CN101332314A - 生物型关节软骨修补件 - Google Patents

生物型关节软骨修补件 Download PDF

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CN101332314A
CN101332314A CNA2008100296537A CN200810029653A CN101332314A CN 101332314 A CN101332314 A CN 101332314A CN A2008100296537 A CNA2008100296537 A CN A2008100296537A CN 200810029653 A CN200810029653 A CN 200810029653A CN 101332314 A CN101332314 A CN 101332314A
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biotype
articular cartilage
cartilage repair
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CN101332314B (zh
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徐国风
徐斌
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Guan Hao biotech inc
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ZHIGUANG BIOLOGICAL SCI-TECH Co Ltd GUANGZHOU
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Abstract

本发明公开了一种生物型关节软骨修补件，它是以动物的关节软骨为基材，按如下步骤制成：(1)预处理；(2)裁取带骨座的软骨；(3)脱细胞处理；(4)环氧交联固定处理；(5)除抗原处理；(6)组织诱导处理；(7)清洗；(8)灭菌灭病毒。本发明的生物型关节软骨修补件的组织相容性好，植入后不引起排斥，可诱导软骨及骨组织再生，对软骨的损伤实现再生性修复。

Description

生物型关节软骨修补件
技术领域
本发明涉及医用植入器械领域，具体地说，涉及一种关节软骨修补件。
背景技术
关节软骨病变和损伤是骨科常见病，会导致关节活动功能障碍，行走疼痛，严重影响工作和生活，至今未有理想的治疗方法。少数骨外科医生用自体骨～软骨栓(如取自体髌骨外侧骨～软骨栓)作移植治疗，有一定疗效。但供体部位常发生继发性病变，甚至得不偿失，而令人却步。也有学者用同种异体(尸体)骨～软骨移植进行治疗，但由于免疫排异问题未解决，疗效不稳定，再加上来源困难，伦理问题及病毒交叉感染等问题，较少被应用。异种骨～软骨制品用于关节软骨的修复，更是由于处理技术未过关，免疫排异、动物源性病毒杀灭等问题未解决，而未被应用。可以说，目前关节软骨损伤的修复，仍处于一种无合适材料可用的被动局面。
发明内容
本发明的目的是提供一种组织相容性好，植入后不引起排斥反应，可诱导软骨及骨组织再生，用于对关节软骨损伤进行再生性修复的生物型关节软骨修补件。
为了实现上述目的，本发明采用如下技术方案：
本发明的生物型关节软骨修补件是直接从猪、牛等动物关节为原料，按如下步骤制成：
(1)预处理；
(2)裁取带骨座的软骨；
(3)脱细胞处理；
(4)环氧交联固定处理；
(5)除抗原处理；
(6)组织诱导处理；
(7)清洗，封装；
(8)灭菌灭病毒。
上述生物型关节软骨修补件是由动物关节软骨层1和与它直接连接的骨座2组成。
在上述步骤中，步骤(1)所述预处理为采用广谱消毒剂浸泡消毒和去除杂质。一般选择0.1％新洁尔灭溶液浸泡消毒。
在上述步骤中，步骤(3)所述的脱细胞处理是用酶将细胞壁酶解或用表面活性剂破坏细胞壁并进行洗脱处理，以脱除其中的细胞，也可以两者兼用。酶解法所用的酶是胃蛋白酶或胰蛋白酶或两者的复合酶。表面活性剂优选曲拉通X100、吐温-20或OP-10。
在上述步骤中，步骤(4)所述的环氧交联固定处理是将环氧化物与软骨及骨中的骨胶原进行开环交联反应，使骨胶原保持稳定，不易变质和被微生物分解。所述环氧化物为
Figure A20081002965300051
R＝CnH2n+1-或者是
Figure A20081002965300052
n为0～12中的整数。反应温度在5℃～40℃之间选取，反应时间随所要求的稳定度而定，时间长稳定度高，不易降解，一般在8～96小时之间。
在上述步骤中，步骤(5)所述的除抗原处理是指用除抗原剂封闭引起免疫排异反应的特异基团和改变其引起免疫排异反应的特异构象。封闭特异基团所用的除抗原剂主要是一些易与-NH2，-OH，-SH等基团中的活泼氢起反应的亲核试剂，它们是酸酐、酰氯、酰胺、环氧化物等；改变特异构象的除抗原剂是胍类化合物(如盐酸胍)等强氢键形成剂。
在上述步骤中，步骤(6)所述的组织诱导处理是将可粘附、聚集生长因子及细胞的活性物质引入制品中，使植入后能征集机体自我修复机制释放并输送到植入部位的生长因子及干细胞，使长时间高效表达，促进软骨及座骨的再生性修复。所用的活性物质是多肽或糖胺聚糖。多肽主要是含16个赖氨酸及精-甘-天冬氨酸的一类多肽，如赖(16)-甘-精-甘-天冬-丝-脯-半胱多肽；糖胺聚糖主要是透明质酸、硫酸软骨素、硫酸皮质素、硫酸角质素、肝素、硫酸乙酰肝素一类粘多糖物质。引入方式可以是偶联、化学吸附、物理吸附和胶原膜包裹等；优选偶联方式，偶联剂可用羧二酸内酐，二酰二胺，二酰二氯，双环氧化物，碳化二亚胺等双官能团物质。
在上述步骤中，步骤(7)所述的灭菌灭病毒是指用中国药典及美国药典规定的≥25KGy的Co60-γ射线辐照灭菌法。该灭菌法已被证明能杀灭除朊病毒外的所有已知病菌病毒。当软骨材料来源于牛关节时，还要在环氧交联固定处理与除抗原处理之间插入一个NaOH处理步骤，即用1mol/LNaOH溶液在25℃～50℃温度下浸泡处理60分钟以上，以杀灭可能存在的朊病毒。
步骤(3)至(7)在我们自行设计的高渗透反应器中进行的；所述高渗透反应器是指反应容器上设有超声发生器和真空脉冲装置。通过超声振动和真空脉冲的联合作用，使试剂能深入骨及软骨微孔深处起反应，保证内外反应一致。
与现有技术相比，本发明具有如下有益效果：
本发明的生物型关节软骨修补件，可为关节软骨损伤的修复提供一种新型的适用材料。本发明的生物型关节软骨修补件以来源广泛的异种关节为原料，保留了软骨及其直接相连接的骨座的基本结构、组成及连接方式，包括具有众多活性组分的有机组成，并使有机组成具有足够的稳定性。本发明采用自主研发的环氧交联固定技术，多方位除抗原技术，粘附生长因子及细胞的组织诱导技术，再配以高渗透技术，对骨、软骨基质(骨胶原)进行科学处理制成，经此系列技术处理后的异种骨～软骨，被有效去除其免疫原性，生物相容性优异，植入后能粘附、富集机体自我修复机制释放并输送到损伤部位，用于促进骨～软骨再生性修复的生长因子及干细胞，如成纤维细胞生长因子(FGF)、转化生长因子β(TGF-β)、胰岛素样生长因子(IGF)、血小块衍生生长因子(PDGF)、骨形态发生蛋白(BMP)、骨髓间充质干细胞等，使在植入体中高效表达，诱导干细胞向成骨细胞和成软骨细胞分化和增殖，诱导软骨组织及骨组织有序地再生，最终实现再生性修复。也可以用人工外加BMP等生长因子及骨髓间充质干细胞的方法，加速其再生效果。
附图说明
图1是圆柱状生物型关节软骨修补件的结构示意图；
图2是方柱状生物型关节软骨修补件的结构示意图；
1为软骨层，2为直接与软骨层连结的骨座。
具体实施方式
实施例1
取新鲜健康猪膝关节，放入0.1质量％新洁尔灭溶液中浸泡消毒30分钟，取出，去除周围杂质，小心切断叉韧带暴露关节软骨，用专用工具裁取一定大小，圆柱状，带基底骨骨座的软骨件，放入高渗透脱细胞反应器中，加入酶解液酶解3小时，温度20℃。酶解液用胃蛋白酶-胰蛋白酶的复合酶，浓度为每升含酶量50mg。酶解完成后将酶洗脱并使其失活，放入高渗透固定反应器中，加入固定液，反应时间36小时。固定液为含环氧化物0.1mol/L的液体，环氧化物为
Figure A20081002965300081
R＝(CH3)3C-CH2-。固定完成后取出，中和环氧化物，洗净。放入高渗透除抗原反应器中，分别加入除抗原试剂，在20℃反应8小时，所用的除抗原试剂为异戊酸酐和盐酸胍，先后用这两种除抗原试剂进行反应，以充分去除抗原性。取出，洗净。放入高渗透组织诱导反应器中，加入可粘附生长因子和细胞的活性物质溶液及偶联剂溶液，使反应8小时，反应温度10℃。活性物质为赖(16)-甘-精-甘-天冬-丝-脯-半胱组成的多肽，偶联剂为戊二酸酐。反应完成后取出，洗净，封装，送辐照中心γ-射线(25KGy)灭菌灭病毒，即得成品。如图1所示。
实施例2
取新鲜健康牛膝关节，放入0.1质量％新洁尔灭溶液中浸泡消毒30分钟，取出，去除周围杂质，小心切断叉韧带暴露关节软骨，用专用工具裁取一定大小，方柱状，带基底骨的软骨件，放入高渗透脱细胞反应器中，加入酶解液酶解7小时，温度为40℃。酶解液用胃蛋白酶-胰蛋白酶的复合酶，浓度为每升含酶量150mg。酶解完成后将酶洗脱并使其失活，放入高渗固定反应器中，加入固定液，反应时间72小时。固定液为含环氧化物2.0mol/L的液体，环氧化物为
Figure A20081002965300091
R＝(CH3)3C-CH2-。固定完成后取出，中和环氧化物，洗净。用1mol/L NaOH溶液在30℃温度下浸泡处理70分钟。取出，用稀醋酸中和残余的NaOH，洗净，放入高渗透除抗原反应器中，分别加入除抗原试剂，在40℃下反应20小时，所用的除抗原试剂为异戊酰氯和盐酸胍。先后用两种除抗原试剂进行反应，以充分去除抗原性。取出，洗净。放入高渗透组织诱导反应器中，加入可粘附生长因子和细胞的活性物质溶液及偶联剂溶液，反应时间15小时，反应温度10℃。活性物质为赖(16)-甘-精-甘-天冬-丝-脯-半胱组成的多肽，偶联剂为异己二酸酐。反应完成后取出，洗净，封装，送辐照中心γ-射线(25KGy)灭菌灭病毒，即得成品。如图2所示。

Claims (10)

1.一种生物型关节软骨修补件，其特征在于它是以动物关节软骨
为基材，按如下步骤制成：
(1)预处理；
(2)裁取带骨座的软骨；
(3)脱细胞处理；
(4)环氧交联固定处理；
(5)除抗原处理；
(6)组织诱导处理；
(7)清洗；
(8)灭菌灭病毒。
2.根据权利要求1所述的生物型关节软骨修补件，其特征在于它是由软骨层(1)和与它直接连结的骨座(2)组成的柱状体。
3.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(1)所述预处理为采用广谱消毒剂浸泡消毒和去除杂质。
4.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(3)所述的脱细胞处理是用酶进行酶解或用表面活性剂进行洗脱处理。
5.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(4)所述的环氧交联固定处理是将环氧化物与其中的骨胶原进行开环交联反应，所述环氧化物为
Figure A2008100296530002C1
R＝CnH2n+1-或者是
Figure A2008100296530003C1
n为0～12中的整数。
6.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(5)所述的除抗原处理是采用除抗原剂进行处理，所述除抗原剂为羧酸酐、酰氯、酰胺、环氧化物及胍类化合物。
7.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(6)所述的组织诱导处理是将活性物质引入制品中；所述活性物质为多肽或糖胺聚糖；引入方式为采用偶联剂偶联、化学吸附、物理吸附或胶原膜包裹。
8.根据权利要求7所述的生物型关节软骨修补件，其特征在于所述多肽为赖(16)-甘-精-甘-天冬-丝-脯-半胱构成的多肽；所述糖胺聚糖为透明质酸、硫酸软骨素、硫酸皮质素、硫酸角质素、肝素或硫酸乙酰肝素；所述偶联剂为羧二酸内酐、二酰二胺、二酰二氯、双环氧化物或碳化二亚胺。
9.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(7)所述的灭菌灭病毒是用≥25KGy的Co60-γ射线辐照灭菌。
10.根据权利要求1所述的生物型关节软骨修补件，其特征在于步骤(3)至(7)是在高渗透反应器中进行的；所述高渗透反应器是指反应容器上设有超声发生器和真空脉冲装置。
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