专题讲座

能否研制一种兼具生物力学与生物相容性的完美人工血管?

Published at: 2014年第1卷第8期

ByromMichael J. 1 , NgMartin K.C. 2 , BannonPaul G. 3
1 The Baird Institute for Applied Heart and Lung Surgical Research, Sydney, Australia; Royal Prince Alfred Hospital, Sydney, Australia; University of Sydney, Sydney, Australia
2 Royal Prince Alfred Hospital, Sydney, Australia; University of Sydney, Sydney, Australia
3 The Baird Institute for Applied Heart and Lung Surgical Research, Sydney, Australia; Royal Prince Alfred Hospital, Sydney, Australia; University of Sydney, Sydney, Australia; The Collaborative Research (CORE) Group, Sydney, Australia

背景介绍

在冠状动脉旁路手术中,完美人工血管应具有通畅故障率低、可长期使用、无取材并发症,并可为所有血运重建者提供足够长度的特点。目前,最佳的移植物仍然是原位乳内动脉(IMA),与游离动脉移植(89.1%)或大隐静脉移植(82.4%)相比,IMA 5年的通畅率为95.8%(1),且左IMA移植15年的通畅率为88%(2)。然而,自体血管的取材可能会有耗时、血管本身质量差或取材过程中受损以及并发症的问题,例如双侧IMA取材后可见胸骨创面重建率增加(双IMA 1.9%,单IMA 0.6%)(3)。尤其对于动脉移植物而言,血管长度也常是限制性因素。由于缺少合适的桥血管,SYNTAX试验中9.1%的患者被列入非手术(PCI)注册组(4)。因此,能够替代小动脉的人工血管被称为血管搭桥术的圣杯(5)。

自1952年人工血管引进以来,已经过去了60年。然而,尽管已就研发一个具生物相容性的小口径血管进行了大量尝试,但仍没有能成功用于冠状动脉旁路移植的人工血管(6)。研发人工血管的方法包括:新的或修饰后的假体材料,将生物分子与模拟生物表面结合或提高机械性能的人工血管,以及包括部分或全部细胞组织的组织工程血管。然而,许多重要的限制性因素抑制了血管生物材料的设计,进而影响到许多方面,如内皮化、血栓形成和生物力学特性的体外评估,以及用于人工血管体内评估的动物模型的选择和使用(6-8)。成功的小动脉替代物研发不仅需要不断创新,还需解决这些限制性因素。最近推出的重组人蛋白原,是一个有前途的血管生物材料,为我们追求完美的人工血管提供了新的视角和可能的解决方法。

高分子血管假体

早期,人工血管的研究旨在生产惰性聚合物血管,它既能被动地输送血液,又可尽量减少与血液和组织的相互作用。第一个植入人体的人工血管移植物名为Vinyon N,生产于1952年,但是膨体聚四氟乙烯(ePTFE)和聚对苯二甲酸乙二醇酯(“Dacron”涤纶)仍然是目前最常用的高分子聚合物(8)。“Dacron”血管用于较大血管的移植,如主动脉、髂骨和股骨近端动脉,这些部位的血流量相对较高,因此合成的导管可保持长时间通畅。例如,主动脉-股动脉旁路移植5-10年通畅率为90%(9)。然而,由于高失败率,心脏搭桥手术很少尝试用假体材料(10)。在主动脉-近端冠状动脉插补移植(移植物规格3.5 mm × 4 cm)中显示,涤纶的通畅性不到16个月(11),而用作主动脉-冠状动脉的ePTFE移植血管显示,45个月内的吻合口通畅率为14%(12)。早期的通畅故障表现在管腔表面生物相容性差。合成血管除吻合口外不发生内皮化,而是包被了一层血浆蛋白(主要是纤维蛋白原)和血小板,此皆称为“伪内膜”,厚度可达1mm(9,13),它可导致持续的表面血栓形成以及易感细菌。早期之后,失败的原因在于内膜增生,这种增生尤其影响远端吻合,部分上是由于有弹性的血管壁和无弹性假体间的机械不匹配(9)。然而,吻合口处的血流紊乱产生低剪切应力区也很重要,很显然,动脉壁的弹性、血管内膜增生与管壁切应力三者是相互的(8,14)。

已有大量研究对表面不兼容进行了探索并取得了一些进展。排尽血管壁的空气可减少血栓形成(15),这意味着可使附壁空气移位的ePTFE涂层法可干扰血栓评估(16-18)。也曾尝试改变血管表面结构,如用理化方法(如氧化、还原、乙酰化)来改变表面化学组成,用射线(包括伽玛射线、紫外线、气体等离子体和离子束)来使众多化合物共价连接,包括氨基酸、肽、抗凝血剂或抗血小板剂(8)。非共价键物理吸附的肝素涂层显示其药物活性迅速丧失(19);但在最近的随机试验中,以端点链接的共价连接显示出可喜的成果,该连接可保护生物活性(20)。简单地改变聚合物表面来增强细胞间的相互作用(如内皮化)是不够的,因为早已认识到,这样的修饰与血栓形成增加相关(21)。

1976年,首次提出缺乏组织相容性的人工血管移植物导致通畅率欠佳的观点(22),并从那时起,许多研究证实了相容性和通畅性之间的关联(23-25)。然而,几乎无可靠证据证实,本身的弹性不匹配是失败的本质原因,因为由此而发生的内膜增生主要发生在下游(不是上游)吻合口和端-侧吻合口(而不是端-端吻合口)(26),以及其它重要的因素,如湍流导致内皮表面产生低剪切应力(27)。研制一个顺应性匹配的人工血管还面临其它问题,如脉管系统中血管顺应性的变化以及患者年龄和合并症的问题(28,29)。为防止发生吻合口动脉瘤,必须使用永久缝合材料(30),通常采用连续缝合,进一步降低吻合口的顺应性(31)。减少顺应性不匹配的方法包括采用间断缝合技术和静脉袖式吻合,这些方法的确降低了不匹配的发生,但费时且不常用(32)。置于移植物外周的金属网支持系统可减少内膜增生,但只有当移植物管径受压(33)和有静脉折叠导致管腔冲击的风险时才起效(34)。另一种方法是研制有弹性力学性能的聚合物血管,主要由于其理想的物理性能和相对的血液相容性(35)。聚酯聚氨酯是通过酯键链接的,因而易水解,而聚醚聚氨酯在体内容易受到氧化裂解(36)。已证实将聚二甲基硅氧烷和聚碳酸酯一起结合到聚合物主链上,能提高材料的抗水解和抗氧化降解性能(37)。然而,目前研究报道中的聚氨酯血管通常结合的是其它材料,来提高表面生物相容性、机体组织反应或机械性能。聚碳酸酯硅氧烷聚氨酯血管结合有胶原蛋白和透明质酸,并涂有肝素和(或)西罗莫司,将其植入兔模型六个月后,证实效果良好(38)。“Myolink”聚碳酸酯脲聚氨酯可通过感知管壁弹性中层的挤压来传递无脉血流,该过程中管壁不会向外膨胀(39)。该血管已结合的药物包括:精氨酸-甘氨酸-天冬氨酸(RGD)肽,肝素,胶原蛋白,硫酸皮肤素,以及内皮细胞和平滑肌细胞种植,并在动静脉瘘手术中已达到临床应用阶段(40-42)。Thoratec公司开发的聚醚聚氨酯血管已用于27例行冠状动脉搭桥手术的患者,并进入了临床试验阶段,进一步的结果要13年后才能得到(43)。

人工血管结合去细胞有机材料的方法和问题

结合有蛋白质和其它生物分子的人工血管,可主动与血液和组织环境相互作用,而非被动地输送血液。其中最简单的方法是在聚合物血管的管腔涂层,以减少血液-材料的不良作用。问题之一是如何既能达到与蛋白质强有力的结合,又能保留该分子的功能(44),然而,非共价结合是弱连接,且所连接的化合物早期易丢失(8)。大量生物分子,如酶、抗体、蛋白质和细胞受体的配体,已被化学或物理地固定到生物材料上,并有详细论述(45,46)。细胞外基质(ECM)环境是一个特别有意义的领域,因其提供了理想的细胞环境。在体外通过细胞种植将ECM转至人工血管上,可增强与体内宿主细胞的结合(47)。将内皮下的ECM成分用作表面涂层尤为诱人,它能促进循环中的内皮细胞内皮化,否则这些细胞的迁移必须经一般不可通透的管道壁或非常缓慢地沿移植物移动(9,48,49)。ePTFE上的纤维连接蛋白涂层可有效增强内皮化,但血管植入术前通常在体外实施内皮细胞(EC)种植,由于该过程与血栓形成的增加相关(50,51)。胶原蛋白涂层也可增强EC与ePTFE或涤纶的结合(52),但天然胶原参与血栓形成过程,且已证实,与无涂层的ePTFE相比,I型胶原蛋白涂层会增加血小板附着(53)。用交联和气体等离子体浸润修饰胶原蛋白法,可通过破坏血小板的结合位点来减少血栓形成(54,55)。改变全ECM蛋白的一种方法是选择所需氨基酸序列。存在于粘附蛋白——纤连蛋白和玻连蛋白的结合位点精氨酸-甘氨酸-冬氨酸(RGD),与细胞表面的整合素受体结合(8),已表明,在体外,RGD涂层表面可增强EC的附着和与剪应力方向一致的增殖(56)。也尝试使用非ECM蛋白,如血浆蛋白,尤其是白蛋白,与纤维蛋白原和g-球蛋白相比,它可减少血小板粘附,但是在动物模型和临床研究中发现,与无涂层的人工血管相比,白蛋白涂层假体几乎没有明显改善(46)。认识到血小板与生物材料表面的粘附与所吸附的纤维蛋白原有关,Sivaraman等认为所吸附纤维蛋白原的构象,而非数量,是血小板粘附的关键决定因素,因为吸附所诱导的纤维蛋白原的展开暴露了血小板的结合位点(57)。

植入后,去细胞ECM支架为宿主细胞浸润到整个假体管壁中提供合适的环境,同时,有可能无需假体材料支持,以及避免与聚合物表面结合蛋白相关的问题。结合弹性成分也将使管道机械性能得到调整,使之与机体血管相符合。一个潜在的ECM源是另一物种的血管或非血管的去细胞组织,但是所有去细胞处理过程的主要问题仍然是ECM破坏、免疫原性和血栓形成(58)。去细胞肠粘膜下层可提供一层I型胶原蛋白,它可卷成一个小直径的管状结构,并作为一个新生血管已成功植入兔模型(59)。去细胞猪输尿管组织显示有与新鲜标本类似的力学特性,且用作异种移植的免疫原性降低(60)。去除犬动脉和静脉血管组织的细胞,剩下有力学特性的管状胶原蛋白/弹力蛋白基质骨架(61),4.5年后,无动脉瘤形成(62)。可使用交联技术来降低免疫原性,并强化骨架,但这改变了机械性能并且有毒残留物抑制细胞的生长(63)。未行减低免疫原性处理的ECM异种移植物可看作是一个异物,它被炎性细胞和瘢痕组织所包裹,而非与周围组织融合(64)。有些品种如猪有较低的免疫原性,但其细胞环境仍逊色,例如与猪基质支架相比,人成纤维细胞在人去细胞真皮基质中的增殖和迁移明显改善(65)。去细胞猪肺动脉瓣异种移植的彻底破坏被视为是人体排异反应所致(66)。获得ECM支架的另一种去细胞方法是用ECM蛋白,特别是胶原蛋白和弹力蛋白,构建管状结构。由于简化模型可能易于受损(67),根据所选的聚合物材料、纤维的厚度和方向以及构造厚度和形状,静电纺丝技术可将直径在0.1-10 μm的纤维募集到靶血管,来实现所需的机械性能。也可使用一种或多种聚合物,能与特定的细胞环境相匹配的合成的(永久的或可降解的)或天然的生物聚合物。然而,异种生物聚合物具有与上面提到的ECM支架相同的缺点,包括免疫原性、降解的敏感性并需动物体内提取的过程,该过程可能会改变其固有结构(8)。

人工血管结合细胞组织的方法和问题

管腔内皮化了的人工血管能达到理想的血液-表面相互作用,而整个管壁与宿主组织相结合的人工血管可能有潜在生长能力并表达血管反应性。植入前假体聚合物血管EC种植是一个诱人的解决体内内皮化失败的方法,然而ePTFE对EC无粘着力(68),且促进EC粘附的方法可能会在移植物上形成一个更加不易形成血栓的表面(64),尤其是当许多EC因暴露于体内剪切应力(在体外未对梯度剪切应力进行预处理)而丢失时。两级种植包括血管种植前的自体EC取材和体外扩增,随后的移植需要再等待几个星期,这期间包括内皮细胞数量扩增和两个手术操作。此外,EC功能如增殖和迁移能力随着年龄增长而下降(69),也可能会因操作过程损伤和(或)暴露于非生理环境而改变(54),并且生物材料的表面特性可能通过影响机械特性以及与细胞周围环境ECM的接触性能,进一步影响EC的表型(70)。已尝试的解决方法包括内皮细胞的基因修饰(71),使用干细胞替代EC,尤其是对于无体外增殖步骤的单级种植(72)。尽管有上述限制,Zilla的研究小组仍成功地将EC种植的ePTFE作为腹股沟下旁路移植物应用于153例周边血管疾病患者(73),EC种植的ePTFE已被用于少数冠状动脉搭桥手术(74),且9年后的一例病例报告显示管腔通畅(75)。然而,制造EC种植的假体所需的时间和费用仍是重要的限制因素。

虽然Campbell等报道在血管的另一位置插入一个芯棒,这样在倒置血管转移到其目的地前,可使宿主组织相结合(76),但在移植前,主要用有ECM蛋白的共培养细胞【内皮细胞,平滑肌细胞,和(或)成纤维细胞】来构建组织工程人工血管。人工血管必须与宿主组织相容,具备无血栓形成的表面(若需体内内皮化)和合适的力学性能,后者可避免增生和动脉瘤形成(64)。Weinberg于1986年研制了一种有平滑肌细胞(SMC)和胶原蛋白的导管,管腔外面涂有成纤维细胞层,内表面涂有内皮细胞层,并指出了纵向SMC的方向、缺乏弹性、低的SMC和胶原蛋白密度以及需Dacron网支持的低的径向强度等问题(77)。Nniklason介绍了膜生物反应器,它是用脉动压力的刺激来提高机械性能,可实现在小型猪的动脉系统行自体组织工程血管移植(78)。然而,他们再次指出缺乏弹力且收缩力差(79),并描述了年老捐献者的平滑肌细胞的终末分化问题(80),这些致使其研究小组转向研究骨髓来源的干细胞(81)。L’Heureux通过用“细胞片组织工程”而不用SMC,将裹有人成纤维细胞和胶原蛋白的细胞片做成管状人工血管,在植入免疫抑制动物模型前,进行搏动血流下预处理,在动物模型体内这些细胞片会被SMC浸润和弹性蛋白沉积(82)。自从将这种人工血管用于人类血液透析通路以来(83),已有不少研究报道了符合自体大隐静脉和乳内动脉力学性能的人工血管设计,以达到冠状动脉旁路移植术使用人工血管替代的目的(84),但同样,需要组织取材过程、体外培养和制造的时间和费用。在体内能够被细胞化的血管移植物将有助于实现人工血管的成功商业化(64)。

重组人蛋白原——一个有前途的生物材料

弹力蛋白是动脉等弹性组织的一个关键性的ECM蛋白,它具有耐用性和机械性能,以及正常功能发挥所必不可少的弹性性能(85),与年龄有关的动脉退行性变就是由于弹性蛋白丢失所致(86)。弹性蛋白缺乏症也与动脉粥样硬化斑块(87),特别是内皮下的内部弹力层的破坏有关(88),罕见的IMA动脉粥样硬化可能部分与其高水平的弹性成分有关(89,90)。弹性蛋白的其它关键生物学性质包括不易形成血栓(91)和内皮细胞内皮化增强(92),但抑制平滑肌细胞(93,94)的增殖和迁移。因此,弹力蛋白非常适合用作血管生物材料,在血管替代品中,它被视为是一个必不可少的“缺少的一环”(95)。尽管弹力蛋白具有显著的特性,但由于天然弹力蛋白很难分离,所以很少将其用作生物材料。直到Weiss及其同事们人工合成了一个基因,该基因能使大肠杆菌表达重组人弹力蛋白原(rhTE)(96),它是多种细胞(包括内皮细胞、平滑肌细胞和成纤维细胞)分泌的弹力聚合物的单体形式(85),从而弹力蛋白降解产物或重组多肽(有时被称为“弹性类似物”)才得以应用。为使保留功能的蛋白质共价结合,我们采用气体等离子体表面改性处理技术(44),本研究小组表明,冠脉支架表面涂覆rhTE在体外显示血栓形成降低且内皮化增强(97),并且在羊颈内动脉插补模型中行rhTE涂层ePTFE血管移植显示,吻合口内膜增生显著减少(98)。这种抑制的发生是由于只进行了表面涂层处理而血管顺应性没有变化,且表明细胞接触的环境比引发增生的机械错配更为重要。不过,实现无顺应性错配的人工血管在小动脉替代品的设计中仍然是终极目标,且弹性蛋白是一个必不可少的组分(95),不仅因其机械性能,还因其能提供合适的ECM环境(99)。由于弹力蛋白纤维的机械性能并不需要其微纤丝组分,因此rhTE是解决这一问题的理想材料。静电纺丝技术使得rhTE能与强度组分(胶原蛋白的替代品)结合,如聚己酸内酯(PCL),一种无毒的可生物降解的聚合物(100),将纳米纤维编织成血管移植物,同时保持纤维的与天然的血管结构和机械性能近似的圆周性排列(101)。PCL纤维本身缺乏必要的机械性能(100),且已证实生物聚合物(纤维蛋白或胶原蛋白)的加入能增强SMC的相互作用(102,103)。我们的小组研制了一种多层rhTE/PCL涂覆的小直径管,具有爆破压力、透水性及与IMA匹配的顺应性,并在体外显示出内皮化和低的血小板附着率,在一项移植到兔颈动脉中的研究中,移植后一个月发现其机械性能未发生改变(92)。

总结

完美的人工血管将具有IMA的持久通畅性,还随时提供“现货供应”。目前,聚合物人工血管正遭受无弹性的机械性能,尤其是表面生物相容性差之苦。用新的聚合物材料、去细胞基质或细胞结构来研制人工血管的方法数不胜数,但只有少数的临床试验,并没有成功的冠状动脉搭桥手术所需的商用替代品。弹力蛋白可模拟胞外环境并提供弹性性能,因此在人工血管设计中提供“缺失的一环”,重组人蛋白原在用作生物相容性涂层和弹性血管成分方面已显示出广阔的前景。通过不断的创新,制造出完美的人工血管仍然是一个可实现的目标。

致谢

声明:作者宣称无利害冲突。

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Cite this article as: Byrom MJ, Ng MK, Bannon PG. Biomechanics and biocompatibility of the perfect conduit—can we build one? Ann Cardiothorac Surg 2013;2(4):435-443. doi: 10.3978/j.issn.2225-319X.2013.05.04

(译者:温燕;北京协和医学院 卫生部北京老年医学研究所呼吸内科;北京 100730)

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