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：
7644722
负责人：
MARK E MEYERHOFF
金额：
$ 34.05万
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 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644722
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 Phase I Clinical Trials Platelet Activation Poisoning Polymer Chemistry Polymers Polytetrafluoroethylene Polyurethanes Preparation Process Production Property Protocols documentation Reducing Agents Research Risk Site Smooth Muscle Myocytes Solutions Staging Stainless Steel Stents Structure Sulfhydryl Compounds Surface Testing Thrombosis Thrombus Time 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 polyion prevent programs public health relevance 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）：建议继续进行研究，旨在制备、表征和测试能够从血液中的内源性 S-亚硝基硫醇（RSNO）物质催化生成一氧化氮（NO）的新型聚合物材料的体内抗血栓性/生物相容性。第一阶段研究的结果表明，用特定的 Cu(II) 配合物以及有机硒 (RSe) 物质改性的聚合物在浸泡在含有 5M 水平 RSNO 的溶液中时能够产生生理相关水平的 NO，RSNO 的浓度发现在新鲜血液中。此外，使用相同的催化聚合物化学物质设计新型电化学 RSNO 传感器已经生产出了能够响应全血中 RSNO 浓度的装置，进一步证明了这些材料在与血液接触时产生 NO 的能力。众所周知，一氧化氮是血小板活化和粘附以及平滑肌细胞增殖的有效抑制剂。因此，在聚合物/血液界面局部生成NO应显着降低聚合物涂层医疗器械表面形成血栓的风险，包括支架、血管移植物、植入导管和传感器等。正在进行的努力（包括阶段性结果）该项目和其他研究的我）已经清楚地表明，早期开发的 NO 释放聚合物以及较新的 NO 生成聚合物确实可以抑制植入装置表面的血栓形成。我们第二阶段的目标现在将集中在：1）进一步合成一系列以共价连接的 Cu(II)-cyclen 配合物作为催化位点的生物医学级聚氨酯 (PU)，以及制备/评估嵌入 Cuo 微米/纳米颗粒的 PU也可以从 RSNO 生成 NO； 2) 开发将 RSe 催化位点附着到 PU 上的方法，并研究一种新的逐层 (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（包括钛和不锈钢）； 3) 研究 (1) 和 (2) 中设计的聚合物涂层在与各种 RSNO 物质接触时催化产生 NO 的能力，并评估催化 NO 产生随时间的变化（由于催化位点浸出、中毒）， ETC。）; 4) 使用标准 ISO 协议对小动物（小鼠和兔子）检查新型 Cu 和 RSe 基涂层的毒性； 5) 在辛辛那提大学医学院的合作者开发的猪外周血管移植动物模型中测试最有前途的新型 NO 生成涂层的长期体内抗血栓能力。我们预计本申请中描述的研究将产生各种新型仿生材料，这些材料将立即应用于制备/涂覆大量医疗植入物，以降低体内血栓形成的风险。公共健康相关性：生物医学界非常需要新型聚合物涂层，这些涂层可以增强各种医疗设备的生物相容性和功能，包括导管、血管移植物、支架、体内化学传感器、体外回路等。，这些血液接触装置的表面存在危及生命的血栓形成的持续风险，这对接受此类干预的患者仍然是严重危害。拟议的研究将产生立竿见影的影响，为设备制造商提供新的涂层，该涂层可以通过内源性 S-亚硝基硫醇物种自发生成一氧化氮（一种有效的抗血小板剂）来防止医疗植入物表面形成血栓。它已经存在于血液中。