CN1935274A - Coronary artery medicinal-coating stent - Google Patents
Coronary artery medicinal-coating stentDownload PDFInfo
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Abstract
Translated fromChineseDescription
Translated fromChinese技术领域technical field
本发明涉及一种人体植入支架，尤其涉及一种用于抑制内膜增殖和预防支架内再狭窄的冠状动脉药物涂层支架。The invention relates to a stent implanted in a human body, in particular to a coronary drug-coated stent for inhibiting intima proliferation and preventing restenosis in the stent.
背景技术Background technique
近十余年来，冠状动脉支架植入术成为冠心病治疗中一种有确切疗效的重要手段，在冠心病的治疗中越来越得到广泛的应用，但支架术后再狭窄大大限制了支架术的发展。In the past ten years, coronary artery stent implantation has become an important method with definite curative effect in the treatment of coronary heart disease, and it has been more and more widely used in the treatment of coronary heart disease. development of.
阐明支架内再狭窄的病理生理和发病机制，则为预防支架内再狭窄的关键所在。近年来一致认为，支架植入早期可引起内皮剥脱，使胶原、vWF因子、纤连蛋白和层粘连蛋白等成分暴露于血液中，促进血小板粘附和聚集，并在支架内形成血栓；支架植入后对血管壁的损伤或使脂核破裂，可引起局部急性炎症反应；动脉的损伤还引起血管平滑肌细胞的增殖和迁移以及细胞外基质的增生，这些因素是发生支架内再狭窄的主要机制。支架内再狭窄的治疗较为困难，新近研究显示，冠脉支架植入后，支架内ISR率为28％，在糖尿病和小血管病变等再狭窄高危因素的患者中，ISR率可高达50％～80％；另有报道，随临床特征、造影结果和操作手段不同，支架术后ISR率达10-50％。因此，寻找一种在临床上能有效预防支架内再狭窄的方法，成为介入性心脏病学研究中的热点。Clarifying the pathophysiology and pathogenesis of in-stent restenosis is the key to preventing in-stent restenosis. In recent years, it has been agreed that the early stage of stent implantation can cause endothelial stripping, exposing components such as collagen, vWF factor, fibronectin and laminin to the blood, promoting platelet adhesion and aggregation, and forming thrombus in the stent; The injury to the vessel wall or the rupture of the lipid core after entry can cause local acute inflammatory response; the injury of the artery also causes the proliferation and migration of vascular smooth muscle cells and the hyperplasia of extracellular matrix, these factors are the main mechanism of in-stent restenosis . The treatment of in-stent restenosis is relatively difficult. Recent studies have shown that after coronary stent implantation, the ISR rate in the stent is 28%. In patients with high risk factors for restenosis such as diabetes and small vessel disease, the ISR rate can be as high as 50%. 80%; according to another report, the ISR rate after stenting can reach 10-50% depending on the clinical characteristics, angiographic results and operation methods. Therefore, finding a clinically effective method to prevent in-stent restenosis has become a hot spot in interventional cardiology research.
针对上述机制，临床上抗血小板药物以及抗凝药的使用大大减少了血栓形成的几率，而针对新生内膜增生，近年来也曾尝试过血管内近距离放射治疗，但总体效果不甚满意。In view of the above mechanism, the clinical use of antiplatelet drugs and anticoagulant drugs has greatly reduced the chance of thrombus formation. For neointimal hyperplasia, intravascular brachytherapy has also been tried in recent years, but the overall effect is not satisfactory.
发明内容Contents of the invention
本发明提供一种能够抑制使用者内膜增殖和预防支架内再狭窄，且疗效高、毒副作用低、费用低廉冠状动脉药物涂层支架。The invention provides a coronary drug-coated stent capable of inhibiting user's intimal proliferation and preventing restenosis in the stent, high in curative effect, low in toxic and side effects, and low in cost.
本发明采用如下技术方案：The present invention adopts following technical scheme:
一种用于抑制内膜增殖和预防支架内再狭窄的冠状动脉药物涂层支架，包括：扩张式支架基体，在扩张式支架基体上涂覆有内涂层，上述内涂层由药物载体和川芎嗪组成，其质量比为：3∶1～1∶3，上述药物载体为丙烯酸甲酯、甲基丙烯酸甲酯共聚物、聚乳酸(PLLA)、聚乙醇酸、聚-消旋乳酸、聚丙交酯-乙交酯聚合物、磷酰胆碱、聚氨甲酸乙酯、无机微孔三氧化二铝、纤维素中的一种或一种以上的组合物。本发明还可在内涂层上涂覆有外涂层，该外涂层为丙烯酸甲酯、甲基丙烯酸甲酯共聚物、聚乳酸(PLLA)、聚乙醇酸、聚-消旋乳酸、聚丙交酯-乙交酯聚合物、磷酰胆碱、聚氨甲酸乙酯中的一种或一种以上的组合物涂层。A coronary drug-coated stent for inhibiting intimal proliferation and preventing in-stent restenosis, comprising: an expandable stent base, an inner coating is coated on the expandable stent base, and the inner coating is composed of a drug carrier and Tetramethylpyrazine composition, its mass ratio is: 3:1～1:3, and above-mentioned drug carrier is methyl acrylate, methyl methacrylate copolymer, polylactic acid (PLLA), polyglycolic acid, poly-racemic lactic acid, polypropylene A combination of one or more of lactide-glycolide polymers, phosphorylcholine, polyurethane, inorganic microporous aluminum oxide, and cellulose. The present invention can also be coated with an outer coating on the inner coating, the outer coating is methyl acrylate, methyl methacrylate copolymer, polylactic acid (PLLA), polyglycolic acid, poly-racemic lactic acid, polypropylene A composition coating of one or more of lactide-glycolide polymer, phosphorylcholine and polyurethane.
与现有技术相比，本发明具有如下优点：Compared with prior art, the present invention has following advantage:
本发明以川芎嗪(TMP)为活性成分，将甲基丙烯酸甲酯共聚物和川芎嗪颗粒的组合物、聚乙醇酸依次涂覆于支架基体表面。川芎嗪有潜在的预防血管内再狭窄的作用。川芎嗪的作用机理为：1.抗血小板聚集和血栓生成作用。川芎嗪抑制血小板花生四烯酸代谢，从而抑制血小板TXA2样物质的生物合成和生物活性，同时又促进血管内皮细胞产生PGI2；增加血小板cAMP含量，置换血小板膜上的Ca2+，使其膜流动性增强，并阻断Ca2+对血小板激活和前列腺素代谢及抑制血小板线粒体耗氧量和氧化磷酸化作用，从而抑制血小板的聚集和释放反应；通过钙拮抗作用使血小板内钙离子浓度降低，阻断钙离子对血小板激活和前列腺素的代谢；增强NOS活性，刺激血小板中NO的生成。2.抑制血管平滑肌细胞和成纤维细胞增殖。而支架内再狭窄的主要机制即是平滑肌细胞增殖为主包括细胞外基质的内膜增生。川芎嗪对血管内皮细胞和平滑肌细胞培养有抑制作用，并抑制平滑肌细胞I、III型前胶原的基因转录，可提高抑制AS形成相关基因如P53、NOS等基因的表达。在凝血酶诱导体外培养的兔主动脉血管平滑肌细胞增殖模型中，实验结果证实川芎嗪能够显著抑制凝血酶诱导的血管平滑肌细胞c-myc基因蛋白表达增加，使血管平滑肌处于G1期的细胞数显著增多，S期和M期细胞数显著减少，从而抑制平滑肌细胞增殖。此外，血管紧张素II可通过血管紧张素受体亚型1介导促进心肌细胞的肥大，也可促进成纤维细胞、胶原细胞、血管细胞的增生。川芎嗪可阻滞AT1从而抑制血管紧张素II对心肌细胞的促肥大作用和对非心肌细胞的促增生作用。3.扩张血管作用。内皮素-1(ET-1)是强烈的缩血管物质。多数研究认为ET-1缩血管的机理与平滑肌细胞的钙离子内流有关，川芎嗪可通过抑制平滑肌细胞的钙离子内流而对抗内皮素-1(ET-1)的缩血管作用。此外，研究显示其扩血管作用还与开放小电导钙激活钾通道和ATP敏感型钾通道有关。4.调节脂质代谢，抗脂质过氧化。川芎嗪通过提高超氧化物岐化酶和谷胱甘肽过氧化物酶的活力，提高清除氧自由基的能力，降低脂质过氧化反应。5.保护冠脉内皮。通过降低机体ET水平，提高一氧化氮水平，改善内皮功能紊乱。此外，川芎嗪还具有抗缺血再灌注损伤、抗心肌缺氧复氧损伤、促进心肌细胞能量代谢等作用。In the invention, ligustrazine (TMP) is used as an active ingredient, and the composition of methyl methacrylate copolymer and ligustrazine particles and polyglycolic acid are coated on the surface of a stent base in sequence. Ligustrazine has the potential to prevent intravascular restenosis. The mechanism of action of ligustrazine is as follows: 1. Anti-platelet aggregation and thrombosis. Ligustrazine inhibits the metabolism of arachidonic acid in platelets, thereby inhibiting the biosynthesis and biological activity of platelet TXA2-like substances, and at the same time promotes the production of PGI2 in vascular endothelial cells; increases the cAMP content of platelets, replaces Ca2+ on platelet membranes, and enhances membrane fluidity , and block Ca2+ on platelet activation and prostaglandin metabolism and inhibit platelet mitochondrial oxygen consumption and oxidative phosphorylation, thereby inhibiting the aggregation and release of platelets; through calcium antagonism, the concentration of calcium ions in platelets is reduced, and calcium ions are blocked On platelet activation and prostaglandin metabolism; enhance NOS activity and stimulate NO production in platelets. 2. Inhibit the proliferation of vascular smooth muscle cells and fibroblasts. The main mechanism of in-stent restenosis is smooth muscle cell proliferation mainly including intimal hyperplasia of extracellular matrix. Tetramethylpyrazine can inhibit the culture of vascular endothelial cells and smooth muscle cells, and inhibit the gene transcription of type I and III procollagen in smooth muscle cells, and can increase the expression of genes related to the formation of AS such as P53 and NOS. In the thrombin-induced proliferation model of rabbit aortic smooth muscle cells cultured in vitro, the experimental results confirmed that ligustrazine can significantly inhibit the thrombin-induced increase in the expression of c-myc gene protein in vascular smooth muscle cells, and significantly increase the number of vascular smooth muscle cells in the G1 phase. The number of cells in S phase and M phase decreased significantly, thereby inhibiting the proliferation of smooth muscle cells. In addition, angiotensin II can promote the hypertrophy of cardiomyocytes through the mediation of angiotensin receptor subtype 1, and can also promote the proliferation of fibroblasts, collagen cells, and vascular cells. Tetramethylpyrazine can block AT1 to inhibit the pro-hypertrophic effect of angiotensin II on cardiomyocytes and the pro-proliferative effect on non-cardiomyocytes. 3. Dilate blood vessels. Endothelin-1 (ET-1) is a potent vasoconstrictor. Most studies believe that the mechanism of ET-1 vasoconstriction is related to the influx of calcium ions in smooth muscle cells. Ligustrazine can resist the vasoconstriction of endothelin-1 (ET-1) by inhibiting the influx of calcium ions in smooth muscle cells. In addition, studies have shown that its vasodilator effect is also related to the opening of small conductance calcium-activated potassium channels and ATP-sensitive potassium channels. 4. Regulate lipid metabolism and resist lipid peroxidation. Ligustrazine increases the activity of superoxide dismutase and glutathione peroxidase, improves the ability to scavenge oxygen free radicals, and reduces lipid peroxidation. 5. Protect coronary artery endothelium. By reducing the level of ET in the body, increasing the level of nitric oxide, and improving endothelial dysfunction. In addition, ligustrazine also has anti-ischemia-reperfusion injury, anti-myocardial hypoxia-reoxygenation injury, and promotes the energy metabolism of myocardial cells.
相对于雷帕霉素和紫杉醇涂层支架，川芎嗪涂层支架有以下优点：首先，川芎嗪的药物毒性和副作用相对较弱。其次，川芎嗪来源便利，价格便宜。Compared with rapamycin and paclitaxel-coated stents, ligustrazine-coated stents have the following advantages: First, the drug toxicity and side effects of ligustrazine are relatively weak. Secondly, Ligustrazine has convenient source and cheap price.
附图说明Description of drawings
图1是支架植入后28天裸支架组(BMS)和川芎嗪涂层支架组(TES)组织病理学检查对照图(H&E染色×40)，图1中A是裸支架组图，图1中B是川芎嗪涂层支架组图，图1中箭头所指为新生内膜。Figure 1 is the comparison of histopathological examination of bare stent group (BMS) and ligustrazine-coated stent group (TES) 28 days after stent implantation (H&E staining×40), A in Figure 1 is the bare stent group, Figure 1 Middle B is the photo of the ligustrazine-coated stent, and the arrow in Figure 1 is the neointima.
图2是支架植入后28天BMS和TES免疫组化检查对照图(PCNA染色×400，箭头所指为染色细胞)，图2中A是裸支架组图，图2中B是川芎嗪涂层支架组图，图2中箭头所指为染色细胞。Figure 2 is the control image of BMS and TES immunohistochemical examination 28 days after stent implantation (PCNA staining ×400, the arrow points to the stained cells). Layer scaffold group diagram, the arrows in Figure 2 indicate the stained cells.
图3是体外对TES及BMS进行的扫描电镜观察图片，图3中A、B分别是显示在体外TES扩张前的表面的1000倍、2000倍显微图片，图3中C、D分别是显示在体外TES扩张后的表面的1000倍、2000倍显微照片。Fig. 3 is a scanning electron microscope observation picture of TES and BMS in vitro. A and B in Fig. 3 are 1000 times and 2000 times micrographs of the surface before TES expansion in vitro, respectively. C and D in Fig. 3 are respectively showing 1000X, 2000X photomicrographs of the surface after TES expansion in vitro.
图4是支架血管段形态学测定(H&E染色，箭头所指为新生内膜)图片，图4中A是裸支架组图，图2中B是川芎嗪涂层支架组图。Figure 4 is a picture of the morphological determination (H&E staining, the arrow points to the neointima) of the stent vessel segment. A in Figure 4 is a picture of the bare stent group, and B in Figure 2 is a picture of the ligustrazine-coated stent group.
图5-1是支架植入后28天显微照片显示TMP对左心室心肌的影响，图5-1中A是裸支架组图，图5-1中B是川芎嗪涂层支架组图。Figure 5-1 is a photomicrograph showing the effect of TMP on left ventricular myocardium 28 days after stent implantation, A in Figure 5-1 is a bare stent group, and B in Figure 5-1 is a ligustrazine-coated stent group.
图5-2是支架植入后28天显微照片显示TMP对支架血管段周边组织的影响，图5-2中A是裸支架组图，图5-2中B是川芎嗪涂层支架组图。Figure 5-2 is a photomicrograph 28 days after stent implantation showing the effect of TMP on the surrounding tissue of the stent vessel segment. A in Figure 5-2 is the bare stent group, and B in Figure 5-2 is the ligustrazine-coated stent group picture.
图5-3是支架植入后28天显微照片显示TMP对肺脏的影响，图5-3中A是裸支架组图，图5-3中B是川芎嗪涂层支架组图。Figure 5-3 is a photomicrograph showing the effect of TMP on the lung 28 days after stent implantation, A in Figure 5-3 is a bare stent group, and B in Figure 5-3 is a ligustrazine-coated stent group.
图5-4是支架植入后28天显微照片显示TMP对肝脏的影响，图5-4中A是裸支架组图，图5-4中B是川芎嗪涂层支架组图。Figure 5-4 is a photomicrograph showing the effect of TMP on the liver 28 days after stent implantation, A in Figure 5-4 is a bare stent group, and B in Figure 5-4 is a ligustrazine-coated stent group.
图5-5是支架植入后28天显微照片显示TMP对肾脏的影响，图5-5中A是裸支架组图，图5-5中B是川芎嗪涂层支架组图。Figure 5-5 is a photomicrograph showing the effect of TMP on the kidney 28 days after stent implantation, A in Figure 5-5 is a bare stent group, and B in Figure 5-5 is a ligustrazine-coated stent group.
图5-6是支架植入后28天显微照片显示TMP对脾脏的影响，图5-6中A是裸支架组图，图5-6中B是川芎嗪涂层支架组图。Figure 5-6 is a photomicrograph showing the effect of TMP on the spleen 28 days after stent implantation, A in Figure 5-6 is a bare stent group, and B in Figure 5-6 is a ligustrazine-coated stent group.
图6是本发明的结构示意图。Fig. 6 is a schematic structural diagram of the present invention.
图7是本发明的A-A截面放大图。Fig. 7 is an enlarged view of the A-A section of the present invention.
具体实施方式Detailed ways
一种用于抑制内膜增殖和预防支架内再狭窄的冠状动脉药物涂层支架，包括：扩张式支架基体1，在扩张式支架基体1上涂覆有内涂层2，上述内涂层2由药物载体和川芎嗪组成，其质量比为：3∶1～1∶3，在本实施例中，其质量比可选取3∶1、1∶3或2∶2，上述药物载体为丙烯酸甲酯、甲基丙烯酸甲酯共聚物、聚乳酸(PLLA)、聚乙醇酸、聚-消旋乳酸、聚丙交酯-乙交酯聚合物、磷酰胆碱、聚氨甲酸乙酯、无机微孔三氧化二铝、纤维素中的一种或一种以上的组合物。本实施例还可在内涂层2上涂覆有外涂层3，该外涂层3为丙烯酸甲酯、甲基丙烯酸甲酯共聚物、聚乳酸(PLLA)、聚乙醇酸、聚-消旋乳酸、聚丙交酯-乙交酯聚合物、磷酰胆碱、聚氨甲酸乙酯中的一种或一种以上的组合物涂层。A coronary drug-coated stent for inhibiting intimal proliferation and preventing in-stent restenosis, comprising: an expandable stent base 1, an inner coating 2 is coated on the expandable stent base 1, and the inner coating 2 Composed of drug carrier and ligustrazine, its mass ratio is: 3:1～1:3, in this embodiment, its mass ratio can be selected as 3:1, 1:3 or 2:2, the above-mentioned drug carrier is methyl acrylate ester, methyl methacrylate copolymer, polylactic acid (PLLA), polyglycolic acid, poly-racemic lactic acid, polylactide-glycolide polymer, phosphorylcholine, polyurethane, inorganic microporous A combination of one or more of aluminum oxide and cellulose. In this embodiment, the inner coating 2 can also be coated with an outer coating 3, and the outer coating 3 is methyl acrylate, methyl methacrylate copolymer, polylactic acid (PLLA), polyglycolic acid, poly-sterile A composition coating of one or more of spiral lactide, polylactide-glycolide polymer, phosphorylcholine, and polyurethane.
本发明可以将川穹嗪和涂层材料溶于溶剂中，并配置成溶液，用精密喷枪喷涂在不锈钢支架上，例如：将川穹嗪和涂层聚合物-聚甲基丙烯酸酯共聚物溶于四氢呋喃中，配制成溶液，用精密喷枪喷涂在不锈钢支架上，在60度烘箱中烘干。用精密天平称量控制支架上的川穹嗪的量。在含药的内涂层外面，用同样的方法喷涂一层含有聚乙二醇侧链的聚甲基丙烯酸酯共聚物，用以改善支架表面的抗凝血性。The present invention can be dissolved in the solvent with the triclodazine and the coating material, and be configured into a solution, and sprayed on the stainless steel support with a precision spray gun, for example: dissolve the trichordazine and the coating polymer-polymethacrylate copolymer Prepare a solution in tetrahydrofuran, spray it on a stainless steel support with a precision spray gun, and dry it in a 60-degree oven. Use a precision balance to weigh the amount of tetracycline on the control stand. On the outside of the drug-containing inner coating, a layer of polymethacrylate copolymer containing polyethylene glycol side chains was sprayed with the same method to improve the anticoagulant property of the stent surface.
川芎嗪为常用的中药，在离体的细胞学试验和动物实验中发现有明显的抑制血小板聚集及血栓生成、抑制血管平滑肌细胞和成纤维细胞增殖的作用，国内也有研究提示口服川芎嗪能降低PCI术后再狭窄发生率。但本发明通过制备川芎嗪涂层支架植入猪冠状动脉中，观察到28天支架内内膜增生明显受抑制、支架内再狭窄率明显降低的作用。在猪冠状动脉再狭窄模型中，以具有抑制平滑肌细胞增殖作用的中药川芎嗪制备的川芎嗪涂层支架抑制了新生内膜增殖，降低了支架术后再狭窄率。组织形态学检查显示新生内膜面积川芎嗪涂层支架组比金属裸支架组明显减少，管腔面积明显增大，支架内狭窄程度较对照组明显下降67％，晚期管径丢失明显下降。与其他试验中或临床应用的DESs对比，支架内狭窄程度降低率分别为雷帕霉素(50％)、紫杉醇(39.5％)、雌二醇(40％)，基本处于相似水平，显示川芎嗪作为支架的涂层药物能显著的降低ISR。Ligustrazine is a commonly used traditional Chinese medicine. In vitro cytological tests and animal experiments have found that it can significantly inhibit platelet aggregation and thrombus formation, and inhibit the proliferation of vascular smooth muscle cells and fibroblasts. Domestic studies have also suggested that oral administration of Ligustrazine can reduce The incidence of restenosis after PCI. However, in the present invention, by preparing the ligustrazine-coated stent and implanting it into the porcine coronary artery, it is observed that the intima hyperplasia of the stent is obviously inhibited and the rate of restenosis in the stent is obviously reduced after 28 days. In the porcine coronary artery restenosis model, the Ligustrazine-coated stent prepared with Ligustrazine, a traditional Chinese medicine that can inhibit the proliferation of smooth muscle cells, inhibited neointimal proliferation and reduced the restenosis rate after stenting. Histomorphological examination showed that the neointimal area of the ligustrazine-coated stent group was significantly smaller than that of the bare metal stent group, the lumen area was significantly increased, the degree of stenosis in the stent was significantly reduced by 67% compared with the control group, and the late caliber loss was significantly reduced. Compared with DESs in other trials or clinical applications, the reduction rates of in-stent stenosis were rapamycin (50%), paclitaxel (39.5%), and estradiol (40%), which were basically at similar levels, showing that ligustrazine Coating drugs as stents can significantly reduce the ISR.
本研究28天动态观察动物血常规，肝肾功能，肌钙蛋白T实验组及对照组均未见明显异常。全身重要脏器心、肝、肾、脾以及支架血管段供血的心室壁行组织病理学检查未发现与TES相关的病理损害。28天复查冠状动脉造影及血管内超声未见明显血栓形成。IVUS及组织形态学检查显示新生内膜面积川芎嗪涂层支架组比金属裸支架组明显减少，管腔面积明显增大，结果表明川芎嗪涂层支架有良好的组织相容性和血液相容性。In this study, the blood routine, liver and kidney function, and troponin T of the animals were observed dynamically for 28 days, and no obvious abnormalities were found in the experimental group and the control group. No pathological damage related to TES was found in histopathological examination of the heart, liver, kidney, spleen, and ventricular walls supplied by stented blood vessels. Coronary angiography and intravascular ultrasonography at 28 days showed no obvious thrombus formation. IVUS and histomorphological examination showed that the neointimal area of the ligustrazine-coated stent group was significantly smaller than that of the bare metal stent group, and the lumen area was significantly increased. The results showed that the ligustrazine-coated stent had good histocompatibility and hemocompatibility sex.
申请人对川芎嗪涂层支架预防支架内再狭窄进行了实验，本发明将纯度为99％的川芎嗪单体与甲基丙烯酸甲酯共聚物的组合物及聚乙醇酸均匀喷涂于金属裸支架上，制成含川芎嗪200μg的涂层支架。观察本发明支架对术后再狭窄的短期影响：选择健康小型猪14头，行冠状动脉造影并在左前降支中段随机植入川芎嗪涂层支架或金属裸支架一枚(支架/血管＝1.1-1.2/1.0)，行IVUS检查证实支架贴壁良好，无局部血管夹层、动脉瘤、血管壁内血肿或血管破裂及较大的新鲜血栓形成。术后第28天行CAG和IVUS检查，并处死动物行组织形态学检查和计算PCNA指数，观察支架内再狭窄情况。The applicant conducted an experiment on the ligustrazine-coated stent to prevent restenosis in the stent. In the present invention, the composition of ligustrazine monomer and methyl methacrylate copolymer with a purity of 99% and polyglycolic acid are uniformly sprayed on the bare metal stent On, a coated stent containing 200 μg of ligustrazine was prepared. Observe the short-term impact of the stent of the present invention on postoperative restenosis: select 14 healthy mini-pigs, perform coronary angiography and randomly implant a ligustrazine-coated stent or a bare metal stent in the middle section of the left anterior descending artery (stent/vessel=1.1 -1.2/1.0), IVUS examination confirmed that the stent was well attached to the wall, without local vascular dissection, aneurysm, intramural hematoma or vascular rupture, and large fresh thrombus formation. On the 28th day after operation, CAG and IVUS examinations were performed, and the animals were sacrificed for histomorphological examination and calculation of PCNA index to observe the situation of in-stent restenosis.
结果：14头小型猪均成功在左前降支中段植入支架，其中4头在支架植入后2小时内死亡，其余10头猪(金属裸支架对照组5只，川芎嗪涂层支架组5只)顺利完成复查。28天QCA检查两组随访期血管直径与支架后血管直径相比均明显减小(P＜0.01)；晚期管径丢失川芎嗪涂层支架组为0.28±0.08mm，与对照组(1.70±0.52mm)相比明显减小(P＝0.004)；支架段血管直径狭窄百分比两组分别为10.0±2.1％和60.2±23.5％，川芎嗪涂层支架组明显减小(P＝0.01)；对照组ISR率为60％，川芎嗪组为0。IVUS检查平均面积狭窄百分比两组分别为19.1±10.5％和71.0±23.3％，川芎嗪涂层支架组降低73％(P＝0.007)。组织形态学检查显示两组血管损伤评分和支架内面积相近(P＞0.05)，但川芎嗪涂层支架组管腔面积(4.34±0.93mm2)较对照组(1.29±1.02mm2)明显增加(P＝0.011)，新生内膜面积(1.51±0.45mm2)较对照组(4.60±1.39mm2)明显减少(P＝0.004)，平均面积狭窄百分比(25.6±5.0％)较对照组(77.9±19.7％)降低67％(P＝0.003)，PCNA指数较对照组明显降低(14.7±2.5％vs23.6±3.2％，P＝0.008)。两组IVUS和组织形态学检查相比较，支架内面积、管腔面积、新生内膜面积、平均面积狭窄百分比均相似，差异无统计学意义。Results: All 14 miniature pigs were successfully implanted with stents in the middle of the left anterior descending artery, 4 of them died within 2 hours after stent implantation, and the remaining 10 pigs (5 in the bare metal stent control group, 5 in the ligustrazine-coated stent group) only) successfully completed the review. The 28-day QCA examination showed that the blood vessel diameter in the follow-up period of the two groups was significantly reduced compared with the diameter of the blood vessel after stenting (P<0.01); the late caliber loss was 0.28±0.08mm in the ligustrazine-coated stent group, which was 0.28±0.08mm compared with the control group (1.70±0.52mm). mm) was significantly reduced (P=0.004); the stenosis percentage of stent segment vessel diameter was 10.0±2.1% and 60.2±23.5% in the two groups respectively, and the ligustrazine-coated stent group was significantly reduced (P=0.01); The ISR rate was 60%, and it was 0 in the Ligustrazine group. The average area stenosis percentage of IVUS examination was 19.1±10.5% and 71.0±23.3% respectively in the two groups, and the ligustrazine-coated stent group decreased by 73% (P=0.007). Histomorphological examination showed that the vascular injury score and stent inner area of the two groups were similar (P>0.05), but the lumen area of the ligustrazine-coated stent group (4.34±0.93mm2) was significantly higher than that of the control group (1.29±1.02mm2) (P>0.05). =0.011), the neointimal area (1.51±0.45mm2) was significantly reduced compared with the control group (4.60±1.39mm2) (P=0.004), and the average area stenosis percentage (25.6±5.0%) was significantly lower than that of the control group (77.9±19.7%) It decreased by 67% (P=0.003), and the PCNA index was significantly lower than that of the control group (14.7±2.5% vs 23.6±3.2%, P=0.008). Compared with IVUS and histomorphological examination, the stent inner area, lumen area, neointimal area, and average area stenosis percentage were similar in the two groups, and the difference was not statistically significant.
结论：本实验成功建立猪冠状动脉再狭窄模型；与金属裸支架相比，川芎嗪涂层支架明显降低支架内再狭窄；血管内超声检查可作为猪冠脉再狭窄模型支架内再狭窄研究的评价手段。Conclusion: This experiment successfully established a porcine coronary restenosis model; compared with bare metal stents, ligustrazine-coated stents significantly reduced in-stent restenosis; intravascular ultrasonography can be used as a basis for the study of in-stent restenosis in porcine coronary restenosis models. means of evaluation.
下表是28天定量冠脉造影(QCA)检查结果：The following table is the 28-day quantitative coronary angiography (QCA) examination results:
下表是28天裸支架组和川芎嗪涂层支架组组织形态学和免疫组化检查结果：The following table is the histomorphological and immunohistochemical examination results of the bare stent group and ligustrazine-coated stent group at 28 days:
川芎嗪涂层冠脉支架生物相容性实验研究：Experimental study on the biocompatibility of ligustrazine-coated coronary stents:
目的：药物涂层支架(DES)能显著减低6个月的支架内再狭窄，但其晚期血栓形成备受关注。采用川芎嗪的提取物-四甲基吡嗪作为金属管状支架的涂层制成川芎嗪涂层冠脉支架(TES)，利用局部缓释技术抑制支架内再狭窄。但其远期疗效及安全性尚不清楚。本研究通过冠状动脉造影(CAG)、血管内超声(IVUS)及组织病理学检查观察较大直径TES置入小型猪正常冠状动脉后的血栓形成及内膜增殖情况，以及TES对全身重要脏器的影响。评价其生物相容性。Objective: Drug-eluting stent (DES) can significantly reduce in-stent restenosis at 6 months, but its late thrombosis has attracted much attention. The ligustrazine-coated coronary stent (TES) is prepared by using tetramethylpyrazine, the extract of ligustrazine, as the coating of the metal tubular stent, and the local slow-release technology is used to inhibit restenosis in the stent. However, its long-term efficacy and safety are still unclear. In this study, coronary angiography (CAG), intravascular ultrasound (IVUS) and histopathological examination were used to observe the thrombus formation and intimal proliferation after the larger diameter TES was implanted in the normal coronary artery of minipigs, and the effect of TES on the important organs of the whole body. Impact. Evaluate its biocompatibility.
方法：实验组：川芎嗪涂层支架为不锈钢316L金属管状支架经喷涂川芎嗪单体制成，为双涂层，内层为甲基丙烯酸甲酯共聚物及川芎嗪颗粒，含川芎嗪200μg。其外为聚乙醇酸(PGA)涂层。制成含川芎嗪200μg的涂层支架。对照组为金属裸支架(BMS)。小型猪14头，其中实验组7头，对照组7头。分别于猪冠状动脉左前降支或右冠状动脉置入较大直径TES及BMS，支架与血管直径比(1.1~1.2/1.0)。支架置入前、术后第1天及第28天抽血观察动物血常规、肝肾功能、肌钙蛋白T(TNT)。全程观察动物血压、心率及行为状态。支架置入前后均行定量冠状动脉照影(QCA)及血管内超声检查。术后第28天行CAG及IVUS观察支架内内膜增殖及血栓形成情况。实验终点处死动物，获取心、肾、肝、肺、脾、支架置入段血管及支架前后5CM处组织行病理学检查。Methods: Experimental group: ligustrazine-coated stents were made of stainless steel 316L metal tubular stents sprayed with ligustrazine monomer. It was double-coated. The inner layer was methyl methacrylate copolymer and ligustrazine particles, containing 200 μg ligustrazine. It is coated with polyglycolic acid (PGA). A coated stent containing 200 μg of ligustrazine was prepared. The control group was bare metal stents (BMS). There are 14 miniature pigs, including 7 in the experimental group and 7 in the control group. Larger-diameter TES and BMS were implanted in the left anterior descending coronary artery or right coronary artery respectively, and the ratio of stent to vessel diameter (1.1-1.2/1.0). Before stent implantation, blood was drawn on the 1st day and 28th day after the operation to observe the blood routine, liver and kidney function, and troponin T (TNT) of the animals. The blood pressure, heart rate and behavior of the animals were observed throughout the process. Quantitative coronary angiography (QCA) and intravascular ultrasonography were performed before and after stent implantation. On the 28th day after operation, CAG and IVUS were performed to observe the intimal proliferation and thrombus formation of the stent. At the end of the experiment, the animals were sacrificed, and the heart, kidney, liver, lung, spleen, blood vessels in the stent-placed segment, and tissues at 5 cm before and after the stent were obtained for pathological examination.
结果：14只动物均成功置入支架。2只动物因心包填塞死于预实验，1只动物支架置入后因麻醉过深死亡。1只动物手术结束结扎股动脉时血管破裂，大出血死亡。5只动物于前降支或右冠状动脉近中段成功置入TES，5只动物置入BMS，支架置入前、术后第1天及第28天动物血常规、肝肾功能无明显差异，TNT未见明显异常。术后第28天复查冠脉造影及血管内超声检查证实实验组、对照组局部管壁完整，管壁无溃疡、血管瘤，无中层坏死，未见血栓形成。均无血管痉挛。术后处死动物后组织病理学检查提示心、肾、肝、肺、脾无明显损害。所有支架置入节段均完全内皮化，TES组及BMS组支架端血管均有不同程度新生内膜增生，无异物巨细胞聚集。28天QCA检查两组随访期血管直径与支架后血管直径相比均明显减小(P＜0.01)，支架段血管直径狭窄百分比两组分别为对照组60.2±23.5％和实验组10.0±2.1％，川芎嗪涂层支架组明显减小(P＝0.01)。组织形态学检查显示两组血管损伤评分和支架内面积相近(P＞0.05)，但川芎嗪涂层支架组管腔面积(4.34±0.93mm2)较对照组(1.29±1.02mm2)明显增加(P＝0.011)，新生内膜面积(1.51±0.45mm2)较对照组(4.60±1.39mm2)明显减少(P＝0.004)。两组IVUS和组织形态学检查相比较，支架内面积、管腔面积、新生内膜面积均相似，具有较好的相关性。Results: All 14 animals were successfully implanted with stents. Two animals died in the pre-experiment due to cardiac tamponade, and one animal died due to deep anesthesia after stent implantation. One animal died of hemorrhage due to blood vessel rupture during femoral artery ligation at the end of the operation. 5 animals were successfully implanted with TES in the anterior descending artery or near the middle part of the right coronary artery, and 5 animals were implanted with BMS. There was no significant difference in blood routine, liver and kidney function before, on the 1st day and 28th day after stenting. TNT showed no obvious abnormality. Coronary angiography and intravascular ultrasonography on the 28th day after operation confirmed that the local wall of the experimental group and the control group was intact, there were no ulcers, hemangiomas, necrosis of the middle layer, and no thrombus formation. There was no vasospasm. Histopathological examination after the animals were sacrificed showed no obvious damage to the heart, kidney, liver, lung and spleen. All stented segments were completely endothelialized, and there were different degrees of neointimal hyperplasia in the stent-end vessels in the TES group and the BMS group, and there was no foreign body giant cell accumulation. The 28-day QCA examination showed that the diameter of blood vessels in the two groups during the follow-up period was significantly reduced compared with the diameter of the blood vessels after stenting (P<0.01). , the ligustrazine-coated stent group was significantly reduced (P = 0.01). Histomorphological examination showed that the vascular injury score and stent inner area of the two groups were similar (P>0.05), but the lumen area of the ligustrazine-coated stent group (4.34±0.93mm2) was significantly higher than that of the control group (1.29±1.02mm2) (P>0.05). =0.011), the neointima area (1.51±0.45mm2) was significantly lower than that of the control group (4.60±1.39mm2) (P=0.004). Compared with the IVUS and histomorphological examinations of the two groups, the stent inner area, lumen area, and neointima area were all similar and had a good correlation.
结论：TES具有显著抑制内膜增殖的作用，无致栓性，对全身重要脏器无毒性反应，具有良好的生物相容性。IVUS结合组织病理学检查能够区别血栓和斑块，能够准确测量新生内膜面积，IVUS和组织病理学检查具有良好的相关性。Conclusion: TES has the effect of significantly inhibiting the proliferation of the intimal membrane, has no thrombogenicity, has no toxic reaction to the important organs of the whole body, and has good biocompatibility. IVUS combined with histopathological examination can distinguish between thrombus and plaque, and can accurately measure the neointimal area. IVUS and histopathological examination have a good correlation.
参照图3、图4，在体外对支架涂层进行的扫描电镜观察显示，在支架扩张前(A、B)，川芎嗪药物涂层能均匀覆盖于支架表面。球囊加压扩张后(C、D)未发现涂层断裂，剥落，表明该涂层能与支架牢固结合，从而避免因涂层与支架分离、脱落所引起的血管闭塞，远端栓塞。Referring to Fig. 3 and Fig. 4, the scanning electron microscope observation of the stent coating in vitro shows that before the stent is expanded (A, B), the ligustrazine drug coating can evenly cover the surface of the stent. After the balloon was pressurized and expanded (C, D), the coating was not broken or peeled off, indicating that the coating can be firmly combined with the stent, thereby avoiding vascular occlusion and distal embolism caused by the separation and shedding of the coating and the stent.
表3：支架植入前后猪外周血细胞计数，血液生化指标及肌钙蛋白T变化Table 3: Peripheral blood cell counts, blood biochemical indicators and troponin T changes in pigs before and after stent implantation
A：TES植入前及植入后1天和28天血细胞计数和肌钙蛋白T溶度A: Blood cell count and troponin T solubility before TES implantation, 1 day and 28 days after implantation
缩写：WBC，白细胞计数；RBC，红细胞计数；HGB，血红蛋白；TNT，肌钙蛋白T.B：TES植入前及后1天，28天生化指标评估Abbreviations: WBC, white blood cell count; RBC, red blood cell count; HGB, hemoglobin; TNT, troponin T.B: Evaluation of biochemical indicators before and 1 day after TES implantation, and 28 days
缩写：ALT，谷丙转氨酶；AST，谷草转氨酶；BUN，血尿素氮；Scr，血肌酐Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Scr, blood creatinine
表4：支架血管段的最小冠脉直径(mm)Table 4: The minimum coronary artery diameter (mm) of the stent segment
*与植入前比较P＝0.001**与植入后比较P＝0.002*P=0.001 compared with pre-implantation **P=0.002 compared with post-implantation
#与植入前比较P＝0.007##与植入后比较P＝0.002#Compared with pre-implantation P=0.007##Compared with post-implantation P=0.002
支架植入后28天TMP对心脏局部组织和全身各重要脏器的影响参见图5-1～图5-6。28 days after stent implantation, the effects of TMP on local cardiac tissue and various important organs of the whole body are shown in Figure 5-1 to Figure 5-6.
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- 2006-10-20CNCN 200610096840patent/CN100493627C/ennot_activeExpired - Fee Related
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| CN102397119A (en)* | 2011-09-29 | 2012-04-04 | 微创医疗器械(上海)有限公司 | Interventional medical instrument and preparation method thereof |
| CN102499798A (en)* | 2011-09-29 | 2012-06-20 | 微创医疗器械(上海)有限公司 | Interventional medical device and preparation method thereof |
| WO2013044603A1 (en)* | 2011-09-29 | 2013-04-04 | 上海微创医疗器械（集团）有限公司 | Interventional medical device and manufacturing method thereof |
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| CN105877881A (en)* | 2015-03-03 | 2016-08-24 | 周玉杰 | Method for preparing personalized bionic drug eluting coronary stent by using 3D printing technology |
| CN108452392A (en)* | 2018-03-28 | 2018-08-28 | 周胜华 | A kind of newtype drug coating bracket and preparation method thereof |
| CN110283296A (en)* | 2019-06-20 | 2019-09-27 | 中国科学院长春应用化学研究所 | Difunctional polyurethane and the preparation method and application thereof |
| CN113425913A (en)* | 2021-06-17 | 2021-09-24 | 江阴市人民医院 | Functional appliance for thoracic surgery |
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