大鼠主动脉支架术模型的建立及光学相干断层扫描评估

目的 建立大鼠主动脉支架术动物模型,为冠状动脉支架再狭窄等研究提供实用的小动物平台。方法 SD雄性大鼠18只(500～700 g),麻醉消毒后,经左髂动脉切口于肾动脉分叉处上方10 mm的腹主动脉处行2.5 mm×16.0 mm支架植入,缝合左髂动脉切口。术前及术后即刻、1个月、2个月、6个月对支架段血管进行光学相干断层扫描(OCT)检测分析。结果 通过切开髂动脉于大鼠腹主动脉行支架植入术均获成功,无大鼠死亡及跛行。OCT检查结果显示：术前大鼠主动脉内膜显示清晰,直径约2 mm;术后即刻支架钢梁突出内膜、贴壁良好;术后1个月可见内皮细胞覆盖;术后2个月见少量内膜增生;术后6个月可见较明显的内膜增生,未见血栓形成。结论 大鼠经髂动脉切开主动脉支架植入可行性强,可通过OCT进行精准评估。     

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。     

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。     

表面磁性膜医用316L不锈钢支架对兔髂动脉内膜增殖的影响

目的 研究表面磁性膜医用316L不锈钢支架对新西兰大白兔髂动脉新生内膜增殖的影响.方法 通过动物体内支架植入,采用定量冠脉造影、光学显微镜图像技术观察不同支架对新生内膜增殖和再狭窄的影响.结果 与普通裸支架相比,表面磁性膜支架可以抑制支架植入后的新生内膜增殖和再狭窄,植入3月后应用表面磁性膜支架和普通裸支架的管腔面积分别为(2.78±0.40)mm2和(2.07±0.62)mm2,再狭窄率分别为3.3%和16.7%,且可能与磁场强度相关.结论 表面磁性膜支架对经皮冠状动脉介入治疗术后的再狭窄可能具有防治作用.     

砷涂层支架置入后的血管组织相容性

背景：研究认为,三氧化二砷可以抑制血管平滑肌细胞的增殖,促进其凋亡,那么砷对血管平滑肌细胞的增生是否也有同样的抑制作用,砷涂层血管支架能否与血管组织相容,早期较好地被血管内膜覆盖或达到减少内膜过度增生的作用？ 目的：观察砷涂层血管支架的血管组织相容性。 方法：取大耳白家兔14只,随机分为2组,分别在腹主动脉处植入砷涂层316 L不锈钢支架和316 L不锈钢裸支架,植入28 d后结扎支架部位血管的远端和近端,取下支架部位的血管行苏木精-伊红染色,光镜检查。 结果与结论：①大体观察：支架处的血管外径稍大于相邻处血管的外径,呈扩张状态,无肉眼可见的血栓,切开支架,支架表面可见光滑的新生内膜形成,新生内膜表面光滑。②光镜观察：支架丝位于血管的中层,中层平滑肌被压,支架丝周边,血管内膜平滑肌增生,使血管内膜增厚。支架丝的血管腔面可见新生的血管内膜形成并覆盖支架丝,支架丝与血管组织之间可见一薄层黑色物质,为涂层药物砷及其化合物,证明砷涂层支架可以被血管组织覆盖,具有良好的血管组织相容性。中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程全文链接：     

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。     

国产钛镍合金血管支架的生物相容性研究

采用国产钛镍形状记忆合金制成４ｍｍ内径的血管支架,通过导管置入８只正常犬的双侧髂动脉。观察１－６个月,发现支架表面业层新生内膜覆盖,光镜及电观察新生内膜表层为血管内皮样细胞,国产钛镍合金血管要有很好的生物相容性     

雷帕霉素联合CD133抗体支架预防血管再狭窄的有效性和安全性北大核心

背景:药物洗脱支架和单纯内皮修复型支架在治疗血管狭窄疾病时可见内皮化延迟以及植入后再狭窄的问题。作者既往的体外研究显示雷帕霉素联合CD133抗体支架可协同抵消抗增殖药物的内皮化延迟和内膜的过度增生。目的:在小型猪冠状动脉损伤模型中,分析雷帕霉素联合CD133抗体复合支架预防血管再狭窄的效果。方法:将冠状动脉损伤小型猪模型随机分为雷帕霉素组、CD133抗体组以及雷帕霉素/CD133抗体组,分别在损伤冠状动脉置入雷帕霉素支架、CD133抗体支架和雷帕霉素联合CD133抗体支架。动物实验于2019-03-15经沈阳医学院附属中心医院实验动物伦理委员会审批,审批号20190017。结果与结论:(1)3组支架植入后14 d和1个月时,内皮化程度存在差异,其中雷帕霉素组支架内皮覆盖程度低于CD133抗体组及雷帕霉素/CD133抗体组。(2)置入后3和6个月,雷帕霉素组和雷帕霉素联合CD133抗体组管腔狭窄率较低,但雷帕霉素支架周围组织存在明显的炎症反应,且CD133抗体支架可引起明显内膜增生及管腔狭窄。(3)提示雷帕霉素联合CD133抗体支架可在体内实现早期内皮化,促进内皮细胞修复,并在置入后降低周围组织炎症反应,且其6个月内抗增殖效果与雷帕霉素支架接近。     

血管支架材料表面改性与血管内膜的增生

目的:评价血管材料改性后对血管内皮增生的影响和应用前景。方法:以"血管支架材料,表面改性,内皮增生,再狭窄,生物相容性"为中文关键词,以"biological vascular scaffold;surface modification;tunica intimal hyperplasia;restenosis;biocompatibility"为英文关键词,采用计算机检索2008-01/2010-04相关文章。纳入有关与血管支架材料,血管支架材料改性相关的文章,排除重复研究或Meta分析类文章,以30篇为重点分析,讨论血管支架材料改性对血管内皮增生、再狭窄的影响。结果:支架植入后血管内膜的增生和再狭窄严重影响了其远期疗效,大量的动物实验和临床分析表明,血管支架材料表面改性及载药复合支架能比裸体支架能更有效解决局部慢性炎症反应、内皮功能障碍、抗凝血等问题,显示出良好的安全性和降低冠状动脉再狭窄的有效性。可降解血管组织工程支架的发展将成为新的里程碑,内皮细胞是血管组织工程中最重要的种子细胞,通过种子细胞在体外种植于生物可吸收材料的血管支架上,达到修复创伤、病变和重建功能的目的。结论:血管支架材料表面改性是目前解决支架植入后抑制内膜增生,防止血栓形成和再狭窄等问题有效方法之一。血管组织工程支架发展前景广阔。     

镍钛形状记忆合金血管内支架组织相容性实验研究

将锥形记忆合金支架分别植入６只猪右侧髂动脉。用以研究镍钛形状记忆合金血管内支架生物相容性，支架植入前入植入后８个月，观测动物血常规，肝肾功能以及毛发中镍钛元素含量，均无明显变化（Ｐ〉０．０５），支架植入后８个月处死动物，全身重要脏器（肝、脾、肾、肺、心、脑等）病理学检查结构正常，无淋巴细胞和单核细胞浸润，支架植入部位上游血管壁内膜光滑，内皮细胞结构正常，内弹力板完整，支架植入段为完整肉芽组织阻塞，     

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.     

Stent-induced coronary artery stenosis characterized by multimodal nonlinear optical microscopy

We demonstrate for the first time the applicability of multimodal nonlinear optical (NLO) microscopy to the interrogation of stented coronary arteries under different diet and stent deployment conditions. Bare metal stents and Taxus drug-eluting stents (DES) were placed in coronary arteries of Ossabaw pigs of control and atherogenic diet groups. Multimodal NLO imaging was performed to inspect changes in arterial structures and compositions after stenting. Sum frequency generation, one of the multimodalities, was used for the quantitative analysis of collagen content in the peristent and in-stent artery segments of both pig groups. Atherogenic diet increased lipid and collagen in peristent segments. In-stent segments showed decreased collagen expression in neointima compared to media. Deployment of DES in atheromatous arteries inhibited collagen expression in the arterial media.     

Endothelialization and in-stent restenosis on the surface of glycoprotein IIIa monoclonal antibody eluting stent

Since the percutaneous transtuminal coronary angioplasty was introduced into China in 1984, this procedure has become widely accepted as an important step in coronary revascularization. This study shows the effect of the monoclonal antibody (mAb) on the platelet glycoprotein IIIa receptor during endothelialization and in-stent restenosis by implanting the mAb-eluting stents into iliac arteries of rabbits. The hard tissue cross sections of the stent-implanted arterial segments were made by polymethylmethacrylate embedding. Arterial intima proliferation was observed and analyzed. The endothelialization of the stent surface was observed using scanning electron microscope, whereas the ultrastructure of the neointima was observed using transmission electron microscope. After one month of stent implantation, the surfaces of both groups were covered by intact endothelial layers, but the neointimal areas and the ratio of stenosis were significantly lesser in the mAb-eluting stent group (p < 0.01). After 3 months, the ratio of stenosis in the mAb-eluting stent group was 14.67 ± 0.79, whereas that of the bare stent group was 21.58 ± 1.76 (p < 0.01). Therefore, the mAb eluting from the stent surface has the potential to accelerate endothelialization, prevent thrombosis formation due to the interaction of stent with blood, and decrease the stenosis ratio by inhibiting neointima proliferation.     

Preclinical restenosis models: challenges and successes

Coronary artery disease remains a major problem for Western societies. The advent of percutaneous interventions, including stents has brought clinical care to a new level of efficacy, yet problems remain. Restenosis following stenting in human coronary arteries appears at last to be yielding to therapeutic strategies, especially drug eluting stents. Because therapeutic percutaneous coronary intervention is widely dominated by the intracoronary stent, restenosis therapies must include the stented coronary artery. Animal models and in particular the porcine coronary model seem to represent the human coronary artery reaction to stenting. It mimics several clinical conditions including thrombosis and neointimal formation. A key question in the era of intravascular technologies is how well this and other models can predict clinical events. This paper discusses the models and their application.     

Proximal atherosclerotic lesion as a cause of very late stent thrombosis

Very late stent thrombosis is defined as in-stent thrombosis occurring after 1 year of an intra-coronary artery stent placement. Drug eluting stents have lately been criticized for increased reports of very late stent thrombosis. The exact cause of these very late stent thromboses is not clearly understood. Virchow's triad describes the three main factors of thrombus formation to be stasis of blood flow, endothelial injury and hypercoagulability. Based on Virchow's triad, we propose the cause of very late stent thrombosis to be formation of a de novo atherosclerotic lesion in the proximal segment of a stented artery. The de novo atherosclerotic lesion narrows the vessel lumen and causes stasis of blood flow in the distal stent. The de novo lesion can also cause myocardial ischemia creating a prothrombotic environment in the stented region. Stasis of blood flow and prothrombotic environment in the stented region can lead to the formation of very late stent thrombosis. Since atherosclerosis is a dynamic aging process in humans, we propose de novo proximal lesions in the coronary arteries can predispose to very late stent thrombosis.     

The role of vascular calcification in inducing fatigue and fracture of coronary stents

Traditional approaches for in-vitro pulsatile and fatigue testing of endovascular stents do not take into consideration the pathologies of the stented vessel and their associated biomechanical effects. One important pathology is calcification, which may be capable of inducing changes in the vessel wall leading to inhomogeneous distribution of stresses combined with wall motion during the cardiac cycle. These local property changes in the region adjacent to stents could directly influence in-vivo stent performance. Seven cases containing a total of 18 stents were obtained from autopsy. Radiographs were evaluated and vessels were sectioned for histology and stent topographical analysis. Stents were retrieved by chemical removal of surrounding tissue and surfaces were evaluated using 3D digital optical and scanning electron microscopy for biomechanical abrasion and fracture features. Pathologic complications such as restenosis and thrombus formation were assessed from histological sections. Direct evidence of fracture was found in 6 of the 7 cases (in 12 out of 18 stents; 9 drug eluting and 3 bare metal). The degree of stent alterations was variable, where separation of segments due to fracture occurred mostly in drug-eluting stents. All fracture surfaces were representative of a high cycle fatigue mechanism. These fractures occurred in complex lesions involving the presence of diffuse calcification alone, or in combination with vessel angulations and multiple overlapping stents. Morphologic analysis of tissue at or near some fracture sites showed evidence of thrombus formation and/or neointimal tissue growth.     

雷帕霉素与紫杉醇洗脱支架置入治疗冠状动脉病变的有效性

背景：药物洗脱支架置入治疗冠状动脉病变具有良好的临床效果,但不同支架的治疗效果可能存在一定差异。 目的：比较不同支架置入治疗冠状动脉病变的临床效果。 方法：纳入278例冠状动脉病变患者,均接受冠状动脉支架置入治疗,其中91例置入雷帕霉素洗脱支架,92例置入紫杉醇洗脱支架,95例置入裸金属支架。支架置入后随访12个月,记录死亡和心肌梗死等不良心脏事件发生情况,以及冠状动脉再狭窄发生情况及材料宿主反应。 结果与结论：雷帕霉素洗脱支架组与紫杉醇洗脱支架组冠状动脉再狭窄率、急性心肌梗死发生率、冠状动脉旁路移植或再次经皮冠状动脉介入治疗率均低于裸金属支架组(P < 0.05),雷帕霉素洗脱支架组与紫杉醇洗脱支架组上述指标比较差异均无显著性意义(P > 0.05)。3组死亡率比较差异无显著性意义(P > 0.05)。3组均未发生支架移位、脱落、断裂、置入位置不良及白细胞增多和血小板减少、溶血等情况。表明两种药物洗脱支架的治疗效果相当,均优于裸金属支架。  中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

Demonstrating the Influence of Compression on Artery Wall Mass Transport

The development of restenosis within the coronary arteries after a stenting procedure has been addressed with the development of the drug eluting stent device. However, in recent times the superiority of the drug eluting stent over bare metal stents has been brought into question. A lack of knowledge regarding the behavior of drug transport from the drug eluting devices contributes to this uncertainty. Questions arise as to whether drug eluting stents deliver sufficient amounts of therapeutic agents into the artery wall to suppress restenosis. Published investigations in this area have focused primarily on trends associated with how variations in stenting conditions affect mass transport behavior. However, experimentally validated numerical models that simulate mass transport within the artery wall are lacking. A novel experimental model was developed to validate computational predictions of species diffusion into a porous medium and an investigation into how stent strut compression influences mass transport was conducted. The study revealed that increased compressive forces on a porous media reduced the ability of species to diffuse through that media, and in relation to drug eluting stents will contribute to a reduction in therapeutic levels of drugs within the wall.     

New biocompatible polymer surface coating for stents results in a low neointimal response

Clinical studies indicate a more pronounced endothelial response after stent implantation than after balloon inflation. This might be related to the metal surface of the stent, and therefore it is speculated that coating of the stent might partially prevent hyperplasia. One coated and one noncoated Palmaz-Schatz stent were implanted in two separate coronary arteries of seven pigs. The coating was composed of methylmethacrylate (MMA) (hydrophobic, 70 mol %) and 2-hydroxyethyl methacrylate (HEMA) (hydrophilic 30 mol %). After sacrifice (3 weeks), cross sections were made of the stented areas. Vessel wall reaction was calculated both independently and dependently of local vessel wall injury due to the stent struts. Overall, vessel wall reaction of the coated stents was lower than that of the noncoated stents. The degree of hyperplasia was linearly related to the degree of stent-induced vessel wall injury. Analyses of all the struts showed that significantly less hyperplasia occurred in the coated versus noncoated stents. In this porcine coronary artery model, the MMA/HEMA stent coating resulted in significantly reduced vessel wall response. However, it remains to be determined whether this favorable outcome will also be present in humans.