聚乳酸血管支架的载药及其生物相容性评价

发布时间：2018-03-19 18:22

本文选题：生物可降解支架　切入点：纳米载药粒子　出处：《青岛科技大学》2016年硕士论文　论文类型：学位论文

【摘要】：1977年9月,Gruentzig医师完成了第一例经皮冠脉成形术(PTCA),开创了心脏病学介入治疗的新纪元。自此以后该学科迅速发展,先后经历了PTCA时代、裸金属支架(BMS)时代与药物洗脱支架(DES)时代。但是永久存在于血管中的金属植入物通常会导致血管壁炎症,并限制血管正常的舒缩活动,继而容易引起术后再狭窄等不良后果的发生,虽然目前临床上广泛使用的药物洗脱支架(DES)成功解决了PTCA术后急性血管闭塞和BMS术后再狭窄的问题,但DES仍不是最完美的支架。DES表面涂覆的抗增殖药物一方面抑制了血管平滑肌的增生,另一方面却延缓了血管内皮的修复。为了降低传统药物洗脱支架(DES)所造成的多种并发症的发生,研究者对植入性支架做了多种改进,生物可降解支架也因此应运而生,该种支架在植入后即刻可支撑病变血管,待血管负性重构完成后即完全降解。生物完全可降解支架的优势在于支架降解后能完成金属支架不能完成的任务,如恢复血管正常的生理功能、缓解血管壁炎症、不会禁锢边支血管、可在同一病变部位反复介入治疗以及与磁共振检查兼容等。良好的内皮化是完全可降解支架在体内安全降解的前提,研究发现,抗增殖纳米载药颗粒能够有效抑制血管平滑肌细胞的增殖,同时对血管内皮细胞的增殖影响不大,这将帮助支架完成良好的内皮化。另外纳米载药粒子由于其大的比表面积,还能够实现高效的载带效率以及药物缓释效果。因而本文利用传统的乳液溶液挥发的方法,将抗增生药物雷帕霉素(sirolimus)以及聚合物载体左消旋旋聚乳酸(PDLLA)溶于丙酮溶剂中,然后在超声条件下将此混合溶液滴加到含有表面活性剂的水溶液中,挥发掉有机溶剂后高速离心得到直径200nm-500nm的纳米载药粒子。测试表明该纳米载药粒子的包封效率在90%左右,在缓释溶液中连续释放15天,药物释放率可达70%。聚乳酸(PLA)具有良好的生物相容性以及可降解性能,但其强疏水性能一定程度上限制了其在可降解支架领域的应用。本文利用Ar低温等离子技术在PLLA血管支架表面接枝亲水性的聚合物聚乙烯吡咯烷酮(PVP)以及聚醋酸乙烯酯(PVAc),接触角测试表明,经等离子接枝的材料表面接触角由原来的105-110°可降至22°,由强疏水性变为亲水性。体外细胞粘附性实验表明,等离子处理后的材料表面表现出亲水性质,其细胞的粘附性也得以明显提高,更加有利于细胞在其表面的生长。经低温等离子接枝处理的PLLA支架,亲水性得到改善的同时也获得了一定的粘附性能,能够有效的吸附纳米载药粒子。因而,我们将等离子处理后的PLLA支架浸于纳米载药粒子的悬浮液中,物理吸附后干燥得到纳米粒子涂层支架。细胞共培养实验表明,该纳米粒子涂层支架具有良好的生物相容性,并且能够有效抑制血管平滑肌细胞的增殖,同时对血管内皮细胞的增殖影响不大,因而能够帮助支架更好地完成内皮化过程,继而减小支架内再狭窄的发生。
[Abstract]:In September 1977, Dr. Gruentzig completed the first cases of percutaneous coronary angioplasty (PTCA), ushered in a new era of interventional cardiology. Since the rapid development of science, has experienced the era of PTCA, bare metal stent (BMS) era with drug eluting stents (DES). When the generation of metal implants but persistent on blood vessels the usually leads to vascular inflammation, and limit the normal vascular vasomotion, then easily lead to restenosis and other adverse consequences, although widely used in clinical drug eluting stents (DES) has successfully solved the problem of acute vascular occlusion and restenosis after BMS after PTCA, but DES is not the most perfect support.DES coated on the surface of the anti proliferation drug inhibits vascular smooth muscle proliferation, on the other hand, delaying the repair of vascular endothelium. In order to reduce the traditional drug eluted stent (DES) made The occurrence of various complications of stent implantation, researchers made many improvements, biodegradable stent also arises at the historic moment, the scaffold can support the vascular lesions after implantation immediately to vascular negative remodeling after completion of complete degradation. Biological completely biodegradable stent has the advantage of degradation of the scaffold can be completed after metal stents can not be completed the task of restoring the normal physiological function of blood vessels, alleviate vascular inflammation, not confined side branch blood vessels, repeated interventional treatment in the same lesion and MRI compatible. Good skin is completely in the premise, degradation of scaffolds in vivo degradation studies found that anti proliferation of nano drug carrier the particles can effectively inhibit the proliferation of vascular smooth muscle cells, while the effects on proliferation of vascular endothelial cells, which will help support good complete endothelialization of other nanoparticles. Drug particles due to its large surface area, but also can be achieved with efficiency and drug release rate. So this paper use efficient loading method of emulsion solvent evaporation of the traditional anti hyperplasia drug rapamycin (sirolimus) and left circumflex racemic polymer carrier polylactic acid (PDLLA) dissolved in acetone, and then under the condition of ultrasound the aqueous solution is dripped into the mixture containing surfactants, volatile organic solvents after high-speed centrifugation to obtain nanometer diameter 200nm-500nm of the drug loaded particles. Tests show that the drug loaded nano particle entrapment efficiency was about 90% in 15 days for the release of sustained-release solution, the drug release rate of 70%. (poly lactic acid PLA) has compatibility and biodegradable properties of good biological, but its strong hydrophobic properties limits its application in biodegradable field. This paper uses the Ar technology in PLLA blood plasma Polymerpolyvinylpyrrolidone tube graft stent surface hydrophilic (PVP) and polyvinyl acetate (PVAc), contact angle measurement showed that the plasma grafting material surface contact angle from 105-110 degrees to 22 degrees, from a strong hydrophobic to hydrophilic. The results indicated that cell adhesion in vitro, material the surface after plasma treatment showed hydrophilic properties, adhesion of the cell can be significantly improved, more conducive to the growth of cells on the surface. The PLLA stent graft treatment of low temperature plasma, and the hydrophilicity was improved also obtained certain adhesion properties, can effectively adsorb nano drug loaded particles. Therefore, we will support the PLLA of the suspension after the plasma treatment is dipped in the drug loaded nano particles, physical adsorption after drying to obtain nanoparticles coated stents. Cell co culture experiments showed that the nanoparticles with coated stent It has good biocompatibility and can effectively inhibit the proliferation of vascular smooth muscle cells, and has little effect on the proliferation of vascular endothelial cells. Therefore, it can help the scaffolds to better perform endothelialization, and then reduce the occurrence of stent restenosis.

【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：TQ460.1;O633.14

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