Biodegradable Metal Stent Alloys for Vascular Applications

项目摘要 心血管疾病仍然是美国发病率和死亡率的主要原因，尽管几十年来， 治疗方面的进展，包括支架涂层和抗血小板疗法。支架的改进 材料技术从裸金属不锈钢、钴铬合金和镍钛诺（高 血栓形成性和高再狭窄）与药物洗脱聚合物涂层金属（降低再狭窄，但 血栓形成的）到可生物降解的聚合物（可能减少再狭窄，但仍然是血栓形成的）。尽管 这些渐进的进展、血栓形成和支架内再狭窄都仍然是重要的临床障碍， 心脏和外周动脉支架应用的救生潜力，需要终身处方 抗凝血剂和抗血小板治疗。最近，可生物降解的金属引起了人们的兴趣， 用于支架应用以减少血栓形成和再狭窄。可生物降解的金属血管支架必须具有 具有足够的机械强度以维持开放管腔至少6个月，必须是非血栓形成性的， 防止再狭窄，并在6个月至2年内降解，同时保持细胞相容性。 可生物降解的金属支架通过腐蚀而生物再吸收，通过腐蚀金属被转化为更稳定的形式， 例如其氧化物、氢氧化物或硫化物状态。对可生物降解的金属如铁（Fe）、镁的初步研究 (Mg)和锌（Zn）在机械性能和降解速率方面显示出前景。重要的是， 这些金属的降解产物是有助于细胞功能的生物相容性离子。单一金属 不符合生物可降解金属支架的要求，但金属合金和材料的优化 加工技术可以满足严格的要求。我们已经建立了设计的能力， 制造和测试含有多达5种基于锌和镁的金属合金元素的合金。通过我们 建议的工作，关键处理步骤的影响（例如，热挤压、冷拉）对材料性能的影响， 特别是微结构、生物降解速率和生物降解均匀性。我们将 量化纯的和合金化的生物可降解金属的生物反应，以确定它们在 血管系统，特别强调血栓形成，再狭窄和炎症反应的合金 金属及其降解离子。在本提案中，我们的目标是开发可生物降解的金属合金， 满足血管支架严格的力学和生物学要求。该项目的总体目标是 确定可生物降解金属材料的合金元素和材料加工要求， 抑制局部血栓炎性反应，通过（1）开发和表征机械，材料， 生物可降解金属合金的生物相容性研究 用于血管支架应用的金属。成功完成本R01将导致识别 可生物降解的金属合金，其满足血管支架的机械和生物学要求，并设置 进行长期临床前试验。

PROJECT SUMMARY Cardiovascular disease remains the leading cause of morbidity and mortality in the US, despite decades of advancements in treatment, including stent coatings and anti-platelet therapies. The improvements in stent material technology progressed from bare metal stainless steel, cobalt-chromium, and nitinol (high thrombogenicity and high restenosis) to drug eluting polymer coated metals (lowered restenosis, but thrombogenic) to biodegradable polymers (potential to decrease restenosis, but still thrombogenic). Despite these incremental advances, thrombosis and in-stent restenosis all remain significant clinical obstacles, limiting the life-saving potential of stent applications in cardiac and peripheral arteries and requiring life-long prescription of anticoagulant and antiplatelet therapies for patients. Recently, biodegradable metals have garnered interest for stent applications to reduce thrombosis and restenosis. Biodegradable metal vascular stents must have sufficient mechanical strength to maintain an open lumen for at least 6 months, must be non-thrombogenic, prevent restenosis, and degrade between 6 months and 2 years, while maintaining cytocompatibility. Biodegradable metal stents bioresorb through corrosion by which the metal is converted to a more stable form, such as its oxide, hydroxide or sulphide state. Initial studies of biodegradable metals like iron (Fe), magnesium (Mg), and zinc (Zn) have shown promise in terms of mechanical properties and degradation rates. Importantly, the degradation products of these metals are biocompatible ions which contribute to cell functions. A single metal does not meet the requirements of a biodegradable metallic stent, yet metallic alloys and optimization of materials processing techniques can satisfy the stringent requirements. We have established the ability to design, manufacture, and test alloys with up to 5 metal alloying elements based on zinc and magnesium. Through our proposed work, the impact of critical processing steps (e.g., hot extrusion, cold drawing) on material properties, particularly microstructure, biodegradation rate, and biodegradation uniformity, will be determined. We will quantify the biological responses of pure and alloyed biodegradable metals to determine their performance in the vascular system, particularly emphasizing thrombosis, restenosis, and inflammatory responses to the alloyed metals and their degraded ions. In the present proposal, our goal is to develop biodegradable metal alloys that meet the strict mechanical and biologic requirements of vascular stents. The overall objective of this project is to identify alloying elements and material processing requirements for biodegradable metal materials that can suppress local thrombo-inflammatory responses by (1) developing and characterizing the mechanical, material, and surface properties of biodegradable metal alloys and (2) establishing the biocompatibility of biodegradable metals for vascular stent applications. Successful completion of this R01 will result in identification of biodegradable metal alloys that meet the mechanical and biological requirements of vascular stents, and set the stage for long-term pre-clinical testing.