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)：一种新型的磺化聚合物具有独特的化学可裁剪特性和加工特性，已显示出作为抗血栓表面的巨大前景，并已被证明是中性粒细胞衍生的蛋白酶的有效抑制剂。建议进行第一阶段SBIR测试，以研究该聚合物作为血液接触生物材料基材的可裁剪界面涂层。这项拟议研究的主要具体目标包括制造和研究几种磺化聚合物的化学修饰版本，不仅可以最大限度地减少血小板的黏附和激活，还可以促进健康内皮细胞的剪切稳定黏附和增殖。这种创新和合理的方法用于生物工程、仿生和抗血栓的血液接触生物材料表面，是基于几项不同的研究，这些研究揭示了这种聚合物具有良好的生物应用属性。这一阶段SBIR的最终目标是开发和识别一种内在的非血栓形成、内皮化和抗炎的水凝胶表面，应用于各种救生心血管设备。项目简介：心血管疾病是美国男性和女性死亡和残疾的主要原因，目前影响着7000多万美国人。总体而言，每年有600多万人因治疗心血管疾病而住院。因此，心血管疾病对我国医疗保健系统的经济影响持续增长，特别是随着人口老龄化。2006年心脏病和中风的成本(美国)超过4000亿美元，其中包括医疗成本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下，动脉粥样硬化性外周动脉疾病(PAD)、冠状动脉疾病(CAD)和脑血管疾病都以血管狭窄(狭窄)和/或闭塞为主要事件，原因是血栓形成的失调以及与之相关的炎症事件，包括平滑肌细胞(SMC)的浸润、新生血管内膜增殖和适应性不良的血管重构。狭窄和闭塞导致顺行血流量减少/丧失。对于PAD，这可能会导致周围肢体的跛行和组织病变，而对于CAD，这可能会导致缺血，通常是致命的心肌梗死，对于脑血管情况，这可能会导致中风。介入血管内和/或外科治疗以清除血栓和重建血管血流对于这些疾病的临床治疗是必要的。血管内治疗包括机械方法，如导管介导的血管成形术、冷冻成形术和血管内膜切开术，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植入术相结合。近年来，药物洗脱支架(DES)得到了发展，在金属支架表面涂覆一层载药聚合物基质，用于治疗药物的持续释放。手术方法包括搭桥术，其中许多是由合成聚合物(例如ePTFE)制成的。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、心室辅助设备和全人工心脏。所有上述设备都依赖于与流动的血液接触的合成材料。这些材料容易导致蛋白质(如纤维蛋白原、纤维蛋白)快速沉积、变性以及随后的血小板黏附和激活，可能导致凝块形成和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，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抗凝治疗，以防止中风和/或设备故障。因此，如上所述，设备上的抗蛋白质和抗血小板血液接触接口可以改善患者的预后，降低总体护理成本。在这一应用中，一种设计新颖的界面材料利用了一种新型聚合物生物材料的功能可裁剪性，是我们研究的主题。该聚合物是一种磺化嵌段共聚物，它不会导致血栓形成，并且可以很容易地进行修饰，以包括一种或多种生物功能治疗剂和/或细胞信号分子，作为一种引导对设计者表面的“愈合反应”的手段。我们预计，由这些研究产生的设计者表面将为接触血液的生物材料提供一种极其有效的表面改性处理，与目前的治疗方案相比，成本更低。