CN107721407A - 一种基于营养元素Sr‑P‑Si的新型生物活性陶瓷支架及其制备方法和用途 - Google Patents
一种基于营养元素Sr‑P‑Si的新型生物活性陶瓷支架及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种基于营养元素Sr‑P‑Si的新型生物活性陶瓷支架及其制备方法和用途，包括：将Sr5(PO4)2SiO4生物活性陶瓷粉体与粘结剂均匀混合，利用计算机辅助设计软件构造生物活性陶瓷支架陶瓷素坯的结构模型，三维打印所述生物活性陶瓷支架陶瓷素坯；将所得生物活性陶瓷支架陶瓷素坯在1400～1500℃下烧结2～3小时。本发明将三维打印技术和生物活性陶瓷硅磷酸锶（Sr5(PO4)2SiO4相结合，利用三维打印技术制备的Sr5(PO4)2SiO4支架具有良好的体外生物学性能，能够更有效地促进rBMSCs和HUVECs在其表面粘附和增殖，并且具有良好的力学强度。
Description
技术领域
本发明涉及一种基于营养元素Sr-P-Si的生物活性陶瓷支架及其制备方法和用途，属于生物材料领域。
背景技术
近年来，随着各种事故、灾害、衰老或疾病造成骨组织受损及骨关节创伤，人们对于骨组织修复材料的需求不断增大。
磷酸钙类陶瓷作为目前研究最为广泛的一类骨缺损修复材料，具有优良的生物相容性和成骨传导性[1,2]。但磷酸钙类生物陶瓷本身缺乏诱导成骨活性，且力学性能较差，这在一定程度上限制了其使用[3]。
硅是动物和人体组织中的一种重要微量元素，其吸收水平直接影响到骨的质量。尤其在幼骨发育阶段，硅会在新骨钙化区域产生“富集”，并协调钙促进骨组织的早期钙化；此外，硅还与骨骼的生长及结构有关，如果缺乏足量的硅，将会导致骨骼异常、畸形[4]。基于此，人们在过去的十年里对硅酸盐类生物陶瓷用作骨修复材料进行了较为系统的探究[5-8]。结果表明，与传统的磷酸钙类生物陶瓷相比，某些硅酸盐陶瓷的力学性能、降解性以及成骨性能等都更为优越。其最为显著的两大特点为：1)具有诱导多种干细胞成骨分化的能力；2)能够显著诱导成血管化[9-11]。众所周知，提高生物材料的成骨诱导性以及成血管化一直是生物材料研究的难题，硅酸盐生物陶瓷的这一特性为解决该难题提供了新的途径。
锶是骨骼的重要组成部分，是生物体内必不可少的一种微量元素。锶已被证实在抑制破骨和促进成骨方面具有突出作用，相关实验结果亦表明，锶离子的释放能够显著促进骨质疏松骨缺损的修复，其修复能力与雌激素相当[12]。
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发明内容
针对上述问题，本发明首次将三维打印技术和生物活性陶瓷硅磷酸锶(Sr5(PO4)2SiO4相结合，其目的在于制备一种具有可控大孔形貌的Sr5(PO4)2SiO4支架。
一方面，本发明提供了一种基于营养元素Sr-P-Si的生物活性陶瓷支架的制备方法，包括：
将Sr5(PO4)2SiO4生物活性陶瓷粉体与粘结剂均匀混合，利用计算机辅助设计软件构造生物活性陶瓷支架陶瓷素坯的结构模型，三维打印所述生物活性陶瓷支架陶瓷素坯；
将所得生物活性陶瓷支架陶瓷素坯在1400～1500℃下烧结2～3小时，得到所述基于营养元素Sr-P-Si的生物活性陶瓷支架。
本发明将三维打印技术和生物活性陶瓷硅磷酸锶(Sr5(PO4)2SiO4相结合，利用三维打印技术制备的Sr5(PO4)2SiO4支架具有良好的体外生物学性能，能够更有效地促进rBMSCs和HUVECs在其表面粘附和增殖，并且相对于传统磷酸三钙陶瓷支架具有良好的力学强度。
较佳地，所述Sr5(PO4)2SiO4生物活性陶瓷粉体的制备方法包括：以氧化锶、磷酸二氢铵和二氧化硅为原料，按照氧化锶、磷酸二氢铵和二氧化硅摩尔比＝5:2:1球磨混合后在1350～1450℃下烧结3～6小时。
又，较佳地，所述球磨混合的球磨速度为300～500转/分钟，球磨时间为4～8小时。
较佳地，所述Sr5(PO4)2SiO4生物活性陶瓷粉体的颗粒尺度为100目以下。
较佳地，所述粘结剂为普朗尼克(F127)、聚乙烯醇(PVA)中的至少一种。
又，较佳地，所述Sr5(PO4)2SiO4生物活性陶瓷粉体与粘结剂的质量比(2～3)：1。
另一方面，本发明还提供了一种基于营养元素Sr-P-Si的生物活性陶瓷支架。再一方面，本发明还提供了基于营养元素Sr-P-Si的生物活性陶瓷支架在骨缺损修复领域的应用。
附图说明
图1为本发明采用固相反应法制备的Sr5(PO4)2SiO4粉体的XRD图谱；
图2为本发明中实施例3采用三维打印技术制备的Sr5(PO4)2SiO4支架的宏观照片(a)、XRD图谱(b)、低倍(c)SEM照片及高倍(d)SEM照片；
图3为本发明中实施例3采用三维打印技术制备的用于力学性能检测的Sr5(PO4)2SiO4支架的宏观照片(a)、抗压测试应力应变曲线(c)和对比例1制备的β-TCP支架的宏观照片(b)和抗压测试应力应变曲线(d)，以及两者的相应的抗压强度值(e)；
图4为不同浓度的Sr5(PO4)2SiO4浸提液对rBMSCs增殖(a)和ALP活性表达(b)的影响；
图5为不同浓度的Sr5(PO4)2SiO4浸提液对rBMSCs成骨相关基因Runx2、ALP、OCN及OPN表达的影响；
图6为不同浓度的Sr5(PO4)2SiO4浸提液对HUVECs增殖的MTT分析结果(a)及其激光共聚焦照片(b)；
图7为不同浓度的Sr5(PO4)2SiO4浸提液对HUVECs成血管化相关基因VEGF、KDR、eNos及HIF 1α表达的影响；
图8为rBMSCs在本发明中实施例3制备的Sr5(PO4)2SiO4(SPS)支架和对比例1制备的β-TCP支架表面培养1、3、7天后的效果对比图；
图9为HUVECs在本发明中实施例3制备的Sr5(PO4)2SiO4支架和对比例1制备的β-TCP支架的表面培养1、3、7天后的效果对比图。
具体实施方式
以下通过下述实施方式进一步说明本发明，应理解，下述实施方式仅用于说明本发明，而非限制本发明。
利用常规方法(例如冷冻干燥技术、气体发泡法、聚氨酯泡沫模板法等)难以制备得到具有可控大孔形貌、力学性能优异的Sr5(PO4)2SiO4支架。本发明以氧化锶、磷酸二氢铵和二氧化硅为原料，固相反应法(优选为不需要在还原气氛下进行)合成了基于营养元素Sr-P-Si的Sr5(PO4)2SiO4生物活性陶瓷粉体，并利用三维打印技术进一步制备了具有可控大孔形貌的Sr5(PO4)2SiO4支架，并深入研究了支架的理化性能及体外生物活性(包括成骨、成血管化等生物学性能)。这种具有特定活性组成的陶瓷材料有望作为一种新型的生物活性材料应用于骨缺损修复领域。
以下示例性地说明本发明提供的基于营养元素Sr-P-Si的生物活性陶瓷支架的制备方法。
固相反应法制备Sr5(PO4)2SiO4生物活性陶瓷粉体。具体来说，以氧化锶、磷酸二氢铵和二氧化硅为原料(采用氧化锶、磷酸二氢铵和二氧化硅分别作为Sr源、P源和Si源原材料)，按照氧化锶、磷酸二氢铵和二氧化硅摩尔比＝5:2:1球磨混合后在1350-1450℃下烧结3～6小时，得到所述Sr5(PO4)2SiO4生物活性陶瓷粉体。所述球磨混合的球磨速度可为300～500转/分钟。球磨时间可为4～8小时。图1为采用固相反应法制备的Sr5(PO4)2SiO4粉体的XRD图谱，从图中可以看出采用该法制备得到的粉体为单相Sr5(PO4)2SiO4相。
3D打印生物活性陶瓷支架陶瓷素坯。具体来说，按照Sr5(PO4)2SiO4生物活性陶瓷粉体和粘结剂的质量比＝(2～3)：1，将其均匀混合。选取的Sr5(PO4)2SiO4生物活性陶瓷粉体的颗粒尺度需为100目以下，若粉体粒度过大，可能导致打印针头堵塞。所述粘结剂可为普朗尼克(F127)、聚乙烯醇(PVA)中的至少一种。然后利用计算机辅助设计软件构造生物活性陶瓷支架陶瓷素坯的结构模型，并打印所述生物活性陶瓷支架陶瓷素坯，如图2(a)中结构所示(还可调节其孔径大小为100～600μm，例如100μm、200μm、300μm等)。
将生物活性陶瓷支架陶瓷素坯在1400～1500℃下烧结2～3小时，得到所述基于营养元素Sr-P-Si的生物活性陶瓷支架，参见图2。图2为本发明中一个示例中采用三维打印技术制备的Sr5(PO4)2SiO4支架的宏观照片(a)、XRD图谱(b)、低倍SEM照片(c)及高倍SEM照片(d)。从图2中可以看出支架仍保持为Sr5(PO4)2SiO4相，支架表面大孔可严格控制在100μm左右，且支架表面烧结致密。
作为一个详细的示例，(1)采用氧化锶、磷酸二氢铵和二氧化硅为原料，按照摩尔比5:2:1，设定球磨速度为300～500转/分钟，球磨时间为4～8小时，充分混合。(2)将混合后的粉体于1400℃煅烧3～6小时，制得Sr5(PO4)2SiO4生物活性陶瓷粉体。(3)将Sr5(PO4)2SiO4粉体过筛，选择100目以下的粉体与F-127按质量比(2-3):1混合均匀，得到打印所需浆料。(4)利用软件设计支架具体参数，调控支架的形状、尺寸等。(5)将打印成型的支架在1400～1500℃煅烧2～3小时，得到Sr5(PO4)2SiO4生物活性陶瓷支架。
Sr5(PO4)2SiO4浸提液的制备。根据ISO/EN10993-5的规定，首先称取1g经高温灭菌锅121℃灭菌处理后的Sr5(PO4)2SiO4粉体加入5g不含血清的培养基(根据细胞培养的需要进行选择)，置于37℃/5％CO2摇床浸提24小时后，离心，取上清液，采用PALL针头过滤器(0.22μm)过滤，得到200mg/mL Sr5(PO4)2SiO4粉体浸提液；采用不含血清的培养基(根据细胞培养的需要进行选择)梯度稀释可进一步得到100mg/mL、50mg/mL、25mg/mL、12.5mg/mL、6.25mg/mL、3.125mg/mL的粉体浸提液。
本发明通过系统研究Sr5(PO4)2SiO4生物活性陶瓷支架是否具有良好的体外生物学性能和力学性能，确定其是否能够用作新型的大块骨缺损修复材料。本发明采用X射线衍射(XRD)、扫描电镜(SEM)等手段对Sr5(PO4)2SiO4粉体及支架的物相组成、支架表面大孔结构、显微形貌等进行分析与表征。
本发明制备出的Sr5(PO4)2SiO4生物活性陶瓷粉体具有良好的体外促进成骨、成血管化特性。本发明以Sr5(PO4)2SiO4生物活性陶瓷粉体为原料制备的Sr5(PO4)2SiO4支架具有可控大孔形貌、理想的力学强度，并能有效促进rBMSCs和HUVECs在其表面粘附和增殖。
下面进一步例举实施例以详细说明本发明。同样应理解，以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例，即本领域技术人员可以通过本文的说明做合适的范围内选择，而并非要限定于下文示例的具体数值。
实施例1
将氧化锶、磷酸二氢铵和二氧化硅粉体按照摩尔比5:2:1，于500转/分钟速度下充分混合4小时后，在1400℃下煅烧3小时，得到Sr5(PO4)2SiO4生物活性陶瓷粉体；
称取-200目～+300目的Sr5(PO4)2SiO4粉体6g，与2gF-127混合后，利用三维打印技术制备支架材料；
将打印支架在1400℃煅烧3小时，得到Sr5(PO4)2SiO4生物活性陶瓷支架；
对支架进行力学性能、成骨活性和成血管活性的评价。
实施例2
将氧化锶、磷酸二氢铵和二氧化硅粉体按照摩尔比5:2:1，于300转/分钟速度下充分混合8小时后，在1400℃下煅烧4小时，得到Sr5(PO4)2SiO4生物活性陶瓷粉体；
称取-300目～+400目的Sr5(PO4)2SiO4粉体5g，与2gF-127混合后，利用三维打印技术制备支架材料；
将打印支架在1500℃煅烧3小时，得到Sr5(PO4)2SiO4生物活性陶瓷支架；
对支架进行力学性能、成骨活性和成血管活性的评价。
实施例3
将氧化锶、磷酸二氢铵和二氧化硅粉体按照摩尔比5:2:1，于400转/分钟速度下充分混合6小时后，在1400℃下煅烧6小时，得到Sr5(PO4)2SiO4生物活性陶瓷粉体；
称取-400目～+500目的Sr5(PO4)2SiO4粉体4g，与2gF-127混合后，利用三维打印技术制备支架材料；
将打印支架在1450℃煅烧2小时，得到Sr5(PO4)2SiO4支架；
对支架进行力学性能、成骨活性和成血管活性的评价。
对比例1
实验同时采用三维打印技术制备了磷酸三钙(β-TCP)支架作为对照：采用市售β-TCP粉体作为原料，将β-TCP粉体与F-127按质量比2:1混合，打印成型后于1100℃煅烧3小时，得到β-TCP支架。
Sr5(PO4)2SiO4生物活性陶瓷支架的力学性能研究
对Sr5(PO4)2SiO4支架(6个平行样)进行抗压强度的测试，并与β-TCP支架进行比较。结果表明，Sr5(PO4)2SiO4支架具有比β-TCP支架更为优异的力学性能。图3为本发明中实施例3采用三维打印技术制备的用于力学性能检测的Sr5(PO4)2SiO4支架的宏观照片(a)、抗压测试应力应变曲线(c)和对比例1制备的β-TCP支架的宏观照片(b)和抗压测试应力应变曲线(d)，以及两者的相应的抗压强度值(e)。从图3中可以看出Sr5(PO4)2SiO4支架的抗压强度可控制在8～30MPa(对应大孔孔径100～300μm)，远远高于β-TCP支架(5～14MPa)。
Sr5(PO4)2SiO4浸提液的体外成骨、成血管化性能研究
体外成骨性能研究。将rBMSCs于不同浓度Sr5(PO4)2SiO4浸提液中分别培养1、3、7天后，采用MTT法检测细胞的增殖能力。通过ALP检测试剂盒检测rBMSCs于不同浓度Sr5(PO4)2SiO4浸提液中分别培养7天和14天后的ALP活性。采用RT-PCR测试rBMSCs在不同浓度Sr5(PO4)2SiO4浸提液中培养7天后成骨相关基因Runx2、ALP、OCN及OPN的表达。图4为Sr5(PO4)2SiO4浸提液对rBMSCs增殖(a)和ALP活性表达(b)的影响。由图4中可以看出，在较低浓度下，Sr5(PO4)2SiO4浸提液能够有效促进rBMSCs增殖，并且能显著促进其ALP活性的表达。图5为Sr5(PO4)2SiO4浸提液对rBMSCs成骨相关基因Runx2、ALP、OCN及OPN表达的影响。由图5中可以看出，Sr5(PO4)2SiO4浸提液能够显著促进成骨相关基因的表达。总的来说，Sr5(PO4)2SiO4浸提液能够有效促进rBMSCs增殖，并能显著促进其ALP活性及成骨相关基因的表达。
体外成血管化性能研究。将HUVECs于不同浓度Sr5(PO4)2SiO4浸提液中分别培养1、3、7天后，采用MTT法检测细胞的增殖能力。采用RT-PCR测试HUVECs在不同浓度Sr5(PO4)2SiO4浸提液中培养7天后成血管化相关基因VEGF、KDR、eNos及HIF 1α的表达。图6为Sr5(PO4)2SiO4浸提液对HUVECs增殖的MTT分析结果(a)及激光共聚焦照片(b)。从图6中可以看出，在所选浓度下，Sr5(PO4)2SiO4浸提液对HUVECs没有毒性。图7为不同浓度的Sr5(PO4)2SiO4浸提液对HUVECs成血管化相关基因VEGF、KDR、eNos及HIF 1α表达的影响。由图7中可以看出，Sr5(PO4)2SiO4浸提液能够显著促进成血管化相关基因的表达。总的来说，Sr5(PO4)2SiO4浸提液能够有效促进HUVECs增殖，并能显著促进其成血管化相关基因的表达。
Sr5(PO4)2SiO4支架对rBMSCs和HUVECs在其表面粘附、增殖的影响研究
将rBMSCs和HUVECs分别种植在实施例3制备的Sr5(PO4)2SiO4支架和对比例1制备的β-TCP支架表面，培养1、3、7天后采用MTT法检测细胞的增殖能力，并利用扫描电镜和激光共聚焦显微镜观察细胞的形貌及铺展状态。图8为rBMSCs在Sr5(PO4)2SiO4支架和β-TCP支架表面培养1、3、7天后的效果对比图，其中(a)为Sr5(PO4)2SiO4支架和β-TCP支架表面培养1、3、7天后的MTT分析图，Sr5(PO4)2SiO4支架在表面培养1天后(c)、3天后(e)粘附情况的SEM照片，以及培养3天时细胞骨架染色的激光共聚焦照片(i-k)和β-TCP支架表面培养1天(b)、3天(d)后粘附情况的SEM照片，以及培养3天时细胞骨架染色的激光共聚焦照片(f-h)。从图8可知Sr5(PO4)2SiO4支架具有良好的促进rBMSCs粘附和增殖能力。图9为HUVECs在Sr5(PO4)2SiO4支架和β-TCP支架表面培养1、3、7天后的效果对比图，其中(a)为Sr5(PO4)2SiO4支架和β-TCP支架表面培养1、3、7天后的MTT分析图，Sr5(PO4)2SiO4支架在表面培养1天后(c)、3天后(e)粘附情况的SEM照片，以及培养3天时细胞骨架染色的激光共聚焦照片(i-k)和β-TCP支架表面培养1天(b)、3天(d)后粘附情况的SEM照片，以及培养3天时细胞骨架染色的激光共聚焦照片(f-h)。从图9可知Sr5(PO4)2SiO4支架具有良好的促进HUVECs粘附和增殖能力。总的来说，Sr5(PO4)2SiO4支架相比于β-TCP支架更能有效促进rBMSCs和HUVECs的粘附和增殖，表明其具有良好的细胞相容性。
综上所述，体外细胞实验表明Sr5(PO4)2SiO4生物活性陶瓷能够显著提高骨髓间充质干细胞(rBMSCs)的碱性磷酸酶(ALP)活性及成骨相关基因Runx2、ALP、OCN及OPN的表达，并具有显著促进人脐静脉内皮细胞(HUVECs)体外成血管化的能力。与传统磷酸三钙(β-TCP)支架相比，三维打印技术制备的Sr5(PO4)2SiO4支架能够更有效地促进rBMSCs和HUVECs在其表面粘附和增殖，并且相对于传统磷酸三钙陶瓷支架具有更为理想的力学强度。因此本发明提供的这种具有特定活性组成、体外生物学性能良好、力学性能优异的生物活性陶瓷支架材料有望用于大块骨缺损的修复与再生。
Claims (8)
1.一种基于营养元素Sr-P-Si的生物活性陶瓷支架的制备方法，其特征在于，包括：
将Sr5(PO4)2SiO4生物活性陶瓷粉体与粘结剂均匀混合，利用计算机辅助设计软件构造生物活性陶瓷支架陶瓷素坯的结构模型，三维打印所述生物活性陶瓷支架陶瓷素坯；
将所得生物活性陶瓷支架陶瓷素坯在1400～1500℃下烧结2～3小时，得到所述基于营养元素Sr-P-Si的生物活性陶瓷支架。
2.根据权利要求1所述的制备方法，其特征在于，所述Sr5(PO4)2SiO4生物活性陶瓷粉体的制备方法包括：以氧化锶、磷酸二氢铵和二氧化硅为原料，按照氧化锶、磷酸二氢铵和二氧化硅摩尔比=5:2:1球磨混合后在1350～1450℃下烧结3～6小时。
3.根据权利要求2所述的制备方法，其特征在于，所述球磨混合的球磨速度为300～500转/分钟，球磨时间为4～8小时。
4.根据权利要求1-3中任一项所述的制备方法，其特征在于，所述Sr5(PO4)2SiO4生物活性陶瓷粉体的颗粒尺度为100目以下。
5.根据权利要求4所述的制备方法，其特征在于，所述粘结剂为普朗尼克F127、聚乙烯醇PVA中的至少一种。
6.根据权利要求5所述的制备方法，其特征在于，所述Sr5(PO4)2SiO4生物活性陶瓷粉体与粘结剂的质量比（2～3）：1。
7.一种根据权利要求1-6中任一项所述的方法制备的基于营养元素Sr-P-Si生物活性陶瓷支架。
8.一种根据权利要求7所述的基于营养元素Sr-P-Si生物活性陶瓷支架在制备骨缺损修复材料中的应用。
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