CN1149497A - 医用材料的原料膜材及其制造方法 - Google Patents
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Abstract
通过本发明可以得到一种可用于生物体的医用人造材料。用于治疗时，这种材料具有与患处缺损组织的再生及在与缺损组织再生同步的分解、吸收的同时与患处正常组织相置换等生理功能。这种材料的制造方法是用通式为[C6H5CH2N(CH3)2R]'Cl的季胺盐水溶液处理生物结缔组织膜，然后用分子量为26,000、等电点为9的巯基蛋白酶处理上述结缔组织膜，得到保持了基质结构的实质上由致密层构成的膜材料。
Description
本发明涉及医用材料的原料膜材及其制造方法。
本发明的目的在于，提供能够符合最理想的人造器官、组织所必须具备的条件的医用材料。最理想的人造器官、组织是指适用于外科手术治疗的可用于生物体的人造材料。它们不仅具有机械方面的功能，还是来源于同种生物的材料，具有患处缺损组织再生、及在与缺损组织的再生同步的分解、吸收的同时与正常组织相置换等的生理功能，这种材料称为同种置换用医用材料。
先有的“The Extracellular Matrix of human Amnioticepithelium”(J.Cell Sci.，79，119-136，1985)和“SurfaceVisualisation of Tissue interfaces by scaning ElectronMicroscopy”(Scaning Microscopy，Vol.2，No.4，Pages 2067-2076，1988)都是T.D.Allen(Department of ultrastructure，Paterson Institute forCancer Research，Christie Hospital，Manchester M20 9BK，Uk.)及其合作者们的学术论文。在这些文章中，T.D.Allen及其合作者们用电子显微镜学方法详细说明了人的羊膜由上皮层、基底层、致密层及纤维母细胞层构成，也详细说明了人羊膜的其他构成成分。将它们在这些研究中采用的去除细胞的步骤、手段、方法简述如下：
通过剖腹产取出妊娠37-39周的胎盘，用剪刀分离胎膜。以100-150ml磷酸盐缓冲液洗涤分离的胎膜3次。为使羊膜与绒毛膜分离，预行放入磷酸盐缓冲液中加温15-20分钟使两膜之间的连接松驰，然后用手术钳分离洗涤过的胎膜。室温下，用0.2M氨水溶液处理洗涤过的羊膜并更换氨水溶液，每5-15分钟重复操作20次。然后，用0.2％或1.0％的十二烷基硫酸钠水溶液处理30分钟至2小时，再用蛋白分解酶胰蛋白酶处理。大致用以上的步骤和方法取得去除了细胞的由基膜层和致密层组成的无细胞层(光学显微镜学把这些总称为基膜，生理学上区別开来分别称为基膜层、致密层)。以上是T.D.Allen等人的技术。
基于优先权日为1983年6月10日的美国专利申请号为503、203和优先权日为1984年2月22日的美国专利申请号为582、504的日本专利第1,842,777号(特公平5～50295号)，发明的名称为“细胞外基质构成的生物体移植片及该移植片的制造、使用方法和手段”权利要求“(1)一种含有来源于生物体结构的无菌生物体移植片，去除了细胞膜、核酸、脂质及细胞质成分的细胞外基质，主要成分是胶原及弹性蛋白。(2)权利要求(1)中记载的生物体移植片为适合所附着的生物体部分组织结构的不同制成的各种尺寸的产品。(3)权利要求(1)中记载的无菌生物体移植片，从生物体中取出后立即进行实质上的化学交联或产生这种交联变化之前用洗涤剂处理其生物体结构。”这些权利要求涉及了下述第28项权利要求。
上述发明的“生物体移植片”及“来源于生物体的结构体”不限于特定的生物体，泛指所有的生物体。远早于上述专利申请之前，与上述发明同样的取自鱼、猪、马的生物体移植片作为医疗产品已经在世界各国销售。如鱼鳔、猪心包、马心包膜等。这些都是去除了形成细胞的物质的细胞外基质，主要成分是胶原及弹性蛋白，是来源于生物体结构的无菌生物体移植片。而且，为适合所附着的生物体部分组织结构的不同可制成各种尺寸的产品。
东京大学的大本、杉江、角田等发表在Arch，Surg.69(4)：549-563，(1954)及Rosenburg，N.et al：“The use of arterial implantsprepared by enzymatic modification of arterial heterografts.”Arch.Surg.74：89，(1957)的论文也都记载了符合上述权利要求(1)、(2)中术语所定义的同样条件的生物体移植片的制造、使用的手段和方法。
申请日为1978年4月25日的英国专利第1,565,340号的申请早于上述日本专利第1,842,777号。英国专利第1,565,340号的权利要求1中记载了如下发明：“是来源于人或动物的纤维组织的材料。作为临时绷带适用于皮肤创伤及软组织损伤。适用于异种间移植，实质上不含有具有抗原性的非纤维蛋白，实质上不含有具有抗原性的多糖及糖蛋白”。这个发明从依据医学、生物化学知识的角度看，与上述日本专利第1,842,777号“含有来源于生物体结构的无菌生物体移植片，去除了细胞膜、核酸、脂质及细胞成分的细胞外基质，主要成分是胶原及弹性蛋白”的权利要求表示的是含义相同的材料。更进一步，两专利的详细说明和发明目的是同种的医用材料这一点也很明确。
以上记载的论文及专利的目的，从科学的角度出发都是同一类医用材料，但是采用的技术手段不同。上述日本专利第1,842,777号的方法的技术特征在于权利要求3-28项记载的使用洗涤剂。
以上记载的现有技术，是利用无机碱水溶液、合成洗涤剂、胰蛋白酶等动物性蛋白酶或无花果蛋白酶等植物性蛋白酶来获得想要的医用材料。
但是现有技术不能完全满足生物体结缔组织的致密层特有的性状，即作为结缔组织学研究课题的“细胞增殖与细胞基质”的条件，不能得到表、里为不对称基质的膜材料。换句话说，现有技术不能得到具有损伤组织的自我再生、修复所必需的组织细胞的生长附着、与增殖及组织的再生同步的分解、吸收、置换等生理功能的医用材料。
目前，迫切需要开发一种来源于生物体结缔组织的并与存在于生物体内的结缔组织具有同样的形状、结构和生理功能的膜材料。其生理功能包括促进组织细胞的生长附着及增殖，与损伤组织的再生同步、在生物体内被分解、吸收并与再生组织相置换。
因此，本发明人等为解决上述课题，经研究完成了本发明，本发明涉及一种医用材料的原料膜及其制造方法，其特征在于，溶解、去除由上皮层、基膜层、致密层、纤维母细胞层构成的生物体结缔组织膜的上皮层、纤维母细胞层而成为无细胞的实质上由致密层构成并保存了其基质结构，特别是同时并用了通式为〔C6H5CH2N(CH3)2R〕’Cl(式中，R代表从C18H17-C18H37中选出的烷基，C12H25及C14H29构成的效果特别好。)的季胺盐水溶和分子量为26,000、等电点为9的巯基蛋白酶作为生物结缔组织膜处理剂。
在生理学领域将结缔组织按功能分类，结构上分为上皮层、基膜层、致密层、纤维母细胞4层。光学显微镜学按视觉所见分为上皮层、基膜、纤维母细胞层3层。即光学显微镜学的分类把生理学分类中的基膜层和致密层总称为基膜。并且上皮层、纤维母细胞层含细胞而基膜层、致密层不含细胞。基膜层是厚度可以用nm表示的超薄层，致密层可以用μm为单位表示。
本发明中的结缔组织指硬脑膜、心包、胸膜、盆腔腹膜、膈、腹膜、筋膜、肠系膜、皮肤、鼓膜、其他的生物体膜及血管壁、食道壁、气管壁、尿道壁、输尿管壁、其他的生物器官的外壁。另外也指胎膜及构成胎膜的羊膜和绒毛膜。人羊膜厚约12,000nm，以基底层(厚50-80nm)和致密层(厚50-80nm)为分界层，其两侧形成了上皮层和纤维母细胞层。本发明中的实质上的致密层是指光学显微学中致密层与基膜的总合体，实质上指生理学上的致密层。
实施例本发明时应用的通式为〔C6H5CH2N(CH3)2R〕’Cl的季胺盐水溶液，是具有杀菌、消毒功能的阳性肥皂(下称该肥皂)，不是洗涤剂。在第12版日本药典C-366-(解说)中记载了其杀菌机理。带正电荷的该肥皂吸附聚集于带负电荷的菌体表面，使细菌蛋白变性。而且，该肥皂稀释至适当浓度后，用于阴道、膀胱的清洗、外科手术创面的杀菌、消毒等方面，使用范围广泛，不损害生物体组织，是安全性、有效性较高的杀菌消毒剂。
东京化学同人社出版的生物化学辞典中，记载了实施本发明所用的分子量为26,000、等电点为9的巯基蛋白酶(下称该蛋白酶)，它在PH近中性时能发挥合适的酶的作用。
本发明可按如下所述实施。生物结缔组织膜实质上是在由致密层构成的膜的两面存在着上皮层、纤维母细胞层等的细胞层质。这些细胞与细菌细胞同样由蛋白质构成，含有大量蛋白质分子所特有的带负电荷侧链。把生物结缔组织膜浸入带有阳电荷的该肥皂水溶液中，通过上述该肥皂的杀菌机理，生物结缔组织膜两面的细胞层逐渐发生蛋白电位变性。
这种已变性的生物结缔组织的蛋白质层，在PH为7的条件下用在PH近中性的电位环境下最能发挥分解作用的该蛋白酶处理使其蛋白质层被分解。这种蛋白质的分解，如果不控制适当的条件必然造成由硬蛋白胶原蛋白构成的致密层也被分解。因此为使致密层残留和保全下来，必须把合适的温度和时间作为控制条件。下面的操作是超声波洗涤。以此去除附着于致密层的上皮层、纤维母细胞层等的分解物，从而得到实质上由致密层构成的膜状材料。
下面，通过实施例对本发明进行详细说明。
实施例1
未感染的产妇分娩后不久娩出胎盘、胎膜、脐带。在分娩室用剪刀剪下并分离它们的胎膜。用流动状态的药典方生理盐水冲洗分离的胎膜进行第一次脱血、除血操作。在室温下，将经脱血、除血的胎膜浸渍、漂浮于该肥皂液中。这样羊膜几乎剥离，绒毛膜与包脱膜之间的组织膨胀浸润呈易剥离状态。用手指仔细剥离处于这种状态的羊膜和绒毛膜，羊膜与绒毛膜就完全分开了。下面以羊膜为例说明。
室温下，把羊膜再次浸渍于药典方生理盐水中，用手指仔细揉洗后，以流动状态的药典方生理盐水进行第二次脱血、除血操作后，将羊膜悬挂于充满了药典方精制水且不断溢流的超声波洗涤装置的水槽中。室温下以40KHZ的频率洗涤15分钟，用lowry法检查得到的干净的羊膜，未检到游离蛋白质的存在。
室温下将完全去除了血液的羊膜浸于药典方杀菌消毒剂0.01％洁尔灭(benzal konium chloricle)水溶液中30分钟以上。其后再浸入含有0.05％(W/V)NaN3的0.01％无花果蛋白酶的0.2M(PH7.4)磷酸缓冲液中静置24小时。然后，室温下将用无花果蛋白酶处理过的膜材料悬挂于充满了药典方精制水且不断溢流的超声波洗涤装置的水槽中，以40KHZ的频率，超声波洗涤15分钟。
将得到的不含细胞质的实质上由致密层构成的含水膜材料置于无菌、减压的干燥机中，30℃下干燥12小时，得到本发明的膜材料。
于电子显微镜下观察这种膜材料的表面和里面，如图1、2、3、4所示，表面和里面是不对称的。
再将得到的人羊膜的致密层膜埋入兔的背部肌肉，测定其吸收性和组织反应性。结果见表1、2。
【表1】兔背部肌肉对人羊膜致密层的吸收
| 2wk | 4wk | 6wk | |
| 致密层膜 | 膜脆化 3/5膜断裂 2/5 | 膜吸收 3/4膜部分残留 1/4 | 膜吸收 3/3 |
| 8wk | 12wk | 16wk | |
| 致密层膜 | 膜吸收 3/3 | 膜吸收 3/3 | 膜吸收 3/3 |
【表2】人羊膜致密层引起的兔背部肌肉的组织反应
| 2wk | 4wk | 6wk | |
| 致密层膜 | 炎症细胞浸润轻度 4/5中度 1/5 | 炎症细胞浸润极轻 2/4(含嗜酸细胞的)纤维性变化 2/4 | 炎症细胞浸润极轻 2/3(含嗜酸细胞的)纤维性变化 1/3 |
| 8wk | 12wk | 16wk | |
| 致密层膜 | 脂肪组织部分纤维组织 3/3 | 脂肪组织部分纤维组织 3/3 | 脂肪组织部分纤维组织 3/3 |
附图说明：
图1：表示本发明产品表面的电子显微镜照片(1,100倍)。
图2：图1中方框的放大照片(5,500倍)。
图3：表示本发明产品里面的电子显微镜照片(1,100倍)。
图4：图3中方框的放大照片(5,500倍)。
Claims (2)
1.一种作为医用材料的原料膜材，其特征在于溶解、去除由上皮层、基膜层、致密层、纤维母细胞层构成的生物结缔组织膜的上皮层及纤维母细胞层等细胞质层，成为保存了基质结构的实质上由致密层构成的无细胞质的膜材料。
2.权利要求1中记载的作为医用材料的原料膜材的制造方法，其特征在于用通式为〔C6H5CH2N(CH3)2R〕’Cl、(R代表从C8H17-C18H37中选出的烷基)的季胺盐水溶液使生物结缔组织膜带正电、变性后，在PH近中性的条件下，以分子量约26,000、等电点为9的一种糖蛋白酶巯基蛋白酶(thiolprotease)进行反应处理，然后进行超声波洗涤处理。
Applications Claiming Priority (2)
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| JP305261/95 | 1995-10-31 | ||
| JP7305261A JPH09122225A (ja) | 1995-10-31 | 1995-10-31 | 医用材料の原料膜材およびその製造方法 |
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| EP (1) | EP0773033A1 (zh) |
| JP (1) | JPH09122225A (zh) |
| CN (1) | CN1149497A (zh) |
| CA (1) | CA2173547C (zh) |
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- 1996-05-08 CN CN96106210A patent/CN1149497A/zh active Pending
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1997
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| CN105551614A (zh) * | 2016-01-21 | 2016-05-04 | 安徽德源电缆集团有限公司 | 一种工业用抗干扰防潮电缆 |
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| Publication number | Publication date |
|---|---|
| US5916266A (en) | 1999-06-29 |
| CA2173547A1 (en) | 1997-05-01 |
| JPH09122225A (ja) | 1997-05-13 |
| CA2173547C (en) | 2000-10-17 |
| EP0773033A1 (en) | 1997-05-14 |
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