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Can Biodegradable Polymer DES Be G Y Better Than 2Nd Generation DES?

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Can Biodegradable Polymer DES Be G Y Better Than 2Nd Generation DES? Can Biodeggyradable Polymer DES Be Better than 2nd Generation DES? G. Nakazawa, MD Tokai Univ. Japan CVCV--HILLsHILLs Receiving Research Grant From Abbott Vascul ar Japan Boston Scientific Japan Medtronic Vascular Japan Cordis Johnson & Johnson Terumo Corp. Biosensors Japan Adv isory Con trac t With Abbott Vascular Japan Terumo Corp. Components of DES Metal/Design Thick struts ~ 81-140 microns Polymer Drugs Non-erodable Sirolimus-135µg Erodable Drug and Release kinetics Everolimus – 100 µg Determine Paclitaxel- 80 µg Antiproliferative effects Biolimus A9 – 225 µg Localized Hypersensitivity Reaction in Cyp her LAD: Cypher (17months) RCA: Cypher (17months) A B E F C D Nakazawa, G et al. J Am Coll Cardiol 2011: 57(4).390-8 Long Term Safety : Future Directions LLonongg--TSftfDESFtDitiTTSftfDESFtDitiTermerm SSaaffeettyy ooff DESDES:: FFuuttureure DiDirecrectitionsons Asymmetric Biodegradable No Polymer Polymer No DrugDrug General criteria for selecting a pollymer for use as bioma ter ia l • Does not evoke an inflammatory/toxic response, disproportionate to its beneficial effect • Is metabolized in the body after fulfilling its purpose, leave no trace • Is easily processed into the final product form • Has acceptable shelf life • Is easily sterilized Middleton JC and Tipton AJ. Biomaterials 2000;21:2335 Syygynthetic Biodegradable Polymers • Poly(lactide) (PLA) • Poly(glycolide) (PGA) • Poly(glycolic-co-lactic acid) (PLGA) • Pl(Poly(e-caprolactone)(PCL)) (PCL) • Poly(dioxanone) (PDS) • Poly(glycolide-co-trimethylene carbonate) (PGA-TMC) Degradation Speed in Various Biod egred abl e PlPolymers Material Degradation Period Polylactic acid (PLA) 9 months Polyglycolic acid (PGA) 2-3 months Poly-L-lactic acid (PLLA) 12-18 months Poly(d, l-lactide/glycolide) copolymer (PGLA) 2-3 months Polyorthoester (POE) 10 months (60%) Pl(hdPoly(hydroxy btbutyra t/hdte/hydroxyva lera t)te)copo lymer 6th6 months (PHBV) Polycaprolactone (PCL) 36 months Degradation 9 The degradation- 9 Factors which accelerate absorption mechanism is polymer degradation are the result of many the following: interrelated factors, More hy drop hilic monomers including: More hydrophilic, acidic The ch emi cal s tabilit y o f the endgroups polymer backbone More reactive hydrolytic The presence of catalysts group in the backbone Additives Less crystallinity Impurities or plasticizers Small device size Geometry of the device LtifthdiLocation of the device Middleton JC and Tipton AJ. Biomaterials 2000;21:2335 PLA Metabolic Pathway H2O PLA Hydrolysis Molecular weight Mass loss Lactic acid Mass transport of lactic acid Krebs cycle CO2+H2O Bioerodable polymer breaks down into Polymer degradation products ands side products. The side products, mostly responsible for titoxic eff fftects Commandeur S, J Interven Cardiol 2006 NOBORI Stent Platform Biodegradable Drug/Carrier: - Biolimus A9® / Poly (Lactic Acid) 50:50 mix - abluminal surface only (contacts vessel wall) - 11 µmeter coating thickness - degrades in 9 months releasing CO2+ water S-Stent™ Platform: - Stainless steel ((129129µm) - Open cell design - Quadrature-link™ connectors BioM atri x S tent strut PlParylene C - Different models for small and large vessels Drug: Biolimus A9 15.6 µg/mm-stent length 2.5-3.0mm (6 crown 2 link) 3.5mm (10 crown 2 link) NOBORI– Strut and polymer thickness Xience ENDEAVOR® DES NOBORI Stent Stent Stent Cobalt Cobalt Stainless Material Chromium Chromium Steel BMS Strut Thickness (in.) 0.0032” 0.0036” 0.0053” BMS Strut Thickness (µm) 81µm 91µm 130µm Polymer Thickness (µm) 7µm 6µm 18µm Drug Dose in various DES 280 240 µg) d (µg 200 160 g Loa uu 120 Dr 80 40 88 µg 150 µg 180 µg 280 µg 0 XIENCE VTM Cypher Endeavor NOBORI 3.0x 18 mm 3.0x 18 mm 3.0x 18 mm 3.0x 18 mm Comparative Elution Profiles 100 ENDEAVORENDEAVOR™™ CYPHER® sedsed 80 XIENCE™ Relea Relea %%%% 60 NOBORI lative lative 40 u uuu CumCum 20 TAXUS® 0 5 10 15 20 25 30 Days Percent Stenosis in Single DES in Rabbit Iliac Arteries following Deployment of Cypher, Taxus and Nobori stents at 28-days Proximal Middle Distal 25 20 P = .0229 Cypher enosis 15 tt 10 ercent S PP 5 0 Taxus Cypher Taxus Nobori Nobori Data from CVPath Institute, Inc. Fibrin Deposition in Single DES in Rabbit Iliac A rt eri es at 28 -days Cypher 12.5 in 10.0 7.5 ith Fibr ww Taxus 5.0 truts SS 2.5 No. 0.0 Cypher Taxus Nobori Nobori Data from CVPath Institute, Inc. Inflammation in Single DES l 150 eterophi Cypher HH 100 Eosinophil/ 50 0 No. Lumen Cypher Taxus Nobori Taxus 15.0 P = <.0001 12.5 10.0 ant Cells 7.5 5.0 No. Gi Nobori 2.5 0.0 Cypher Taxus Nobori Data from CVPath Institute, Inc. Overlapping Drug-Eluting Stents (Cypher, Taxus and Nobori) at 28-day Proximal Middle Distal Cypher )) 0.25 0.20 ness (mm kk 0.15 Taxus 0.10 mal Thic ii 0.05 Neoint 0.00 Cypher Taxus Nobori Nobori Data from CVPath Institute, Inc. Fibrin Depos itio n in Overla pped DES at 28 d ays Cypher™ 20 P=0.01 15 Fibrin hh Taxus™ 10 truts wit SS 5 No. 0 Cypher Taxus Nobori Nobori™ Data from CVPath Institute, Inc. Giant cells in Overlapped DES at 28-Days Cypher™ 30 25 20 15 iant Cells GG 10 P=0.0007 Taxus™ No. 5 0 Cypher Taxus Nobori Nobori™ Data from CVPath Institute, Inc. Single Nobori™ Biolimus A9-Eluting Coronary Stents 14 Dayyg Single 28 Dayyg Single Comparison of Various BMS and DES In Rabbit Iliac Arteries at 28-days Bx Velocity Cypher Express Taxus Tsunami Nobori apped ll over 28 Day Endothelialization 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다 컴퓨터를 다시 시작한 후 파일을 다시 여십시오 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다 P0002P=0.002 P=0.02 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다 컴퓨터를 다시 시작한 후 파일을 다시 여십시오 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다 ) 100 %% 80 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다 컴퓨터를 다시 시작한 후 파일을 다시 여십시오 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다 Cypher tion ( aa 60 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다 컴퓨터를 다시 시작한 후 파일을 다시 여십시오 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다 Taxus 이미지를 표시할 수 없습니다. 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다. 컴퓨터를 다시 시작한 후 파일을 다시 여십시오. 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다. elializ 40 Nobori hh 20 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다 컴퓨터를 다시 시작한 후 파일을 다시 여십시오 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다 Endot 0 이미지를 표시할 수 없습니다 컴퓨터 메모리가 부족하여 이미지를 열 수 없거나 이미지가 손상되었습니다 컴퓨터를 다시 시작한 후 파일을 다시 여십시오 여전히 빨간색 x가 나타나면 이미지를 삭제한 다음 다시 삽입해야 합니다 Non-overlapNon-Overlap Overlap Overlap Data from CVPath Institute, Inc. Endothelial Function in NOBORI Hamilos, MI et al. J Am Coll Cardiol 2008;51:2123–9 Is the biodegradable polymer really better than durable ones? Ongoing Pre-clinical Study Study Title : Comparison of long -term safety following new generation drug eluting stents implantation in porcine coronary artery Purpose: Hypersensitivity reaction due to lack of biocompatibility has emerged as one of the major concerns in 1st generation drugrug--eeltiluting st ent s (DES) (DES)N. Newer generati on DES DESh has applied better polymer but the longlong--termterm safety is still unclear. The aim of this study is to evaluate the long -term safety following Xience V, Cypher, and Nobori DES in porcine coronary artery model. Test Articles:1. Xience V everolimus eluting stent 2. Cypher Select sirolimus eluting stent 3. NbNobor iBio limus el uti ng st ent Collaborators Kobe University Graduate School of Medicine Toshiro Shinke, MD (Study Co-Director) Daisuke Matsumoto, MD Hiromasa Otake, MD Junya Shite, MD Tokai University School of Medicine Takeshi Ijichi, MD Abbott Vascular Japan Masaharu Osa GOODMAN CO., LTD. Masaru Uchiyama Kentaro Asada Akiji Kato Toshio Kimura Yoshihiro Odagawa Study Design Implantation of DES Sacrifice 6 animals for Histo Animal N=12 • Ach challenge test Each animal receives 3 DESs • OCT observation (XV, CS , an d NB) BfBefore sacr ifice N=6 03M NN6=6 0 1M 6M Sacrifice 6 animals for Histo • Acetylcholine challenge test • Ach challenge test • OCT observation • OCT observation 6 animals for 6M Before sacrifice Protocol ffyor Acetylcholine challeng e test Baseline Angiography 10--66mol/l of acetylcholine (1ml/min) 2.5 mins 10--55mol/l of acetylcholine 2.5 mins (1m l/mi n) ISDN (200 -400ug) Final Angiograph y OCT Imaging Distal Proximal 100 100 75 75 MLD following Ach Challenge@1M MLD following Baseline Baseline Xience Ach 10-6 Ach 10-6 Ach 10-5 Ach 10-5 ISDN ISDN Baseline Baseline Cypher Ach 10-6 Ach 10-6 Ach 10-5 Ach 10-5 ISDN ISDN Baseline Baseline NOBORI -6 Ach 10-6 Ach 10 -5 Ach 10-5 Ach 10 ISDN ISDN Maximum Change in MLD following Ach Challenge@1M Proximal Distal Xience ChCypher NbNobor i Xience ChCypher NbNobor i 0 -10 -20 -30 (%) - Preliminary OCT results - 1 and 3 months 1-month group OCT Analysis Status 6 pigs 18 lesions enrolled XienceTM NoboriTM CypherTM 6 cases received 6 cases received 6 cases r eceiv ed Void: 1 case (poor image quality) 6 cases analyzed 5 cases analyzed 6 cases analyzed 17 lesions available Kobe Univ. Follow-up OCT Results ~ Neointima proliferation ~ Average Neointimal Area Average %Neointimal Area (NIA /Stent area) 2 (mm )(%)p=0.005* p=0.01* 2.4 35 2 30 222.2±060.6 31.
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