting
UnfinishedExpanded Metal
Stent
Finishing
FinishedExpanded Metal
Stent
Assembled StentSystem
Crimping Catheter/BallonCatheter
Coated ExpandedStent
Coating Process
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Fabrication: Crimping
Stents are typically produced in their expanded form
Crimping collapses the stent
Reference: Machine Solutions, Inc.
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Outline
Contemporary DES design Platform
Design Materials
Drug Drug Eluting Matrix Fabrication techniques DES Risks
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DES Risks
Material/ drug hypersensitivity
Adverse effects of stent after complete drug elution
Thrombosis and late incomplete stent apposition
Restenosis
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DES Risks – FDA update
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Cypher Risks – Case Study
A 34-year-old woman underwent placement of Cypher in the proximal left circumflex artery for acute myocardial infarction 2 years antemortem.
At the site of thrombus formation (sections 5 and 6), neointimal thickness is minimal, and the number of uncovered stent struts is maximal
Pathological Correlates of Late Drug-Eluting Stent Thrombosis, Finn et al, Circulation. 2007
Images I, II show uncovered stent struts with extensive underlying fibrin deposition (gray arrow-head), luminal platelet-rich thrombus (Thr)Image II present lack of endothelialization (black arrow-head)
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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