CN110384828B - 一种磁性载镁人工骨及利用3d打印制备磁性载镁人工骨的方法 - Google Patents
一种磁性载镁人工骨及利用3d打印制备磁性载镁人工骨的方法 Download PDFInfo
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Abstract
本发明公开了一种磁性载镁人工骨及利用3D打印制备磁性载镁人工骨的方法，所述人工骨包括如下重量份的组分：PLA 6～10，β‑TCP 0.8～1.2，MgSO4 0.3～0.7，Fe3O4 0.3～0.7。该方法利用计算机辅助设计软件对骨支架的模型进行仿生设计，然后按照组分仿生原理，将PLA、β‑TCP、MgSO4、Fe3O4四种原料按照8：1：0.5：0.5的比例进行混合，所得粉末经离心、清洗、干燥、研磨制得复合粉末，所得复合粉末采用3D打印机经选择性激光烧结制备磁性载镁人工骨。
Description
技术领域
本发明属于生物医用骨科材料制备技术领域，具体涉及一种磁性载镁人工骨及利用3D打印制备磁性载镁人工骨的方法。
背景技术
我国每年因创伤、感染、肿瘤等导致的骨组织缺损患者约1500万人，亟需进行有效的骨缺损修复。临床用于骨组织缺损修复方式主要有机械重建和生物学重建，机械重建常用的材料主要是人工金属假体，其相比于生物材料存在显著的弊端：①金属假体修复骨组织缺损是一种机械重建方式，其存在使用寿面有限，远期需要反复翻修；②金属假体力学强度高、密度大，会造成应力遮挡，引起假体周围骨质疏松甚至骨溶解并最终导致界面松动甚至假体周围骨折；③金属假体容易磨损产生许多磨损颗粒，且假体与骨组织及周围软组织无法有效结合，其抗感染能力差，远期并发症较生物学重建多。生物学重建是一种远期疗效佳、并发症少、更受临床推崇的骨组织缺损修复选择，其常用的材料主要有自体骨、异体骨及人工骨等。自体骨是骨组织缺损修复的金标准，但其来源有限，也难以满足不同缺损部位各种形状和大小的需求，且常伴有感染、疼痛、神经功能障碍等供区并发症；异体骨虽然来源相对丰富，但存在免疫排斥、疾病传播以及伦理安全等问题。人工骨则是一种可以替代人体骨或者修复骨组织缺损的人工生物材料，人工骨材料通过单独使用或几种材料复合使用来促进骨愈合，其作用原理主要由骨生成、骨传导及骨诱导三个方面实现。理想的人工骨需具备以下基本特性：1）具有良好的生物相容性；2）具有合适的力学性能；3）有微孔结构，使新生骨组织得以长入；4）其吸收速度与新骨生长速度大致保持同步；5）易于加工成所需的大小和形状。因此理想人工骨材料的研制是医学和生物材料科学领域的一个重要课题。
目前研究开发出来的人工骨根据材料的结构和性能大致可分为无机材料、有机材料和复合材料。这些材料制备的人工骨往往仅能达到理想人工骨材料的部分性能需求：①无机材料制成的生物陶瓷类人工骨其生物相容性好，但是机械性能较差，硬而脆，易断裂，而且缺乏骨诱导性能；②有机材料制成的生物活性人工骨虽具备一定的骨诱导性能，但是生物力学性能较差，不能与人体骨组织的力学性能相匹配；③复合材料则是兼具无机材料与有机材料的优点，能够同时具备骨传导与一定程度的骨诱导性能，但其制备方法单一，无法实现不同骨组织缺损部位的个性化需求，无法实现长期有效的骨诱导作用。此外由于人体骨组织是由有机质和无机盐结合而构成，其比例约为1：2，且松质骨与皮质骨结构上存在显著差异，而目前人工骨材料的制备方法尚无法实现骨组织结构上和组分构成上的个性化需求，更无法赋予人工骨材料长效的骨诱导性能。
发明内容
本发明旨在克服现有技术的不足，提供一种磁性载镁人工骨及利用3D打印制备磁性载镁人工骨的方法。
为了达到上述目的，本发明提供的技术方案为：
所述磁性载镁人工骨包括如下重量份的组分：PLA（聚乳酸） 6～10，β-TCP（低温β相磷酸三钙） 0.8～1.2，MgSO4 （硫酸镁）0.3～0.7，Fe3O4（四氧化三铁）0.3～0.7。
优选地，所述人工骨包括如下重量份的组分：PLA 6～10，β-TCP 1，MgSO4 0.3～0.7，Fe3O4 0.3～0.7。
优选地，所述人工骨包括如下重量份的组分：PLA 8，β-TCP 1，MgSO4 0.3～0.7，Fe3O4 0.3～0.7。
优选地，所述人工骨包括如下重量份的组分：PLA 8，β-TCP 1，MgSO4 0.5，Fe3O4 0.5。
优选地，所述PLA粒径为20～80μm，密度为1.20～1.30 kg/L，熔点为155～185℃；所述β-TCP粒径为40～80μm，密度为3.07 kg/L，熔点为1670℃；所述MgSO4粒径为0.1～1mm，密度为2.66 kg/L，熔点为1124℃；所述Fe3O4粒径为10～100nm，密度为5.18 kg/L，熔点为1538℃。
利用3D打印制备上述磁性载镁人工骨的方法是：所述方法是：利用计算机辅助设计软件对骨组织缺损部位进行三维重建，构建立体仿真模型，然后将PLA、β-TCP、MgSO4、Fe3O4混合后，经选择性激光烧结技术制备成载磁性纳米颗粒的复合人工骨。
优选地，所述方法包括如下具体步骤：
（1）根据不同骨组织缺损部位的结构特点，采用CT断层扫描采集缺损部位的数据资料，将数据资料导入计算机辅助设计软件（EasyPrint 3D、3DPrinterOS等）中进行缺损部位的三维重建，同时根据骨组织自身结构的特点，设计出内层为松质骨、外层为皮质骨的结构模型；
（2）按权利要求1至4任一项所述的比例准备PLA、β-TCP、MgSO4和Fe3O4，将PLA加入无水乙醇溶液中制备成PLA混悬液，所述PLA与无水乙醇溶液的比例为（6～10）g：（180～220）mL，然后将β-TCP、MgSO4和Fe3O4加入到PLA混悬液中，经磁力搅拌和超声分散混合均匀后得到PLA/β-TCP/MgSO4/Fe3O4复合悬浮液；
（3）将PLA/β-TCP/MgSO4/Fe3O4复合悬浮液经离心分离、清洗、干燥和研磨后得到复合粉末；
（4）用3D打印机将复合粉末按步骤（1）所述结构模型，经选择性激光烧结制备磁性载镁人工骨，所述烧结的工艺参数为：激光功率2.0～4.0W，扫描速度200～400mm/min。
优选地，步骤（2）中所述磁力搅拌的时间为30～40min，磁力搅拌速度为400～600r/min，磁力搅拌温度为50～60℃；所述超声分散时间为30～60min，超声分散温度为50～60℃。
优选地，步骤（3）中所述离心分离的转速为2000～3000r/min，离心时间为20～30min；所述干燥时的温度为50～60℃，干燥后的保温时间为16～24h。
本发明所述人工骨是基于骨组织内层为松质骨，外层为皮质骨的结构仿生原理和骨组织中有机相与无机相比例为1：2的组分仿生原理制备而得的。
与现有技术相比，本发明的有益效果为：
1、本发明利用PLA优异的生物相容性、降解性、无毒性和良好的力学相容性特点，提高了人工骨支架的生物活性和可控降解性能。
2、本发明利用有机物和无机材料的有效配比，使其组分构成接近正常人体骨组织中有机相与无机相的比例，实现了人工骨支架的组分仿生制备，同时使其生物力学性能与人体骨组织接近，以更好的与人体骨组织的弹性模量相适应。
3、本发明利用纳米级Fe3O4产生的超微磁场，诱导人体骨髓间充质干细胞（hBMSCs）向骨支架的迁移与粘附，进一步调节成骨-破骨平衡来促进新骨形成；赋予人工骨支架优良的细胞趋化作用和成骨诱导性能。
4、本发明利用MgSO4降解产生的Mg2+，促进hBMSCs向成骨细胞分化，同时加快细胞外基质矿化，进一步提高了人工骨支架的骨诱导性能。
5、本发明利用计算机辅助设计软件，以多元组分为原料，采用3D打印技术一体化制备磁性载镁人工骨支架，实现了人工骨支架的组分仿生和结构仿生，同时赋予了人工骨支架优良的骨传导与骨诱导性能。
本发明解决了现有人工骨材料无法同时兼备骨传导、长效骨诱导、骨组织结构与组分上的个性化需求，以及人工骨材料的降解速率无法与人体骨愈合速度相匹配等问题。
本发明方法制备的人工骨支架具有类似人体正常骨组织的内层松质骨、外层皮质骨的仿生结构，人工骨支架的组分构成也与人体骨组织中有机物与无机物比例1：2相同。β-TCP、MgSO4、Fe3O4能够均匀地被PLA基体包裹，有机相与无机相之间具有较强的界面结合。人工骨支架具有与人体正常骨接近的生物力学性能，同时具备优良的成骨诱导活性。
具体实施方式
实施例1
所述磁性载镁人工骨包括如下重量份的组分：PLA 6，β-TCP 1，MgSO4 0.7，Fe3O4 0.3。
实施例2
所述磁性载镁人工骨包括如下重量份的组分：PLA 10，β-TCP 1，MgSO4 0.3，Fe3O4 0.7。
实施例3
所述磁性载镁人工骨包括如下重量份的组分：PLA 8，β-TCP 1，MgSO4 0.5，Fe3O4 0.5。
实施例4
（1）运用计算机辅助设计软件EasyPrint 3D将CT扫描结果进行三维重建，根据人体骨组织自身结构的特点，设计出内层为松质骨、外层为皮质骨的结构模型。
（2）以PLA、β-TCP、MgSO4、Fe3O4为原料，按照8：1：0.5：0.5的比例混合。首先称量80gPLA粉末颗粒置于200ml的无水乙醇溶液中制备PLA混悬液，随后称量10g β-TCP、5g MgSO4、5g Fe3O4共同加入到PLA混悬液中。经磁力搅拌和超声分散混合均匀制备PLA/β-TCP/MgSO4/Fe3O4复合悬浮液。所述的磁力搅拌时间为30min，磁力搅拌速度为600r/min，搅拌温度为50℃，超声分散时间为60min，超声分散温度为50℃；
（3）将复合悬浮液经离心分离、蒸馏水清洗、干燥、研磨制备复合粉末；所述的离心分离转速为3000r/min，时间为30min，干燥温度为50℃，保温时间为24h。
（4）运用3D打印机，将复合粉末经选择性激光烧结技术制备个性一体化磁性载镁复合人工骨支架，其烧结工艺参数为：激光功率为2.5W，扫描速度为300mm/min。
（5）复合人工骨支架经物相检测分析发现支架的主要组分为PLA、β-TCP、MgSO4和Fe3O4，拉伸实验测得复合人工骨支架的拉伸强度为54.7MPa，抗压实验测得复合人工骨支架的抗压强度为163.8MPa。磁场强度检测得：无外磁场作用时，复合人工骨支架的磁场强度近于无；有外磁场干预时，复合人工骨支架的磁场强度随外磁场强度成正向相关性增加。
实施例5
（1）运用计算机辅助设计软件EasyPrint 3D将CT扫描结果进行三维重建，根据人体骨组织自身结构的特点，设计出内层为松质骨、外层为皮质骨的结构模型。
（2）以PLA、β-TCP、MgSO4、Fe3O4为原料，按照8：1：0.5：0.5的比例混合。首先称量80gPLA粉末颗粒置于200ml的无水乙醇溶液中制备PLA混悬液，随后称量10g β-TCP、5g MgSO4、5g Fe3O4共同加入到PLA混悬液中。经磁力搅拌和超声分散混合均匀制备PLA/β-TCP/MgSO4/Fe3O4复合悬浮液。所述的磁力搅拌时间为30min，磁力搅拌速度为600r/min，搅拌温度为50℃，超声分散时间为60min，超声分散温度为50℃；
（3）将复合悬浮液经离心分离、蒸馏水清洗、干燥、研磨制备复合粉末；所述的离心分离转速为3000r/min，时间为30min，干燥温度为50℃，保温时间为24h。
（4）运用3D打印机，将复合粉末经选择性激光烧结技术制备个性一体化磁性载镁复合人工骨支架，其烧结工艺参数为：激光功率为2.5W，扫描速度为300mm/min。
（5）将复合人工骨支架置入细胞培养基中浸提48h，然后分别以正常培基、支架浸提液、支架浸提液加外磁场与hBMSCs进行体外共培养120h，然后对其成骨相关标志物进行检测。
（6）复合人工骨支架浸提液与细胞共培养，运用茜素红染色检测细胞外钙盐沉积量、碱性磷酸酶染色检测细胞内碱性磷酸酶含量得出，支架浸提液加外磁场作用下hBMSCs细胞外钙盐沉积量和碱性磷酸酶含量显著大于单纯支架浸提液组合空白对照组。
对比实施例1
（1）运用计算机辅助设计软件EasyPrint 3D将CT扫描结果进行三维重建，根据人体骨组织自身结构的特点，设计出内层为松质骨、外层为皮质骨的结构模型。
（2）以PLA、β-TCP、MgSO4、Fe3O4为原料，按照5：1：0.2：0.8的比例混合。首先称量50gPLA粉末颗粒置于200ml的无水乙醇溶液中制备PLA混悬液，随后称量10g β-TCP、2g MgSO4、8g Fe3O4共同加入到PLA混悬液中。经磁力搅拌和超声分散混合均匀制备PLA/β-TCP/MgSO4/Fe3O4复合悬浮液。所述的磁力搅拌时间为25min，磁力搅拌速度为600r/min，搅拌温度为65℃，超声分散时间为60min，超声分散温度为50℃；
（3）将复合悬浮液经离心分离、蒸馏水清洗、干燥、研磨制备复合粉末；所述的离心分离转速为3000r/min，时间为30min，干燥温度为45℃，保温时间为24h。
（4）运用3D打印机，将复合粉末经选择性激光烧结技术制备个性一体化磁性载镁复合人工骨支架，其烧结工艺参数为：激光功率为1.5W，扫描速度为420mm/min。
（5）将复合人工骨支架置入细胞培养基中浸提48h，然后分别以正常培基、支架浸提液、支架浸提液加外磁场与hBMSCs进行体外共培养120h，然后对其成骨相关标志物进行检测。
（6）复合人工骨支架浸提液与细胞共培养，运用茜素红染色检测细胞外钙盐沉积量、碱性磷酸酶染色检测细胞内碱性磷酸酶含量得出，支架浸提液加外磁场作用下hBMSCs细胞外钙盐沉积量和碱性磷酸酶含量显著大于单纯支架浸提液组合空白对照组，但是明显小于实施例5。
对比实施例2
（1）运用计算机辅助设计软件EasyPrint 3D将CT扫描结果进行三维重建，根据人体骨组织自身结构的特点，设计出内层为松质骨、外层为皮质骨的结构模型。
（2）以PLA、β-TCP、MgSO4、Fe3O4为原料，按照11：1：0.8：0.2的比例混合。首先称量110g PLA粉末颗粒置于200ml的无水乙醇溶液中制备PLA混悬液，随后称量10g β-TCP、8gMgSO4、2g Fe3O4共同加入到PLA混悬液中。经磁力搅拌和超声分散混合均匀制备PLA/β-TCP/MgSO4/Fe3O4复合悬浮液。所述的磁力搅拌时间为45min，磁力搅拌速度为400r/min，搅拌温度为45℃，超声分散时间为60min，超声分散温度为50℃；
（3）将复合悬浮液经离心分离、蒸馏水清洗、干燥、研磨制备复合粉末；所述的离心分离转速为3000r/min，时间为30min，干燥温度为65℃，保温时间为24h。
（4）运用3D打印机，将复合粉末经选择性激光烧结技术制备个性一体化磁性载镁复合人工骨支架，其烧结工艺参数为：激光功率为4.5W，扫描速度为180mm/min。
（5）将复合人工骨支架置入细胞培养基中浸提48h，然后分别以正常培基、支架浸提液、支架浸提液加外磁场与hBMSCs进行体外共培养120h，然后对其成骨相关标志物进行检测。
（6）复合人工骨支架浸提液与细胞共培养，运用茜素红染色检测细胞外钙盐沉积量、碱性磷酸酶染色检测细胞内碱性磷酸酶含量得出，支架浸提液加外磁场作用下hBMSCs细胞外钙盐沉积量和碱性磷酸酶含量显著大于单纯支架浸提液组合空白对照组，但是明显小于实施例5。
Claims (4)
1.一种磁性载镁人工骨，其特征在于，所述人工骨由如下重量份的组分组成：PLA 8，β-TCP 1，MgSO4 0.5，Fe3O4 0.5；所述人工骨按如下方法制备：（1）根据不同骨组织缺损部位的结构特点，采用CT断层扫描采集缺损部位的数据资料，将数据资料导入计算机辅助设计软件中进行缺损部位的三维重建，同时根据骨组织自身结构的特点，设计出内层为松质骨、外层为皮质骨的结构模型；（2）按重量份8:1:0.5:0.5的比例准备PLA、β-TCP、MgSO4和Fe3O4，将PLA加入无水乙醇溶液中制备成PLA混悬液，所述PLA与无水乙醇溶液的比例为80g：200mL，然后将β-TCP、MgSO4和Fe3O4加入到PLA混悬液中，经磁力搅拌和超声分散混合均匀后得到PLA/β-TCP/MgSO4/Fe3O4复合悬浮液；（3）将PLA/β-TCP/MgSO4/Fe3O4复合悬浮液经离心分离、清洗、干燥和研磨后得到复合粉末；（4）用3D打印机将复合粉末按步骤（1）所述结构模型，经选择性激光烧结制备磁性载镁人工骨，所述烧结的工艺参数为：激光功率2.0～4.0W，扫描速度200～400mm/min。
2.如权利要求1所述的人工骨，其特征在于，所述PLA粒径为20～80μm，密度为1.20～1.30 kg/L，熔点为155～185℃；所述β-TCP粒径为40～80μm，密度为3.07 kg/L，熔点为1670℃；所述MgSO4粒径为0.1～1mm，密度为2.66 kg/L，熔点为1124℃；所述Fe3O4粒径为10～100nm，密度为5.18 kg/L，熔点为1538℃。
3.如权利要求1所述的磁性载镁人工骨，其特征在于，步骤（2）中所述磁力搅拌的时间为30～40min，磁力搅拌速度为400～600r/min，磁力搅拌温度为50～60℃；所述超声分散时间为30～60min，超声分散温度为50～60℃。
4.如权利要求1所述的磁性载镁人工骨，其特征在于，步骤（3）中所述离心分离的转速为2000～3000r/min，离心时间为20～30min；所述干燥时的温度为50～60℃，干燥后的保温时间为16～24h。
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