CN106267358B - 一种促进成骨生长的复合纳米材料 - Google Patents
一种促进成骨生长的复合纳米材料 Download PDFInfo
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Abstract
本发明涉及纳米材料领域，具体是一种促进成骨生长的复合纳米材料，由纳米二氧化钛和羟丁基壳聚糖制成。本发明将纳米TiO2与壳聚糖形成新的纳米材料：温敏性羟丁基壳聚糖二氧化钛纳米微球复合体，并通过一系列细胞分子生物学和动物学实验进行研究，提供了一种生物安全性高、可注射、可填充并促进成骨细胞生长，同时具有抗炎性和抗菌性的纳米复合材料，可作为用于骨组织缺损修复的新材料。
Description
技术领域
本发明涉及医学填充纳米材料技术领域，具体地说，是一种可用于缺损骨质的填充，促进成骨生长的纳米复合材料。
背景技术
纳米二氧化钛(TiO2)作为无机纳米材料的闪光点，已经广泛应用在包括医药和食品在内的诸多领域，但是由于它能够产生大量的活性氧，可破坏细胞膜，并可以影响蛋白质和基因，存在一定的缺陷。温敏性羟丁基壳聚糖是一种可生物降解的聚阳离子多糖，具有生物降解，具有独特的跨细胞膜的能力，具有稳定的“立体”效应，能增强纳米粒子在溶液中的稳定性，避免团聚。
但是关于将纳米TiO2与温敏性羟丁基壳聚糖组合形成新的促进成骨生长的纳米符合材料目前还未见报道。
发明内容
本发明的目的在于提供一种生物安全性高、可注射、可填充并促进成骨细胞生长，同时具有抗炎性和抗菌性的纳米复合材料。
本发明的第一方面，提供一种促进成骨生长的复合纳米材料，由纳米二氧化钛和羟丁基壳聚糖制成，所述的纳米二氧化钛和羟丁基壳聚糖的重量比是(1-3):1。
优选的，所述的促进成骨生长的复合纳米材料是采用微乳液法制备的温敏性羟丁基壳聚糖二氧化钛纳米微球复合体(缩写TiO2@CTS)。
优选的，所述的温敏性羟丁基壳聚糖二氧化钛纳米微球复合体的制备方法包括以下步骤：将纳米二氧化钛，羟丁基壳聚糖，环己烷，TritonX-100，正己醇，共同加入ddH2O，37℃磁力搅拌，所得溶液体系用PBS 3000rpm离心清洗2遍，4℃保存。
本发明的第二方面，提供上述促进成骨生长的复合纳米材料的制备方法，包括以下步骤：将纳米二氧化钛，羟丁基壳聚糖，环己烷，TritonX-100，正己醇，共同加入ddH2O，37℃磁力搅拌，所得溶液体系用PBS 3000rpm离心清洗2遍，4℃保存。
优选的，所述的促进成骨生长的复合纳米材料的制备方法，包括以下步骤：用微乳液法制备，将纳米二氧化钛50mg～150mg，羟丁基壳聚糖50mg，3～5ml环己烷，1～2mlTritonX-100，1～2ml正己醇，共同加入18ml ddH2O，37℃磁力搅拌2h，所得溶液体系用PBS3000rpm离心清洗2遍，4℃保存。
在本发明的一个优选实施例中，所述的促进成骨生长的复合纳米材料的制备方法，包括以下步骤：用微乳液法制备，将纳米二氧化钛50mg，羧丁基壳聚糖50mg，4.2ml环己烷，1mlTritonX-100，1ml正己醇，共同加入18ml ddH2O，37℃磁力搅拌2h，所得溶液体系用PBS 3000rpm离心清洗2遍，4℃保存。
本发明的第三方面，提供上述促进成骨生长的复合纳米材料在制备骨质填充材料中的应用。
本发明的第四方面，提供一种促进成骨生长的骨质填充材料，所述的促进成骨生长的骨质填充材料中包含上述复合纳米材料。
优选的，所述的促进成骨生长的骨质填充材料中上述复合纳米材料和骨形态发生蛋白(BMPs)联用。
本发明优点在于：
本发明将纳米TiO2与壳聚糖形成新的纳米材料：温敏性羟丁基壳聚糖二氧化钛纳米微球复合体，并通过一系列细胞分子生物学和动物学实验进行研究，提供了一种生物安全性高、可注射、可填充并促进成骨细胞生长，同时具有抗炎性和抗菌性的纳米复合材料，可作为替代骨粉、效果更好的新材料。
附图说明
图1.透射电镜观察及Zeta电位值。
图2.MTT比色法细胞活性检测结果。
图3.血液相容性实验结果。
图4.TiO2@CTS的成骨水平的观察。
图5.在软件中选取观察范围。
图6.在Image-Pro软件中选取新生骨区域并测量。
具体实施方式
下面结合实施例对本发明提供的具体实施方式作详细说明。
实施例1
1、TiO2@CTS的制备：
用微乳液法制备TiO2@CTS，纳米二氧化钛50mg，羧丁基壳聚糖50mg，4.2ml环己烷，1mlTritonX-100，1ml正己醇，共同加入18ml ddH2O，37摄氏度磁力搅拌2h，所得溶液体系用PBS 3000rpm离心清洗2遍，4度冰箱放置留用。
2、TiO2@CTS的表征：
应用透射电子显微镜观察形态(图1a)：TiO2呈边界清晰的球形，粒径约20-30nm，颗粒分散均匀。与壳聚糖结合后形成球形的TiO2@CTS颗粒后边界模糊，电镜观察羟基壳聚糖已成功复合至二氧化钛的表面。图1b显示三组材料的Zeta电位值分别为：壳聚糖-19mv、TiO2 8.3mv，TiO2@CTS通过静电相互作用表现出轻微的负电荷约-2.9mv。上述结果充分说明羟基-壳聚糖可以结合二氧化钛复合材料，并可用于进一步的生物学研究。
3、TiO2@CTS生物安全性评价：
应用MTT比色法检测证明，经不同浓度TiO2@CTS处理的MC3T3细胞均保持良好增长(图2)。
血液相容性实验：
如图3所示：与对照组相比，TiO2@CTS组未见明显的溶血反应，进一步证实了TiO2@CTS纳米粒子的生物安全性。
4、TiO2@CTS的成骨水平的观察：
采用12只新西兰大白兔，每只体重2.5Kg，于兔顶盖骨区制作骨缺损模型，并在各缺损区域内植入不同材料。手术过程如下：兔全身麻醉后颅顶部备皮，常规外科消毒后沿颅顶中线切开皮肤，暴露骨膜，切开颅骨骨膜，于颅骨骨膜下分离，显露顶骨。以直径5mm取骨环钻在两侧顶骨以颅骨中线对称制造4处环形骨缺损区，去除外侧颅骨板，直径5mm，深约1mm。4处环形骨缺损区分别充填：Matrigle(A组空白对照组)、TiO2@CTS(B组)、TiO2@CTS+BMPs(C组)、异种异体骨粉(D组即阳性对照组)，将软组织复位逐层缝合。术后8周处死动物，颅骨取材后应用甲苯胺蓝染色对不脱钙骨组织标本观察，评价温敏性羟基几丁糖与rhBMP-2/TiO2纳米微球缓释系统的成骨水平。
结果显示：术后1周，新西兰兔颅顶伤口均达到I期愈合，未出现伤口感染或裂开现象。术后8周，处死动物并取标本。肉眼观察A组无明显骨组织生长，B组、C组和D组可见骨组织生长。
组织病理学观察比较各组不脱钙的骨组织切片：除A组未见明显骨组织生长外(图4a)，其余3组均可见新骨组织形成，有哈弗氏管样结构出现，B组可见新骨片状形成，材料区较稀疏边缘区较致密(图4b)；C组可见骨组织形成片状互相连接，结构较均匀(图4d)；D组可见骨组织由边缘区向材料区生长(图4b)；上述实验结果证实TiO2@CTS能够有效促进成骨的生长。
骨形态测量学检查：光学显微镜(Olympus P70，日本)下不同放大倍数(×4，×10，×20，×40)观察骨组织再生情况并采集图片，使用Image-ProPlus6.0(MediaCybemetics,美国)图像分析软件，选定新生骨区域，测量新生骨组织所占面积(见图5、图6)。结果表明：A组新生骨所占面积为(2.99±5.11)％，B组为(42.23±5.69)％，C组为(63.04±4.56)％，D组为(37.71±7.23)％。经统计学分析，两两组间比较，结果A组与其他各组有明显差异，C组与B、D组有明显差异，B组与D组间无明显差异。表明TiO2@CTS具有与骨粉类似的成骨作用，而TiO2@CTS+BMPs成骨作用更好。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (5)
1.一种促进成骨生长的复合纳米材料，其特征在于，由纳米二氧化钛和羟丁基壳聚糖制成，所述的纳米二氧化钛和羟丁基壳聚糖的重量比是(1-3):1；所述的复合纳米材料是采用微乳液法制备的温敏性羟丁基壳聚糖二氧化钛纳米微球复合体；所述的温敏性羟丁基壳聚糖二氧化钛纳米微球复合体的制备方法包括以下步骤：将纳米二氧化钛，羧丁基壳聚糖，环己烷，TritonX-100，正己醇，共同加入ddH2O，37℃磁力搅拌，所得溶液体系用PBS3000rpm离心清洗2遍，4℃保存。
2.一种促进成骨生长的复合纳米材料的制备方法，其特征在于，包括以下步骤：用微乳液法制备，将纳米二氧化钛50mg～150mg，羟丁基壳聚糖50mg，3～5ml环己烷，1～2mlTritonX-100，1～2ml正己醇，共同加入18ml ddH2O，37℃磁力搅拌2h，所得溶液体系用PBS3000rpm离心清洗2遍，4℃保存。
3.根据权利要求1所述的复合纳米材料在制备骨质填充材料中的应用。
4.一种促进成骨生长的骨质填充材料，其特征在于，所述的促进成骨生长的骨质填充材料中包含权利要求1所述的复合纳米材料。
5.根据权利要求4所述的促进成骨生长的骨质填充材料，其特征在于，所述的促进成骨生长的骨质填充材料中复合纳米材料和骨形态发生蛋白联用。
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