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定制特性和加工特性的新型磺化聚合物，已显示出巨大的希望，作为一种耐血管性的表面，已被证明是有效的抑制剂，以抗性粒细胞衍生的蛋白酶。提出了第1期SBIR测试，以研究该聚合物作为血液接触生物材料底物的可调整界面涂料。提出的研究的主要特定目的是制造和研究几种化学修饰的磺化聚合物，不仅是为了最大程度地减少血小板的粘附和激活，还鼓励剪切稳定的附着和健康内皮细胞的增殖。这种创新和合理的方法是基于几项不同的研究，揭示了该聚合物的有希望的生物申请属性，建立了生物工程，仿生和血栓接触的生物材料表面。该第1阶段SBIR的最终目标是开发和确定固有的非血栓形成，内皮化和抗炎性水凝胶表面，并应用于广泛的救生心血管设备。心血管叙事：心血管疾病是导致美国和女性在美国的死亡和残疾人的主要原因，在美国的男性和女性中都有比700万千万的美国人的影响。总体而言，每年有超过600万次住院治疗心血管疾病。因此，心血管疾病对我们国家医疗保健系统的经济影响不断增长，尤其是随着人口年龄的增长。当医疗保健成本支出和死亡和残疾的生产力下降时，2006年（美国）心脏病和中风的成本大于4000亿美元。在心血管疾病的伞下，动脉粥样硬化引起的周围动脉疾病（PAD），冠状动脉疾病（CAD）和脑血管疾病均遭受血管变窄（狭窄）的主要事件（狭窄）和/或闭塞，这引起了垂直肌肉的阳离子，并相关的肿胀型细胞（Smc）置于炎症性阳性阳性（Smc），并具有相关性的延伸（Smc）。血管重塑。狭窄和闭塞导致降低/流动血流的损失。对于PAD来说，这可能导致外围肢体的laurauration和组织发病率，而对于CAD，这可能会导致缺血，并且通常会导致致命的心肌梗塞，并且对于脑血管情况，这可能会导致中风。介入的血管内和/或手术治疗以去除血栓并重新建立血管流量，对于这些疾病的临床管理是必要的。血管内治疗涉及机械方法，例如导管介导的血管成形术，冷冻术和内部术以及药物治疗方法，例如经导管递送溶栓，抗血域和抗增殖药物。这些方法通常与支架结合在一起。近年来，有药物洗脱支架（DES）的发展，其中金属支架表面涂有载有药物的聚合物基质，以持续释放治疗剂。手术方法涉及旁路移植物，其中许多是由合成聚合物制成的（例如EPTFE）。对于其他心血管疾病，生物材料也起着重要作用。使用了包括起搏器，心室辅助设备和人造心脏的设备。上述所有设备都取决于与流血接触的合成材料。这些材料易于快速蛋白质（例如纤维蛋白原，纤维蛋白）沉积，变性和随后的血小板的粘附和激活可能导致凝块形成以及随后激活凝结和炎症事件。反过来，材料性能可能会受到损害，需要重复的血管内或外科手术。因此，这些患者通常需要永久性抗凝治疗，以防止中风和/或装置衰竭。因此，如上所述，设备上的蛋白质和血小板耐血液接触界面可以改善患者的预后并降低总体护理成本。在此应用中，我们研究了新型设计的新型设计的界面材料是我们研究的主题。该聚合物是一种磺化的块共聚物，它是非具有超强的，并且可以很容易地修饰，以包括一种或多种生物功能治疗剂和/或细胞信号分子，以作为指导对设计师表面的“愈合反应”的一种手段。我们预计，与当前的治疗方案相比，这些研究产生的设计师表面将为血液接触生物材料提供非常有效的表面修饰处理，以降低的成本。