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：
7226193
负责人：
MARK E MEYERHOFF
金额：
$ 26.5万
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 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7226193
关键词：
Adhesions Animal Model Animals Back Bathing Biomimetic Materials Blood Catalysis Catalytic Domain Catheters Cell Proliferation Chemicals Chemistry Communities Complex Copper Cysteine Devices Diffusion Drug Formulations Endothelial Cells Family suidae Film Generations Glutathione Goals Goretex Hand Implant In Situ In Vitro Inflammatory Response Laboratories Length Life Ligands Link Medical center Modeling Mus Nitric Oxide Nitric Oxide Synthase Nitrites Oryctolagus cuniculus Oxidation-Reduction Patients Physiologic arteriovenous anastomosis Platelet Activation Platelet Inhibitors Polymers Polytetrafluoroethylene Polyurethanes Property Protocols documentation Rate Reaction Research Personnel Shunt Device Site Smooth Muscle Myocytes Solutions Staging Standards of Weights and Measures Stents Stream Surface Sus scrofa Tecoflex Test Result Testing Thrombosis Thrombus Time Toxic effect Universities Vascular Graft Vertebral column adduct ascorbate base biomaterial compatibility copper(I)-thiolate cyclen desire diazeniumdiolate hazard implantable device improved in vivo in vivo Model novel novel strategies oxidation platelet adhesion inhibitor programs sensor

项目摘要

DESCRIPTION (provided by applicant): Studies aimed at preparing and testing the in vivo thromboresistivity/biocompatibility of novel polymeric materials capable of biomimetically generating nitric oxide (NO) from endogenous nitrosothiol species in blood are proposed. It has been discovered recently in these laboratories that organic polymers doped with certain lipophilic Cu(II)-ligand complexes generate, via a catalytic reaction, physiologically relevant levels of NO at their interface, when bathed in solutions containing nitrite and/or various nitrosothiols. Nitric oxide is known to be a potent, naturally occurring inhibitor of platelet adhesion and activation as well as smooth muscle cell proliferation. Ongoing studies in the Pi's laboratories have already demonstrated the greatly enhanced thromboresisitivity of synthetic polymers that liberate NO from novel NO adducts (diazeniumdiolates) with fluxes = to normal endothelial cells (1 x 10-10 mol/cm2min). However, use of existing NO release polymers for long-term biomedical implants (e.g., as coatings on shunts, grafts, stents, etc.) is limited by the relatively small reservoir of NO adduct that can be loaded within thin polymeric coatings. In contrast, normal blood already possesses a substantial reservoir of NO precursors in the form of nitrosothiols; formed from the oxidation of endogenous NO produced by nitric oxide synthase (NOS). It is believed that these species can be used to generate locally enhanced NO levels for extended time periods in vivo at the interface of polymers possessing Cu(II) complexes (cyclen derivatives) either doped within or covalently linked to certain biomedical grade polyurethane (PU) polymers. Complexed copper(II) can be readily reduced to Cu(I) by thiolates (e.g., glutathione, cysteine, etc.) and ascorbate in blood. The Cu(I) is then capable of reducing nitrosothiols back to NO. The principal objectives of this program will be to prepare and examine a variety of Cu(II/I)-ligand/polyurethane materials that can carry out this novel redox chemistry and further test the resulting materials for toxicity/pyrogenicity/inflammatory response in small animals, as well as thromboresistivity/biocompatibility in a longer term (28 d) implant model for arteriovenous shunts (in pigs) by co-investigators at the University of Cincinnati Medical Center. If the proposed in vivo studies with PU polymers containing Cu(II) complexes yield the expected evidence of reduced thrombosis (vs. control coatings) due to local NO generation, it is anticipated that these new biomimetic materials would have immediate applications for preparing/coating a host of biomedical implants.

描述（由申请人提供）：提出了旨在制备和测试新型聚合物材料的体内抗血栓性/生物相容性的研究，该新型聚合物材料能够从血液中的内源性亚硝基硫醇物种仿生地产生一氧化氮（NO）。最近在这些实验室中发现，掺杂有某些亲脂性 Cu(II)-配体复合物的有机聚合物在浸泡在含有亚硝酸盐和/或各种亚硝基硫醇的溶液中时，通过催化反应在其界面处产生生理相关水平的 NO。已知一氧化氮是血小板粘附和活化以及平滑肌细胞增殖的有效天然抑制剂。 Pi实验室正在进行的研究已经证明，合成聚合物的血栓抵抗力大大增强，可以从新型NO加合物（二醇二氮烯鎓）中释放出NO，并流入正常内皮细胞（1 x 10-10 mol/cm2min）。然而，现有的 NO 释放聚合物用于长期生物医学植入物（例如，作为分流器、移植物、支架等上的涂层）的使用受到可装载在薄聚合物涂层内的相对较小的 NO 加合物储库的限制。相比之下，正常血液已经拥有大量以亚硝基硫醇形式存在的一氧化氮前体。由一氧化氮合酶（NOS）氧化产生的内源性NO形成。据信，这些物质可用于在体内长时间内在具有 Cu(II) 络合物（cyclen 衍生物）的聚合物界面处产生局部增强的 NO 水平，该络合物掺杂在某些生物医学级聚氨酯 (PU) 中或与某些生物医学级聚氨酯 (PU) 共价连接。聚合物。络合的铜 (II) 很容易被血液中的硫醇盐（例如谷胱甘肽、半胱氨酸等）和抗坏血酸还原为 Cu(I)。然后，Cu(I) 能够将亚硝基硫醇还原回 NO。该计划的主要目标是制备和检查各种可以进行这种新型氧化还原化学反应的 Cu(II/I)-配体/聚氨酯材料，并进一步测试所得材料在小动物中的毒性/热原性/炎症反应以及辛辛那提大学医学中心联合研究人员在动静脉分流术（猪）的长期（28 天）植入模型中的抗血栓性/生物相容性。如果所提出的含有 Cu(II) 复合物的 PU 聚合物的体内研究产生了因局部 NO 生成而减少血栓形成的预期证据（与对照涂层相比），则预计这些新的仿生材料将立即应用于制备/涂层大量生物医学植入物。