CN85101396A - 可被生物降介的衬质和生产它的方法 - Google Patents

可被生物降介的衬质和生产它的方法 Download PDF

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CN85101396A
CN85101396A CN198585101396A CN85101396A CN85101396A CN 85101396 A CN85101396 A CN 85101396A CN 198585101396 A CN198585101396 A CN 198585101396A CN 85101396 A CN85101396 A CN 85101396A CN 85101396 A CN85101396 A CN 85101396A
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collagen
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basic collagen
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费雷德里克·里尔弗
理查德·伯格
戴维·伯克
凯文·威克
康拉德·怀恩
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New Jersey (us) 100 Bergen Street Newark, University of, Medicine and Dentistry of
University of Medicine and Dentistry of New Jersey
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Abstract

制备一种新的可被生物降介的基础胶原衬质的方法，包括把液体基质与从一组包括I、II、III型胶原中选出的一种胶原混合形成基础胶原底物，再与碳化二亚胺及双功能琥珀亚胺基活性酯选出的交联剂接触，严格脱水而成。在基础胶原衬质中加入载体化合物，这些化合物从下列物质中选择：IV、V型胶原，纤维结合素，昆布氨酸，透明质酸盐，蛋白多糖，表皮生长因子，血小板衍生生长因子，血管发生因子，抗菌素，抗真菌因子，杀精子因子，酶及酶的抑制剂。

Description

本发明涉及可被生物降介的衬质，特别涉及到多功能胶原基础衬质和/或它的载体。
将药物，生长因子，激素，多肽及糖肽投送至外伤上传统方法为直接局部应用，内伤上为注射于血液中或通过消化系统吸收至血液中。控制这些因子的释放，可将其在大量或微量水平上用合成多聚物包装在胶囊中，如硅酮;或用天然多聚物，如明胶和纤维素。用特殊选择的多聚系统控制扩散速率〔兰格，R.S.和比拍司，N.A，生物材料2.201，1981.（Longer，R.S.and    Peppbs，N.A.，Biomaterials    2.201，1981）〕，释放速率可控制到一年的时间。天然多聚物如明胶或纤维素可在几分钟到数小时内缓慢溶解，而硅酮在数月至数年期间仍可保持完整。由于仅需要一次外科处理，可被生物降介的多聚物具有可控制的释放到内部伤面的优点。
胶原是可被生物降介的在动物和人体中存在的多聚物，曾被用为血浆容积扩张剂，投药运载工具，玻璃体代用物，止血剂，缝合材料，角膜代用物，血液透析膜，伤口敷料及人造皮肤，疝修补，人造脉管，阴道内避孕用具以及组织增加物的可注射因子。（齐瓦比里等，“结缔组织研究国际综述”6，1，1973;齐瓦比里“胶原生物学”，A·维的克和J·吴司特主编，科学院印刷，第22章，1980）（Ckvapil等;Tnt.Review    of    Connective    Tissue    Rescarch    6.1，1973;Chvapil，in    Biology    of    Callageneditecl    by    A.Viidik    ang    J    Vaust，Acagemic    Press;Chapter    22，1980）。上述应用中的大多数情况，胶原须经重建并交联成不溶的形式。
延纳司等（Yanas    it    al）人介绍（美国专利4，06，081）（U.S.Patent    4，060，081），应用胶原及粘多糖为人造皮肤。这些材料用戊二醛交联，戊二醛为双功能交联剂，可与自由胺类反应。在许多实用中，应用交联胶原的一个主要缺点是用于制备交联和不溶性胶原的共同试剂游离戊二醛具有有害的生物学作用。自交联胶原中漏出的戊二醛表明对细胞有毒性作用，特别是对成纤维细胞（司比尔等，生物医学材料研究杂志14，753，1980;柯克等，“英国实验病理学杂志”64，172，1983（Speer    et    al，J.Biomegjcal    Mbterials    Research    14，753，1980;Coohe    et    al;British    J.Exp.Pafh.64，172，1983）。最新的证据指出戊二醛多聚物，而不是单体戊二醛，在胶原分子间形成交联;交联可再重排而释放游离戊二醛和戊二醛多聚物（琼，D·T和尼姆尼，M·D;结缔组织研究10，187-217，1982）（Cheung，D.T.ang    Nimni，M.D，Connective    Tissue    Research    10，187-217，1982）
本发明的目的之一是提供新的可被生物降介的衬质。
另一目的是提供新的基础胶原衬质。
另一目的是提供海绵状或页状新的基础胶原衬质。
再一目的是提供浸有载体复合物的新的可被生物降介的衬质。
还有一目的是提供浸有运载复合物的新的可被生物降介的基础胶原衬质。
另一目的是提供以海绵或纸页形式浸有载体复合物的新的可被生物降介的基础胶原衬质。
进一步的目的是提供浸有载体复合物的新的可被生物降介的基础胶原衬质，并且它是无毒的并能促进细胞生长。
再一目的是提供可控制药物释放的浸有载体复合物的新的可被生物降介的基础胶原衬质。
再一目的是提供为外伤局部应用的浸有载体复合物新的可被生物降介的基础胶原衬质。
再一目的是提供为内伤应用的浸有载体复合物新的可被生物降介的基础胶原衬质。
本发明是通过形成海绵或纸页形基础胶原衬质来实现这一目的。包括自一组包含有Ⅰ型Ⅱ型Ⅲ型胶原中选择胶原、海绵或纸页型胶原与交联剂接触，交联剂自一组包含有碳化二亚胺或琥珀亚胺基活性酯中选择，形成胶原-基础衬质中间物，再经严格脱水，形成海绵形或纸页形基础胶原衬质。另一具体实施为，海绵状或纸页状基础胶原材料先经严格脱水，形成的中间物再与碳化二亚胺交联合物接触，形成海绵或纸页形胶原基础衬质。本发明的另一实施是，将交联剂在海绵状或纸页状基础胶原中间物形成之前，与基础胶原材料混合，再经严格脱水的加工步骤。本发明特别推荐的形式是形成浸有载体复合物的海绵状或纸页状基础胶原衬质的过程中，掺合载体复合物，载体复合物是自下列一组化合物中选择的：Ⅳ型Ⅴ型胶原，纤维结合素，昆布氨酸透明质酸盐，蛋白多糖，表皮生长因子，血小板衍生的生长因子，血管发生因子，抗菌素，抗真菌因子杀精子剂，酶及酶的抑制剂。
本发明的基础胶原载体体系，基于利用可溶性或不溶性胶原为原材料，这些胶原是从一组含有Ⅰ、Ⅱ、Ⅲ型胶原及其混合物中选出的。
Ⅰ、Ⅱ、Ⅲ型胶原的可溶性胶原部分是从含这些胶原丰富的组织中经部分酶降介制备并形成基础胶原溶液（如，可溶性胶原溶于适当溶剂中如盐酸、稀醋酸或相似物）
不溶性胶原从下列有代表性的来源中得到：Ⅰ型胶原：牛、鸡和鱼皮肤，牛和鸡肌腱，包括胎儿组织的牛和鸡骨骼;Ⅱ型胶原：牛关节软骨，鼻中隔，胸骨软骨;Ⅲ型胶原：牛和人的表皮及皮肤。
本发明中的一个实施是把在适当液体（如稀盐酸，稀醋酸或类似物）中悬浮或溶胀的基础胶原液或不溶性胶原放于大约0℃到-100℃之间。使基础胶原材料固化，此后，固化的基础胶原材料置于50毫乇（Millitorr）在22℃到-100℃下减压，形成基础胶原海绵，再按下文详述的方法进一步加工，通常，可溶或不溶胶原对溶剂或悬浮剂的重量比，分别从1到10，000或从1到15，用于形成基础胶原溶液或悬浮液。
另一实施是这个基础胶原溶液或基础胶原悬浮液在如下较详尽叙述的进一步加工程序之前干燥为纸页形。在4℃到40℃，2到48小时之间干燥是有效的。
本发明另一实施是形成基础胶原衬质。基础胶原海绵或纸页首先与自一组包括碳化二亚胺或N-羟基琥珀亚胺衍生的活性酯（琥珀亚胺活性酯）选择出的交联剂接触，再严格脱水，形成基础胶原衬质。
碳化二亚胺衍生物，例如：氨基氰和1-乙基-3-（3-二甲基氨基丙基）-碳化二亚胺盐酸盐。
双功能琥珀亚胺活性酯衍生物，例如，双功能N-羟基琥珀亚胺，3，3′-二硫（磺基琥珀亚胺基）丙酸酯和双（磺基琥珀亚胺基）辛二酸酯，当应用碳化二亚胺交联剂时，基础胶原海绵或纸页浸入碳化二亚胺溶液中，浓度自大约0.1到10%（重量/体积，W/V），温度保持在大约2℃到40℃，氢离子浓度（PH）在2到11之间，大约反应2到96小时。当应用琥珀亚胺活性酯交联剂时，基础胶原海绵或纸页浸入上述溶液，浓度自大约0.1到15.0%（重量/体积W/V），温度保持在大约2℃到40℃，反应大约2到96小时。基础胶原海绵或纸页置于含有0.1到大约15%（重量/体积W/V）的N-羟基琥珀亚胺和碳化二亚胺溶液中，氢离子浓度（PH）在2到11之间，反应2到96小时，温度2℃到40℃，这样处理的基础胶原衬质中间物经彻底洗涤，以除去过多的交联剂。
基础胶原的中间物严格脱水条件，温度自50到200℃，真空度50毫乇或以下，时间2到96小时，直至形成基础胶原衬质。在严格脱水之前，海绵状基础胶原衬质中间物需先在大约0℃到-100℃间固化，然后减压到至少50毫乇，在22℃-100℃之间进行。
本发明的另一实施是利用碳化二亚胺交联剂形成基础胶原衬质时，严格脱水对用以上的交联剂缩合为基础胶原衬质的中间物之前形成基础胶原衬质中间物。
本发明的另一实施是交联剂在干燥或冰冻干燥步骤开始前与胶原一基础材料混合。
按照本发明制备的基础胶原衬质，可被认为是“类珊瑚”状或“支架”结构，具有孔度为3到100微米（m）的孔隙，分子量自10×106至50×106以上，通过共价键形成的交联度自1，000到100，000。
本发明的另一实施是把载体复合物掺合到基础胶原衬质中。载体复合物是从一组包括有Ⅳ、Ⅴ型胶原，纤维结合素，昆布氨酸，透明质酸盐，蛋白多糖，表皮生长因子，血小板衍生的生长因子，血管发生因子，抗菌素，抗真菌因子，杀精子剂，激素，酶和酶的抑制剂中选择的。
一般地说来，载体复合物可在基础胶原材料加工成海绵状或纸页状基础胶原衬质的过程中，随时可以加入的，本文推荐载体复合物在形成基础胶原衬质中间物可溶性或不溶的胶原过程固化之前掺合;或在严格脱水之前，基础胶原衬质中间物固化之前掺合。载体材料加入量基于可溶性与不溶胶原的重量的1%到30%（重量/重量）。一般地，结缔组织因子，如纤维结合素，Ⅳ、Ⅴ型胶原，昆布氨酸，氨基多糖和透明质酸盐在形成胶原基础海绵的开始加工步骤中掺合，或在基础胶原衬质中间物交联以后掺合;最好在形成基础胶原衬质中间物形成过程中掺合纤维结合素及透明质酸盐。
掺合到基础胶原衬质的各式各样载体复合物有许多来源。本发明的实施中的Ⅳ型、Ⅴ型胶原，发现分别与组织中基底膜及平滑肌细胞相关联。Ⅳ型代表性的来源，包括EHS小鼠肉瘤，牛及人胎盘，眼水晶体膜，肾脏;Ⅴ型胶原来源有胎盘膜，眼组织和胎儿皮肤（见实例，垂司特得，“细胞外间质的免疫化学”卷1，H福斯美主编，CRC印刷，第二章1982年）（Trelstad    In    Immunochemistry    g    the    Extracellular    Matrix    vol1    edited    by    H    Furthmayr    CRC    Press    Chapter    2，1982）。
蛋白多糖代表性的来源包括牛及人软骨及滑液，鼻中隔和胸骨软骨和皮肤，糖蛋白的典型来源包括EHS肿瘤，牛及人肾脏，软骨，骨骼，胎盘以及牛及人血液。透明质酸盐的典型来源包括鸡冠及牛玻璃体。
用于基础胶原衬质的最佳载体化合物包括纤维结合素，昆布氨酸，Ⅳ型胶原和透明质酸盐和蛋白多糖。与暴露伤面接触的基础胶原衬质需有溶胀比值在2.5到5之间，皮下植入用的有载体复合物的基础胶原衬质，其溶胀比值2.5到10之间是有用的。溶胀比的定义为单位体积的基础胶原衬质所吸收水的体积。
在内伤及短期内药物释放的情况下，带有载体化合物的基础胶原衬质，做成纸页形或管形放在直接与组织接触的部位。
可被生物降介的速率及释放速率可由改变交联度来调节。在实用中，希望长时间释放时，可被生物降介的多聚物的无孔扩散层如：多聚-3-（羟基丁酸盐）放在基础胶原衬质的两侧。用于全厚度伤面的物质，如在前面所提到的给延纳司美国专利信件所述，用一个扩散控制层来阻止水或其它小的挥发性分子自基础胶原衬质扩散;扩散控制层必须紧粘到基础胶原衬质层上。基础胶原衬质层和扩散控制层的结合必须强到能缝合在一起，并需每平方英吋至少有100磅的张力强度，并在失效前能至少变形10%，合成的，不能被生物降介的多聚物如：硅酮多聚物（硅橡胶医用级粘合剂）或可被生物降介的多聚物，如多聚乳酸，多聚乙醇酸，多聚3-（羟丁酸盐）和这些物质的共聚物可用为扩散控制层。
硅酮多聚物最好用于控制小分子扩散速率的材料，在扩散控制层粘合剂的治疗作用可完成而不会弄湿在室温干燥的基础胶原衬质上的载体化合物。
0.5到1.5毫米厚的薄膜用于衬质层，可允许在14英吋汞柱的真空度及室温下治疗至少2小时。
基础胶原衬质的厚度可从1毫米变化到几百毫米，对全厚度伤口，需要用2到3毫米厚度，并要使在基础胶原衬质上的载体化合物与伤面紧密接触。
当皮下移植或直接用于全厚度皮肤伤口时，本发明的任何基础胶原衬质不会刺激产生炎症。另外，慢性植入可使成纤维细胞和内皮细胞移动至基础胶原衬质上。基础胶原衬质的降介及重吸收速率用体外分析法，测定1mg材料对抗100单位细菌胶原酶溶介的时间，1单位胶原酶于37℃下，保温5小时，释放的胶原氨基酸相当于1微克分子L-亮氨酸。琥珀亚氨基活性酯的生成和严格脱水相结合，或碳化二亚胺处理和严格脱水相结合，可明显增加对抗胶原酶的时间，并超过了以前所用的任何方法。这些研究指出本发明的交联方法可抗胶原酶降介，并且不刺激炎症发生。
下列实例说明本发明实验过程中的条件，应了解。但发明的范围不限于此。
例    1
可溶性及不溶性胶原的制备
所用的胶原来自肉芽层与真皮及表皮分离后的小牛皮革。真皮切成小块，洗净，溶胀，冰冻干燥并贮存于-20摄氏度。
可溶性胶原是通过下列方法得到：把250克冰冻干燥不溶的胶原放于1.5升盐酸（HCl），氢离子浓度（PH）2.5及1.5克结晶胃蛋白酶（西格马化学公司Sigma）混合物于4℃搅拌过夜，然后连续经过干酪包布，4号华特曼滤纸，华特曼42号滤纸，格尔曼5微米和1.2微米滤膜过滤，最后经过0.65微米及0.45微米微孔滤膜过滤。经一系列过滤得到的可溶部分含有Ⅰ、Ⅲ、Ⅴ型胶原。可溶性胶原部分对含50毫克分子浓度三羟甲基氨基甲烷（Trls）的1.0克分子浓度（M）氯化钠（Nacl）透析，透析液的氢离子浓度调到7.5（PH7.5）。然后加入固体氯化钠使克分子浓度增至1.7，在1.7克分子浓度氯化钠沉淀的是Ⅲ型胶原。把它于10，000×重力加速度（g）离心60分钟收集，再对0.005克分子浓度乙酸透析，冰冻干燥，并贮存于-20℃。上清液中再加入氯化钠至2.5克分子浓度，离心，沉淀，（Ⅰ型胶原）对0.005克分子浓度乙酸透析，冰冻干燥，-20摄氏度保存。剩余的上清液含Ⅴ型胶原，并对0.005克分子浓度乙酸透析，冰冻干燥，-20摄氏度保存。
不溶性胶原溶液得自冰冻干燥的真皮，用魏
Figure 85101396_IMG1
研磨器（Wiley Mill）在盐酸中，氢离子浓度2.5时研磨成悬液。溶胀的胶原对0.005克分子浓度乙酸透析，并冰冻干燥，如果用熟牛革为真皮的来源，则产生的不溶性胶原是典型的Ⅰ型。
可溶性Ⅳ型胶原自小鼠EHS肉瘤提取。瘤组织用冷蒸馏水洗三次。在10，000×重力加速度（g）离心过滤30分钟。沉淀（0.500克）在0.5升0.5克分子浓度乙酸，PH用盐酸调至2.5的溶液中匀浆，并加入0.5克胃蛋白酶。匀浆物在4℃混合24到48小时，通过干酪包布过滤，在10，000×重力加速度离心30分钟。沉淀重新悬浮在含50毫克分子浓度三羟甲基氨基甲烷的0.5克分子浓度氯化钠中，再加入氯化钠至其终浓度为4.5克分子浓度，在10，000×重力加速度（g）离心30分钟。所得沉淀对0.1当量浓度乙酸透析三次，并冰冻干燥。
例    2
制备牛血清纤维结合素
新鲜放出的牛血〔80毫升（ml）〕收集在含有20毫升5%枸橡酸三钠和0.1毫升苯基甲基磺酸基氟化物的聚丙烯管中，在300×重力加速度（×g）离心10分钟以分开血浆及细胞层。再在30，000×重力加速度15℃下离心30分钟，血浆中再加入苯基甲基磺酸基氟化物，使其达1mM，再加到明胶-琼酯糖柱上。用磷酸盐缓冲液洗脱（0.182克分子浓度磷酸盐和0.145克分子浓度氯化钠），再用2倍柱床体积磷酸缓冲液的1克分子浓度氯化钠洗，然后用2倍柱床体积磷酸缓冲液洗，最后用2倍柱床体积含4克分子浓度尿素的磷酸缓冲液的洗脱，洗脱部分的光密度在波长280毫微米处，检测在含4克分子浓度尿素溶液正常存在的纤维结合素的量，含纤维结合素的部分光密度大于0.1。洗脱液对含有0.145克分子浓度氯化钠的0.180克分子浓度磷酸缓冲液（氢离子浓度7.2）透析，再对含4.5克分子浓度尿素的0.05克分子浓度三羟甲基氨基甲烷-盐酸盐（氢离子浓度7.2）透析。并在室温下加到DEAE（二乙基氨基乙基纤维素）离子交换柱子，用含4.5克分子浓度尿素的、0.05克分子浓度三羟甲基氨基甲烷-盐酸缓冲液（氢离子浓度7.2）洗脱，洗脱液具有0到3克分子浓度氯化钠直线梯度。洗脱的纤维结合素，对含0.145克分子浓度氯化钠和1.0克分子浓度尿素的0.180克分子浓度磷酸盐透析，并于-20摄氏度冰冻保存。
例    3
制备昆布氨酸
昆布氨酸从C57/6J小鼠胶原松介的EHS肿瘤制备，肿瘤切碎并在含50毫克分子三羟甲基氨基甲烷盐酸（氢离子浓度调到7.4）及蛋白酶抑制的3.4克分子浓度氯化钠溶液中匀浆。并在16，000×（g）重力加速度离心60分钟，收集沉淀，并重悬浮于3.4克分子浓度氯化钠中，再在16，000×重力加速度第二次离心60分钟。匀浆物悬浮于0.5克分子浓度氯化钠含50毫克分子三羟甲基氨基甲烷-盐酸盐，氢离子浓度7.4，和蛋白酶抑制剂溶液中，于4℃揽拌18到24小时。再在16，000×重力加速度离心60分钟。上清液加入固体氯化钠至3.5克分子浓度，于4℃揽拌过夜。离心后收集沉淀，进一步纯化。将昆布氨酸重溶于0.5克分子氯化钠含50毫克分子浓度三羟甲基氨基甲烷-盐酸盐，氢离子浓度7.4的溶液中。再于10，000×重力加速度离心60分钟。上清液对2克分子浓度尿素含2.5克分子浓度氯化钠和50毫克分子浓度三羟甲基氨基甲烷-盐酸盐、氢离子浓度为8.6的溶液透析。并进行DEAE纤维素柱层析。柱2.5×2.5厘米，用相同的缓冲液在4℃下平衡，未结合部分对2克分子尿素含50毫克分子浓度三羟甲基氨基甲烷-盐酸盐、氢离子浓度8.6的溶液透析。然后在DEAE柱上再层析。用相同缓冲液平衡。未结合部分经真空透析浓缩，并在葡聚糖丙烯酰胺凝胶S-300柱层析。用1.0克分子浓度氯化钙，50毫克分子浓度三羟甲基氨基甲烷-盐酸盐（氢离子浓度7.5）的溶液，在22℃下平衡。收集空间体积部分并对0.4克分子浓度氯化钠，50毫克分子浓度三羟甲基氨基甲烷-盐酸盐，氢离子浓度7.4的溶液透析，于4℃下保存。昆布氨酸（Laminin）重溶于0.1克分子浓度氢氧化铵氢离子浓度11.0的溶液中，然后，将氢离子浓度调至7.2。
例    4
制备基础胶原海绵或纸页
可溶或不溶性胶原（1.2克）加到120毫升稀盐酸溶液，氢离子浓度3.0溶液中。混合物于瓦伦匀浆器（Waring    Blender）中低速研磨一分钟，然后高速磨一分钟。溶液或悬浮液再倒入真空瓶中，于100毫乇减压抽气10分钟，转变成海绵状的胶原悬液或溶液。然后在-65℃10毫乇以下真空度冰冻干燥之前，在0℃冷却，再在-100℃冰冻。加工成纸页状的胶原溶液或悬浮液放于无菌罩中于22℃中干燥24到48小时。
例    5
制备琥珀酸盐，琥珀二亚胺酯
交联的基础胶原衬质中间物
9克琥珀酐，溶于80毫升蒸馏水中，在37℃下混合30分钟。琥珀酸酐溶介后，氢离子浓度调到7.2，体积加到100毫升，放于匀浆器中（Waring    Blender），加入1克胶原研磨2分钟，22℃下放1小时后，放在华特曼4号滤纸上，除去未反应的琥珀酐，再用100毫升蒸馏水洗。
剩余物放于20毫升磷酸缓冲液（0.182克分子浓度磷酸盐和0.145克分子浓度氯化钠）中，加入2克N-羟基琥珀亚胺和2克氨基氰：溶液的氢离子浓度调到7.2，室温反应3小时，用蒸馏水在布氏漏斗中在14英吋汞柱减压洗涤，胶原-基础衬质中间物经琥珀酸盐，琥珀亚胺酯交联的海绵和纸页形成过程，与例4所述过程相同。
例    6
制备含有纤维结合素的基础胶原衬质
1.2克可溶性或不溶性胶原在120毫升盐酸氢离子浓度3.0的溶液中，再加0.12克纤维结合素（2.5毫克纤维结合素/毫升）与0.1克分子尿素含0.182克分子浓度磷酸盐和0.145克分子浓度氯化钠的溶液混合，混合物在匀浆器中搅拌2分钟，纸页及海绵按例4所述过程制备。
例    7
用昆布宁（Laminin）纤维结合素Ⅳ型胶原
做Ⅰ型胶原的外膜制成海绵及纸页
按例4及6做成的胶原纸页及海绵在0.1M乙酸铵氢离子浓度7.2，含1到5%昆布氨酸，纤维结合素或Ⅳ型胶原的溶液中溶胀，溶胀的海绵或纸页冰冻，再于-65℃50毫乇以下真空度冰冻干燥。
例    8
制备含有透明质酸盐和蛋白多糖
的基础胶原衬质
1.2克可溶性及不溶性胶原于氢离子浓度3.0的盐酸溶液中，加入到0.12克透明质酸盐和蛋白多糖（西格马化学公司，Ⅲ    P级，Sigma    Chemical    Campany    Grade    Ⅲ-P）复合物氢离子浓度2.0的盐酸溶液中，经体积120毫升，混合物于匀浆器中被散开，冰冻干燥或空气干燥与例4过程相同。
例    9
制备含Ⅳ型胶原的基础胶原衬质
1.2克可溶及不溶性Ⅰ型胶原及氢离子浓度2.0的盐酸溶液加到0.012克Ⅳ型胶原的0.1克分子浓度乙酸铵，氢离子浓度7.2溶液中，终体积120毫升，混合物于匀浆器中匀浆2分钟使成分散开，按例4相同的过程制成海绵或纸页。
例    10
氨基氰交联基础胶原衬质
例4、6及9的产物，浸入含1%重量的氨基氰，氢离子浓度5.5的水溶液中，在22℃，24小时使其交联。除去试剂以后，海绵和纸页被彻底清洗24小时，换几次水，冰冻并在50毫乇真空度以下于-65摄氏度冰冻干燥。
例    11
基础胶原衬质经严格脱水交联
例4、6及10产物于室温放于真空炉上减压至50毫乇以下，1小时后，加热至110℃，并维持72小时，在此期间温度降低至40℃，然后自炉上移出，于-20℃保存。
例    12
基础胶原衬质用琥珀亚胺活性酯交联
按例5制备的琥珀亚胺基活性酯、2克被放入有400毫升氢离子浓度2的盐酸溶液的匀浆器中，研磨二分钟，混合物于300毫乇真空下抽气。再放在100%相对湿度的环境中，室温放24小时，然后冷却到0℃，并在50毫乇真空度，-65℃下冰冻干燥。或空气干燥。分别做为海绵或纸页形。
例    13
含有蛋白酶抑制剂的基础胶原衬质的制备
按例4到9制备的海绵和纸页放于20毫升氢离子浓度2.0的盐酸中，含25%半脱氨酸或1%（重量/体积）α-2巨球蛋白，混合物冰冻，并在50毫乇以下的真空中，-65℃下冰冻干燥，或室温空气干燥。
例    14
体外酶降介
取上述各例中的产物1平方厘米，放入2毫升10毫克分子浓度三羟甲基氨基甲烷-盐酸，氢离子浓度7.4含25毫克分子浓度氯化钙溶液中。每毫克样品加入100单位自溶组织授菌来源的Ⅳ型胶原酶（西格马化学公司），放于37℃下保温，每10分钟用肉眼检查每样品的完整性，当样品可见降介成0.5微米以下的碎片时，记录时间，结果见表1。
例    15
体外测定溶胀率
变性胶原的溶胀率，与交联度成反比，上述实例中的产物在蒸馏水中煮沸2分钟，放在二层餐巾之间吸去水份，在夹有实验材料的餐巾的上部放1公斤重量压20秒钟，记下湿样的重量
Figure 85101396_IMG2
Figure 85101396_IMG3
再于110℃干燥3小时，再记录干燥后的重量，自下列关系式计算溶胀率（r）
r＝1/Vf
V f = D W / P C ( D W ) ( P C ) + ( WW - D W ) ( P H 2 O )
DW及WW为干重及湿重，Pc和PH2O分别为实验材料及水的密度，结果在前面所列的表1中。
例    16
基础胶原衬质的机械性质
在以上实例中制备的海绵及纸页，切成直角形（4.0厘米×1.0厘米）的小条，在机械试验之前浸入氢离子浓度7.5的磷酸缓冲液中20分钟，在22℃下，用Instron型1122测试仪每分钟10%的张力率测试小条的单轴张力，小条的末端放在充气的夹子上，夹子有-20毫米长的口径在40磅/英吋（计示）（Psig）压力下可关紧。张力-应力曲线可测得，从曲线上可计算在高（HSM）和低张力时的杨氏系数。在低系数区终点的张力标志为eL，张力破碎时标示为lf。张力计算结果在上面的表1中。
例    17
基础胶原衬质的皮下生物适应性
按上述实例制备的海绵和纸页在用2.5百万拉得（Mrads）的r-射线灭菌后，测试其在皮下的生物适应性。在灭菌条件下用350g重的雌性白豚鼠为实验动物进行植入。
在背部侧切一厘米长的皮肤切口，并与筋膜层分开，放入1厘米×1厘米大小的植入物，用外伤夹子从植入物上边将皮肤边缘夹紧，在植入后第六、第九，第十二天杀死动物，将含有载体的组织放入卡森氏（Carsons）固定液中，并进行组织学研究，结果在表11中。
例    18
在衬质层上制备扩散控制层
应用在例4到例10中制备的海绵及纸页，用刮刀在衬质层表面放上一层1毫米厚的硅橡胶医用级粘合剂。扩散控制层经22℃100毫乇减压处理2小时。得到的扩散控制及衬质层复合物与全厚度皮肤创伤接触。
例    19
在全厚度皮肤伤口上扩散控制与
衬质层的生物适应性
按例18制备的海绵及纸页，照射灭菌后在雌性阿拜脑（Hartley    Albino）350克白豚鼠的皮肤伤口上做为敷料，进行测试。每只动物分别喂养，测试前连续称体重4天，测试前一天用电动刮刀去毛，再用纳氏脱毛机（Nair）脱毛，并洗净，用乙醚麻醉，背部用碘-聚乙烯氮五环酮复合物和乙醇洗净，浸在磷酸缓冲液中（0.182克分子浓度磷酸盐和0.154克分子浓度氯化钠），由衬质及扩散控制层组成的2厘米×2厘米大小的被测材料，敷在全厚度切除的皮肤伤口上，与衬质层一样，与肌层的位置相对应。
衬质与扩散控制层，用鞣化铬肠线在敷料边缘处缝合到伤面上。在伤面敷料上放以消毒棉敷料，用绷带包扎，用弹性胶条（约翰森和约翰森产品公司）围绕颈部固定，在实验过程中动物每三个放在一个笼中。
每天监视绷带撕裂情况，在植入后第6
9、12天杀死动物，切下植入物及伤面，固定，并做组织学研究。结果在表Ⅲ中。
在上述讲授的方法中，本发明中可能有许多修改和变化。因此，在附属权利要求的范围内，本发明根据其特殊的叙述来实施。
Figure 85101396_IMG5
Figure 85101396_IMG6

Claims (50)

1、一种制备新的基础胶原衬质的方法，其特征包括
(1)用液体基质与从一组包括Ⅰ、Ⅱ、Ⅲ型胶原中选出的一种胶原混合，形成基础胶原底物。
(2)在步骤(1)的产物中加入自碳化二亚胺及双功能琥珀亚胺基活性酯组中选出的交联剂。
(3)将步骤(2)中所述产物在真空条件下升高温度，产生所述基础胶原衬质。
2、根据权利要求1所述方法，其中步骤（3）在步骤（2）之前进行。
3、根据权利要求1或2所述方法，其中所述液体基质是所述胶原的溶剂。
4、根据权利要求1或2所述的方法，其中所述液体基质是所述胶原的分散剂。
5、根据权利要求1或2所述的方法，其中所述交联剂是碳化二亚胺，并在溶液中，其浓度大约自0.1至10%（重量/体积）。
6、根据权利要求5所述的方法，其中所述碳化二亚胺溶液及基础胶原底物在进一步加工前，保持在2到40℃，2到96小时。
7、根据权利要求6中所述的方法，其中所述碳化二亚胺溶液的氢离子浓度自2到11。
8、根据权利要求1或2的方法，其中所述交联剂为双功能琥珀亚胺活性酯，是在浓度自大约0.1至大约15.0%（重量/体积）的溶液中。
9、根据权利要求8所述的方法，其中所述双功能琥珀亚胺活性酯溶液及基础胶原底物，在进一步加工前，保持于2到40℃，2到96小时。
10、根据权利要求1或2所述的方法，其中的过剩的交联剂在步骤（3）之前除去。
11、根据权利要求1或2所述的方法，其中步骤（3）在50毫乇以下的真空中，自50到大约200℃的温度条件下进行。
12、根据权利要求11所述方法，其中的步骤（3）是在2到96小时的时间内进行的。
13、根据权利要求1或2中所述的方法，其中所述基础胶原底物在步骤（2）之前，经冰冻干燥。所述方法使基础胶原衬质形成海绵状。
14、根据权利要求13中所述的方法，其中所述基础胶原底物在冰冻干燥步骤之前固化。
15、根据权利要求14所述的方法，其中的冰冻干燥步骤在50毫乇以下的真空中，温度自大约22到-100℃下进行的。
16、根据权利要求15所述的方法，其中所述基础胶原底物是在0℃到-100℃下固化的。
17、根据权利要求13所述的方法，其中所述基础胶原衬质中间物在步骤（3）之前进行冰冻干燥。
18、根据权利要求17所述的方法，其中所述基础胶原衬质中间物在步骤（3）之前的冰冻干燥之前固化。
19、根据权利要求17所述的方法，其中冰冻干燥的步骤在50毫乇以下的真空条件下，温度自大约22℃到-100℃间进行的。
20、根据权利要求17所述的方法，其中所述基础胶原底物在温度自0℃到-100℃间固化。
21、根据权利要求1或2所述的方法，其中所述基础胶原底物在步骤（2）之前干燥。所述方法形成纸页形基础胶原衬质。
22、根据权利要求21所述的方法，其中干燥步骤是在温度自4℃到40℃，时间自2到96小时的条件下进行的。
23、根据权利要求1或2所述的方法，其中载体复合物在所述基础胶原衬质形成时加到所述基础胶原衬质中。所述载体复合物是从一组包括有Ⅳ型胶原、Ⅴ型胶原、纤维结合素、昆布氨酸、透明质酸盐、蛋白多糖、表皮生长因子、血小板衍生的生长因子、血管发生因子、抗菌素、抗真菌因子、杀精剂、酶和酶的抑制剂中选择的。
24、根据权利要求23所述的方法，其中所述基础胶原衬质在步骤（2）之前冰冻干燥，所述方法形成海绵形式的基础胶原衬质。
25、根据权利要求24所述的方法，其中所述基础胶原衬质在冰冻干燥步骤之前固化。
26、根据权利要求25所述的方法，其中冰冻干燥的步骤在50毫乇以下的真空中，温度自22℃到-100℃之间进行。
27、根据权利要求26所述的方法，其中所述基础胶原衬质在温度自0℃到-100℃下固化。
28、根据权利要求24所述的方法，其中所述基础胶原衬质中间物在步骤（3）之前冰冻干燥。
29、根据权利要求28所述的方法，其中所述基础胶原衬质在步骤（3）之前的冰冻干燥之前固化。
30、根据权利要求28所述的方法，其中冰冻干燥步骤是在50毫乇以下的真空中，温度自22℃到-100℃间进行的。
31、根据权利要求28所述的方法，其中所述的基础胶原衬质在温度自0℃到-100℃之间固化。
32、根据权利要求23所述的方法，其中所述的基础胶原衬质在步骤（2）之前干燥。所述方法形成纸页形基础胶原衬质。
33、根据权利要求32所述的方法，其中所述的干燥在温度4℃到40℃，时间2到96小时之间进行。
34、根据权利要求33所述的方法，进一步包括在所述纸页形基础胶原衬质上安置扩散层的步骤。
35、根据权利要求34所述的方法，其中所述扩散层是无孔的。
36、根据权利要求34所述的方法，其中所述无孔的扩散层是可被生物降介的。
37、根据权利要求34所述的方法，所述扩散层是由不被生物降介的多聚物制成的。
38、一种基础胶原衬质，其特征是构成这种衬质的胶原由包括有其分子量至少为1.0×106的Ⅰ、Ⅱ、Ⅲ型一组胶原中选择的。
39、根据权利要求36所述的基础胶原衬质，其中分子量大于50×106的部分。
40、根据权利要求39所述的基础胶原衬质，基于通过共价键交联之间的分子量从1000到100，000。
41、根据权利要求38所述的基础胶原衬质，具有自3到100微米孔度的孔隙。
42、根据权利要求38所述的基础胶原衬质，进一步包含从下列一组材料中选出的载体复合物，包括有：Ⅳ型胶原，Ⅴ胶原、纤维结合素、昆布氨酸、透明质酸盐、蛋白多糖、表皮生长因子、血小板衍生的生长因子、血管发生因子、抗菌素、抗真菌因子、杀精子剂（Spermacidal）酶及酶的抑制剂。
43、根据权利要求38或42所述的基础胶原衬质，其特征是呈纸页形。
44、根据权利要求43所述的基础胶原衬质，其特征是进一步包括扩散层。
45、根据权利要求44所述的基础胶原衬质，其特征是进一步包括非孔扩散层，它可应用于所述基础胶原衬质的两侧。
46、根据权利要求45所述的基础胶原衬质，其中所述无孔度扩散层是可被生物降介的。
47、根据权利要求44所述的基础胶原衬质，其中所述扩散层紧密粘合在所述的基础胶原衬质上。
48、根据权利要求47所述的基础胶原衬质，其中所述基础胶原衬质及所述扩散层具有至少每平方英吋有100磅的结合张力强度。
49、根据权利要求47所述的基础胶原衬质，其中所述基础胶原衬质和扩散层应有至少10%的变形性。
50、根据权利要求43所述的基础胶原衬质，具有至少约为2.5的溶胀比。
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