CN1500447A - 自体移植术的方法、工具和用具盒 - Google Patents
自体移植术的方法、工具和用具盒 Download PDFInfo
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- CN1500447A CN1500447A CNA031553281A CN03155328A CN1500447A CN 1500447 A CN1500447 A CN 1500447A CN A031553281 A CNA031553281 A CN A031553281A CN 03155328 A CN03155328 A CN 03155328A CN 1500447 A CN1500447 A CN 1500447A
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Abstract
本发明公开了向关节连接面缺损部分进行有效的软骨细胞/软骨移植的方法以及实施本发明所用的特定工具和用具盒。
Description
本申请是申请日为19970829、申请号为97199207.x、发明名称为“自体移植术的方法、工具和用具盒”的中国发明专利申请的分案申请。
技术领域
本发明涉及的领域为软骨细胞的移植术、骨和软骨的移植及愈合、关节修复和关节炎疾病的预防，具体地说为移植位点的准备方法、该准备工作所用的工具以及向已准备好的移植位点进行自体移植所用的工具。
背景技术
在美国，每年要作超过50万例关节成形手术和整个关节的替换。在欧洲，类似手术的数量与此相近。这个数目中包括欧洲每年约有9万例整个膝部替换和5万例左右的膝部缺损修复手术。在美国，各种手术数量亦基本相同(载于：Praemer A.，Fumer S.，Rice D.P.，美国肌骨胳动态Musculoskeletal Conditions in the United States)，美国整形外科研究院，ParkRidge III，1992，125)。一种软骨再生疗法可能是非常有用的，这种方法可以在关节损伤的早期实施，从而减少必须作人造关节替换外科手术患者的数目。这种预防性疗法也会减少发展成为骨关节炎的患者数目。
关节内软骨构造的表面修整技术曾经主要是试图采用软骨下钻、磨和其它方法来作软骨修复，结果是切除了病变软骨和软骨下的骨质，使血管已经形成的网状骨质裸露(Insall，临床整形杂志(J.，Clin.Orthop.)1974，101，61；Ficat R.P.等，临床整形杂志(Clin.Orthop.)1979，144，74；Johnson L.L.，手术整形(Operative Arthroscopy)，McGinty J.B.编，Raven Press，New York，1991，341)。
Coon和Cahn在科学(Science)1966，153，1116上描述了一种由小鸡胚胎体节合成的软骨细胞的培养技术。Later Cahn和Lasher(PNAS USA 1967，58，1131)利用此系统来分析作为软骨分化的前提的DNA合成所涉及到的事物。软骨细胞通过生长来应答EFG和FGF二者(Gospldarowicz和Mescher细胞生理杂志(J.，Cell Physiology)1977，93，117)，但最终失去其分化功能(Benya等，细胞(Cell)1978，15，1313)。种植软骨细胞的方法是由Brittberg，M.等人描述并经较小修正后主要由他们进行应用的(新英格兰医学杂志(New Engl.J.Med.)1994，331，889)。这种方法种植的细胞被用于患者膝关节中的自体移植。另外，Kolettas等人借助于延长细胞培养研究了诸如胶原和含蛋白多糖等软骨特性分子的表达(细胞科学杂志(J.Cell Science)1995，108，1991)。他们发现，尽管在单层培养物中进行培养时存在形态学变化(Aulthouse，A.等，体内细胞发育生物学(In vitro Cell Dev.Biol.)1989，25，659；Archer，C.等，细胞科学杂志(J.Ceu Sci.)1990，97，361；Hanselmann，H.等，细胞科学杂志(J.Cell Sci.)1994，107，17；Bonaventure，J.等，实验细胞研究(Exp.Cell Res，)1994，212，97)，但当与琼脂糖凝胶、海藻胶质珠粒上生长的悬浮体培养物或与由不同的科学家所试验过的旋转培养物(保持圆的细胞形态)相比，诸如II型和IX型胶原的软骨细胞表达标记没有变化，大的聚集态含蛋白多糖、aggrecan、versican以及键合蛋白质没有变化(Kolettas，E.等，细胞科学杂志(J.Cell Science)1995，108，1991)。
关节软骨细胞是只存在于软骨中的特殊的间质衍生细胞。软骨是一种无血管供应的组织，它的物理性质取决于软骨细胞产生的胞外间质。软骨内的骨化软骨细胞的老化导致细胞肥大，其特征为X型胶原表达的出现(Upholt，W.B和Olsen，R.R.，载于Cartilage Molecular Aspects(hall，B&Newman，S.编)，CRC Boca Raton 1993，43；Reichenberger，E.等，Dev.Biol.1991，148，562；Kirsch，T.等，Differentiation，1992，52，89；Stephens，M.等，J.Cell Sci.1993，103，1111)。
关节软骨的表面或外层中的II型胶原亦可由于骨关节炎而使其过度退化。胶原网状组织因而削弱并随之发生原纤维化，这样含蛋白多糖一类的基质材类丢失并最终完全被排出。被骨关节炎削弱的软骨的纤维化可以发展到软骨钙化并扩展到软骨下骨质内(Kempsos，G.E.等，Biochim.Biophys，Acta 1976，428，741；Roth，V.和Mow，V.C，，J.Bone Joint Surgery，1980，62A，1102；Woo，S.L.-Y等，Handbook of Bioengineering(R.Skalak和S.Chien编)，McGraw-Hill，New York，1987，P.4.1～4.44)。
有关基础研究、骨的组织解剖学和微观解剖学、软骨和其它类似的结缔组织的描述可从例如Wheater，Burkitt和Daniels的Functional Histology第二版(Churchill Livingston，London，1987，chp.4)中找到。有关骨、软骨和其它类似的结缔组织中的缺损的组织解剖学基础的论述可从例如Wheater，Burkitt，Stevens和Lowe的Basic Histipathology(Churchill Livingston，London，1985，Chp.21)中找到。
尽管在软骨细胞培育、骨和软骨的处理方面取得进展，用于修理受损的铰接表面的软骨或软骨细胞移植工作却并末取得很大的成功。本发明所具有的技术提供了实在而有效的手段，有助于在关节的接缝和其它为软骨所覆盖的骨表面损伤处进行软骨和/或软骨移植，从而使软骨再生以修整缺损。本发明还提供了用于移植位点准备工作的外科手术工具，从而更容易使移植材料与移植位点有效地成为一体。
发明内容
本发明提供一种通过一个止血屏障和无细胞的覆盖补片将适宜基质中的软骨移植到待治疗表面上来有效地治疗关节连接表面软骨的方法，该方法包括：首先在紧贴待治疗表面的位置上放置一止血屏障，再在该待治疗表面上方止血屏障的顶部上置放处于适宜基质中的软骨细胞，然后在该待治疗表面上覆盖一无细胞的覆盖补片。止血屏障如同后面将进一步说明那样是一道抑制或阻止正经形成血管的细胞和组织渗透到移植材料内的屏障。具体地说，本方法所提供的止血屏障是一种可吸收的半渗透材料，该材料抑制或阻止血管渗过屏障。在一个实施方案中，该止血屏障包含了胶原。这里所用的无细胞一词与本领域中的一样，是指一种材料基本上没有完整的，具有进一步细胞分裂、传播能力或具有生物活性的细胞。在一个优选实施方案中，无细胞材料中是没有任何完整的有核细胞的。在一个实施方案中，本方法使用了一种包含半渗透胶原基质的无细胞覆盖补片。在本方法的一个优选实施方案中，无细胞覆盖补片的多孔的一面朝向移植材料。
本发明还提供了将胶原或软骨细胞移植到移植位点的自体移植术，其中首先是用外科操作进行移植位点的准备工作，以使其更好地接受移植材料。在一个实施方案中，移植位点经过雕刻，因而移植位点的壁面整修成波纹状，因此当置放在移植位点内的移植材料膨胀而与移植位点壁面相接触时，该壁面将阻挡整个移植物相对于移植位点迁移或被挤出。本发明还提供设计成可按照本发明的方法所教导对移植位点进行雕刻的外科工具。
本发明还提供一种用来在关节的连接表面上作软骨和/或软骨细胞移植的用具盒，其中所述用具盒内装有止血屏障、无细胞半渗透覆盖补片以及有机胶。在另一实施方案中，该用具盒带可任选地装有一种或多种能按照本发明所提供的方法对移植位点进行雕刻的外科工具。
附图说明
下面诸图说明了本发明的某些性质，通过这些图可对本发明有更好的理解，这些图为：
图1A所示为一典型的关节骨端。典型地，在骨质的铰接表面上覆盖了一层软骨质。
图1B所示为一软骨质帽出现缺损或受伤(软骨裂)的例子，这种缺损可以直接治疗、稍予扩大或在治疗以前先用外科方法加以雕刻以接受移植物。
图1C表示止血屏障(1)如何置放在软骨质帽的缺损内以抑制或阻止血管化从原来的骨中进入再生软骨中。然后，将要植入缺损穴内的软骨细胞放置在该止血屏障的顶部上。
图2所示为软骨质帽内经过治疗的缺损(软骨裂)被一层无细胞半渗透材料(2)所覆盖，该材料(2)是用来在缺损位点上面形成一个盖子/补片或绷带的。此盖子被安放在适当的位置上，或是与穴边缘的健康软骨相缝接或是贴附在上面。此盖子遮盖住关节的缺损部位，培养好的软骨细胞/软骨或是预先放置在缺损部位内，或是事后放到部分贴附在穴上的盖子下面。
图3A所示为分界区两侧的较硬软骨和较软软骨对压缩力和剪切力的不同响应。
图3B所示为缺损处经过雕刻以后移植位点具有的波纹状壁。
图3C所示为处于关节表面软骨(4)内，带有止血屏障(1)，移植物质(3)和无细胞覆盖补片(2)的经过雕刻的移植位点。
图4A所示为本发明外科器械的一个实施方案，图中可见到切削牙(5)和凸出的定位销(6)。右边的截面图所示为切削刀片的两个可能的构形。
图4B所示为本发明外科器械的第二个实施方案。
图5所示为移植位点经过雕刻以后较硬软骨和较软软骨对压缩力和剪切力的不同响应得到改良的情况。
图6A为一头猪膝部的磁共振图象，显示出在左(中)髁处的软骨缺损。
图6B为同一头猪膝部治疗后三个月时的磁共振图象。
具体实施方式
本发明提供一种通过一个止血屏障和一个覆盖补片将适宜基质中的软骨细胞移植到待治疗表面上来有效地治疗关节连接表面软骨的方法，包括：将一个止血屏障放到紧贴待治疗表面的位置上，将适宜基质中的软骨细胞放到待治疗表面上的止血屏障的顶部，以及用一个覆盖补片覆盖在待治疗表面上。
在本发明的上述方法中，所述覆盖补片是首先被贴附到把移植位点覆盖起来的软骨表面上，然后将所述覆盖补片下的所述软骨放到所移植位点内。
在本发明的上述方法中，所述覆盖补片含有半渗透胶原基质。
在本发明的上述方法中，所述覆盖补片含有带有一个疏松面的半渗透胶原基质。
在本发明的上述方法中，所述疏松面与被移植的软骨细胞接触。
在本发明的上述方法中，覆盖补片含有半渗透胶原基质，该胶原基质是基本上没有完整细胞的；所述止血屏障是一种可吸收的半渗透材料，该材料抑制或阻止血管穿透屏障。并且其中所述止血屏障含有胶原。
本发明还提供一种通过一个移植位点、一个止血屏障和一个覆盖补片把适宜基质中的软骨细胞移植到等治疗表面的方法，包括：首先对移植位点进行雕刻，使得移植位点的壁成为非直线的和/或波纹形的，将一止血屏障放到经雕刻的移植位点内紧贴待治疗表面的位置上，将适宜基质中的软骨细胞放到移植位点内的止血屏障上，以及用覆盖补片覆盖在待治疗表面上。
在本发明的上述方法中，所述覆盖补片在软骨细胞放到移植位点内的止血屏障上之前已部分地贴附好。所述止血屏障是一种可吸收的半渗透材料，该材料抑制或阻止血管穿透屏障；其中所述止血屏障含有胶原。
在本发明的上述方法中，其中所述覆盖补片为无细胞半渗透胶原基质。
本发明还提供一个用于将软骨细胞/软骨移植到关节连接表面的用具盒，所述用具盒包括一个经过预处理来抗吸收以适于置放到所述表面的止血屏障，一个经过预先处理来抗吸收以适于覆盖所述表面的覆盖补片，以及适于将所述止血屏障和/或所述覆盖补片贴附到所述表面上去的有机胶液。
在本发明的上述用具盒包括一个经过处理来抗吸收的止血屏障，一个经过处理来抗吸收的覆盖补片，一种有机胶液，以及任选的用来雕刻移植位点壁的外科工具和任选的适于支承放入所述移植位点的软骨细胞的基质材料。
本发明还提供一种用来雕刻移植位点的外科工具，该移植位点包括铰接骨软骨表面内的壁和底，该外科工具包括一个连接在一根杆或柄上的刀口，当它在所述移植位点内转动或在圆周方向上刻划时，该移植位点受到雕刻，因而移植位点的壁或为非直线的，或为任选的波纹形。
在上述的外科工具中，所述刀口成形为如图4A或图4B所示。
在上述的外科工具中，所述刀口成形为沿着一管状或环状杆表面盘旋上升的螺旋形刀片。
本发明涉及到某些产品的使用，这些产品在向软骨的缺损处进行自体软骨细胞移植过程中能防止血管组织的形成，如能防止诸如毛细血管绊伸到正在建立的软骨中去。来自原来的骨质的血管组织的形成将倾向于伸到将要形成的新软骨中去，这导致除了所要求的间质的特殊软骨细胞以外的其它细胞的出现。
由血管形成所导致的污染细胞可能侵蚀并过度发育而进入通过软骨细胞的植入而将要形成的软骨中。商品中有一种叫做Surigcel(Ethicon有限公司，英国)的可以用在本发明中，它可以在7至14天后被吸收。这种材料在本发明的方法中的使用与诸如Surigcel包装插页中Ethicon有限公司所登载的止血器材的正常使用是相反的。
我们意外地发现，在希望防止软骨内血管形成的情况下，一种止血材料会起凝胶状人造凝结物的作用。本应当出现在关节软骨缺损处整个厚度内的血红细胞被这样的止血屏障遮盖住时，该血细胞会化学变化成高铁血红素，从而不能诱发血管发育。于是一种例如Surigcel这样的止血产品用作血管再形成的抑制屏障(无论有没有血纤蛋白粘结剂)，对于本发明所设想的方法都是有效的。本发明的另一部分内容是使用一个无细胞元件作为补片来遮盖住关节的受损部位，该受损部位中使用自体软骨细胞培养出来的软骨细胞/软骨正在进行移植。本发明的方法也考虑使用同种异体的软骨细胞或异种的软骨细胞来修理软骨缺损。
因此，本发明教导了对关节的连接骨质表面上的软骨缺损进行有效地修理或治疗的方法，该方法包括提供一种药剂或器件来阻断血管向软骨等修理位点的侵入；还包括提供一种无细胞的屏障来隔离修理位点并保持被移植细胞的应有位置。因此本发明还提供一个用具盒，该工具盒中装有用来放入待修理位点的止血屏障元件，这对血管形成的侵入待修理位点具有有效的抑制作用。一旦待移植的软骨细胞放入待修理位点，一种无细胞半通透屏障便覆盖在修理位点上，这使得软骨细胞保持在正确的位置，而且仍能获得通向营养素的通道。
一种采用体外实验系统进行的关于软骨细胞在其与某种阻止血管组织形成的产品或几种产品的复合物接触时的行为的研究结果已经给本发明的某些方面作了例证。该体外试验结果预示了某些试验物质所具有的对血管形成的抑制能力，这种血管形成将发生在体内对软骨的缺损部位进行软骨细胞自体移植过程中，在该过程中毛细血管绊会伸入正在建立的软骨中。
适用的止血产品将具有能抑制血管组织、骨细胞、成纤维细胞等发育或侵入正生长中的软骨的特征。一种适用的止血材料必将实现本发明的方法的目标，因为为了使软骨的形成最佳，以及使关节软骨中的任何缺损在整个厚度上都得到修复，应当防止血管以及细胞向正在发育的软骨入侵。理想的情况是在整个软骨得到修复的期间内止血屏障都是稳定的，而过了这段时间后是能被吸收的，否则便被分解掉。有一种鉴定为适用的材料叫做SurigcelW1912(一种可吸收止血剂，含有氧化再生的无菌纤维素；LotGG3DH，Ethicon有限公司，英国)。另一例适用材料为BioBide(一种商业供应的I型胶原基质衬垫；Geistlich Sohne瑞士)。
可以从商品中找到的适用的有机胶液材料例如为TisseelTissucol(血纤蛋白基粘结剂；ImmunoAG，奥地利)，粘性蛋白(Cat.#A-2707，SigmaChemical，美国)以及Dow Coming医用粘结剂B(Cat.#895-3，Chemical，美国)。
本发明所考虑的外科工具可用适宜于制作一次性使用或多次重复使用外科工具的金属和/或塑料制造。切削工具上的切削齿可以是整圆周的或平板的，或两者之间的任何装置。因为软骨是一种相对较软的物质，用硬塑料切削刀刃来加工比较好，这样就能在雕刻软骨的时候不致损坏骨层。这种切削工具可以制成带有通路的，以便用来引入液体、吸去切屑和液体以及插入用来对缺损位点进行照明和观察的光学纤维索。
通过下面几个实例的说明可以对本发明的某些方面有更好的了解，这些实例的含意是对发明的说明，而不是对发明的限制。
实施例1
为了使Surgice得以按照本发明用来阻止血管发育进入自体移植的软骨或软骨细胞，首先要用戊二醛那样的固定剂对Surgicel进行处理。简单地说，Surgicel要在0.6％戊二醛中处理1分钟，然后多次清洗以去除残留的戊二醛，否则可能会使组织中毒。也可以在进行戊二醛处理之前，先将Surgicel用叫做Tisseel的血纤蛋白粘结剂如例2所述进行处理。这里发现，Surgicel用戊二醛这样的固定剂固定，并用无菌生理盐水(0.9％)洗涤后在冰箱里保存1至2月不会分解。一般地说，外科用料在7至14天期间会被吸收。这个时间可能是太短了，因为在植入的软骨细胞发育成为固态的软骨层，从而得以从周围的软骨中获取营养之前要阻止血管或血管化由骨结构进入所植入的软骨需要一个更长的时间。换句话说，必须在更长的时间，例如1个月之内能够有效地防止血管形成。在这个时间之前，产品不应显著地被吸收；另一方面，产品最终必须被吸收。因此，用作抑制屏障的有机物质都应具有这些能力。已经发现，经上述方法处理过的Surgicel具有这个功能。
实施例2
在Surgicel上还包覆上一种有机胶液。在本例中，该胶液用的是Tisseel。但也可以采用其它胶液。该产品与Surgicel一起产生了一个对本发明的特殊目的适用的屏障。任何其它止血剂或血管抑制屏障均可以使用。Tisseel按后面所述的方法配制。Surgicel上包覆Tisseel的方法为：先在Surgicel材料的两面喷洒Tisseel直至湿透，然后让Tisseel(血纤蛋白胶液)在室温下固化。在完全固化之前要及时地将包覆好的Surgicel放入0.6％的戊二醛中1分钟，然后用0.9％的无菌生理盐水洗涤。然后用磷酸盐缓冲盐水(PBS)和/或NaOH调整PH值，直至PH值稳定在7.2至7.4之间。在这之后，经如此处理的Surgice要在诸如最低必需培养基/F12加15毫摩尔的Hepes缓冲剂组成的组织培养剂中洗涤。
如本例所述，我们使用了Tisseel作为血纤蛋白粘结剂来包覆Surgicel。除此之外，血纤蛋白粘结剂或胶液亦可直接加到损伤的底层，面向骨层，在这上面再粘上Surgicel。用来替代体内试验的体外试验系统包括一个用作细胞研究的NUNCLONTMDelta 6穴无菌一次性使用培养皿。每个穴的直径约为4厘米。
任何一种粘结剂，只要它与血纤蛋白组分一起制得的胶液可为人体所容许，便可用作本发明血纤蛋白粘结剂中的粘结剂(Ihara，N等，Burus Incl.Therm.Inj.，1984，10，396)。本发明亦考虑可用任何其它胶液成分来替代血纤蛋白粘接剂。在本发明中，我们用了Tisseel或Tissucol(ImmunoAG，Vienna，奥地利)。Tisseel用具盒装有下列组分：
Tisseel，冻干，病毒灭活封闭剂，包括可凝蛋白质、它的血纤蛋白质、血浆纤连蛋白(CIG)和第十三因子以及纤溶酶原。
抑肽酶溶液(牛的)
凝血酶4(牛的)
凝血酶500(牛的)
氯化钙溶液
Tisseel用具盒中还装有一套DUPLOJECT涂敷系统。血纤蛋白粘结剂或使用Tisseel用具盒的双成分封密剂用下文根据Immuno AG的产品盒插页中的方法混合。
实施例3
软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5％的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S，Symbion Science Park的100级实验室内进行操作。软骨细胞还可能用别的成分的培养基进行培养。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化，并在Burker-Turk箱中用台盼兰(Trypan Bule)生存力染色进行计数。细胞计数调整到每毫升7.5×105个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。
将Surgicel止血屏障切割成合适的尺寸，置放在NUNCLONTM组织培养皿的井穴的底部。本例的具体情况为，尺寸约为4厘米的圆片(亦可为任何可能的尺寸)在无菌条件下放到6穴NUNCLONTM Delta细胞研究工作用无菌一次性使用培养皿(NUNC，IterMed，Roskilde，丹麦)的穴底上。放到穴底上的止血屏障按照例1中所述进行过预处理。该处理明显地延缓了Surgicel的吸收。该止血屏障然后在蒸馏水中洗几次，接着又是几次，直到未反应的戊二醛被洗掉。再加上少量的含血清细胞培养基，它们将被吸收进入止血屏障内，同时会保持穴底的止血屏障潮湿。
每毫升约106个细胞的培养基直接放到止血屏障的顶上，分散在如上面所说用0.4％戊二醛预处理过的止血屏障的表面上。接下来将培养皿在CO2培养箱内在37℃下培养60分钟。然后小心地向装有细胞的穴内倒入2至5毫升含5至7.5％血清的组织培养基。为了避免溅到细胞上，在倒入培养基时，滴管口要与穴的侧壁相切。可以看到，培养基的PH值是太低了(约6.8)。将PH值调到7.4至7.5。第二天，有些软骨细胞已开始在止血屏障上生长并排列成簇，有一些细胞由于调整PH值之前暴露在低PH下而已经死亡。培养皿要培养3至7天，第3天时要更换培养基。
培养期终了时，轻轻地倒出培养基，并倒入冷藏的作为细胞标本和以后电子显微镜标本的载体(止血屏障)的固定剂的、含0.1摩尔二甲次胂酸钠盐(亦称作卡可酸钠，用HCL将PH值调到7.4)的2.5％戊二醛。
实施例4
软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5％的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S，Symbion Science Park的100级实验室内进行操作。软骨细胞还可能用别的成分的培养基进行培养。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化，并在Burker-Turk箱中用台盼兰(Trypan Bule)生存力染色进行计数。细胞计数调整到每毫升7.5×105个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。
用作止血屏障的Surgicel如例1所述那样以0.6％的戊二醛处理1分钟，并以0.9％无菌氯化钠溶液或最好以PBS那样的缓冲剂或MEM/F12那样的培养剂清洗，因为在戊二醛处理以后，PH为6.8，而最好的应当为7.0至7.5。用DUPLOJECT系统将Tisseel喷洒在Surgicel的两面，从而对Surgicel的两面进行了包覆，即为带有血纤蛋白粘结剂的待用的补片。胶液在无菌条件下干燥至少3至5分钟。“包覆”好的止血屏障被放到NUNCLONTM Delta细胞研究工作用的6穴无菌一次性使用培养皿的穴底，加上少量的血清的组织培养基，它们将被吸收进入止血屏障。每毫升约106个细胞的含血清的组织培养基直接放到止血剂的顶上，分散在止血屏障的表面上。然后将培养皿在CO2培养箱内在37℃下培养10分钟。接下来小心地向装有细胞的穴内倒入2至5毫升含5至7.5％血清的组织培养基。为了避免溅到细胞上，在倒入培养剂时，滴管口要与穴的侧壁相切。3到6天后，显微镜检测表明，细胞正附着在Surgicel上并正在向里面生长。这很好地说明了Surgicel对软骨细胞不显现毒性。骨细胞在Surgicel中以良好的方式生长。
培养皿培养3到7天，第3天时要更换培养基。培养期终了时，轻轻地倒出培养基，并倒入冷藏的作为细胞标本和以后电子显微镜标本的载体(止血屏障)的固定剂的、含0.1摩尔二甲次胂酸钠盐(亦称作卡可酸钠，用HCL将PH值调到7.4)的2.5％戊二醛。
实施例5
软骨细胞在包含HAM F12和15毫摩尔的Hepes缓冲剂和5至7.5％的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S，Symbion Science Park的100级实验室内进行操作。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化，并在Burker-Turk箱中用台盼兰(Trypan Bule)生存力染色进行计数。细胞计数调整到每毫升7.5×105至2×106个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。
已经发现，Bio-Gide可以作为一种可吸收的双层薄膜来用作覆盖在关节缺损部位上的补片或绷带，该缺损内放置有止血屏障和正在移植的培育软骨细胞。Bio-Gide是由标准的受控加工工艺过程生产出来的一种纯胶原薄膜(由E.D.Geistlish Sohne AG，CH-6110 Wolhusen生产)。该胶原是从兽医认证的猪身上萃取，经小心地精制以避免抗原反应，并在双重泡形罩内以伽玛射线消过毒的。该薄膜是用I型和III型胶原制成的，没有经过进-步的交联或化学反应。胶原可在24周以内被吸收。薄膜甚至在湿的时候也能保持其结构完整性，并且可以用缝合线或钉子来固定。也可用Tisseel那样的血纤蛋白粘结剂来替代缝合线或是与缝合线一起将薄膜“胶合”在周围的软骨或组织上。
在100级实验室中将Bio-Gide启封，并且在无菌的条件下将其放入到细胞研究工作用NUNCLONTM Delta 6穴无菌一次性使用培养皿的穴底部，双层薄膜或是疏松面朝上或是致密面朝上。每毫升约106个细胞的含血清的组织培养基直接放到Bio-Gide顶上，分散在Bio-Gide的疏松表面或致密表面上。将培养皿在CO2培养箱内在37℃下培养60分钟，然后小心地向装有细胞的穴内倒入2至5毫升含5至7.5％血清的组织培养基。为了避免溅到细胞上，在倒入培养基时，滴管口要与穴的侧壁相切。
在软骨细胞放入带有Bio-Gide的穴内二天之后，用一台Nikon倒装显微镜来对细胞进行检测。我们注意到，有些软骨细胞附着在Bio-Gide的边缘上。当然用显微镜是不可能透过Bio-Gide看它自己的。
培养皿培养3至7天，第3天时要更换培养基。培养期终了时，轻轻地倒出培养基，将冷藏的、作为细胞标本和Bio-Gide载体标本的固定剂的含0.1M二甲次胂酸钠盐(也称为卡可酸钠，用HCL将PH值调到7.4)的2.5％戊二醛。该载体的疏松面或致密面上繁殖有细胞。然后将Bio-Gide补片送到丹麦Herlev医院病理部作电子显微镜检测。
电子显微镜检测表明，繁殖在Bio-Gide致密面上的软骨细胞没有生长进入Bio-Gide的胶原结构中，而繁殖在疏松表面上的确实生长进入了胶原结构，而且还显示有蛋白聚糖的存在，而没有成纤维细胞构造的征兆。此结果表明，当胶原补片，例如Bio-Gide补片在缝合到软骨缺损处时，补片的疏松面应该朝下，面向将要注入培育好的软骨细胞的缺损位点。这样，软骨细胞便能透入胶原而形成一个平滑的，与未受损表面齐平的软骨表面，而且在此区域内将建立起平滑的蛋白聚糖层。反之，若胶原的致密表面朝向缺损里面，则植入的软骨细胞便不与胶原合成一体，而细胞将不会形成如上所述的平滑表面。
实施例6
软骨细胞在包含HAM F12和15亳摩尔的Hepes缓冲剂和5至7.5％的自身血清的最低必需培养基中放在37℃的CO2培养箱中培育。在丹麦哥本哈根的Verigen Europe A/S，Symbion Science Park的100级实验室内进行操作。细胞用EDTA胰蛋白酶进行5至10分钟的胰酶消化，并在Burker-Turk箱中用台盼兰(Trypan Bule)耐久性染色进行计数。细胞计数调整到每毫升7.5×105至2×106个细胞。在100级实验室中将一个NUNCLONTM培养皿启封。
Bio-Gide用作可吸收的双层薄膜也可以与Tisseel这样的有机胶一起使用，但附加的抑肽酶含量要比Tisseel产品使用说明所说的正常值明显地高。将抑肽酶增加到约25000KIU/ml，材料的吸收期将从正常范围的几天延长到几个星期。
为了在体外检验该项性能，将Tisseel加到NUNCLONTM培养皿的穴底上，并且允许不完全凝固。然后将Bio-Gide那样的胶原补片加到Tisseel上面并粘在穴底上。这样的Bio-Gide和Tisseel组合是设计用作止血屏障的，它将抑制或阻止血管的发展或渗透进入软骨细胞移植区。这种复合胶原现在可用来既作为伤口底部紧贴待修理表面的止血屏障，同时又是软骨形成的支撑物，因为胶原补片朝上的一面可以是疏松面，从而促进软骨细胞和软骨基质的渗透。这种复合胶原也可用来盖在植入物顶上，胶原的疏松面朝下，面向植入的软骨细胞和形成顶部的屏障。抑肽酶含量增高了的复合胶原又可以直接放入缺损处，靠本身的固有粘力粘附，而不需用Tisseel那样的有机胶液，因而这种胶原补片既可用作止血屏障，又可将其疏松面朝向植入物的软骨细胞/软骨而用作修理位点/移植位点的无细胞盖罩。另一个变型是由II型胶原组成的胶原补片(即使用Geistlich Sohne AG，CH-6110Wolhusen)。
这样，本发明提供了一种复合胶原补片，所述补片具胶原基材料其抑肽酶组分增高，最好约为25000KIU/ml，与一种有机材料胶液配套使用。这里胶原组分为类似于Bio-Gide的可吸收双层材料或II型胶原，而有机胶液为类似于Tisseel的材料。另一个实施方案为复合胶原补片不使用任何有机胶液来贴到修理位点上。
实施例7
由于骨关节炎软骨构造已被削弱，植到受损软骨移植位点中去的培育好的自体软骨细胞的附着力会受到抑制，因此在新植入的软骨/软骨细胞和周围的已有软骨之间形成了一个边缘区(分界线区)。如果移植位点在作移植准备时将壁面制备成为直的平滑的直线方式，则该边缘区将是非常明显的。在移植位点被切割成直线形时，跨越这种边缘区两边的剪切力和压缩力将对移植物作用以很大的力来将其排出。这个边缘区以及材料沿着这个边缘区的不同的运动将抑制移植材料与周边材料之间的愈合。当邻接材料的硬度不相同时，这种边缘区剪切会更恶化。在很多情况下，移植材料较周边材料更软，然而在某些骨关节炎病例中，周边软骨可能事实上较植入的软骨细胞/软骨还要硬。
所以，为了解决这个问题，本发明的方法教导了使用外科工具来雕刻移植位点的壁面，使壁面是非直线型的，因而提供了波纹状表面，这将减轻边缘区剪切力，并使移植材料得以锚固。也可以对移植位点整形，使其接近骨表面处的直径大于远离骨表面并位于待修理软骨表面处的直径，因而存在一个“倒漏斗”效应。表面上的狭窄开口将有助于减小边缘区的剪切力，减轻移植物从移植位点的挤出。在一个优选实施方案中，移植位点雕刻成类似一个可以拧入螺栓或螺钉的螺孔(图3B)，这可称作“阴”和“阳”螺纹，因而提供了抵御移植位点对移植物的压缩和排斥的机械阻力。
本发明所考虑的外科工具可用适宜于制作一次性使用或多次重复使用外科工具的金属和/或塑料制造。因为软骨是一种相对较软的物质，用硬塑料切削刀刃来加工较好，这样就能在雕刻软骨的时候不致损坏骨层。这种切削工具可以制成带有通路的，以便用来引入液体、吸去切屑和液体以及插入用来对缺损位点进行照明和观察的光学纤维索。在工具的某些实施方案中，工具的基面可以具有凸出点或销形构造，这将有助于将工具导引并定位在移植位点内。当然，这样的销必定设计成对底下的骨层破坏最小。
尽管工具的切削表面可以是单齿的、多齿的，或象在金属零件上加工螺孔的丝锥那样成为螺旋形状的，切削工具必须具有的性能为移植位点最后雕成的侧面为波纹形的和非直线的。例如，在某些实施方案中，工具的切削刃可整修成类似于图4A或图4B所示的形状。在绕着切削工具直径的方向上，切削刃可以是平直的或是圆形的。可以设计出很多其它形状来达到本发明的方法的目的，产生一个界面来对作用在移植材料和周边材料上的压缩和剪切力所引起的各种反作用力提供机械阻抗。
实施例8
一头出生四个月的约克郡混种猪在受到一般的麻醉后腹部朝上地平躺着。猪在经过清洗后送进亚利桑那州费尼克斯Harrington炎研究中心的外科手术室。整个外科程序是在无菌状态下实施的。猪的左后腿和邻近的腿关节部以及腹股沟区域用碘酒清洗。膝关节作了定位并固定髌骨。从髌骨后部起做个约3厘米的正中切口，并基本上割去皮下组织、肌肉层和韧带，形成通向中股髁的通道。用一圆形切割器在覆盖在中髁后中部上的白软骨内制造一个伤口，伤口与该软骨的外缘间的边缘宽度为0.5至1厘米。该0.5至1厘米大的缺损的位置是在中髁(左髁，见图6A)承受尾部重量的部位内。整个外科进程中，左股骨上没有用止血带。皮肤和各层进行了适当的缝合。
第3天时，又将动物带进外科手术室，与上面一样地放在手术台上并施以一般的麻醉。左后腿、腹部和腹股沟区域如上面所述用碘酒离子化(ionized)。割掉缝合线，打开手术区。注意到膝关节内存在中度的血肿。除去血液凝块并检查缺损处。缺损中存在血液凝块。将该血液凝块除去。将一个具有阳螺纹形切削刃、尺寸相当于伤痕的周边或稍大的无菌外科工具小心地拧入缺损处。将一块Bio-Gide补片剪裁成与缺损的底部尺寸相同。将一种粘性蛋白(A-2707，Sigma Chemical，美国)首次用胶涂覆在经过整修的止血屏障补片的致密面上，并将该补片致密面朝下放入伤痕的底部，形成上面所说的屏障。我们发现，该胶液似乎干得不是非常快，此时伤痕底面轻微的出血立刻停止了。第二块Bio-Gide的周边剪裁得比伤痕要大一些，并且如前面所说致密面朝上(所以其疏松面朝向移植物)地放在伤痕上。
然后将该无细胞覆盖补片缝合在空穴上，留下一个边缘敞着口，将要取出的软骨细胞可从这个开口处注入移植位点。补片的四周边缘涂盖上第二次用胶，即Dow Corning医用粘结剂B(Cat.#895-3，Dow Corning，美国)。这种第二次用胶干得非常快，而且较首次用胶更有效。我们发现，在上述这一特定的操作过程中，在着手进行盖罩的缝合时，首次胶尚末充分干燥到可使止血屏障就位。紧贴移植位点表面上的主要屏障是由该胶液本身形成的。
用一个1毫升的注射管和一个16号针头将约0.6毫升的软骨细胞的细胞悬浮体吸入注射管的圆筒内。再将16号针头换成23号短针头，并将细胞悬浮体(约10×106个细胞)注入所缝合的覆盖补片下面的移植位点内。接下来在撤出针头之前粘合盖罩的敞口边缘，然后再小心地撤去针头。没有看到细胞的漏出。然后如前面那样将伤口缝合，并且没有使用止血带，也没有看到出血。最后将皮肤层缝合。缝合后没有发生皮肤隆起，这表明不存在血肿。术后恢复是没有事故的。
正如希望的那样，植入的软骨细胞所生成的软骨基质充分地修复了试验猪膝关节软骨表面内所制造的缺损。图6A为猪膝部的磁共振图象，表示在膝内(左髁，中髁)处造成的软骨损伤；图6B为同一头猪膝部治疗后三个月时的磁共振图象，表示该缺损的修复。
实施例9
一个由实施本发明的方法有用的元件组成的用具盒可使本发明的方法在外科移植中得以方便地实施。在一个优选实施方案中，本发明的用具盒将提供适于在外科条件下容易地使用的无菌元件，并将提供适用的止血屏障、适用的覆盖补片，如果需要还将提供有机胶液。一个本发明的用具盒还可提供无菌的，适于用来承载自体软骨细胞的无细胞基质材料，该自体软骨细胞是将植入关节铰接表面缺损内的。在一个实施方案中，一个本发明的用具盒内装有Surgicel止血屏障和带有适宜的涂覆层Tisseel有机胶的Bio-Gide覆盖补片。这里的Surgicel和Tisseel是已经按照本发明的教导作了延长吸收时间处理的。在Tisseel预先涂覆好的情况下，在一个实施方案中，Tisseel增补了额外的抑肽酶来增长吸收时间。
在另一个优选实施方案中，止血屏障和覆盖补片二者都是一种半渗透胶原基质，它们都是经过处理来延长吸收时间的。也还可能以增强型的形式将Tisseel胶液作为独立的组分来提供，在需要的时候再涂覆。这是因为每个修复/移植程序会遇到的固有可变性以及各种独特的情况。
本发明用具盒的又一个实施方案内装有如例7中所说的那种外科工具或它的适用的改进型。
本专业人员都了解，由具体的实施方案所表示的本发明可以进行许多变更和/或修改，这些变更和/或修改没有脱离本发明的所述精神和范围。
Claims (3)
1、一种用来雕刻移植位点的外科工具，该移植位点包括铰接骨软骨表面内的壁和底，该外科工具包括一个连接在一根杆或柄上的刀口，当它在所述移植位点内转动或在圆周方向上刻划时，该移植位点受到雕刻，因而移植位点的壁或为非直线的，或为任选的波纹形。
2、如权利要求1的外科工具，其中所述刀口成形为如图4A或图4B所示。
3、如权利要求1的外科工具，其中所述刀口成形为沿着一管状或环状杆表面盘旋上升的螺旋形刀片。
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- 1997-08-29 EP EP04008116A patent/EP1459709A1/en not_active Withdrawn
- 1997-08-29 DE DE69728569T patent/DE69728569T2/de not_active Expired - Lifetime
- 1997-08-29 SI SI9730655T patent/SI1006950T1/xx unknown
- 1997-08-29 TR TR1999/00437T patent/TR199900437T2/xx unknown
- 1997-08-29 EP EP97939677A patent/EP1006950B1/en not_active Expired - Lifetime
- 1997-08-29 ES ES97939677T patent/ES2218697T3/es not_active Expired - Lifetime
- 1997-08-29 CA CA002419644A patent/CA2419644C/en not_active Expired - Lifetime
- 1997-08-29 EP EP01126359A patent/EP1181908B1/en not_active Revoked
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1999
- 1999-02-26 NO NO990933A patent/NO990933D0/no not_active Application Discontinuation
- 1999-05-26 US US09/320,246 patent/US6283980B1/en not_active Expired - Lifetime
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2000
- 2000-10-17 US US09/690,252 patent/US6379367B1/en not_active Expired - Lifetime
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2002
- 2002-01-23 US US10/055,105 patent/US6592598B2/en not_active Expired - Lifetime
- 2002-02-08 RU RU2002103570/14A patent/RU2002103570A/ru not_active Application Discontinuation
- 2002-03-04 US US10/091,006 patent/US6599300B2/en not_active Expired - Lifetime
- 2002-03-05 US US10/090,922 patent/US6592599B2/en not_active Expired - Lifetime
- 2002-03-06 US US10/093,129 patent/US6599301B2/en not_active Expired - Lifetime
- 2002-06-04 DK DK200200178U patent/DK200200178U1/da unknown
- 2002-06-04 DK DK200200177U patent/DK200200177U1/da unknown
- 2002-10-30 JP JP2002316043A patent/JP2003159266A/ja active Pending
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2003
- 2003-05-23 US US10/444,391 patent/US7048750B2/en not_active Expired - Fee Related
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2006
- 2006-03-14 US US11/375,180 patent/US20060195122A1/en not_active Abandoned
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2007
- 2007-06-13 JP JP2007155993A patent/JP2007296371A/ja active Pending
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