CN110624128B - 一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备 - Google Patents

一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备 Download PDF

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CN110624128B
CN110624128B CN201910899353.2A CN201910899353A CN110624128B CN 110624128 B CN110624128 B CN 110624128B CN 201910899353 A CN201910899353 A CN 201910899353A CN 110624128 B CN110624128 B CN 110624128B
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裴佳
于梦娇
张健
张磊
袁广银
阎作勤
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Abstract

本发明公开了一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备；所述涂层包括设于所述可降解镁及镁合金材料表层的氟化膜和掺锶生物活性钙磷涂层；制备时，将镁及镁合金材料恒温浸没于氢氟酸中，形成氟转化膜；然后将氟化处理过的镁及镁合金材料恒温浸没于磷酸盐混合液，在氟转化膜表面沉积一层掺锶生物活性钙磷涂层。本发明制备的涂层，操作工艺简便、易行，制备的涂层与基体结合力强，既提高了基体的耐蚀性和生物相容性，又为基体镁及镁合金材料提供了优异的抗骨质疏松性能，促成骨抑制破骨。

Description

一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备
技术领域
本发明属于生物医用材料制备技术领域，具体为一种可降解镁基骨修复材料钙磷掺锶功能涂层及其制备。
背景技术
在骨修复材料领域，镁及镁合金被认为是“革命性的医用植入材料”，与传统植入物材料不锈钢、钛及钛合金等相比，镁及镁合金有独特的生物可降解性、生物相容性以及生物力学相容性等优势。但镁及镁合金作为骨植入物材料在体内存在降解速率过快的问题，同时生物相容性有待进一步提高。
骨质疏松症作为影响公共健康的问题之一，表现为骨质量降低和微结构退化，使骨骼变得脆弱，并易引起骨折。针对骨质疏松性骨折，一种能够促使骨愈合的同时能够治疗骨质疏松的骨修复材料是有必要的。锶作为人体必须的微量元素之一，被认为与骨骼的形成密切相关。由于锶具有抑制骨吸收和增进骨生成的双重作用，锶制剂被认为是预防和治疗骨质疏松症的一种有效途径。锶防治骨质疏松症的主要药理作用为：1、抑制破骨细胞功能，通过抑制破骨细胞分化活化、缩短生存周期等机制，同时减少破骨细胞前体向破骨细胞分化，达到抑制骨吸收的作用；2、促进成骨细胞功能，通过促进成骨细胞分化，增强碱性磷酸酶活性等方式促进骨生成；3、调控间充质干细胞和骨髓间充质细胞的分化转归，促使间充质干细胞向成骨细胞分化同时组织向脂肪细胞等分化，促进骨生成，增加骨量。
在镁及镁合金表面构筑生物活性钙磷涂层，能够提高镁合金的生物相容性，引导骨组织在镁及镁合金表面沉积和促进骨生长，减缓镁基体在体液中的降解速率，是镁及镁合金表面改性的一个重要方向。镁及镁合金的与人体骨骼相近的机械力学性能以及通过钙磷涂层表面改性调控适宜的降解速率与骨愈合进程相匹配，并有良好的生物相容性和促成骨性能，但镁及镁合金以及钙磷涂层并没有抑制破骨细胞的作用，因此并不足以治疗骨质疏松性骨折，而在钙磷涂层中掺锶元素，可以在促进骨生成的同时抑制骨吸收，能够有效的治愈骨质疏松引起的骨缺损。因此，开发一种针对镁及镁合金上钙磷掺锶功能涂层的制备方法，对于镁及镁合金骨修复材料治愈骨质疏松性骨折的临床应用具有重要的意义。
而目前，对于将锶元素掺入镁及镁合金表面钙磷涂层的相关方法较少。公开号为CN 104888271A的专利公布了一种生物可降解镁合金表面锶羟基磷灰石涂层的制备方法，该方法是通过水热反应制备锶羟基磷灰石涂层，主要注重涂层的抗腐蚀性能，而对生物相容性、是否抑制破骨等其他性能没有涉及。而本发明专利采用化学溶液沉积法制备的可降解镁基钙磷掺锶功能涂层，制备方法和制备条件更简单，能够有效提高镁基体的抗腐蚀性能、生物相容性以及抑制破骨。
发明内容
本发明的目的在于针对镁及镁合金钙磷涂层无法抑制破骨的问题，提供一种新的可降解镁基骨修复材料钙磷掺锶功能涂层及其制备方法。本发明制备的钙磷掺锶功能涂层的制备方法具体是指在可降解镁基骨修复材料表面制备氟化膜后，在有氟化膜的材料上反应沉积掺锶生物活性钙磷涂层。本发明解决了镁及镁合金表面钙磷涂层无法抑制破骨的问题，在镁及镁合金表面制备掺锶生物活性钙磷涂层，能够在满足提高基体生物相容性、延缓基体腐蚀速率的同时，起到促进成骨和抑制破骨的双重作用。制备工艺简单、易行，制备的钙磷掺锶涂层与基体结合力强，锶/钙比可控。
本发明的目的是通过以下技术方案来实现：
第一方面，本发明涉及一种骨修复用可降解镁基钙磷掺锶功能涂层，所述涂层包括氟化膜和掺锶生物活性钙磷涂层，所述氟化膜设于可降解镁及镁合金表层。
作为优选技术方案，所述氟化膜厚度为140nm～3μm；所述掺锶生物活性钙磷涂层的厚度为120nm～200μm。
作为优选技术方案，所述掺锶生物活性钙磷涂层与氟化膜结合力≥10MPa，所述掺锶生物活性钙磷涂层成分为CaxSryHPO4(x+y＝1)。所述掺锶生物活性钙磷涂层的成骨细胞毒性为0级。
第二方面，本发明涉及一种骨修复用可降解镁基钙磷掺锶功能涂层的制备方法，所述制备方法包括如下步骤：
A、将可降解镁及镁合金骨内植物恒温浸泡于氢氟酸中；
B、配制含锶/钙的磷酸盐混合水溶液，加入无机碱调整至合适的pH值；
C、将步骤A处理过的可降解镁及镁合金骨内植物置于步骤B所得的含锶/钙的磷酸盐混合液中恒温浸泡，取出干燥，表面沉积一层掺锶生物活性钙磷涂层。
作为优选技术方案，所述镁为纯镁，所述镁合金为Mg-Al系、Mg-Zn系、Mg-Ca系、Mg-Mn系或Mg-RE系等未经任何处理的裸金属镁合金系列。
作为优选技术方案，步骤A中，所述恒温浸泡的浸泡温度为5～45℃，更优选为20℃，氢氟酸浓度为15wt.％～40wt.％，浸泡时间为4～48h。氟化处理后生成的氧化膜可作为镁及镁合金基体的表面保护膜，防止基体被腐蚀。
作为优选技术方案，所述含锶/钙的磷酸盐混合液为1～5重量份的磷酸盐、3～9重量份的锶/钙盐的混合水溶液；所述无机碱的加入量为1～2重量份。
作为优选技术方案，步骤B中，所述磷酸盐为NH4H2PO4、Ca(H2PO4)2、Ca(H2PO4)2·H2O中的一种或其组合；所述锶/钙盐为Sr(NO3)2和Ca(NO3)2；所述无机碱为NaOH、KOH、NH3·H2O中的一种，更优选无机碱为NaOH。
作为优选技术方案，步骤B中，通过加入无机碱调整至pH为3.5-5.5。磷酸氢钙、磷酸氢锶在酸性条件下反应制得，无机碱调整前溶液pH约3.3～3.4，加无机碱调整的目的为提高磷酸盐混合液的pH以促进反应的进行，但pH过高时会导致过饱和溶液中的锶盐、钙盐析出形成悬浊液，继而无法在镁合金表面形核沉积，无法得到涂层。
本专利中所述Sr(NO3)2和Ca(NO3)2可以任意摩尔比配制，其中优选Sr(NO3)2和Ca(NO3)2的摩尔比为1:9、2:8、4:6、6:4和8:2，但Sr(NO3)2和Ca(NO3)2的摩尔比不限于以上五种。
为保证得到期望钙锶摩尔配比的无机盐涂层，需保证溶液中Sr(NO3)2和Ca(NO3)2的摩尔浓度比与产物锶钙摩尔配比一致，同时，Sr(NO3)2和Ca(NO3)2的摩尔浓度之和与磷酸二氢根摩尔浓度保持一致。
作为优选技术方案，所述含锶/钙的磷酸盐混合液具体为以下任意配方：
a.NH4H2PO4：Sr(NO3)2：Ca(NO3)2＝10:1:9(摩尔比)；
b.Ca(H2PO4)2：Sr(NO3)2：Ca(NO3)2＝5:2:8(摩尔比)；
c.NH4H2PO4：Sr(NO3)2：Ca(NO3)2＝10:4:6(摩尔比)；
d.Ca(H2PO4)2·H2O：Sr(NO3)2：Ca(NO3)2＝5:6:4(摩尔比)
e.NH4H2PO4：Sr(NO3)2：Ca(NO3)2＝10:8:2(摩尔比)。
作为优选技术方案，步骤C中，所述恒温浸泡的浸泡温度为10～40℃，浸泡时间为6～48h。镁及镁合金的静态腐蚀速率随温度的升高而升高，因此如该浸泡温度过高，会导致加快镁及镁合金的腐蚀；而钙盐、锶盐的溶解度随温度降低而降低，因此为保证过饱和溶液的浓度，该浸泡温度也不能过低。
作为优选技术方案，所述掺锶生物活性钙磷涂层与基底的结合力≥10MPa，成骨细胞毒性为0级。所述掺锶生物活性钙磷涂层有良好的生物相容性，可显著调控镁基底降解速率，并具有抑制破骨细胞抑制骨吸收、同时促成骨的功效，有益于骨修复。
本发明将骨修复用镁及镁合金材料置于氢氟酸中恒温浸泡，使表面生成一层致密的氟化膜；配置锶/钙盐的混合磷酸水溶液，将氟化处理过的镁及镁合金置于磷酸盐混合液中恒温浸泡，得到掺锶生物活性钙磷涂层。与现有技术相比，本发明具有如下有益效果：
(1)本发明提出一种可降解镁及镁合金骨内植物掺锶生物活性钙磷涂层及制备的新方法，所述涂层包括氟化膜和掺锶生物活性钙磷涂层，所述氟化膜设于镁及镁合金表层；
(2)本发明解决了镁及镁合金以及钙磷涂层无法抑制破骨细胞而不足以治疗骨质疏松性骨折的问题，在钙磷涂层中掺锶元素能够有效的治愈骨质疏松引起的骨缺损，在促进骨生成的同时抑制骨吸收，能够有效改善骨质疏松症；
(3)本发明工艺简单，操作简便，成本低；
(4)本发明适用于目前所有的镁及镁合金，适用范围广。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为镁及镁合金骨内植物掺锶生物活性钙磷涂层表面形貌的SEM图；
图2为镁及镁合金骨内植物掺锶生物活性钙磷涂层样品横截面SEM图；
图3为镁及镁合金骨内植物掺锶生物活性钙磷涂层上成骨细胞3day粘附染色结果。
具体实施方式
下面结合附图及具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以进行若干变形和改进，这些都属于本发明的保护范围。
实施例1
在骨修复用镁及镁合金表面制备掺锶生物活性钙磷涂层。将纯镁通过线切割制成
Figure BDA0002211298590000041
的试样，用丙酮和无水乙醇分别超声清洗5min后吹干；在室温下，将试样浸泡在40％氟化氢溶液中12h后，用去离子水、无水乙醇先后清洗并吹干；以Ca(H2PO4)2·H2O＝0.05M，Sr(NO3)2＝0.06M，Ca(NO3)2＝0.04M的浓度制得钙磷溶液，并使用NaOH将制得的钙磷溶液pH调整至4.5，将氟化处理过的样品放入所得溶液中，在20℃恒温水浴中浸泡36h后取出用超纯水洗净吹干，既得骨修复用镁及镁合金表面制备掺锶生物活性钙磷涂层。通过扫描电镜观察，其表面形貌见附图1，化学转化膜厚度为1.5μm，成分分析测得化学转化膜成分为MgF2，掺锶钙磷涂层厚度约为40μm，EDS测该掺锶钙磷涂层组分为Ca0.9Sr1.1(HPO4)2。SEM观测到掺锶钙磷涂层表面形貌为一层完整的层片状晶体，晶粒尺寸约为100μm。经该涂层处理后，相比于裸镁合金样品，体外降解速率降低了97％，成骨细胞毒性为0级,满足细胞相容性要求。
实施例2
在Mg-Nd-Zn-Zr合金表面制备掺锶生物活性钙磷涂层。首先将Mg-Nd-Zn-Zr合金制成
Figure BDA0002211298590000051
的试样，用丙酮和无水乙醇分别超声清洗10min并吹干；将所得式样置于20％HF溶液中，在20℃水浴恒温中浸泡14h后用去离子水、无水乙醇分别清洗吹干；配置NH4H2PO4＝0.1M，Sr(NO3)2＝0.04M，Ca(NO3)2＝0.06M浓度的钙磷溶液，并使用NaOH将制得的钙磷溶液pH调整至4.5，然后将试样放入所得钙磷溶液中在25℃浸泡24h，取出后使用超纯水清洗两次并吹干，即得到Mg-Nd-Zn-Zr合金表面制备掺锶生物活性钙磷涂层。扫描电镜下观察到化学转化膜厚度约为2μm，掺锶钙磷涂层厚度约10-15μm(附图2)。EDS测该掺锶钙磷涂层组分为Ca1.2Sr0.8(HPO4)2。使用破骨细胞评价制备的掺锶钙磷涂层对破骨细胞生长的作用，结果表明，与对照组相比掺锶钙磷涂层样品能够有效抑制破骨细胞的活性和增殖。
实施例3
在AZ31(Mg-Al系)合金多孔骨组织工程支架表面制备用于骨缺损修复的掺锶生物活性钙磷涂层。将AZ31合金制成
Figure BDA0002211298590000052
的试样，用丙酮和无水乙醇分别超声清洗10min并吹干；将所得式样置于35％HF溶液中，在20℃水浴恒温中浸泡8h后用去离子水、无水乙醇分别清洗吹干；制备NH4H2PO4＝0.1M，Sr(NO3)2＝0.08M，Ca(NO3)2＝0.02M浓度的钙磷溶液，并使用NH3·H2O将制得的钙磷溶液pH调整至5.5，将氟化处理后的试样放入置得溶液中，在10℃下恒温浸泡12h，取出后用超纯水清洗并吹干，得到掺锶生物活性钙磷涂层。扫描电镜下观察到化学转化膜厚度约为900nm，成分分析结果表明该化学转化膜为MgF2，掺锶钙磷涂层厚度约为5μm。EDS测该掺锶钙磷涂层组分为Ca0.3Sr1.7(HPO4)2。经该涂层处理后，相比于裸镁合金样品，体外降解速率降低了91％。使用MC3T3-E1成骨细胞对镁合金上掺锶钙磷涂层的细胞相容性进行评价，3day细胞直接粘附染色(附图3)结果表明，与对照组相比，掺锶钙磷涂层比未掺锶钙磷涂层更可有效促进成骨细胞的粘附和增殖，掺锶钙磷涂层的成骨细胞毒性为0级，满足细胞相容性要求。
实施例4
在WE43(Mg-RE系)合金表面制备用于骨缺损修复的掺锶生物活性钙磷涂层。将AZ31合金制成
Figure BDA0002211298590000061
的试样，用丙酮和无水乙醇分别超声清洗10min并吹干；将所得式样置于40％HF溶液中，在20℃水浴恒温中浸泡10h后用去离子水、无水乙醇分别清洗吹干；制备NH4H2PO4＝0.1M，Sr(NO3)2＝0.01M，Ca(NO3)2＝0.09M浓度的钙磷溶液，并使用NH3·H2O将制得的钙磷溶液pH调整至4.0，将氟化处理后的试样放入置得溶液中，在25℃下恒温浸泡10h，取出后用超纯水清洗并吹干，得到掺锶生物活性钙磷涂层。使用MC3T3-E1成骨细胞对镁合金上掺锶钙磷涂层的细胞活性进行评价，CCK-8细胞活性实验结果表明，与对照组相比，掺锶钙磷涂层比未掺锶钙磷涂层组细胞活性更高，并均超过100％(与对照组相比)，掺锶钙磷涂层的成骨细胞毒性为0级，满足细胞相容性要求。
实施例5
在ZK60(Mg-Zn系)合金骨钉表面制备掺锶生物活性钙磷涂层。首先将ZK60合金制成
Figure BDA0002211298590000062
的试样，用丙酮和无水乙醇分别超声清洗10min并吹干；将所得式样置于40％HF溶液中，在20℃水浴恒温中浸泡24h后用去离子水、无水乙醇分别清洗吹干；制备Ca(H2PO4)2·H2O＝0.05M，Sr(NO3)2＝0.02M，Ca(NO3)2＝0.08M的浓度制得钙磷溶液，并使用NaOH将制得的钙磷溶液pH调整至3.5，比将得到的氟化处理过的试样放置于所制备的钙磷溶液中，在20℃浸泡12h后，用超纯水清洗两次并吹干，得到掺锶生物活性钙磷涂层。扫描电镜观察到化学转化膜厚度为3μm，成分分析结果表面该化学转化膜为MgF2，掺锶钙磷涂层厚度为20μm，EDS测该掺锶钙磷涂层组分为Ca1.6Sr0.4(HPO4)2。经该涂层处理后，相比于裸镁合金样品，体外降解速率降低了93％。该掺锶生物活性钙磷涂层的细胞毒性为0级，满足细胞相容性要求，显示具有促成骨活性。使用破骨细胞评价其抑制破骨性能，结果表明其能够有效抑制破骨。将掺锶生物活性钙磷涂层样品植入骨质疏松大鼠髓内腔中评价固定股骨骨折的功效，结果显示出掺锶钙磷涂层样品良好的大鼠骨髓间充质干细胞的体外细胞相容性，增强大鼠骨髓间充质干细胞的ALP活性和矿化作用；同时，破骨细胞的密度和铺展状态显著抑制。植入2个月后，基本完成骨修复，新生骨组织明显比对照组裸镁合金和医用钛合金丰富，表明有掺锶钙磷涂层的镁合金能够显著促进骨质疏松引起的骨缺损治愈。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (2)

1.一种骨修复用可降解镁基钙磷掺锶功能涂层的制备方法，其特征在于，所述涂层包括氟化膜和掺锶生物活性钙磷涂层，所述氟化膜设于可降解镁表层；
所述骨修复用可降解镁基钙磷掺锶功能涂层的制备方法包括如下步骤：
A、将可降解镁骨内植物恒温浸泡于氢氟酸中；
B、配制含锶/钙的磷酸盐混合液，加入无机碱调整pH至预设pH值；
C、将步骤A处理过的可降解镁骨内植物置于步骤B所得的含锶/钙的磷酸盐混合液中恒温浸泡，取出洗净干燥，表面沉积一层掺锶生物活性钙磷涂层，涂层表面形貌为一层完整的层片状晶体；
所述预设pH值为4.5；
所述氟化膜厚度为1.5μm；所述掺锶生物活性钙磷涂层的厚度为40μm，所述掺锶生物活性钙磷涂层的成分为Ca0.9Sr1.1(HPO4)2；
所述磷酸盐为Ca(H2PO4)2·H2O；所述锶/钙盐为Sr(NO3)2和Ca(NO3)2；所述无机碱为NaOH；
所述含锶/钙的磷酸盐混合液中Ca(H2PO4)2·H2O的浓度为0.05M，Sr(NO3)2的浓度为0.06M，Ca(NO3)2的浓度为0.04M；
步骤C中，所述恒温浸泡的浸泡温度为20℃，浸泡时间为36h。
2.如权利要求1所述的制备方法，其特征在于，步骤A中，所述恒温浸泡为在室温下在40wt.％氢氟酸中浸泡12h。
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