Peptide-Modified Sulfonated Styrene Block Copolymers for Vascular Applications

描述（由申请人提供）：具有独特的化学可定制性质和加工特性的新型磺化聚合物已经显示出作为抗血栓表面的相当大的前景，并且已经被证明是针对嗜中性粒细胞衍生的蛋白酶的有效抑制剂.一个阶段1 SBIR测试，建议调查这种聚合物作为一个定制的界面涂层的血液接触生物材料基板。拟议研究的主要具体目标涉及制造和研究几种化学改性版本的磺化聚合物，不仅可以最大限度地减少血小板粘附和激活，而且还可以促进健康内皮细胞的剪切稳定附着和增殖。这种创新和合理的生物工程，仿生和抗血栓血液接触生物材料表面的方法是建立在几个不同的研究的基础上，这些研究揭示了这种聚合物有前途的生物适用性。SBIR的第一阶段的最终目标是开发和鉴定一种固有的非血栓形成的、内皮化的和可膨胀的水凝胶表面，并应用于各种各样的救生心血管设备。项目叙述：心血管疾病是美国男性和女性死亡和残疾的主要原因，目前有超过七千万美国人受到影响。总体而言，每年有600多万人因心血管疾病住院治疗。因此，心血管疾病对我国卫生保健系统的经济影响持续增长，特别是随着人口老龄化。2006年心脏病和中风的费用（美国）超过4000亿美元，其中包括医疗保健成本支出和死亡和残疾造成的生产力损失。在心血管疾病的保护伞下，动脉粥样硬化诱导的外周动脉疾病（PAD）、冠状动脉疾病（CAD）和脑血管疾病都遭受血管狭窄（狭窄）和/或闭塞的主要事件，这是由于凝块的失调形成以及涉及平滑肌细胞（SMC）浸润、新生内膜增殖和适应不良的血管重塑的相关炎症事件。狭窄和闭塞导致顺行血流减少/丧失。对于PAD，这可能导致跛行和外周肢体的组织发病，而对于CAD，这可能导致缺血和通常致命的心肌梗死，对于脑血管情况，这可能导致中风。介入性血管内和/或手术治疗以清除血栓并重建血管血流是这些疾病的临床管理所必需的。血管内治疗涉及机械方法，如导管介导的血管成形术、冷冻成形术和内膜切除术，以及药物治疗方法，如经导管递送溶栓、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。近年来已经看到药物洗脱支架（DES）的发展，其中金属支架表面涂覆有用于持续释放治疗剂的载药聚合物基质。手术方法涉及旁路移植物，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、心室辅助设备和全人工心脏。所有上述装置都依赖于与流动的血液接触的合成材料。这些材料易于发生快速蛋白质（例如纤维蛋白原、纤维蛋白）沉积、变性和随后的血小板粘附和活化，可能导致凝块形成和随后的凝血活化和炎症事件。反过来，材料性能可能会受到影响，需要重复血管内或外科手术。因此，这些患者通常需要永久抗凝治疗，以防止卒中和/或器械失效。因此，如上所述的装置上的抗蛋白质和抗血小板的血液接触界面可以改善患者结果并降低护理的总成本。在这种应用中，利用新型聚合物生物材料的功能可定制性的新型设计的界面材料是我们研究的主题。该聚合物是磺化嵌段共聚物，其是非血栓形成的，并且可以容易地被改性以包括一种或多种生物功能治疗剂和/或细胞信号分子，作为引导对设计者表面的“愈合反应”的手段。我们预计，从这些研究中产生的设计师表面将提供一个非常有效的表面改性处理与血液接触的生物材料，在降低成本相比，目前的治疗方案。

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.