Peptide-Modified Sulfonated Styrene Block Copolymers for Vascular Applications

用于血管应用的肽改性磺化苯乙烯嵌段共聚物

• 批准号: 7393608
• 负责人: DAVID J VACHON
• 金额: $ 16.15万
• 依托单位: AEGIS BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393608
• 关键词: Accounting; Adhesions; Aerosols; Affect; Agar; Age; Alkanesulfonates; American; Ammonium; Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulation; Arginine; Arteries; Atherosclerosis; Atomic Force Microscopy; Binding; Biocompatible Materials; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Biomimetics; Blood; Blood Platelets; Blood Vessels; Blood flow; Bypass; Cardiovascular Diseases; Cardiovascular system; Caring; Catheters; Cause of Death; Cell Adhesion; Cell Survival; Cerebrovascular Disorders; Cessation of life; Characteristics; Chemicals; Chemistry; Clinical Management; Coagulation Process; Combined Modality Therapy; Construction Materials; Coronary Arteriosclerosis; Data; Deposition; Development; Devices; Disease; Drug Formulations; Economics; Elastases; Electron Microscopy; Endopeptidases; Endothelial Cells; Equipment Malfunction; Evaluation Studies; Event; Expenditure; Family; Fibrin; Fibrinogen; Fibroblasts; Film; Future; Goals; Health Care Costs; Healthcare Systems; Heart Diseases; High Pressure Liquid Chromatography; Hospitalization; Human; Hydrogels; In Vitro; Infiltration; Inflammatory; Intention; Investigation; Ion Exchange; Ions; Ischemia; Kidney; Lacquer; Lead; Leukocyte Elastase; Ligand Binding; Limb structure; Mechanics; Mediating; Metals; Methods; Modification; Morbidity - disease rate; Myocardial Infarction; Operative Surgical Procedures; Outcome; P-Selectin; Pacemakers; Pancreatic Elastase; Parents; Patients; Peptide Hydrolases; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Phase; Platelet Activation; Play; Polymers; Population; Positron-Emission Tomography; Preparation; Process; Productivity; Property; Proteins; Research; Resistance; Role; Scanning; Signal Transduction; Signaling Molecule; Site; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Sodium Chloride; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Stainless Steel; Stenosis; Stents; Sterility; Sterilization for infection control; Stroke; Stroke prevention; Surface; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Thrombus; Time; Tissue Engineering; Tissues; Treatment Protocols; Urethane; Vascular remodeling; Vertebral column; Water; Woman; base; biomaterial compatibility; blood treatment; cerebrovascular; claudication; copolymer; cost; cytotoxicity; design; disability; drug development; hydrophilicity; improved; in vivo; inhibitor/antagonist; innovation; insight; isobutylene; men; neutrophil; novel; polycarbonate; pulmonary artery endothelial cell; response; scaffold; total artificial heart; ventricular assist device

DESCRIPTION (provided by applicant): A novel sulfonated polymer with unique chemically tailorable properties and processing characteristics has shown considerable promise as a thrombo- resistant surface and has been proven to be effective inhibitor against neutrophil- derived proteases. A phase 1 SBIR testing is proposed to investigate this polymer as a tailorable interface coating for blood-contact biomaterial substrates. The major specific aims of the proposed research involves the fabrication and investigation of several chemically modified versions of the sulfonated polymer, not only to minimize platelet adhesion and activation, but also, to encourage the shear-stable attachment and proliferation of healthy endothelial cells. This innovative and rational approach to a bioengineered, biomimetic, & thromboresistant blood contacting biomaterial surface is founded on the basis of several different studies that have revealed promising bioapplicable attributes of this polymer. The end-goal of this Phase 1 SBIR is to develop and identify an inherently non-thrombogenic, endothelialized and antiinflammatory hydrogel surface with application to a wide array of lifesaving cardiovascular devices.Project Narrative: Cardiovascular disease is the leading cause of death and disability for both men and women in the U.S., affecting more than 70 million Americans at present. Overall, more than 6 million hospitalizations occur each year for treatment of cardiovascular diseases. Consequently, the economic impact of cardiovascular diseases on our nation's health care system continues to grow, especially as the population ages. The cost of heart disease and stroke in 2006 (U.S.) was greater than $400 billion, when healthcare cost expenditures and lost productivity from death and disability are accounted for. Under the umbrella of cardiovascular diseases, atherosclerosis-induced peripheral artery disease (PAD), coronary artery disease (CAD) and cerebrovascular disease all suffer from the primary event of vessel narrowing (stenosis) and/or occlusion due to dysregulated formation of clots and associated inflammatory events involving smooth muscle cell (SMC) infiltration, neointimal proliferation and maladaptive vascular remodeling. Stenosis and occlusion lead to reduction/loss of antegrade blood flow. For PAD, this may lead to claudication and tissue morbidity of peripheral extremities, while for CAD this can lead to ischemia and often fatal myocardial infarction and, for cerebrovascular situations, this may lead to stroke. Interventional endovascular and/or surgical treatment to remove thrombus and to reestablish vascular flow is necessary for clinical management of these diseases. Endovascular treatments involve mechanical approaches like catheter-mediated angioplasty, cryoplasty and enderactomy and, pharmacotherapeutic approaches like transcatheter delivery of thrombolytic, anti-platelet and anti-proliferative drugs. Often these approaches are combined with stenting. Recent years have seen the development of drug eluting stents (DES) where the metal stent surface is coated with a drug-loaded polymer matrix for sustained release of therapeutic agents. Surgical approaches involve bypass grafts, many of which are made of synthetic polymers (e.g. ePTFE). For other cardiovascular diseases biomaterials also play an important role. Devices including pacemakers, ventricular assist devices, and the total artificial heart are used. All of the aforementioned devices depend upon synthetic materials that come into contact with flowing blood. These materials are prone to rapid protein (e.g. fibrinogen, fibrin) deposition, denaturation and subsequent adhesion and activation of blood platelets potentially leading to clot formation and the subsequent activation of coagulation and inflammatory events. In turn, material performance can be compromised necessitating recurring endovascular or surgical procedures. As such, these patients generally require perpetual anticoagulation therapy in order to prevent stroke and/or device failure. Thus, protein- and platelet-resistant blood-contacting interfaces on devices as mentioned above can improve patient outcomes and reduce the overall cost of care. In this application, an interface material of novel design that leverages the functional tailorability of a novel polymeric biomaterial is the subject of our investigation. The polymer is a sulfonated block copolymer which is non-thrombogenic and can be readily modified to include one or more biofunctional therapeutic agents and/or cell-signaling molecules as a means of guiding the `healing response' to the designer surface. We anticipate that the designer surfaces resulting from these studies will provide an extremely efficient surface-modification treatment for blood-contacting biomaterials, at a reduced cost when compared to current treatment regimens.

描述（由申请人提供）：一种具有独特的化学可定制特性和加工特性的新型磺化聚合物已显示出作为抗血栓表面的巨大前景，并已被证明是针对中性粒细胞衍生蛋白酶的有效抑制剂。建议进行一期 SBIR 测试，以研究这种聚合物作为血液接触生物材料基材的可定制界面涂层。拟议研究的主要具体目标涉及磺化聚合物的几种化学改性版本的制造和研究，不仅是为了最大限度地减少血小板粘附和活化，而且是为了促进健康内皮细胞的剪切稳定附着和增殖。这种创新且合理的生物工程、仿生和抗血栓血液接触生物材料表面方法是建立在多项不同研究的基础上的，这些研究揭示了这种聚合物有前景的生物应用属性。第一阶段 SBIR 的最终目标是开发和鉴定一种本质上不形成血栓、内皮化和抗炎的水凝胶表面，并将其应用于各种救生心血管设备。项目叙述：心血管疾病是导致死亡和残疾的主要原因。在美国，男性和女性都受到影响，目前影响着超过 7000 万美国人。总体而言，每年有超过 600 万人因心血管疾病住院治疗。因此，心血管疾病对我国医疗保健系统的经济影响持续增加，特别是随着人口老龄化。 2006 年（美国）心脏病和中风造成的损失超过 4000 亿美元，其中包括医疗费用支出以及死亡和残疾造成的生产力损失。在心血管疾病的范畴内，动脉粥样硬化引起的外周动脉疾病（PAD）、冠状动脉疾病（CAD）和脑血管疾病都因血栓形成失调和相关的血管狭窄（狭窄）和/或闭塞而遭受血管狭窄（狭窄）和/或闭塞的主要事件的影响。炎症事件涉及平滑肌细胞（SMC）浸润、新内膜增殖和适应不良的血管重塑。狭窄和闭塞导致顺行血流减少/丧失。对于外周动脉疾病（PAD），这可能导致跛行和周围四肢的组织发病，而对于冠心病（CAD），这可能导致缺血，并且常常导致致命的心肌梗塞，对于脑血管情况，这可能导致中风。介入性血管内和/或手术治疗以去除血栓并重建血管血流对于这些疾病的临床治疗是必要的。血管内治疗涉及机械方法，如导管介导的血管成形术、冷冻成形术和内皮切除术，以及药物治疗方法，如经导管输送溶栓、抗血小板和抗增殖药物。这些方法通常与支架置入术相结合。近年来，药物洗脱支架（DES）得到了发展，其中金属支架表面涂有载药聚合物基质，用于持续释放治疗剂。手术方法涉及旁路移植，其中许多由合成聚合物（例如 ePTFE）制成。对于其他心血管疾病生物材料也发挥着重要作用。使用的设备包括起搏器、心室辅助装置和全人工心脏。所有上述装置都依赖于与流动的血液接触的合成材料。这些材料容易发生快速的蛋白质（例如纤维蛋白原、纤维蛋白）沉积、变性以及随后的血小板粘附和激活，可能导致凝块形成以及随后的凝血和炎症事件的激活。反过来，材料性能可能会受到影响，从而需要反复进行血管内或外科手术。因此，这些患者通常需要永久性抗凝治疗，以预防中风和/或装置故障。因此，上述设备上的抗蛋白质和血小板血液接触界面可以改善患者的治疗效果并降低总体护理成本。在此应用中，我们研究的主题是利用新型聚合物生物材料的功能可定制性的新颖设计的界面材料。该聚合物是磺化嵌段共聚物，其不形成血栓，并且可以容易地进行修饰以包含一种或多种生物功能治疗剂和/或细胞信号分子，作为引导设计表面“愈合反应”的手段。我们预计，这些研究产生的设计表面将为血液接触生物材料提供极其有效的表面改性处理，与当前的治疗方案相比，成本更低。