A Novel Thin Film Nitinol Covered Carotid Artery Embolic Protection Stent

描述(申请人提供)：中风和动脉粥样硬化性脑血管疾病在全世界大约9%的人口中发生，近75%的中风发生在65岁以上的人中。大约30%的中风患者被归因于动脉粥样硬化性颈动脉狭窄。虽然目前治疗颈动脉狭窄的血管内治疗显示出可行性和安全性，但它们需要多个步骤，如球囊血管成形术和使用单独的血栓保护过滤装置放置支架。因此，迫切需要开发血管内技术来治疗颈动脉狭窄，这种技术简单、安全和有效，在手术过程中不需要额外放置滤器(即血栓保护的“滤器”装置)。一个例子是在裸露的金属支架上覆盖超薄微图案膜(即覆盖支架移植物)的栓塞性保护支架。由于缺乏合适的、生物相容的材料来覆盖血栓保护支架，限制了颈动脉狭窄支架移植技术的进步。可用于血管内装置的合适的抗血栓材料可显著改善颈动脉狭窄引起的中风的总体死亡率和发病率。匹兹堡大学开发了一种新型的微图案薄膜镍钛醇(TFN)覆膜支架。我们还开发了一种独特的工艺，可以生产超亲水和抗血栓的TFN。我们的假设是，这种新开发的包含微图案TFN膜的装置可以产生超低轮廓的内移植物，并降低在颈动脉支架置入术中/后的栓塞风险。此外，这种材料独特的表面质量将在治疗颈动脉狭窄时显著减少支架血栓形成和新生内膜生长。该提案概述了一种新型薄膜镍钛包被颈动脉血栓保护支架的研究和开发计划，该支架具有无血栓形成和超低轮廓，并能够连续预防术中/术后远端血栓形成。讨论了与目前颈动脉狭窄治疗程序相关的问题和并发症，以及低轮廓、非血栓形成、微图案TFN覆盖支架的必要性和有效性。一项基本的体外静态生物相容性研究表明，带负电的超亲水TFN表面具有优异的细胞毒性、细胞生长行为和抗血栓性能。将利用结构建模工具(即有限元求解和计算机辅助设计软件)来研究防止血栓或胆固醇从血管壁移出的新设计。随后，提出了两阶段制造方案(在匹兹堡大学纳米/微制造设施和生物制造-血管装置实验室进行)。设计的第一阶段将微图案TFN与商业上可获得的裸金属支架结合在一起。设计的第二阶段将整个装置折叠成分娩导管(例如5.0Fr)，显示该装置可折叠并与现有的分娩导管兼容。介绍了一种在微流控装置中使用人工栓子和可生物降解聚合物涂层的新型体外装置，以展示该装置的设计如何提供TFN接枝膜中微孔的最佳尺寸和几何形状。提出了一种用于定量测量不同微图案TFN接枝膜上分离的微粒(即人工栓子)的体外装置。

DESCRIPTION (provided by applicant): Stroke and atherosclerotic cerebrovascular disease occurs in approximately 9% of the population worldwide and nearly 75% of all strokes occur in persons over 65 years. Approximately 30% of the stroke patients have been attributed to atherosclerotic carotid artery stenosis. While current endovascular therapies for carotid artery stenosis show feasibility and safety, they require multiple steps such as balloon angioplasty and placement of stents with the separate embolic protection filter devices. Therefore, a critical need exists for developing endovascular technology to treat carotid artery stenosis that is simple, safe and effective without additional placement of filter devices (i.e., emboli-protection "filter" device) during the procedure. One example would be an embolic protection stent covered with ultra-thin micro-patterned membrane (i.e., covered stent graft) on bare metal stents. Advancements in stent graft technologies for carotid artery stenosis are limited by the lack of a suitable, biocompatible material for the covering of the embolic protection stent. The availability of an appropriate, thrombus resistant material for endovascular devices could lead to significant improvements in the overall mortality and morbidity of strokes induced by carotid artery stenosis. The University of Pittsburgh has developed a novel micro-patterned thin film nitinol (TFN) covered stent. We have also developed a unique process that can produce superhydrophilic and thrombus resistant TFN. It is our hypothesis that this newly developed device containing the micro-patterned TFN membrane can produce endografts which is ultra-low profile and decrease the risk of embolization during/after carotid artery stenting. In additio, the unique surface qualities of this material will provide a substantial reduction in stent thrombosis and neointima growth in the treatment of carotid artery stenosis. This proposal outlines a plan for research and development of a novel thin film nitinol covered carotid artery embolic protection stent that is non-thrombogenic and ultra-low profile, as well as capable of continuously preventing intra-/post-operative distal embolization. Problems and complications associated with current carotid artery stenosis treatment procedures, as well as the need and usefulness of low profile, non- thrombogenic, micro-patterned TFN covered stents are discussed. A fundamental in vitro static biocompatibility studies are proposed to demonstrate superior in cytotoxicity, cell growth behavior, and thromboresistance of the negatively-charged superhydrophilic TFN surface. A novel design which prevents the dislodgement of thrombosis or cholesterol from the vascular wall will be studied with structural modeling tools (i.e., finite element solution and computer aided design software). Subsequently, a two-stage fabrication scheme (to be carried out at University of Pittsburgh Nano/Microfabrication facilities and Biomanufacturing-Vascular Device Laboratory) is proposed. The first stage of the design incorporates a micro-patterned TFN with a commercially available bare metal stent. The second stage of the design collapses the whole device into delivery catheters (e.g.,5.0Fr), showing collapsibility and compatibility of the device with existing delivery catheters. A novel i vitro apparatus for the efficacy of the device using an artificial emboli and biodegradable polymer coating in microfluidic devices is presented in order to show how the device design provides optimal dimension and geometry of micro pores in TFN graft membrane. The in vitro apparatus is proposed to quantitatively measure the detached micro particles (i.e., artificial emboli) with the various micro-patterned TFN graft membrane.