Coronary Stent Design Part B - Drug Eluting Stents

Dr. Amir Kraitzer

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Outline Contemporary DES design Platform

Materials Design

Drug Drug Eluting Matrix Fabrication techniques DES Risks

Contemporary DES design

DESPlatform DrugDrug

Coating

Outline

Contemporary DES design Platform

Design Materials

Drug Drug Eluting Matrix Fabrication techniques DES Risks

Platform DesignConsiderations Strength and fatigue Deliverability Arterial wall interaction Hemodynamic factors

May be controlled by Structure design

Open cell Closed cell

Surface Area Struts

Structure design

Tubular Slotted (Closed cell) Coiled (Open cell) Modular design

Crown Bar arms Links

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

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

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

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

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

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

Outline

Contemporary DES design Platform

Design Materials

Drug Drug Eluting Matrix Fabrication techniques DES Risks

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

Cobalt Chrome

Outline

Contemporary DES design Platform

Design Materials

Drug Drug Eluting Matrix Fabrication techniques DES Risks

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

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

The drug

mTor binding

Pimecrolimus Tacrolimus Everolimus Zotarolimus SirolimusBiolimus

Anti-inflammatory

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

Outline

Contemporary DES design Platform

Design Materials

Drug Drug Eluting Matrix Fabrication techniques DES Risks

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

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

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

Taxus – SIBSBare metal stent SIBS-coated stent

1ug/mm2 0.6ug/mm2

2ug/mm2 4ug/mm2

180 days post implantation

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

EndeavorMedtronic

Cobalt Chrome alloy platform

Drug - Zotarolimus (ABT-578) Phosphorylcholine coatingMinimal late thrombosis between 1 and 9 months

Uncoated stentPC Coated

Coating - Biodegradable Biomatrix

Biolimus/ Poly (Lactic Acid) 50:50 mix 10 microns coating thickness Degrades in 9 months

Coating - Biodegradable

Conor/Cordis Eluting Stent System Controlled drug release from adjacent reservoirs Dual drug release

Outline

Contemporary DES design Platform

Design Materials

Drug Drug Eluting Matrix Fabrication techniques DES Risks

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

Fabrication: Crimping

Stents are typically produced in their expanded form

Crimping collapses the stent

Reference: Machine Solutions, Inc.

Outline

Contemporary DES design Platform

Design Materials

Drug Drug Eluting Matrix Fabrication techniques DES Risks

DES Risks

Material/ drug hypersensitivity

Adverse effects of stent after complete drug elution

Thrombosis and late incomplete stent apposition

Restenosis

DES Risks – FDA update

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)

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