Exercise - Cantilever Beam

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1 인체적용스텐트 Prof. Dong-Wook HAN Department of Nanomedical Engineering, College of Nanoscience & Nanotechnology, Pusan National University

2 스텐트 (stent) 란? 스텐트 (stent) : 혈관및비혈관의협착된부위를확장시켜주는그물망형태의이식물 스텐트분류 1) 혈관계 : 관상동맥, 말초혈관 2) 비혈관계 : 위장관, 비위장관 비혈관스텐트 말초혈관스텐트 관상동맥스텐트

3 비혈관및혈관스텐트 장골동맥, 대퇴슬와동맥, 신동맥, 경동맥, 정맥등 Coronary artery 식도, 기도, 담도, 요도, 위장관, 누관등 Restenosis Stent Stent Stent in insertion expansion coronary artery 관상동맥의시술예

4 스텐트의형상및명칭 금속스텐트시스템 Stent Catheter Radiopaque Marker Balloon

5 말초혈관용스텐트 Balloon expandable Selfexpandable

Self Expandable (Nitinol shape memory) 1)

Scientific) 2) Nitinol: - SMART (Cordis),

6 팽창방식에따른스텐트의종류 1. Balloon Expandable (Laser-cut 316L SUS) Stainless Steel: - Palmaz (Cordis), - Express (Boston Scientific) 2. Self Expandable (Nitinol shape memory) 1) Stainless steel - Wallstent (Boston Scientific) 2) Nitinol: - SMART (Cordis), Zilver (COOK), - Sentinol (Boston Scientific), - Nitis-S ( 태웅메디칼 ), - Hanaro stent( 엠아이텍 )

7 Prevalence of PAD (2000)

8 Recurrence of Angioplasty

9 Renal Artery Stenosis (RAS)

10 말초혈관용스텐트 1. 종류 1) SMART stent (Nitinol, Cordis, J&J) 2) Wallstent (SS alloy, Boston Scientific) 3) Dynalink/Absolute stent (Abott Vascular) 4) Palmaz & Palmaz-Schatz stent (J&J) 2. 특성 1) SFA: - Restenosis: SMART>>Wallstent, Palmaz - Stent fracture: Dyralink/Absolute 2%> Wall 19%>SMART 28% 2) IA: 1Y - Restenosis: SMART=Wallstent - Patency: 94% at 4Y (Palmaz-Schatz)

11 말초혈관의재협착 32%; 4SES:4PES=None at 12M 3-8%; 6.3% BMS 12-18%; SES:BMS=6.7%:14.3% at 6M 13%; No DES 4Y failure: 43% reduction in BMS vs PTA 22-65%; SES:BMS=0%:17.6%(7.7%) at 6M 20.7%:17.9% at 1.5Y PES:BMS(Nitinol w/o polymer); pending Sirolimus (Patency: 97% at 6M); SES:BMS=0%:4% at 6M DES for coronary artery 29SES:29BMS=4%:55% at 6M

12 대퇴동맥스텐트의적용 (I)

13 대퇴동맥스텐트의적용 (II) 6M

14 생체적합성고분자 - Molecular cilia: poly(ethylene glycol)(peg) - Biomembrane: phospholipid (MPC: -P - -N + ) zwitterionic group: -N + -SO Negative cilia: PEG-SO We introduced a novel, blood-compatible zwitterionic PEG on the Nitinol substrate (PEG-N + -SO 3- ) Zw Zw Zw Zw Zw Zw Zw Zwitterion PEG chain Zwitterionic cilia Nitinol Stent Nano-manipulated surface

15 생체적합성 Nitinol 스텐트 SO 3 - N + SO 3 - N + SO 3 - SO 3 - SO 3 - PEG N + N + N + PEG (DLC: Diamond-like carbon) OH OH OH O O O O O O DLC Si TiNi TiNi TiNi TiNi TiNi-DLC control TiNi-DLC-OH TiNi-DLC-PEG TiNi-DLC-PEG-N + -S - 1. TiNi-DLC-OH(Chemical) 2. TiNi-DLC-OH(Plasma)

16 Albumin/Fibrinogen Adsorption Albumin/Fibrinogen (ug/cm 2 )

17 Platelet Adhesion (SEM, x3,000) TiNi control TiNi-DLC-PEG2K TiNi-DLC-PEG2K-N + -S -

18 Cytotoxicity 100 OD 460 nm NC PC TiNi TiNi- DLC TiNi- DLC- PEG2K TiNi- DLC- PEG2K- N + -S -

19 잡견대퇴동맥스텐트삽입실험 (6W)

20 atherosclerotic artery & coronary artery disease

21 심혈관계질환 우리나라현황 - 심혈관질환 : 심근경색, 뇌졸증 ( 사망원인 1 위 ) - 심장돌연사 : 한해 5 만명발생 - 돌연사요인 : 심근경색, 고혈압, 당뇨병, 고지혈증, 비만, 흡연등

22 심장관상동맥질환 - 심장병 : 우리나라 5대사망원인질환의하나사망원인 3위 (2003); 5위 (10년전) (1위: 암, 2위 : 뇌혈관질환, 4위 : 당뇨병, 5위 : 자살 ) - 관상동맥질환 : 심장질환의 80% 차지 - 심장관상동맥질환진행동맥경화 협심증 심근경색 심장마비 ( 돌연사 )

23 심장관상동맥질환치료법 1. 약물치료 : 혈전용해제투여 2. 관상동맥우회술 (CABG) : 내유동맥이나복재정맥이용한개심수술 3. 관상동맥성형술 (PTCA) - 풍선 (balloon) 확장술 - 스텐트 (stent) 시술 혈관성형술 (Angioplasty)

24 관상동맥성형술 (PTCA)

25 angiotherapy 약물치료 외과적수술 동맥류치료 중재적시술 항응고제, 항혈소판제, 혈전용해제 비교적큰혈관 혈관클립 도관 (Catheter) 삽입 혈전을녹이는약물로치료가능 ( 발병후 3~5시간내에치료되어야함 ) 출혈이다량으로발생 하여환자의생명이 위험 가능한경우가많지않고환자에게정신적, 육체적으로상당히부담 수술을하지않고환자 의대퇴동맥으로도관을 삽입

26 혈관성형술 협착된혈관 (PTCA, percutaneous transluminal coronary angioplasty) X선을이용한혈관조영술 (Angiography) 을실시하여혈관이협착되어있는상태를파악하고협착이있는병변을풍선도자 (Balloon catheter) 을이용하여확장시켜넓혀주는중재적시술법 삽입된풍선도자 정상혈관 협착된혈관 PTCA 시술한혈관 시술 6 개월후 치료후

27 스텐트삽입술 (Stenting) 혈관성형술시술후에최대 50% 정도에서재협착 (Restenosis) 이발생하기때문에이를해결하기위한시술로풍선위에그물망구조로된금속성재질의스텐트 (Bare metal stent) 를탑재하여협착부위에도달시킨후팽창시키는스텐트삽입술이널리시행 관상동맥 혈전 스텐트 스텐트삽입풍선도자팽창스텐트고착

28 신생내막세포의증식 스텐트의재질로주로사용되고있는스테인레스스틸과같은금속은표면의이온이조직과반응하는과정에서혈소판을활성화하고혈전형성을유발하여신생내막세포의증식을초래 스테인레스스틸스텐트 신생내막세포가증식한스텐트

혈관평활근 ) 세포의과다증식으로재협착 stent struts intimal hyperplasia

29 혈관재협착 혈관손상 스텐트삽입과정에서혈관에손상유발로혈전이생기고혈관이급격히폐쇄 혈전발생 재협착 손상된혈관의내막과중막에혈소판이점착되어혈전발생 스텐트시술후 6 개월내에그중약 20% 가신생내막 ( 혈관평활근 ) 세포의과다증식으로재협착 stent struts intimal hyperplasia residual plaque lumen 스텐트내재협착 (In-stent restenosis, ISR)

30 삽입후스텐트혈전증 LAD artery stenosis Stent Cordis LAD stent 3.0x18mm occlusion Thrombus extraction using catheter 혈전형성 스텐트삽입후에혈소판이점착되어혈전발생 혈전증 스텐트시술후 6-12 개월이후에혈전의과다형성으로혈전증발생 E. thrombus, a mixture of fibrin & platelet aggregates F. inflammatory cell infiltrate consisting of neutrophils & eosinophils

31 Coronary Arterial Stent Coronary Arterial Stent Balloon Guide Catheter

33 스텐트 bare metal stent (BMS) vs. drug-eluting stent (DES) bare metal stent (BMS): 일반금속스텐트 ( 제 1 세대 ) drug-eluting stent (DES): 약물 - 용출스텐트 ( 제 2 세대 )

restenosis in BMS & late thrombosis in DES Potential complications of coronary stenting: restenosis in a traditional BMS (upper) and late thrombosis in

34 restenosis in BMS & late thrombosis in DES Potential complications of coronary stenting: restenosis in a traditional BMS (upper) and late thrombosis in a DES (lower) From: New Eng J Med 07,356(10) ges/data/nejme068306/dc1/nejm_nejme v1.swf

35 Restenosis Recoil and remodeling Neointimal hyperplasia

36 Why do stents fail? Causes of stent ISR Stent under-expansion Asymmetric strut distribution Stent fracture Polymer disruption Peri-stent vessel wall injury Drug failure or resistance Polymer (or drug) hypersensitivity

$deployment Crack in the polymer during stent expansion Stent strut fracture Courtesy of John$

37 pathophysiology of stent restenosis Mechanical Under expansion or stent malapposition during deployment Crack in the polymer during stent expansion Stent strut fracture Courtesy of John Ormiston, MD

38 Polymer disruption Courtesy of John Ormiston, MD

39 Main branch ostium after Taxus stent crush and Repeated high pressure kissing post-dilatation Courtesy of John Ormiston, MD

$fracture$ pre post

40 Stent fracture pre post after 8 mon Stent cypher 3.0x33.0mm

41 pathophysiology of stent restenosis Biological Smooth muscle cell proliferation due to lack of sufficient drug inhibition Lack or delay of re-endothelialization Fibrin deposition Polymer induced chronic inflammation Rebound from vessel toxicity

42 patterns of ISR FOCAL DIFFUSE Articulation or Gap Margin Intra-stent Proliferative Focal Body Multifocal Total Occlusion From: Circulation 99,100(18) BMJ 03,327(7409)274-9

43 관상동맥혈관성형술의재협착 40% 26% 20% 4% 1989 년풍선확장술 1991 년스텐트시술 1999 년방사선치료 2001 년약물방출형스텐트

45 국가별특허동향

46 출원인별특허동향

48 약물방출스텐트의시장규모및점유율 구분 현재시장규모 (2007 년 ) 단위 : 억원 향후시장규모 (2010 년 ) 세계시장규모 70, ,000 한국시장규모 800 1,000 생산기업 국내시장 (%) 세계시장 (%) 미국 J & J 미국 BS 미국 Medtronic 20 20

49 Wood Mackenzie s forecast

51 Stent 재료코팅 1. Polymer coating 1) Nondegradable: 상품화 2) Biodegradable: PLLA, PLGA, PCL 3) Hybrid: 비분해성 + 분해성고분자 4) Biodegradable stent 2. Ceramic coating - SiC, Al 2 O 3, 산화이리듐, TiNOx 3. Metal coating - C-C, DLC, Ti-O, Ti-N, TiN, TaN - Bare metal stent(bms) 4. Bioactive agents - Peptide, Protein, Cell

52 국내외스텐트연구동향 1. 관상동맥재협착방지용약물함유스텐트개발동향 : 헤파린, 히루딘, ReoPro, α-lipoic acid, Molsidomine, Ho-166, 베타 / 감마선, LacZ, VEGF, CD34 receptor 등 2. 국외의경우 ( 상품화 ) 1) Cyper stent (J & J사 ): Sirolimus ( 면역억제제 ) 이용 2) Taxus stent (BS사): Paclitaxel ( 항증식성약제 ) 이용 3) Endeavor stent (Medtronic사): Zotarolimus ( 면역억제제 ) 이용 3. 국내의경우 년 휴메드가 Core stent라는약물미함유스텐트개발 - 재협착방지용약물부착스텐트는연구한바있으나고기능성의생분해성매트릭스약물방출스텐트 (DES) 의개발은전무함

53 국내연구개발의필요성 - 식생활문화의변화및생활환경의영향으로심장질환환자수가매년 25% 이상증가추세 - 스텐트시장의성장율은매년 30% 이상증가예상 - 국내년간스텐트시술건수는약 5만건으로, 약 800억원이상의국내시장형성 - 특히약물방출스텐트는 100% 수입함으로국산화가시급함 - 기존의상품화된약물방출스텐트의경우, 고가이고신생내막의과도한증식 (late catch-up) 및후기혈전증현상있음 - 저가이면서약물의부작용이적고장기간항증식성및항혈전성을보이는재협착율이낮은생분해성매트릭스의다중약물방출제어스텐트의연구개발이절실히필요함

54 국내의연구개발현황 연구수행기관연구개발의내용연구개발수준 전남의대 전남의대 ReoPro ( 혈소판당단백 IIb/IIIa 수용체차단제 ) 유리스텐트 Alpha-lipoic acid ( 항산화제 ) 유리스텐트 임상연구및제품개발전단계 시제품개발단계 연세의대 CD34 receptor 코팅스텐트시제품개발단계 광주과기원이중약제코팅스텐트시제품개발단계 휴메드 Core 스텐트 (bare metal stent) 판매중단상태

55 Drug-Coated Stent: Heparin Conclusions in animal study: Heparin-coated stent Inhibits neointimal cell proliferation within stent compared with non-coated stent Bare Stent Heparin -Coated Stent

56 Platelet GP IIb/IIIa Receptor Blocker (ReoPro )-Coated Stent Control stent ReoPro-coated stent Anti-thrombotic, anti-proliferative and anti-inflammatory stent

57 Histopathology

58 Alpha-Lipoic Acid (ALA) Stent Control Alpha-lipoic acid

59 교과부미래유망파이오니어사업 고령친화형나노바이오융합소재 BT Biomaterials Cell Engineering DDS NT Nanomaterials Nanofabrication Nanodevices

60 Technical Evolution in Interventional Cardiology Drug eluting stent

61 국외약물방출스텐트의개발현황

62 혈관재협착의단계

63 약물방출스텐트 (DES) vs Bare 스텐트 (BMS)

64 DES Component Interaction

vascular smooth muscle cells (VSMCs) VSMCs in vascular

excessive proliferation of VSMCs migration of VSMCs from

intimal hyperplasia lumen Atherosclerosis in coronary

65 vascular smooth muscle cells (VSMCs) VSMCs in vascular diseases atherosclerosis and restenosis after angioplasty excessive proliferation of VSMCs migration of VSMCs from tunica media to subendothelial region lumen stent struts intimal hyperplasia lumen Atherosclerosis in coronary artery narrowed lumen by half residual plaque In-stent restenosis (ISR)

66 스텐트에사용되는약물

other potential toxicity (genotoxicity, dermal, acute and short-term toxicity,

67 Problems of PTX & SRL toxicity to endothelial cells (ECs): late thrombosis, lack or delay of re-endothelialization in stent restenosis: lack of sufficient drug inhibition other potential toxicity (genotoxicity, dermal, acute and short-term toxicity, teratogenicity and reproductive toxicity): not fully elucidated yet Paclitaxel (PTX) Sirolimus (SRL)

68 평활근세포증식을억제하는약물의기전

69 inhibition of neointimal formation by sirolimus impregnated stent From: BMJ 03,327(7409)274-9

70 VSMCs vs. drug (PTX & SRL) Cell cycle & drug From: J Invasive Cardiol 03,15(3) From: Nature Med 02,8(11)

Mechanisms of restenosis after stent implantation and targets of therapy with sirolimus and paclitaxel. Sirolimus analogues act through the same pathway as sirolimus.

71 Mechanisms of restenosis after stent implantation and targets of therapy with sirolimus and paclitaxel. Sirolimus analogues act through the same pathway as sirolimus. The restenosis cascade that is initiated after stent implantation is shown in red. The mechanism of action of sirolimus (and analogues) is shown in blue, whereas the mechanism of action of paclitaxel is shown in yellow. From: New Eng J Med 06,354(5) mtor (mammalian target of rapamycin)

72 platelets Atherosclerosis in coronary artery occluded with thrombus Platelets in thrombosis early or late thrombosis after stenting excessive activation and cytokine release of platelets stimulation of VSMC s responses & behaviors normal coronary artery thrombus lumen

73 상품화된약물방출스텐트 (DES) STENT POLYMER DRUG

74 1. 상품화된약물방출스텐트

Strut 모양및두께 CYPHER TAXUS Liberté ENDEAVOR XIENCE

75 Strut 모양및두께 CYPHER TAXUS Liberté ENDEAVOR XIENCE V Strut Thickness: Strut Thickness: Strut Thickness: Strut Thickness: 140 µm Polymer Thickness: 12.6 µm 97 µm Polymer Thickness: 16.1 µm 91 µm Polymer Thickness: 5.3 µm 81 µm Polymer Thickness: 7.6 µm 3.0 mm diameter stents, 500x magnification

76 Drug Eluting Stent (DES) In-stent Restenosis 3 days 30 days Control Sirolimus-eluting

77 Binary Restenosis in Stent

79 Late Stent Thrombus (I) Leon B. ACC 2005

80 Late Stent Thrombus (II)

81 Long-Term Clinical Outcomes (I)

82 Long-Term Clinical Outcomes (II)

84 금속스텐트 (BMS) 및약물방출스텐트 (DES) 의비교 혈전증 사망율 BMS DES 혈관재협착 후기혈전증 심근경색 재협착율

85 다양한스텐트에서의약물방출전략

88 FDA/CE/CA

90 초음파노즐을이용한스텐트코팅기술

91 전기방사장치를이용한스텐트코팅기술 bare stent

92 Layer-by-Layer Assembly Activated stainless steel substrate Titania coated substrate PAA coated substrate Microparticle adsorption After annealing the microparticles PAA coated substrate PHEMA coated substrate

93 2. 분해성고분자코팅 DES(Costar) Different drugs from different holes Different drugs from different layers

94 Why absorbable stents?

95 Bio-Absorbable Stent Program

97 3. 분해성고분자 DES(BioMatrix)

100

101

102

103

104

105

106 Ideal Coronary Stent 1) To provide a scaffold - to prevent acute recoil - to seal any significant dissection flaps - deliberable & visible 2) To allow sufficient endothelialization - to prevent stent thrombosis - to minimize the natural vessel healing reaction 3) Next generation of DES - Use of biocompatible & biodegradable polymer coating - Fully degradable stents - Use of new or combinations of drugs

107

108 Ideal Scenario for Drug Releasing Cumulative drug amount Dexamethasone Sirolimus/ Paclitaxel Estradio l 2 week Time 4 week

109

110 뇌졸중 (Stroke)

111 혈관성형술 : 터졌을경우

112 Watch Your Artery!

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<30332EB0ADC1C22DC1A4B8EDC8A32E687770> 대한내과학회지 : 제 76 권제 5 호 2009 의학강좌 - 개원의를위한모범처방 (Current Clinical Practice) 새로운관상동맥스텐트의개발및가능성 전남대학교의과대학순환기내과, 보건복지가족부지정심장질환특성화연구센터 정명호 Current status of the development of new-drug eluting stents Myung Ho