CN100506293C - 促进内皮细胞粘附的涂层 - Google Patents

促进内皮细胞粘附的涂层 Download PDF

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Publication number
CN100506293C
CN100506293C CNB018066801A CN01806680A CN100506293C CN 100506293 C CN100506293 C CN 100506293C CN B018066801 A CNB018066801 A CN B018066801A CN 01806680 A CN01806680 A CN 01806680A CN 100506293 C CN100506293 C CN 100506293C
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China
Prior art keywords
instruments
medical apparatus
substrate
antibody
fullerene
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CNB018066801A
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CN1418115A (zh
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M·J·B·库特凯
R·J·小科顿
S·M·罗兰
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OrbusNeich Medical Appliance (Shenzhen) Co., Ltd.
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Orbus Medical Technologies Inc
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    • C12N2510/00—Genetically modified cells

Abstract

本发明提供生产包涂了基质和与内皮细胞抗原反应的抗体的医疗器械(如斯腾特固定膜或合成移植物)的组合物和方法。包涂所述医疗器械的所述基质可由合成的材料组成，如聚尿烷、聚L-乳酸、纤维素酯或聚乙二醇。在另一实施方式中，所述基质由天然的材料如胶原蛋白、血纤蛋白、弹性蛋白、无定形炭组成。在第三个实施方式中，所述基质可由长约为C60-C100的呋仑碳组成。所述抗体促进内皮细胞粘附在所述医疗器械上。所述抗体可与所述基质混合，或者可提供连接物分子共价连接于所述基质。在粘附到所述医疗器械上后，内皮细胞在所述医疗器械上分化和增殖。所述抗体可以是不同类型的单克隆抗体。

Description

促进内皮细胞粘附的涂层
本申请要求拥有2000年3月15日提交的美国临时申请第60/189,674号和2000年5月4日提交的60/201,789号的权益。
技术领域
本发明涉及植入体内脉管中的医疗器械领域。具体而言，本发明涉及植入血管中、加入了促进内皮细胞粘附于其上的斯腾特固定膜或合成移植物。
背景技术
动脉粥样硬化是世界上引起死亡和劳动能力丧失的主要原因之一。动脉粥样硬化涉及脂肪斑在动脉的管腔表面沉积。脂肪斑在动脉管腔表面的沉积引起动脉的横截面面积变窄。最终，这种沉积作用阻断血液流向该病灶的远端，引起由该动脉提供血液的组织的局部缺血性损伤。
冠状动脉向心脏提供血液。冠状动脉粥样硬化(CAD)是美国最常见、严重、慢性、威胁到生命的疾病，它影响到1千1百万人以上。冠状动脉粥样硬化的社会和经济成本远远超过绝大多数其它疾病。冠状动脉腔变窄导致心脏肌肉被破坏，结果首先会引起绞痛，接着导致心肌梗塞，最终导致死亡。美国每年有超过一百五十万人患有心肌梗塞。这些患者中有六十万人(或者40％)患有急性心肌梗塞，并且他们当中超过三十万的患者在到达医院前就已经死亡(Harrison′s Principles of Internal Medicine，第14版，1998)。
可采用经皮跨腔冠状气囊血管形成术(PTCA)治疗CAD。美国每年有400,000例以上患者进行这种治疗。在PTCA中，将气囊导管插入外周动脉，然后使其穿过动脉系统，到达受阻塞的冠状动脉。然后使该气囊充气，这样将使该动脉拉伸，结果使该阻塞的脂肪斑变平，从而增加了通过该受影响的动脉的横截面的血流。但是，这种治疗不一定使该受影响的冠状动脉永久开放。经PTCA治疗的患者中有多达50％的人需要在六个月内重复该治疗，以矫正重新变窄的冠状动脉。在PTCA治疗后动脉的这种再变窄在医学上称为再狭窄。准确地说，再狭窄涉及脉管的弹回和收缩。脉管弹回和收缩之后是由PTCA治疗引起的动脉的损伤导致的中层平滑肌细胞的增殖。平滑肌细胞的增殖部分是由损伤区域释放的各种炎症因子介导的，包括血栓素A2、血小板衍生生长因子(PDGF)和成纤维细胞生长因子(FGF)。可采用许多不同的技术来克服再狭窄问题，其中包括使用各种药物制剂对患者进行治疗，或者使用斯腾特固定膜从机械上维持动脉开放(Harrison′s Principles of Internal Medicine，第14版，1998)。
在克服再狭窄所采用的各种方法中，已证明斯腾特固定膜是最有效的。斯腾特固定膜是放在患病血管部分以产生正常的血管腔的金属支架。将斯腾特固定膜放置在受影响动脉部分可防止该动脉的弹回和随后的闭合。斯腾特固定膜还可防止动脉沿着其中间层分离。通过维持着比单独采用PTCA所产生的腔更大的腔，斯腾特固定膜减少再狭窄发病多达30％。尽管斯腾特固定膜具有这样的成功，但是它仍未能完全消除再狭窄(Suryapranata等人，1998，《在经选择的急性心肌梗塞患者中使用气囊血管形成术进行的冠状斯腾特固定膜治疗的随机比较》，Circulation，97：2502-2502)。
动脉的狭窄可在非冠状动脉的动脉中发生，包括主动脉骼动脉、腹股沟下动脉、远端股深动脉、远端腘部动脉、胫动脉、锁骨下动脉和肠系膜动脉。外周动脉粥样硬化(PAD)的发病率依赖于受影响的具体的解剖学位点以及用于诊断该阻塞的标准。通常，医师进行间歇性跛行测试，以确定是否存在PAD。但是，这种测量可能会极大地低估了人群中这种疾病的准确发病率。PAD的例子似乎根据年龄而改变，年龄较大的个体PAD的发病率增加。国家医院发放调查(NationalHospital Discharge Survey)得到的数据估计，每年有55,000位男性和44,000位女性在第一次诊断中就诊断出患有慢性PAD，而60,000位男性和50,000位女性在第一次诊断中诊断出患有急性PAD。急性PAD患者中有91％累及下肢。PAD患者合并CAD的发病率可超过50％。此外，在PAD患者中脑血管疾病的发病率在增加。
可采用经皮跨腔气囊血管形成术(PTA)治疗PAD。共同采用斯腾特固定膜与PTA进行治疗可降低再狭窄的发病率。但是，使用医疗器械(如斯腾特固定膜)所获得的术后结果与采用标准的手术性换血管术(即，那些使用静脉的或修补术用的分流术用材料)所获得的结果不匹配(Principles of Surgcry，Schwartz等人编辑，第20章，Arterial Disease，第7版，McGraw-Hill Health Professions Division，纽约，1999)。
较佳的是，采用分流术治疗PAD，其中，使用移植物对动脉的阻塞部分进行分流(Principles of Surgery，Schwartz等人编辑，第20章，Arterial Disease，第7版，McGraw-Hill Health Professions Division，纽约，1999)。移植物可由自体静脉部分(如隐静脉)组成，或者移植物是如由聚酯、聚四氟乙烯(PTFE)或发泡的聚四氟乙烯(ePTFE)制成的合成移植物。术后的开放比例取决于许多不同的因素，包括该分流术用移植物的腔大小、该移植物的合成材料的类型以及流出的位点。但是，即使使用了分流术用移植物，再狭窄和血栓形成仍然是个显著的问题。例如，对于股骨-腘分流术，使用ePTFE分流术用移植物的腹股沟下分流术在3年后的开放比例是54％，而对于股骨-胫骨分流术，这个比例仅为12％。
结果，仍明显需要改进斯腾特固定膜和合成分流术移植物的性能，以进一步减少CAD和PAD的发病率和死亡率。
已使用各种抗血栓形成或抗再狭窄制剂包涂斯腾特固定膜，以便减少血栓形成和再狭窄。例如，植入具有放射性物质的斯腾特固定膜似乎通过抑制成肌纤维细胞的迁移和增殖而抑制了再狭窄(美国专利第5,059,166号、第5,199,939号和第5,302,168号)。经治疗的血管的辐射可能或给医师和患者提出安全性问题。此外，辐射并未给受影响的血管带来均匀的治疗。
或者，也已使用化学制剂(如肝素或磷酸胆碱，这两者似乎都可减少血栓形成和再狭窄)包涂斯腾特固定膜。虽然肝素和磷酸胆碱似乎在短期内都可明显减少动物模型的再狭窄，但是使用这些制剂进行的治疗似乎不具有阻止再狭窄的长期效果。此外，肝素可导致血小板减少，结果导致严重的血栓栓塞性并发症如中风。尽管如此，使用具有足够的治疗有效量的肝素或者磷酸胆碱的斯腾特固定膜，以以这样的方式治疗再狭窄的做法在实践上仍是不可行的。
已将合成的移植物处理成各种形式，以用其减少术后再狭窄和血栓形成(Bos等人，1998，《小直径血管移植物修补术：目前的状况》，Archives Physio.Biochem.，106：100-115)。例如，已报道，与ePTFE移植物相比，聚尿烷的合成材料如将筛选的聚碳酸酯尿烷可减少再狭窄。也已采用射频辉光放电对移植物的表面进行修饰，以将聚对苯二酸酯(polyterephalate)加到ePTFE移植物上。也已用生物分子(如胶原蛋白)浸渍合成的移植物。但是，这些方法中没有哪一种可长时间明显地减少血栓形成和再狭窄的发病率。
因为内皮细胞具有某些内在的特性，如具有降低血栓形成或再狭窄的发病率的细胞调节分子，所以刺激内皮细胞单层在斯腾特固定膜或合成移植物表面上的发育可阻止再狭窄和血栓形成的发生(Belle等人，1997，《斯腾特固定膜内皮化》(Stent Endothelialization)，Circulation，95：438-448；Bos等人，1998，《小直径血管移植物修补术：目前的状况》，Archives Physio.Biochem.，106：100-115)。
通过一种内皮细胞促分裂原——血管内皮生长因子(VEGF)的局部传送，使得内皮细胞在植入斯腾特固定膜中后沉积在其表面上(Belle等人，1997，《斯腾特固定膜内皮化》，Circulation，95：438-448)。因为VEGF的应用可具有全身及局部的效果，所以这种形式的治疗可能是不可靠的。
也已在合成移植物上植入内皮细胞，但这类移植物的临床结果通常很差，即其术后开放比例低(Lio等人，1998，《微血管移植中的新概念和材料：修补术用移植物内皮细胞植入和基因治疗》，Microsurgery，18：263-256)。
因此，仍需要开发出使用内皮细胞涂布医疗器械(如斯腾特固定膜和合成移植物)的新方法和组合物。这种类型的涂料将不仅仅阻止再狭窄，还可阻止由植入斯腾特固定膜所产生的血栓栓塞性并发症。提供这种改进的方法和组合物将消除现有技术的缺陷，并对CAD和PAD相关的发病率和死亡率具有显著的积极的影响。本发明的目的是以刺激内皮细胞粘附到医疗器械(如斯腾特固定膜或合成移植物)上的方式制备斯腾特固定膜和合成移植物。
发明内容
本发明提供使用促进内皮细胞粘附于医疗器械的基质包涂医疗器械的方法和组合物。该基质中加入了促进内皮细胞粘附于医疗器械表面的抗体。
“医疗器械”在本文中指暂时或永久引入哺乳动物中，以预防或治疗医学病症的器械。这些器械包括皮下、经皮或者经外科手术引入，并停留在器官、组织或内腔中的任何器械。医疗器械可包括斯腾特固定膜、覆盖的斯腾特固定膜〔如覆盖了聚四氟乙烯(PTFE)或发泡的聚四氟乙烯(ePTFE)的固定膜〕、合成移植物、人工心脏瓣膜、将修补的器官连接于血管循环系统的人工心脏或固定物、静脉瓣膜、腹部主动脉瘤(AAA)移植物、下腔静脉过滤器、永久性药物灌注导管、栓塞环、用于血管栓塞形成的栓塞用材料(如PVA泡沫)以及血管缝合线。
采用本发明的组合物和方法对上述医疗器械进行的包涂可刺激内皮细胞层在所述医疗器械上的发育，从而组织再狭窄以及由植入该医疗器械所产生的血栓栓塞性并发症。
可使用合成移植物和斯腾特固定膜治疗CAD或PAD。斯腾特固定膜或合成移植物可被加入了刺激循环的原始内皮细胞粘附于该医疗器械的抗体的基质所包涂。所述抗体可包括与内皮细胞表面抗原(如CD34，一种在原始内皮细胞表面上表达的抗原)反应的单克隆抗体。也可使用单克隆抗体的Fab片段。在另一实施方式中，也可使用针对其它内皮细胞表面抗原(如KDR或Tie-2)的单克隆抗体。在一个实施方式中，可使用与一个抗原反应的单一类型的抗体。或者，可将针对不同内皮细胞表面抗原的许多不同抗体混合，然后将其加到基质中。
包涂所述医疗器械的基质可由合成材料如聚尿烷、聚L-乳酸、纤维素酯或聚乙二醇组成。在另一实施方式中，该基质由天然的材料如胶原蛋白、血纤蛋白、弹性蛋白或无定形炭组成。该基质可几个层，第一层由合成的或天然的物质组成，第二层由抗体组成。这些层可顺次排放，第一层直接与斯腾特固定膜或合成移植物的表面接触，第二层的一面与第一层接触，而另一面与血管腔接触。
在第三个实施方式中，该基质可含有呋仑碳(fullerene)，其中，呋仑碳的范围是约C60到约C100。也可将呋仑碳排列成毫微管(nanotube)，加入分子或蛋白质。还可将呋仑碳与PTFE或ePTFE或者抗体混合。或者，可先将PTFE或ePTFE作为医疗器械上的第一层，而将呋仑碳作为第二层。
基质可非共价或共价地与医疗器械连接。可使用不同或相同的双官能交联剂将抗体共价连接于所述基质。
本发明还提供了治疗动脉粥样硬化的方法。所述动脉可以是冠状动脉或者外周动脉(如股骨动脉)。
附图描述
图1显示通过交联分子共价连接于基质的抗体。
图2显示C60O分子锚定基质的图解。
具体实施方式
综述
本发明提供使用基质对医疗器械(如斯腾特固定膜或合成移植物)进行包涂的方法和组合物。在一个实施方式中，该基质加入了促进内皮细胞粘附于所述医疗器械的治疗有效量的至少一种类型的抗体。粘附后，所述内皮细胞在所述基质表面上分化并增殖。在将所述医疗器械植入血管中后，它上面的内皮细胞的存在减少了再狭窄和血栓形成的发生。
术语“抗体”在本文中指一类单克隆抗体或多克隆抗体，其中所述单克隆抗体或多克隆抗体结合于一种抗原或该抗原的功能等价物。术语抗体包括抗体的任何片段，如Fab、F(ab′)2或Fc片段。(抗体包括许多单独的抗体分子，其量等于每摩尔抗体6.022×1023个分子)。
“治疗有效量的抗体”在本文中指促进内皮细胞粘附于医疗器械的抗体的量。实施本发明所需的抗体的量随所使用的抗体的性质而变。例如，所使用的抗体的量将依赖于抗体与与之反应的抗原之间的结合常数。本领域熟练的技术人员已经知道如何测定将用于具体抗原的抗体的治疗有效量。
“医疗器械”在本文中指暂时或永久引入哺乳动物中，以预防或治疗医学病症的器械。这些器械包括皮下、经皮或者经外科手术引入，并停留在器官、组织或内腔中的任何器械。医疗器械可包括斯腾特固定膜、覆盖的斯腾特固定膜〔如覆盖了聚四氟乙烯(PTFE)或发泡的聚四氟乙烯(ePTFE)的固定膜〕、合成移植物、人工心脏瓣膜、将修补的器官连接于血管循环系统的人工心脏或固定物、静脉瓣膜、腹部主动脉瘤(AAA)移植物、下腔静脉过滤器、永久性药物灌注导管、栓塞环、用于血管栓塞形成的栓塞用材料(如PVA泡沫)以及血管缝合线。
“再狭窄”在本文中指动脉壁的内膜中平滑肌细胞层和基质蛋白的积累。血管可以由于再狭窄的缘故而变得阻塞。在PTCA或PTA治疗后，中膜和外膜中的平滑肌细胞(不常存在于内膜)增殖，并迁移到内膜中，并在那分泌蛋白质，形成平滑肌细胞和基质蛋白的积累。这种积累引起动脉腔变窄，减少血液流向该狭窄处的远端。“再狭窄的抑制”在本文中指对平滑肌细胞的迁移和增殖的抑制作用，这种抑制作用伴随着防止蛋白质分泌，从而防止再狭窄和由再狭窄引起的并发症而实现。
可采用本发明的方法和组合物进行治疗的对象可以是哺乳动物，或者，具体而言是人、狗、猫、猪、啮齿动物或者猴。
本发明方法可在活体内或活体外实施。
术语“内皮细胞”指从原始到成熟阶段的任何发育阶段的内皮细胞。可从动脉或静脉(如人脐带静脉)分离得到完全分化的内皮细胞，而从外周血或骨髓中分离得到原始内皮细胞。通过使内皮细胞与包涂了具有与其粘附的抗体或其它制剂的基质的医疗器械一起培育，可将该内皮细胞结合到该医疗器械上。
本发明的方法可在任何动脉或静脉中实施。包括在本发明范围内的是包括冠状动脉、腹股沟下动脉、腹主动脉与骼动脉、锁骨下动脉肠系膜动脉和肾动脉在内的任何动脉的动脉粥样硬化。其它类型的血管阻塞(如从解剖的动脉瘤获得那些)也包括在本发明的范围内。
可在医疗器械被插入血管中后再用内皮细胞将其包被。或者，在插入之前就将其包被。在任何一种情况中，医疗器械腔表面上内皮细胞的存在都会抑制或防止再狭窄和血栓形成。
内皮细胞
根据Jaffe等人(J.Clin.Invest.，52：2745-2757，1973)的方法(本文纳入作为参考)从脐带获得人脐带静脉内皮细胞(HUVEC)。简言之，使用胶原蛋白酶进行处理，从血管壁剥离得到细胞，然后将其放在明胶包涂的组织培育瓶中的M199培养基中培养，该培养基含有10％低内毒素胎牛血清、90μg/ml无防腐剂猪肝素、20μg/ml内皮细胞生长添加物(ECGS)、谷氨酰胺和抗体。
根据Asahara等人(《用于血管生成的推定原始内皮细胞的分离》，Science，275：964-967，1997，本文纳入作为参考)等人的方法从人外周血分离得到原始的内皮细胞。使包涂有针对CD34的抗体的磁珠与人外周血一起培育。培育后，洗脱出结合的细胞，然后将其培育在含有20％胎牛血清和牛脑抽提物的M-199培养基(Clonetics，San Diego，CA)中。以针对CD45、CD34、CD31、Flk-1、Tie-2和E-选择蛋白的荧光抗体表征细胞。
采用常规的方法将内皮细胞转染含有编码诸如血小板衍生生长因子(PDGF)、成纤维细胞生长因子(FGF)或一氧化氮合成酶(NOS)之类的蛋白质的任何克隆基因的任何哺乳动物表达载体(例如可参见，哺乳动物表达载体和可从Stratagene，SanDiego，CA购得的转染试剂盒)。例如，根据Rosengart等人的方法，使用表达VEGFcDNA的腺病毒表达载体使猪的原始内皮细胞转染上血管内皮生长因子(VEGF)〔《心肌内给予表达VEGF121cDNA的腺病毒载体对冠状动脉疾病进行血管生成基因治疗的I期试验的6个月评估》，Ann.Surg.，230(4)：466-470(1999)，本文纳入作为参考〕。
抗体
可根据Kohler和Milstein的标准技术(《分泌预先确定的特异性的抗体的融合细胞的连续培养》，Nature，265：495-497，1975，本文纳入作为参考)生产用于本发明方法的单克隆抗体。可使用内皮细胞作为免疫原来生产针对内皮细胞表面抗原的单克隆抗体。
通过将HUVEC或纯化的原始内皮细胞注射到小鼠或大鼠中，可制得针对内皮细胞的单克隆抗体。经过足够的时间后名将小鼠处死，获得其脾细胞。通常在非离子型去污剂(如聚乙二醇)的存在下，通过使用骨髓瘤细胞或者淋巴瘤细胞与这些脾细胞融合，从而使它们无限繁殖。使所产生的细胞(包括融合的杂交瘤)在选择培养基(如HAT培养基)中生长，然后采用有限稀释条件使存活的细胞在这种培养基中生长。使这些细胞在合适的容器中生长，如微滴定孔，然后从上清液中筛选出具有所需特性(即，与内皮细胞抗原反应)的单克隆抗体。
存在提高单克隆抗体产量的各种技术，如将杂交瘤细胞注射到接受该细胞的哺乳动物宿主的腹膜腔中，然后收集腹水。当从腹水中收集不到足量的单克隆抗体时，从宿主的血液中收集抗体。存在分离和纯化单克隆抗体以便使其不含有其它蛋白质或污染物的各种常规方法。
还包括在本发明的范围中的是抗内皮细胞的单克隆抗体的有用的结合片段，如这些单克隆抗体的Fab、F(ab′)2或Fc片段。采用常规的方法获得这些抗体片段。例如，可使用木瓜蛋白酶或胃蛋白酶对抗体进行肽酶消化，从而制得有用的结合片段。
本发明的抗体涉及从鼠科动物获得的IgG类的抗体；但是，这并不意味着本发明受限于此。上述抗体和那些具有与上述抗体等价功能的抗体，不论是从鼠科动物、哺乳动物(包括人)或者其它来源获得，还是从这些来源的组合物中获得，这些抗体以及其它类别(如IgM、IgA、IgE等等，包括这写类别的同种型)都包括在本发明的范围之内。对于抗体，术语“功能上等价的”指两种不同的抗体各自结合于一个抗原的相同抗原位点上，换言之，这些抗体竞争与相同的抗原结合。抗原可以是相同或不同的分子。
在一个实施方式中，使用到与内皮细胞表面抗原CD34反应的单克隆抗体。结合于固体支持物上的抗-CD34的单克隆抗原已显示出可俘获从人的外周血获得的原始内皮细胞。在被俘获后，这些原始细胞能分化成内皮细胞(Asahara等人，1997，《用于血管生成的推定原始内皮细胞的分离》，Science，275：964-967)。可从美国典型组织保藏所(Rockville，MD)获得产生针对CD34的单克隆抗体的杂交瘤。在另一实施方式中，使用与内皮细胞表面抗原Flk-1或Tie-2的单克隆抗体。
也可使用从与接受该医疗器械相同的物种获得的内皮细胞反应的多克隆抗体。
斯腾特固定膜
术语“斯腾特固定膜”在本文中指当被插入血管腔中时使该血管腔的横截面扩张的任何医疗器械。术语“斯腾特固定膜”包括覆盖的斯腾特固定膜，如那些覆盖了PTFE或ePTFE的固定膜。在一个实施方式中，这种固定膜包括经皮传送以治疗冠状动脉闭塞或者使脾、颈动脉、骼骨和腘部血管的切开部分或动脉瘤闭合的斯腾特固定膜。在另一实施方式中，斯腾特固定膜被传送到静脉血管中。斯腾特固定膜可由聚合的或金属的结构元件组成，在其上施加了基质，或者斯腾特固定膜可以是基质与聚合物混合而得到的复合材料。例如，可使用可变形的金属线斯腾特固定膜，如Wiktor在美国专利第4,886,062中所公开的，本文将此文献纳入作为参考。也可使用由有弹性的聚合材料制成的自我扩张型斯腾特固定膜，如已出版的题为《腔内药物洗脱修补术》的国际专利申请WO91/12779中所公开的，本文将其纳入作为参考。也可使用不锈钢、聚合物、镍-钛、钽、金、铂-铱或耐蚀游丝合金(Elgiloy)和MP35N以及其它含铁物质来制备斯腾特固定膜。通过导管的体腔将斯腾特固定膜传送到治疗位点，在那将其从导管中放出，使它扩大到与血管的腔壁直接接触。本领域熟练的技术人员将会明白，其它自我扩张型斯腾特固定膜设计(如弹性金属斯腾特固定膜设计)可与本发明的抗体和基质一起使用。
合成移植物
术语“合成移植物”指具有生物相容特征的任何人工修补物。在一个实施方式中，这种移植物包括由Dacron(聚对苯二甲酸乙二醇酯，PET)或Teflon(ePTFE)制成的合成移植物。在另一实施方式中，合成移植物由聚尿烷制成。在第三个实施方式中，合成移植物由经筛选的聚碳酸酯尿烷内层和经筛选的Dacron外层组成。本领域熟练的技术人员将明白，任何生物相容的合成移植物可与本发明的抗体和基质一起使用(Bos等人，1998，《小直径血管修补术：目前的状态》，Archives Physio Biochem.，106：100-115，本文将其纳入作为参考)。合成移植物可用于血管的端到端的接合或者患病血管部分的分流。
基质
(A)合成材料——用于包涂斯腾特固定膜或合成移植物的基质可选自合成材料，如聚尿烷、嵌段聚尿烷-脲/肝素、聚L-乳酸、纤维素酯或聚乙二醇。
(B)天然材料——基质可选自天然物质，如胶原蛋白、层粘连蛋白、肝素、血纤蛋白或碳。对于基质的基本要求是，它具有足以在斯腾特固定膜或合成移植物的暴露表面上维持不被破坏的弹性和柔韧性。
(C)呋仑碳——基质还可含有呋仑碳(术语“呋仑碳”包括许多呋仑碳分子)。呋仑碳是碳-笼分子。各类呋仑碳中碳(C)的数量从约60个到约100个不等。采用本领域熟练技术人员周知的方法使用碳元素或含碳的物质进行高温反应可制得呋仑碳；例如，通过碳的激光汽化作用、在电弧中加热碳或者在炭灰火焰中燃烧烃类物质(Patel等人的美国专利第5,292,813号、Bhushan等人的美国专利第5,558,903号，本文将其纳入作为参考)。在各种情况中，产生含碳的沉积物或烟灰。通过使用适当的溶剂进行抽提，可从这种烟灰中获得各种呋仑碳。采用已知的方法分离呋仑碳，具体是采用高效液相色谱法(HPLC)。可合成呋仑碳，或者从DynamicEnterprises，Ltd.(Berkshire，英国)或者SouthernChemical Group，LLC(Tucker，格鲁吉亚)购得。
可以各种不同的方式将呋仑碳沉积在表面上，包括如美国专利第5,558,903号中所公开的升华、激光汽化作用、溅射、离子束、喷涂、浸涂、辊涂或刷涂方法。
呋仑碳的一个重要特征是它们能形成“激活的碳”。呋仑碳的电子结构是交叠的π-轨道系统，这样大多数的成键电子被协作性呈递在该分子的表面上(Chemical and Engineering News，1991年4月8日，第59页，本文纳入作为参考)。至于激活的碳的形式，呋仑碳具有产生弱的相互作用的相当的范德华力。为了指导特异的细胞膜相互作用，可根据呋仑碳表面的吸附性质而使其被额外修饰。例如，可将具有选择性结合于特殊细胞类型的细胞膜或者细胞膜的特殊成分的化学性质的特异分子(如外源凝集素或抗体)吸附到呋仑碳表面上。也可对吠仑碳的表面进行修饰，以使其给细胞膜呈递特别活跃的基团，如氧化剂或还原剂。可对不同分子与呋仑碳表面的结合进行处理，以产生选择性结合各种细胞类型(如上皮细胞、成纤维细胞、主要外植体或T细胞亚类)的表面。本文在此纳入Richmond等人的美国专利第5,310,669号作为参考；Stephen R.Wilson，《呋仑碳的生物学方面》，Fullerenes：Chemistry，Physics and Technology，Kadish等人编辑，John Wiley和Sons，纽约，2002，本文将其纳入作为参考。
呋仑碳还可形成加入其它原子或分子的毫微管〔Liu等人，Science，280：1253-1256(1998)，本文纳入作为参考〕。碳毫微管的合成和制备在本领域中是周知的(Olk等人的美国专利第5,753,088号和Ebbsen等人的美国专利第5,641,466号，本文纳入作为参考)。也可将分子(如蛋白质)加到碳毫微管之中。例如，可在切割毫微管的端部后用酶填充该毫微管，如Zn2Cd2-金属硫因、细胞色素C和C3以及β-内酰胺酶〔Davis等人，Inorganica Chim.Acta，272：261(1998)；Cook等人，Full Sci.Tech.，5(4)：695(1997)，本文将其纳入作为参考〕。
也可使用三维的呋仑碳结构。Mirkin等人的美国专利第5,338,571号(本文将其纳入作为参考)公开了三维多层的呋仑碳结构，该结构如下形成：(i)对呋仑碳进行化学修饰，以获得形成键的种类；(ii)对基质的表面进行化学处理，以在溶液中产生有效与上述呋仑碳的形成键的种类共价结合的形成键的种类；(iii)使修饰的呋仑碳的溶液与经处理的基质表面接触，以形成共价结合于该经处理的基质表面的呋仑碳层。
(D)将基质用于医疗器械
基质应紧紧地粘附于斯腾特固定膜或合成移植物的表面上。较佳的是，通过将基质用于连续的薄层上而实现上述粘附。或者，可仅仅将抗体用于直接与血管腔接触的层上。可将不同类型的基质连续应用于接连着的层上。在将基质用于斯腾特固定膜上后，可使抗体共价或非共价包涂于该基质上。
为了对医疗器械(如斯腾特固定膜)进行包涂，可将斯腾特固定膜浸渍在中等粘度的基质液体溶液中，或者用这样的溶液喷射。在给下一层进行包涂之前，先使先前包涂的层干燥。在一个实施方式中，薄的、涂料样的基质涂层的总厚度不超过100微米。
例如，在无菌条件下，通过将480毫克(mg)的药物载体(如聚D，L-丙交酯，从Boehringer Inc.，Ingelheim德国购得的R203)溶解在3毫升(ml)的氯仿中而制得合适的基质涂液。但是，原则上，是血液和组织相容的(生物相容的)并且可被溶解、分散或乳化的任何可生物降解(或非生物可降解)的基质都可用作基质，只要在应用后，它的干燥速度相对快，从而在医疗器械表面上获得自我粘附的漆样或涂料样涂层即可。
例如，使用血纤蛋白包涂斯腾特固定膜对于本领域熟练的技术人员是周知的。在Muller等人的美国专利第4,548,736号中(本文将其纳入作为参考)，通过使血纤蛋白原与凝血酶接触可使血纤蛋白凝结。较佳的是，如Gerendas的美国专利第3,523,807号或已出版的欧洲专利申请第0366564号所公开的(本文将这两篇文献纳入作为参考)，在凝结期间，本发明含有血纤蛋白的斯腾特固定膜中的血纤蛋白有XIII因子和钙存在，以便改进植入器械的机械性能和生物稳定性。较佳的是，用来制备本发明血纤蛋白的血纤蛋白原和凝血酶从要植入斯腾特固定膜的相同的动物种类或人种中获得，这样可避免物种间的免疫反应，如人抗牛。血纤蛋白制品可以成细微的血纤蛋白膜形式，它通过将混合的血纤蛋白原和凝血酶浇注在膜上，然后使水分从该膜渗透过半透膜将其去除，从而制得该种形式。在欧洲专利申请0366564中，使(较佳对任一种物质(凝血酶或血纤蛋白原)具有高孔隙率或高亲和力的〕基质与血纤蛋白溶液接触以及与凝血酶溶液接触。结果是由血纤蛋白原在医疗器械的表面上发生聚合作用，形成血纤蛋白层。采用此方法形成的多层血纤蛋白可提供任何所需厚度的血纤蛋白层。或者，可先使血纤蛋白凝结，然后将其研磨成粉末，再将该粉末与水混合，并在热模上压制成所需的形状(美国专利第3,523,807号)。通过使成形的血纤蛋白与固定剂(如戊二醛或甲醛)接触，也可使其稳定性增加。这些和其它本领域熟练的技术人员所周知的方法都可用在本发明中。
如果使用胶原蛋白包涂合成移植物，则制备胶原蛋白并将其形成于合成移植物器械上的方法是周知的，如Weadock等人的美国专利第5,851,230号提出的方法，本文将其纳入作为参考。这个专利描述使用胶原蛋白包涂合成移植物的方法。将胶原蛋白粘附于多孔的移植物基材上的方法一般包括将胶原蛋白分散物应用于基材上，使其干燥，并重复此过程。胶原蛋白分散物通常是通过在酸性pH(2-4的pH范围)下，在分散物中混合可溶性的胶原蛋白(大约1-2重量％)而制得。该分散物一般通过注射器注射到移植物的腔中，人工按压该移植物，使该胶原蛋白浆液覆盖整个移植物的内表面面积。从该移植物的一个开放端除去过量的胶原蛋白浆液。重复进行包涂和干燥步骤几次，以提供足够的处理。
在又一实施方式中，用无定形炭包涂斯腾特固定膜或合成的移植物。美国专利第5,198,263号(本文将其纳入作为参考)描述了在氟化或其它卤化物气体的存在下生产高速、低温沉积的无定形炭膜的方法。本发明方法所述的沉积可在低于100℃(包括环境室温)的温度下，采用射频、等离子辅助的化学蒸气沉积法进行。采用本发明方法制得的无定形炭很好地粘附在许多种基材上，包括如玻璃、金属、半导体和塑料。
可如美国专利第5,292,813号所述将呋仑碳部分粘附到含胺聚合物的反应性氨基位点上，以形成呋仑碳-移植物、含胺聚合物。以此方式进行的化学修饰使得呋仑碳可直接结合于斯腾特固定膜上。在另一实施方式中，可如上述加工呋仑碳沉积在斯腾特固定膜或合成移植物的表面上(参见，Leone等人，WO99/32184，本文将其纳入作为参考)。呋仑碳也可通过醛键连接〔Yamago等人，《有机呋仑碳诵讨氧化作用、还原作用的化学衍生作用以及C-O和C-C键的形成反应》，J.Org. Chem.，58：4796-4798(1998)，本文将其纳入作为参考)。也可通过呋仑碳上的环氧化物基团将C60O直接连接于斯腾特固定膜。这种连接是通过与氧的共价键连接。这种化合物和偶联的方法可从BuckyUSA(BuckyUSA，Houston，Texas)购得。
(E)将抗体加到基质中——可将促进原始内皮细胞粘附的抗体以共价或非共价的方式加到基质中。可通过使抗原与基质涂液混合使抗体结合到基质的各个层中。或者，可将抗体共价或非共价结合于基质的最后一层，此基质被用于医疗器械。
在一个实施方式中，将抗体加到含有基质的溶液中。例如，使抗-CD34单克隆抗体的Fab片段与含有浓度为500-800mg/dl的人血纤蛋白原的溶液培育。可理解的是，抗-CD34 Fab片段将可改变，本领域熟练的技术人员将可在不需要作过多试验的情况下确定最优的浓度。将斯腾特固定膜加到Fab/血纤蛋白混合物中，该血纤蛋白由加入的浓的凝血酶(浓度至少为1000U/ml)激活。在斯腾特固定膜或合成移植物的表面上，将所得的含有直接加到基质中的Fab片段的聚合血纤蛋白混合物压制成薄膜(厚度小于0.12cm)。事实上，任何类型的抗体或抗体片段都可以这种方式在对斯腾特固定膜或合成移植物进行包涂之前加到基质溶液中。
在另一实施方式中，可将抗体共价结合于基质。在一个实施方式中，可通过使用不同或相同的双官能连接物分子将抗体以共价方式栓在基质上。术语“栓”在本文中指抗体通过连接物分子共价偶联于基质上。本发明中连接物分子的使用涉及在连接物分子粘附到斯腾特固定膜上后它与基质进行共价偶联。在连接物分子共价偶联到基质上后，连接物分子提供具有大量的功能上活跃的基团的基质，这些基团可用于与一种或多种类型的抗体共价偶联。图1阐述了通过交联分子的偶联作用。内皮细胞1.01通过细胞表面抗原1.02结合于抗体1.03。该抗体通过交联分子1.04栓在基质1.05-1.06上。基质1.05-1.06粘附于斯腾特固定膜1.07上。连接物分子可直接偶联于基质(如通过羧基)，或者通过已知的偶联化学过程(如酯化、酰胺化或酰化)进行偶联。连接物分子可以是通过直接形成胺键排列于基质的二胺或三胺官能化合物，它可提供与抗体反应的胺-官能团。例如，连接物分子可以是聚胺官能聚合物，如聚1，2-亚乙基亚胺(PEI)、聚烯丙胺(PALLA)或聚乙二醇(PEG)。可从Shearwater公司(Birmingham，Alabama)购得各种PEG衍生物(如mPEG-琥珀酰亚胺基丙酸酯或mPEG-N-羟基琥珀酰亚胺)以及共价偶联的方案〔还可参见Weiner等人，《聚乙二醇间隔基对被固定的抗体俘获的抗原的影响》，J.Biochem. Biophys.Methods，45：211-219(2000)，本文将其纳入作为参考〕。将可理解，具体的偶联剂的选择可依赖于所使用的抗体的类型，并且这种选择可在无需过多试验的情况下进行。也可使用这些聚合物的混合物。这些分子含有大量的侧接的胺官能团，这些官能团可用于使一种或多种抗体在表面固定化。
可将抗体连接到已被直接沉积在斯腾特固定膜表面上的C60O呋仑碳层上。交联剂可与该呋仑碳共价连接。然后将抗体连接到该交联剂上，该交联剂又与斯腾特固定膜连接。图2阐述了通过C60O进行的偶联。内皮细胞2.01通过细胞表面抗原2.02连接于抗体2.03，而抗体2.03与基质2.04共价或非共价连接。基质2.04通过C60O 2.05共价连接于斯腾特固定膜2.06。
试验实施例
本发明将以下述试验细节部分进行描述。这些部分给出了对本发明的理解，但不是试图也不应认为是以任何方式对之后给出的权利要求所提出的本发明范围的限制。
实施例1
人内皮细胞粘附于包涂了CD34 Fab的斯腾特固定膜
材料和方法
1.细胞
采用Jaffe的方法(Jaffe，E.A.，“Biology of Endothclial Cells”，E.A.Jaffe编辑，Martinus-Nijhoff，The Hague(1984)，本文将其纳入作为参考)从人的脐带获得HUVEC，并将其培育在补充了20％胎牛血清(FCS)、L-谷氨酰胺、抗生素、130μg/ml肝素和1.2mg/ml内皮细胞生长添加物(Sigma-Aldrich，St.Louis，MO)的培养基199中。
采用Asahara等人的方法(《用于血管生成的推定原始内皮细胞的分离》，Science，275：964-967)从人的外周血分离出原始的内皮细胞。将抗-CD34的单克隆抗体连接到磁珠上，然后使其与人全血的白细胞部分培育。培育后，洗脱下结合的细胞，并将其放在含有20％胎牛血清以及牛脑抽提物(Clonetics，San Diego，CA)的M-199中培育。通过针对CD45、CD34、CD31、Flk-1、Tie-2和E-选择的荧光抗体表征细胞。
2.斯腾特固定膜的包涂
A.将Orbus International B.V.(Leusden，The Nethcrlands)生产的R斯腾特固定膜与500-800mg/ml人血纤蛋白原(Sigma，St.Louis，MO)以及抗CD34的单克隆抗体的Fab片段培育，该血纤蛋白原将通过加入1000单位/ml的凝血酶而发生聚合。在该斯腾特固定膜与含有抗CD34的单克隆Fab片段的聚合的血纤蛋白混合物培育后，在R斯腾特固定膜上将该血纤蛋白压制成薄膜(小于0.12cm)。室温下，用含有0.5％牛血清白蛋白(BSA)的磷酸缓冲盐溶液将具有该薄的含有Fab片段的血纤蛋白膜的R-斯腾特固定膜洗涤3次。
B.或者，使用mPEG-琥珀酰亚胺基丙酸酯(Shearwater公司，Birmingham，Alabama)包涂R斯腾特固定膜。根据制造商的说明，琥珀酰亚胺基将与抗-CD34单克隆Fab片段反应(Fab-PEG包涂的R斯腾特固定膜)，在PEG衍生物与该Fab片段间形成稳定的酰胺键。
3.内皮细胞结合试验
在37℃，在5％ CO2湿润空气中，将包涂了血纤蛋白-抗-CD34 Fab的R斯腾特固定膜或包涂了Fab-PEG的R斯腾特固定膜与含有0.5％ BSA的M199中的分离的HUVEC或分离的原始内皮细胞(细胞浓度为100,000到1,000,000个细胞/ml之间)培育。在与斯腾特固定膜培育之前，先用[3H]-胸苷将人脐静脉内皮细胞或原始内皮细胞标记24小时。在标记的内皮细胞与包涂了血纤蛋白和Fab抗-CD34的斯腾特固定膜培育4-72小时后，从溶液中取出斯腾特固定膜，用含有0.5％ BSA的M-199洗涤5次。通过胰蛋白酶作用除去结合的内皮细胞，通过[3H]-胸苷的闪光计数评价标记的内皮细胞与斯腾特固定膜的结合。作为阴性对照，将仅包涂血纤蛋白的斯腾特固定膜或者未包涂的斯腾特固定膜与标记了[3H]-胸苷的内皮细胞培育。采用t-test从统计学上评估结果，以确定不同的结合。与未包涂的斯腾特固定膜相比，加入了抗-CD34单克隆Fab片段的包涂了血纤蛋白的斯腾特固定膜将显示内皮细胞的结合明显地增加。
实施例2
人内皮细胞在包涂了CD34 Fab的斯腾特固定膜上的增殖
内皮细胞增殖试验
在含有0.5％ BSA的M199中，使包涂了血纤蛋白并加了抗CD-34Fab片段的R斯腾特固定膜与人脐静脉内皮细胞或原始内皮细胞培育4-72小时。在斯腾特固定膜与HUVEC或原始内皮细胞培育后，用含0.5％ BSA的M199将这些斯腾特固定膜洗涤5次，然后使其与[3H]-胸苷培育。将在洗涤并收集的人脐静脉内皮细胞或原始内皮细胞(用胰蛋白酶收集细胞)中评估[3H]-胸苷的掺入。将人脐静脉内皮细胞或原始内皮细胞在包涂了血纤蛋白的斯腾特固定膜上的增殖与标准微滴定盘上内皮细胞的增殖比较。包涂了血纤蛋白的斯腾特固定膜上的人脐静脉内皮细胞或原始内皮细胞的增殖将等于或大于微滴定盘上内皮细胞的增殖。
实施例3
与人脐静脉内皮细胞和原始内皮细胞反应的单克隆抗体的生产
BLAB/c小鼠用在PBS中的1.5×106人脐静脉内皮细胞或1.5×106原始内皮细胞免疫接种，在2-4周的间期中共腹腔注射3-4次，在取得脾细胞之前3天，用1.5×106人脐静脉内皮细胞或1.5×106原始内皮细胞激发。制备脾细胞的悬浮液，将其与骨髓瘤NS1/1 AG4.1融合，使所得杂交瘤生长并克隆。为了提高杂交瘤的生长和克隆率，在培养基中加入了10％内皮细胞调节培养基(人脐静脉内皮细)。起初，采用免疫荧光流式细胞计数(FACS)测试杂交瘤培养物上清液对HUVEC或原始内皮细胞的反应性。简言之，将HUVEC(1.5×104)或原始内皮细胞(1.5×104)与未稀释的杂交瘤上清液培育(30分钟，4℃)，之后洗涤，再使其与异硫氰酸荧光素(FITC)-绵羊F(ab′)2抗小鼠Ig(100μg/ml)培育。最终洗涤之后，进行FACS分析，以检测单克隆抗体与内皮细胞的结合。在人黑素瘤细胞系MM-170上筛选阳性杂交瘤上清液，以消除非内皮细胞特异性mAb。通过在人肿瘤细胞系以及人淋巴细胞、单核细胞、嗜中性白细胞、红细胞和血小板的平板中筛选单克隆抗体来进一步确定内皮细胞的特异性。
实施例4
猪气囊损伤研究
在重25-30kg的幼龄约克夏猪中进行覆盖了抗体的斯腾特固定膜的植入。动物的饲养遵从“试验用动物的饲养和使用指南”(NIH出版号80-23，1985年校订)。在过夜禁食后，给动物服盐酸氯胺酮(20mg/kg)，使其安静。注射硫喷妥钠(12mg/kg)使动脉麻醉后，给它们插上插管，并使插管与呼吸机连接，该呼吸机将给予氧气和一氧化二氮的混合物(体积比1：2)。用0.5-2.5体积％异氟烷维持动物麻醉状态。通过肌肉内注射普鲁卡因青霉素-G和苄星青霉素G(链霉素)的1000mg混合物向动物提供抗菌预防。
在无菌的条件下，对左颈动脉进行动脉切开术，然后将9F-导入器套放在左颈动脉中。向所有的动物静脉给予7,500IU肝素钠和100mg乙酰基水杨酸。在整个过程中按时给予另外的每剂2,500IU的肝素，以维持活化凝血时间在300秒以上。通过上述颈动脉套插入8F导管，并使其到达骼骨动脉的起点。在给予1mg硝酸异山梨醇酯后进行血管造影术，使用定量的冠状血管造影术系统分析影像。将3F栓子切除术用管插入总股骨动脉中，使其到达进行斯腾特固定膜植入的远端部分。使该栓子切除术用气囊膨胀到0.5mm大小，大于该动脉部分，然后收回两次，以使该血管剥露。剥露后，立即将结合了单克隆抗体的Fab片段的包涂过血纤蛋白的斯腾特固定膜插入该导管中，并使其位于股骨动脉经剥露的部分。植入斯腾特固定膜后第3天和第8周分别将动物处死。首先如上述使动物安静，然后将其麻醉。取出放置了斯腾特固定膜的股骨动脉部分，然后将其放置在4％多聚甲醛的4℃、pH 7.2的0.1M磷酸缓冲盐溶液中48小时。获得一块成长方形的血管壁，将其用于内皮细胞的表面覆盖的电子显微评价。将放置了斯腾特固定膜的这部分血管放置在0.15M二甲胂酸盐缓冲液中，进一步用2.5％戊二醛在0.15M二甲胂酸盐中的溶液进行固定。然后用含有1％ OsO4和50mM氰铁酸盐的0.1M二甲胂酸盐缓冲液对该组织进行后固定处理，然后对其进行进一步的处理(《在正常的猪冠状动脉中由包涂了肝素的Palmaz-Schatz斯腾特固定膜产生的血栓形成事件的减少》，Circulation，93：423-430，本文将其纳入作为参考)。采用van Beusekom等人所述的方法〔Cardiovasc Pathol，5：69-76(1996)，本文将其纳入作为参考〕，用甲基丙烯酸甲酯的三种变化浸渍放置了斯腾特固定膜的动脉部分的其余部分。在马达驱动的旋转切片机(HM-350，Microm GmbH，Munich，Germany)上用不锈钢的可处理的刀片将植入斯腾特固定膜的动脉片段切成厚3-5μm的切片。在铬铝包涂的载片上，使用60％的2-丁氧基乙醇和10％的乙醇水溶液的混合物使切片在40℃的热盘中拉伸。用塑料膜覆盖切片，除去过量的丁氧基乙醇-乙醇混合物，留置该载片过夜，使其在40℃烘箱中干燥。然后在等体积比的二甲苯-氯仿溶液中使切片去塑化30-60分钟。然后对所制得的切片进行用于光学显微术的标准染色法。统计：数据是各独立试验的平均值±标准差(SD)。通过方差分析(ANOVA)和Fisher′s PLSD测试(StatView 4.01；Brain Power，Inc.，Calabasas，Calif)确定统计学的显著性。对于股骨动脉的经处理和未处理部分的数据，将进行配对t检验(StatView 4.01)。p<0.05将被认为是平均值间具有统计学上的显著差异。与植入未包涂的斯腾特固定膜的对照相比，结合了抗猪的内皮细胞单克隆Fab片段的斯腾特固定膜处理的动物将显示出增加的内皮细胞的覆盖，并且其再狭窄的发生明显减少。
实施例5
猪原始内皮细胞的转染
根据Asahara等人(《用于血管生成的推定原始内皮细胞的分离》，Science，275：964-967，1997)等人的方法从猪外周血分离得到原始的内皮细胞。将单克隆的抗-CD34抗体偶联到磁珠上，然后使其与猪全血的白细胞部分培育。培育后，洗脱出结合的细胞，并将其培育在含有20％胎牛血清和牛脑抽提物的M-199(Clonetics，San Diego，CA)中。通过针对CD45、CD34、CD31、Flk-1、Tie-2和E-选择的抗体表征细胞。
例如，根据Rosengart等人的方法，使用表达VEGF cDNA的腺病毒表达载体使猪的原始内皮细胞转染上血管内皮生长因子(VEGF)〔《心肌内给予表达VEGF121 cDNA的腺病毒载体对冠状动脉进行血管生成基因治疗的I期试验的6个月评估》，Ann.Surg.，230(4)：466-470(1999)，本文纳入作为参考〕。
在如实施例4所述使用使股动脉放置斯腾特固定膜部分分离的双气囊室灌注管(Cordis Corp)进行气囊损伤和植入斯腾特固定膜后，将表达VEGF的经转染的纯化的猪原始内皮细胞灌注到猪股骨动脉模型中。对灌注了VEGF-转染的猪原始内皮细胞的经气囊血管形成术用斯腾特固定膜处理的猪与灌注了未转染的猪原始内皮细胞的猪的再狭窄进行比较。再灌注猪的原始内皮细胞中的VEGF的表达将导致包涂了抗-CD34的斯腾特固定膜中再狭窄的发病率和严重性的降低。
实施例6
结合了氨基硅烷PEO的抗体的制备
斯腾特固定膜的制备——使用316L不锈钢制备斯腾特固定膜，在超声波清洁器中使用阴离子去污剂对其进行第一次清洗，使其变得清洁和钝化，然后将其浸在热的硝酸中，同时搅拌，最后将其放在去离子水中清洗。
衍生化的斯腾特固定膜将如下制备——使斯腾特固定膜在2％的N-(2-氨乙基-3-氨丙基)三甲氧基硅烷在95％乙醇中的混合物中浸渍3分钟，取出，使其在室温下空气中干燥，然后在110℃处理10分钟。
聚乙二醇(PEG)间隔基偶联——将衍生化的斯腾特固定膜放置在100ml、0.1M的含有10mM二羰基甲基-PEG和500mg EDC的MES缓冲液中，然后在不停搅拌的情况下，在25℃培育2小时。
结合的抗体——通过将斯腾特固定膜浸渍在150ml的0.1M MES缓冲液(pH4.5)中，并在25℃培育2小时，使得发生一步碳二亚胺偶联反应，从而将针对内皮细胞的抗体固定在PEG官能化的斯腾特固定膜上，其中，在该缓冲液中溶解了0.1mg的鼠的抗-CD34 IgG1抗体。从该溶液中取出斯腾特固定膜，并用50ml含有0.02％Tween 20的磷酸缓冲盐溶液(pH7.2)清洗5次。
试剂包括：N-(2-氨乙基-3-氨丙基)三甲氧基硅烷(Dcgussa-Huls)；MES缓冲液-吗啉乙烷磺酸缓冲液(Sigma，St.Louis，MO)；EDC-1-乙基-3-(3-二甲基氨丙基)碳二亚胺(Sigma，St.Louis，MO)；二羰基甲基-PEG-二羰基甲基-聚(乙二醇)〔MW3400〕(Shearwater，Huntsville，AL)。
已描述了本发明的几个不同的实施方式，本发明并不想受到这些实施方式的限制，在不偏离有权利要求限定的本发明的实质和范围的情况下，本领域熟练的技术人员可对本发明作出修改和变动。

Claims (37)

1.一种医疗器械，它包涂有治疗有效量的至少一类与内皮细胞表面抗原反应的抗体或其片段和一层或多层基质，所述基质包括合成的或天然的材料，其中，在所述包涂的医疗器械植入血管中后，所述抗体或其片段和基质促进所述内皮细胞在所述医疗器械表面上体内粘附和增殖。
2.如权利要求1所述的医疗器械，其特征在于，所述抗体通过连接物分子共价连接于包涂所述医疗器械的基质的最后一层。
3.如权利要求1所述的医疗器械，其特征在于，所述抗体是单克隆抗体。
4.如权利要求1所述的医疗器械，其特征在于，所述医疗器械是斯腾特固定膜。
5.如权利要求1所述的医疗器械，其特征在于，所述医疗器械是合成移植物。
6.如权利要求1所述的医疗器械，其特征在于，所述内皮细胞表面抗原在人的细胞上。
7.如权利要求3所述的医疗器械，其特征在于，所述单克隆抗体与内皮细胞表面抗原CD34反应。
8.如权利要求3或7所述的医疗器械，其特征在于，所述单克隆抗体包括Fab或F(ab＇)2片段。
9.如权利要求1所述的医疗器械，其特征在于，所述基质的第一层与所述医疗器械非共价连接。
10.如权利要求1所述的医疗器械，其特征在于，所述基质的第一层与医疗器械共价连接。
11.如权利要求1所述的医疗器械，其特征在于，所述合成的或天然的材料选自聚尿烷、嵌段聚尿烷-脲/肝素、聚L-乳酸、纤维素酯、聚乙二醇、胶原蛋白、层粘连蛋白、肝素、血纤蛋白、纤维素和碳。
12.如权利要求1所述的医疗器械，其特征在于，所述材料是呋仑碳。
13.如权利要求12所述的医疗器械，其特征在于，所述呋仑碳长度为C60—C100。
14.如权利要求1所述的医疗器械，其特征在于，所述基质是C60O。
15.如权利要求12所述的医疗器械，其特征在于，所述呋仑碳以毫微管排列。
16.如权利要求1所述的医疗器械，其特征在于，所述基质是聚D，L-丙交酯。
17.如权利要求12所述的医疗器械，其特征在于，所述呋仑碳与聚四氟乙烯或发泡的聚四氟乙烯混合。
18.一种用于包涂医疗器械以使该医疗器械植入血管中后适合于内皮细胞在其表面上体内粘附和增殖的组合物，其特征在于，该组合物含有基质和治疗有效量的至少一类与内皮细胞表面抗原反应的抗体或其片段，其中所述基质包括合成的或天然的材料。
19.如权利要求18所述的组合物，其特征在于，所述合成的或天然的材料选自聚尿烷、嵌段聚尿烷-脲/肝素、聚L-乳酸、纤维素酯、聚乙二醇、胶原蛋白、层粘连蛋白、肝素、血纤蛋白、纤维素和碳。
20.如权利要求18所述的组合物，其特征在于，所述材料为呋仑碳。
21.如权利要求20所述的组合物，其特征在于，所述呋仑碳是长为C60-C100的呋仑碳。
22.如权利要求18所述的组合物，其特征在于，所述抗体是单克隆抗体。
23.如权利要求18所述的组合物，其特征在于，所述内皮细胞表面抗原在人的细胞上。
24.如权利要求22所述的组合物，其特征在于，所述单克隆抗体与内皮细胞表面抗原CD34反应。
25.如权利要求22或24所述的组合物，其特征在于，所述单克隆抗体包括Fab或F(ab＇)2片段。
26.如权利要求20所述的组合物，其特征在于，所述基质是C60O。
27.如权利要求18所述的组合物，其特征在于，所述基质是聚D，L-丙交酯。
28.如权利要求20所述的组合物，其特征在于，所述呋仑碳与聚四氟乙烯或发泡的聚四氟乙烯混合。
29.一种包涂医疗器械以使该医疗器械植入血管中后适合于内皮细胞在其表面上体内粘附和增殖的方法，它包括如下步骤：
(a)使用至少一层基质包涂该医疗器械，其中，该基质包括合成的或天然的材料；
(b)将治疗有效量的至少一类与内皮细胞表面抗原反应的抗体或其片段加到所述基质层中。
30.如权利要求29所述的方法，其特征在于，所述抗体与包涂所述医疗器械的基质的最后一层非共价连接。
31.如权利要求29所述的方法，其特征在于，所述抗体通过连接物分子与包涂所述医疗器械的基质的最后一层共价连接。
32.如权利要求29所述的方法，其特征在于，所述合成的或天然的材料选自聚尿烷、嵌段聚尿烷-脲/肝素、聚L-乳酸、纤维素酯、聚乙二醇、胶原蛋白、层粘连蛋白、肝素、血纤蛋白、纤维素和碳。
33.如权利要求29所述的方法，其特征在于，所述材料是呋仑碳。
34.如权利要求33所述的方法，其特征在于，所述呋仑碳长度为C60—C100。
35.如权利要求33所述的方法，其特征在于，所述基质是C60O。
36.如权利要求29所述的方法，其特征在于，所述基质是聚D，L-丙交酯。
37.如权利要求33所述的方法，其特征在于，将所述呋仑碳与聚四氟乙烯或发泡的聚四氟乙烯混合。
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