CN110151361B - 一种骨缺损的修复装置及其制备方法和缓释药物组合物 - Google Patents
一种骨缺损的修复装置及其制备方法和缓释药物组合物 Download PDFInfo
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Abstract
本发明提供一种骨缺损的修复装置及其制备方法和缓释药物组合物，所述修复装置包括若干支架层和若干药物缓释层，支架层和药物缓释层从上至下交替排布，支架层包括若干平行的支架凸棱，药物缓释层包括若干平行的药物缓释凸棱，相邻的支架层和药物缓释层中支架凸棱与药物缓释凸棱交叉。所述修复装置包括若干支架层和若干药物缓释层，所述支架层和所述药物缓释层从上至下交替排布，通过3D打印技术制备，外形与缺损区完全匹配，具有利于骨长入的孔径与良好的连通性，优选地，所述药物缓释层的材料包括唑来磷酸和磷酸三钙，具有良好的药物缓释性能，可双向调控成骨细胞、破骨细胞功能，促进骨质疏松性骨缺损的修复。
Description
技术领域
本发明属于骨修复技术领域，特别是涉及一种骨缺损的修复装置及其制备方法和缓释药物组合物。
背景技术
骨质疏松症是一种全身性骨骼病变，其病理特征为骨质量降低，骨微结构破坏。骨质疏松症的最严重危害是并发骨质疏松性骨折。骨质疏松性骨折以粉碎性骨折多见，骨折复位后多存在骨缺损，固定后骨折区稳定性差，易发生骨折移位、内固定松动、固定钢板拔出等，导致内固定的完全失败，最终引发骨折延迟愈合或不愈合，严重影响患者生活质量，提高死亡率。目前，临床上骨缺损修复的“金标准”是自体骨移植，除了手术时间延长、二次手术、供区感染、疼痛、数量有限等常见问题外，骨质疏松患者还存在供区骨质量低和受区骨环境差等因素，难以广泛应用。因此，骨质疏松性骨缺损的修复仍是一个棘手的临床问题。
目前，被广泛研究与使用的骨修复组织支架主要为高分子材料。天然的高分子材料如壳聚糖、透明质酸、胶原等，生物活性高，利于细胞生长与粘附，促进骨缺损区修复，但力学强度不足，无法承重或仅部分承重，易出现缺损区塌陷，影响骨质疏松性骨缺损区域的修复，严重限制其应用范围。人工合成高分子材料(磷酸三钙、聚乳酸、聚羟基乙酸、聚乳酸聚乙醇酸等)力学强度高、易于生产，但生物活性较低。更重要的是，上述材料均无法针对性调控骨质疏松性骨缺损区成骨、破骨细胞，促进缺损区修复。
发明内容
鉴于以上所述现有技术的缺点，本发明的目的在于提供一种骨缺损的修复装置及其制备方法和缓释药物组合物，所述修复装置包括若干支架层和若干药物缓释层，支架层和药物缓释层从上至下交替排布，支架层包括若干平行的支架凸棱，药物缓释层包括若干平行的药物缓释凸棱，相邻的支架层和药物缓释层中支架凸棱与药物缓释凸棱交叉。所述修复装置包括若干支架层和若干药物缓释层，所述支架层和所述药物缓释层从上至下交替排布，通过3D打印技术制备，外形与缺损区完全匹配，具有利于骨长入的孔径与良好的连通性，优选地，所述药物缓释层的材料包括唑来磷酸和磷酸三钙，具有良好的药物缓释性能，可双向调控成骨细胞、破骨细胞功能，促进骨质疏松性骨缺损的修复。
为实现上述目的及其他相关目的，本发明第一方面提供一种骨缺损的修复装置，包括若干支架层和若干药物缓释层，所述支架层和所述药物缓释层从上至下交替排布，所述支架层包括若干平行的支架凸棱，所述药物缓释层包括若干平行的药物缓释凸棱，相邻的支架层和药物缓释层中支架凸棱与药物缓释凸棱交叉。
优选地，还包括如下技术特征中的至少一项：
1)每相隔药物缓释层的两层支架层中的支架凸棱平行排布；所述支架凸棱可以平行交错排布，也可以平行重合或部分重合排布；
2)每相隔支架层的两层药物缓释层中的药物缓释凸棱平行排布；所述药物缓释凸棱可以平行交错排布，也可以平行重合或部分重合排布；
3)相邻的支架层和药物缓释层中支架凸棱与药物缓释凸棱交叉的角度α为45～90°，如45～60°或60～90°。
更优选地，特征1)中，每相隔药物缓释层的两层支架层中的支架凸棱平行错位排布。
更优选地，特征2)中，每相隔支架层的两层药物缓释层中的药物缓释凸棱平行错位排布。
优选地，还包括如下技术特征中的至少一项：
1)所述药物缓释层包括以下原料及质量百分比：
磷酸三钙5～30％，如5～25％或25～30％；
唑来磷酸0～30％，如0～5％、5～10％或10～30％；
水62～94.5％，如62～63％、63～67％或67～94.5％；
成型剂0.5～8％，如0.5～2％、2～3％或3～8％；
磷酸三钙的主要成分为钙、磷，与骨基质的无机成分相似，是骨缺损修复的理想材料。
更优选地，所述药物缓释层包括唑来磷酸和磷酸三钙，唑来磷酸具有双向调控成骨细胞、破骨细胞功能，利用唑来磷酸双向调节功能，改善骨缺损区微环境，促进骨质疏松性骨缺损的修复。磷酸三钙降低唑来磷酸释放速度，防止药物快速释放。骨质疏松性骨缺损的缺损区破骨细胞功能异常活跃，影响缺损区修复，用唑来磷酸调控破骨细胞功能，促进缺损区修复。
2)所述支架层包括以下原料及质量百分比：
生物可降解聚合物60～100％，如60～70％、70～90％或90～100％；
羟基磷灰石0～40％，如0％～10％、10％～30％或30％～40％。
所述羟基磷灰石能提高生物可降解聚合物的力学性能与生物活性，降低其降解速度，支架层的生物学、力学性能与骨质疏松性骨缺损修复需求相匹配。
更优选地，还包括如下技术特征中的至少一项：
a)特征1)中，所述成型剂选自单油酸甘油酯、三油酸甘油酯和单硬脂酸甘油酯中的至少一种；
b)特征1)中，唑来磷酸与磷酸三钙的质量比为1：6～6：1，如1：6～1：5、1：5～2.5：1或2.5：1～6：1；
c)特征2)中，所述生物可降解聚合物选自聚己内酯、聚乳酸和聚乳酸-羟基乙酸共聚物中至少一种。
优选地，骨缺损的修复装置的孔隙率为50～80％。所述孔隙率指骨缺损的修复装置中孔隙体积与骨缺损的修复装置在自然状态下总体积的百分比。
本发明第二方面提供上述骨缺损的修复装置的制备方法，包括如下步骤：
1)通过CT扫描获得骨缺损区形态；
2)修复装置建模以获得修复装置模型，所述修复装置模型以步骤1)得到的骨缺损区形态为外轮廓；
3)依据修复装置模型进行3D打印。
优选地，3D打印时使用2个喷头，一个喷头用于打印支架层，另一个喷头用于打印药物缓释层。
本发明第三方面提供一种用于骨缺损的修复装置的缓释药物组合物，包括磷酸三钙和唑来磷酸，唑来磷酸与磷酸三钙的质量比为1：6～6：1，如1：6～1：5、1：5～2.5：1或2.5：1～6：1。
如上所述，本发明至少具有以下有益效果之一：
1)所述修复装置包括若干支架层和若干药物缓释层，所述支架层和所述药物缓释层从上至下交替排布，具有利于骨长入的孔径与良好的连通性，其中所述药物缓释层作为修复装置中的骨架并且与所述支架层共同组成该装置，更利于促进骨质疏松性骨缺损的修复；
2)3D打印技术的引入，可以个性化定制与缺损区完全匹配的个性化的骨缺损的修复装置，骨缺损的修复装置与缺损区完全匹配，具有利于骨长入的孔径(可通过软件预设)与良好的连通性；
3)3D打印唑来磷酸/磷酸三钙药物缓释体系具有良好的药物缓释性能，其中唑来磷酸可双向调控成骨细胞、破骨细胞功能，促进骨质疏松性骨缺损的修复，达到了材料功能化的目的。
4)3D打印技术可以精确控制唑来磷酸在多孔支架中的位置与浓度，相比传统工艺制备的药物缓释体系，可以获得更好的药物缓释性能。
5)避免了繁琐的加工工艺，通过3D打印技术制备骨修复材料，可重复性好，可进行快速批量生产。
附图说明
图1显示为本发明骨缺损的修复装置的俯视图。
图2显示为本发明骨缺损的修复装置的侧视图。
图3显示为使用实施例1的骨缺损的修复装置(使用21天)后的吸光值。
附图标记：
1 支架层
11 支架凸棱
2 药物缓释层
21 药物缓释凸棱
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效。
请参阅图1和图3。须知，本说明书所附图式所绘示的结构、比例、大小等，均仅用以配合说明书所揭示的内容，以供熟悉此技术的人士了解与阅读，并非用以限定本发明可实施的限定条件，故不具技术上的实质意义，任何结构的修饰、比例关系的改变或大小的调整，在不影响本发明所能产生的功效及所能达成的目的下，均应仍落在本发明所揭示的技术内容得能涵盖的范围内。同时，本说明书中所引用的如“上”、“下”、“左”、“右”、“中间”及“一”等的用语，亦仅为便于叙述的明了，而非用以限定本发明可实施的范围，其相对关系的改变或调整，在无实质变更技术内容下，当亦视为本发明可实施的范畴。
实施例1
一种骨缺损的修复装置，如图1和图2所示，包括若干支架层1和若干药物缓释层2，所述支架层1和所述药物缓释层2从上至下交替排布，所述支架层1包括若干平行的支架凸棱11，所述药物缓释层2包括若干平行的药物缓释凸棱21，相邻的支架层1和药物缓释层2中支架凸棱11与药物缓释凸棱21交叉呈90°即α角的角度，每相隔药物缓释层2的两层支架层中的支架凸棱11平行错位排布，每相隔支架层1的两层药物缓释层2中的药物缓释凸棱21平行错位排布，孔隙率为63％，所述药物缓释层2包括以下原料及质量百分比：唑来磷酸ZA5％；磷酸三钙TCP 25％；水67％；单油酸甘油酯3％，所述支架层1包括以下原料及质量百分比：聚己内酯PCL 90％；羟基磷灰石HA 10％。
制备方法包括如下步骤：
1)通过CT扫描获得骨缺损区形态；
2)修复装置建模以获得修复装置模型，所述修复装置模型以步骤1)得到的骨缺损区形态为外轮廓；
3)依据修复装置模型进行3D打印，3D打印时使用2个喷头，一个喷头用于打印支架层，另一个喷头用于打印药物缓释层。
该装置可促进骨髓间充质干细胞成骨分化，钙结节生成数量显著增加，见图3中PCL/HA/ZA/TCP(使用21天)，图3中PCL/HA为现有的骨缺损的修复装置(与实施例1的孔隙率相同)，可见效果显著；另外，减少破骨细胞数量，将破骨细胞数量减少45％。
实施例2
一种骨缺损的修复装置，包括若干支架层1和若干药物缓释层2，所述支架层1和所述药物缓释层2从上至下交替排布，所述支架层1包括若干平行的支架凸棱11，所述药物缓释层2包括若干平行的药物缓释凸棱21，相邻的支架层1和药物缓释层2中支架凸棱11与药物缓释凸棱21交叉呈60°即α角的角度，每相隔药物缓释层2的两层支架层中的支架凸棱11平行错位排布，每相隔支架层1的两层药物缓释层2中的药物缓释凸棱21平行错位排布，孔隙率为63％，所述药物缓释层2包括以下原料及质量百分比：唑来磷酸ZA 10％；磷酸三钙TCP 25％；水63％；单油酸甘油酯2％，所述支架层1包括以下原料及质量百分比：聚己内酯PCL70％；羟基磷灰石HA 30％。
制备方法包括如下步骤：
1)通过CT扫描获得骨缺损区形态；
2)修复装置建模以获得修复装置模型，所述修复装置模型以步骤1)得到的骨缺损区形态为外轮廓；
3)依据修复装置模型进行3D打印，3D打印时使用2个喷头，一个喷头用于打印支架层，另一个喷头用于打印药物缓释层。
该装置可促进骨髓间充质干细胞成骨分化，将骨髓间充质干细胞碱性磷酸酶活性提高27.3％(使用7天)，将破骨细胞数量减少56.7％(使用4天)。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (8)
1.一种骨缺损的修复装置，其特征在于，包括若干支架层（1）和若干药物缓释层（2），所述支架层（1）和所述药物缓释层（2）从上至下交替排布，所述支架层（1）包括若干平行的支架凸棱（11），所述药物缓释层（2）包括若干平行的药物缓释凸棱（21），相邻的支架层（1）和药物缓释层（2）中支架凸棱（11）与药物缓释凸棱（21）交叉；相邻的支架层（1）和药物缓释层（2）中支架凸棱（11）与药物缓释凸棱（21）交叉的角度α为45~90°；
其中，所述药物缓释层（2）包括以下原料及质量百分比：
磷酸三钙 5~30%；
唑来磷酸 0~30%；
水 62~94.5%；
成型剂 0.5~8%；
所述支架层（1）包括以下原料及质量百分比：
生物可降解聚合物 60~100%；
羟基磷灰石 0 ~40%。
2.如权利要求1所述的骨缺损的修复装置，其特征在于，还包括如下技术特征中的至少一项：
a）每相隔药物缓释层（2）的两层支架层中的支架凸棱（11）平行排布；
b）每相隔支架层（1）的两层药物缓释层（2）中的药物缓释凸棱（21）平行排布。
3.如权利要求2所述的骨缺损的修复装置，其特征在于，特征a）中，每相隔药物缓释层（2）的两层支架层中的支架凸棱（11）平行错位排布。
4.如权利要求2所述的骨缺损的修复装置，其特征在于，特征b）中，每相隔支架层（1）的两层药物缓释层（2）中的药物缓释凸棱（21）平行错位排布。
5.如权利要求1所述的骨缺损的修复装置，其特征在于，还包括如下技术特征中的至少一项：
a）所述成型剂选自单油酸甘油酯、三油酸甘油酯和单硬脂酸甘油酯中的至少一种；
b）唑来磷酸与磷酸三钙的质量比为1：6~6：1；
c）所述生物可降解聚合物选自聚己内酯、聚乳酸和聚乳酸-羟基乙酸共聚物中至少一种。
6.如权利要求1所述的骨缺损的修复装置，其特征在于，骨缺损的修复装置的孔隙率为50~80%。
7.如权利要求1至6任一项所述的骨缺损的修复装置的制备方法，其特征在于，包括如下步骤：
a）通过CT扫描获得骨缺损区形态；
b）修复装置建模以获得修复装置模型，所述修复装置模型以步骤a）得到的骨缺损区形态为外轮廓；
c）依据修复装置模型进行3D打印。
8.如权利要求7所述的骨缺损的修复装置的制备方法，其特征在于，3D打印时使用2个喷头，一个喷头用于打印支架层，另一个喷头用于打印药物缓释层。
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