生物全降解药物支架植入小型猪冠状动脉:安全性及组织相容性

背景:为解决聚左旋乳酸支架支撑力不足、代谢的酸性产物容易导致血管局部无菌性炎症等缺点,本课题组设计出新型支架,在聚左旋乳酸基础上融入无定型磷酸钙纳米颗粒。目的:评价新型生物全降解支架聚左旋乳酸/无定型磷酸钙纳米颗粒的安全性及组织相容性。方法:取16头健康西藏小型猪,随机选取左前降支、左回旋支或右冠状动脉支相同管腔大小的血管段,植入新型生物全降解支架1枚,于植入前、植入后1个月取股动脉血标本,行血液学检测。植入1,6个月后,复查冠状动脉造影后对支架段标本行苏木精-伊红染色,观察支架血管损伤、炎症及内皮化程度。结果与结论:支架植入前后血常规、血生化指标无明显变化。支架植入1,6个月后,冠状动脉造影提示冠状动脉通畅,无血栓形成,支架段血管与周围组织界限清楚,无组织粘连、坏死、贴壁不良等异常表现。与支架植入1个月时比较,植入6个月后的炎症积分降低(P0.05)、内皮化积分增加(P0.05),植入部位损伤积分无明显变化;并且支架周围未见心肌梗死灶及炎性细胞浸润。结果表明新型生物全降解支架具有良好的安全性及组织相容性。     

冠状动脉内可吸收的镁合金支架

背景：目前以钴铬合金为基础的冠状动脉内药物洗脱支架不能从根本上解决亚急性血栓形成和再狭窄问题,于是生物可吸收支架成为关注的焦点。 目的：评估自行设计制作冠状动脉内可吸收镁合金支架的生物相容性、有效性和安全性。 方法：35只犬均于冠状动脉和/或股动脉置入可吸收镁合金支架1枚,分别于支架置入后24 h、3 d、5 d、1周、2周、3周、4周(n=5)复查冠状动脉及血管造影后取材,分离支架段血管行组织病理观察及计算机图像分析,测量内弹力板面积、管腔面积、内膜增生面积及内膜增生面积百分比。 结果与结论：51枚支架成功置入35只犬的冠状动脉和股动脉,支架置入后不同时点各组冠状动脉及股动脉造影均证实管腔通畅,无狭窄病变,无血栓形成,置入后1周左右支架完全降解。组织病理学结果显示,支架置入后2周开始出现轻微内膜增生,内膜增生面积百分比随着时间的推移逐渐增高。提示自行研发的冠状动脉内可吸收镁合金支架1周内降解,置入早期未见明显炎症反应及血栓形成,再狭窄程度轻,具有良好的生物相容性,安全有效。     

可降解心血管支架材料发展的优势与趋势

目的:阐述生物可降解材料的生物相容性,生物可降解性材料对动脉平滑肌及动脉内膜的影响以及生物可降解性支架在临床的应用进展。方法:作者以"生物可降解;药物洗脱支架;雷帕霉素;紫杉醇;经皮冠状动脉;急性冠脉综合征"为检索词,在中国期刊全文数据库(CNKI:2002/2010)中,采用电子检索的方式进行文献检索。排除重复性研究和陈旧文献,共入选19篇文献。结果:目前可降解支架材料应用较多的为聚左旋乳酸、聚羟基乙酸/聚乳酸共聚物,且生物相容性较好。生物可降解性材料对人脐动脉平滑肌细胞的生长没有影响,但含紫杉醇或雷帕霉素的可降解材料对动脉平滑肌细胞生长有抑制作用,也对动物冠状动脉内膜增殖有抑制作用。生物可降解性药物支架在近、中期临床研究中证明是安全和有效的。结论:生物可降解性支架有很好的生物相容性,置入后血栓形成、异物反应及新生内膜增生均减少,而内皮化更完全。载药局部释放可抑制早期的血栓形成和晚期的新生内膜增生,这一结论有待大规模、多中心的随机对照试验进一步证实。     

冠状动脉支架材料类型与置入后的效果评价

目的:冠状动脉内支架有金属裸支架、药物涂层支架、生物降解支架以及新型支架如放射性血管支架、静脉覆盖支架和基因支架等多种。如何选择适宜的支架,以取得最佳的治疗效果,是目前医学界研究的热点。目的:阐述冠状动脉支架的临床应用进展,并探讨冠状动脉支架置入后的治疗效果。方法:作者以"冠状动脉内支架,金属裸支架,药物涂层支架,生物降解支架,心血管新型支架,凝血系统,炎症反应"为检索词,在中国期刊全文数据通信(CNKI:2002/2010)中,采用电子检索的方式进行文献检索。排除Meta分析及重复性研究,共检索到27篇文献,从冠状动脉支架的种类、研究进展及其生物相容性,冠状动脉支架置入后凝血系统的变化,以及冠状动脉支架置入后炎症反应等方面进行探讨。结果:①不论是金属裸支架、药物涂层支架、生物可降解支架以及新型支架,其支架材料的改进更新均以改善生物相容性和生物力学性能为目标。②心血管支架的生物相容性是一个复杂的连锁过程,血液相容性和组织相容性是评定生物相容性的两项基本内容。③利用有限元分析心血管支架材料的力学特性可为未来支架的优化设计提供有益的帮助。结论:现行的心血管支架尚未完全解决生物相容性问题,理想的心血管支架还有待进一步的深入开发与研究。     

冠状动脉支架材料与置入后炎症因子的变化

目的：总结冠状动脉支架材料及置入后炎症因子变化的关系。 方法：以“冠状动脉支架,生物相容性,炎症因子,细胞因子,血栓”为关键词,采用计算机检索万方数据网1998-01/2010-12相关文章。纳入冠状动脉支架置入后炎症因子水平变化方面的文献,排除重复研究或Mata分析类文章。 结果：冠状动脉内支架置入有可能会引起冠状动脉血管的损伤,促进体内细胞释放炎症因子,通过炎症因子和细胞因子的表达,能很好的反映支架置入后局部血管损伤程度和炎症水平。药物涂层支架能够显著降低支架置入后再狭窄发生率及靶病变再次血运重建率,但显著增加晚期支架血栓形成。通过凝血系统各因子水平评估,药物涂层支架置入前后充分地抗血小板治疗能够降低支架血栓的发生。 结论：支架置入体内后与血液及血管壁接触可产生炎症和致敏反应,因此支架置入前后应充分控制炎症状态和抗凝血治疗。     

雷帕霉素与紫杉醇洗脱支架置入冠状动脉预防心血管事件:有效性和安全性

背景:目前,雷帕霉素和紫杉醇药物洗脱支架在临床冠状动脉疾病治疗中的应用较为广泛,但关于二者在预防各种心血管事件方面的研究相对较少。目的:比较雷帕霉素与紫杉醇洗脱支架置入冠状动脉预防心血管事件的有效性和安全性。方法:纳入冠状动脉疾病患者117例,其中男89例,女28例,年龄35-81岁,59例在冠状动脉置入雷帕霉素洗脱支架进行治疗,58例在冠状动脉置入紫杉醇洗脱支架进行治疗,治疗后随访12个月,记录两组心脏不良事件发生率与血栓形成发生率,分析两种支架预防心血管事件的有效性和安全性。结果与结论:两种药物洗脱支架与宿主之间具有良好的生物相容性,未出现支架脱落和移位等情况。随访9个月时,雷帕霉素洗脱支架组与紫杉醇洗脱支架组血栓形成发生率分别为3.4%、3.5%,组间比较差异无显著性意义(P0.05);随访12个月时,雷帕霉素洗脱支架组与紫杉醇洗脱支架组心脏不良事件发生率分别为13.6%、13.8%,组间比较差异无显著性意义(P0.05)。表明雷帕霉素洗脱支架和紫杉醇洗脱支架置入冠状动脉预防心血管事件方面的有效性和安全性相当。     

复合材料气管内可降解支架的降解性能CSCD

背景:经过对目前国内外可降解材料支架研究的充分调研,以及在镍钛记忆合金支架设计、制作、实验和临床应用的经验基础上,提出一种新型自膨式左旋聚乳酸可降解覆膜气管内支架的研究。目的:自行制作左旋聚乳酸复合羟基磷灰石生物可降解材料气管内支架,测试其机械力学、生物相容性及降解性能。方法:利用计算机辅助设计支架模型,应用相对分子质量150000的左旋聚乳酸和羟基磷灰石按一定比例混合后研制直径分别为20,21,22,23,24,25,26mm的可降解气管内支架,采用万能实验机检测其力学性能。将研制的可降解气管内支架以合适的尺寸置入杂种犬气管狭窄模型,置入后4,8,12,16周观察支架黏均分子质量及质量变化,同时检测可降解气管内支架体外降解黏均分子质量及质量的变化。结果与结论:复合材料可降解气管内支架的平均径向支撑力为7.8kPa,支架表面覆盖率小于20%,支架扩张率≥4%,支架纵向缩短率≤9%,已达到气管内可降解支架的力学要求。支架置入后4-16周组织病理学观察未见明显炎症反应。支架体内降解解组不同时间点的黏均分质量下降程度及质量损失率高于体外降解组(P均<0.05)。表明左旋聚乳酸/羟基磷灰石复合材料支架具有良好力学性能、生物相容性及可降解性。     

生物可降解心血管支架与人体相容性的系统评价

背景：冠状动脉支架置入后的再狭窄等并发症越来越引起关注。 目的：系统评价生物可降解心血管支架材料与人体相容性的研究。 方法：计算机检索 EMbase(1980/2011-08)、MEDLINE(1966/2011-08)和中国生物医学文献数据库(CBM,1978/2011-08)、中文学术期刊全文数据库(CNKI),筛查相关文章的参考文献收集发表的生物可降解心血管支架生物相容性的动物实验和临床实验中文献,对可降解心血管支架材料生物相容性的总结。 结果与结论：当血管内皮化完成之后,生物可降解支架如期降解,从而克服了支架本身作为异物的血栓源性,抑制早期血栓形成及晚期新生内膜增生,具有良好的生物相容性,有效降低了再狭窄的发生率。同时,生物可降解支架还可作为药物局部投放的载体,达到有效防止支架置入后血管急性闭塞和降低再狭窄发生率。     

置入心血管支架后冠状动脉粥样硬化性心脏病患者的C-反应蛋白变化

背景:心血管支架作为一种异体物质,置入后存在明显的炎症反应过程,主要表现在凝血系统的激活以及炎性标志物血清C-反应蛋白的显著升高。目的:总结探讨支架置入后冠状动脉粥样硬化性心脏病患者炎症反应及C-反应蛋白的变化。方法:应用计算机检索中文期刊全文数据库1990/2009相关文献,检索词为"心血管支架,C-反应蛋白,炎症反应",同时检索PubMed数据库1990/2009相关文献,检索词为"cardiovascular stent on plasma,c-reactive protein"。结果与结论:药物涂层支架以金属支架为载体携带药物到达血管损伤局部,使药物在较长的时间内充分释放到血管壁内,减少支架置入后再狭窄的发生。抗炎药物涂层支架主要药物为地塞米松、甲泼尼龙等。抗迁移、抗增生药物涂层支架主要药物为雷帕霉素、紫杉醇、放线菌素D等。支持内膜愈合的药物涂层支架主要药物为雌二醇等。经皮冠状动脉支架置入可诱导和加重局部炎症反应,这对血管内皮的增生与再狭窄有重要影响。反映急性炎症反应的敏感指标如血清C-反应蛋白的浓度对于经皮冠状动脉支架置入后心血管事件的发生有预测价值。冠状动脉内支架置入可显著升高血浆C-反应蛋白水平,所以应充分认识炎症反应及血浆C-反应蛋白、细胞因子的变化对防止心血管支架置入后再狭窄起到的重要作用,及早进行预防及干预,从而减少再狭窄率,提高介入治疗效果。     

药物洗脱冠状动脉支架系统动物实验研究

目的通过观察在猪动脉中置人心畅可降解聚合物涂层药物洗脱冠状动脉支架（天津百畅公司开发）及对照组支架后的植入后管腔丢失、内皮化、炎症反应、损伤及血栓形成情况来评价国产可降解聚合物涂层药物洗脱支架临床应用的可行性。方法将2种共60枚支架分别置入30头猪冠状动脉的前降支、回旋支以及右冠状动脉。支架植入后的2,5,12,25周,将不同数量的猪处死行组织形态学检查,观察炎症、血栓形成情况和内皮化评价。结果支架置入术后的冠脉通畅,无明显狭窄;支架贴血管内壁良好,血管内腔表面光滑;2种支架均无血栓形成,心畅可降解聚合物涂层药物洗脱支架炎症反应及内皮化与对照组无明显差异,其管腔丢失较对照组轻或无明显差异。结论实验提示心畅可降解聚合物涂层药物洗脱支架置入后有良好的血液相容性,生物性能稳定,支架内表面迅速内皮化,血管有良好的开通率。说明可降解聚合物涂层药物洗脱支架是安全、有效的。     

Vascular delivery of c-myc antisense from cationically modified phosphorylcholine coated stents

c-Myc is involved in the formation of neointimal hyperplasia. We investigated in vitro, ex vivo and in vivo release of antisense c-myc from cationically modified phosphorylcholine-coated stents, as well as the effects on c-Myc expression and neointima formation in a porcine coronary stent model. In vitro experiments were performed to determine optimal loading of stents with antisense. Stents loaded with labelled antisense were deployed in porcine arteries ex vivo and in vivo. Antisense was detected in the vessel wall directly surrounding the stent of pig carotid and coronary artery up to 48 h after stent deployment. Nuclear uptake was observed in endothelial and vascular smooth muscle cells. Labelled antisense within peripheral tissues in vivo was <1.0% of that within stented arterial segments. Control and antisense loaded stents implanted into 10 pig coronary arteries and analysed at 28 days post-stenting showed that lumen area within the antisense stents was significantly increased (i.e. 30.5% greater, P<0.01), whilst both neointimal area and neointimal thickness were significantly reduced (17.5% and 19.5%, respectively, P<0.01) compared to control stents. Cationically modified phosphorylcholine coated stent-based delivery of c-myc antisense is feasible with minimal systemic delivery and is associated with a reduction of in-stent neointimal hyperplasia in pig coronary arteries.     

Effect of inflammation on endothelial cells induced by poly-L-lactic acid degradation in vitro and in vivo

Abstract

As a promising candidate, biodegradable Poly-L-lactic Acid (PLLA) has been extensively used in coronary artery stents. In our previous reports, PLLA stents implanted in porcine coronary arteries showed safety without stent thrombosis. However, inflammatory responses were observed, which needed further study. In this study, human aortic endothelial cells (HAEC) were treated with different volume percentages of extract of pre-degraded PLLA (extract of PLLA) in vitro, and the cell growth curve and morphological changes were examined. The expression of inflammatory cytokines such as NF-κB, VEGF and VCAM-1 were also observed by ELISA. In addition, PLLA stent was implanted in porcine coronary artery to examine morphological changes, functional marker eNOS and inflammatory responses. The extract of PLLA caused significant growth inhibition and release of NF-κB, VEGF and VCAM-1 in HAEC with volume percentage-dependence. Although re-endothelialization and expression of eNOS was observed, expression of NF-κB and lymphocytes surrounding PLLA were also found after PLLA stents were implanted in the artery. This study demonstrated the effects of inflammation on endothelial cells induced by PLLA degradation in vitro and showed the inflammation in vivo, suggesting that anti-inflammatory strategy is necessary for PLLA stent implantation in the artery.     

载药复合支架的抗血管组织增生的研究

在氧化钛表面改性的国产不锈钢支架上涂覆一定量药物,制备出新型复合的抗增生载药支架.观察支架植入猪冠状动脉3个月后血管的开通情况及血管的内膜反应.将7枚国产的普通不锈钢支架和7枚制备的新型载药支架植入14头小型猪冠状动脉内,3个月后对支架植入段血管进行血管造影、光镜及电镜检查并进行免疫组织化学分析.冠状动脉造影显示动物处死前支架段血管开通率100%,支架X光下清晰可见,未经特殊抗血栓治疗,支架段血管内无血栓形成.扫描电镜显示两组支架表面都完全被血管内膜覆盖,表面光滑,无血栓形成.覆盖的血管内膜中内皮细胞沿血流方向成典型的铺路石状排列.组织学形态分析显示植入支架3个月后,所有支架植入段血管内膜都有明显的增生,增生内膜主要由细胞外基质和平滑肌细胞构成.结论:含有新型载药支架的冠状动脉血管段内膜增生厚度比普通不锈钢支架的冠状动脉血管段内膜增生厚度小,这种载药复合支架具有良好的应用前景,需扩大样本进行深入研究.     

Local delivery of nitric oxide from an eluting stent to inhibit neointimal thickening in a porcine coronary injury model

To assess the effect of a NO-eluting stent on reducing neointimal thickening in a porcine coronary artery stent injury model, sodium nitroprusside (SNP), a NO donor, was incorporated into polyurethane (PU) polymer and coated onto metallic coil stents, and two types of stents with thin and thick barrier coatings were characterized. In vivo biological activity of the NO-eluting stents was assessed by measurement of coronary arterial cGMP levels in 32 pigs/64 arteries at days 1, 2, 7 and 14. Morphometric analyses were performed in 16 pigs to determine the effect of NO-eluting stents on neointimal hyperplasia 28 days following arterial injury. The SNP-coated stents released NO in a controlled manner for up to 4 weeks in the in vitro experiments and an increase in local tissue cGMP levels was demonstrated for up to 14 days. The neointimal area at 28 days was not diminished, however, by NO eluded from either stents of thin or thick barriers (control bare stent - 0.66 mm2, control PU stent - 0.68 mm2, SNP-PU thin coating stent - 0.78 mm2, SNP-PU thick coating stent - 0.85 mm2; all p=NS). In conclusion, the SNP-coated polymer stent exerted a local biological effect on the arterial wall, with sustained elevation of cGMP level. Although local delivery of NO from this device did not reduce neointimal hyperplasia in this porcine model, this polymer-coated stent might be a promising tool for administration of other agents that may modify the reparative tissue responses leading to restenosis.     

PGLA降解产物对机体主要生理功能的影响

降解产物的生物安全性是生物降解类材料生物学评价的重要内容。本文采用自体对照的方法,通过测定聚乙交酯丙交酯(PGLA)材料植入前后动物体内某些生化指标的变化,研究降解产物对机体主要脏器——肝肾功能的影响,探讨降解产物的在体生物可接受性。实验分别将不同大小的PGLA材料植入Wistar大白鼠和新西兰兔的背部皮下组织内,在动物的相同部位进行同样的手术切口和缝合作为对照,植入前和植入后2~10周的各不同时段,分别采集兔血和大鼠的尿液,测定尿素氮和尿肌酐、血清谷丙转氨酶、尿素和肌酐等生化指标。结果显示:植入后2~3周实验组尿样中的尿素氮和尿肌酐浓度出现明显的增高,与植入前比较,统计学上具有显著性差异(P<0.01);植入后第2周血清谷丙转氨酶略有所下降(P<0.05),而血尿素和血肌酐有较明显的增高(P<0.01),但自第4周起所有变化均恢复到了植入前的水平,且基本维持在一个相对恒定的范围。对照组手术前后的所有指标均未见明显的变化(P>0.05)。由此提示:(1)PGLA降解产物对肾脏和肝脏组织无永久性的损伤;(2)选用自体对照法,通过检测动物血液和尿液中主要生化指标的变化来评价PGLA降解产物对生物体全身生物学的影响作用被初步证明是一种有效而可行的研究方法;(3)在活体上评价降解产物的生物可接受性具有客观、灵敏、减少动物使用数量、可直接观察体内动态变化、能评估产物对生理功能影响等优点,为生物可降解材料的生物学评价提供新的检测途径。     

可完全生物降解材料聚乳酸-聚羟基乙酸复合壳聚糖在人工心血管支架制备中的应用

裸金属支架（bare metal stents,BMS）和涂层支架（drug eluting stents,DES）介入治疗冠心病已在临床广泛应用,但由于金属支架的异物刺激或携带药物的干扰容易引起支架内再狭窄和血管栓塞,由聚酯、聚碳酸酐及聚磷酸酯等高分子材料制备的完全可生物降解吸收支架及药物洗脱支架应运而生。目前由共聚物材料制备的人工心血管植入支架的安全性、组织及血液相容性已得到证实,然而这些支架具有各自的问题,如降解的速度、材料的柔韧度、硬度以及支撑力不均一等,尚不能满足实际应用的要求。本文就聚乳酸（polylactic acid,PLA）、聚羟基乙酸（polyglycolic acid,PGA）和壳聚糖在人工冠脉血管支架制备中的应用现状及研发方向予以综述。     

Long-term effect of stents eluting 6-mercaptopurine in porcine coronary arteries

Background

Drug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty. The anti-proliferative nature of the drugs reduces smooth muscle cell (SMC) proliferation effectively, but unfortunately also negatively affects endothelialization of stent struts, necessitating prolonged dual anti-platelet therapy. Cell-type specific therapy may prevent this complication, giving rise to safer stents that do not require additional medication. 6-Mercaptopurine (6-MP) is a drug with demonstrated cell-type specific effects on vascular cells both in vitro and in vivo, inhibiting proliferation of SMCs while promoting survival of endothelial cells. In rabbits, we demonstrated that DES locally releasing 6-MP during 4 weeks reduced in-stent stenosis by inhibiting SMC proliferation and reducing inflammation, without negatively affecting endothelialization of the stent surface. The aim of the present study was to investigate whether 6-MP-eluting stents are similarly effective in preventing stenosis in porcine coronary arteries after 3 months, in order to assess the eligibility for human application.

Methods

6-MP-eluting and polymer-only control stents (both n?=?7) were implanted in porcine coronary arteries after local balloon injury to assess the effect of 6-MP on vascular lesion formation. Three months after implantation, stented coronary arteries were harvested and analyzed.

Results

Morphometric analyses revealed that stents were implanted reproducibly and with limited injury to the vessel wall. Unexpectedly, both in-stent stenosis (6-MP: 41.1?±?10.3 %; control: 29.6?±?5.9 %) and inflammation (6-MP: 2.14?±?0.51; control: 1.43?±?0.45) were similar between the groups after 3 months.

Conclusion

In conclusion, although 6-MP was previously found to potently inhibit SMC proliferation, reduce inflammation and promote endothelial cell survival, thereby effectively reducing in-stent restenosis in rabbits, stents containing 300 μg 6-MP did not reduce stenosis and inflammation in porcine coronary arteries.

     

Angiographic follow-up after placement of a self-expanding coronary-artery stent

BACKGROUND. The placement of stents in coronary arteries after coronary angioplasty has been investigated as a way of treating abrupt coronary-artery occlusion related to the angioplasty and of reducing the late intimal hyperplasia responsible for gradual restenosis of the dilated lesion. METHODS. From March 1986 to January 1988, we implanted 117 self-expanding, stainless-steel endovascular stents (Wallstent) in the native coronary arteries (94 stents) or saphenous-vein bypass grafts (23 stents) of 105 patients. Angiograms were obtained immediately before and after placement of the stent and at follow-up at least one month later (unless symptoms required angiography sooner). The mortality after one year was 7.6 percent (8 patients). Follow-up angiograms (after a mean [+/- SD] of 5.7 +/- 4.4 months) were obtained in 95 patients with 105 stents and were analyzed quantitatively by a computer-assisted system of cardiovascular angiographic analysis. The 10 patients without follow-up angiograms included 4 who died. RESULTS. Complete occlusion occurred in 27 stents in 25 patients (24 percent); 21 occlusions were documented within the first 14 days after implantation. Overall, immediately after placement of the stent there was a significant increase in the minimal luminal diameter and a significant decrease in the percentage of the diameter with stenosis (changing from a mean [+/- SD] of 1.88 +/- 0.43 to 2.48 +/- 0.51 mm and from 37 +/- 12 to 21 +/- 10 percent, respectively; P less than 0.0001). Later, however, there was a significant decrease in the minimal luminal diameter and a significant increase in the stenosis of the segment with the stent (1.68 +/- 1.78 mm and 48 +/- 34 percent at follow-up). Significant restenosis, as indicated by a reduction of 0.72 mm in the minimal luminal diameter or by an increase in the percentage of stenosis to greater than or equal to 50 percent, occurred in 32 percent and 14 percent of patent stents, respectively. CONCLUSIONS. Early occlusion remains an important limitation of this coronary-artery stent. Even when the early effects are beneficial, there are frequently late occlusions or restenosis. The place of this form of treatment for coronary artery disease remains to be determined.