Thromboresistant Polymers Via Catalytic Generation of NO

通过催化生成 NO 的抗血栓聚合物

基本信息

批准号：
8241135
负责人：
MARK E MEYERHOFF
金额：
$ 31.92万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241135
关键词：
Adhesions Animal Model Animals Bathing Biomimetic Materials Blood Blood Platelets Catalytic Domain Catheters Cell Proliferation Chemicals Chemistry Coagulation Process Communities Complex Copper Deposition Devices Endothelium Exhibits Family Family suidae Generations Goals Hand Health Heating Human Implant In Vitro Inflammatory Response Intervention Ions Lead Life Ligands Light Manufacturer Name Medical Device Metals Methods Modeling Mus Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Oryctolagus cuniculus Patients Performance Peripheral Phase Platelet Activation Poisoning Polymer Chemistry Polymers Polytetrafluoroethylene Polyurethanes Preparation Process Production Property Protocols documentation Reducing Agents Research Risk S-Nitrosothiols Site Smooth Muscle Myocytes Solutions Staging Stainless Steel Stents Structure Sulfhydryl Compounds Surface Testing Thrombosis Thrombus Time Titania Titanium Toxic effect Universities Vascular Graft Whole Blood base biomaterial compatibility catalyst cyclen diazeniumdiolate hazard implantable device implantation improved in vitro testing in vivo inhibitor/antagonist medical implant medical schools nanoparticle novel phase 1 study polyion prevent programs sensor

项目摘要

DESCRIPTION (provided by applicant): Continued studies aimed at preparing, characterizing and testing the in vivo thromboresistivity/biocompatibility of novel polymeric materials capable of catalytically generating nitric oxide (NO) from endogenous S- nitrosothiol (RSNO) species in blood are proposed. Results from Phase I studies have demonstrated that polymers modified with given Cu(II)-complexes as well as organoselenium (RSe) species are capable of generating physiologically relevant levels of NO when bathed in solutions containing 5M levels of RSNOs, the concentrations of RSNOs found in fresh blood. In addition, use of the same catalytic polymer chemistries to devise novel electrochemical RSNO sensors has yielded devices that respond to RSNO concentrations in whole blood, further proving the capability of these materials for generating NO when in contact with blood. Nitric oxide is well known to be a potent inhibitor of platelet activation and adhesion as well as smooth muscle cell proliferation. Hence, the local generation of NO at a polymer/blood interface should significantly reduce the risk of thrombus formation on the surface of polymer coated medical devices, including stents, vascular grafts, implanted catheters and sensors, etc. Ongoing efforts (including results from Phase I of this project and other studies) have shown clearly that NO release polymers developed earlier as well as the newer NO generating polymers do inhibit thrombus formation on the surface of implanted devices. Our goals for Phase II will now focus on: 1) further synthesizing an array of biomedical grade polyurethanes (PUs) with covalently attached Cu(II)-cyclen complexes as catalytic sites, as well as preparing/evaluating PUs with embedded Cuo micro/nanoparticles that can also generate NO from RSNOs; 2) developing methods to attach RSe catalytic sites to PUs and also examining a new Layer-by-Layer (LbL) polyelectrolyte deposition method to immobilize the RSe sites on any biomedical polymer or device surface (including titanium and stainless steel); 3) studying the ability of the polymer coatings devised in (1) and (2) for producing NO catalytically when in contact with various RSNOs species, and assessing changes in catalytic NO generation as a function of time (due to catalytic site leaching, poisoning, etc.); 4) examining the toxicity of the new Cu and RSe-based coatings using standard ISO protocols with small animals (mice and rabbits); and 5) testing the longer-term in vivo thromboresistance of the most promising new NO generating coatings in porcine animal model of peripheral vascular grafts developed by collaborators at the University of Cincinnati Medical School. We anticipate that the studies described in this application will lead to a variety of novel biomimetic materials that will have immediate applications for preparing/coating a host of medical implants to reduce the risk of in vivo thrombosis. PUBLIC HEALTH RELEVANCE: There is a great need in the biomedical community for novel polymeric coatings that can enhance the biocompatibility and functionality of a wide range of medical devices including catheters, vascular grafts, stents, in vivo chemical sensors, extracorporeal circuits, etc. Indeed, there exists a lingering risk of life- threatening thrombosis on the surface of these blood-contacting devices that continues to be a serious hazard to patients who receive such interventions. The proposed research will have an immediate impact by providing device manufacturers with new coatings that can prevent clots from forming on the surface of medical implants via spontaneous generation of nitric oxide, a potent anti-platelet agent, from a pool of endogenous S-nitrosothiol species that already exists in blood.

描述（由申请人提供）：旨在准备，表征和测试的持续研究，以催生催化产生血液中硝基硫醇（RSNO）的新型聚合物材料的体内动力孔/生物相容性。第一阶段研究的结果表明，用给定的Cu（II）复合物以及有机凝胶（RSE）物种修饰的聚合物能够在含有5M水平RSNO的溶液中沐浴的生理相关水平的NO水平，这些水平含有5M水平的RSNO，在新鲜血液中发现了RSNO的浓度。此外，使用相同的催化聚合物化学设计新型电化学RSNO传感器已经产生了对全血的RSNO浓度响应的设备，进一步证明了这些材料在与血液接触时产生NO的能力。一氧化氮众所周知是血小板激活和粘附以及平滑肌细胞增殖的有效抑制剂。因此，聚合物/血液接口处的本地发电应大大降低聚合物涂层的医疗设备表面上血栓形成的风险植入设备。我们的第二阶段目标现在将重点放在：1）进一步合成一系列生物医学级聚氨酯（PU），将共同附着的Cu（II） - 环元络合物作为催化位点，并用嵌入的CuO Micro/Nanoparticles制备/评估PUS，这些pus也可以从RSNOS中产生，也可以从RSNOS中产生pus; 2）开发将RSE催化位点附加到脓液上的方法，并检查新的逐层（LBL）聚电解质沉积方法，以将RSE位点固定在任何生物医学聚合物或设备表面（包括钛和不脏钢）上； 3）研究在（1）和（2）中设计的聚合物涂层在与各种RSNOS物种接触时不产生催化性的能力，并评估催化无产生的变化随时间的函数（由于催化部位浸出，中毒等）； 4）使用具有小动物（小鼠和兔子）的标准ISO方案检查新的CU和RSE涂料的毒性； 5）测试辛辛那提大学医学院合作者开发的最有希望的新的无产生涂料的最有前途的新无涂料模型中最有希望的新的无产生涂料的长期体内动力孔。我们预计，本应用中描述的研究将导致各种新型的仿生材料，这些材料将立即应用/涂层一系列医疗植入物，以降低体内血栓形成的风险。公共卫生相关性：生物医学界非常需要新型聚合涂层，可以增强各种医疗设备的生物兼容性和功能性，包括导管，血管移植物，体内化学传感器，体内化学传感器，体内化学传感器，体外循环等。的确，存在着一种危险的危险性，这些危险范围内的危险范围是这些危险的危险性，这些危险范围是这些危险的危险性，这些危险范围在这些危险中，这些危险范围在这些危险中，这些危险范围在这些危险中的危险性，这些势力是造成的，这是造成的，这些危险性在这些危险中，这些潮流的变化是造成的。谁接受这种干预措施。拟议的研究将通过为设备制造商提供新的涂料，从而防止凝块通过自发产生的氮氧化物（一种有效的抗平台剂）从已经存在于血液中的内源性S-硝基硫醇物种中，从而防止凝块在医疗植入物表面形成血液。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

External beam radiation therapy for PTFE dialysis grafts: a pilot study.

PTFE 透析移植物的外束放射治疗：一项试点研究。

DOI：
10.5301/jva.5000052
发表时间：
2012
期刊：
The journal of vascular access
影响因子：
0
作者：
Roy-Chaudhury,Prabir;Duncan,HeatherJ;Zuckerman,Darryl;Faiyaz,Rashid;Munda,Rino;Kant,Shashi;Kelly,Burnett;Narayana,Ashwatha
通讯作者：
Narayana,Ashwatha

Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis.

DOI：
10.1053/j.ackd.2009.06.009
发表时间：
2009-09
期刊：
Advances in chronic kidney disease
影响因子：
2.9
作者：
Lee T;Roy-Chaudhury P
通讯作者：
Roy-Chaudhury P

Of veins, valves, and vascular access!

静脉、瓣膜和血管通路！

DOI：
10.1038/ki.2012.316
发表时间：
2012
期刊：
Kidney international
影响因子：
19.6
作者：
Roy-Chaudhury,Prabir;Chan,Jenq-Shyong;Lee,Timmy;Mistry,Meenakshi;Campos,Begoña;Wang,Yang;Munda,Rino
通讯作者：
Munda,Rino

Reversible detection of heparin and other polyanions by pulsed chronopotentiometric polymer membrane electrode.