CN105311681A - 一种可注射的骨修复用复合材料及其制备方法 - Google Patents
一种可注射的骨修复用复合材料及其制备方法 Download PDFInfo
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- CN105311681A CN105311681A CN201510891068.8A CN201510891068A CN105311681A CN 105311681 A CN105311681 A CN 105311681A CN 201510891068 A CN201510891068 A CN 201510891068A CN 105311681 A CN105311681 A CN 105311681A
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Abstract
本发明涉及一种可注射的骨修复用复合材料，该复合材料以生物组织材料和生物陶瓷有机结合，形成一种具有三维支架功能的可注射用医学材料。本发明所涉及的生物组织材料基质为天然交联结构的微纤维，无需额外涉及物理或化学交联，生物相容性优良，并且可以在体内被缓慢完全降解。生物组织材料和生物陶瓷可以用多种方式结合。该复合材料中，作为增强相的生物陶瓷与生物组织材料结合后，可以为体内骨组织再生提供良好的模板，能有效地诱导骨生长。本发明制备的可注射材料，可以用以无缝填充任何尺寸的骨缺损，并在过程中添加包括骨髓在内的生物制剂，进一步增强其生物活性。因此，该材料可广泛用于由于创伤，肿瘤切除，骨坏死及感染等造成的骨缺失。
Description
技术领域
本发明属于材料科学领域，具体涉及一种可注射的骨修复用复合材料及其制备方法，该复合材料可广泛应用于骨科及整形科领域。
背景技术
受损骨组织修复与重建在世界范围内是整形外科医生需要面对的重要任务，而修复受损的骨组织就需要用到骨移植材料。在世界范围内修复受损骨组织使用的黄金标准为人的自体骨组织，即取自病人自身的健康骨组织。自体骨具有修复骨组织需要的全部特性，比如优异的骨诱导性，骨传导性，成骨性以及安全性。但是，使用自体骨在临床上具有不可避免的缺陷。由于使用自体骨需要从病人身体的供体部位获得骨组织，这额外的手术便增加了手术的时间，费用，以及病人恢复的时间。同时，供体部位的病变及供体部位提供骨组织的有限性都是目前面临的突出问题。
组织器官基质是由各种复杂的结构蛋白质和功能蛋白质构成的三维立体框架，并含有许多有活性的其他复合物。主要成分包括胶原纤维、糖蛋白、黏蛋白等，其他成分有氨基葡聚糖(透明质酸、硫酸软骨素)等糖类、一些脂质和生长因子，可以为细胞黏附提供优异的基底，并且在其降解过程中，会释放大量活性多肽，能够促进细胞***及分化。
生物活性组织基质作为一种理想的生物材料，具备几乎一切组织工程及再生医学材料所需的特质，因而已被广泛用于各类组织和器官的修复和再生。目前，从各类组织如小肠，皮肤，肝脏，脾脏，膀胱等提取的生物活性基质，由于其各自不同的宏观微观结构，生物力学性能，体内降解速率，以及细胞-基质相互作用，被用于不同组织的修复与再生。基本上市场上所有的生物基质产品都是以生物膜的方式存在，大致分为干燥和含水两类。他们的应用主要集中在皮肤溃疡，腹腔膜重建，软组织再生，伤口愈合和脑膜创伤修复。
磷酸钙基生物陶瓷，由于和人体骨组织的无机成分相似，具备优异的生物相容性，生物降解性，和骨传导性能，被长期用于骨修复材料的制备和改性。目前常见的磷酸钙生物陶瓷包括羟基磷灰石，β相磷酸三钙，磷酸氢钙及它们的复合物相陶瓷。大量研究表明磷酸钙生物陶瓷能够吸附/富集骨形成所需的蛋白及，促进成骨细胞增殖和分化，从而诱导新骨的生成。近期研究表明，磷酸钙生物陶瓷降解过程中所释放的钙离子和磷酸根离子，能够积极地影响骨环境中的成骨及破骨细胞，在骨修复及再生过程中扮演重要的角色，因此调控生物陶瓷降解速率也成为一种调控其生物活性的新的途径，具有重大的潜力。
目前市面上几乎所有涉及生物制剂的骨修复材料都使用化学提纯的I型胶原蛋白。这一类胶原蛋白的缺点在于提取过程复杂，蛋白在提取过程中变性，无法发挥其最佳生物学性能；此外，其成分相对单一，无法满足骨修复过程中的复杂的信号通路需求；使用过程中需要使用毒性较大的化学交联剂，易在植入过程中引起免疫及炎症反应。
发明内容
本发明的目的在于提供一种可注射的骨修复用复合材料及其制备方法，这种新的复合材料是以这两种材料为主要成分的，既吸取天然生物基质具有生物活性且能有效调节细胞行为等多方面的优点，又兼备生物陶瓷等无机材料在骨修复过程中的优异成骨能力，具有高度骨诱导性及成骨性的活性生物支架，因此能够通过多重生物学机理快速在骨缺损处诱导新骨生成。同时，本发明所涉及的材料还规避了大量现存骨修复存在的影响其临床疗效的缺点，因此提供了一种完备的骨缺损修复解决方案。
本发明的目的是通过以下技术方案来实现：
一种可注射的骨修复用复合材料，包括以下重量份数的原料：1-7份的生物组织基质材料、1-9份的生物陶瓷和2-8份的生理盐水或其他等渗水溶液。
优选地，所述生物组织基质材料为由哺乳动物软组织制备的、以胶原纤维为主的、保持其天然交联结构的细胞外基质。
优选地，所述哺乳动物的软组织为猪的软组织、牛的软组织或人体的软组织；所述软组织包括皮肤、真皮、血管、隔膜、肌腱、韧带、大肠、小肠和神经组织。
优选地，所述生物组织基质材料呈微纤维状，微纤维状的所述生物组织基质材料的直径为1-1500微米，微纤维状的所述生物组织基质材料的直径和长度的比值分布区间为0.05-0.95。
优选地，用生物玻璃、含锶、锌、镁、或者硅的矿物质或含锶、锌、镁、或者硅的盐代替所述生物陶瓷作为增强相所用材料。
优选地，所述生物陶瓷为羟基磷灰石[Ca5(PO4)3OH]、α-磷酸三钙、β-磷酸三钙[α-Ca3(PO4)2或β-Ca3(PO4)2]、磷酸氢钙[CaHPO4]、二水合磷酸氢钙[CaHPO4·2H2O]、磷酸二氢钙[Ca(H2PO4)2]、磷酸四钙[Ca4(PO4)2O]、磷酸八钙[Ca8H2(PO4)6·5H2O]、硫酸钙[CaSO4]或碳酸钙[CaCO3]。
优选地，所述生物陶瓷以颗粒形式分布于所述生物组织基质材料内，生物陶瓷颗粒在所述生物组织基质材料内形成三维的网状结构。
优选地，所述生物陶瓷颗粒的粒径为1-500微米。
所述的可注射的骨修复用复合材料的制备方法，包括以下步骤：
1)微纤维状的生物组织基质材料的制备，包括以下步骤：
1.1)收集组织原材料，清洗血污后，切割成宽为0.5-2厘米、长为4-8厘米的长条状，-20℃保存；
1.2)消毒灭菌：组织原材料使用质量浓度为0.1％氨水溶液灭菌，将组织原材料浸泡于溶液中缓慢摇动6-36小时；并用无菌去离子水充分清洗，然后用无菌生理盐水漂洗；
1.3)组织破碎：将消毒过的组织原材料用研磨器粉碎，打匀；
1.4)采用脱细胞液脱去细胞后，采用脱氧核糖核酸酶溶液脱去剩余脱氧核糖核酸；并采用α-半乳糖苷去除液脱去α-半乳糖苷；采用双氧水，乙酸和过氧乙酸的混合溶液进行病毒灭活；
1.5)组织基质清洗：用质量浓度为0.9％的生理盐水对步骤1.5)的产物清洗三遍以上，去除步骤1.4)处理产生的残余物；
1.6)清洗：将步骤1.5)的产物用无菌去离子水清洗三次以上；
1.7)终端灭菌：采用Co60伽玛射线、X射线或者电子束进行灭菌，将得到的生物组织基质微纤维密封于密闭容器内保存，生物组织基质材料保存于pH值中性的缓冲液内，所述缓冲液包括生理盐水和磷酸缓冲液；
2)生物陶瓷微颗粒的制备，包括以下步骤：
2.1)生物陶瓷根据具体应用，经机械粉碎，高速球磨，以及过筛步骤后，得到粒径在0.1-500微米范围的生物陶瓷颗粒，再经高温高压消毒，除菌及杀灭病毒；
2.2)将生物陶瓷微颗粒与无菌生理盐水以1:1到1：5的比例混合，并经充分搅拌及震荡，形成均匀的悬浊液；
3)将步骤1.7)得到的生物组织基质微纤维悬浊在1-5倍重量的生理盐水中，充分摇匀，形成均匀的生物组织基质微纤维悬浊液；
4)本发明所述的原料配比，将生物陶瓷颗粒与生物组织基质微纤维混合；
5)将混合物置于涡旋混合器上充分混合一个小时，直至生物陶瓷颗粒完全吸附于生物组织基质微纤维上；
6)用离心法以200～10000rpm转速去除多余水分，并使混合物以固态方式沉积于底部；
7)加入1-5倍混合物重量的生理盐水，置于涡旋混合器上形成均匀的流体状混合物，其中水分含量的质量百分比为20-80％；
8)终端灭菌：将得到的流体状混合物密封于密闭容器内保存，用伽玛射线、X射线或者电子束进行灭菌。
优选地，所述步骤1.1)所选用的组织原材料来源于哺乳动物的软组织，其包括皮肤、小肠、大肠、隔膜、膀胱、胃和肌腱。
优选地，所述步骤1.4)所述脱细胞溶液为每升含1-10％脱氧胆酸钠、2-15mM乙二胺四乙酸以及10-50mM4-羟乙基哌嗪乙磺酸，所述脱细胞溶液pH值为6.8-7.2；所述脱氧核糖核酸酶溶液每升含0.5-5毫克脱氧核糖核酸酶、10-50mM4-羟乙基哌嗪乙磺酸、1-20mM氯化钙以及1-20mM氯化镁；所述α-半乳糖苷去除液为每升含0.2-10毫克α-半乳糖苷酶、2-40mM4-羟乙基哌嗪乙磺酸，所述α-半乳糖苷去除液pH值为5.0-7.5；所述用病毒灭活的溶液为浓度为0.10％双氧水、0.50％乙酸和0.50％过氧乙酸的混合溶液。
进一步地，用于分散生物陶瓷颗粒和生物组织基质材料的溶液用血液、骨髓或高浓度血小板血浆替代所述步骤7)中的生理盐水。
进一步地，一种向骨缺损处输送干细胞的方法，将骨髓间充质干细胞、脂肪干细胞或者提取自血液的干细胞形成细胞悬液，再与本发明所获得的骨修复用复合材料混合，作为一种向骨缺损处输送干细胞的方式。
本发明的有益效果为：本发明涉及一种基于生物组织材料和生物陶瓷的可注射用的生物复合材料及其制备方法。该复合材料以生物组织材料和生物陶瓷有机结合，形成一种具有三维支架功能的可注射用医学材料。本发明所涉及的生物组织材料基质为天然交联结构的微纤维，无需额外涉及物理或化学交联，生物相容性优良，并且可以在体内被缓慢完全降解。生物组织材料和生物陶瓷可以用多种方式结合。本发明的复合材料中，作为增强相的生物陶瓷与生物组织材料结合后，可以为体内骨组织再生提供良好的模板，能有效地诱导骨生长。本发明制备的可注射材料，可以用以无缝填充任何尺寸的骨缺损，并在过程中添加包括骨髓在内的生物制剂，进一步增强其生物活性。因此，该材料可广泛用于由于创伤，肿瘤切除，骨坏死及感染等造成的骨缺失。
附图说明
图1为生物组织微纤维的差示扫描量热图谱；
图2为生物组织基质/磷酸氢钙复合材料的可注射性展示；
图3为生物组织基质/磷酸氢钙复合材料的扫描电镜照片：
A.复合材料典型形貌；
B&C.磷酸氢钙微颗粒的分布；
D.微纤维内的胶原蛋白三螺旋结构；
图4为生物组织基质/磷酸氢钙复合材料的头盖骨缺损修复的植入实验：
A.修复后的小鼠头盖骨形貌；
B.修复后小鼠头盖骨的X射线观察；
C.骨缺损处组织染色；
图5为生物组织基质/磷酸氢钙复合材料与新鲜骨髓复合后修复小鼠头盖骨的植入修复实验：
A.修复后小鼠头盖骨的X射线观察；
B.修复后小鼠头盖骨的微型CT扫描图谱；
C.微型CT扫描的定量分析
图6为生物组织基质/磷酸氢钙复合材料与新鲜骨髓复合后修复小鼠头盖骨修复后的组织学观察：
A.Von-Kassa染色(骨钙沉积)；
B.MASSON三色染色法；
C.苏木精—伊红染色法。
具体实施方式
下面通过实施例对本发明作进一步的详细说明，旨在用于说明本发明而非限定本发明。
实施例1：生物组织基质/磷酸氢钙复合材料的制备及表征
1)取经过Co60伽马射线灭菌的猪皮脱细胞去抗原后的微纤维状生物组织基质材料，以10毫克/毫升的浓度悬浮于0.9％生理盐水中；
2)用无菌去离子水清洗三次以上，所制备的脱细胞基质微纤维参数如图1所示，其平均长宽比为0.05-0.95，其粒径分布为40-1000微米；
3)取磷酸氢钙微颗粒，加入无菌去离子水，制备成10毫克/毫升的均匀悬浊液
4)将磷酸氢钙微颗粒迅速通过粒径40微米的滤膜，除去其中过大的团聚颗粒；
5)将悬浊液在1200rpm离心2分钟，去除上清液；
6)在1g磷酸氢钙微颗粒内加入0.5毫升无菌去离子水，反复漩涡震荡及搅拌，制备成糊状物；
7)以脱细胞微纤维基质与磷酸氢钙微颗粒的质量比为4：6的比例，将磷酸氢钙微颗粒加入脱细胞微纤维基质内；
8)置于涡旋混合器上充分混合一个小时，使二者混合均匀；
9)在1200rpm下离心2分钟，去除上清液；
10)在4重量份脱细胞基质微纤维及6重量份磷酸氢钙微颗粒内，加入2重量份的无菌生理盐水；
11)充分搅拌后，获得可注射的复合材料，如图2所示，可以用标准注射器将该材料应用于患者伤处；
12)复合材料以糊状物形态保存，其微观结构如图3所示，扫描电镜照片表明磷酸氢钙微颗粒非常均匀地分布于脱细胞基质微纤维的周围，没有发生明显团聚；其外，高放大倍数照片显示，脱细胞基质由大量胶原蛋白纤维构成，并且胶原蛋白完整保持了其天然的三螺旋结构，并且成束状分布于复合材料内。
实施例2：生物组织基质/磷酸氢钙复合可注射材料的骨缺损修复实验
用此发明所制备的可注射的生物组织基质/磷酸氢钙复合材料，以无胸腺裸鼠的头骨缺损模型来评估该材料的骨缺损修复能力。小鼠(6例)麻醉后，剃去头部皮毛，在头顶开一个1厘米的口子，拨开皮肤后，用牙科钻头在头盖骨上打一个直径3.5毫米的原型缺损；用本发明制备的材料将骨缺损填充满后，将伤口缝合；六周后，人道牺牲小鼠，肉眼观察修复后头盖骨发现，材料和周围骨组织复合良好，X射线观测表明在缺损处有大量骨组织形成；骨缺损的横切面用组织学切片观察，发现骨缺损处被细胞填满，并通过骨钙染色表明，有大量骨钙在缺损处沉积，骨缺损在很大程度上得到修复，见图4，本实施例是第一次实现仅通过生物材料，而不添加任何生物活性因子或干细胞的大面积骨缺损修复。
实施例3：生物组织基质/磷酸氢钙复合可注射材料作为新鲜骨髓载体的骨缺损修复实验
将实例1制备的可注射的生物组织基质/磷酸氢钙复合材料与新鲜提取的小鼠全骨髓混合，调制成糊状材料；使用实例2中所使用小鼠模型，将混合小鼠全骨髓的混合复合材料填充骨缺损，然后缝合伤口；六周后，X射线观测发现，整个原型骨缺损已被新形成的骨组织填满，没有在骨缺损边缘发现任何组织间隙。微型CT扫描图谱显示同样结果，整个骨缺损已被新形成的骨组织填充，并在新骨和自体骨之间形成无缝连接。骨形成定量分析表明，实施例1制备的材料可以形成远远多于Healos产品的骨量，并且其骨密度更接近于自体骨组织(图5)。组织学观察表明，整个骨缺损已被钙化的骨组织所连接，大量骨小梁已经形成；Masson三色染色说明大量胶原蛋白沉积于骨缺损处，并发现有成骨细胞在新骨表明，参与新骨形成。苏木精—伊红染色法的结果与前面两种染色得到的结论一致，并且没有在骨缺损周围发现有纤维组织形成，新骨和自体骨以之间为骨连接，使得本实例所展示的修复方法为一种可行的临床策略。
上述仅对本发明中的几种具体实施例加以说明，但并不能限定为本发明的保护范围，凡是依据本发明中的设计精神所作出的等效变化或修饰，均应认为落入本发明的保护范围。
Claims (10)
1.一种可注射的骨修复用复合材料，其特征在于，包括以下重量份数的原料：1-7份的生物组织基质材料、1-9份的生物陶瓷和2-8份的生理盐水或其他等渗水溶液。
2.根据权利要求1所述的可注射的骨修复用复合材料，其特征在于：所述生物组织基质材料为由哺乳动物软组织制备的、以胶原纤维为主的、保持其天然交联结构的细胞外基质。
3.根据权利要求1所述的可注射的骨修复用复合材料，其特征在于：所述哺乳动物的软组织为猪的软组织、牛的软组织或人体的软组织；所述软组织包括皮肤、真皮、血管、隔膜、肌腱、韧带、大肠、小肠和神经组织。
4.根据权利要求1所述的可注射的骨修复用复合材料，其特征在于：所述生物组织基质材料呈微纤维状，微纤维状的所述生物组织基质材料的直径为1-1500微米，微纤维状的所述生物组织基质材料的直径和长度的比值分布区间为0.05-0.95。
5.根据权利要求1所述的可注射的骨修复用复合材料，其特征在于：用生物玻璃、含锶、锌、镁、或者硅的矿物质或含锶、锌、镁、或者硅的盐代替所述生物陶瓷作为增强相所用材料；所述生物陶瓷为羟基磷灰石、α-磷酸三钙、β-磷酸三钙、磷酸氢钙、二水合磷酸氢钙、磷酸二氢钙、磷酸四钙、磷酸八钙、硫酸钙或碳酸钙。
6.根据权利要求5所述的可注射的骨修复用复合材料，其特征在于：所述生物陶瓷以颗粒形式分布于所述生物组织基质材料内，生物陶瓷颗粒在所述生物组织基质材料内形成三维的网状结构，其中陶瓷颗粒的粒径为1-500微米。
7.权利要求1-6任一项所述的可注射的骨修复用复合材料的制备方法，其特征在于，包括以下步骤：
1)微纤维状的生物组织基质材料的制备，包括以下步骤：
1.1)收集组织原材料，清洗血污后，切割成宽为0.5-2厘米、长为4-8厘米的长条状，-20℃保存；
1.2)消毒灭菌：组织原材料使用质量浓度为0.1％氨水溶液灭菌，将组织原材料浸泡于溶液中缓慢摇动6-36小时；并用无菌去离子水充分清洗，然后用无菌生理盐水漂洗；
1.3)组织破碎：将消毒过的组织原材料用研磨器粉碎，打匀；
1.4)采用脱细胞液脱去细胞后，采用脱氧核糖核酸酶溶液脱去剩余脱氧核糖核酸；并采用α-半乳糖苷去除液脱去α-半乳糖苷；采用双氧水，乙酸和过氧乙酸的混合溶液进行病毒灭活；
1.5)组织基质清洗：用质量浓度为0.9％的生理盐水对步骤1.5)的产物清洗三遍以上，去除步骤1.4)处理产生的残余物；
1.6)清洗：将步骤1.5)的产物用无菌去离子水清洗三次以上；
1.7)终端灭菌：采用Co60伽玛射线、X射线或者电子束进行灭菌，将得到的生物组织基质微纤维密封于密闭容器内保存，生物组织基质材料保存于pH值中性的缓冲液内，所述缓冲液包括生理盐水和磷酸缓冲液；
2)生物陶瓷微颗粒的制备，包括以下步骤：
2.1)生物陶瓷根据具体应用，经机械粉碎，高速球磨，以及过筛步骤后，得到粒径在0.1-500微米范围的生物陶瓷颗粒，再经高温高压消毒，除菌及杀灭病毒；
2.2)将生物陶瓷微颗粒与无菌生理盐水以1:1到1：5的比例混合，并经充分搅拌及震荡，形成均匀的悬浊液；
3)将步骤1.7)得到的生物组织基质微纤维悬浊在1-5倍重量的生理盐水中，充分摇匀，形成均匀的生物组织基质微纤维悬浊液；
4)按权利要求1所述的原料配比，将生物陶瓷颗粒与生物组织基质微纤维混合；
5)将混合物置于涡旋混合器上充分混合一个小时，直至生物陶瓷颗粒完全吸附于生物组织基质微纤维上；
6)用离心法以200～10000rpm转速去除多余水分，并使混合物以固态方式沉积于底部；
7)加入1-5倍混合物重量的生理盐水，置于涡旋混合器上形成均匀的流体状混合物，其中水分含量的质量百分比为20-80％；
8)终端灭菌：将得到的流体状混合物密封于密闭容器内保存，用伽玛射线、X射线或者电子束进行灭菌。
8.根据权利要求7所述的可注射的骨修复用复合材料的制备方法，其特征在于：所述步骤1.4)所述脱细胞溶液为每升含1-10％脱氧胆酸钠、2-15mM乙二胺四乙酸以及10-50mM4-羟乙基哌嗪乙磺酸，所述脱细胞溶液pH值为6.8-7.2；所述脱氧核糖核酸酶溶液每升含0.5-5毫克脱氧核糖核酸酶、10-50mM4-羟乙基哌嗪乙磺酸、1-20mM氯化钙以及1-20mM氯化镁；所述α-半乳糖苷去除液为每升含0.2-10毫克α-半乳糖苷酶、2-40mM4-羟乙基哌嗪乙磺酸，所述α-半乳糖苷去除液pH值为5.0-7.5；所述用病毒灭活的溶液为浓度为0.10％双氧水、0.50％乙酸和0.50％过氧乙酸的混合溶液。
9.根据权利要求7所述的可注射的骨修复用复合材料的制备方法，其特征在于：用于分散生物陶瓷颗粒和生物组织基质材料的溶液用血液、骨髓或高浓度血小板血浆替代所述步骤7)中的生理盐水。
10.一种向骨缺损处输送干细胞的方法，其特征在于：将骨髓间充质干细胞、脂肪干细胞或者提取自血液的干细胞形成细胞悬液，再与权利要求7-9任一项所获得的骨修复用复合材料混合，作为一种向骨缺损处输送干细胞的方式。
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| CN111166941A (zh) * | 2020-01-17 | 2020-05-19 | 上海贝奥路生物材料有限公司 | 组织缺陷修复剂及其制备方法和使用方法 |
| CN116492510B (zh) * | 2023-06-27 | 2023-09-19 | 圣至润合(北京)生物科技有限公司 | 一种基于脱细胞基质微球的组织填充修复材料及其制备方法 |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2017097105A1 (zh) | 2017-06-15 |
| CN105311681B (zh) | 2018-12-25 |
| JP6622416B2 (ja) | 2019-12-18 |
| EP3338819B1 (en) | 2021-07-28 |
| EP3338819A1 (en) | 2018-06-27 |
| EP3338819A4 (en) | 2019-05-29 |
| US20180264172A1 (en) | 2018-09-20 |
| US11471561B2 (en) | 2022-10-18 |
| JP2018530411A (ja) | 2018-10-18 |
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