CN108837184A - 一种用于引导骨再生的复合膜及其制备方法 - Google Patents
一种用于引导骨再生的复合膜及其制备方法 Download PDFInfo
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- CN108837184A CN108837184A CN201810446632.9A CN201810446632A CN108837184A CN 108837184 A CN108837184 A CN 108837184A CN 201810446632 A CN201810446632 A CN 201810446632A CN 108837184 A CN108837184 A CN 108837184A
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Abstract
本发明公开一种用于引导骨再生的复合膜及其制备方法。该复合膜的制备方法包括以下操作步骤：猪空肠经机械方法处理得到小肠粘膜下层，经酸、去污剂和碱处理等过程后多层横纵叠加得到致密层，将制备的胶原溶液均匀涂覆在致密层复合后经真空冷冻干燥得到复合膜。用该方法制备的复合膜具有优异的生物相容性和生物活性，易被组织吸收，结构中的致密层可以选择性阻止软组织向骨缺损区域，疏松层为疏松多孔结构，可以结合生物活性因子或药物，支持新组织再生，促进伤口愈合。该复合膜的结合，使其获得优异的机械性能，能在一定时间保持再生空间的稳定。
Description
技术领域
本发明涉及生物医用材料领域的引导骨再生膜及其制备方法。更具体而言，该引导骨再生膜属于天然复合膜，用于骨组织和牙周组织的修复。
背景技术
引导骨组织再生术是目前临床上对组织缺损修复的最佳选择，其原理是通过再生膜的物理屏障等作用，阻止软组织进入骨生长区，为骨缺损区域的新骨生长预留再生空间，并引导成骨类细胞在骨缺损区生长成新骨，从而达到骨性愈合的目的。
早期用于引导骨再生的第1代再生膜材料是以聚四氟乙烯（e-PTFE）为代表的不可降解材料，该类材料易操作且生物相容性好，临床效果佳。但是由于不能被组织吸收，放置4~6周后需要二次手术取出，增加了创伤的机会，再次手术可能对牙周组织造成损伤，且对新附着产生破坏作用。
生物可降解材料是目前引导骨再生膜研究较多的一类材料。由于该类材料生物相容性好，分解代谢产物无毒，易于成型和加工，有一定的强度以维持组织增生所需的空间，在组织再生后，材料完全降解或被组织吸收，是一类具有理想前景的材料。生物可降解材料分为人工合成高分子材料和天然高分子材料。其中以聚乳酸类等代表的人工合成高分子材料，具有优异的力学性能和生物相容性，中国专利申请号201010105573.2和201310586143.0均以聚乳酸类材料制备引导组织再生膜。但由于聚乳酸水解酯键断裂后使羧基显露增加导致局部pH值下降，易导致患者出现无菌性炎症反应。以胶原为代表的天然高分子再生膜具有抗原性低、生物相容性好，且有凝血作用，可参与组织愈合过程，降解速率可根据需要调节等优点，是目前国内外使用最多的引导组织再生膜，如国内已经上市的Bio-Gide胶原膜、海奥口腔修复膜、博特医用胶原膜等。但目前临床广泛应用的单纯的来自猪胶原、牛皮或牛腱的胶原作为引导组织再生膜，均存在以下缺陷：一是体内降解时间短；二是相对于再生膜的要求，胶原膜的抗张力较小，在应用过程中容易发生塌陷而失去空间维持能力；三是胶原膜容易导致局部慢性炎症反应。之前的研究表明，暴露在口腔内的胶原膜（Bio-Gide胶原膜和海奥口腔修复膜）会加速降解，增加感染的风险。（白彭，叶平，吴润发，戴勇中.两种胶原膜暴露于口腔环境中降解作用的对照研究.中国口腔种植学杂志，2011,16(01):56-57.）在胶原膜的制备过程中可以通过不同的交联技术及加工工艺降低胶原的抗原性，提高生物相容性并调节其降解速度，增加其机械强度。博特医用胶原修复膜就为醛类交联加工制成的白色片状多孔薄膜。中国专利CN201710126662.7和CN201710124188.4均采用戊二醛为交联剂以到达提高机械性能和降低降解速度的效果，但交联剂的引入，特别是醛类交联剂的引入，会对人体产生潜在的毒副作用，长远来看，找到一种无需添加交联剂且能满足临床需求的引导组织再生膜势在必行。
另外，目前报道的引导组织再生膜大多设计成双层膜或多层膜的形式，但是容易出现分层和撕裂问题。为了避免多层膜粘结不紧密，需要机械压合等复杂工序，而影响了再生膜的微观结果和修复效果。同时多层复合膜间机械强度不均一，多层复合的结构使得植入后有异物感，而临床应用效果不好。中国专利申请号CN201710126698.5所述的一种骨膜制备方法，虽然均能克服上述缺点，但其繁琐的制备工艺，很不利于今后的实际生产。
因此，临床上急需一种生物相容性好、可诱导组织再生，机械强度好的可降解引导骨组织再生膜，而且该种膜的生产方式应适合产业化生产。
发明内容
本发明的目的在于克服现有技术的不足，提供一种生物相容性和机械强度好、能在体内降解，同时能引导组织再生的生物活性再生膜及其制备方法。该再生膜是天然材料复合引导再生膜，其致密层可以阻止不需要的软组织长入缺陷区，疏松层为疏松多孔结构，可以结合生物活性因子或药物，支持新组织再生，促进伤口愈合。该复合膜的结合，使其获得优异的机械性能，能在一定时间保持再生空间的稳定。
上述一种用于引导骨再生的复合膜及其制备方法，具体步骤如下：
（1）致密层猪小肠粘膜下层的制备
将猪空肠清洗干净，用机械方法刮除去除粘膜层、肌层、浆膜层等组织，得到小肠粘膜下层，剖开管状的粘膜下层，用纯化水清洗至无污物；
将小肠粘膜下层置于体积浓度为0.5~5%的盐酸或过氧乙酸溶液中浸泡1~2小时进行消毒，然后用纯化水清洗2~3次；
将小肠粘膜下层置于去污剂溶液中，控温超声 15-40min，然后用纯化水清洗 3 次。其中去污剂可以是含有曲拉通100/200、脱氧胆酸钠或十二烷基硫酸钠的任一种或几种的混合溶液，浓度为0.01%~0.1%（w/v）；
将小肠粘膜下层浸泡于碱溶液中，2~8℃下浸泡10~30 min进行脱细胞处理，然后再用等量纯化水处理2~3小时，如此循环1~3次，直至纯化水溶液pH至7.0-7.4。所述碱溶液为氢氧化钠、氢氧化钾或氢氧化钙水溶液，溶液浓度为0.01~0.1M。经过碱溶液处理，脱细胞更彻底，而且多次循环处理可以降低DNA残留；
将脱细胞处理后的单层猪小肠粘膜下层铺展开，按照横向和纵向交替的方式叠加2~10层，铺于冻干模具上。
（2）胶原溶液的制备
用有机酸溶解胶原，形成胶原溶液；胶原溶液的质量体积比浓度范围为0.05~8%，粘度系数为1000~4000cp。搅拌溶解好的胶原溶液，静置脱泡处理；
可选择地，在胶原溶液中加入药物的浓度的0.1~20 mg/mL；
可选择地，在胶原溶液中加入生长因子的含量为2~10 μg/mL。
（3）复合膜的制备
将（1）得到的致密层置于模具中，将（2）制备好的胶原溶液均匀涂敷在致密层上，然后真空冷冻干燥后脱模即可。
其中，步骤（3）所述的均匀涂覆，可以采用真空旋转涂膜技术，通过转速和时间来控制胶原层的厚度。
其中，步骤（3）采用真空冷冻干燥，可以是-20℃~-80℃下预冻8~24h后，转移至冷冻干燥机中冻干，干燥条件可以是-50℃~-60℃下干燥24~48h。
与现有技术相比，本发明具有以下显著优点和有益效果：
1．本发明选用天然可降解材料制备引导骨再生膜，具有优异的生物相容性和生物活性，且易被组织吸收，不需二次取出；
2．本发明在再生膜的结构上，采用复合膜结构，致密层为猪小肠粘膜下层，可以选择性阻止软组织向骨缺损区域生长；疏松层为I型胶原，疏松多孔的结构有利于新骨的再生；制备方法为胶原溶液涂覆在多层猪小肠粘膜下层上，冷冻干燥后，二者具有优异的结合强度和机械强度，同时该复合膜具有较好的贴附性和柔韧性，不易撕裂破碎，利于手术操作；
3．本发明的引导组织再生膜制备方法简单，易于控制，易于生产，同时可添加不同药物或生长因子获得更好地骨组织再生效果。
附图说明
图1为本发明猪小肠粘膜下层的扫描电子显微镜照片。
图2为本发明胶原层的扫描电子显微镜照片。
图3为动物实验Micro CT的扫描结果。
图4为动物实验缺损区骨再生情况用骨体积分数（BV/TV）表示。
图5为本发明复合再生膜的抗菌效果图
具体实施方式
下面通过具体实施例对本发明的技术方案做进一步说明，但这些具体实施方案不以任何方式限制本发明的保护范围。
实施例1：
一种用于骨组织再生的复合再生膜，按下述方法制备：
（1）致密层猪小肠粘膜下层的制备
将猪空肠清洗干净，用机械方法刮除去除粘膜层、肌层、浆膜层等组织，得到小肠粘膜下层，剖开管状的粘膜下层，用纯化水清洗至无污物；
将小肠粘膜下层置于体积浓度为2%的过氧乙酸溶液中浸泡1.5小时进行消毒，然后用纯化水清洗3次；
将小肠粘膜下层置于0.05%(w/v)的十二烷基硫酸钠溶液中，控温超声20min，然后用纯化水清洗3次；
将小肠粘膜下层浸泡于0.05M的氢氧化钠溶液中，4℃下浸泡30 min进行脱细胞处理，然后再用等量纯化水处理3小时，如此循环2次，直至纯化水溶液pH至7.0-7.4；
将脱细胞处理后的单层猪小肠粘膜下层铺展开，按照横向和纵向交替的方式叠加6层，铺于冻干模具上；
（2）胶原溶液的制备
用醋酸溶解胶原，形成胶原溶液，粘度系数为1800 cp。在胶原溶液中加入骨形态发生蛋白生长因子，含量为5.0 μg/mL，混合均匀后静置脱泡；
（3）复合膜的制备
将（1）获得的致密层裁剪成长方形模具大小，置于模具中，将（2）制备好的胶原溶液均匀涂敷在致密层上，在-40℃下预冻8 h后，转移至冷冻干燥机中-50℃下干燥48h。脱模即可获得引导骨组织再生的复合再生膜；
（4）冻干胶原的制备
将（2）制备的溶液，在-40℃下预冻8 h后，转移至冷冻干燥机中-50℃下干燥48h。脱模即可获得含骨形态发生蛋白生长因子的冻干胶原；
（5）动物实验
方法：采用（1）获得的致密补片层、（4）获得的冻干胶原及（3）获得的复合膜分别用于Beagle犬下颌骨缺损区覆盖口腔的修复研究；
植入3个月后，Micro CT 扫描结果见附图3，缺损区骨再生情况用骨体积分数（BV/TV）表示见附图4，结果显示，复合膜的复合修复效果远比单一的致密补片层或冻干胶原层好很多。
实施例2：用于牙周组织再生的复合再生膜
（1）致密层猪小肠粘膜下层的制备
将猪空肠清洗干净，用机械方法刮除去除粘膜层、肌层、浆膜层等组织，得到小肠粘膜下层，剖开管状的粘膜下层，用纯化水清洗至无污物；
将小肠粘膜下层置于体积浓度为1.5%的盐酸溶液中浸泡1小时进行消毒，然后用纯化水清洗3次；
将小肠粘膜下层置于0.08%(w/v)的脱氧胆酸钠溶液中，控温超声30min，然后用纯化水清洗3次；
将小肠粘膜下层浸泡于0.05M的氢氧化钠溶液中，4℃下浸泡20 min进行脱细胞处理，然后再用等量纯化水处理3小时，如此循环3次，直至纯化水溶液pH至7.0-7.4；
将脱细胞处理后的单层猪小肠粘膜下层铺展开，按照横向和纵向交替的方式叠加4层，经干燥后获得骨引导再生膜的致密层；
（2）胶原溶液的制备
用醋酸溶解胶原，形成0.5%质量体积比的胶原溶液。在胶原溶液中加入甲硝唑，浓度为1.0 mg/mL，混合均匀后静置脱泡；
（3）复合膜的制备
将（1）获得的致密层裁剪成长方形模具大小，置于模具中，将（2）制备好的胶原溶液均匀涂敷在致密层上，在-20℃下预冻20 h后，转移至冷冻干燥机中-54℃下干燥24h。脱模即可获得引导牙周组织再生的复合再生膜。
将上述获得的含有甲硝唑的复合再生膜，采用牙周炎主要病原菌—牙龈卟啉单细胞菌进行体外抗菌活性实验，结果可验证复合再生膜的抗菌效果，见附图5。其中图5（左）显示的为生长的牙龈卟啉单细胞菌菌落，（中）显示的为被杀灭的牙龈卟啉单细胞菌，（右）显示的是所有的牙龈卟啉单细胞菌。由此可以看出，本发明的含甲硝唑的复合再生膜，可以保持甲硝唑的药效，达到明显抑制牙龈卟啉单细胞菌生长的作用。
本发明的上述实施例是对本发明的说明而不能用于限制本发明，与本发明的权利要求书相当的含义和范围内的任何改变，都应认为是包括在权利要求书的范围内。
Claims (7)
1.一种用于引导骨再生的复合膜，其特征在于：包括致密层和疏松层，所述的致密层由猪小肠粘膜下层构成，疏松层由胶原膜构成。
2.根据权利要求1所述的复合膜，其特征在于：所述的致密层为猪小肠粘膜下层通过多层横纵方向交替叠加而成，致密层均匀分布着互相贯穿的孔，孔径＜30μm，其中横向是与猪小肠肠道垂直的方向，纵向是与猪小肠肠道平行的方向，横向、纵向交替叠加2~10层，厚度100~600μm。
3.根据权利要求1所述的复合膜，其特征在于：所述疏松层是胶原溶液真空冷冻干燥形成，厚度300~500μm，其中胶原为I型胶原。
4.根据权利要求1或3所述的复合膜，其特征在于：所述疏松层中可添加药物和/或生物活性因子，药物可以为紫杉醇、阿霉素、庆大霉素、乙酰螺旋霉素、阿莫西林、甲硝唑、四环素、阿奇霉素、青霉素等中的一种或多种组合，生长因子可以为骨形态发生蛋白、血小板衍生生长因子、成纤细胞生长因子的一种或几种。
5.根据权利要求1所述的一种用于引导骨再生的复合膜制备方法，其特征在于包括以下步骤：
（1）致密层猪小肠粘膜下层的制备
将猪空肠清洗干净，用机械方法刮除去除粘膜层、肌层、浆膜层等组织，得到小肠粘膜下层，剖开管状的粘膜下层，用纯化水清洗至无污物；
将小肠粘膜下层置于体积浓度为0.5~5%的盐酸或过氧乙酸溶液中浸泡1~2小时进行消毒，然后用纯化水清洗2~3次；
将小肠粘膜下层置于去污剂溶液中，控温超声 15-40min，然后用纯化水清洗 3 次；其中去污剂可以是含有曲拉通100/200、脱氧胆酸钠或十二烷基硫酸钠的任一种或几种的混合溶液，浓度为0.01%~0.1%（w/v）；
将小肠粘膜下层浸泡于碱溶液中，2~8℃下浸泡10~30 min进行脱细胞处理，然后再用等量纯化水处理2~3小时，如此循环1~3次，直至纯化水溶液pH至7.0-7.4；
所述碱溶液为氢氧化钠、氢氧化钾或氢氧化钙水溶液，溶液浓度为0.01~0.1M；
经过碱溶液处理，脱细胞更彻底，而且多次循环处理可以降低DNA残留；
将脱细胞处理后的单层猪小肠粘膜下层铺展开，按照横向和纵向交替的方式叠加2~10层，铺于冻干模具上；
（2）胶原溶液的制备
用有机酸溶解胶原，形成胶原溶液；胶原溶液的质量体积比浓度范围为0.05~8%，粘度系数为1000~4000cp；搅拌溶解好的胶原溶液，静置脱泡处理；
可选择地，在胶原溶液中加入药物的浓度为0.1~20 mg/mL；
可选择地，在胶原溶液中加入生长因子的含量为2~10 μg/mL；
（3）复合膜的制备
步骤（1）得到的致密层置于模具中后，将步骤（2）制备好的胶原溶液均匀涂敷在致密层上，然后真空冷冻干燥后脱模即可。
6.根据权利要求5所述的复合膜制备方法，其特征在于：所述步骤（3）中所述的均匀涂覆可以采用真空旋转涂膜技术，通过转速和时间来控制胶原层的厚度。
7.根据权利要求5所述的复合膜制备方法，其特征在于：所述步骤（3）中采用真空冷冻干燥，可以是-20℃~-80℃下预冻8~24h后，转移至冷冻干燥机中冻干，干燥条件可以是-50℃~-60℃下干燥24~48h。
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| CN113425904A (zh) * | 2020-03-23 | 2021-09-24 | 成都中科奥格生物科技有限公司 | 一种口腔补片材料及其制备方法和用途 |
| CN115006597A (zh) * | 2022-06-02 | 2022-09-06 | 上海威高医疗技术发展有限公司 | 一种口腔修复膜及其制备方法 |
| CN115429939A (zh) * | 2022-09-23 | 2022-12-06 | 博纳格科技(天津)有限公司 | 一种产品性能可控的口腔生物膜的制备方法 |
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