CN116999618B - 多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法 - Google Patents
多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法 Download PDFInfo
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Abstract
一种多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，步骤包括：通过气雾化法制得钛铜合金粉末；通过3D打印技术将钛铜合金粉末送入SLM设备中进行扫描打印并进行喷砂酸蚀处理；将光引发剂LAP与PBS溶液混合，再加入GelMA，充分振荡后水浴加热溶解，然后再将特定量的雷奈酸锶粉末加入到水凝胶溶液中；最后将载药水凝胶注入到多孔钛铜合金的孔隙中，获得具有抗菌与骨修复能力的新型生物复合材料。多孔钛铜合金支架模拟天然松质骨的微观结构和性能，其多孔结构有助于新生骨与血管的长入，释放的铜离子在骨缺损周围起到抗菌作用；渗透到孔隙中的软水凝胶可模拟细胞外基质的微环境并作为雷奈酸锶的载体进行药物的局部缓释，从而促进骨修复。
Description
技术领域
本发明属于生物医用材料技术领域，涉及一种多孔钛铜合金复合水凝胶抗菌骨修复材料及制备方法。
背景技术
由创伤、肿瘤、感染、手术等各种因素导致骨质的部分丧失，称为骨缺损。骨缺损在临床上发病率很高，现有的临床治疗方案主要是使用自体骨或异体骨移植恢复损伤处相应的组织结构。自体骨存在供应不足及供骨区损伤的缺点，而异体骨移植所造成的免疫排斥反应和交叉感染风险的增加也限制了在临床上的进一步应用。人工骨替代材料的研发与应用为上述问题提供了解决方法与思路。钛及钛合金因其良好的生物相容性和力学稳定性被作为骨替代材料广泛应用于临床领域。但医用钛合金材料在骨修复重建过程中依旧存在两个问题亟待解决。第一，内植物相关感染的发生：骨缺损重建过程中，细菌附着于内植物表面形成生物膜，一方面会增加细菌定植；另一方面会阻止抗菌药物的渗透，从而形成内植物相关的深部组织感染，尤其对于人工关节假体置换和颈腰椎深部手术，需再次或多次手术清创、灌洗，甚至取出内植物，造成灾难性后果。第二，由于钛合金本身的生物惰性，导致其作为内植物材料时存在骨诱导活性差、骨整合能力不足的缺陷。因此，开发具有抗菌与骨修复能力的新型生物复合材料具有重要的临床意义与研究价值。
常用的降低内植物相关感染的方法有控制手术时间及出血量、手术中脉冲清洗创面、复合抗菌药物材料混合植入等，但这些措施均无法降低内植物表面生物膜形成的几率。当前改善内植物自身抗菌能力的方法是进行表面涂层改性，但抗菌涂层与基体的结合限制了其临床应用，且由于涂层厚度限制，其抗菌成分往往含量不足，释放时间过短，影响抗菌效果。近年来部分金属离子的抗菌作用越来越受到重视：金属离子（银、铜、镓等）可通过破坏细菌的细胞膜以及诱导氧化应激反应等机制发挥抗菌作用，实验表明含有抗菌金属成份的内植物可显著降低手术相关感染的发生率。铜作为人体内不可缺少的微量元素，参与了体内多种物质的代谢，同时具有优异的抗菌活性，研究表明含铜质量分数3%~10%的钛铜合金对金黄色葡萄球菌均具有稳定强效的抑制作用。采用钛铜合金作为基材制备的内植物可利用铜离子的持续析出发挥抗菌功能，抑制细菌增殖，减少局部感染的发生。
甲基丙烯酰化明胶（GelMA）为双键改性明胶，其可通过紫外及可见光在光引发剂的作用下快速交联固化成胶。GelMA 作为一种常见的光固化水凝胶，兼具天然和合成生物材料的特征，不仅具有优异的生物相容性、生物降解性和细胞反应特性，而且价格低廉容易获得，在医学领域上备受关注。
目前已有相关研究制备得到了性能良好的具有抗菌与骨修复能力的双功能生物材料，例如中国专利CN114366849B。该发明通过在基材表面覆盖生物玻璃涂层，并负载抗菌药物，提高了骨修复材料表面的抗菌、抗感染性能。但抗菌涂层与基材的结合强度欠佳，以及复合材料中单一促成骨能力的不足，均限制了其临床应用前景。
发明内容
本发明旨在提供一种兼具抗菌与骨修复能力的新型生物复合材料及制备方法，使用该制备方法制造出来的多孔钛铜合金复合水凝胶抗菌骨修复材料生物相容性好、力学性能优异、抗菌活性高、诱导成骨能力强。
本发明的技术方案：
多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，包括以下步骤：
(1)将钛铜按质量百分比钛90%~97%、铜3%~10%的比例进行配料、熔炼，再通过气雾化法制取钛铜预合金粉末，然后将其筛分、烘干，得到粒度200目以上的钛铜合金粉末；
(2)创建三维模型，设定打印路径和工艺参数，将制好的钛铜合金粉末送入SLM设备中进行扫描打印，打印完成后进行喷砂酸蚀处理；
(3)将光引发剂与PBS溶液混合，再加入GelMA，充分振荡后水浴加热溶解，然后再将特定量的雷奈酸锶粉末加入到水凝胶溶液中；
(4)最后将载药水凝胶注入到多孔钛铜合金的孔隙中，待其固化成胶，获得具有抗菌与骨修复能力的新型生物复合材料。
进一步的， 步骤(1)所述的气雾化法制备钛铜预合金粉末时采用小型真空感应气雾化制粉设备进行，整个过程控制氧含量在600 ppm以下；将制得的钛铜预合金粉末放入真空干燥箱内烘干2h以上，最终得到粒度200目以上、球形度为95%以上的钛铜合金粉末。
进一步的，步骤(2)中使用计算机辅助设计CAD软件，创建多孔钛铜合金零件的3D模型，设定打印路径与工艺参数，将多孔钛铜合金的孔隙率控制在60%～80%之间，孔径设定在450～800μm之间，孔隙形状为菱形十二面体结构。
进一步的，在步骤(3)中，将光引发剂LAP与PBS溶液混合制备得到LAP标准溶液，再取所需质量的GelMA加入到该标准溶液中，制备得到浓度为5~10 %的GelMA水凝胶溶液，以60~70°C水浴避光加热溶解20~30分钟，期间振荡数次，待其完全溶解后立即使用无菌针头过滤器灭菌。
进一步的，在步骤(3)中，将特定量的雷奈酸锶粉末与上述GelMA水凝胶溶液混合，充分均匀搅拌，制备出浓度约为0.25~0.5 mmol/L的雷奈酸锶水凝胶溶液。
进一步的，在步骤(4)中，使用医用注射器将浓度为0.25~0.5mmol/L的雷奈酸锶水凝胶溶液均匀注入到3D打印多孔钛铜合金的孔隙中，再以波长为405nm的便携式固定光源照射10~30秒使其固化成胶，就获得了具有抗菌与骨修复能力的新型生物复合材料。
本发明的原理：
钛合金由于其优异的力学强度和弹性模量广泛应用于硬组织替代及内植物的制备，但其本身为惰性金属，不具备成骨活性。研究人员模仿天然的骨小梁结构将钛合金制备成具有良好孔隙结构和连通性的多孔金属，从而有利于骨组织的长入。一方面，多孔化可以明显降低其弹性模量，减小应力屏蔽；另一方面，相互交联的孔洞结构可以为骨与血管组织的长入提供空间，最终形成种植体-骨嵌合的牢固结构，并且应用3D打印技术可以最大限度地满足个性化的制作需求, 为患者量身设计具有生物相容性的个性化生物材料。
为了降低内植物相关手术深部感染并发症的可能，我们在前期研究的基础上将一定比例的铜与钛粉混合，进行3D打印制备多孔钛铜合金。通过释铜离子持续的析出、释放，促进细菌超氧化物的形成, 抑制其呼吸作用，同时促进其遗传物质的分解，从而达到持续而有效的抗菌作用。多孔钛铜合金具有骨传导活性及良好而持久的抗菌活性，但仍然缺少骨诱导活性，因此在合金支架上负载促成骨药物联合多孔化结构协同促骨修复成为可能。
雷奈酸锶是抗骨质疏松药物中少有的同时具有促进成骨和抑制破骨能力的临床应用药物。体外研究表明雷奈酸锶可以上调骨形态发生蛋白-2和血管内皮生长因子的表达，促进成骨与成血管，临床实验也证明其具有长期卓越的临床效益和较高的安全性。研究证明，将具有成骨诱导活性的药物与多孔金属有效复合为临床应用提供了一种良好的前景。雷奈酸锶促骨修复的研究在局部应用上取得成功，不仅能够提高其生物利用度，避免口服引起的胃肠道反应，而且可以减轻致血栓的潜在风险与安全隐患。将雷奈酸锶加载到水凝胶中，随着水凝胶在体内的逐步降解，药物在局部能够得到长期有效地释放，协同钛铜合金多孔化的空间构型，进一步促进骨修复。
本发明的有益效果：通过3D打印技术实现了对多孔钛铜合金的孔隙率、孔径和孔隙形状的精确控制，硬质的钛铜合金支架模拟天然松质骨的微观结构和机械性能，其多孔结构有助于新生骨与血管的长入，释放的铜离子在骨缺损周围起到抗菌作用，预防感染的发生；渗透到孔隙中的软水凝胶可模拟细胞外基质的微环境并作为雷奈酸锶的载体进行药物的局部缓释，从而促进骨修复。用本发明方法制造出来的多孔钛铜合金复合水凝胶抗菌骨修复材料生物相容性好、力学性能优异、抗菌活性高、诱导成骨能力强。
附图说明
图1 为实施例1制备的钛铜合金粉末电镜照片（3000×）。
图2 为实施例1制备的多孔钛铜合金材料实物图。
图3 为实施例2制备的多孔钛铜合金材料实物图。
图4 为实施例2制备的多孔钛铜合金复合水凝胶抗菌骨修复材料实物图。
图5 为实施例1实物电镜照片（50×）。
图6 为实施例1实物电镜照片（100×）。
图7 为实施例1 制备的多孔钛铜合金材料的EDS能谱图，图示多孔钛铜合金材料的主要成分为钛和铜，质量百分比计为: 钛97wt%，铜3wt%。
具体实施方式
下面结合实施例进一步说明。
实施例1
多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，包括以下步骤：
（1）将钛铜按照比例配料、熔炼，再通过气雾化法制取钛铜预合金粉末，然后将其筛分、烘干，得到钛铜合金粉末；多孔钛铜合金的主要成分按质量百分比计为: 钛97wt%，铜3wt%；钛铜合金粉末的粒度在200目以上；气雾化法制备钛铜预合金粉末时采用小型真空感应气雾化制粉设备进行，整个过程控制氧含量在600 ppm以下，通过气雾化法制得钛铜预合金粉末后，对钛铜预合金粉末过200目筛网，而后放入真空干燥箱内烘干2h以上，最终得到粒度200目以上、球形度为95%以上的钛铜合金粉末（如图1）。
（2）创建三维模型、设定打印路径和工艺参数，将制好的钛铜合金粉末送入SLM设备中进行扫描打印，打印完成后进行喷砂酸蚀处理。所述的SLM设备为BLT-A320选区激光熔化金属3D打印机。所述的SLM设备在扫描打印时，先将SLM设备的粉仓清理干净，关闭成型室仓门，通入氩气，待成形室内氧含量低于100ppm，基板温度升至80℃；制得的钛铜合金粉末送入SLM设备中，进行手动铺粉，进入打印程序；每完成一层的制造，工作台下降一个铺粉层厚，刮刀重新将钛铜合金粉末铺平，进行下一层的制造，不断循环往复，直至完成整个零件的打印；打印件完成后，取下带有打印件的基板，将基板和打印件置于炉内保温，去应力退火，冷却至室温后将打印件从基板上切割下，后续进行喷砂及酸蚀处理。
使用计算机辅助设计（CAD）软件，创建多孔钛铜合金零件的3D模型，设定打印路径与工艺参数，将多孔钛铜合金的孔隙率设定为70 %，孔径为550 μm，孔隙形状为菱形十二面体结构。步骤(2)中所述的工艺参数设定如下：激光功率为180W，扫描速度为1000mm/s，扫描间距为100μm，光斑直径为70μm，铺粉层厚为30μm，激光能量密度为35 J/mm3。
（3）将0.05g的光引发剂LAP与20ml PBS溶液混合后置于温度为50°C的水浴锅中加热溶解15分钟，得到LAP标准溶液。取1g的GelMA加入到该标准溶液中，制备得到浓度为5 %的GelMA水凝胶溶液，以60°C水浴避光加热20分钟，期间振荡数次，待其完全溶解后立即使用0.22μm的无菌针头过滤器进行灭菌。然后将2.43 mg的雷奈酸锶粉末与上述GelMA水凝胶溶液混合，充分均匀搅拌，制备出浓度约为0.25 mmol/L的雷奈酸锶水凝胶溶液。
（4）使用医用注射器将浓度为0.25 mmol/L的雷奈酸锶水凝胶溶液均匀注入到3D打印多孔钛铜合金的孔隙中，再以波长为405nm的便携式固定光源照射15秒使其固化成胶，得到多孔钛铜合金复合水凝胶抗菌骨修复材料，该复合材料具有优异的抗菌活性与成骨能力，不仅可以降低内植物感染的发生率，而且能够诱导成骨、抑制破骨，有利于骨缺损的修复与重建，能够最大限度地满足个体的需要以及适应人体的内部环境。
所得多孔钛铜合金材料实物图片如图2，电镜照片如图5、图6，EDS能谱图如图7。
实施例2
多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，包括以下步骤：
（1）将钛铜按比例进行配料、熔炼，再通过气雾化法制取钛铜预合金粉末，然后将其筛分、烘干，得到钛铜合金粉末；多孔钛铜合金的主要成分按质量百分比计为: 钛97wt%，铜3wt%；钛铜合金粉末的粒度在200目以上；气雾化法制备钛铜预合金粉末时采用小型真空感应气雾化制粉设备进行，整个过程控制氧含量在600 ppm以下，通过气雾化法制得钛铜预合金粉末后，对钛铜预合金粉末过200目筛网，而后放入真空干燥箱内烘干2h以上，最终得到粒度200目以上、球形度为95%以上的钛铜合金粉末（如图1）。
（2）创建三维模型、设定打印路径和工艺参数，将制好的钛铜合金粉末送入SLM设备中进行扫描打印，打印完成后进行喷砂酸蚀处理。所述的SLM设备为BLT-A320选区激光熔化金属3D打印机。所述的SLM设备在扫描打印时，先将SLM设备的粉仓清理干净，关闭成型室仓门，通入氩气，待成形室内氧含量低于100 ppm，基板温度升至80℃时；制得的钛铜合金粉末送入SLM设备中，进行手动铺粉，进入打印程序；每完成一层的制造，工作台下降一个铺粉层厚，刮刀重新将钛铜合金粉末铺平，进行下一层的制造，不断循环往复，直至完成整个零件的打印；打印件完成后，取下带有打印件的基板，将基板和打印件置于炉内保温，去应力退火，冷却至室温后将打印件从基板上切割下，后续进行喷砂及酸蚀处理。
使用计算机辅助设计（CAD）软件，创建多孔钛铜合金零件的3D模型，设定打印路径与工艺参数，将多孔钛铜合金的孔隙率设定为70 %，孔径为720 μm，孔隙形状为菱形十二面体结构。步骤(2)中所述的工艺参数设定如下：激光功率为180W，扫描速度为1000mm/s，扫描间距为100μm，光斑直径为70μm，铺粉层厚为30μm，激光能量密度为35 J/mm3。
（3）将0.05g的光引发剂LAP与20ml PBS溶液混合后置于温度为50°C的水浴锅中加热溶解15分钟，得到LAP标准溶液。取2g的GelMA加入到该标准溶液中，制备得到浓度为10%的GelMA水凝胶溶液，以60°C水浴避光加热20分钟，期间振荡数次，待其完全溶解后立即使用0.22μm的无菌针头过滤器进行灭菌。然后将4.86mg的雷奈酸锶粉末与上述GelMA水凝胶溶液混合，制备出浓度约为0.5 mmol/L的雷奈酸锶水凝胶溶液。
（4）使用医用注射器将浓度为0.5 mmol/L的雷奈酸锶水凝胶溶液均匀注入到3D打印多孔钛铜合金的孔隙中，再以波长为405nm的便携式固定光源照射15秒使其固化成胶，得到多孔钛铜合金复合水凝胶抗菌骨修复材料，该复合材料具有优异的抗菌活性与成骨能力，不仅可以降低内植物感染的发生率，而且能够诱导成骨、抑制破骨，有利于骨缺损的修复与重建，能够最大限度地满足个体的需要以及适应人体的内部环境。
所得多孔钛铜合金材料实物图片如图3，多孔钛铜合金复合水凝胶抗菌骨修复材料实物图片如图4。
Claims (3)
1.多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，其特征在于包括以下步骤：
(1)将钛铜按质量百分比钛90%~97%、铜3%~10%的比例进行配料、熔炼，再通过气雾化法制取钛铜预合金粉末，然后将其筛分、烘干，得到粒度200目以上的钛铜合金粉末；
(2)使用计算机辅助设计CAD软件，创建多孔钛铜合金零件的3D模型，设定打印路径与工艺参数，将多孔钛铜合金的孔隙率控制在60%~80%之间，孔径设定在450～800μm之间，孔隙形状为菱形十二面体结构；将制好的钛铜合金粉末送入SLM设备中进行扫描打印，打印完成后进行喷砂酸蚀处理；
(3)将光引发剂LAP与PBS溶液混合制备得到LAP标准溶液，再取所需质量的GelMA加入到该标准溶液中，充分振荡后水浴加热溶解，制备得到浓度为5%~10%的GelMA水凝胶溶液，以60~70°C水浴避光加热溶解20~30分钟，期间振荡数次，待其完全溶解后立即使用无菌针头过滤器灭菌；然后再将特定量的雷奈酸锶粉末与GelMA水凝胶溶液混合，充分均匀搅拌，制备出浓度约为0.25~0.5 mmol/L的雷奈酸锶水凝胶溶液；
(4)将载药水凝胶注入到多孔钛铜合金的孔隙中，待其固化成胶，获得具有抗菌与骨修复能力的新型生物复合材料。
2. 根据权利要求1所述的多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，其特征在于: 步骤(1)所述的气雾化法制备钛铜预合金粉末时采用小型真空感应气雾化制粉设备进行，整个过程控制氧含量在600 ppm以下；将制得的钛铜预合金粉末放入真空干燥箱内烘干2h以上，最终得到粒度200目以上、球形度为95%以上的钛铜合金粉末。
3.根据权利要求1所述的多孔钛铜合金复合水凝胶抗菌骨修复材料的制备方法，其特征在于：步骤(4)中，使用医用注射器将浓度为0.25~0.5mmol/L的雷奈酸锶水凝胶溶液均匀注入到3D打印多孔钛铜合金的孔隙中，再以波长为405nm的便携式固定光源照射10~30秒使其固化成胶，获得具有抗菌与骨修复能力的新型生物复合材料。
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