Biodegradable Metal Stent Alloys for Vascular Applications

项目总结 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治疗。支架技术的改进 材料技术从裸露的金属不锈钢、钴铬和镍镍(高 血栓形成和高再狭窄)对药物洗脱聚合物涂层金属(降低再狭窄，但 血栓)到可生物降解的聚合物(有可能减少再狭窄，但仍然会导致血栓)。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，限制了 心脏和外周动脉支架应用的救命潜力和需要终生处方 为患者提供抗凝剂和抗血小板治疗。最近，可生物降解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。可生物降解金属血管支架必须具备 足够的机械强度以保持开放的管腔至少6个月，必须是非血栓形成的， 防止再狭窄，在保持细胞相容性的同时，在6个月至2年内降解。 可生物降解金属支架通过腐蚀生物吸收，从而将金属转化为更稳定的形式， 如其氧化物、氢氧化物或硫化物状态。铁(铁)、镁等可生物降解金属的初步研究 (镁)和锌(锌)在机械性能和降解率方面显示出良好的前景。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离子。一块金属 不符合生物降解要求的金属支架，尚需对金属合金和材料进行优化 加工工艺可以满足苛刻的要求。我们已经建立了设计的能力， 制造和测试最多含有5种以锌和镁为基础的金属合金元素的合金。通过我们的 拟议的工作，关键加工步骤(如热挤压、冷拉拔)对材料性能的影响， 特别是微观结构、生物降解率和生物降解性，将被确定。我们会 量化纯和合金化生物可降解金属的生物响应，以确定其在 血管系统，特别强调血栓形成、再狭窄和炎症反应 金属及其降解的离子。在目前的提案中，我们的目标是开发可生物降解的金属合金， 满足严格的机械和生物要求的血管支架。这个项目的总体目标是 确定可生物降解金属材料的合金化元素和材料加工要求 通过以下方式抑制局部血栓炎症反应：(1)开发和表征机械、材料、 和可生物降解金属合金的表面性质以及(2)建立可生物降解金属合金的生物相容性 血管支架用金属。成功完成此R01将导致确定 可生物降解的金属合金，满足血管支架的机械和生物要求，并设定 长期临床前试验阶段。

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.