CN101172168B - 胺糖聚糖负载cd133抗体的金属血管支架涂层与制法 - Google Patents
胺糖聚糖负载cd133抗体的金属血管支架涂层与制法 Download PDFInfo
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Abstract
本发明涉及一种胺糖聚糖负载抗体的金属血管支架涂层与制法。本发明选择壳聚糖和透明质酸等天然可生物降解胺糖聚糖作为载体材料，采用静电自组装技术，首次将CD133抗体固定在金属血管支架纳米涂层中，具有良好的生物相容性、保湿性、柔韧性、耐冲刷性和生物稳定性。CD133抗体涂层支架植入体内后，能特异性迅速捕获外周血液中的血管内皮祖细胞，胺糖聚糖载体良好的生物相容性为血管内皮细胞分化提供了合适的场所，2天内支架表面被分化的单层血管内皮细胞所覆盖，有效地避免局部“假性内膜”的形成，从而加速血管内皮化，快速修复支架在植入过程中，由于球囊扩张导致的血管内膜损伤，是一种更加自然、安全的防止血栓形成与再狭窄的新措施。
Description
技术领域
本发明涉及医疗器械领域中一种金属血管支架生物抗体涂层的配方与制备方法。
背景技术
冠状动脉和外周血管栓塞已成为危害人类健康的第一大杀手，血管内支架置入术已经成为迅速缓解此类疾病的最有效的手段之一。但是裸金属血管支架本身多为金属材料制成，植入血管内可引起炎症反应，在血管内长期牵拉导致内膜增生，并进一步刺激生长因子和细胞因子的分泌，最终导致平滑肌细胞增生和迁移，引起支架内再狭窄。第二代抗排斥药物雷帕霉素和抗癌药物紫杉醇等药物涂层金属血管支架显著地降低了再狭窄和血管不良事件的发生率。然而，这些药物能使细胞分裂停止，从而阻碍支架植入后的血管内膜重建，会造成晚期再狭窄，并导致动脉壁组织坏死。此外涂层载体应用较多的是人工合成聚合物，这些材料生物相容性差，远期易引起炎症反应，可导致更明显的内膜增生反应，临床治疗结果显示药物涂层支架会造成术后的晚期再狭窄。药物涂层在抑制平滑肌细胞增殖的同时，也能抑制血管内皮细胞的再生，导致支架植入后血管内皮化过程延迟，增加了迟发性血栓形成风险。有研究表明，安装裸金属支架并没有影响支架近端和远端的血管对运动的生理性反应。但是，安装药物涂层支架后，运动却导致了支架近端和远端血管的反常收缩。这些发现提示药物涂层支架上抗增殖药物的扩散可能会引起的血管内皮损伤，并可能是引起血管异常反应的原因。美国食品药品监督管理局已相继报道了50例由冠脉药物涂层支架植入术后6个月发生如皮疹、呼吸困难、荨麻疹、瘙痒症和发热等过敏反应，并导致支架内或全身系统性过敏反应，出现的过敏反应会导致一部分患者形成晚期血栓甚至导致死亡，支架载体涂层的聚合物是导致过敏反应发生的最主要原因。
1997年Asahara从外周血中分离出带有CD34和血管内皮因子(VEGFR)2抗原的血管内皮祖细胞(EPCs)，并诱导分化成有功能的血管内皮细胞，证明了具有生成血管的能力，使血管得到了快速修复。[Science，1997，275(5320)：964]2003年Toshihiko等以明胶或微多孔聚氨酯为载体负载狗自体骨髓带有CD34抗原的EPCs种植于人造血管内，然后放植入狗胸主动脉和颈动脉，一周后内皮覆盖率高达92％，而用外周血成熟的内皮细胞种植的对照组内皮覆盖率仅为26％。四周后的组织学发现，EPCs种植的人造血管表面仅由血管内皮祖细胞组成的新生内膜覆盖，而血管内皮细胞种植的对照组则为“假性内膜”所覆盖，假性内膜主要由红色纤维血栓、巨噬细胞、中性细胞和极少数α-肌动蛋白阳性细胞组成，表面无血管内皮细胞覆盖。表明EPCs分化能力比血管内皮细胞更强。[Biomaterials 2003，24：2295]
2005年Kutryk等将干细胞研究分离技术用于金属血管支架涂层，制备出CD34抗体金属血管支架，并2006年5月2日取得了美国专利(U.S.P 7037332)。这种支架是以聚四氟乙烯为载体负载CD34抗体于支架表面，置入血管内能捕获患者自身循环的血管内皮祖细胞EPCs，使支架在48小时内形成单层血管内皮细胞覆盖层，这不仅能降低再狭窄，而且也能对血栓形成有即刻的保护。这种第三代抗体涂层支架是从促进血管内皮细胞愈合角度出发提出的支架设计新构想，与药物支架的抗增殖效应(同时也抑制了血管内皮化)的基本概念截然不同，它是通过以快速和可调控的方式来促进自然愈合过程，在防止血栓形成和再狭窄方面是一个令人瞩目的进展。[J.American College of Cardiology 2005，45(10)：1574]。然而，CD34单克隆抗体为免疫球蛋白IgG，属于水溶性的蛋白聚糖，而涂层载体材料为聚四氟乙烯等脂溶性材料，二者之间几乎无任何生物相容性。当采用聚四氟乙烯四氢呋喃溶液与CD34抗体水溶液混合，乳化后涂于金属支架表面，干燥后，在无水体系下由于CD34抗体天然状态的蛋白质二级结构逐渐改变而使之失活，因此这种CD34抗体支架还不能以满足商品货架期要求，难以大规模商品化。Kutryk等也曾将CD34抗体经过化学交联到人工合成聚合物上，再涂布到金属血管支架上，这种化学交联存在的主要问题不但是抗体部分决定基被化学键合导致失活，也存在抗体在无水涂层中逐渐失活的问题。此外，CD34抗体对EPCs缺乏特异性，在吸附EPCs同时，也能吸附带有CD34抗原的其它内皮细胞，聚四氟乙烯载体也为不能为血管内皮细胞分化提供合适的场所，结果有可能在局部形成“假性内膜”。[Criculation July，5，2005，12-17]
1997年Miraglia首先报道了AC133(2000年被国际干细胞学会定名为CD133)，CD133是一个新发现的造血干细胞(HSCs)表面标志抗原。[Blood 90：5002-5012；5013-5021]缺血、损伤和应激等内源性因素以及细胞因子和药物等外源性因素均可刺激骨髓中的HSCs向外周血释放，在生理和病理性血管处分化成血管内皮细胞。2005年王明元等研究结果表明：在扩增过程中HSCs中的CD34+CD133+细胞，向CD34+CD133-的仍然具有分化能力细胞演变，最后分化为不再分化CD34-CD133-的细胞；CD34+CD133+细胞在体外集落形成以粒细胞和单细胞集落为主，而CD34+CD133-细胞以红系暴式集落占多数，代表早期祖细胞的混合集落和高增殖潜能集落的数量CD34+CD133+细胞显著高于CD34+CD133-细胞；长期启动细胞CD34+CDl33+细胞远多于CD34+CD133-细胞。因此，CD133+可能是较CD34+更为原始的造血干细胞表面标志抗原。外周血中的CD34+/CD133+/VEGFR2+的HSCs为血管内皮祖细胞亚群EPCs，约为0.080％，而CD34+/CD133-/VEGFR2+细胞约为0.034％。EPCs区别于内皮细胞的主要标志是CD133抗原，具有分化能力的内皮细胞(ECs)区别于无分化能力的功能内皮细胞(EC)的主要标志是CD34抗原。CD34并非是EPCs特异性抗原，而CD133则为EPCs特异性抗原，迄今为止，CD133抗原被认为是区分人EPCs细胞最特异性的方法。来源于外周血的CD34+/CD133+/VEGFR2+的EPCs体外诱导分化内皮细胞的潜能比CD34+/CD133-/VEGFR2+细胞更强，分化结果更单一。[J.ClinInvest，2002，109：337]
胺糖聚糖分为碱性胺糖聚糖和酸性胺糖聚糖，在体内均可被溶菌酶逐步降解。碱性胺糖聚糖主要为壳聚糖(Chitosan，CH)，是由几丁质水解产物天然氨基葡萄糖组成的直链高分子聚合物，具有良好的生物相溶性、生物可降解性和抗菌性。CH作为可生物降解的手术缝合线材料获得美国食品药品监督管理局(FDA)批准。CH能抑制血管平滑肌细胞的增生，促进内皮细胞的增长，对伤口愈合有明显的促进作用，为CH用于支架涂层材料预防再狭窄提供了依据。[第二军医大学学报1999，20(12)：962；中国修复重建外科杂志1993，7(4)：244]羧甲基壳聚糖为壳聚糖经过羧甲基化改性后成为一种酸性胺糖聚糖，具有良好的生物相容性、生物可降解性、保湿性和柔韧性。CH和CMCH结合成为最早用于制造手术缝合线的材料。[中国修复重建外科杂志1994，8(2)：81；第二军医大学学报1994，15(5)：452]人体重要的酸性胺糖聚糖有6种：透明质酸(Hyaluronic acid，HA)，肝素，硫酸软骨素，硫酸皮肤素，硫酸角质素和硫酸类肝素。其中只有HA不含有硫酸基而含有羧基，HA是由D-葡萄糖醛酸和N-乙酰氨基葡萄糖双糖单元交替连接而成的一种线性酸性粘多糖，广泛存在于人和动物的细胞间质、眼睛玻璃体、脐带、皮肤、关节滑液等许多软结缔组织中，现在已用生物工程法实现了规模化生产与商品供应。HA具有极高的保湿性、粘弹性、润滑性和良好的生物可降解性，在维持细胞外空间、调节渗透压、润滑、促进细胞修复的等方面具有重要的生理功能，已成为重要的医用生物高分子材料，在医学方面已得到广泛应用，可用作眼科人工晶体植入手术的粘弹剂，骨性关节炎和类风湿性关节炎等关节手术的填充剂，滴眼液和皮下注射药物的辅助媒介，还用于预防术后粘连和促进皮肤伤口的愈合。[Primaphamr公司，FDA 2005批准]高分子量的HA对受损组织显示出高亲和性，为细胞增殖与分化提供合适的场所，直接促进细胞生长、分化、重建与修复，可预防和修复皮肤损伤。尤其是HA在体内可促进内皮细胞的增殖和血管生成的作用，为HA作为支架涂层材料预防再狭窄提供了依据。[J.Biomed MaterRes，2000，05：101-109；International Congress Series，2001，1223：2279-2284；Biomacromolecules 2003，4：1564-1571]
理想的金属支架涂层不但应具有良好的生物相容性，而且能促进受伤组织愈合，防止细胞过度增生，加速血管内皮化，防止血栓和再狭窄，同时应具有一定的生物稳定性。本发明的目的是提供一种金属血管支架生物抗体纳米涂层的配方与制备方法。这种涂层也是从促进受伤血管组织愈合、加速内皮化形成的角度出发，以天然生物可降解的胺糖聚糖为载体，采用静电自组装技术负载CD133抗体于金属血管支架纳米涂层中，置入血管内能特异性迅速捕获患者自身循环的EPCs。胺糖聚糖载体良好的生物相容性为EPCs分化为血管内皮细胞提供了合适的场所，使支架在48小时内形成单层血管内皮细胞覆盖层，可有效地避免局部“假性内膜”的形成，这不仅能降低再狭窄，而且也能对血栓形成有即刻的保护，是一种更加自然也是更加安全的防止血栓形成与再狭窄的新构想。
发明内容
本发明的目的是选用胺糖聚糖为载体材料，采用静电自组装技术负载具有疗效数量的CD133抗体，制得具有良好生物相容性、可生物降解性、保湿性、柔韧性和稳定性的生物抗体纳米涂层金属血管支架。
本发明的技术方案
生物抗体纳米涂层的配方包括：
壳聚糖 占涂层的重量百分数为25-70％；
酸性胺糖聚糖 占涂层的重量百分数为30-75％；
CD133抗体 占涂层的重量百分数为0.000001-0.01％。
配方中的CD133抗体选自单克隆抗体或多克隆抗体，能与人血管内皮祖细胞表面CD133抗原反应。
配方中的酸性胺糖聚糖选自透明质酸(HA)，肝素(HP)，硫酸软骨素或羧甲基壳聚糖(CMCH)。
生物抗体涂层的制法：
在316L不锈钢或镍钛合金血管支架表面上，采用静电自组装技术，交替浸涂喷涂0.1-5.0％酸性胺糖聚糖溶液与0.1-5.0％壳聚糖溶液5-15次，每次浸涂后水洗，热风吹干，使涂层厚度达50-150纳米，再浸涂0.1-5.0％酸性胺糖聚糖溶液与0.0001-0.1％CD133抗体溶液的体积比1∶1混合溶液，水洗，除湿干燥，4℃保存，即得胺糖聚糖负载CD133抗体的金属血管支架涂层。
依据胺糖聚糖与抗体有良好的亲和性，我们首次提出采用静电自组装技术将胺糖聚糖负载CD133抗体于金属血管支架表面，制成生物CD133抗体纳米涂层金属血管支架。上述涂层，具有良好的生物相容性、可降解性、保湿性、柔韧性和生物稳定性，支架被撑开后，涂层不易脱落。目前，尚未见有采用胺糖聚糖通过静电组装负载CD133抗体金属支架生物纳米涂层的文献与专利报道。本设计的这种新构想有可能从根本上改变人们对金属支架涂层的设计初衷，将从新的角度诠释再狭窄问题。
静电自组装负载抗体原理：
CH为碱性胺糖聚糖，结构中具有游离的氨基(CH-NH3 +)而显正电性。酸性胺糖聚糖中游离羧酸根(HA-COO-、HP-SO3 2-、CMCH-COO-)显负电性。CD133抗体为免疫球蛋白G(IgG1)，属于偏酸性的水溶性蛋白聚糖，在pH7.4磷酸盐缓冲溶液(PBS)中，可形成CD133-COO-阴离子，与胺糖聚糖有良好的亲和性。碱性胺糖聚糖和酸性胺糖聚糖通过静电自组装将CD133抗体负载于金属血管支架表面，形成具有保水性和柔韧性良好的生物复合纳米涂层。
静电自组装负载CD133抗体纳米涂层设计原理(以CH与HA组装为例)
(1)基础涂层
(HA-COO-/CH-NH3 +)n
(2)抗体涂层
(HA-COO-/CH-NH3 +)n/HA-COO-§CD133-COO-
(3)抗体涂层吸附血液中EPCs
(HA-COO-/CH-NH3 +)n/HA-COO-§CD133-COO-*EPCs
(4)抗体涂层在体内吸附血液中EPCs并分化为ECs
(HA-COO-/CH-NH3 +)n/HA-COO-§CD133-COO-*EPCs→ECs
上述涂层中：/表示静电组装；§表示混合静电组装；*表示吸附；→表示分化
静电自组装基础涂层检测：
(1)在316L不锈钢片上涂布基础涂层，最外层为CH-NH3 +。置于阳离子菁荧光染料水溶液中5分钟后，用PBS溶液冲洗数次，置荧光显微镜下观察，无红色荧光。而置于阴离子菁荧光染料水溶液中5分钟后，用PBS溶液冲洗数次，置荧光显微镜下观察，呈红色荧光。表明最外涂层为阳离子。
(2)在316L不锈钢片上涂布基础涂层，最外层为HA-COO-。置于阴离子菁荧光染料水溶液中5分钟后，用PBS溶液冲洗数次，置荧光显微镜下观察，无红色荧光。而置于阳离子菁荧光染料水溶液中5分钟后，用PBS溶液冲洗数次，置荧光显微镜下观察，呈红色荧光；表明最外涂层为阴离子。
生物涂层表面特性检测：
在316L不锈钢片上涂布基础涂层(HA-COO-/CH-NH3 +)7/HA-COO-，小角X-射线衍射分析结果显示，每个双分子层厚度约为14.4nm，总厚度约为100nm。基础涂层原子力学三维显微镜扫描结果：线粗糙度Ra为2.528nm，Rp为3.188，Rmax为16.416；面粗糙度Ra为2.556nm，Rp为3.218，Rmax为53.236。可以观察到该涂层表面呈岛状排列均匀致密，有利于提高涂层表面的耐腐蚀性、抗凝血性和稳定性。在316L不锈钢片上涂布基础涂层、抗体涂层和抗体溶液，红外光谱测定结果显示抗体涂层中含有大量的水分，其红外光谱与抗体溶液基本一致，显示出抗体涂层中的抗体仍保持其天然状态的蛋白质二级活性结构。
生物涂层中胺糖聚糖检测：
对照品溶液的制备：精密盐酸氨基葡萄糖对照品适量，加水制成每1ml含10μg的溶液。
供试品溶液的制备：将待测支架置入带有塞的A瓶中(含有0.1mol/L盐酸溶液0.5ml)，超声洗涤30秒后将支架取出，再置入B瓶中(含有0.1mol/L氢氧化钠溶液0.5ml)，超声洗涤30秒后将支架取出，再依次在A与B瓶中循环洗涤10次。将A与B瓶供试品溶液合并，转移置具塞试管中，加浓盐酸溶液1ml，充氮气，密塞，水浴加热1小时，放置室温，用氢氧化钠饱和溶液中和至中性。
取供试品溶液转移置5ml量瓶中，加乙酰丙酮溶液0.5ml，密塞，水浴加热30分钟，放置室温，加对二甲胺基苯甲醛溶液0.5ml，摇匀，加水至刻度，摇匀，显粉红色，约在530nm波长处有最大吸收。另取精密盐酸氨基葡萄糖对照品溶液3ml，置5ml量瓶中，同法测定，即得。[药物分析，第5版，人民卫生出版社，2003年，P329，282]
基础涂层生物相容性：
将(HA-COO-/CH-NH3 +)n/HA-COO-)基础涂层316L不锈钢片上置于新鲜枸橼酸钠抗凝人全血中，37℃孵育1小时，取出用PBS溶液冲洗数次。用2.5％戊二醛溶液固定，再用乙醇系列脱水，乙腈系列脱醇，经临界点干燥，喷银，电子显微镜扫描结果见图1。结果表明：基础涂层与316L不锈钢片比较，有效地减少了对人血的粘附和伪足的生成，改善了金属表面的生物相容性，具有良好的抗凝血性能。
抗体涂层体外捕获EPCs：
将涂布(HA-COO-/CH-NH3 +)7/HA-COO-)基础涂层316L不锈钢片和(HA-COO-/CH-NH3 +)7/HA-COO-§CD133-COO-涂层的316L不锈钢片置新鲜肝素抗凝人全血液中，37℃孵育1小时，取出用PBS溶液冲洗数次。用2.5％戊二醛溶液固定，再用酒精系列脱水，乙腈系列脱醇，经临界点干燥，喷银，电子显微镜下扫描结果见图2，EPCs呈白色球状。实验结果表明：CD133抗体涂层能够特异性迅速捕获外周血中的EPCs。
抗体涂层支架体外稳定性：
将(HA-COO-/CH-NH3 +)7/HA-COO-§CD133-COO-涂层316L不锈钢支架，置于模拟体外循环仪中，在37℃ PBS溶液中进行耐冲刷实验1小时；将(HA-COO-/CH-NH3 +)7/HA-COO-§CD133-COO-涂层316L不锈钢支架，密封置于4℃冷藏保存1年后，分别按荧光免疫组化检测。将支架置荧光素(FITC)标记抗小鼠IgG抗体溶液中，37℃孵育半小时，用PBS溶液冲洗半分钟，在荧光显微镜下观察，表面呈黄绿色荧光，(HA-COO-/CH-NH3 +)7/HA-COO-§CD133-COO-涂层316L不锈钢支架检测结果见图3。实验结果表明：CD133抗体涂层金属血管支架具有良好的耐冲刷性和生物稳定性，在4℃冷藏条件下，至少可保存1年。
抗体涂层支架体内捕获EPCs并分化为ECs：
将(HA-COO-/CH-NH3 +)7/HA-COO-§CD133-COO-涂层丝状316L不锈钢支架，置入新西兰大白兔耳动脉中，于1，24和48小时后取出支架，用PBS溶液冲洗，分成若干片断部分。PBS冲洗，按荧光免疫组化方法将支架置于兔抗人血管内皮生长因子-2多克隆抗体溶液(VEGFR-2)中37℃孵育半小时，取出用PBS溶液冲洗数次，再置罗丹明(TRITC)标记抗兔IgG抗体溶液中，37℃孵育半小时，用PBS溶液冲洗数次，在荧光显微镜下观察，表面呈红色荧光。结果分别见图4，5，6。结果显示：体内1小时，支架约10-20％表面呈红色荧光斑点，表明已捕捉到EPCs；24小时，支架约50％表面呈红色荧光斑点，部分已连成片，表明EPCs已开始分化；体内48小时，支架约80％以上表面呈红色荧光，表明已被单层ECs所覆盖，局部未见有“假性内膜”的形成。基础涂层支架同法试验则不显荧光。上述检测结果表明：CD133抗体涂层在体内血管中能特异性地迅速捕获EPCs，胺糖聚糖载体良好的生物相容性为血管内皮细胞其分化提供了合适的场所，2天后可见到支架表面大部分已被单层ECs所覆盖，局部未见有“假性内膜”的形成。
附图说明
图1.为316L不锈钢基体和316L不锈钢片基础涂层体外对血液的黏附性(图1-1为316L不锈钢片机械抛光，图1-2为涂布了(HA-COO-/CH-NH3 +)2/HA-COO-，图1-3为涂布了(HA-COO-/CH-NH3 +)4/HA-COO-，图1-4为涂布了(HA-COO-/CH-NH3 +)7/HA-COO-)
图2.为316L不锈钢片基础涂层和CD133抗体涂层体外捕获人外周全血液中EPCs(白色类球状)电镜扫描图(图2-1为基础生物涂层，图2-2为抗体涂层，图2-3和图2-4为抗体涂层局部放大图)。
图3.为316L不锈钢支架CD133抗体涂层与FITC标记抗小鼠IgG抗体结合的荧光显微镜图(白色部分为黄绿色荧光)
图4.为CD133抗体涂层316L不锈钢支架置入兔耳动脉内1小时，捕获外周血液中EPCs，与VEGFR-2抗体结合后，再与TRITC标记抗兔Ig61抗体结合的荧光显微镜图(白色部分为红色荧光)
图5.为CD133抗体涂层316L不锈钢支架置入兔耳动脉内24小时，捕获外周血液中EPCs，并分化为ECs，与VEGFR-2抗体结合后，再与TRITC标记抗兔IgG1抗体结合的荧光显微镜图(白色部分为红色荧光)
图6.为CD133抗体涂层316L不锈钢支架置入兔耳动脉内48天，捕获外周血液中EPCs，并分化为ECs，与VEGFR-2抗体结合后，再与TRITC标记抗兔IgG1抗体结合的荧光显微镜图(白色部分为红色荧光)
本发明最大的特点与效果：
(1)本发明选用全天然生物可降解的胺糖聚糖作为载体材料，采用静电自组装技术，首次提出将CD133抗体负载于金属血管支架纳米涂层中，具有良好的生物相容性、保湿性、柔韧性、耐冲刷性和生物稳定性，能够满足商品货架期要求，可大规模商品化。
(2)本发明CD133抗体纳米涂层金属血管支架植入体内后能特异性迅速捕获外周血液中的血管内祖皮细胞，胺糖聚糖载体良好的生物相容性为血管内皮细胞分化提供了合适的场所，2天内支架表面被分化的单层血管内皮细胞所覆盖，同时有效地避免局部“假性内膜”的形成，患者也不需要服用抗排斥药物，实现了支架快速内皮化，并修复受损组织，促进快速愈合，是一种更加自然、安全的防止血栓形成与再狭窄的新措施。
具体实施方式
实施例1
在316L不锈钢金血管支架表面上，采用静电自组装技术，交替浸涂1.0％透明质酸钠溶液与1.0％壳聚糖溶液7次，再浸涂1.0％透明质酸钠溶液1次，每次喷涂后水洗，热风吹干，即得胺糖聚糖金属血管支架基础涂层。
实施例2
在316L不锈钢金血管支架表面上，采用静电自组装技术，交替浸涂1.0％透明质酸钠溶液与0.5％壳聚糖溶液7次，再浸涂1.0％透明质酸钠溶液-0.001％CD133单克隆抗体溶液的体积比1∶1混合溶液，水洗，除湿干燥，4℃保存，即得胺糖聚糖负载CD133抗体的金属血管支架涂层。
实施例3
在镍钛合金血管支架表面上，采用静电自组装技术，交替浸涂1.5％透明质酸钠溶液与1.0％壳聚糖溶液7次，再浸涂1.5％透明质酸钠溶液-0.0005％CD133兔多克隆抗体溶液的体积比1∶1混合溶液，水洗，除湿干燥，4℃保存，即得胺糖聚糖负载CD133抗体的金属血管支架涂层。
实施例4
在316L不锈钢金血管支架表面上，采用静电自组装技术，交替浸涂1.5％肝素钠溶液与1.5％壳聚糖溶液7次，再浸涂1.5％肝素钠溶液-0.0007％CD133单克隆抗体溶液的体积比1∶1混合溶液，水洗，除湿干燥，4℃保存，即得胺糖聚糖负载CD133抗体的金属血管支架涂层。
实施例5
在镍钛合金血管支架表面上，采用静电自组装技术，交替浸涂1.0％羧甲基壳聚糖钠溶液与1.0％壳聚糖溶液7次，再浸涂1.0％羧甲基壳聚糖钠溶液-0.02％CD133单克隆抗体溶液的体积比1∶1混合溶液，水洗，除湿干燥，4℃保存，即得胺糖聚糖负载CD133抗体的金属血管支架涂层。
Claims (4)
1.一种胺糖聚糖负载CD133抗体的金属血管支架涂层，其特征在于金属血管支架表面上生物抗体纳米涂层的配方包括：
壳聚糖 占涂层的重量百分数为25-70％；
酸性胺糖聚糖 占涂层的重量百分数为30-75％；
CD133抗体 占涂层的重量百分数为0.000001-0.01％。
2.按照权利要求1所述胺糖聚糖负载CD133抗体的金属血管支架涂层，其特征在于所述的CD133抗体选自单克隆抗体或多克隆抗体，能与人血管内皮祖细胞表面CD133抗原反应。
3.按照权利要求1所述胺糖聚糖负载CD133抗体的金属血管支架涂层，其特征在于所述的酸性胺糖聚糖选自透明质酸，肝素，硫酸软骨素或羧甲基壳聚糖。
4.一种按照权利要求1所述胺糖聚糖负载CD133抗体的金属血管支架涂层的制备方法，其特征在于：在316L不锈钢或镍钛合金血管支架表面上，采用静电自组装技术，交替浸涂0.1-5.0％酸性胺糖聚糖溶液与0.1-5.0％壳聚糖溶液5-15次，每次浸涂后水洗，热风吹干，使涂层厚度达50-150纳米，再浸涂0.1-5.0％胺糖聚糖溶液与0.0001-0.1％CD133抗体溶液的体积比1∶1混合溶液，水洗，除湿干燥，4℃保存，即得胺糖聚糖负载CD133抗体的金属血管支架涂层。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101574499A CN101172168B (zh) | 2007-10-10 | 2007-10-10 | 胺糖聚糖负载cd133抗体的金属血管支架涂层与制法 |
| PCT/CN2008/072660 WO2009049550A1 (fr) | 2007-10-10 | 2008-10-10 | Revêtement de support de vaisseau sanguin en polysaccharide d'amidoglucosane chargé en anticorps cd133 et son procédé de préparation |
| US12/602,976 US8414873B2 (en) | 2007-10-10 | 2008-10-10 | Blood vessel stent of amidoglucosan polysaccharide loaded with CD133 antibody and its preparation method |
Applications Claiming Priority (1)
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| CN2007101574499A CN101172168B (zh) | 2007-10-10 | 2007-10-10 | 胺糖聚糖负载cd133抗体的金属血管支架涂层与制法 |
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| CN101172168B (zh) * | 2007-10-10 | 2010-06-02 | 大连理工大学 | 胺糖聚糖负载cd133抗体的金属血管支架涂层与制法 |
| CN101357241B (zh) * | 2008-09-12 | 2012-06-13 | 西南交通大学 | 一种钛及其合金心血管植入装置的表面定向固定cd34抗体或cd133抗体的方法 |
| CN101947353B (zh) * | 2010-09-26 | 2012-10-31 | 苏州同科生物材料有限公司 | 含有功能性纳米涂层的可降解医用复合导管及其制备方法 |
| US9597434B2 (en) * | 2013-04-12 | 2017-03-21 | Colorado State University Research Foundation | Surface treatments for vascular stents and methods thereof |
| CN103691007B (zh) * | 2013-12-16 | 2014-12-17 | 安毅 | 一种温敏水凝胶复合涂层血管支架的制备方法 |
| CN104758985B (zh) * | 2015-03-20 | 2017-10-24 | 西南交通大学 | 一种捕获内皮祖细胞EPCs的新型抗凝血支架涂层的制备方法 |
| CN104826177B (zh) * | 2015-06-01 | 2017-11-28 | 巩晓东 | 一种在医疗器械表面固定乙肝抗体的方法 |
| CN110755609A (zh) * | 2018-07-27 | 2020-02-07 | 上海微创医疗器械（集团）有限公司 | 一种特异性抗体的用途、一种植入医疗器械及其制备方法 |
| CN110755608A (zh) * | 2018-07-27 | 2020-02-07 | 上海微创医疗器械（集团）有限公司 | 一种特异性抗体的用途、一种植入医疗器械及其制备方法 |
| CN110895283A (zh) * | 2019-12-10 | 2020-03-20 | 宁波奥丞生物科技有限公司 | 一种高灵敏度的d-二聚体检测试剂盒及其使用方法 |
| CN111544658B (zh) * | 2020-06-24 | 2022-02-01 | 中国人民解放军陆军军医大学 | 一种调控免疫反应和促进内膜再生的心血管植入物及其制备方法 |
| CN113244462B (zh) * | 2021-05-20 | 2022-05-24 | 太原理工大学 | 一种防止支架内再狭窄的药物涂层血管支架及制备方法 |
| CN114225115B (zh) * | 2021-09-27 | 2023-03-17 | 南开大学 | 无损修饰的含有活细胞的血管替代物及制备方法 |
| CN114246992B (zh) * | 2021-12-28 | 2022-12-20 | 湖南华翔医疗科技有限公司 | 一种缓释药物涂层的可降解血管支架及制备方法 |
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| AU3124793A (en) * | 1991-10-29 | 1993-06-07 | Clover Consolidated, Limited | Crosslinkable polysaccharides, polycations and lipids useful for encapsulation and drug release |
| TW381975B (en) | 1997-09-01 | 2000-02-11 | Nrc Group Ltd | A roulette wheel assembly and table arrangement |
| CN1094945C (zh) | 1998-12-24 | 2002-11-27 | 中国科学院长春应用化学研究所 | 稀土配合物组合催化剂的制备方法 |
| US20050267560A1 (en) * | 2000-02-03 | 2005-12-01 | Cook Incorporated | Implantable bioabsorbable valve support frame |
| US8088060B2 (en) | 2000-03-15 | 2012-01-03 | Orbusneich Medical, Inc. | Progenitor endothelial cell capturing with a drug eluting implantable medical device |
| US7919075B1 (en) * | 2002-03-20 | 2011-04-05 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices |
| CN1257753C (zh) * | 2003-04-28 | 2006-05-31 | 浙江大学 | 采用静电自组装制备抗凝血生物材料的方法 |
| CN1278743C (zh) * | 2004-08-13 | 2006-10-11 | 重庆大学 | 药物洗脱性血管支架的制备方法 |
| EP1984035A2 (en) * | 2006-02-13 | 2008-10-29 | Medtronic, Inc. | Medical devices having textured surfaces |
| WO2007100895A2 (en) * | 2006-02-27 | 2007-09-07 | The Johns Hopkins University | Cancer treatment with gamma-secretase inhibitors |
| CN101172168B (zh) * | 2007-10-10 | 2010-06-02 | 大连理工大学 | 胺糖聚糖负载cd133抗体的金属血管支架涂层与制法 |
| CN101161300B (zh) * | 2007-11-27 | 2011-03-16 | 北京美中双和医疗器械有限公司 | 三氧化二砷药物洗脱支架及其制备方法 |
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| US20100215712A1 (en) | 2010-08-26 |
| CN101172168A (zh) | 2008-05-07 |
| US8414873B2 (en) | 2013-04-09 |
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