CN1612715A - 自体移植的方法,器械和试剂盒 - Google Patents
自体移植的方法,器械和试剂盒 Download PDFInfo
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Abstract
本发明提供一种通过植入动物用于软骨修复的植入物件。所述植入物件包括支持基质,和粘附在支持基质边缘的软骨细胞和生物相容性胶合剂,其中所述支持基质可为动物吸收。所述支持基质是一种生物相容性材料,如胶原蛋白,并且所述胶合剂是自体纤维蛋白。
Description
技术领域
本发明涉及软骨细胞移植,骨和软骨移植,愈合,关节修复和预防关节炎病理变化的领域。特别是提供准备移植位点的方法,作所述准备和将细胞自体移植到所准备移植位点的器械。
发明背景
美国每年进行500,000例以上的关节形成术和全关节置换术。在欧洲进行类似手术的数量基本相同。该数字包括欧洲每年的大约90,000例全膝盖置换术和大约50,000例修复膝盖缺损的手术。该项手术的数量与美国基本相等。(In:Praemer A.,Furner S.,Rice,D.P.,Musculoskeletal conditions in theUnited States,American Academy of Orthopaedic Surgeons,Park Ridge,Ill.,1992,125)。软骨的再生处理方法会很有用,并且可在关节损害的早期阶段进行,从而减少需要人工关节置换外科手术的病人数量。通过此种预防性处理方法,骨关节炎的发病病人的数量也会减少。
用于关节内软骨结构表面重建的技术主要用软骨下钻孔,磨损和其它切除患病软骨和软骨下的骨,暴露血管化松质骨的方法(Insall,J.,Clin.Orthop.1974,101,61;Ficat R.P.等Clin Orthop.1979;144,74;Johnson L.L.,In:Operative Arthroscopy,McGinty J.B.,Ed.,Raven Press,New York,1991,341)来诱导软骨修复。
Coon和Cahn(Science 1966,153,1116)描述了一种从小鸡胚胎体节进行软骨合成细胞培养的方法。之后Cahn和Lasher(PNAS USA 1967,58,1131)用此系统分析作为软骨分化先决条件所涉及的DNA合成。软骨细胞会响应EFG和FGF而生长(Gospodarowicz和Mescher,J.Cell Physiology 1977,93,117),但最终会失去它们的分化功能(Benya等Cell 1978,15,1313)。过去描述的软骨细胞生长方法已被Brittberg,M.等(New Engl.J.Med.1994,331,889)稍做调整来主要应用。用这些方法生长的细胞被用作病人膝盖关节的自体移植物。另外,Kolettas等(J.Cell Science 1995,108,1991)检查了软骨-特异性分子如胶原蛋白和蛋白聚糖在延长的细胞培养中的表达。他们发现除了在单层培养物的培养中的形态学变化外(Aulthouse,A.等.,In Vitro Cell Dev.Biol.,1989,25,659;Archer,C.等,J.Cell Sci.1990,97,361;Hanselmann,H.等,J.Cell Sci.1994,107,17;Bonaventure,J.等,Exp.Cell Res.1994,212,97),当与在琼脂糖凝胶,藻胶珠子上生长的悬浮培养物相比时,或者当很多科学家所检测的离心培养物(保持圆形细胞形态)不变时,所述软骨细胞-表达标记如II型和IX型胶原蛋白及大聚集蛋白聚糖,聚集蛋白聚糖,多功能蛋白聚糖和连接蛋白不发生变化(Kolettas,E.等,J.Cell Science 1995,108,1991)。
关节软骨细胞是仅发现于软骨的特化间充质衍生的细胞。软骨为一类其物理性质依赖于所述软骨细胞产生的细胞外基质的无血管组织。在软骨内骨化过程中,软骨细胞成熟从而导致了以X型胶原蛋白开始表达为特征的细胞肥大(Upholt,W.B.and Olsen,R.R.,In:Cartilage Molecular Aspects(Hall,B &Newman,S,Eds.)CRC Boca Raton 1991,43;Reichenberger,E.等,Dev.Biol.1991,148,562;Kirsch,T.等,Differentiation,1992,52,89;Stephens,M.等,J.Cell Sci.1993,103,1111)。
II型胶原蛋白在关节的外层或关节表面的过度降解也由骨关节炎造成。所述胶原蛋白网络相应变弱结果发展了原纤维形成作用,其中基质材料如蛋白聚糖丢失并最后被完全置换。该变弱的骨关节炎性软骨的原纤维形成作用可深达钙化软骨并达到所述软骨下的骨(Kempson,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,in Handbook of Bioengineering(R.Skalak和S.Chien eds.),McGraw-Hill,New York,1987,pp.4.1-4.44)。
关于骨,软骨和其它此类结缔组织的基本发育,组织学和显微解剖学描述可见例如Wheater,Burkitt和Daniels,Functional Histology,2nd Edition,(Churchill Livingstone,London,1987,Chp.4)。关于骨,软骨和其它此类结缔组织的缺损的基本组织解剖学描述可见例如Wheater,Burkitt,Stevens和Lowe,Basic Histopathology(Churchill Livingstone,London,1985,Chp.21)。
除了在培养软骨细胞,和处理骨和软骨上的进步外,在试图移植软骨或软骨细胞用于修复受损关节表面上没有太大突破。本发明提供了有效并且高效的方法,它可以促进软骨和/或软骨细胞移植到在关节(articulating joint)或其它软骨覆盖的骨表面的缺损,其中使软骨再生从而修复所述缺损。本发明也提供了被设计用来准备移植位点从而有利于移植材料高效整合到移植位点的外科手术器械。
发明内容
本发明提供了一种有效处理关节面软骨的方法,该方法是通过在合适基质中将软骨细胞与止血屏障和无细胞盖片(covering-patch)移植到要处理的表面,具体包括:首先将止血屏障临近要处理的表面,将合适基质中的软骨细胞置于远离止血屏障的要处理的表面上,用无细胞盖片覆盖要处理的表面。如下进一步介绍的止血屏障,为抑制血管化细胞穿透并组织化进入要移植材料的屏障。具体来说,本方法提供了一种为可重吸收(resorbable),半渗透性材料的止血屏障,其抑制或阻止血管穿过所述屏障。在一项实施方案中,所述止血屏障含有胶原蛋白。在本领域中如本文所用的无细胞,是指一种材料基本上不带有能进一步进行细胞分裂,播散或具有生物活性的完整细胞。在优选实施方案中,无细胞材料不带有所有完整的有核细胞。在一实施方案中,本方法包括含有半渗透性胶原蛋白基质的无细胞盖片的用途。在本方法一优选实施方案中,所述无细胞盖片的有孔表面直接导向(directed towards)所述植入材料。
本发明进一步提供了将胶原蛋白或软骨细胞自体移植到移植位点,其中所述移植位点首先通过外科手术处理来准备从而更容易接纳所述移植材料。在一项实施方案中,造型(sculpt)所述移植位点来使此移植位点的壁轮廓呈波动型,从而在把所述移植材料置于该移植位点内并伸展以接触所述移植位点壁时,会抗拒整个移植物从所述移植位点移动或者排除。本发明进一步提供了如本发明方法所授设计用来造型所述移植位点的外科手术器械。
本发明还提供了将软骨和/或软骨细胞移植到关节表面的试剂盒,其中该试剂盒包括止血屏障,无细胞半渗透性盖片,和有机胶。在另一实施方案中,所述试剂盒还可选提供一或多种根据本发明方法用来造型所述移植位点的外科手术器械。
本发明还提供了用于动物软骨修复的植入物。在一实施方案中,所述植入物为1)支持基质,2)软骨细胞,和3)粘附到支持基质边缘的生物相容性胶合剂。在一实施方案中,所述支持会被所述动物吸收。
附图简述
通过下述说明本发明某些性质的图表将有利于更好理解本发明,其中:
图1A用绘图显示了骨的典型关节末端。通常,骨材料覆盖在带有软骨帽的关节表面(见交叉影线所示)。
图1B的实例显示了软骨帽出现缺损或损伤的位置(交叉影线中的间隙),此缺损可被直接处理,轻微放大,或造型从而在处理前通过外科手术来接受所述移植材料。
图1C显示止血屏障(实心黑色,附图标记1)如何被置于软骨帽内的缺损来抑制或避免从下面的骨血管化进入再生软骨。然后将要植入缺损腔的软骨细胞置于所述止血屏障的顶部。
图2用绘图显示了在软骨帽(交叉影线区域)内为无细胞半渗透性材料(实心黑色,附图标记2)所覆盖的要处理的缺陷(交叉影线区域中的间隙),所述材料被用于形成覆盖于缺损位点的帽/贴片(patch)或绷带。通过粘附,或缝合在位于所述腔和健康软骨的边缘来将该帽固定。该帽覆盖所述关节的缺损区域,此区域中已经置入胶和所培养的软骨细胞/软骨移植物。
图3A用图表说明较硬和较软的软骨对压缩和剪切力量的差别(differential)反应及所得的分界区。
图3B图示在造型所述缺陷使其具有波动形壁之后的移植位点。
图3C图示造型后的移植位点,其中止血屏障(1),移植材料(3),和无细胞盖片(2)位于关节表面软骨(4)内。
图4A图示了本发明外科手术装置的一实施方案,所示为切齿(5)和突出的定位针(placement pin)(6)。
图4B图示了本发明外科手术装置的另一实施方案。
图5用图表说明较硬和较软的软骨在造型所述移植位点后对压缩和剪切力量的改进差别反应。
图6A为显示左侧(内侧)髁的软骨缺陷的猪膝盖的MRI影像。
图6B为处理3月后同一只猪膝盖的MRI影像。
图7图示了无止血屏障的移植位点或缺陷(23),其包括移植细胞(21)和生物相容性胶(22)在具有有孔面的支持基质(18)上的混合物,软骨材料和移植材料的界面(30),软骨(10),骨材料和软骨材料的界面(12),可重吸收针(24)和骨材料(14)。
发明详述
本发明涉及某些抑制血管组织形成,例如如在软骨细胞自体移植到软骨内缺陷过程中毛细血管袢(capillary loop)突入所形成软骨的产品的用途。从其下的骨形成的血管组织会趋向于突入要形成的新软骨从而导致出现所需间充质特化软骨细胞以外的细胞。
由血管化引入的污染细胞会引起植入的软骨细胞侵蚀和过度生长进入所形成的软骨。本发明可用的商品之一是Surgicel(Ethicon Ltd.,UK),它会在7-14天的阶段后被吸收。该材料在本发明方法中的用途与Ethicon Ltd的止血装置,如Surgicel在其包装插页中所述的一般用途相反。
我们惊喜地发现在希望抑制血运重建(revascularization)进入软骨时,止血材料会象凝胶样人工凝结物一样作用。如果红细胞位于被止血屏障帽状覆盖的关节软骨全层(full-thickness)缺损内,这些血细胞会化学变化成为血色素,从而不能诱导血管生长。由此,用作血运重建抑制屏障的止血产物有或无纤维蛋白胶粘剂,如例如Surgicel,对如本发明所授构思的方法都是有效的。本发明的另一部分是无细胞组分的应用,该组分被用作贴片来覆盖移植入所培养的软骨细胞/软骨的关节缺损区域,用自体软骨细胞来移植。本发明方法也考虑应用合适的同种软骨细胞或异种软骨细胞来修复软骨缺损。
从而本发明教导了有效修复或处理关节骨表面内软骨缺损的方法,该法包括给予制剂或装置来阻断血管侵入需修复的软骨位点,并提供无细胞屏障来分离修复位点并保持所移植细胞在位。本发明也提供了包含插入要修复位点的止血屏障组分的试剂盒,由此可有效抑制所修复位点的血管化;一旦把要移植的软骨细胞置于要修复的位点,就将无细胞半渗透性屏障帽状覆盖到所述修复位点上来将被移植的软骨细胞保持在位,但仍有途径能获得营养。
本发明的某些方面已经举例应用体外系统来研究所述软骨细胞在接触到抑制血管组织形成的某产品或某些产品组合物时的行为。该体外试验预测了某些待测材料抑制血管化的能力,所述情况就如同在体内,在软骨细胞自体移植入软骨内缺陷的过程中毛细血管袢突入所建立的软骨时会出现的那样。
合适的止血产品以能抑制血管组织,骨细胞,成纤维细胞等生长或侵入发育中的软骨为特征。合适的止血材料可实现本发明方法的目的,因为可以防止从血管和细胞侵入发育中的软骨来最优化软骨形成并全层修复关节软骨内的任何缺损。理想的话,所述止血屏障将稳定足以完全修复软骨的较长(extended)一段时间,然后被重吸收或者随时间而降解。一种经鉴定认为合适的材料被称作SurgicelW1912(含有氧化的可再生无菌纤维素的可吸收止血剂(hemostat);Lot GG3DH,Ethicon Ltd.UK)。另一种合适材料的实例为BioGide(商品化I型胶原蛋白基质垫(pad);Geistlich Sohne,Switzerland)。
发现可以商品化的合适有机胶材料有,例如Tisseel或Tissucol(纤维蛋白基的胶合剂;Immune AG,Austria),Adhesive Protein(Cat.#A-2707,SigmaChemical,USA),和Dow Cornling Medical Adhesive B(Cat.#895-3,DowCorning,USA)。
本发明包括的外科手术器械可以用适合制备一次使用的一次性或多次使用的重复使用的外科手术器械的金属和/或塑料制造。所述切割器械可包含闭合环状(fully circular)或扁平的,或介于之中的切割齿。当软骨为相对软的材料时,它对于制备可以不损坏骨就造型软骨的较硬塑料切割边缘是有利的。制造的该切割器械可以结合给予液体和吸取除去切割残渣和液体的开口,以及为缺损位点照明和可视的光导纤维线(fiber optic threads)。
在另一实施方案中,本发明包括细胞21和胶22以(1)胶22和细胞21的混合物或(2)支持基质18上细胞21和胶22的一或多交替层来组合(combine)在一起。
在一个此类实施方案中,认为细胞21是要移植到缺损23的自体软骨细胞。在把软骨细胞/胶混合物用到支持基质18之前,以均匀或非均匀方式将软骨细胞21与合适的胶22混合。优选,立即混合胶22和软骨细胞21(也就是说,在操作台上)是在把胶22和细胞21用到支持基质18,并且把胶22,细胞21和支持基质18的组合物植入缺损23之前。或者细胞21和胶22以一或多层交替应用到支持基质18上。在一实施方案中,胶22是生物相容性胶,如纤维素胶,更具体为自体纤维蛋白胶或非自体纤维蛋白胶。优选应用自体纤维蛋白胶。
当软骨细胞21在支持基质23上与胶22组合,将所述胶/软骨细胞/支持基质组合物植入缺损23,具有或不具有骨14和胶/软骨细胞/支持基质组合物之间的止血屏障(如本文所述)。在一实施方案中,如图2所示,被处理的缺损23不含有骨14和胶/软骨细胞/支持基质组合物之间的止血屏障。
在一实施方案中,如图7所示,不用通过在胶/软骨细胞/支持基质组合物和缺损23的基底之间应用止血屏障,就可根据本发明类似处理缺损23。
另外,在图7所示的实施方案中,胶22和软骨细胞21的组合物只存在于支持基质18的一部分。例如,胶22和软骨细胞21优选只存在于支持基质18有孔面的外边缘。或者,软骨细胞21和/或胶22穿入支持基质18有孔面达到理想水平,例如支持基质18深度的2-50%。典型地,所述支持基质18在离粗糙面,也就是细胞21和胶22沉积的一面最近时,其有孔性最高,而在支持基质18的相反面其有孔性最低。如图7进一步阐述,支持基质18的有孔性以阴影来表示,阴影越深表示有孔性越低,阴影越浅表示有孔性越高。
在另一实施方案中,将软骨细胞21用到支持基质18,然后用一层合适的生物相容性胶22覆盖。尽管在支持基质18上的一单层软骨细胞21和位于(positioned)软骨细胞21上的一单层胶22足以有效处理缺损,还是可用一层以上的胶22和软骨细胞21交替层。或者,首先将一层生物相容性胶22沉积到支持基质18上,再将一层软骨细胞21沉积到胶22上。
在一实施方案中,支持基质18为能支持软骨细胞21生长并赋予所述移植物件物理完整性来方便其处理的片状膜。在一实施方案中,支持基质18包括多肽或蛋白如胶原蛋白。特别的是,支持基质18包括马,猪,牛,羊和鸡的胶原蛋白。另外,所述胶原蛋白可以为I型或II型胶原蛋白。适宜胶原蛋白支持基质18的实例包括ChondraGide和BioGide(商品化I型胶原蛋白基质垫;购自Geistlich Sohne,Switzerland)。另外,支持基质18可以可逆变形并或者具有如上所述的一有孔粗糙面,或者一光滑面,或者两粗糙面。尽管任何一面都可以是有孔的,在本文所述的一实施方案中,相对于光滑面所述粗糙面还是具有较高的有孔性。如图7所示,支持基质18和位于其上的细胞21可用额外的生物相容性胶22和/或一或多枚生物可相容重吸收针24来被保持在缺损内。
在一实施方案中,支持基质18的一或多个部分在性状上或者是固体或者是凝胶样的。
通过下面的实施例可能更容易理解本发明某些方面,所述实施例是为阐述而不是为了限定。
实施例1
为了根据本发明将Surgicel用于避免血管发展入自体植入的软骨或软骨细胞,首先用固定剂,如戊二醛处理Surgicel。简单讲,用0.6%戊二醛处理Surgicel1分钟,之后多次洗涤去除另外对组织有毒的戊二醛残基。或者如实施例2所述,Surgicel与称作Tisseel的纤维蛋白胶粘剂在用戊二醛处理前进行处理。我们发现例如用固定剂如戊二醛固定,之后用无菌生理盐水(0.9%)洗涤并储藏在冰箱中的Surgicel,在1到2月内不溶解。通常,Surgicel在7到14天的阶段会再吸收。这段时间可能过短,因为在植入的软骨细胞已经生长进入固体软骨层来从临近软骨得到它所需要的营养之前,避免血管发展或血管化如从骨结构进入植入软骨需要更长的时间。换言之,完全抑制血管化需要更长时间,如例如1个月。因此,该产品在这段时间之前不应该被明显吸收。另外最后也需要重吸收。因此,用作抑制屏障的所述有机材料应该具有这些能力,而且发现以这种方式处理的Surgicel也具有该功能。
实施例2
也用有机胶包被所述Surgicel,在此实施例中所用的胶为Tisseel但其它的也可用。该产品和Surgicel产生用于本发明特定目的的屏障。可用任何其它的止血剂或血管抑制屏障。如下所述混合Tisseel。然后通过在Surgicel材料的两面喷涂Tisseel直至吸收来将Surgicel包被。然后让该Tisseel(纤维蛋白胶)在室温固化。在马上完全固化之前,将所包被的Surgicel置于0.6%戊二醛中1分钟然后用无菌生理盐水(0.9%)洗涤。再用PBS和/或NaOH调整pH直到pH稳定在7.2到7.4。之后在组织培养基中用如有15mM Hepes缓冲液的极限必需培养基/F12洗涤所述处理的Surgicel。
如本实施例所述我们用Tisseel作为纤维蛋白胶粘剂包被Surgicel。而且所述纤维蛋白胶粘剂或胶也会被直接用于Surgicel所胶着之上的朝向骨的损伤底部。所用的体外系统,替代体内试验,由用于细胞研究工作的NUNCLONTM Delta 6-孔无菌一次性平板(NUNC.InterMed,Roskilde,Denmark)组成。每孔测量的直径为大约4厘米。
在本发明中所述纤维蛋白胶粘剂可为任何与纤维蛋白组分生成在人可耐受的胶(Ihara,N,et al.,Burns Incl.Therm.Inj.,1984,10,396)的胶粘剂。本发明也期望任何其它可替代纤维蛋白胶粘剂使用的胶组分。在本发明中我们使用Tisseel或Tissucol(Immuno AG,Vienna,Austria)。所述Tisseel试剂盒由以下组分组成:
-Tisseel,一种冻干的病毒灭活的封闭剂(Sealer),其中含有如下的可凝固蛋白:纤维蛋白原,血浆纤连蛋白(CIG)和因子XIII,和纤溶酶原;
-抑酶肽(Aprotinin)溶液(牛的);
-纤维蛋白原4(牛的);
-纤维蛋白原500(牛的);和
-氯化钙溶液。
该Tisseel试剂盒包含DUPLOJECT应用系统。用Tisseel试剂盒的所述纤维蛋白胶粘剂或二组分封闭剂(sealant)根据Immuno AG产品插页按如下方式结合。
实施例3
软骨细胞在含有HAM F12和15mM Hepes缓冲液及5-7.5%自体血清的极限必需培养基中在37℃的CO2孵箱生长,并在Verigen Europe A/S,Symbion Science Park,Copenhagen,Denmark的100级实验室(Class 100laboratory)操作。其它培养基组合物可被用于培养所述软骨细胞。在Burker-Turk室中用胰蛋白酶EDTA胰蛋白酶化所述细胞5-10分钟并用台盼兰(Trypan Blue)生存力染色计数。将所述细胞计数调整到7.5×105细胞/ml。在100级实验室中一个NUNCLONTM平板不盖盖。
将所述Surgicel止血屏障切割为适宜尺寸装入NUNCLONTM组织培养盘的孔底。在此是一个尺寸约为4cm(但可以是任何可能尺寸)的环并且在无菌环境中被置于NUNCLONTM Delta 6-孔无菌一次性平板的孔底用于细胞研究工作(NUNC,Intered,Roskilde,Denmark)。如实施例1所述对置于孔底的止血屏障进行预处理。该处理显著延迟了所述Surgicel的吸收。然后在蒸馏水中洗涤此止血屏障多次然后再洗涤多次直到不反应的戊二醛被洗脱干净。用含血清的少量细胞培养基使其被止血屏障吸收同时使止血屏障在孔底保持湿润。
将1ml培养基中大约106个细胞直接置于所述止血屏障的顶部,在如上所述用0.4%戊二醛预处理的止血屏障表面分散。然后在37℃的CO2孵箱中培养所述平板60分钟。将含5-7.5%血清的2-5ml的量的组织培养基小心加入到含有所述细胞的孔中,在排出培养基时,通过使所持的吸管端与孔侧面成切角以避免所述细胞溅出。此时所述培养基表现为pH值太低(pH值~6.8)。之后将pH值调整到7.4-7.5。隔日一些软骨细胞已经以群状(cluster)排列开始在止血屏障上生长。一些所述细胞由于在调整pH值前接触太低的pH值已经死亡。孵育所述平板3-7天,在第3天置换培养基。
在培养末期倒出培养基,冷藏加入含有0.1M二甲胂酸的钠盐(也称为二甲胂酸钠,pH值用HCl调整到7.4)的2.5%戊二醛作为固定剂,用于制备后来用于电镜检查的所述细胞和支持物(止血屏障)制品。
实施例4
软骨细胞在含有HAM F12和15mM Hepes缓冲液及5-7.5%自体血清的极限必需培养基中在37℃的CO2孵箱生长,并在Verigen Europe A/S,Symbion Science Park,Copenhagen,Denmark的100级实验室(Class 100laboratory)操作。其它培养基组合物可被用于培养所述软骨细胞。在Burker-Turk室中用胰蛋白酶EDTA胰蛋白酶化所述细胞5-10分钟并用台盼兰生存力染色计数。将所述细胞计数调整到7.5×105细胞/ml。在100级实验室中一个NUNCLONTM平板不盖盖。
如实施例1所述用0.6%戊二醛处理Surgicel(用作止血屏障)1分钟,然后用0.9%无菌氯化钠溶液或,优选,缓冲液如PBS缓冲液或所述培养基如MEM/F12洗涤,因为戊二醛处理后的pH值为6.8并应该优选为7.0-7.5。用DUPLOJECT系统将Tisseel用于Surgicel的两面,然后用纤维蛋白粘合剂来包被要用的贴片,Surgicel的两面。在无菌条件下令所述粘干燥至少3-5分钟。将所述“包被的”止血屏障置于NUNCLONTM Delta 6-孔无菌一次性平板的孔底用于细胞研究工作。用含血清的少量细胞培养基使其被止血屏障吸收。将1ml含血清组织培养基中大约106个细胞直接置于所述止血剂的顶部,分散于所述止血屏障的表面。然后在37℃的CO2孵箱中培养所述平板60分钟。将含5-7.5%血清的2-5ml组织培养基小心加入到含有所述细胞的孔中,在排出培养基时,通过使所持的吸管端与孔侧面成切角以避免所述细胞溅出。3-6天后,显微镜检查显示所述细胞以满意的方式附着并生长进入Surgicel,这表明Surgicel对软骨细胞不显示毒性并且所述软骨细胞以满意方式生长进入Surgicel。
孵育所述平板3-7天,在第3天置换培养基。在培养末期倒出培养基,冷藏,加入含有0.1M二甲胂酸的钠盐(也称为二甲胂酸钠,pH值用HCl调整到7.4)的2.5%戊二醛作为固定剂,用于制备后来用于电镜检查的所述细胞和支持物(止血屏障)制品。
实施例5
软骨细胞在含有HAM F12和15mM Hepes缓冲液及5-7.5%自体血清的极限必需培养基中在37℃的CO2孵箱生长,并在Verigen Europe A/S,Symbion Science Park,Copenhagen,Denmark的100级实验室(Class 100laboratory)操作。在Burker-Turk室中用胰蛋白酶EDTA胰蛋白酶化所述细胞5-10分钟并用台盼兰生存力染色计数。将所述细胞计数调整到7.5×105到2×106细胞/ml。在100级实验室中一个NUNCLONTM平板不盖盖。
已经发现Bio-Gide可被用作重吸收的双层膜,它将作为贴片或绷带被用于覆盖所培养的软骨细胞和止血屏障所移植进入的关节缺损区域。所述Bio-Gide是通过标准化控制制造过程(由E.D.Geistlich Sohne AG,CH-6110Wolhusen)获得的纯胶原蛋白膜。所述胶原蛋白从兽医检验的猪提取并且被小心纯化来避免抗原反应,还通过γ辐射在两重水疱(double blisters)中灭菌。该双层膜具有一有孔表面和一致密表面。该膜由I型和III型胶原蛋白制成不需要进一步交联或化学处理。所述胶原蛋白在24星期内被重吸收。该膜保持其结构完整性甚至当它是湿的,它仍可通过缝合线或钉子被固定。该膜也可以或者用纤维蛋白粘合剂如Tisseel或者与缝合线一起“胶着”到邻近的软骨或组织。
所述Bio-Gide在100级实验室中不盖盖并且在无菌条件下置于NUNCLONTMDelta 6-孔无菌一次性平板的孔底用于细胞研究工作,该双层膜的有孔表面或者致密表面朝上。将1ml含血清的组织培养基中大约106个细胞直接置于所述Bio-Gide的顶部,分散于所述Bio-Gide的有孔表面或致密表面。然后在37℃的CO2孵箱中培养所述平板60分钟。将含5-7.5%血清的2-5ml组织培养基小心加入到含有所述细胞的孔中,在排出培养基时,通过使所持的吸管端与孔侧面成切角以避免所述细胞溅出。
在软骨细胞被置于含有Bio-Gide的孔的第2天,在Nikon倒置显微镜下检查所述细胞。我们注意到一些软骨细胞已经粘附到所述Bio-Gide的边缘。当然用此显微镜不可能透视Bio-Gide自身。
孵育所述平板3-7天,在第3天置换培养基。在培养末期倒出培养基,冷藏加入含有0.1M二甲胂酸的钠盐(也称为二甲胂酸钠,pH值用HCl调整到7.4)的2.5%戊二醛作为固定剂,用于制备所述细胞和在其有孔表面或致密表面有细胞培养的Bio-Gide支持物。然后将所述Bio-Gide贴片送到Department of Pathology,Herlev Hospital,Denmark进行电镜检查。
该电镜检查显示在Bio-Gide致密表面培养的所述软骨细胞并不生长进入所述Bio-Gide的胶原蛋白结构,而在Bio-Gide有孔表面培养的所述细胞的确生长进入该胶原蛋白结构并且,显示出存在蛋白聚糖但无成纤维结构的迹象。此结果显示当所述胶原蛋白贴片,例如Bio-Gide贴片作为覆盖软骨缺损的贴片被缝合,其有孔表面应当朝下面对要注入所培养软骨细胞的缺损。然后它们能够穿入所述胶原蛋白并产生符合完整表面的光滑软骨表面,并且在这个区域将会构建一层光滑的蛋白聚糖。然而,如果所述胶原蛋白的致密表面朝下面对植入所述软骨细胞的缺损,将不会与所述胶原蛋白整合,并且所述细胞将不会如上述产生相同的光滑表面。
实施例6
软骨细胞在含有HAM F12和15mM Hepes缓冲液及5-7.5%自体血清的极限必需培养基中在37℃的CO2孵箱生长,并在Verigen Europe A/S,Symbion Science Park,Copenhagen,Denmark的100级实验室(Class 100laboratory)操作。在Burker-Turk室中用胰蛋白酶EDTA胰蛋白酶化所述细胞5-10分钟并用台盼兰生存力染色计数。将所述细胞计数调整到7.5×105到2×106细胞/ml。在100级实验室中一个NUNCLONTM平板不盖盖。
如产品插页所述,用作重吸收双层膜的Bio-Gide也可与有机胶如比一般在Tisseel中发现的抑酶肽含量额外明显较高的Tisseel一起作用。通过将抑酶肽的量增加到大约25,000KIU/ml,所述材料的重吸收将会延迟数周而不是通常的几天。
为在体外检测该特性,将Tisseel用到NUNCLONTM平板的孔底,并使其不完全固化。然后将一胶原蛋白贴片如Bio-Gide应用到Tisseel上并胶着到孔底。此Bio-Gide和Tisseel的组合物被设计为会抑制或阻止血管发展或浸润到所述软骨细胞移植区域的止血屏障。现在此混合(hybrid)胶原蛋白贴片既能用作所述损伤底部的止血屏障(离待修复表面最近)也能用作软骨形成的支持,因为此远端表面可以是所述胶原蛋白贴片的有孔面并进而促进软骨细胞和软骨基质的浸润。因而,此混合胶原蛋白贴片也可用于覆盖所述植入物的顶部,其胶原蛋白有孔表面朝下面对所植入的软骨细胞,并且该屏障形成顶部。此抑酶肽成分提高的混合胶原蛋白贴片也可在没有任何有机胶如Tisseel时使用并且直接置于缺损内,以自然力粘附。因此,所述胶原蛋白贴片既可被用作止血屏障,也被用作所述修复/移植位点的无细胞覆盖物,该贴片的有孔表面朝向所移植的软骨细胞/软骨。另一变体将会使用由II型胶原蛋白(例如从Geistlich Sohne AG,CH-6110 Wolhusen)组成的胶原蛋白贴片。
因此本发明提供了混合胶原蛋白贴片,其中所述贴片为抑酶肽组分水平升高,优选大约25,000KIU/ml,与有机基质胶连接(in association with)的胶原蛋白基质,其中所述胶原蛋白组分与所述Bio-Gide重吸收双层材料或II型胶原蛋白类似,并且所述有机胶与所述Tisseel材料类似。在另一实施方案中,所述混合胶原蛋白贴片不使用任何有机胶来粘附到所述修复位点。
实施例7
因为骨关节炎软骨的衰弱(weakened)结构,可以抑制移植到缺损软骨内移植位点的所培养自体软骨细胞的粘附,从而在新植入的软骨/软骨细胞和围绕建立的软骨之间产生边缘区(分界区)。如果以线性方式创造直的,光滑的壁切口来为移植物准备移植位点,此边缘区将会非常显著。当以线性方式切割所述移植位点时,此边缘区的剪切和压缩力(如图3A所示)将会施加强大的力量移去该移植物。此边缘区,以及沿此区的材料差别运动会抑制所述移植材料和环绕材料之间的会合痊愈。在很多例子中,所述移植物材料通常比环绕材料轻柔,然而,在一些骨关节炎疾病案例中,事实上所述环绕软骨可以比植入的软骨细胞/软骨更柔软。
所以,为了解决这个问题,本发明方法教授了应用外科器械来塑型所述移植位点的壁从而使此壁为非线性,并且因而提供了波动形表面。同样也可塑型所述移植物位点从而使临近骨表面位点的直径比远离骨,并位于软骨表面的开口尺寸大。然而,优选实施方案描述了以类似于穿线开口的方式来塑型移植位点的壁来接受螺钉或螺丝(如图3B所述),从而提供了来自所述移植位点对所述移植材料压缩和或排出的机械抗拒,其被称为“雄性(male)”和“雌性(female)”穿线(threading)。
本发明构思的外科器械可用适合制造一次性使用,或多次使用的重复使用外科器械的金属和/或塑料制造。当软骨是相对柔软的材料,制造能够塑型软骨而不会损坏骨的较硬的塑料切割边缘将是有利的。能够制造此切割器械来引入(incorporate)给予液体,吸取除去切割残渣和液体,和用于缺损位点的照明和可视的光导纤维线的开口。在某些器械的实施方案中,器械的基底可能具有突出的点或针状结构,它会帮助指导并且将所述器械置于移植位点。当然,可将此针设计成对其下的骨损伤最小化。
当所述器械的切割表面可能是单齿,或多齿,或被描述为如用在金属水龙头的螺丝样形状从而在金属部分产生穿线孔时,所述切割器械需要的特性可能是所得移植位点的塑型表面是波动型,并且非线性的。例如,在某些实施方案中,所述器械的切割边缘能够以图4A,或如图4B所示相似的方式塑型。所述切割边缘可能是扁平,或环状的因为它包绕所述切割器械的直径。可以设计很多其它达到本发明方法目的的形状来产生提供机械抵抗的界面,此抵抗是对于在移植材料及周围材料上的压缩和剪切力的差别反应。
实施例8
一只四个月的混血Yorkshire种猪被全身麻醉并躺倒放置。将此猪清洗并用布包裹置于Harrington Arthritis Research Center,Phoenix,Ariz的外科套间。无菌完成所有的外科步骤。用碘酒清洁其左后腿和临接的腹部及腹股沟区域。定位其膝关节及其髌。从距离髌的后部大约3cm进行内侧切口,并大致切割多处皮下组织,肌肉层和韧带来到达内侧股骨髁。用环状切割器在内侧髁内侧部分上的白色软骨制备损伤,在距离覆盖所述髁后内侧部分的软骨边缘留下0.5到1cm间隔(左髁,图6A)。所述0.5到1cm的缺损被置于内侧髁承受尾重的部分。在左股骨无止血带完成整个外科手术。适当缝合不同层和皮肤。
在第3天,将该动物再次送到手术套间并如上被放置在手术台上并给予全身麻醉。如上用碘酒清洁其左后腿,腹部和腹股沟区域。切开缝合线打开所述区域。可注意到在膝关节里存在一中等的血肿。除去血凝块检查缺损。缺损内的血凝块被除去。将一设计为具有雄性穿线切割边缘,尺寸对应,或略大于所述损伤圆周的无菌外科器械小心旋入(screwed)所述缺损。将Bio-Gide垫切割为等于所述缺损底部的尺寸。将所用的第一胶,称作Adhesive Protein(A-2707,Sigma Chemical,USA)用到所剪齐的(trimmed)止血屏障垫的致密面,并且将该垫以致密面朝下放入所述损伤底部,如上所述将其用作屏障。发现此胶看起来不会干燥很快。所述缺损底部轻微的出血立即停止。如上所述,将第二Bio-Gide切割为圆周稍大于所述缺损并以致密面朝上放置(于是所述有孔面朝下对所述移植物)。
然后缝合此无细胞盖片(covering-pad)来覆盖腔,留下一边缘打开,其中可以注入要移植的软骨细胞。所述垫边缘的环绕部分用第二胶CowComing Medical Adhesive B(Cat.#895-3,DowCorning,USA)覆盖。第二胶比第一胶干燥更快并且更有效。据发现在此特定过程中,当试图缝合所述帽时,第一胶没有完全干燥来将所述止血屏障保持在位。因而,在所述移植位点近表面上形成的屏障主要是通过胶自身。
用一1ml注射器和计量注射针16,将所述软骨细胞悬液(大约0.6ml)吸入所述注射器的针筒中。用计量注射短针23替换计量注射针16,并将所述细胞悬液从所述缝合盖片下注入所述移植位点(大约10×106细胞)。然后在除去所述针之前胶着所述帽的开口边缘,再小心抽出针。未见到任何漏出的细胞。如上缝合所述伤口并未用止血带,没有见到出血。缝合最后的皮肤层。在缝合后没出现皮肤的突出,这表明没有血肿。手术后的恢复无事故。
如所希望的那样,所移植的软骨细胞产生的软骨基质足以修复在受试猪膝关节关节软骨表面所产生的缺损。图6A是表明在膝盖产生软骨缺损的猪膝盖的MRI影像(左髁,内侧髁),图6B是同一猪膝盖在处理后三个月显示所述缺损修复的MRI影像。
实施例9
包含用于操作本发明方法的成份的试剂盒,可使得在外科装置中便利操作本发明方法。在优选实施方案中,本发明的试剂盒将提供适于在外科手术环境简单操作的无菌组分,并将提供适合的止血屏障,适合的盖片,和如果需要的有机胶。本发明的试剂盒也可提供无菌,无细胞基质材料,其适合用来支持自体软骨细胞被植入关节膝盖表面缺损。在一实施方案中,本发明的试剂盒包含适当包被了有机胶Tisseel的Bio-Gide盖片和Surgical止血屏障,其中所述Surgical及Bio-Gide已根据本发明教授被处理来延长直至重吸收的时间。例如,当Tisseel被预包被时,在一实施方案中向所述Tisseel补充附加的抑酶肽来延长直至重吸收的时间。
在另一优选实施方案中,所述止血屏障和盖片都是半渗透性胶原蛋白基质,处理它们可延长所述材料直至被重吸收的时间。也可以提供强化形式的Tisseel胶作为需要时应用的分离组分,因为每次修复/移植过程都会面对遗传变化和特定环境。
所述试剂盒的进一步实施方案将包括如上实施例7所述的外科器械。
本领域技术人员可以理解对本发明所示具体实施方案可以做大量变化和/或修改而不会背离本发明大致所述的精神和范围。
Claims (15)
1.通过植入动物用于软骨修复的植入物件,包含支持基质,和粘附在所述支持基质边缘的软骨细胞及生物相容性粘合剂,其中所述支持基质可被所述动物吸收。
2.权利要求1所述的植入物件,其中所述支持基质为能够支持所述软骨细胞生长并赋予所述植入物件物理完整性来方便对其处理的片状膜。
3.权利要求1所述的植入物件,其中所述支持基质包含多肽或蛋白。
4.权利要求1所述的植入物件,其中所述支持基质是胶原蛋白。
5.权利要求1所述的植入物件,其中所述胶原蛋白主要选自马,猪,牛,羊和鸡胶原蛋白。
6.权利要求1所述的植入物件,其中所述支持基质是固体。
7.权利要求1所述的植入物件,其中所述支持基质是凝胶样的。
8.权利要求4所述的植入物件,其中所述胶原蛋白是I型胶原蛋白。
9.权利要求4所述的植入物件,其中所述胶原蛋白是II型胶原蛋白。
10.权利要求1所述的植入物件,其中所述植入物件是可逆变形的。
11.权利要求1所述的植入物件,其中所述支持基质具有粗糙面。
12.权利要求11所述的植入物件,其中所述粗糙面是有孔的。
13.权利要求1所述的植入物件,其中所述支持基质具有光滑面。
14.权利要求1所述的植入物件,其中所述支持基质具有粗糙和光滑面。
15.权利要求1所述的植入物件,其中所述软骨细胞和所述生物相容性胶合剂是混合的。
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- 2002-10-03 AU AU2002334852A patent/AU2002334852B2/en not_active Expired
- 2002-10-03 DE DE60239351T patent/DE60239351D1/de not_active Expired - Lifetime
- 2002-10-03 MX MXPA04003177A patent/MXPA04003177A/es active IP Right Grant
- 2002-10-03 EP EP02800483A patent/EP1437969B1/en not_active Expired - Lifetime
- 2002-10-03 CA CA002462306A patent/CA2462306A1/en not_active Abandoned
- 2002-10-03 AT AT02800483T patent/ATE499887T1/de not_active IP Right Cessation
- 2002-10-03 PL PL368351A patent/PL210783B1/pl unknown
- 2002-10-03 DK DK02800483.6T patent/DK1437969T3/da active
- 2002-10-03 JP JP2003531890A patent/JP2005504576A/ja active Pending
-
2003
- 2003-03-26 US US10/397,404 patent/US7137989B2/en not_active Expired - Fee Related
-
2004
- 2004-09-10 HK HK04106893.1A patent/HK1064021A1/xx not_active IP Right Cessation
-
2006
- 2006-03-14 US US11/375,183 patent/US20060167483A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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US20040019361A1 (en) | 2004-01-29 |
HK1064021A1 (en) | 2005-01-21 |
WO2003028545A2 (en) | 2003-04-10 |
EP1437969A4 (en) | 2008-06-11 |
WO2003028545A3 (en) | 2003-06-19 |
US6569172B2 (en) | 2003-05-27 |
PL210783B1 (pl) | 2012-02-29 |
PL368351A1 (en) | 2005-03-21 |
ATE499887T1 (de) | 2011-03-15 |
DE60239351D1 (de) | 2011-04-14 |
US7137989B2 (en) | 2006-11-21 |
EP1437969A2 (en) | 2004-07-21 |
RU2004113440A (ru) | 2005-03-20 |
MXPA04003177A (es) | 2005-05-16 |
US20060167483A1 (en) | 2006-07-27 |
EP1437969B1 (en) | 2011-03-02 |
JP2005504576A (ja) | 2005-02-17 |
BR0213114A (pt) | 2004-09-21 |
US20020151986A1 (en) | 2002-10-17 |
CA2462306A1 (en) | 2003-04-10 |
DK1437969T3 (da) | 2011-05-02 |
IL161152A0 (en) | 2004-08-31 |
AU2002334852B2 (en) | 2007-08-09 |
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