Exercise - Cantilever Beam
Transcript of Exercise - Cantilever Beam
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인체적용 스텐트
Prof. Dong-Wook HAN
Department of Nanomedical Engineering, College of Nanoscience & Nanotechnology, Pusan National University
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스텐트(stent) : 혈관 및 비혈관의 협착된 부위를 확장시켜 주는 그물망 형태의 이식물
스텐트 분류
말초혈관 스텐트
비혈관 스텐트
관상동맥 스텐트
1) 혈관계: 관상동맥, 말초혈관 2) 비혈관계: 위장관, 비위장관
스텐트(stent)란 ?
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관상동맥의 시술예
비혈관 및 혈관 스텐트
장골동맥, 대퇴슬와동맥, 신동맥, 경동맥, 정맥 등
식도, 기도, 담도, 요도, 위장관, 누관 등 Restenosis Stent insertion
Stent expansion
Stent in coronary artery
Coronary artery
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스텐트의 형상 및 명칭
Catheter Radiopaque Marker Balloon
Stent
금속 스텐트 시스템
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말초혈관용 스텐트
Balloon expandable
Self- expandable
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팽창방식에 따른 스텐트의 종류
1. Balloon Expandable (Laser-cut 316L SUS)
2. Self Expandable (Nitinol shape memory)
Stainless Steel: - Palmaz (Cordis), - Express (Boston Scientific)
1) Stainless steel - Wallstent (Boston Scientific) 2) Nitinol:
- SMART (Cordis), Zilver (COOK), - Sentinol (Boston Scientific),
- Nitis-S (태웅메디칼), - Hanaro stent(엠아이텍)
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Prevalence of PAD (2000)
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Recurrence of Angioplasty
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Renal Artery Stenosis (RAS)
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말초혈관용 스텐트
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)
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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
12-18%; SES:BMS=6.7%:14.3% at 6M
3-8%; 6.3% BMS
32%; 4SES:4PES=None at 12M
13%; No DES 4Y failure: 43% reduction in BMS vs PTA
DES for coronary artery 29SES:29BMS=4%:55% at 6M
말초혈관의 재협착
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대퇴동맥 스텐트의 적용(I)
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6M
대퇴동맥 스텐트의 적용(II)
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- Molecular cilia: poly(ethylene glycol)(PEG) - Biomembrane: phospholipid (MPC: -P--N+) zwitterionic group: -N+-SO3
- - Negative cilia: PEG-SO3
-
- We introduced a novel, blood-compatible zwitterionic PEG on the Nitinol substrate (PEG-N+-SO3
-)
생체적합성 고분자
Nitinol Stent
Zw
PEG chain
Zw Zw Zw Zw Zw Zw Zwitterion
Nano-manipulated surface
Zwitterionic cilia
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생체적합성 Nitinol 스텐트
TiNi-DLC control TiNi-DLC-PEG-N+-S- TiNi-DLC-OH
OH OH OH
TiNi-DLC-PEG
O O O
PEG
O O O
N+ N+ N+
SO3- SO3
- SO3-
Si DLC
TiNi TiNi TiNi TiNi
(DLC: Diamond-like carbon)
1. TiNi-DLC-OH(Chemical) 2. TiNi-DLC-OH(Plasma)
PEG
N+
SO3-
N+
SO3-
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0.0
0.2
0.4
0.6
0.8
1.0
1.2 A
lbum
in/F
ibrin
ogen
(ug/
cm2 )
Albumin/Fibrinogen Adsorption
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Platelet Adhesion (SEM, x3,000)
TiNi control TiNi-DLC-PEG2K TiNi-DLC-PEG2K-N+-S-
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0
20
40
60
80
100
NC PC TiNi TiNi- DLC
TiNi- DLC-
PEG2K
TiNi- DLC-
PEG2K- N+-S-
OD
460
nm
Cytotoxicity
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잡견 대퇴동맥 스텐트삽입 실험(6W)
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atherosclerotic artery & coronary artery disease
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심혈관계 질환
우리나라 현황 - 심혈관질환 : 심근경색, 뇌졸증 (사망원인 1위) - 심장 돌연사 : 한해 5만명 발생 - 돌연사 요인 : 심근경색, 고혈압, 당뇨병, 고지혈증, 비만, 흡연 등
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심장 관상동맥 질환
- 심장병: 우리나라 5대 사망원인 질환의 하나
사망원인 3위(2003); 5위(10년전)
(1위: 암, 2위: 뇌혈관질환, 4위: 당뇨병, 5위: 자살)
- 관상동맥 질환: 심장질환의 80% 차지
- 심장 관상동맥 질환 진행
동맥경화 → 협심증 → 심근경색 → 심장마비(돌연사)
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심장 관상동맥 질환 치료법
1. 약물 치료
: 혈전용해제 투여
2. 관상동맥우회술(CABG)
: 내유동맥이나 복재정맥
이용한 개심수술
3. 관상동맥성형술(PTCA)
- 풍선(balloon) 확장술
- 스텐트(stent) 시술
혈관성형술(Angioplasty)
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관상동맥 성형술(PTCA)
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약물치료
항응고제,
항혈소판제,
혈전용해제
혈전을 녹이는 약물로
치료 가능 (발병 후
3~5시간 내에 치료되
어야 함)
외과적 수술
비교적 큰 혈관
출혈이 다량으로 발생
하여 환자의 생명이
위험
동맥류 치료
혈관클립
가능한 경우가 많지
않고 환자에게 정신
적, 육체적으로 상당히
부담
중재적 시술
도관(Catheter)
삽입
수술을 하지 않고 환자
의 대퇴동맥으로 도관을
삽입
angiotherapy
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혈관성형술
(PTCA, percutaneous transluminal coronary
angioplasty)
X선을 이용한 혈관조영술(Angiography)을
실시하여 혈관이 협착되어 있는 상태를
파악하고 협착이 있는 병변을
풍선도자(Balloon catheter)을 이용하여
확장시켜 넓혀주는 중재적 시술법
삽입된 풍선도자
협착된 혈관
치료 후
정상 혈관
협착된 혈관
PTCA 시술한 혈관
시술 6개월 후
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스텐트 삽입술(Stenting)
혈관성형술 시술 후에 최대 50% 정도에서
재협착(Restenosis)이 발생하기 때문에 이를
해결하기 위한 시술로 풍선 위에 그물망
구조로 된 금속성 재질의 스텐트(Bare
metal stent) 를 탑 재하여 협착부위에
도달시킨 후 팽창시키는 스텐트 삽입술이
널리 시행
스텐트 삽입 풍선도자 팽창 스텐트 고착
관상동맥
혈 전
스텐트
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신생내막 세포의 증식
스텐트의 재질로 주로 사용되고 있는 스테인레스 스틸과 같은 금속은 표면의 이온이 조직과 반응하는 과정에서 혈소판을 활성화하고 혈전형성을 유발하여 신생내막세포의 증식을 초래
스테인레스 스틸 스텐트 신생내막세포가 증식한 스텐트
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혈관 손상
• 스텐트 삽입과정에서 혈관에 손상 유발로 혈전이 생기고 혈관이 급격히 폐쇄
혈전 발생
• 손상된 혈관의 내막과 중막에 혈소판이 점착되어 혈전 발생
재협착
• 스텐트 시술 후 6개월 내에 그 중 약 20%가 신생내막(혈관 평활근)세포의 과다증식으로 재협착
lumen
stent struts
intimal hyperplasia
residual plaque
스텐트 내 재협착 (In-stent restenosis,
ISR)
혈관 재협착
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혈전 형성
• 스텐트 삽입 후에 혈소판이 점착되어 혈전 발생
혈전증
• 스텐트 시술 후 6-12개월 이후에 혈전의 과다 형성으로 혈전증 발생
삽입 후 스텐트 혈전증 LAD artery stenosis
Stent Cordis 3.0x18mm
LAD stent occlusion
Thrombus extraction using catheter
E. thrombus, a mixture of fibrin & platelet aggregates
F. inflammatory cell infiltrate consisting of neutrophils & eosinophils
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Coronary Arterial Stent
Coronary Arterial Stent
Balloon Guide
Catheter
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스텐트 – bare metal stent (BMS) vs. drug-eluting stent (DES)
bare metal stent (BMS): 일반 금속 스텐트(제1세대)
drug-eluting stent (DES): 약물-용출 스텐트(제2세대)
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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)
http://content.nejm.org/content/vol0/issue2007/images/data/NEJMe068306/DC1/NEJM_NEJMe068306v1.swf
From: New Eng J Med 07,356(10)105
9-60
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Restenosis
Neointimal hyperplasia
Recoil and remodeling
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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
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Courtesy of John Ormiston, MD
pathophysiology of stent restenosis
Mechanical – Under expansion or stent malapposition during deployment
– Crack in the polymer during stent expansion
– Stent strut fracture
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Courtesy of John Ormiston, MD
Polymer disruption
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Courtesy of John Ormiston, MD
Main branch ostium after Taxus stent crush and Repeated high pressure kissing post-dilatation
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pre post after 8 mon
Stent cypher 3.0x33.0mm
Stent fracture
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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
pathophysiology of stent restenosis
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Articulation or Gap
Margin
Focal Body
Multifocal
FOCAL
Intra-stent Proliferative
Total Occlusion
DIFFUSE
patterns of ISR
From: Circulation 99,100(18)1872-78 BMJ 03,327(7409)274-9
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관상동맥 혈관성형술의 재협착
40%
26% 20%
4%
1989년 풍선
확장술
1991년 스텐트 시술
1999년 방사선 치료
2001년 약물방출형
스텐트
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국가별 특허동향
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출원인별 특허 동향
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약물방출 스텐트의 시장규모 및 점유율
구 분 현재 시장규모
(2007년) 향후 시장규모
(2010년)
세계시장 규모 70,000 100,000
한국시장 규모 800 1,000
생산기업 국내시장(%) 세계시장(%)
미국 J & J 40 45
미국 BS 40 35
미국 Medtronic 20 20
단위 : 억원
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Wood Mackenzie’s forecast
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Stent 재료 코팅
1. Polymer coating 1) Nondegradable: 상품화 2) Biodegradable: PLLA, PLGA, PCL 3) Hybrid: 비분해성 + 분해성 고분자 4) Biodegradable stent 2. Ceramic coating - SiC, Al2O3, 산화이리듐, TiNOx 3. Metal coating - C-C, DLC, Ti-O, Ti-N, TiN, TaN - Bare metal stent(BMS) 4. Bioactive agents - Peptide, Protein, Cell
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국내외 스텐트 연구동향
1. 관상동맥 재협착 방지용 약물함유 스텐트 개발 동향
: 헤파린, 히루딘, ReoPro, α-lipoic acid, Molsidomine,
Ho-166, 베타/감마선, LacZ, VEGF, CD34 receptor 등
2. 국외의 경우(상품화)
1) Cyper stent (J & J사): Sirolimus (면역억제제) 이용
2) Taxus stent (BS사): Paclitaxel (항증식성 약제) 이용
3) Endeavor stent (Medtronic사): Zotarolimus (면역억제제) 이용
3. 국내의 경우
- 2004년 ㈜휴메드가 Core stent라는 약물 미함유 스텐트 개발
- 재협착 방지용 약물부착 스텐트는 연구한 바 있으나 고기능성
의 생분해성 매트릭스 약물방출 스텐트(DES)의 개발은 전무함
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국내 연구개발의 필요성
- 식생활 문화의 변화 및 생활 환경의 영향으로 심장질환
환자수가 매년 25% 이상 증가 추세
- 스텐트 시장의 성장율은 매년 30% 이상 증가 예상
- 국내 년간 스텐트 시술건수는 약 5만건으로, 약 800억원
이상의 국내시장 형성
- 특히 약물방출 스텐트는 100% 수입함으로 국산화가 시급함
- 기존의 상품화된 약물방출 스텐트의 경우, 고가이고 신생내
막의 과도한 증식(late catch-up) 및 후기혈전증 현상 있음
- 저가이면서 약물의 부작용이 적고 장기간 항증식성 및
항혈전성을 보이는 재협착율이 낮은 생분해성 매트릭스의
다중 약물방출 제어 스텐트의 연구개발이 절실히 필요함
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국내의 연구개발 현황
연구 수행기관 연구개발의 내용 연구개발 수준
전남의대 ReoPro (혈소판 당단백 IIb/IIIa 수용체
차단제) 유리 스텐트 임상연구 및 제품개발 전단계
전남의대 Alpha-lipoic acid (항산화제) 유리
스텐트 시제품개발 단계
연세의대 CD34 receptor 코팅 스텐트 시제품개발 단계
광주과기원 이중 약제 코팅 스텐트 시제품개발 단계
㈜휴메드 Core 스텐트 (bare metal stent) 판매중단 상태
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Conclusions in animal study: Heparin-coated stent Inhibits neointimal cell proliferation within stent compared with non-coated stent
Drug-Coated Stent: Heparin
Bare Stent
Heparin-Coated
Stent
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Control stent ReoPro-coated stent ↓
Anti-thrombotic, anti-proliferative and anti-inflammatory stent
Platelet GP IIb/IIIa Receptor Blocker (ReoPro)-Coated Stent
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Histopathology
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Alpha-lipoic acid
Control
Alpha-Lipoic Acid (ALA) Stent
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BT Biomaterials
Cell Engineering DDS
NT Nanomaterials
Nanofabrication Nanodevices
고령친화형 나노바이오 융합소재
교과부 미래유망 파이오니어사업
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Technical Evolution in Interventional Cardiology
Drug eluting stent
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국외 약물방출 스텐트의 개발현황
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혈관 재협착의 단계
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약물방출스텐트(DES) vs Bare 스텐트(BMS)
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DES Component Interaction
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VSMCs in vascular diseases – atherosclerosis and restenosis after angioplasty – excessive proliferation of VSMCs – migration of VSMCs from tunica media to subendothelial region
vascular smooth muscle cells (VSMCs)
lumen
stent struts
intimal hyperplasia
residual plaque
► In-stent restenosis (ISR) ► Atherosclerosis in coronary artery
narrowed lumen by half
lumen
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스텐트에 사용되는 약물
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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)
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평활근세포 증식을 억제하는 약물의 기전
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inhibition of neointimal formation by sirolimus impregnated stent
From: BMJ 03,327(7409)274-9
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VSMCs vs. drug (PTX & SRL)
From: Nature Med 02,8(11)1249-56
From: J Invasive Cardiol 03,15(3)109-14
Cell cycle & drug
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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.
mTOR (mammalian target
of rapamycin) From: New Eng J Med 06,354(5)483-95
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► 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
platelets
► normal coronary artery
thrombus lumen
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DRUG
POLY
MER
STE
NT
상품화된 약물방출스텐트(DES)
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1. 상품화된 약물방출 스텐트
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Strut Thickness:
81 µm
Polymer Thickness:
7.6 µm
Strut Thickness:
91 µm
Polymer Thickness:
5.3 µm
3.0 mm diameter stents, 500x magnification
Strut Thickness:
97 µm
Polymer Thickness:
16.1 µm
Strut Thickness:
140 µm
Polymer Thickness:
12.6 µm
XIENCE V ENDEAVOR TAXUS® Liberté CYPHER
Strut 모양 및 두께
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3 days
30 days
Control Sirolimus-eluting
Drug Eluting Stent (DES) In-stent Restenosis ↓
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Binary Restenosis in Stent
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Leon B. ACC 2005
Late Stent Thrombus (I)
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Late Stent Thrombus (II)
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Long-Term Clinical Outcomes (I)
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Long-Term Clinical Outcomes (II)
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금속스텐트(BMS) 및 약물방출스텐트(DES)의 비교
혈관 재협착 후기 혈전증
혈전증 사망율
심근경색 재협착율
BMS DES
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다양한 스텐트에서의 약물방출 전략
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FDA/CE/CA
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초음파 노즐을 이용한 스텐트 코팅기술
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bare stent
전기방사장치를 이용한 스텐트 코팅기술
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Layer-by-Layer Assembly
Activated stainless steel substrate
Titania coatedsubstrate
PAA coatedsubstrate
Microparticleadsorption
After annealingthe microparticles
PAA coatedsubstrate
PHEMA coatedsubstrate
Activated stainless steel substrate
Titania coatedsubstrate
PAA coatedsubstrate
Microparticleadsorption
After annealingthe microparticles
PAA coatedsubstrate
PHEMA coatedsubstrate
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Different drugs from different holes
Different drugs from different layers
2. 분해성 고분자 코팅 DES(Costar)
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Why absorbable stents?
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Bio-Absorbable Stent Program
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3. 분해성 고분자 DES(BioMatrix)
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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
Ideal Coronary Stent
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Ideal Scenario for Drug Releasing
Time
Cum
ulat
ive
drug
am
ount
Dexamethasone
Paclitaxel
Estradio
2 week Time
Cum
ulat
ive
drug
am
ount
Dexamethasone
Paclitaxel
Estradio
2 week
l
Sirolimus/
4 week
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뇌졸중(Stroke)
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혈관성형술: 터졌을 경우
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Watch Your Artery!