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Biologically Selective Drug-Eluting Stent

生物选择性药物洗脱支架

基本信息

批准号：
10428372
负责人：
WILLIAM SALTZMAN
金额：
$ 65.24万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428372
关键词：
Anticoagulation Apoptosis Aspirin Binding Bioreactors Blood Vessels Blood flow CD95 Antigens Cell Death Cell Proliferation Cell Survival Cell surface Cellular Metabolic Process Cessation of life Clinical Complex Computer Models Coronary Coronary Arteriosclerosis Coronary artery Diffusion Dose Effectiveness Endothelial Cells Endothelium Ethylenes Family suidae Goals Growth Hemorrhage Hyperplasia In Vitro Inhibition of Apoptosis Injury Investigation Kinetics Ligands Measures Mediating Metals Modeling Myocardial Infarction Nitric Oxide Nitric Oxide Donors Oryctolagus cuniculus Patient risk Patient-Focused Outcomes Patients Perfusion Pharmaceutical Preparations Platelet Activation Plavix Polymers Receptor Cell Resistance Risk SDZ RAD Signal Transduction Sirolimus Smooth Muscle Myocytes Stenosis Stents Thrombosis Treatment Failure Tumor Necrosis Factor Ligand Superfamily Member 6 Work cell growth cell injury clopidogrel combat comparative copolymer design efficacy evaluation efficacy testing iliac artery improved inhibitor injured mTOR Inhibitor mTOR inhibition metallicity next generation novel novel drug combination patient safety porcine model pressure prevent receptor response restenosis standard of care stroke risk thrombotic vinyl acetate

项目摘要

ABSTRACT: Metallic stents are often used to restore blood flow in stenotic coronary arteries. Bare metal stent deployment under high pressure leads to vascular wall and smooth muscle cell (SMC) damage, with subsequent SMC proliferation, neointimal hyperplasia and treatment failure. To combat in-stent restenosis, drug-eluting stents delivering mTOR inhibitors such as sirolimus or everolimus, have become standard of care for coronary stenting. However, these stents typically require long-term dual anti-platelet therapy with aspirin and Plavix (clopidogrel), to prevent thrombotic occlusion of the stented arterial segment. This is due to the relatively non-specific action of mTOR inhibitors: endothelium does not efficiently recover after injury from DESs, rendering the stent struts and arterial lumen vulnerable to platelet activation and thrombosis. Unfortunately, long-term dual anti-platelet therapy leads to increased bleeding/stroke risk and, paradoxically, to increased risk of myocardial infarction. Therefore, finding an alternative drug elution strategy, that would spare endothelium while preventing re-stenosis, would be hugely beneficial to patients with coronary artery disease. Nitric oxide (NO⋅)-releasing stents, which are still under investigation, are attractive because their mechanism of action inhibits growth of SMC but not EC, and because NO⋅ has a very short diffusion distance, thereby limiting its effects to a localized region. However, to date no stent has succeeded in delivering sufficient doses of NO⋅ to reliably inhibit SMC growth. Since NO⋅ is a selective inhibitor of SMC, how can we increase its potency? For this work, we leverage the fact that NO⋅ increases Fas receptors on the SMC surface, while not having a similar effect on EC. Fas a death-inducing signaling complex upon binding to Fas ligand (FasL). Fas-mediated apoptosis of SMCs is known to decrease hyperplasia significantly in injured vessels. Indeed, the Fas-FasL interaction that kills SMC may create an even more potent DES than do mTOR inhibitors, since mTOR inhibition can arrest cell growth but may not cause apoptosis. Clinically, DES with better SMC inhibition are sorely needed, since current DES still suffer from significant rates of in-stent restenosis after 5 years. Since SMCs are significantly more sensitive to Fas-FasL interaction than are EC, we hypothesize that delivery of both FasL and NO by a next generation stent has the potential to potently block intimal hyperplasia, while retaining EC viability, more efficiently than other DES. This, in turn, could provide a way to shorten post-stent anticoagulation therapy and inhibit in-stent restenosis, thereby decreasing patient risk following coronary stent placement.

文摘:

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Pulmonary Vascular Model From Endothelialized Whole Organ Scaffolds.

DOI：
10.3389/fbioe.2021.760309
发表时间：
2021
期刊：
Frontiers in bioengineering and biotechnology
影响因子：
5.7
作者：
Yuan Y;Leiby KL;Greaney AM;Raredon MSB;Qian H;Schupp JC;Engler AJ;Baevova P;Adams TS;Kural MH;Wang J;Obata T;Yoder MC;Kaminski N;Niklason LE
通讯作者：
Niklason LE

Challenges and novel therapies for vascular access in haemodialysis.