CN1181893C - 导引组织再生的薄膜 - Google Patents

导引组织再生的薄膜 Download PDF

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Publication number
CN1181893C
CN1181893C CNB988117347A CN98811734A CN1181893C CN 1181893 C CN1181893 C CN 1181893C CN B988117347 A CNB988117347 A CN B988117347A CN 98811734 A CN98811734 A CN 98811734A CN 1181893 C CN1181893 C CN 1181893C
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China
Prior art keywords
thin film
collagen
barrier layer
hypothallus
cartilage
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Expired - Fee Related
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CNB988117347A
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English (en)
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CN1280509A (zh
Inventor
�˵á���˹����ϣ
彼得·盖斯特利希
�ˡ�������Ү
泽德尼克·埃克马耶
I
洛瑟·施洛瑟
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Ed Geistlich Soehne AG fuer Chemische Industrie
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Ed Geistlich Soehne AG fuer Chemische Industrie
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Abstract

本发明提供了一种多层薄膜，该薄膜包括一层主要为胶原II并具有开放的海绵状构造的基质层及至少一层具有封闭、相对不透性构造的阻挡层。这样的薄膜特别适用于导引组织再生，具体地说，适用于体内骨或软骨组织的重建。

Description

导引组织再生的薄膜
本发明涉及一种用于导引组织再生的胶原薄膜植入物，具体地说，该植入物用于骨或软骨组织的体内重建。
在组织再生中，长久以来已证明软骨组织的重建，如在软骨损伤中重建是很困难的。软骨损伤可以发生在任何关节上，尽管在诸如膝关节及踝关节等大关节上危险性最大。这种损伤可以是由于外伤、退化性状态或分离性骨软骨炎引起。软骨损伤是形成关节病的一个主要机械致病(pathomechanical)因素。酶的释出导致一种滑液的炎症过程并转而导致软骨磨损及关节表面的破损。在体内软骨缺陷中再生关节软骨的近期尝试方法包括植入培养的自身关节软骨细胞(CACs)。然而这种技术仅取得有限的成功。
现在普遍接受的一点是，需要提供一种具有细胞导引作用的基质来进行组织重建，细胞将沿着该基质的纤维及在该纤维之间生长。最近有人主张将CAC接种在合成的和天然的可被再吸收的基质中。然而使用基于聚乳酸、聚乙醇酸及胶原I或III的基质进行软骨组织重建就要求在植入体内之前先在体外将软骨细胞装载在该基质上。这就引起了软骨细胞无菌培养方面的复杂问题，即植入物与组织界面上的巨细胞及成纤维细胞的免疫学的炎症反应问题。
WO-A-96/25961中提出了一种基于胶原II的基质植入物，该植入物可植入到体内部位并依靠本原软骨细胞在基质表面上的生长来实现软骨的重建。然而这种基质实现软骨组织完全重建的能力是有限的。
因此，需要提供一种能使自身的软骨细胞成功地向内生长，因此植入体内后可使软骨组织再生的基质植入物。现在我们已经发现，用一种胶原II基质可以重建软骨组织以及最终也重建新的骨组织，这种胶原II基质在体内不但与周围的结缔组织相隔离而且也与下面的骨或软骨缺陷相隔离。我们预见到，使用一种多层的薄膜植入物可以达到上述目的，这种植入物本身能防止任何周围组织发生不需要的向内生长而进入基质，这种植入物可以外科植入到缺陷部位从而起到上述作用。
从一个方面看，本发明提供了一种多层薄膜，该多层薄膜包括一个主要为胶原II并具有开放的海绵状结构的基质层，以及至少一层具有封闭的相对不透性结构的阻挡层。
本发明的薄膜在使用时的特殊的优点在于本原细胞不能透过或生长进入具有封闭的、相对不透性构造的阻挡层。
虽不希望受理论的束缚，但我们现在相信，为了使软骨成功地再生就必须不但要阻挡住如结缔组织、血管等本原组织细胞向内快速生长而且要阻挡住任何新的骨组织快速向内生长进入缺陷部位。而这可以通过使用本发明的双层薄膜来实现，这种薄膜可以保护胶原基质以免本原组织细胞从一侧向内生长的影响。在外科植入时，该薄膜可与组织移植物，例如骨膜移植物联合使用，有效防止本原组织细胞从对侧向内生长。因此，例如，骨膜移植物可以先缝合到位成为骨或软骨缺陷上的覆盖物。然后可将一片本发明的双层薄膜植入缺陷部位以与植入物相接触，以及以这样的方式安置，即双层薄膜的基质层一面朝向骨缺陷。更为优选的是，先将本发明的双层薄膜植入缺陷部位，其阻挡层朝向骨或软骨缺陷。然后将骨膜植入物放在与基质层相接触的位置上。移植物可用如血纤蛋白胶那样的生物相容粘合剂粘住，或用可吸收的聚乳酸别针(pins)别住，或如果需要和可能，将它们以这样的方式缝合起来以使其用于提供一个不透性的阻挡层以防止任何周围结缔组织向内生长。
在本发明的另一个实施方案中，薄膜本身可有效阻挡任何本原组织细胞向内生长。因此，从另一方面看，本发明提供了一种至少包括三层的薄膜，其中的基质层主要由胶原II制成，并具有开放的海绵状组织，该基质层位于两个阻挡层之间，该阻挡层具有封闭、相对不透性结构。
基质层可用作使本原软骨细胞向内生长的培养基，从而使得软骨组织再生。然而，为了更有助于软骨组织的再生，基质层可在植入体内之前或之后灌注软骨细胞。尽管可以在基质层临植入之前，用例如注射方法，灌注软骨细胞，但预期在植入之后直接灌注软骨细胞悬浮液一般也会使软骨细胞进入基质层中。通过这种方法，存在于薄膜基质层中的软骨细胞能够完成软骨的再生，并最终再生成新骨。同时该薄膜还阻挡周围组织中的其它类型细胞的向内生长。
本发明所用的软骨细胞可得自包括他生的或自生细胞的细胞源，这些细胞是从关节软骨、骨膜及软骨膜、产生于骨髓的间充质(间质)的干细胞中分离出来的。由于他生细胞携带有潜在的免疫反应及传染并发症，因此优选从自生细胞特别是自生的关节软骨中分离软骨细胞。获取细胞的技术是公知的，包括酶消化(enzymatic digestion)或旁枝(outgrowth)培养。然后将所收获的细胞在重新注入人体之前在细胞培养物中膨胀。为了得到最佳的软骨组织再生，植入基质层的细胞数通常至少为106个，优选至少为107个。
本发明薄膜的基质层一般要求含有诸如透明质酸、软骨素6-硫酸盐、角蛋白硫酸盐、皮肤素(dermatan)硫酸盐等葡萄糖胺聚糖(GAGs)，其作用是提供一种软骨细胞可以埋入并生长的天然培养基。尽管有可能将来自不同来源的葡萄糖胺聚糖并入胶原基质中，这些葡萄糖胺聚糖没有必要与来自软骨的葡萄糖胺聚糖有同样的成分、分子量及生理学性质，但优选的葡萄糖胺聚糖是从软骨本身提取而得。通常，基质层中优选含有1到10％(重量)，例如2％到6％(重量)的葡萄糖胺聚糖。虽然不透层中可能也存在某些葡萄糖胺聚糖，但其中大部份将存在于基质层中。
在本原胶原组织中，至少有一部分GAGs是以蛋白多糖(PGs)组分形式存在。由于PGs中的蛋白质成分可以引起潜在的免疫学问题，使用PGs形式的GAGs是不符合要求的，所以优选地，基质层中基本上没有任何蛋白多糖。可以用净化的无调聚肽(telopeptide-free)胶原II材料和葡萄糖胺聚糖的混合物来制备基质层，便可方便地做到这一点。
基质层内还可能存在的其它添加物包括：例如，帮助软骨细胞贴附在胶原II纤维上的软骨粘连蛋白(chondronectin)、层粘连蛋白(laminin)、纤连蛋白、藻酸钙或锚定蛋白-II；生长因子，如软骨诱导因子(CIF)、类胰岛素生长因子(IGF)、作为同型二聚体或异型二聚体存在的转化生长因子β(TGFβ)；以及骨形态形成因子(BMP)，如本原的或重组的人类BMP-2、BMP-3(生骨素)、BMP-4及BMP-7(OP-1，生骨蛋白质-1)。BMP-2独立地影响骨形成的两种途径：直接形成骨以及先形成软骨然后除去，被骨取代。BMPs和胶原的复合物由90％的胶原和10％的作为BMP活性物质或BMP/NCP诱导软骨原的非胶原蛋白质(NCP)组成，其中的胶原包括从各种来源的皮质骨中萃取的骨基质或脱矿质的骨基质。骨基质—不可溶胶原基质及层粘连蛋白(laminin)或纤维结合素可用作BMP的载体。不透层内也可能存在若干生长因子，但是大部分生长因子存在于基质层中。薄膜一般含有100微克到5毫克生长因子。
如上所述，薄膜至少包括两个不同构造的层。薄膜的阻挡层优选地主要由胶原I及胶原III制成。或者，阻挡层可以由合成材料制成，例如由一种合成的可被再吸收的聚合物网络制成，网络上可选择性地包覆有如胶原I和/或胶原III那样的胶原材料。
适用的合成材料的例子包括聚酯、聚乙醇酸及聚乳酸(PLA)的均聚物及共聚物，乙交酯和丙交酯共聚物、聚原酸酯及聚己内酯。以上这些例子中有许多是公开销售的，例如Boehringer Ingelheim的RESOMER系列。优选的PLA聚合物为蜡状物，适宜的分子大小约为650-1200并且降解速度不太快。一种特别优选的生物降解聚合物是聚(D，L-乳酸)，其中D-丙交酯与L-丙交酯的比率约为70∶30。这种合成材料的优点是机械稳定性高，使薄膜植入物在复杂的三维骨缺陷上伸展而不会撕破。这种材料也适于进行缝合。
阻挡层由长胶原纤维制成是有益的，所述纤维之间连接得如此紧密以致高分子物质不能穿透此屏障。长的纤维提供了高的抗张强度及抗撕裂强度，以致于该材料不但是一种良好的隔离薄膜而且还便于缝合。在外科手术中很重要的一点是薄膜植入物应能缝合或钉(pinned)在相应的位置上，过去所提出的许多薄膜都不具有这一性能。本发明的薄膜具有足够的机械稳定性而适于外科植入。
基质层非常疏松，其比重低至0.02，因此细胞可以很快的生长进入基质层。薄膜的含有葡糖胺聚糖的这一层，可以强烈地膨胀而吸收多至5000％的液体。理想的是，基质层应具有孔结构(孔体积分数及孔尺寸)，这种构造容许细胞贴附及生长，并容许所接种的细胞保持其软骨细胞的表型，特征为合成软骨特异性蛋白质。孔大小取决于制造胶原II基质的冻干工艺，但可预期孔大小在10到120微米范围内，例如为20到100微米，也可选择为85微米上下。通过在-5到-10℃温度下缓慢冷冻约24小时随后进行冻干，或是在冻干之前向浆料中加入碳酸氢氨的方法很容易得到这样的微孔尺寸。
薄膜的基质层优选地用取自软骨、优选是取自猪的透明软骨的胶原II材料制成。
虽然所需要的基质层的厚度要根据待处理的骨或软骨缺陷的性质而定，一般可以预期其厚度在2到10毫米范围内，例如4到6毫米。阻挡层的厚度优选是0.2到2毫米，例如0.2到0.7毫米。
阻挡层可以采用含有胶原I及III的天然的动物薄膜制成。由于是取自天然源，因此在体内可完全吸收，不形成有毒的降解产物。这种薄膜无论在湿态还是干态都具有特别高的撕裂强度，所以如果有需要便可进行外科缝合。在潮湿的情况下这种材料弹性非常大，因此可以在不规则成型的骨缺陷上伸展。
除了胶原以外，天然的动物薄膜还含有许多必须去除的其它生物物质。已经知道可用诸如酶、溶剂或其它化学品对这种薄膜进行处理以纯化并将其用于医药。这种材料中的大多数都是太薄而常常不特别容易使用。胶原纤维已经失去其原来的特征；并有更进一步的缺点：作为一种可缝合材料来说其强度常不充分，且不具有遇水膨胀的性能，并且没有光滑的颗粒面及纤维质的肉面之分。净化的无调聚肽的I型或II型胶原的纤维型材料可以生物降解，并具有较小可溶性，是已经发现的优点最多的载体材料。
提供本发明产品的阻挡层的薄膜包括保持其天然胶原构造取自小牛或猪腹膜的薄膜。取自猪龄为6到7周(重量为60到80千克)的幼猪腹膜的薄膜是特别优选的。
阻挡层优选含有纯净的、天然的(未变性的)不可溶的胶原，并可以按照WO-A-95/18638所述方法来制备。因此天然的薄膜可首先用碱，例如使用浓度为0.2到4％(重量)的含水NaOH进行处理。该处理的作用为将任何脂肪及对碱敏感的蛋白质进行皂化。第二步用酸，一般使用如HCl那样的无机酸对材料进行处理，其目的为消除对酸敏感的污染物。然后将材料进行水洗直至pH值达到2.5到3.5范围。这样，薄膜便具有一个光滑的或颗粒状面以及一个更松散的更为纤维质的面。这对通过加热到100到120℃来实现薄膜的某些交联是有益的。
可以用与上述获取主要由胶原I及III组成的阻挡层相似的方法来从软骨中获取提供薄膜基质层的胶原II材料。软骨优选地用丙酮进行处理以去除水分，随后使用诸如正己烷那样的烃溶剂进行脂肪萃取，尽管也可使用诸如乙醇那样的链烷醇、二乙醚那样的醚、三氯甲烷那样的氯代烃或它们的混合物。然后对脱脂后的材料用碱进行处理以使任何残存的脂肪皂化并使存在的某些蛋白质降解。材料最后要用酸进行处理以便蛋白质进一步降解。处理后的材料在水中膨胀后用胶体磨制成浆料。
在制作多层薄膜时，可按照如WO-A-95/18638所述，将柔软的含有胶原II的浆料加到制备好的光滑薄膜的纤维质面上。正常情况下，薄膜应该颗粒面朝下平放在一个平整的表面上，这样就可使胶原II浆料能够方便地用例如涂抹的方法施加到薄膜的纤维质面上。浆料形成任何所需厚度的一层，牢固地附着在胶原薄膜上。然后将如此形成的双层薄膜进行冷冻及冻干，得到具有所需要的微孔尺寸的海绵状构造。如果需要，可能要去除某些基质层以得到一个厚度均匀的双层薄膜。为了制作一个三层薄膜，要将第二层平整的薄膜放到基质层的上面，其纤维质面与基质层相接触。
加到薄膜上的胶原II浆料一般含1.0到4.0％(重量)，有利的是含2到3％(重量)的胶原。这种混合物的pH值一般应调整到2.5到4.5，最好为3.0到4.0。
最好是胶原II材料在冻干步骤之后进行交联以使基质层稳定。这样做也可增加基质层的机械稳定性并降低其被身体再吸收的速率。理想的交联程度应使基质层的降解速率与组织的再生速率相匹配。可以通过加热这样的物理作用来实施交联，但必须小心操作以避免再吸收能力的不合要求的损失。优选的是加热到100到120℃，保持30分钟到5小时。更为优选的实施交联的方法是使用紫外线灯泡照射最多达8小时。
胶原II材料有利的是含有葡萄糖胺聚糖。后者的实际作用是与胶原II发生反应而完成某些交联作用并生成一种不可溶的产物。如果需要，还可用上述的将材料加热或用紫外线照射的方法来实施进一步的交联。葡萄糖胺聚糖与胶原间的反应可在室温及pH值为2.5到3.5的条件下进行。葡萄糖胺聚糖的含量可在1到10％(重量)之间。在上述处理之后必须立刻对材料进行冷冻及冻干处理。
另一方面，也可以用升高胶原II物料(mass)pH值的方法来生成浆料。在此过程中，将物料冷却到约4℃，然后在此温度下加入冷的含水NaOH将pH值缓慢的升至6.5到7.5范围内。随后将物料在室温下保持15到25小时。这时便生成了浆料，浆料生成之后便可将物料进行冷冻及冻干。
还有一种可供选择的方法是在除去空气后，中和胶原II物料使其pH值达到6.8-7.4的范围。再将混合物放到模具内在37℃温度下温育15到20小时，便得到一种精细的浆料，随后便可对其进行冷冻及冻干。
根据所需产品的性能在以上三种方法中进行选择。第一种方法可得到最稳定的产品，然而沉淀物中可能有结块存在，因此必须非常小心地操作。第二种方法可得到柔软而均匀的产品，然而比第一种方法的产品更易溶解。
在浆料的生产中可能要另外加入一些诸如药品等需要的物质，例如抗菌药(甲双二嗪)或抗生素(如庆大霉素)。
把浆料施加到薄膜上后就对材料进行冷冻。为了获得重复性好的微孔尺寸，必须小心地控制冷冻过程，冷冻的速率及时间、pH值及颗粒尺寸也要准确控制。为了得到非常小的微孔，材料必须在非常低的温度突然冻结。
然后将冻结了的薄膜进行冻干并随后加热到110到130℃，用这种方法完成某些交联。随后可对冻干后的生物薄膜进行修整达到要求厚度。基质层的厚度一般为约2毫米。然后对双层薄膜用如γ射线或环氧乙烷进行灭菌处理。用钴-60这样的强射线以25kGy的剂量对薄膜进行灭菌处理时，BMPs可能会失活。在这种情况下，无菌基质在植入之前要在无菌盐水中灌注BMPs。
本发明的薄膜可按下述途径用于医药中：
用作导引组织再生的材料。基质层会促进细胞生长，其阻挡层会抑制不符合要求的细胞的生长。
用作软骨缺陷修补材料，亦即未穿透软骨下板(subchondral plate)病变的修补材料及骨软骨(osteochondral)缺陷的修补材料。
本发明还提供了用上述的多层胶原薄膜来导引组织再生。该薄膜中所含的胶原II成分特别适用于软骨组织的再生，也适用于其它类型的组织再生。
本发明还提供了用前面所述的薄膜作为导引组织再生的植入物。
本发明还提供了一种对人体内或非人的动物体内的骨或软骨缺陷进行处理的方法，该方法包括向缺陷施用一种前面所述的薄膜，该薄膜的取向要保证其阻挡层能防止不符合要求的组织类型向内生长到骨或软骨再生区域内。
以下实施例仅为说明而给出。在实施例中，所有步骤都必须在无菌的环境中如清洁的房间内实施。
实施例1
(A)用机械方法将取自小牛身上的腹膜上的肌肉和油脂完全去净，在流动的水中洗涤并在2％的NaOH的溶液中处理12小时。然后再将薄膜在流动的水中洗涤并用浓度为0.5％的HCl进行酸化。在薄膜的整个厚度都酸化以后(约3小时)进行洗涤直至pH值达到3.5。然后将薄膜用7％的盐溶液收缩，用1％的NaHCO3溶液中和并在流动水中洗涤。然后将材料用丙酮脱水并用正己烷脱脂。
(B)将冷冻的取自新屠宰的猪身上的软骨浸在冷水中完全地清洗并用机械方法纯化至没有残存的肉质、骨及硬块。随后将材料在流动的水中洗涤30分钟。
随后将材料放在均化器内研磨三次。在减少尺寸结束时，颗粒的目视尺寸约为8毫米。
然后将软骨块用丙酮洗4次而脱水，每次8小时。随后将软骨块用正己烷萃取4次脱脂，每次处理至少8小时，己烷与软骨的比例为1∶10。
脱脂以后，将软骨放在饮用水中膨胀，水与材料的比例为10∶1，处理时间是24小时。
然后将材料用5％(重量)的NaOH进行处理，处理时间32小时，软骨与溶液的比例为1∶4。处理时软骨块要很好的搅动。随后将碱从软骨中洗出，pH值从起始的14降到9-11。已溶解的杂质被洗出而与软骨分开。碱处理所形成的残液要收集起来以回收葡萄糖胺聚糖。
然后用3％(重量)的浓HCl处理胶原材料，起始pH值为1.0，处理时间4-6小时。
随后将材料用冷水充分洗涤，使得pH值升到3-3.5。所有杂质被去除，产品成为一个无盐的适于制作海绵状或其它胶原材料的胶原物料。为此，根据最终所要求的结果，该胶原物料将进行脱气、冷冻及冻干。
上述碱处理所得的萃取液中含有葡萄糖胺聚糖、碱、变性蛋白质及盐。该萃取液首先要用HCl进行中和，中和后的pH值为6。然后用硅藻土助滤剂处理，这种助滤剂能够去除变性蛋白质。将0.5重量％的硅藻土加入到萃取液中并用过滤方法将其与变性蛋白质一起去除。
随后将上清液提交超滤，所用的超滤膜的分子量截止值约为10,000道尔顿。用这种方式去除盐分，留下的是净化了的葡萄糖胺聚糖。
将如此得到的葡萄糖胺聚糖溶液与上面所得到的胶原材料相掺合便成为含葡萄糖胺聚糖的胶原II基质。
胶原II物料的性质如下：
TG＝     2.8％(重量)
GAG＝    3％(重量)(以胶原为基础计算)
pH值     3.5
(C)把按上述(A)项制作的新鲜的腹膜薄膜在水中均匀浸湿并在玻璃板上摊平，纤维质面朝上。随后将按上述(B)项制作的胶原II物料把薄膜彻底湿透。将薄膜向各个方向平直地展开而贴附在板上。这样，胶原II物料会渗入薄膜内。
薄膜上抹了一厚层物料以后将玻璃板放入冰箱，在约4℃温度下保持一整夜。在此期间便形成了浆料。
浆料在下列条件下冷冻：
浴槽温度＝-12℃
时    间＝40分钟
随后对冷冻浆料进行冻干，然后加热到125℃。
冻干时间＝14小时。
然后将胶原II基质层劈成为1毫米的厚度。
实施例2
把按例1(A)制作的新鲜的腹膜薄膜施加到玻璃板上，并将具有例1所述性质的稠密的胶原II物料磨擦入薄膜内。将50克胶原II物料用蒸馏水稀释到100毫升并彻底搅拌。在搅拌的时候缓慢地加入100毫升的葡萄糖胺聚糖溶液。胶原与GAG一起成为整体而沉淀下来。沉淀以后的物料是均化的。如此所得的分散体被施加在薄膜上。经过一夜便形成了浆料，经过如此处理的薄膜按例1所述的方法进一步加工。

Claims (13)

1.一种适用于骨或软骨组织体内重建的多层薄膜，该薄膜包括：(i)一层主要为胶原II并具有开放的海绵状构造的基质层，和(ii)至少一层具有封闭构造的阻挡层，该阻挡层是不透性的，足以阻挡细胞穿过和向其中生长，所述的至少一层阻挡层主要由I型和III型胶原制成，而所述的薄膜是通过将胶原II浆料施加到所述阻挡层的表面，随后通过冻干来使所述胶原II基质层具有开放的海绵状结构而制成的。
2.如权利要求1的薄膜，该薄膜包括单一的阻挡层。
3.如权利要求1的薄膜，其中的基质层设置在两层阻挡层之间。
4.如权利要求1的薄膜，其中所述胶原II材料取自天然软骨。
5.如权利要求4的薄膜，其中的胶原II材料取自猪的透明软骨。
6.权利要求4或5的薄膜，其中的胶原II材料是经过加热或用紫外线照射交联的。
7.如权利要求1的薄膜，其中的一个或多个阻挡层是取自小牛或猪的腹膜。
8.如权利要求1的薄膜，其中的基质层浸渗有分离自关节软骨、骨膜、软骨膜的软骨细胞或来自骨髓的间质干细胞。
9.如权利要求1的薄膜，其中至少一个基质层和/或阻挡层浸渗有葡萄糖胺聚糖。
10.如权利要求9的薄膜，其中的葡萄糖胺聚糖为透明质酸、软骨素6-硫酸盐、角蛋白硫酸盐或皮肤素硫酸盐。
11.如权利要求1的薄膜，其中的基质层及阻挡层基本上没有蛋白聚糖。
12.如权利要求1的薄膜，其中至少一层基质层和/或阻挡层还包括软骨粘连蛋白、层粘连蛋白、纤连蛋白、藻酸钙、锚定蛋白-II、生长因子或骨形态形成因子。
13.权利要求1的薄膜在制造导引组织再生的植入物中的用途。
CNB988117347A 1997-10-10 1998-10-05 导引组织再生的薄膜 Expired - Fee Related CN1181893C (zh)

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US20040234577A1 (en) 2004-11-25
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EP1023091A1 (en) 2000-08-02
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