Drug eluting stent

A drug-eluting stent is a peripheral or coronary stent placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that, together with clots, could otherwise block the stented artery, a process called restenosis

1. DRUG ELUTING CORONARY STENT DIBYASUNDAR MAHANATA

2. B ACKGROUND The introduction of angioplasty led to the development of a completely new approach to treat CAD. Until 1994, the percutaneous transluminal coronary angioplasty (PTCA) was the alone treatment for coronary artery disease. However, the incidence of restenosis of coronary arteries was an important problem, necessitating repeated interventional procedures in 30% of patients treated with PTCA alone.

3. Coronary artery stents were developed to provide a metal scaffolding for the angio-plastied vessel, in an attempt to limit negative re-modelling. Sigwart et al first reported the efficacy of stents in reducing restenosis rates in 1987. By 1994, the Food and Drug Administration (FDA) had approved two stents (Gianturco-Roubin stent and the Palmaz- SchatzTM stent ).

4. G IANTURCO -R OUBIN II Flat wire coil attached to a single longitudinal strut 316 L stainless steel The first coronary stent approved by the FDA in June 1993.

5. P A L MA Z - S C H A TZ Balloon expandable; slotted tube 316 L stainless steel

6. The wide acceptance of coronary stenting was based on the results of the BElgian NEtherlands STENT (BENESTENT) and the STent REStenosis Study (STRESS) trials, which showed the superiority of stenting over balloon angioplasty. After the wide acceptance of coronary stents the primary concern of stent development is the need to reduce device profiles and to increase flexibility to facilitate safe delivery.

7. STENT SELECTION

8. STENT SELECTION- PERFORMANCE & EASE OF USE

9. S TENT SELECTION -G OOD ACUTE ANGIOGRAPHIC RESULTS

10. TYPES OF STENTS Mechanism of expansion (self-expanding or balloon- expandable) Materials (stainless steel, cobalt-based alloy, tantalum, nitinol, Pt,Ir,Cr, inert coating, biodegradable) Forms (sheet, wire or tube) Manufacturing methods (laser cut, water-jet cutting ) Geometrical configurations/design (mesh structure, coil, slotted tube, ring, multi-design) Addition to stent (grafts, radio-opaque markers, coatings )

11. S TENT GEOMETRIC DESIGN MECHANISM OF EXPANSION Balloon-expandable stents The stent is pre-mounted on a balloon and the inflation of the balloon plastically expands the stent with respect to the balloon diameter. Self-expanding stents- The smart material auto expands to a calculated size .

12. M A TE R IALS Corrosion resistance Biocompatibility Adequately radio-opaque Create minimal artifacts during MRI

13. S TENT PLATFORMS S TENT MATERIALS - N ON DEGRADABLE MATERIAL 316L stainless steel- Excellent mechanical properties and corrosion resistance Ferromagnetic nature and low density make it a non-MRI compatible Poorly visible fluoroscopic material First generation DESs, Cypher (sirolimus-eluting stent, Cordis, Warren, NJ) and Taxus (paclitaxel- eluting stent, Boston Scientific, Natick, MA )

14. C O - C R Superior radial strength and improved radiopacity Thinner stent struts The second generation DES, Xience V (everolimus- eluting stent, Abott Vascular, CA) and Endeavor (zotarolimus-eluting stent,Medtronic Vascular, Santa Rosa, CA).

15. T A - TANTALUM Excellent corrosion resistant material Coated on 316L SS to improve corrosion properties and biocompatibility High density and non-ferromagnetic properties Fluoroscopically visible and MRI compatible Higher rates of recoil- poor mechanical properties

16. T I Excellent biocompatibility and corrosion resistance Low tensile strength and ductility Ti alloys in combination with Ni-Ti Ti-nitride oxide coating on 316L SS

17. N I - T I Good biocompatibility, radial force and shape memory Coated by some materials such as polyurethane, Ti nitride and polycrystalline oxides to improve the corrosion resistance Inadequate visibility under fluoroscopy

18. P T -I R Pt-Ir alloy of 90% platinum and 10% iridium Excellent radiopacity and a reduction in both thrombosis and neointimal proliferation with less inflammatory reactions Recoiling percentage was much higher (16%) than the 316L SS stents

19. B IODEGRADABLE METALLIC MATERIALS Pure Fe Oxidation of Fe into ferrous and ferric irons Mg alloys There are two Mg alloys, AE2153 and WE4357, used for making stents Radiolucent

20. R ATIONAL FOR B IODEGRADABLE STENTS Metal stent drawbacks Cause permanent physical irritation Risk of long term endothelial dysfunction and chronic inflammation Metal have thrombogenic properties Inability for the vessel to restore its a normal physiology Biodegradable stent advantages May eliminate early and late complications of bare-metal stents Restore the vasoreactivity Allow a gradual transfer of the mechanical load to the vessel Higher capacity for drug incorporation and complex release kinetics The need for a permanent prosthesis decreases dramatically 6 months post-implantation

21. S TENT DESIGN On the basis of design, stents can be divided into three groups: coil, tubular mesh, and slotted tube . Coil stents are characterised by metallic wires or strips formed into a circular coil shape Tubular mesh stents consist of wires wound together in a meshwork, forming a tube. Slotted tube stents are made from tubes of metal from which a stent design is laser cut .

22. C OIL VS . T UBE Coil design had greater strut width with gaps and fewer or no connections between struts The strut width is greater; there are gap between struts, and no connections between struts which give it more flexibility. However, the design lack radial strength, and the wide gap allow tissues to dangle.

23. COIL VS TUBE

24. As a result, coil design has become obsolete and replace by the more superior in radial strength, the tube design. In tubular, there are two type of specification, a slotted tube and modular tube. .

25. S LOTTED TUBE VS . M ODULAR (TUBULAR)

26. MODULAR DESIGN

27. S LOTTED TUBE VS . M ODULAR (TUBULAR) Slotted tube stents resisted restenosis more than the modular stents (22.1% vs 25.2%) Slotted tube- Closed cell design, and open cell design

28. C LOSED CELL Sequential ring construction All Internal inflection points of the structural members are connected by bridging elements. Regular peak-to-peak connections. Optimal scaffolding and a uniform surface, regardless of the degree of bending. Less flexible than a similar open-cell design.

29. C YPHER STENT BY CORDIS

30. O PEN CELL Some or all the internal inflection points of the structural members are not connected by bridging elements. Periodic peak-to-peak connections, peak-to-valley connections, and mid-strut to mid strut connections The unconnected structural elements contribute to longitudinal flexibility. Ann Ist Super Sanita 2007;43,no1:89-100

31. OPEN CELL DESIGN

32. STENT DESIGN IMPACTS DRUG DELIEVERY

33. LENGTH & DIAMETER OF STENT Long vs. Short Stent length is associated with restenosis rate and clinical events (mainly target lesion revascularization) Short stent has lower cases of restenosis than long stent. Wide vs. Narrow The wide diameter stent is more favorable than the narrow one

34. N UMBER OF STRUTS More struts vs. less Less struts induce less chance of restenosis compare to more struts.

35. S TRUT THICKNESS Although the immediate stent performance may be improved by increasing strut thickness (which increases radiovisibility, radial strength and arterial wall support) excessive strut thickness, on the other hand, may impart more vascular injury, trigger more intimal hyperplasia, and engender a higher risk for restenosis than thinner struts. Strut thickness was observed to be an independent predictor of in-stent restenosis

36. In an effort to further reduce strut thickness while maintaining adequate radiovisibility and radial strength, novel metallic materials such as cobalt- chromium alloy are being used for the production of stent.

37. T HICK VS . THIN STRUTS The stents with thinner struts is preferred for the design of new stents as they can reduce angiographic and clinical restenosis more than those with thicker struts

38. S QUARE VS . ROUND STRUT CROSS - SECTION The round strut cross-section without corners or sharp edges is popular at present Round strut cross-section area is ideal for smoothness design. Square strut cross-section area in not recommend because it interferes with blood flow due to their sharp edge which can slice blood cells.

39. S QUARE VS . ROUND STRUT CROSS - SECTION

40. R OUGH VS . SMOOTH SURFACE Smoothness of a stent can affect the performance and biocompatibily of the stent. Smooth surface can reduce thrombus adhesion and neointimal growth. To obtain smoothness, the stent need to be treated with acid-pickling and then electrochemical polishing. The process removes slag which includes depositions and burrs, formed on the surface of stents due to the laser cutting production process.

41. ELEMENT OF STENT DESIGN - BALLOON OVERHANG

42. D RUG DELIVERY VEHICLES – C OATING POLYMER - DRUG CARRIERS IN DES S Nonbiodegradable and biodegradable polymers Non biodegradable polymers First and the second generation of DESs The first generation of DES Cypher - polyethylene-co-vinyl acetate (PEVA)/poly-n-butyl methacrylate (PBMA) Taxus - polystyrene-b-isobutylene-b-styrene (SIBS) The second generation of DES Xience V – fluoropolymer Endeavor - phosphorylcholine (PC)

43. Biodegradable polymers Polylactic acid (PLA) Polyglycolic acid (PGA) Polylactic-co-glycolic acid (PLGA) NON POLYMER Titanium–nitric oxide alloy Microporous stainless steel stent (Yukon, Translumina, Germany) A nanoporous hydroxyapetite (a biocompatible crystalline derivative of calcium phosphate) coating Magnetic nanoparticles (MNPs )

44. T HERAPEUTIC AGENTS Sirolimus (Rapamycin ) m TOR inhibitor A macrocyclic lactone Inhibits the migration and proliferation of SMCs Zotarolimus The sirolimus analogues Developed by Abbott laboratories Extremely lipophilic property and low water solubility Everolimus Sirolimus analogue Immunosuppressive agent Absorbs to local tissue more rapidly and has a longer celluar residence time and activity Biolimus

45. P ACLITAXEL AND ITS ANALOGUES Paclitaxel Promoting tubulin polymerization and cell cycle arrest between G2 and M phase Inhibiting the migration and proliferation of SMCs Coroxane Nanoparticle albumin bound paclitaxel (nab-paclitaxel) To improve the solubility Docetaxel Semi-synthetic analogue Better anti-proliferative properties

46. OTHE RS Tacrolimus Pimecrolimus Curcumin Resveratrol CD 34 antibody Anti-VEGF

47. R ADIO - OPACITY ENHANCEMENTS Stainless steel or nitinol - hard to see fluoroscopically To improve X-ray visibility, markers are often attached to the stents. These additions are typically made from gold, platinum or tantalum Electroplating (with gold) is also being used to enhance X-ray visibility

48. C O A TINGS To increase biocompatibility Heparin was one of the first. Its mode of action is to reduce the coagulation cascade (and thus possibly the thrombogenic risk) after the deployment of a stent. Phosphorylcoline and silicon-carbide have been used in order to reduce platelet activation and interaction, thus possibly controlling their adhesion to the stent struts during the acute phase of stent re-endothelization.

49. COMMONLY USED CORONARY STENTS IN CLINICAL PRACTICE

50. XIENCE FAMILY OF STENTS Ste n t M a nu f a c t u D r u g B ase rer Fo rm/ D esi gn P o l y mer D iameter L e ng th XIENCE Xpedition Abott v ascular FDA Approved E v erol i m u s 100 μ g /c m 2 L-605 CoCr Hybrid cell Multilink 0.0032" strut thickness, laser cut PBMA Non erodible S V -2 . 2 5 MV- 2 . 5 , 2 . 7 5 , 3 . , 3 . 25,3.5,4.0 LL 2 . 5 , 2 . 7 5 , 3 . , 3.25 ,3.5,4.0 8,12,15,18,23 , 2 8 33 , 3 8 XIENCE V Abott v ascular FDA Approved E v erol i m u s 100μ g /c m 2 Multi-layer Coating MULTI-LINK VISION CoCr stent Hybrid cell Multilink 0.0032" strut thickness, laser cut, PBMA Non erodible 2.25,2.5,2.75, 3.0,3.5,4.0 8,12,15,18,23 ,28 XINCE PRIME Abott v ascular FDA Approved E v erol i m u s 100 μ g /c m 2 Cobalt Chro m ium Hybrid cell Multilink 0.0032" strut t h ickn ess,las er cut, bioc o m pa ti b l e fluorinated copolymer S V -2 . 2 5 MV 2 . 5 , 2 . 7 5 , 3 . , 3.5,4.0 LL- 2 . 5 , 2 . 7 5 , 3 . , 3.5,4.0 8,12,15,18,23 ,28 S a m e 33,38

51. Ste n t M a nu f a c t u r er D r u g B ase Fo rm/ D esi gn P o l y mer D iameter L e ng th Promus element Plus Boston scientific E v ero li m us Platinum Chro m i um Tubular open cell,thin strut,high radial strength,good delieverality & trackability Thin, fluorinated copolymer matrix for controlled drug release (100% drug elution in 120 days) 2.25,2.5,2.75,3.0 ,3.5,4.0 8,12,16,20,24,28 ,32,38 Endeavor Sprint M e dtron i c Zot a ro l i m u s - Eluting 10μg/mm cobalt-based alloy (cobalt, nickel, chromium, and molybdenum) Modular design,Sinusoid al form wire,helical wrap,laser fused Phosphorylcholi ne polymer 2.25,2.5,2.75,3.0 ,3.5,4.0 8,12,14,18,22,26 ,30,34,38 Resolut Integrity M e dtron i c Zot a ro l i m us eluting cobalt-based alloy (cobalt, nickel, chromium, and molybdenum) Modular de sig n ,Sin u s o id a l form wire,helical wrap,laser fused BioLinx b i oco m p a t i b l e polymer 2.25,2.5,2.75,3.0 ,3.5,4.0 8,12,14,18,22,26 ,30,34,38

52. Ste n t M a nu f a c t u r er D r u g B ase Fo rm/ D esi gn P o l y mer D iameter L e ng th Taxus Liberte Boston Scientific Paclitaxel 1 μg/mm2 paclitaxel in a slow release (SR)* 316L surgical grade stainless steel Sinusoidal ring modules linked via curved link elements SIBS [poly(styrene-b- isobutylene-b- styrene)], a tri- block copolymer (trade name: Translute) 2.50, 2.75, 3.00, 3.50, 4.00 8, 12, 16, 20, 24, 28, 32 TAXUS Express Boston Scientific Paclitaxel 1μg/mm2 paclitaxel in a slow release (SR) 316L surgical grade stainless steel modular ring strut pattern consists of two separate module designs: short, narrow sinusoidal Micro elements linked via straight articulations to long, wide sinusoidal Macro elements SIBS [poly(styrene-b- isobutylene-b- styrene)], a tri- block copolymer (trade name: Translute) 2.50, 2.75, 3.00, 3.50 8, 12, 16, 20, 24, 28, 32 Taxus Element Boston Scientific Paclitaxel 1.0 μg/mm 2 Platinum Chro m i um Sinusoidal ring modules consisting of alternating long and short crowns linked SIBS [poly(styrene-b- isobutylene-b- styrene)], a tri- block copolymer (trade name: 2.25,2.50,2.75,3. 0,3.5,4.0,4.5 8,12,16,20,24,28 ,32,38

53. Stent Coracto M a nu f a c t u r er Alvimedica Drug Rapamycin Base Stainless steel Form/Design Tubular,open cell design Polymer Ultrathin polymer layer absobes 100% in 10-12 week Diameter 2.5,2.75, 2.90,3 .00,3.5,4.0 Length 9,13,17,21,26, 28,32 Coroflex B.Braun Paclitaxel Stainless Multicellular ring P matrix- 2.5,2.75,3.0,3. 8,13,16,19,25, please 1μg/cumm steel design,Hybrid Superb polysulfone coating 5,4.0 28,32 radioopacity Cypher cordis Sirolimus 100% drug release with in 1 month S ta i n l ess steel Tubular,laser cut,sinusoidal pattern,closed cell two non-erodible polymers: polyethylene-co- vinyl acetate (PEVA) and poly n-butyl methacrylate (PBMA) 2.50, 2.75, 3.00, 3.50 8, 13, 18, 23, 28, 33

54. Ste n t M a nu f a c t u rer D r u g B ase Fo rm/ D esi gn P o l y mer D iameter L e ng th YUKON Choice 4DES T ra n s l umi n a, German CE mark Sirolimus Medical Stainless Steel, 316 LVM, Surface containing micro-pores 1million pores/sqcm Balloon marker material Platinum / Iridium m i cro p orous PEARL Surface Strut thickness 0,0034” / 87 μm Hybrid design Non polymeric Shellac resin bio compatible resin 6 to 8 weeks release 2.0,2.25,2.50, 2 .75,3.0,3.5,4.0 8,12,1 6 ,1 8 , 2 1 , 24,28,32, 40 GEN X Sync MIV th e ra p e u t i cs India pvt ltd Sirolimus Co Cr Open cell, alternate S link,uniform sinusoidal strut design Bio resorb PLLA-poly L lactic acid polymer Ultrathin coating(3μm) Drug sudden release f/b release upto 40- 50 days. 2.0,2.25,2.50,2 .75,3.00,3.50,4 .0,4.5 8,13,1 6 ,1 9 , 2 4 , 29,32,37 Supralimus Sahajanand Medical T ec h n o l o g i es Pvt Ltd, India Sirolimus Sainless steel H y brid b i o d e g ra d a b l e drug- carrier ,50% drug release in 7 days next 50% in 41days 2.5 , 2.75 , 3 . , 3. 5 8,12,1 6 ,2 , 2 4 , 2832,36,40 S u p ra li mus- Core Sahajanand Medical T ec h n o l o g i es Pvt Ltd, India Sirolimus cobalt- chrom i um H y brid b i o d e g ra d a b l e drug- carrier ,50% drug release in 7 days next 50% in 41days same same

55. Ste n t M a nu f a c t u r er D r u g B ase Fo rm/ D esi gn P o l y mer D iameter L e ng th YUKON Choice PC T ra n s l u m i n a , German CE mark Rapamycin (Sirolimus) Release of sirolimus up to 4 weeks Medical Stainless Steel, 316 LVM, Surface containing micro-pores 1million pores/sqcm Favours better endothel i ali s atio n Balloon marker material Platinum / Iridium microporous PEARL Surface Strut thickness 0,0034” / 87 μm Hybrid design The biodegradable components polylactide and shellac 2.0,2.50, 2.75,3.0 ,3.5,4.0 8,12,16,18,21,24 ,28,32, 40

56. Ste n t M a nu f a c t u rer D r u g B ase Fo rm/ D esi gn P o l y mer D iameter L e ng th BioMatrix Biosensors Inc, Newport Beach, Calif CE mark biolimus A9 highly lipophilic, semi synthetic sirolimus analogue (≈15.6 μg/mm of stent length) S-Stent (316 L) stainless steel stent with a strut thickness of 0.0054 inches (137 μm) laser-cut, tubular stent S-Stent platform Open cell, quadrature link B io d e g ra da bl e, Polylactic acid (PLA) applied to the abluminal surface 2 . 2 5 , 2 . 50 , 2 .7 5,3.0,3.5,4.0 8,11,14,18,24 ,28, 33,36 Pronova Vascular Sirolimus Co Cr Hybrid Biocompatibl 2.25,2.50,2.7 13,18,23,28,3 concepts,UK S shaped e,biostable 5,3.0,3.25,3.5 3,38 articulations polymer,drug 0,4.0 release upto 30 days B io m ime Meril Life S cie n ce s, India Sirolimus 1.25μgm/sqm m of stent surface,30 day elution kinetics Co Cr Hybrid cell design 65μm strut thickness B io d e g ra da bl e polymer 2 . 5 , 2 . 7 5 , 3 . ,3 .5,4.0,4.5 8,13,16,19,24 ,29,32,37,40

57. Stent M a nu f a c t u r er Drug Base Fo rm/ D esi gn Polymer Diameter Length ACTIVE& IHT Paclitaxel Stainless steel Open P5 - 2.0,2.25,2.5,2. 9,14,18,19,23, ACTVE small cell,tubular Biocompatible 75,3.0,3.5,4.0, 28,36 polymer 4.5 EVERLITE Unimark Everolimus Co Cr Open Biodegradable 2.25,2.5,2.75,3.0 8,13,16,19,24,29 remedies Low drug dose 1.2μg/sqmm cell,Sinosoidal strut d e s i g n ,a l ternat i v ,3.5,4.0,4.5 ,32,37,40 e S link,ultrathin strut 65μm Flexy Rap Lancer medical Rapamycin Co Cr Open Biodegradable 2.25,2.5,2.75,3.0 7,10,13,15,17,20 technology 1μg/sqmm cell, Radial star segments polymer ,3.5,4.0 ,24,28,33,38,42 combined with flexible links,Strut 65μm, INDOLIMUS Ce mark S a h aja n a n d medical sirolimus Co Cr Open cell,laser cut,seamless tube,60 micm strut thickness Biodegradable polymer matrix 2.5,2.75,3.0,3.5 8,12,16,20,24,28 ,32,36,40

58. T H A N KS