CN1142749C - 弹性蛋白、基于弹性蛋白的生物材料及其制备方法 - Google Patents

弹性蛋白、基于弹性蛋白的生物材料及其制备方法 Download PDF

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CN1142749C
CN1142749C CNB951973444A CN95197344A CN1142749C CN 1142749 C CN1142749 C CN 1142749C CN B951973444 A CNB951973444 A CN B951973444A CN 95197344 A CN95197344 A CN 95197344A CN 1142749 C CN1142749 C CN 1142749C
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biomaterial
elastin laminin
absorbing material
energy absorbing
energy
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CN1197383A (zh
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肯托恩·W·格雷戈里
÷
J·格伦克梅尔
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Kenton W. Gregory
Oregon Tianyou Healthcare System
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Abstract

本发明涉及基于弹性蛋白的生物材料和用它进行组织修复和替换的方法。本发明还涉及将生物材料固定在活组织上的方法。

Description

弹性蛋白、基于弹性蛋白的生物材料及其制备方法
技术领域
本发明涉及弹性蛋白和基于弹性蛋白的生物材料和用它们进行组织修复和替换的方法。本发明还涉及将弹性蛋白和基于弹性蛋白的生物材料固定在活组织上的方法。
发明背景
弹性蛋白是广泛存在于哺乳动物中的细胞外基质蛋白。弹性蛋白存在于例如皮肤、血管和肺组织中，给予这些组织以强度、弹性和柔性。此外，广泛存在于正常动脉的内弹性层(IEL)和外弹性层(EEL)的弹性蛋白可以抑制平滑肌细胞迁移到内膜中。已表明可溶肽形式的弹性蛋白在应答血小板生成的因子后，可以抑制平滑肌细胞的迁移(Ooyama等，Arteriosclerosis 7：593(1987))。弹性蛋白重复六肽吸引牛主动脉内皮细胞(Long等，J.Cell.Physiol.140：512(1989))并且弹性蛋白九肽被表明吸引成纤维细胞(USP 4,976,734)。本发明利用了弹性蛋白的物理和生化特性。
百分之三十到四十的用气球血管成形术扩张的动脉粥样硬化性狭窄会因血管内侧细胞向内生长而变得再狭窄(restenose)。平滑肌向内膜的内向生长看来在动脉的断面上更普遍，在该处，动脉的IEL因气球血管成形术的严重膨胀损伤、血管吻合术或其他导致弹性层撕裂或剥离的血管创伤而被剥离、撕裂或缺失。尽管动脉壁的修复在损伤后发生，弹性蛋白结构IEL和EEL并不重组。因为这些组分起主要的结构和调节作用，它们的破坏伴随着肌细胞的移行。
也有与血管壁脆弱相关的疾病，血管壁脆弱导致最终会破裂的动脉瘤以及至少部分与弹性蛋白异常有关的其他事件。
修复装置，比如血管斯坦特固定模(Vascular stent)，在一定程度上已被成功地用于克服由损伤后肌细胞内生而带来的血管壁再狭窄的问题。此外，修复装置会使潜在的动脉粥样硬化恶化。不过，修复术还是经常应用。
直到最近，可用于将修复材料固定到组织上(或将组织固定到组织上)的主要方法包括应用缝线和钩环(staple)。纤维蛋白胶，一种与凝血酶聚合的纤维蛋白聚合物，也已被用作组织密封剂和止血剂(主要在欧洲)。
已表明激光能量可以用于动脉切口的组织熔接，这被认为是通过纤维蛋白、胶原和其他蛋白的热熔而进行的。应用光敏染料可以增强激光能量向靶位点的选择性传递并允许使用低能激光系统，这两个因素可以减少不期望的热损伤的程度。
本发明将基于弹性蛋白的产品的优点和激光熔接技术的优点结合起来，提供了组织修复和替换的独特方法。本发明使得这样的组织修复术(特别是血管修复术)成为可能，它们不具有与本领域已知的修复术有关的问题。
发明目的和概述
本发明的一般目的是提供一种影响组织修复和替换的方法。
本发明的具体目的是提供一种弹性蛋白或基于弹性蛋白的生物材料，该材料可用作斯坦特固定模(stent)，例如血管斯坦特固定模，或用作导管替换物，例如动脉、静脉或输尿管的替换物。该生物材料也可用作斯坦特固定模或导管的覆盖物或衬层。
本发明的进一步的目的是提供一种弹性蛋白或基于弹性蛋白的移植物，该移植物适用于修复腔壁。
本发明的另一目的是提供这样一种弹性蛋白或基于弹性蛋白的生物材料，它适用于组织替换或修复，例如膀胱内替换或修复，肠、食管或结肠修复或替换，或皮肤修复或替换。
本发明的另一目的是提供一种将弹性蛋白或基于弹性蛋白的生物材料固定在活组织上的方法，该方法不使用缝线或钩环。
优选地，本发明提供一种可与组织融合的弹性蛋白或基于弹性蛋白的生物材料，其包括一层具有第一和第二外表面的弹性蛋白或基于弹性蛋白的生物材料，该生物材料包含施加到所述第一和/或第二外表面的能量吸收材料，所述能量吸收材料渗入弹性蛋白或基于弹性蛋白的生物材料之中，该能量吸收材料在一个预定的光波长范围内吸收能量，从而当用预定波长范围内足够强度的光能照射能量吸收材料时，弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面中的一个与组织基物融合在一起。
本发明也提供一种制备可与组织融合的弹性蛋白或基于弹性蛋白的生物材料的方法，该生物材料包含一层具有第一和第二外表面的弹性蛋白或基于弹性蛋白的生物材料，所述方法包括提供一层具有第一和第二外表面的弹性蛋白或基于弹性蛋白的生物材料，将能量吸收材料施加到所述第一或第二外表面，该能量吸收材料渗入到生物材料中，能量吸收材料在预定的光波长范围内吸收能量，从而当用预定波长范围内足够强度的光能照射能量吸收材料时，弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面中的一个与组织基物融合在一起。
本发明涉及对身体组织的一部分进行修复、替换或支持的方法。该方法包括将弹性蛋白或基于弹性蛋白的置于该部分的一个部位，使所述生物材料与该部位或该部位周围的组织结合。结合受到将生物材料和该部位或该部位周围组织，在所述结合将受影响的位点，与能量吸收剂接触的影响。随后将能量吸收剂暴露于一定量的可被该药剂吸收的能量中，所用的量足以使该部位或该部位周围组织与生物材料结合。
更特别地，可用本发明的方法制备可与组织融合的弹性蛋白或基于弹性蛋白的生物材料，所述材料包含组织基物以及一层弹性蛋白或基于弹性蛋白的生物材料，它们各自具有第一和第二外表面；一种能量吸收材料，它被施加于至少一个外表面上，该能量吸收材料渗入生物材料中。
能量吸收材料可以在一个预定的光波长范围内吸收能量。能量吸收材料的选择应使得当它受到强度足够的预定波长范围的光能照射后，弹性蛋白或基于弹性蛋白的生物材料的第一或第二外表面之一与组织基物融合。优选地，弹性蛋白或基于弹性蛋白的生物材料的第一或第二外表面是主要表面。典型地，能量吸收材料是通过将光能首先通过弹性蛋白或基于弹性蛋白的生物材料或组织基物，再导入能量吸收材料，而被间接照射的。
在本发明的优选方法中，能量吸收材料包含一种生物相容性生色团，更优选的是一种能量吸收染料。在本发明的一个方式中，能量吸收材料在弹性蛋白或基于弹性蛋白的生物材料与组织基物融合在一起后基本上耗尽。在本发明的另一个方式中，能量吸收材料包含对弹性蛋白或基于弹性蛋白的生物材料进行染色的材料。
也可以将能量吸收材料这样施加于生物材料的一个外表面上，即将能量吸收材料掺入一个单独的弹性蛋白层，然后将掺入能量吸收材料的单独的弹性蛋白层与弹性蛋白或基于弹性蛋白的弹性蛋白融合。无论如何，优选地将能量吸收材料基本上均匀地施加于至少一个外表面上，典型地，能量吸收材料基本上覆盖弹性蛋白或基于弹性蛋白的生物材料的整个外表面。
影响和弹性蛋白或基于弹性蛋白的生物材料与组织基物融合有关的本发明方法的一些关键参量包括：用光能照射能量吸收材料时波长的幅度、能量水平、吸收和光强度，以及光吸收材料的浓度。这些参量的设置使得在用能够使弹性蛋白或基于弹性蛋白的生物材料的第一或第二外表面之一与组织基物融合的光能进行照射的一段时间中，温度处于约40至140℃，更优选的是约50至100℃。而且，在本发明的优选方法中，能量吸收材料的平均厚度是约0.5至300微米。
本发明的其他目的和优点将在如下说明中阐明。
附图简述
图1将激光能量施加于生物材料和暴露的天然组织。
图2将弹性蛋白生物材料置于动脉。
图3将生物材料用于肠补片(patch)。
图4用连续波二极管激光将基于弹性蛋白的生物材料(根据Rabaud等的方法用弹性蛋白、纤维蛋白原和凝血酶制备)与猪主动脉融合后的扫描电镜照片。
图5用脉冲二极管激光将基于弹性蛋白的生物材料与猪主动脉融合后的光学显微镜照片。E＝弹性蛋白生物材料；A＝主动脉。
图6得自动脉消化物的基于弹性蛋白的生物材料与猪颈动脉熔接后的光学显微镜的显微照片。E＝弹性蛋白生物材料；A＝主动脉。
发明详述
本发明涉及基于弹性蛋白的生物材料和用激光能量将该生物材料与组织熔接的方法。适用于本发明的基于弹性蛋白的生物材料可以从如下材料制备，例如弹性蛋白(如得自猪颈韧带)、血纤维蛋白原和凝血酶，如Rabaud等所述(USP 5,223,420)。(另见Aprahamian等，J.Biomed.Mat.Res.21：965(1987)；Rabaud等，Thromb.Res.43：205(1986)；Martin，Biomaterials9：519(1988).)这些生物材料可能具有血栓形成特性，适用于某些类型的组织修复中。适用于本发明的基于弹性蛋白的生物材料也可由弹性蛋白和III型胶原蛋白制备，亦如Rabaud及其同事所述(Lefebvre等，Biomaterials13(1)：28-33(1992))。这些制备物不形成血栓，因此可用于血管斯坦特固定模等。适用于本发明的另一类型的基于弹性蛋白的生物材料是按Urry等的描述(见，例如，USP 4,132,746和4,500,700)(另见USP 4,187,852、4,589,882、4,693,718、4,783,523、4,870,055、5,064,430、5,336,256)制备的。也可应用从含有弹性蛋白的组织(例如动脉)消化得到的弹性蛋白基质。消化过程清除了细胞、蛋白和脂肪，但保留了完整的弹性蛋白基质。所用的生物材料应依赖于具体的应用。
由可溶性弹性蛋白制备的本发明基于弹性蛋白的生物材料(见上述Rabaud等)可被塑造成形，以赋予它用于特殊目的的适当大小和形状。塑造的生物材料可按如下方法制备。将弹性蛋白(例如可溶弹性蛋白，分子量12-32,000道尔顿)清洗并在缓冲液中膨胀。将纤维蛋白原或冷沉球蛋白(根据例如Pool等，New Engl.J.Med.273(1965)的方法制备)加入膨胀的弹性蛋白中，随后加入硫脲，加或不加蛋白酶抑制剂(如抑肽酶)，以及胶原蛋白。边搅拌边入凝血酶，得到的混合物立即被倒入一个适当的模子中。将模子温育(例如在37℃下)，使血纤维蛋白/弹性蛋白聚合过程得以进行，有利地，温育时间为15分钟至1小时，优选30分钟。该反应可以在低于37℃的温度下进行，但在77℃下反应会更快。但是，将反应加热超过40℃，会导致凝血酶变性。搅拌时混合物的冷却使得混合的时间变长。为了产生聚合，在缓冲液中加入钙和镁并使用非变性的凝血酶是重要的。
在模子中聚合后，所得的生物材料可用γ射线或如戊二醛(优选戊二醛、甲酸和苦味酸的溶液)这样的试剂进一步交联。当使用射线时，样品最好置于钴60源的γ射线中。辐射的量可以是10-100MRAD，优选25MRAD。有资料表明，γ射线的量可以影响材料的强度(Aprahamian，J.Biomed.Mat.Res.21：965(1987))。
生物材料的薄片可用适当的模子制备，其厚度是可控制的。生物材料的薄片的厚度可以是，例如200微米至5毫米。薄片通常被制得尽可能地薄，以使激光能量在穿透后仍维持足够的强度。作为实例，适用于肠补片的薄片的厚度范围是200微米至5毫米，优选大约2毫米。需要更大强度的补片，例如用于膀胱的补片，一般更厚。动脉斯坦特固定模或补片可以薄些(例如100微米-1000微米)。
从可溶弹性蛋白或非可溶弹性蛋白片段制备的生物材料也可被塑造成管状体，方法是例如将该材料注入管状模子。在内管和外管之间的弹性蛋白溶液的交联可以在将生物材料撤出模子之前或在将管子移出后完成。不同内径和外径，以及不同长度的管状体可以通过改变内管和外管的直径，用这个方法来制备。具有不同直径的内管和外管的这种类型的模子实际上可被制成任意大小。小的管子可用于冠状动脉斯坦特固定模。1-5英寸直径的大管可以被制成并用作角形熔接补片，用于小肠或结肠吻合术。可应用不同的塑造技术和塑造材料；以上所述只是一个实例。
如上所述，适用于本发明的生物材料可通过消化含有弹性蛋白基质的组织来制备。适于用作起始材料的组织包括：动脉(例如猪的冠状动脉或股动脉)、脐带、肠、输尿管等。优选地，基质材料得自与要进行移植的动物同样种类的动物，以提高生物相容性。可应用任何可以将细胞物质、蛋白和脂肪从天然基质中除去(消化掉)，同时保持细胞外弹性蛋白基质完整的方法。这些方法包括这样一些方式的组合：酸性、碱性、去污剂、酶促、热或腐蚀方式，以及应用有机溶剂。这可以包括在这样一些溶液中温育：氢氧化钠、甲酸、胰蛋白酶、胍、乙醇、乙醚、丙酮、叔丁醇，以及超声处理。典型地，在较高温度下可以加快消化过程。温育的最适温度和时间依赖于所用的起始材料和消化药剂，并且很容易被确定。
本领域技术人员意识到，从管状起始材料消化得到管状体后，可将它们打开并制成适于组织移植的薄片。此外，可将管状体打开，然后重新构建成管状体，新管状体的直径与起始组织的不同。然而，优选地，当需要管状产物时，起始材料的选择应使得消化后得到的管状体具有合适的直径，从而不需要后续的操作(调整长度之外的)。
本发明的生物材料，不论是从弹性蛋白粉末制备还是从组织消化制备，通常被固定于活组织。可应用多种可以实现附着的技术，包括本领域所知的技术。但是，优选地用组织熔接能源，以及可以吸收由该能源发出的能量的药剂来固定生物材料。有利地，能源是电磁能源，比如激光，并且吸收药剂是一种染料，该染料的吸收峰所在的波长对应于激光的波长。弹性蛋白生物材料和要熔接的组织在此波长下具有很少的光吸收能力，因此所产生的效应被限制在染料层周围的区域内。优选的能源是激光二极管，其主要波长是大约808nm，优选的染料是绿靛花青(indocyanine green，ICG)，最大吸收795-805nm(见WO 91/(,4073)。也可用其他激光/染料组合。染料优选地被施加于生物材料的将要与活组织接触和固定的那部分上。染料也可被施加于将要与弹性蛋白生物材料熔接和固定的结构的表面。染料可以被直接施加于生物材料，或者先用控制生物材料对染料吸收的组合物对生物材料的表面进行处理或包被(例如预涂)，从而使染料成为分立的一层或包被。此外，可将染料与弹性蛋白生物材料结合，使它固定于表面，避免渗入材料中。染料可以以溶液形式施加，或将染料溶入或悬于一种介质中，随后将其以薄片或薄膜形式施加，优选地，厚度和染料浓度是均匀的。
使用熔接剂(soldering agent)的组织熔接技术可以被应用。这样的技术是已知的(WO 91/04073)。任何在加热时热变性的蛋白类物质都可以用作熔接剂(例如，任意的血清蛋白，如白蛋白、纤维结合素、Von Willebrand因子、玻连蛋白或任意蛋白或肽的混合物)。含有凝血酶聚合的纤维蛋白原的熔接剂是优选的，但不包括在例如血管腔中引起血栓或凝固的物质。对熔接剂的选择是根据它们在生物材料和组织之间提供更大的粘合强度的能力，熔接剂应当是无毒的并通常是生物相容性的。
根据本发明，激光能量可通过组织的暴露(例如在外科手术中)由激光器直接导向靶位点(例如染料)。在某些情况下，即在基于血管内导管的治疗中，不存在开放的外科性暴露，可用光导纤维将激光能量导向结合位点。当ICG被用作染料时，可以用约800nm的靶介质波长。该波长不能被许多组织(特别是血管组织)很好地吸收，因此，对这些组织的影响可以忽略，热效应仅限制在染料层。类似地，本发明的生物材料与能量吸收染料相比，在这个波段上具有较小的光吸收能力。因此，激光能量或者通过生物材料或者通过活组织而被染料层吸收，如图1所示。一旦外科医生暴露了需要进行生物材料补充或替换的表面或血管，便可以将生物材料的含有染料的表面与天然组织在该部位接触，并通过将激光束导向所需位置而给予激光能量。染料(例如ICG)层的吸收最好预先或同时确定，以给予最适量的光从而得到最佳的结合。可以施加压力以保证组织和生物材料充分接近。使用二极管激光源时，可将二极管激光器本身或基于聚光管或光导纤维的光传递系统置于所述材料上，以保证均匀地给予光照。
当需要新的弹性蛋白衬层或新的内弹性层(例如在开放性的动脉内膜剥脱术后，动脉被手术清除粥样斑或其他损伤)时，可将生物材料置入，染料侧向下(见图2)。生物材料可以以平的补片或管状体形式应用。管状体可以是中空的，或用在替换过程中支持管腔的材料填充，填充材料在低热度下融化或可用其他方式溶解或除去。必要时，可使用少量的外科缝线(例如固定用缝线)，以使血管的边缘对齐，或缝合血管。一旦生物材料被置入，激光能量可以通过血管壁或通过生物材料而导向吸收性染料，适当的激光能量由对生物材料中的吸收的测量来预先确定。此外，可以在手术中向生物材料和/或血管壁施加染料，然后给予激光能量。在此实施例中，可以在手术中确定生物材料和/或血管壁的吸收，然后给予激光能量，或用一个反馈装置估计结合是否充分以及热效应。(图4是与猪主动脉融合的基于弹性蛋白的生物材料的扫描电镜图。)
除上述之外，本发明的生物材料可用作修复材料，用于肠或结肠修复，而它们是难以用常规技术治愈的，特别是当患者有营养或其他方面的问题，或患者处于休克状态(例如在多重枪伤或其他腹部损伤的情况下)时(见图3)。这种补片的应用可以，例如，封闭肠容物，从而减少腹膜炎倾向。此外，补片可用于出现裂伤的固形器官，例如肝。类似地，本发明的生物材料可用于修复或替换泌尿系统的若干部分，即从肾盂到尿道。补片也可被用于封闭心室中的缺损，例如动脉瓣缺损，以及支气管瘘或直肠瘘。该生物材料也可被用作治疗动脉瘤的脑血管补片。用定向激光融合，该生物材料可以在一定位置进行封闭。为了在不能或不需要直接照射的地方应用，可采用不同的导管或内窥镜系统将激光导向靶位点。
本发明涉及的基于弹性蛋白的生物材料可用于多种其他临床或外科方案以实现组织修复移植。为了以血管内斯坦特固定模的形式传送该生物材料，可将生物材料预先装置在收缩的气球导管上。用标准技术将气球导管通入所需的动脉或静脉位置。然后使气球膨胀，将斯坦特固定模(生物材料)压向血管壁，再通过气球给予激光以在该位置封闭斯坦特固定模(染料可以在生物材料的外侧)。然后使气球收缩并移出，在该位置留下斯坦特固定模。可使用一种保护性的套管(例如塑料的)，在斯坦特固定模通过血管时对它进行保护，一旦斯坦特固定模处于所需的位置，就将该套管撤出。本发明的生物材料也可用作生物相容性覆盖物，用于金属的或合成的骨骼或斯坦特固定模。在某些情况下，可使用简单的机械作用而不必使用激光结合。但是，根据特殊的需要，例如在不能进行充分机械结合的地方，如置于腹主动脉瘤中的斯坦特固定模中，可以用激光结合。
一种可选的基于导管的血管斯坦特固定模采用带有或不带有气球递送装置的临时性血管斯坦特固定模。
另一种基于导管的血管斯坦特固定模采用了热变形金属(如镍钛诺或其他类似金属)支架或斯坦特固定模或包被，可将其加入导管中，位于斯坦特固定模生物材料的下面。将该斯坦特固定模通入所需的位置，使斯坦特固定模的可变形金属激活，将斯坦特固定模贴附于血管壁上。然后通过也装配到导管中的基于光导纤维的系统传递激光。
基于弹性蛋白的生物材料也可用于替换生病的或损伤的血管或非血管组织的某些部分，如食管、心旁、肺plura等。该生物材料也可用于皮肤替换，用于例如烧伤或创伤的治疗中。同样，该生物材料可用作永久性的敷料，作为上皮细胞再生的支架。该生物材料可以包含抗生素、凝血剂或其他各种治疗所需的药物，这样可以提供高的局部药物浓度，而全身的药物浓度很低。弹性蛋白生物材料可以与染料一起施加在组织一侧，然后用适当波长的激光能量将其融合。
除修复管状体结构之外，本发明的生物材料也可用于器官重建。例如，该生物材料可以被塑造或以其他方式形成袋状物，用于膀胱的重建。本发明的生物材料也可以被塑造或以其他方式成形，用于食管替换。如果需要外壁支持物以控制食物从咽到胃的通路，可以将金属或合成的网状物与植入物结合。这可被用于食管狭窄，酸反流腐蚀食管的修复，或更优选地，用于重新修复在食管癌的手术或化疗治疗当中或之后损伤的食管。
对于某些应用，可能需要将本发明的生物材料与具有强的机械特性的支持材料结合使用。对于这些应用，该生物材料可被包被在支持材料上(见上面关于斯坦特固定模的描述)，例如，采用本文描述的熔接技术。适当的支持材料包括聚合物，如编织的聚乙烯对苯二酸酯(Dacron)、特氟隆、聚烯共聚物、聚氨基甲酸乙酯聚乙烯醇或其他聚合物。此外，可以使用天然聚合物和非天然聚合物的混合型聚合物，天然聚合物比如血纤维蛋白和弹性蛋白，非天然聚合物比如聚氨基甲酸乙酯，聚丙烯酸或聚乙烯醇(Giusti等，Trends in Polymer Science 1：261(1993))。这样的混合材料既有聚合物的机械特性的优点，又有所需的基于弹性蛋白的材料的生物相容性。其他可以从包被了弹性蛋白生物材料的合成物或金属，或由生物材料/合成物混合物制成的修复物，包括心瓣环和食管斯坦特固定模。
本发明的基于弹性蛋白的修复物可以包含药物，这样可将药物通过修复物传递到特定的身体部位。例如在血管斯坦特固定模可以包含防止凝血的药物(如肝素)，或抗血小板药物(如水蛭素)，防止平滑肌内生的药物或刺激在食管癌的手术或化疗当中或之后内皮受损的食管的药物。
对于某些应用，可能需要将本发明的生物材料与具有强的机械特性的支持材料结合使用。对于这些应用，该生物材料可被包被在支持材料上(见上面关于斯坦特固定模的描述)，例如，采用本文描述的熔接技术。适当的支持材料包括聚合物，如编织的聚乙烯对苯二酸酯(Dacron)、特氟隆、聚烯共聚物、聚氨基甲酸乙酯聚乙烯醇或其他聚合物。此外，可以使用天然聚合物和非天然聚合物的混合型聚合物，天然聚合物比如血纤维蛋白和弹性蛋白，非天然聚合物比如聚氨基甲酸乙酯，聚丙烯酸或聚乙烯醇(Giusti等，Trends in Polymer Science 1：261(1993))。这样的混合材料既有聚合物的机械特性的优点，又有所需的基于弹性蛋白的材料的生物相容性。其他可以从包被了弹性蛋白生物材料的合成物或金属，或由生物材料/合成物混合物制成的修复物，包括心瓣环和食管斯坦特固定模。
本发明的基于弹性蛋白的修复物可以包含药物，这样可将药物通过修复物传递到特定的身体部位。例如在血管斯坦特固定模可以包含防止凝血的药物(如肝素)，或抗血小板药物(如水蛭素)，防止平滑肌内生的药物或刺激在食管癌的手术或化疗当中或之后内皮受损的食管的药物。也可包含血管舒张剂。由基于弹性蛋白的生物材料形成的修复物可以用在食管癌的手术或化疗当中或之后受损的食管活细胞包被。
对于某些应用，可能需要将本发明的生物材料与具有强的机械特性的支持材料结合使用。对于这些应用，该生物材料可被包被在支持材料上(见上面关于斯坦特固定模的描述)，例如，采用本文描述的熔接技术。适当的支持材料包括聚合物，如编织的聚乙烯对苯二酸酯(Dacron)、特氟隆、聚烯共聚物、聚氨基甲酸乙酯聚乙烯醇或其他聚合物。此外，可以使用天然聚合物和非天然聚合物的混合型聚合物，天然聚合物比如血纤维蛋白和弹性蛋白，非天然聚合物比如聚氨基甲酸乙酯，聚丙烯酸或聚乙烯醇(Giusti等，Trends in Polymer Science 1：261(1993))。这样的混合材料既有聚合物的机械特性的优点，又有所需的基于弹性蛋白的材料的生物相容性。其他可以从包被了弹性蛋白生物材料的合成物或金属，或由生物材料/合成物混合物制成的修复物，包括心瓣环和食管斯坦特固定模。
本发明的基于弹性蛋白的修复物可以包含药物，这样可将药物通过修复物传递到特定的身体部位。例如在血管斯坦特固定模可以包含防止凝血的药物(如肝素)，或抗血小板药物(如水蛭素)，防止平滑肌内生的药物或刺激在食管癌的手术或化疗当中或之后内皮受损的食管的药物。也可包含血管舒张剂。由基于弹性蛋白的生物材料形成的修复物也可以用活细胞包被，优选地，细胞来自修复装置的接受者。内皮细胞，优选自体内皮细胞(例如在liposuction中收集到的)可以在移植(例如血管斯坦特固定模适应症)前，被接种到弹性蛋白生物移植物上。此外，弹性蛋白生物材料可用作皮肤替换物或修复介质，其中培养的皮肤细胞在移植前被置于生物材料上。因此，可将皮肤细胞用于包被弹性蛋白生物材料。
在如下非限制性实施例中，对本发明的某些方面作了更详细的描述。
实施例1  从可溶性肽制备基于弹性蛋白的生物材料的薄片
用于生物材料制备的材料：
磷酸缓冲液：所用的磷酸缓冲液含有1mM磷酸钠，150mM氯化钠，2mM氯化钙，1mM氯化镁，pH7.4。
可溶性弹性蛋白肽：牛颈韧带弹性蛋白粉末得自Sigma，St.Louis，Missouri。用以下方法  得到可溶性弹性蛋白肽：将2.7克弹性蛋白粉末悬于35毫升溶于80％乙醇中的1M KOL溶液。将悬液在50C下搅拌2.5小时。然后加入10毫升去例子水，用浓缩的12M HCl中和至pH7.4。将溶液在4℃下冷却12小时。从盐晶体中倾析出澄清的溶液，将上清在2000rpm下离心15分钟。溶液对自来水透析三次，两次间隔2小时，一次间隔15小时，使用10,000MW截至分子量的透析袋。再对去离子水透析六次，间隔为2小时，有一次间隔为15小时。所得的透析产物被冷冻干燥，保存于-20℃。产率为40％。
冷沉球蛋白的制备：用Pool和Shannon的方法的改进方法来制备冷沉球蛋白(New Engl.J.Med.273(1965))。冷沉球蛋白主要是血纤维蛋白原(40mg/ml)和纤维粘连素(10mg/ml)(血纤维蛋白原的浓度与纤维粘连素的不同)。简单地说，在含有腺嘌呤、柠檬酸、右旋葡萄糖抗凝血剂的标准500毫升血液收集袋中收集猪血。将血液转移到12个50毫升塑料离心管中，在1500rpm下离心15分钟。从血球层上倾析出血浆，在-70℃下冷冻12小时。然后将血浆在4℃下融化。通过4℃，1500rpm离心血浆15分钟收集冷沉球蛋白。倾析出上清液，用pasteur pipette移出沉淀从而收集冷沉球蛋白。将各管用3毫升柠檬酸钠溶液清洗，柠檬酸钠溶液中含有0.9％NaCl和0.66％柠檬酸钠。将冷沉球蛋白合并，-70℃下冷冻，冷冻干燥并保存于-20℃，直到使用。
硫脲：试剂级硫脲得自Sigma，St.Louis，Missouri。使用0.5mg/ml溶液。
I型胶原蛋白：酸性可溶I型胶原蛋白得自Sigma。优选地，它是用Bornstein的方法的改进方法，从大鼠的尾腱中得到的。将2毫克胶原蛋白在0.6毫升的磷酸缓冲液中加热到60℃ 10分钟直至胶原蛋白溶解。它被冷却到37℃并被使用。
凝血酶：牛血浆凝血酶以冷冻干燥的形式得自Sigma。当用1毫升水重建后，每毫升溶液含有106NIH单位。
抑肽酶：牛肺抑肽酶得自Sigma。每毫升含有15-30胰蛋白酶抑制单位。
制备：
六个模子如下制备：在～40mm×25mm的玻璃板的一侧粘上620μm石英丝，用橡胶带将另一玻璃板绑在第一玻璃板上。如此构建的各模子容积约0.5毫升。
通过连续加入和混合如下成分来制备生物材料：200毫克可溶卡巴弹性蛋白或卡巴弹性蛋白粉末，溶于37℃磷酸缓冲液(PB)(1mM P041 150mMNaCl，2mM Ca21 1mM Mg21 PH7.4)
160毫克溶于1毫升P：B(37℃)的冷沉球蛋白
2毫克溶于0.6毫升PB(60℃ 37℃)的2毫克胶原蛋白
200)11硫脲(0.5mg/ml)
200 CLl抑肽酶(5单位)
将上述溶液的0.6毫升等分试样装入试管，并加入50μl凝血酶溶液(～6单位)。将得到的溶液立即倒入模子。用戊二醛将某些得到的薄片交联2分钟。
结果：
如上述制得的薄片呈微黄色而且混浊。用戊二醛固定的薄片比未固定的薄片伸展性差并且容易撕开。用电镜检查戊二醛固定的薄片。在100倍和1000倍下，这些薄片看来具有光滑的有粘性的表面。
实施例2  基于弹性蛋白的生物材料薄片的组织熔接
熔接前步骤：1mg/ml的ICG溶液被施加到新鲜的猪主动脉上，猪主动脉已被仔细地剪去外膜，用无菌的0.9％NaCl溶液清洗，并切成1cm2的方块。将1mg/ml的ICG溶液施加到主动脉的腔侧约3分钟，然后擦去。(ICG得自Sigma，含有90％染料和10％碘化钠。用7.25×10-6M溶液在780nm下测得的吸收系数是175,000M-1cm-1。当ICG与血清蛋白结合时，吸收最大值移到805nm(Landsman等，J.Appl.Physiol.40(1979))。)含有大约40mg/ml血纤维蛋白原和10mg/ml掺有ICG的纤维粘连素的少量冷沉球蛋白也被施加，将生物材料置于其上。两种材料被置于两个玻璃片之间。将其浸入0.9％盐水中。熔接步骤：如实施例1制备的生物材料薄片在pH7.4和磷酸缓冲液中平衡，用铝镓砷二极管阵列激光器将其熔接到用ICG染色的猪主动脉上。最大输出在808+/-1.5nm。激光器与带有聚乙烯包被材料的1μm的石英纤维偶合。通过调整聚光镜和纤维末端之间的距离，纤维末端的斑点大小可以从1毫米到4毫米不等。激光器可连续操作，用连续波，纤维末端输出的测量值是1.5瓦。将石英纤维直接置于玻璃片、生物材料、主动脉上。在熔接前测量激光的斑点大小。在盐溶液下的的熔接看来是在0.85W而不是1.32W的照射下完成的。对熔接来说，20秒的时间是足够的，40秒会导致棕色变化和生物材料的碳化。
实施例3  由动脉消化制备基于弹性蛋白的生物材料
将新鲜的4厘米长的猪主动脉剥离干净，用两次0.9％盐水清洗过夜。血管被置于0.5M NaOH中并超声120分钟(对Crissman，R.1987的方法的改进)(Crissman，Rogert S.“两种用于制备电镜观察所用的血管弹性蛋白网络的消化技术的比较”，电镜技术杂志6：335-348(1987))。然后在蒸馏水中清洗被消化的血管并在225°F下高压灭菌30分钟。被消化的血管看起来是半透明的，颜色纯白，从水中移出后崩解，表明没有胶原蛋白和其他结构支持蛋白。
动脉消化物与猪主动脉的熔接按如下方法完成。用5mJ/ml的ICG将新鲜的猪主动脉包被5分钟。过量的ICG溶液被吸除。将1×1cm见方的NaOH-超声过的被消化的颈动脉弹性蛋白片段置于新染色的主动脉上。用脉冲铝镓砷二极管激光阵列(Star Medical Tehno.Logies)熔接该片段。发出790-810的5毫秒脉冲光，能量为2焦耳，并通过集光管施加到组织上，该集光管能产生4×4mm的均匀光束，并被置于覆盖了玻璃盖片的弹性蛋白消化物上。最多10个脉冲即可得到好的熔接。图6显示了与猪主动脉熔接的弹性蛋白消化物的光学显微照片。
实施例4基于弹性蛋白的生物材料的制备和与猪主动脉的融合
材料：将牛颈弹性蛋白粉末(Sigma St.Louis MO)过40μm筛并在磷酸缓冲液中膨胀。弹性蛋白片段随后与下述物质反应：磷酸缓冲液中的67毫克血纤维蛋白原(Sigma)，2m酸性可溶I型胶原蛋白(Sigma)，2.8毫克硫脲，2mM Ca2+，1mM Mg2+和75单位的凝血酶，并被注入模子中，加热至77℃。移出该生物材料的1毫米厚的薄片和管子，并保存在33％乙醇中备用。
绿靛花青染料被溶于去离子水中以得到1％的溶液并被施加到新鲜的猪主动脉腔的表面。染料在该处停留5分钟，然后将残余的染料吸去。将弹性蛋白生物材料置于ICG染色的主动脉上，并用玻璃盖片覆盖。用一个集光管施加激光能量，该集光管收集镓砷二极管激光器阵列的输出，所述激光器在800nm下发出5毫秒的脉冲光。用2.89焦耳的能量照射6平方毫米的斑点，进行1-10个脉冲以得到适当的熔接。然后将样品剖开，用甲醛固定，用于显微研究。图5是用弹性蛋白染料染色的熔接物的光学显微照片。弹性蛋白生物材料与猪主动脉的好的熔接表现为对生物材料或主动脉没有可检测的热或其他损害。
实施例5  基于弹性蛋白的生物材料的制备和与猪主动脉的融合
材料：牛颈韧带弹性蛋白、来自猪血浆的血纤维蛋白原和酸性可溶I型胶原蛋白和来自大鼠尾腱的胶原蛋白得自Sigma化学品公司(St.Loouis，MS.)。在50℃下用2.5小时将弹性蛋白溶于1M KOL/80％乙醇中。(Hornebreck)。用Pool和Shannon的方法(Pool和Shannon)从猪血浆中得到冷沉淀物。新鲜的猪主动脉得自Carlton Packaging Co.(Carlton，Ore)并保存在-20℃直到融化使用。
用类似于Rabaud发展的方法(Rabaud)制备弹性蛋白-血纤维蛋白生物材料。用溶解的弹性蛋白和冷沉淀物制备的补片可以通过连续加入下列物质来制备：溶于2毫升缓冲液的充分混合的200mg可溶弹性蛋白，溶于1毫升缓冲液中的160mg冷冻干燥的冷沉淀物，溶于0.6毫升缓冲液中的2mgI型胶原蛋白，0.2毫升硫脲溶液(0.5mg/ml水)。加入6个单位的凝血酶使体积达到0.5毫升。混合物的等分试样在1毫升注射器中充分混合，然后被注入4cm2的玻璃模子中。将模子在37℃下保温30分钟，用25mrad的ofg射线(钴源)照射。将生物材料在33％乙醇中保存在4℃下。在使用前用盐水将生物材料清洗几次。
也可用不可溶弹性蛋白和血纤维蛋白原制备补片。使用前将得自Sigma的冷冻干燥的弹性蛋白通过U.S.no 4000目筛(Tyler)。只使用40微米或更小的颗粒。28-0毫克的过滤的弹性蛋白在过量的磷酸缓冲液中膨胀和清洗过夜。将混合物离心(1000rpm，10min)，去掉过量的缓冲液。将膨胀的弹性蛋白悬于2毫升磷酸缓冲液中。向悬液连续地加入下列物质：溶于1毫升缓冲液中的67毫克的冷冻干燥的血纤维蛋白原，溶于0.6毫升缓冲液中的2毫克I型胶原蛋白，0.2毫升硫脲溶液(0.5mg/ml水)。最后，加入33单位的凝血酶，将混合物充分涡旋混匀，迅速倒入3厘米×7厘米的模子中。在37℃下将模子保温30分钟。生物材料在33％的乙醇中在4℃下保存。在使用前将生物材料用盐水清洗几次。
用AlGaAr二极管阵列激光器将可溶性的弹性蛋白-冷沉淀的补片与猪主动脉融合，所述激光器发出808nm的连续波光辐射。用0.9％的NaCl清洗新鲜的猪主动脉，把它剪成2平方厘米的小份。用pasteur pipette将浓度为1或5mg/ml的溶于水的绿靛花青(Sigma)施加到主动脉上，保持5分钟，然后被吸去。随后将组织用0.9％盐溶液平衡15分钟以除掉未结合的染料。再将该生物材料施加到主动脉腔表面。通过1微米的融合的硅纤维(Polymicro Technologies Phoenix，Az.)，并透过玻璃盖片将激光光束导向生物材料表面，如图1所示。在不同距离下，激光光束的斑点大小在1-4毫米之间变化。从纤维末端测到的激光输出是1.5瓦，照射时间从5到4秒不等。
用AlGaAr二极管阵列激光器将不可溶的弹性蛋白-血纤维蛋白原的补片与猪主动脉融合，所述激光器发出790-810nm的脉冲光辐射(StarMedical Technologies)。同上面对新鲜主动脉的描述一样制备融化的猪主动脉并用5mg/ml的ICG水溶液染色。在将生物材料施加到染色的主动脉腔表面之后，通过用铜包覆的集光管将激光导向生物材料，所述集光管置于玻璃盖片上。激光输出被设为2焦耳，脉冲持续时间为5毫秒。
实施例6
牛颈韧带弹性蛋白、来自猪血浆的血纤维蛋白原和酸性可溶I型胶原蛋白和来自大鼠尾腱的胶原蛋白得自Sigma化学品公司(St.Loouis，MS.)。
将1毫克的绿靛花青溶于1毫升的24％人血清白蛋白中。67毫克的血纤维蛋白原被溶于1毫升磷酸缓冲液中(37℃)。就在混合之前，向绿靛花青溶液加入16.6单位的凝血酶。将混合物冷却至4℃。这两种混合物被迅速混合并被注入或倒入3×7厘米的模子中，在37℃下保温30分钟。
在使用前，将得自Sigma的冷冻干燥的弹性蛋白通过U.S.no 400目筛(Tyler)。只使用40μm或更小的颗粒。210毫克过滤的弹性蛋白在过量的磷酸缓冲液中膨胀并清洗过夜。将混合物离心(1000rpm，10分钟)，去掉过量的缓冲液。将膨胀的弹性蛋白悬于1.5毫升的磷酸缓冲液中。向悬液连续地加入下列物质：溶于0.75毫升缓冲液中的67毫克的冷冻干燥的血纤维蛋白原，溶于0.45毫升缓冲液中的2毫克I型胶原蛋白，0.15毫升硫脲溶液(0.5mg/ml水)。最后，加入26单位的凝血酶，将混合物充分涡旋混匀，迅速倒入3厘米×7厘米模子中的掺有绿靛花青的血纤维蛋白基质上。在37℃下再次将模子保温30分钟。在从模子中移出之后，两层物质不能分离，制备得到单一的补片。
上面引用的全部文献在此被完整地引入作为参考。
本领域的技术人员在阅读了本发明公开后将会意识到，在不背离本发明的真实范围的情况下，可以对本发明的形式或细节作不同的改进。

Claims (28)

1.一种可与组织融合的弹性蛋白或基于弹性蛋白的生物材料，其包括一层具有第一和第二外表面的弹性蛋白或基于弹性蛋白的生物材料，该生物材料包含施加到所述第一和/或第二外表面的能量吸收材料，所述能量吸收材料渗入弹性蛋白或基于弹性蛋白的生物材料之中，该能量吸收材料在一个预定的光波长范围内吸收能量，从而当用预定波长范围内足够强度的光能照射能量吸收材料时，弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面中的一个与组织基物融合在一起。
2.权利要求1的生物材料，其中弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面是主要表面。
3.权利要求1或2的生物材料，其中能量吸收材料被间接地照射，方法是将光能首先导入弹性蛋白或基于弹性蛋白的生物材料或组织基物，然后导入能量吸收材料。
4.权利要求1或2的生物材料，其中能量吸收材料包含生物相容性生色团。
5.权利要求1或2的生物材料，其中能量吸收材料包含能量吸收染料。
6.权利要求1或2的生物材料，其中当弹性蛋白或基于弹性蛋白的生物材料与组织基物融合在一起时，能量吸收材料基本上被耗尽。
7.权利要求1或2的生物材料，其中能量吸收材料包含对弹性蛋白或基于弹性蛋白的生物材料的第一或第二表面进行染色的材料。
8.权利要求1或2的生物材料，其中能量吸收材料被施加到生物材料的一个外表面，方法是将能量吸收材料掺入单独的弹性蛋白层，然后将掺入能量吸收材料后的单独的弹性蛋白层与弹性蛋白或基于弹性蛋白的生物材料融合。
9.权利要求1或2的生物材料，其中在一段时间的光能照射过程中，温度是大约40到140℃，所述的光能照射可以使弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面之一与组织基物融合在一起。
10.权利要求1或2的生物材料，其中能量吸收材料的平均厚度是大约0.5到300微米。
11.权利要求1或2的生物材料，其中在用光能照射能量吸收材料的过程中的光波长的大小、能量水平、吸收和光强度，以及能量吸收材料的浓度被如此设置，使得弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面之一与组织基物在大约40到140℃的温度下融合在一起。
12.权利要求1或2的生物材料，其中能量吸收材料被基本上均匀地施加到至少一个所述外表面上。
13.权利要求1或2的生物材料，其中能量吸收材料基本上覆盖弹性蛋白或基于弹性蛋白的生物材料的整个外表面。
14.权利要求1或2的生物材料，其中在一段时间的光能照射过程中，温度是大约50到100℃，所述的光能照射可以使弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面之一与组织基物融合在一起。
15.一种制备可与组织融合的弹性蛋白或基于弹性蛋白的生物材料的方法，该生物材料包含一层具有第一和第二外表面的弹性蛋白或基于弹性蛋白的生物材料，所述方法包括：
提供一层具有第一和第二外表面的弹性蛋白或基于弹性蛋白的生物材料，将能量吸收材料施加到所述第一或第二外表面，该能量吸收材料渗入到生物材料中，能量吸收材料在预定的光波长范围内吸收能量，从而当用预定波长范围内足够强度的光能照射能量吸收材料时，弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面中的一个与组织基物融合在一起。
16.权利要求15的方法，其中第一和第二外表面是主要表面。
17.权利要求15或16的方法，其进一步包括间接照射能量吸收材料的步骤，方法是将光能首先导入弹性蛋白或基于弹性蛋白的生物材料或组织基物，然后将光能导入能量吸收材料。
18.权利要求15或16的方法，其中能量吸收材料含有生物相容性生色团。
19.权利要求15或16的方法，其中能量吸收材料含有能量吸收染料。
20.权利要求15或16的方法，其进一步包括在弹性蛋白或基于弹性蛋白的生物材料与组织基物融合在一起时，将能量吸收材料基本上耗尽的步骤。
21.权利要求15或16的方法，其进一步包括用能量吸收材料将弹性蛋白或基于弹性蛋白的生物材料的第一或第二表面染色的步骤。
22.权利要求15或16的方法，其进一步包括将能量吸收材料施加到所述生物材料的一个外表面上的步骤，施加方法是将能量吸收材料掺入一个单独的弹性蛋白层，然后使掺入能量吸收材料后的单独的弹性蛋白层与弹性蛋白或基于弹性蛋白的生物材料融合。
23.权利要求15或16的方法，其中能量吸收材料被基本上均匀地施加到至少一个所述外表面上。
24.权利要求15或16的方法，其进一步包括将能量吸收材料基本上覆盖弹性蛋白或基于弹性蛋白的生物材料的整个外表面的步骤。
25.权利要求15或16的方法，其进一步包括在一段时间内，在大约40到140℃温度下，用光能照射能量吸收材料的步骤，所述的光能照射可以使弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面之一与组织基物融合在一起。
26.权利要求15或16的方法，其进一步包括在一段时间内，在大约50到100℃温度下，用光能照射能量吸收材料的步骤，所述的光能照射可以使弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面之一与组织基物融合在一起。
27.权利要求15或16的方法，其中能量吸收材料的平均厚度是大约0.5到300微米。
28.权利要求15或16的方法，其进一步包括在用光能照射能量吸收材料的过程中，设置光波长的大小、能量水平、吸收和光强度，以及设置能量吸收材料的浓度的步骤，使得弹性蛋白或基于弹性蛋白的生物材料的第一和第二外表面与组织基物的温度维持在大约40到140℃，由此将弹性蛋白或基于弹性蛋白的生物材料与组织基物融合在一起。
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US5989244A (en) 1999-11-23
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ATE283004T1 (de) 2004-12-15
US5990379A (en) 1999-11-23
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DE69533806T2 (de) 2005-12-15
CN1197383A (zh) 1998-10-28
ES2233949T3 (es) 2005-06-16
KR970706765A (ko) 1997-12-01
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