CN114213147A - 一种可调控细胞粘附性能的磷酸钙生物活性支架 - Google Patents
一种可调控细胞粘附性能的磷酸钙生物活性支架 Download PDFInfo
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 21
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Abstract
本发明涉及一种可调控细胞黏附性能的磷酸钙陶瓷活性支架。该发明通过对磷酸钙生物陶瓷支架表面个性化设计钙磷微纳活性涂层，实现对细胞在黏附行为方面的精确调控，进而调控组织的修复进程。本发明中，可以通过3D打印、发泡法、压片法等工艺得到磷酸钙陶瓷支架，利用水热、矿化、电沉积等工艺得到表面钙磷微纳活性涂层。该设计在微纳米级别精确作用于细胞的黏附蛋白，进而实现细胞粘附行为的改变。本发明使材料对细胞的黏附、活性、增殖、分化的调控作用明显增强，并具有更高的亲水性、蛋白吸附性、募集干细胞以及促组织修复能力。
Description
技术领域
本发明涉及生物医用材料技术领域，公开了一种可调控细胞粘附性能的磷酸钙生物活性支架。
背景技术
由于骨外伤、骨老化、骨肿瘤等疾病造成的骨骼缺损日趋增多。目前应用于骨修复的材料主要有三种：自体骨、异体骨和骨组织工程。由于自体骨的来源有限，异体骨存在着严重的免疫排斥反应，使得骨组织工程的应用变得越来越广泛。其中生物活性陶瓷是一种良好的骨修复材料，并且在研究中发现，具有一定孔隙(通常200μm～600μm)的生物活性陶瓷具备一定的骨诱导能力，这为骨组织再生领域带来了无限希望。用于骨修复的生物陶瓷一般要求具有一定的力学性能，因此，烧结这一程序成为了制备骨组织陶瓷修复支架十分重要的一环。但是烧结后的陶瓷支架表面致密而光滑，而表面形貌对细胞行为的调控具有重要作用。由于表面形貌的缺失，致使陶瓷对细胞的黏附和募集性能大打折扣。
近些年的一些研究发现，材料表面可控的微纳米形貌能够指导间充质干细胞定向分化，例如，钛合金支架表面制备的不同直径的钛纳米管能够使骨髓间充质干细胞向成骨方向分化，并对细胞的黏附和增殖有显著的促进作用。与此同时，就我们之前研究的结果来看，具有亚微米尺寸表面晶须的双相磷酸钙，能够对周围环境的蛋白质进行大量募集，在后期成骨分化中起到至关重要的作用。在目前研究中，关于材料表面的微纳米级表面形貌对细胞的影响机制尚未完全了解。一种可能的机制是表面形貌对细胞刺激产生收缩力，从而增大细胞对材料的黏附以及亲和作用。另一种可能的机制是通过材料表面微纳形貌对周围环境中的蛋白质选择性吸附，间接影响细胞的一系列行为。所有的研究均表明，在制备生物活性陶瓷支架时，要充分考虑到表面形貌的设计，进而去调控陶瓷支架的一系列生物学功能。
基于此，一种能够在纳米级别精确作用于细胞的黏附蛋白，进而实现细胞粘附行为的改变的陶瓷活性支架是目前行业内急需的。
发明内容
本发明提供了一种可调控细胞黏附性能的磷酸钙陶瓷活性支架的制备方案。该设计能够在纳米级别精确作用于细胞的黏附蛋白，进而实现细胞粘附行为的改变。本发明使材料对细胞的黏附、活性、增殖、分化的调控作用明显增强，并具有更高的亲水性、蛋白吸附性、募集干细胞以及促组织修复能力。
为了实现上述发明目的，本发明提供以下技术方案：
一种可调控细胞黏附性能的磷酸钙陶瓷活性支架，包括：基体磷酸钙支架以及表面钙磷微纳活性涂层。
进一步的，所述基体磷酸钙支架选用陶瓷材料作为基体材料；所述陶瓷材料包括：羟基磷灰石、磷酸三钙、双相磷酸钙、磷酸四钙等一种或多种材料。
进一步的，所述基体磷酸钙支架的成型方法包括：3D打印法、压片法、发泡法中的一种或多种成型方法。
进一步的，所述陶瓷材料的孔隙率为0-90％。
进一步的，所述陶瓷材料的宏观孔径尺寸范围是100μm-1000μm。
进一步的，所述陶瓷材料的的烧结温度范围为1000℃-1300℃。
进一步的，所述钙磷微纳活性涂层制备方法包括：水热法、矿化法、电化学沉积法中的一种或多种。
进一步的，所述钙磷微纳活性涂层形状包括：棒状、针状、片状等中的一种或多种。
进一步的，所述钙磷微纳活性涂层形貌的尺寸范围为10-1000nm。
进一步的，所述钙磷微纳活性涂层具有促进细胞黏附的功能。
本发明还公开了一种上述任一可调控细胞黏附性能的磷酸钙陶瓷活性支架在制备骨修复材料中的应用。
本发明的有益效果在于：
(1)本发明制备的磷酸钙陶瓷支架可以进行个性化定制，可实现支架复杂形状、孔隙率与结构的制备。
(2)本发明制备的磷酸钙陶瓷支架活性涂层能够在纳米级别精确作用于细胞的黏附蛋白，进而实现细胞粘附行为的改变，促进细胞黏附。
(3)在超高温烧结陶瓷支架基体的情况下(1050℃～1200℃)，涂层仍旧可以保持支架的良好的生物学功能，具有良好的生物相容性，增加细胞亲和性。
(4)涂层制备的工艺方法简便，原料价格低廉，易于实施和实现大规模制备，有良好的市场应用前景。
附图说明
图1为3D打印生物活性陶瓷宏观孔结构SEM；
图2为采用EDTA-二钠钙和磷酸二氢钠作为水热介质，pH值为7时，支架的表面形貌SEM细节图；
图3为采用EDTA-二钠钙和磷酸二氢钠作为水热介质，pH值为7时，支架的表面钙磷微纳活性涂层SEM形貌图；
图4为细胞在支架钙磷微纳活性涂层表面黏附SEM图；
图5为采用模拟体液作为水热介质，支架的钙磷微纳活性涂层形貌呈现片状结构的SEM图。
具体实施方式
为了使本发明要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合实施例与附图，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。
实施例1
(1)采用挤出式3D打印设备制备陶瓷修复支架。首先将10％的聚乙烯醇缩丁醛(PVB，分子量：170000-250000)的酒精溶液和羟基磷灰石粉末用脱泡仪混合均匀。将混合好的陶瓷浆料装进打印料筒中进行3D打印。其中打印速度8mm/s，打印层厚0.32mm，挤出压力0.3MPa，孔隙间距1mm。
(2)采用马弗炉对打印好的羟基磷灰石支架进行高温烧结，以去除支架内部的粘结剂，使陶瓷支架固化。所采用的烧结温度是1200℃，烧结时间2小时。烧结后，支架的宏观孔隙率是69％，整体收缩率为35％。
(3)采用水热法制备支架的钙磷微纳活性涂层以增加烧结陶瓷对细胞的黏附募集作用。首先配置好水热介质：将2.3g EDTA-二钠钙粉末和1.5g磷酸二氢钠放入37℃的去离子水中，采用磁力搅拌器将药品充分溶解后，用1mol的HCL和NaOH溶液调节pH值至7，然后将溶液倒出备用。
(4)将制备好的水热介质连同烧结后的陶瓷支架装入水热釜中的聚四氟乙烯内胆中，水热介质放置70ml，陶瓷支架铺满内胆底部。将水热釜组装拧紧后放入烘箱中加热至120℃，反应12小时。
(5)将水热釜水冷至常温后打开，取出制备好的陶瓷支架，用去离子水洗去表面残留物后，放入烘箱烘干。经过上述步骤制备的3D打印陶瓷支架如附图1所示，陶瓷支架丝径纵横交错并层层相叠，丝径直径约300μm，支架孔隙约500μm。其通过水热方式制备的表面钙磷微纳活性涂层如附图2和附图3所示，涂层呈纳米棒状，长度约为1μm，直径约为90nm。对上述步骤中制备的具有表面钙磷微纳活性涂层的陶瓷支架进行细胞黏附实验，结果如附图4所示，细胞大面积平铺在3D打印支架表面钙磷微纳活性涂层上，伪足明显黏附在涂层纳米棒表面，表明细胞黏附效果良好。
实施例2
选用磷酸三钙作为打印原料。按照实施例1的方法，支架基体部分采用3D打印制备，随后采用水热法制备其表面钙磷微纳活性涂层，其余参数选择及制备过程与实施例1相同，不同之处在于，在水热介质选用pH为4的HNO3溶液。最终得到具有微米级钙磷活性涂层的陶瓷支架。由于磷酸三钙在酸性溶液中易释放大量钙离子，因此水热介质仅采用酸性溶液即可得到具有涂层的陶瓷支架。其涂层棒状结构长度约50μm。
实施例3
选用双相磷酸钙作为打印原料。按照实施例1的方法，支架基体部分采用3D打印制备，随后采用水热法制备其表面涂层，其余参数选择及制备过程与实施例1相同，不同之处在于，在水热介质选用pH为4的HNO3溶液。最终得到具有微米级涂层的陶瓷支架。由于双相磷酸钙内部的磷酸三钙在酸性溶液中易释放大量钙离子，因此水热介质仅采用酸性溶液即可得到具有涂层的陶瓷支架。其涂层棒状结构长度约5μm。
实施例4
选用矿化法制备陶瓷表面涂层。按照实施例1的方法，支架基体部分采用3D打印制备，随后采用矿化法制备其表面涂层，支架的制备参数选择及制备过程与实施例1相同，不同之处在于，将烧结好的陶瓷支架浸泡在模拟体液(SBF)中。浸泡约72小时后，支架表面形成一层钙磷微纳活性涂层，如附图5所示，其形态与上述棒状结构不同，表现为尺寸约2-10μm的片状结构。
实施例5
按照实施例1的方法，支架基体部分采用3D打印制备，随后采用水热法制备其表面钙磷微纳活性涂层，其余参数选择及制备过程与实施例1相同，不同之处在于，水热时间为7小时，最终得到具有纳米级涂层的陶瓷支架。由于水热时间较短，支架表面涂层尺寸较小，纳米棒长度约800nm，直径70nm。
实施例6
按照实施例1的方法，支架基体部分采用3D打印制备，随后采用水热法制备其表面钙磷微纳活性涂层，其余参数选择及制备过程与实施例1相同，不同之处在于，水热时间为24小时。最终得到具有纳米级涂层的陶瓷支架。由于水热时间较长，支架表面涂层尺寸较大，纳米棒长度约1.5μm，直径100nm。
实施例7
按照实施例1的方法，采用压片法制备陶瓷支架基体。随后采用水热法制备其表面钙磷微纳活性涂层，其余参数选择及制备过程与实施例1相同。通过上述方法制备的陶瓷支架孔隙率较3D打印法制备的陶瓷支架大幅度降低，约为10％。
实施例8
按照实施例1的方法，支架基体部分采用3D打印制备，随后采用水热法制备其表面钙磷微纳活性涂层，其余参数选择及制备过程与实施例1相同，不同之处在于，将2.3gEDTA-二钠钙粉末和1.5g磷酸二氢钠放入37℃的去离子水中，采用磁力搅拌器将药品充分溶解后，用1mol的HCL和NaOH溶液调节pH值至4，然后将溶液进行水热反应。采用上述制备方法制成的陶瓷支架表面涂层尺寸更小，纳米棒长度约为500nm，直径约为30nm。
实施例9
按照实施例1的方法，支架基体部分采用3D打印制备，随后采用水热法制备其表面钙磷微纳活性涂层，其余参数选择及制备过程与实施例1相同，不同之处在于，将2.3gEDTA-二钠钙粉末和1.5g磷酸二氢钠放入37℃的去离子水中，采用磁力搅拌器将药品充分溶解后，用1mol的HCL和NaOH溶液调节pH值至12，然后将溶液进行水热反应。采用上述制备方法制成的陶瓷支架表面涂层尺寸更大，纳米棒长度约为1.3μm，直径约为70nm。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种可调控细胞黏附性能的磷酸钙陶瓷活性支架，包括：
基体磷酸钙支架；以及
表面钙磷微纳活性涂层。
2.如权利要求1所述的磷酸钙陶瓷活性支架，其中：
所述基体磷酸钙支架选用陶瓷材料作为基体材料；
陶瓷材料包括：羟基磷灰石、磷酸三钙、双相磷酸钙、磷酸四钙等一种或多种材料。
3.如权利要求2所述的磷酸钙陶瓷活性支架，其中：
所述基体磷酸钙支架的成型方法包括：3D打印法、压片法、发泡法中的一种或多种成型方法。
4.如权利要求2所述的磷酸钙陶瓷活性支架，其中：
所述陶瓷材料的孔隙率为0-90％。
5.如权利要求2所述的磷酸钙陶瓷活性支架，其中：
所述陶瓷材料的宏观孔径尺寸范围是100μm-1000μm。
6.如权利要求2所述的磷酸钙陶瓷活性支架，其中：
所述陶瓷材料的的烧结温度范围为1000℃-1300℃。
7.如权利要求1所述的磷酸钙陶瓷活性支架，其中：
所述钙磷微纳活性涂层制备方法包括：水热法、矿化法、电化学沉积法中的一种或多种。
8.如权利要求1所述的磷酸钙陶瓷活性支架，其中：
所述钙磷微纳活性涂层形状包括：棒状、针状、片状等中的一种或多种。
9.如权利要求1所述的磷酸钙陶瓷活性支架，其中：
所述钙磷微纳活性涂层形貌的尺寸范围为10-1000nm。
10.一种如权利要求1～9任一所述可调控细胞黏附性能的磷酸钙陶瓷活性支架在制备骨修复材料中的应用。
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Application publication date: 20220322 |