Drug Eluting Stents Stent Structure Engineering requirements

1. 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

2. Outline
 Contemporary DES design
 Platform
 Materials
 Design
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

3. Contemporary DES design
Platform Drug
DES
Coating

4. Outline
 Contemporary DES design
 Platform
 Design
 Materials
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

5. Platform Design
Considerations
 Strength and fatigue
 Deliverability
 Arterial wall interaction
 Hemodynamic factors
May be controlled by
 Structure design
 Open cell
 Closed cell
 Surface Area
 Struts

6. Structure design
 Tubular Slotted (Closed cell)
 Coiled (Open cell)
 Modular design
 Crown
 Bar arms
 Links

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. 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. Number of Struts
α=0
α=1
As struts become more numerous and evenly distributed,
neointimal area fell in a predictable manner
Garasic et al , Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury
Circulation 2000

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. 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. .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. Outline
 Contemporary DES design
 Platform
 Design
 Materials
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

14. Platform - Material
Considerations
 Mechanical properties
 Biocompatibility
 Radiopacity
 Expansion properties
Current 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. Cobalt Chrome

16. Outline
 Contemporary DES design
 Platform
 Design
 Materials
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

17. The Drug
Anti-Proliferative Immunosupressives Migration Inhibitors Enhanced Healing
Factors
(Taxol (paclitaxel Sirolimus Batimistat BCP671
Actinomycin Tacrolimus Prolyl Hydrosylase VEGF
Inhibitors
Methotraxate Everolimus Halofunginone Estradiols
Angiopeptin Leflunomide C-preteinase NO Donor
Inhibitors Compounds
Vincristine M-Prednisolone Probucol EPC antibodies
Mitmycine Dexamethasone
Statins Cyclosporine
C MYC antisense Mycophenolic Acid
Abbott ABT-578 Mizoribine
RestenASE Interferon ?-1b
choloro--2 Tranilast
deoxyadenosine
PCNA Ribozyme

18. The Drug
Optimal 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

19. The drug
Pimecrolimus Tacrolimus Everolimus Zotarolimus Sirolimus
Biolimus
Anti-inflammatory mTor binding

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. Outline
 Contemporary DES design
 Platform
 Design
 Materials
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

22. DES Coating - general
Considerations
Controlled drug release is important for:
 Mechanical properties
2. Obtaining appropriate kinetics to eventually
 Drug release kinetics
eliminate restenosis
 Biocompatibility
3. Maintaining a confluent endothelial coverage in
order to suppress thrombosis
Release mechanisms
 Dip coated
 Durable polymer
 Degradable polymer
 Porous ceramic coating

23. Cypher
Johnson & Johnson (Cordis)
316L platform
Drug – Sirolimus
Copolymer of ethylene and vinyl acetate
and poly butyl methacrylate
(PEVAC:PBMA ) + Parylene coating
100% drug released in within ~1month

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. Taxus– SIBS
Bare metal stent SIBS-coated stent
180 days post implantation
0.6ug/mm2 1ug/mm2
2ug/mm2 4ug/mm2

26. Defects in Polymer Coatings
Taxus
Cypher
Scanning Electron Microscopic Analysis of Defects in Polymer Coatings of Three
Commercially Available Stents, Otsuka et al, JOURNAL OF INVASIVE CARDIOLOGY, 2007

27. Endeavor
Medtronic
Cobalt Chrome alloy platform
Drug - Zotarolimus (ABT-578)
Phosphorylcholine coating
Minimal late thrombosis between
1 and 9 months
PC Coated Uncoated stent

28. Coating - Biodegradable
 Biomatrix
 Biolimus/ Poly (Lactic Acid) 50:50 mix
 10 microns coating thickness
 Degrades in 9 months

29. Coating - Biodegradable
 Conor/Cordis Eluting Stent System
 Controlled drug release from adjacent reservoirs
 Dual drug release

31. Outline
 Contemporary DES design
 Platform
 Design
 Materials
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

32. 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

33. Fabrication: Crimping
 Stents are typically produced
in their expanded form
 Crimping collapses the stent
Reference: Machine Solutions, Inc.

34. Outline
 Contemporary DES design
 Platform
 Design
 Materials
 Drug
 Drug Eluting Matrix
 Fabrication techniques
 DES Risks

35. DES Risks
 Material/ drug
hypersensitivity
 Adverse effects of stent
after complete drug elution
 Thrombosis and late
incomplete stent apposition
 Restenosis

36. DES Risks – FDA update

37. 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
maximal
Pathological Correlates of Late Drug-Eluting Stent
Thrombosis, Finn et al, Circulation. 2007

38. 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