A Novel Thin Film Nitinol Covered Carotid Artery Embolic Protection Stent

描述（由申请人提供）：中风和动脉粥样硬化性脑血管疾病发生在全球约9%的人口中，近75%的中风发生在65岁以上的人群中。大约30%的中风患者归因于颈动脉粥样硬化性狭窄。虽然目前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放置带有单独栓塞保护过滤装置的支架。因此，迫切需要开发一种简单、安全、有效的治疗颈动脉狭窄的血管内技术，在手术过程中不需要额外放置过滤装置（即栓塞保护“过滤器”装置）。一个例子是在裸金属支架上覆盖超薄微图案膜的栓塞保护支架（即覆盖支架移植物）。由于缺乏一种合适的、生物相容性的材料来覆盖栓塞保护支架，颈动脉狭窄支架移植技术的进步受到限制。适当的抗血栓材料用于血管内装置可以显著改善颈动脉狭窄引起的卒中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诺（TFN）覆盖支架。我们还开发了一种独特的工艺，可以生产超亲水性和抗血栓性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，并降低颈动脉支架置入期间/之后的栓塞风险。此外，这种材料独特的表面质量将大大减少支架血栓形成和颈动脉狭窄治疗中的新内膜生长。本提案概述了一种新型薄膜镍钛诺覆盖颈动脉栓塞保护支架的研究和开发计划，该支架具有非血栓性和超低轮廓，并且能够持续防止术中/术后远端栓塞。本文讨论了当前颈动脉狭窄治疗过程中存在的问题和并发症，以及低轮廓、非血栓性、微模式TFN覆盖支架的必要性和实用性。一个基本的体外静态生物相容性研究被提出，以证明在细胞毒性，细胞生长行为，和血栓抵抗的负电荷超亲水TFN表面优越。将使用结构建模工具（即有限元解决方案和计算机辅助设计软件）研究一种防止血栓或胆固醇从血管壁脱落的新设计。随后，提出了一个两阶段的制造方案（将在匹兹堡大学纳米/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与市售裸金属支架结合在一起。设计的第二阶段将整个设备折叠成输送导管（例如5.0Fr），显示设备与现有输送导管的可折叠性和兼容性。本文提出了一种新型的体外装置，在微流控装置中使用人工栓子和可生物降解的聚合物涂层来验证该装置的有效性，以展示该装置设计如何在TFN移植膜中提供最佳的微孔尺寸和几何形状。提出了一种体外装置，用于定量测量各种微图案TFN移植膜分离的微颗粒（即人工栓塞）。

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.