CN112870450A - 载二甲双胍人工骨材料以及制备人工骨的方法 - Google Patents
载二甲双胍人工骨材料以及制备人工骨的方法 Download PDFInfo
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Abstract
本发明公开一种载二甲双胍人工骨材料以及制备人工骨的方法，该方法包括：将羟基磷灰石颗粒、胶原蛋白粉末、分散剂、二甲双胍和微量元素溶于去离子水，并调节PH值，混合均匀得到浆料；将浆料球磨和超声振荡后，制得墨水悬浮液；将墨水悬浮液装入3D直写成型设备的喷筒中，将计算机与直写成型设备连接，设置3D直写设备的程序以及仿骨结构模型，通过控制墨水悬浮液的流变性能逐层叠加在空气中打印，干燥后得到载二甲双胍仿骨结构材料；其中，仿骨结构模型的建立步骤为采集患者骨缺损部位信息，通过CAD软件建立个体化骨支架三维模型。本发明人工骨材料，可发挥修复骨缺损和药物载体的双重作用，具有良好的生物相容性及诱导骨再生能力。
Description
技术领域
本发明属于生物医学材料制备成型领域，具体涉及载二甲双胍人工骨材料以及制备人工骨的方法。
背景技术
骨缺损是骨科临床常见的一种疾病，可由创伤，肿瘤侵蚀，骨髓炎等多种因素导致，目前其治疗主要是用合适的植入骨填充缺损部位，恢复骨组织的解剖关系和生理功能。自体骨、异体骨移植是传统的骨缺损修复方法，但存在着很多缺陷。自体骨来源有限，不能满足大块的骨缺失，会对患者造成二次伤害，还会遗留术后感染和疼痛等并发症。异种骨和同种异体骨都会存在免疫排斥的问题，且同种异体骨的骨诱导性较差，不能满足骨缺损的修复需求。骨组织工程支架近来成为骨组织工程的研究热点。天然骨的结构十分精密复杂，由有机质，无机质和少量的水组成。有机质主要为胶原纤维，90％以上是I型胶原蛋白，赋予了骨良好的韧性和弹性，无机质主要为羟基磷灰石晶体，赋予了骨足够的硬度和强度。因此，理想的骨支架应与天然骨在材料组成和结构上尽量接近。其应该满足以下条件：1)具有良好的生物相容性；2)具有合适的力学性能；3)有微孔结构，使新生骨组织得以长入；4)其吸收速度与新骨生长速度大致保持同步；5)易于加工成所需的大小和形状。生物陶瓷是比较常用的骨支架制备材料，主要分为羟基磷灰石、磷酸三钙和生物活性玻璃。羟基磷灰石具有良好的骨诱导和骨结合能力，同时能够较好地支持成骨细胞的黏附、增殖及分化，在人体中的降解速度十分缓慢。但其脆性较大，断裂韧性远小于正常密质骨，抗张抗压强度也不能完全模仿生理骨组织。β-磷酸三钙同样具有良好的骨诱导性和生物相容性，其降解过程中释放钙离子和磷酸根离子，有助于促进新骨形成，但其降解速度过快，不适用于大面积骨缺损的修复，脆性也较大，抗张抗压强度不够。生物活性玻璃可与骨组织紧密结合，促进骨组织的再生和血管化，但其成骨活性不如羟基磷灰石和β-磷酸三钙。有学者将羟基磷灰石与高分子材料混合，通过控制材料比例一定程度解决了生物陶瓷脆性过大，抗压能力不够的问题。如何将有机材料、无机材料的优缺点互补，制备机械性能和生物性能均较好的复合支架，是目前的研究热点。
发明内容
本发明提供一种载二甲双胍人工骨材料及利用3D直写成型技术制备载药人工骨材料的方法。本发明运用直写成型技术可实现骨支架的个体化制备，将有机和无机材料的结合可改善骨支架性能，制备出生物相容性，机械性能均较好的骨支架。同时，本发明在骨支架中加入二甲双胍成分，制得的骨支架具有治疗骨质疏松、糖尿病、减轻肥胖病人体重，促进骨缺损恢复等多种功效。
为实现上述目的，本发明提供的一种载二甲双胍人工骨材料包括羟基磷灰石颗粒、胶原蛋白粉末、分散剂、二甲双胍、微量元素和去离子水。
为实现上述目的，本发明提供的一种利用3D直写成型技术制备载二甲双胍人工骨材料的方法包括以下步骤：
(1)将羟基磷灰石颗粒、胶原蛋白粉末、分散剂、二甲双胍和微量元素溶于去离子水，并调节PH值，混合均匀得到浆料；
(2)将浆料球磨和超声振荡后，制得墨水悬浮液；
(3)将墨水悬浮液装入3D直写成型设备的喷筒中，将计算机与直写成型设备连接，设置3D直写设备的程序以及仿骨结构模型，通过控制墨水悬浮液的流变性能逐层叠加在空气中打印，干燥后得到载二甲双胍仿骨结构材料；其中，仿骨结构模型的建立步骤为采集患者骨缺损部位信息，通过CAD软件建立个体化骨支架三维模型。
优选地，所述羟基磷灰石颗粒的粒径范围为0.8-10um。
优选地，所述分散剂为柠檬酸盐、聚丙烯酸、聚丙烯酸铵、聚乙酰亚胺中的一种或几种。
优选地，所述浆料中的二甲双胍含量为150mg/mL。
优选地，所述分散剂的加入量为羟基磷灰石颗粒质量的0.2-3％。
优选地，调节PH值范围为4-10。
优选地，调节PH值的酸碱调节剂包括碳酸、磷酸、柠檬酸、氢氧化镁、氢氧化钙中的一种或几种。
优选地，所述微量元素包括镁、锌、氯中的一种或几种。
优选地，所述步骤(2)中的球磨时间为12h，转速为90-200rmp；超声震荡时间为12h。
本发明的发明构思如下：
有研究表明，二甲双胍在24小时内可呈剂量依赖性地促进成骨细胞的增生，Ⅰ型胶原、骨形态发生蛋白2的表达和矿化结节的形成。还可通过上调骨保护素/骨保护素配体的比值抑制破骨细胞的形成和分化。还有研究证实，二甲双胍可促进间充质干细胞向成骨细胞转化。刺激间充质干细胞细胞碱性磷酸酶的活性，促进矿化结节的形成，增加成骨标志物，RUNX2和OSX的表达。而间充质干细胞表面有功能性有机阳离子转运蛋白-1(OCT-1)的表达，OCT-1是介导二甲双胍转运的跨膜蛋白，说明间充质干细胞和二甲双胍可联合作用促进骨的再生。二甲双胍还可通过促进外源性骨形成相关蛋白的合成，对小鼠脂肪干细胞的促骨生成作用产生影响。由此可见，二甲双胍可通过多种途径促进骨的再生，在骨质疏松和骨缺损的治疗中可发挥积极的作用。
直写成型技术是一种新型的3D打印技术，可使骨支架的制备个体化，在材料性能、生物活性、结构组成上与天然骨更接近。其工作过程为：在计算机上进行建模，将模型输入造型设备，通过控制特定成分的墨水材料的流变性能，将墨水喷出，在空气中固化成型。固化成型的方式可分为自固化成型和外固化成型。与现有的3D打印技术相比，直写成型技术可打印材料来源广泛，墨水材料可混合有机、无机材料，改善骨支架的性能。甚至可打印蛋白、细胞、细胞因子等生物活性成分，包容性很强。固化成型过程简便易操作，生产周期短，效率高。而制备可自固化成型的墨水材料是十分关键的一步。自固化成型为凭借悬浮液自身的条件实现快速固化，对墨水材料的要求较高。悬浮液必须满足以下3个要求：1)在高剪切作用下，悬浮液的黏度很低，保证悬浮液可顺利通过喷嘴而不发生堵塞；2)无剪切作用时迅速固化，且固化后的线形流体有较好的弹性性能和强度，即使在无支撑条件下也可保持原有形状；3)悬浮液需有尽可能高的固相体积分数，高固相体积分数可避免成型结构在干燥和烧结过程中因收缩引起的开裂或变形。
因此，3D直写成型技术能够很好满足制备个体化人工骨的需求。而良好的墨水材料是成功实现3D直写成型制备人造骨的前提。同时，基于二甲双胍在降糖、体重减轻、抗肿瘤和骨代谢等多方面发挥的显著作用，其对于改善合并有骨质疏松或糖尿病的骨缺损病人的恢复和预后可发挥重要的作用。因此，对于本领域的技术人员而言，发展载二甲双胍人工骨材料对于骨缺损的术后修复具有重要意义。
本发明所采用的技术方案与现有技术相比，至少具有下列优点：
1)本发明的载二甲双胍人工骨材料，可发挥修复骨缺损和药物载体的双重作用，具有良好的生物相容性及诱导骨再生能力。此外，二甲双胍可促进骨的再生，对骨质疏松和糖尿病均可发挥一定的治疗作用。
2)本发明的载二甲双胍人工骨材料采用直写成型技术，可根据患者骨缺损实现支架的个性化定制。墨水材料中包含仿骨的无机成分羟基磷灰石，以及有机成分胶原蛋白，在结构仿骨的同时，将无机材料和有机材料结合，使得支架具有良好的生物性能和力学性能。
3)本发明采用的直写成型技术制备过程简单，成型快速便捷，易于操作。成型过程不需要热塑加工，不需要后续加工过程，生产周期短，成本低。
具体实施方式
为了更好的理解本发明，下面通过具体实施方式对本发明进一步描述，但所列举的实施例并不限制本发明的保护范围。
实施例1
羟基磷灰石粒径为0.8um，胶原蛋白粉末，去离子水，聚乙酰亚胺，二甲双胍，氯化铵混合形成墨水浆料；其中，聚乙酰亚胺为羟基磷灰石干粉含量的0.6％，氯化铵用量为墨水质量的0.06％，二甲双胍浓度为150mg/mL，采用磷酸调节PH值为4。制得的墨水浆料固相含量为44％。
混合好的浆料置于球磨机上以90rmp转速球磨12h，超声振荡12h，即得到所需墨水悬浮液。所得墨水悬浮液具有很好的剪切致稀性，在10s-1剪切速度下的粘度为2Pa·s；具有很好的粘弹性，其在1pa弹性模量高达103Pa，具有良好的保形性，能顺利通过针嘴堵塞且保持三维立体形状。
将该墨水悬浮液装入3D直写成型设备的喷筒中，喷嘴直径为160um。将计算机与直写成型设备连接，设置3D直写设备的程序以及仿骨结构模型，开启通过逐层叠加的方式在空气中打印即可得到三维立体结构，将得到的三维立体结构在室温下干燥6h后放于60℃下干燥12h，随后至于80℃干燥12h，得到三维立体结构的生坯，也即载二甲双胍人工骨。其中，仿骨结构模型的建立步骤为采集患者骨缺损部位信息，通过CAD软件建立个体化骨支架三维模型。
体外药物释放实验：本实施例制备的载二甲双胍人工骨为样品进行检测，参考2000年版药典释放度测定法。释放介质为PBS，温度为37.0℃。每48小时测定一次，更换等量PBS。结果显示：药物持续释放，药物浓度逐渐降低，第8天药物浓度降为第一次测的药物浓度一半。
实施例2：
β-TCP(羟基磷灰石的一种)粒径为1um，胶原蛋白粉末，去离子水，聚丙烯酸，二甲双胍，醋酸锌混合形成墨水浆料；其中，聚丙烯酸为β-TCP干粉含量的0.8％，醋酸锌用量为墨水质量的0.05％，二甲双胍浓度为150mg/mL，采用氢氧化镁调节PH值为9。制得的墨水浆料固相含量为56％。
混合好的浆料置于球磨机上以100rmp转速球磨12h，超声振荡12h，即得到所需墨水悬浮液。所得墨水悬浮液具有很好的剪切致稀性，在10s-1剪切速度下的粘度为3Pa·s)；具有很好的粘弹性，其在10pa弹性模量高达103Pa，具有良好的保形性，能顺利通过针嘴堵塞且保持三维立体形状。
将该墨水悬浮液装入3D直写设备的喷筒中，喷嘴直径为100um。将计算机与直写成型设备连接，设置3D直写设备的程序以及仿骨结构模型，开启通过逐层叠加的方式在空气中打印即可得到三维立体结构，将得到的三维立体结构在室温下干燥6h后放于60℃下干燥12h，随后至于80℃干燥12h，得到三维立体结构的生坯，也即载二甲双胍人工骨。其中，仿骨结构模型的建立步骤为采集患者骨缺损部位信息，通过CAD软件建立个体化骨支架三维模型。
体外药物释放实验：本实施例制备的载二甲双胍人工骨为样品进行检测，参考2000年版药典释放度测定法。释放介质为PBS，温度为37.0℃。每48小时测定一次，更换等量PBS。结果显示：药物持续释放，药物浓度逐渐降低，第8天药物浓度降为第二天药物浓度一半。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种载二甲双胍人工骨材料，其特征在于，所述材料包括羟基磷灰石颗粒、胶原蛋白粉末、分散剂、二甲双胍、微量元素和去离子水。
2.一种利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述方法包括以下步骤：
(1)将羟基磷灰石颗粒、胶原蛋白粉末、分散剂、二甲双胍和微量元素溶于去离子水，并调节PH值，混合均匀得到浆料；
(2)将浆料球磨和超声振荡后，制得墨水悬浮液；
(3)将墨水悬浮液装入3D直写成型设备的喷筒中，将计算机与直写成型设备连接，设置3D直写设备的程序以及仿骨结构模型，通过控制墨水悬浮液的流变性能逐层叠加在空气中打印，干燥后得到载二甲双胍仿骨结构材料；其中，仿骨结构模型的建立步骤为采集患者骨缺损部位信息，通过CAD软件建立个体化骨支架三维模型。
3.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述羟基磷灰石颗粒的粒径范围为0.8-10um。
4.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述分散剂为柠檬酸盐、聚丙烯酸、聚丙烯酸铵、聚乙酰亚胺中的一种或几种。
5.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述浆料中的二甲双胍含量为150mg/mL。
6.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述分散剂的加入量为羟基磷灰石颗粒质量的0.2-3％。
7.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，调节PH值范围为4-10。
8.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，调节PH值的酸碱调节剂包括碳酸、磷酸、柠檬酸、氢氧化镁、氢氧化钙中的一种或几种。
9.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述微量元素包括镁、锌、氯中的一种或几种。
10.如权利要求2所述的利用3D直写成型技术制备载二甲双胍人工骨材料的方法，其特征在于，所述步骤(2)中的球磨时间为12h，转速为90-200rmp；超声震荡时间为12h。
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