CN114014647B - 一种硅酸锌复合磷酸三钙陶瓷支架及其制备方法与应用 - Google Patents
一种硅酸锌复合磷酸三钙陶瓷支架及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于骨损伤修复医用材料领域,公开了一种硅酸锌复合磷酸三钙陶瓷支架及其制备方法和应用。本发明将固相粉体和增稠剂混合均匀后,加入聚乙烯醇水溶液调和,得到打印浆料;所述固相粉体包括硅酸锌粉体、β‑磷酸三钙粉体;将打印浆料进行3D打印,得到支架坯体,支架坯体经过梯度干燥和烧结,得到所述硅酸锌复合磷酸三钙陶瓷支架。本发明制得的硅酸锌/磷酸三钙陶瓷支架纤维保形性好、三维连通程度高,具有良好的力学性能、成骨和成血管性能,使得磷酸三钙陶瓷具有更广阔的应用前景。
Description
技术领域
本发明属于骨缺损再生修复生物医用陶瓷支架领域,具体涉及一种硅酸锌复合磷酸三钙陶瓷支架及其制备方法与应用。
背景技术
骨作为人体中的坚硬器官,具有支撑机体各种复杂运动、保护内脏器官、贮存身体所需的各种矿物质等重要作用。当骨缺损大于一定尺寸时,骨的自愈合能力有限,需要植入器械进行治疗。磷酸三钙(β-TCP)陶瓷因其组成相似于骨的无机成分,能与骨组织、软组织进行化学结合,具有良好的生物相容性、骨传导性,被广泛应用于口腔、骨科、载药等领域。其中,多孔磷酸钙陶瓷支架更是显示出了应用于骨修复领域的巨大潜能,但从临床实际看,其还存在许多不足,如孔隙率与强度之间的平衡问题、促血管化和促成骨的效果不够理想等。此外,孔的三维连通性对气体交换、营养物质的传输、代谢废物的排出、支架的降解、细胞的调控、血管和骨组织的长入都有着重要影响。传统的支架制备方法有冷冻干燥法、造孔剂法、发泡法、水凝胶技术、模板法、挤出成型法、静电纺丝技术等。这些方法虽然操作简单、经济性强,但难以调控孔径大小、孔径分布、孔的形状、孔的连通性,很难满足个性化定制-精准医疗这一需求。相较于传统的支架制备方法,3D打印技术不仅能针对复杂规则或不规则的内部孔结构进行仿生,还能够针对骨缺损部位的特征进行个性化定制,具有可控性好、加工速度快、自动化程度高、可重复性好等特点。3D打印技术中的三维纤维沉积(3DF)是将料筒中具有粘连性的高分子溶液或无机粉体与粘结剂混合而成的浆料通过针头沉积纤维,利用三维模型的分层数据逐层进行打印。溶剂会在挤出成型的过程中逐渐挥发,使沉积纤维成半湿状态互相粘连。3DF在支架制备过程中无需移除多余材料、无需激光致熔和加热熔融,避免了三维印刷技术对粘结剂与粉体之间相互作用实验参数的研究,是一种高精度、高连通率、低能耗、简便快捷的支架制备方法。但目前,该方法制备的多孔磷酸钙陶瓷支架仍存在挤出纤维保形性不佳、支架侧向孔不明显、三维连通度不佳等不足。
针对多孔磷酸钙生物陶瓷生物学性能方面的不足,引入功能性离子不仅可以诱导缺损区细胞分泌成骨、成血管相关的蛋白和细胞因子,进而促进骨缺损区域的原位自修复,还具有低成本、更长保质期、低监管负担和低风险等优势。同时,不同功能性离子的结合具有协同效应,如改变降解动力学、协同增强材料成骨、成血管性能等。硅是人体健康所必须的微量元素之一,存在于人的结缔组织和骨组织中,在骨骼的生长和修复中起重要作用。锌具有维持骨骼的正常生长发育、参与蛋白质和核酸的形成与代谢、参与免疫过程和细胞间的信号传导、维持细胞膜的稳定性、增强成骨细胞活性、抑制破骨细胞活性,促进成骨细胞骨钙素分泌从而使得骨基质更加成熟等作用。硅酸锌(ZS)是一种耐高温的硅酸盐,最早应用于介电发光材料。Jindal等制备的孔尺寸为2~3nm、比表面积为292.06m2/g的介孔硅酸锌,最低抑菌浓度为0.15mg/mL,最低杀菌浓度为0.9mg/mL,具有生物相容性、吸附染料的特性,可以应用于涂层、骨填充材料、骨水泥、载药等领域,但该研究未深入研究其成骨分化性能(A.Jindal,S.Juneja,M.Bakshi,P.Chaudhuri,J.Bhattacharya.Mesoporous zincsilicate bio-composite:Preparation,characterization and in vitroevaluation.Microporous and Mesoporous Materials,2019,277:124-131.)。综上,研究出一种三维连通程度高、力学性能良好、生物学性能良好的复合钙磷陶瓷支架具有重要意义。
发明内容
为了克服上述现有技术的缺点和不足,本发明的首要目的在于提供一种硅酸锌复合磷酸三钙陶瓷支架的制备方法。
本发明的另一目的在于提供根据上述方法制备得到的硅酸锌复合磷酸三钙陶瓷支架。
本发明的再一目的在于提供上述硅酸锌复合磷酸三钙陶瓷支架的应用。
本发明的目的通过下述方案实现:
一种硅酸锌复合磷酸三钙陶瓷支架的制备方法,包括以下步骤:
(1)将固相粉体和增稠剂混合均匀后,加入聚乙烯醇(PVA)水溶液调和,得到打印浆料;所述固相粉体包括硅酸锌粉体、β-磷酸三钙粉体;
(2)将打印浆料进行3D打印,得到支架坯体,支架坯体经过梯度干燥和烧结,得到所述硅酸锌复合磷酸三钙陶瓷支架。
优选的,步骤(1)中所述固相粉体包括以下质量百分数的组分:硅酸锌粉体的含量大于0wt.%、小于15wt.%,β-磷酸三钙粉体含量大于85wt.%、小于100wt.%。
优选的,步骤(1)中所述增稠剂为甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素中的至少一种,增稠剂的添加量为所述固相粉体的1~5wt.%;需要注意的是,增稠剂添加量越高,浆料粘度越高,支架纤维的保形性越强,但添加量越高,支架烧结后支架纤维残留孔隙越大,对强度不利。
优选的,步骤(1)中所述聚乙烯醇水溶液的浓度为6~10wt.%,聚乙烯醇水溶液的添加量为所述固相粉体的90~110wt.%。需要注意的是,聚乙烯醇水溶液添加量越高,浆料粘度越低,支架纤维的保形性越差,对强度同样不利。
优选的,步骤(1)中所述硅酸锌粉体的制备包括以下步骤:搅拌状态下,将正硅酸乙酯加入至乙酸锌溶液中充分反应后,将带有白色沉淀的反应液转入反应釜中,经水热、离心、洗涤、烘干、过筛,得到硅酸锌粉体。
优选的,步骤(1)中所述β-磷酸三钙粉体的制备包括以下步骤:搅拌状态下,将磷酸氢二铵溶液加入到硝酸钙溶液中充分反应后,经陈化、离心、冻干、煅烧、过筛得到磷酸三钙粉体。
优选的,步骤(2)中,所述3D打印的条件为针头直径260~600μm、层高208~640μm、纤维间距660~1000μm、挤出压力0.1~0.6MPa、打印速度1~25mm/s。
优选的,步骤(2)中,所述梯度干燥为先室温干燥1~2d,然后50~80℃烘干1~2d,最后100~140℃烘干1~2d。
优选的,步骤(2)中,所述烧结为先升温至150~250℃保温1~2h,然后升温至600~800℃保温1~2h,再升温至1050~1150℃保温2~3h后,降温至室温,升温速率和降温速率均为1~10℃/min。
上述制备方法制备得到的硅酸锌复合磷酸三钙陶瓷支架。
上述的硅酸锌复合磷酸三钙陶瓷支架在制备骨修复材料中的应用。
本发明将硅酸锌(Zn2SiO4)、β-磷酸三钙(β-Ca2(PO4)3)与增稠剂粉体混合均匀后倒入聚乙烯醇水溶液中,经过搅拌调和后得到具有可打印性的打印浆料,再利用三维纤维沉积3D打印技术(3DF)制备出支架坯体,支架坯体经过干燥和烧结后得到硅酸锌复合磷酸三钙(ZS/β-TCP)陶瓷支架,制得的硅酸锌复合磷酸三钙陶瓷支架具有多元活性离子、纤维保形性良好、孔道三维连通程度高等特点。纤维保形性良好、孔道三维连通程度高不仅有利于磷酸三钙陶瓷的降解,还使得新生血管和骨组织能够长入到陶瓷支架内部。同时,二元活性离子化合物—硅酸锌的引入对提高磷酸三钙陶瓷支架的骨诱导性和骨修复效果、推动其更为广泛的临床应用具有重要意义。
与现有技术相比,本发明具有如下优点和有益效果:
1、本发明通过增稠剂的添加,在一定程度上克服了单纯以PVA为粘结剂的浆料的挤出纤维保形性不佳、支架侧向孔不明显、孔道三维连通度不佳等不足。
2、本发明首次将ZS与β-TCP复合制备成陶瓷支架,且通过3DF制备的ZS/β-TCP陶瓷支架的纤维保形性好、孔道三维连通程度高,力学性能也在复合后得到显著提升。
3、本发明的ZS/β-TCP陶瓷支架能显著促进小鼠间充质干细胞的细胞增殖和碱性磷酸酶活性,具有良好的生物学性能。
附图说明
图1是对比例1和实施例1~3所得陶瓷支架的体式图和表面及断面SEM图,分别对应a、b、c、d。
图2是对比例1和实施例1~3所得陶瓷支架的开口孔隙率图。
图3是对比例1和实施例1~3所得陶瓷支架的抗压强度图。
图4是对比例1和实施例1~3所得陶瓷支架的细胞增殖测试结果图。
图5是对比例1和实施例1~3所得陶瓷支架的碱性磷酸酶活性测试结果图。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。下列实施例中使用的试剂均可从商业渠道获得。需要说明的是,本发明的室温为22~26℃。
实施例1
(1)硅酸锌粉体的制备:将5.895g乙酸锌加入60ml去离子水中,磁力搅拌至溶解,滴加稀氨水将反应液的pH调至7后用注射器将3ml正硅酸乙酯滴入上述溶液中,滴加完毕后继续搅拌10min,然后将带有白色沉淀的反应液转入反应釜中,170℃下反应4.5h,待反应釜冷却后,将产物转移至离心管中,离心水洗4次,无水乙醇洗2次,60℃烘干,过53μm的筛以备打印用。
(2)磷酸三钙粉体的制备:称取79.34g磷酸氢二铵溶于1.2L去离子水中配成0.5mol/L磷酸氢二铵溶液,再称取212.54g四水硝酸钙溶于2L去离子水中配成0.45mol/L溶液。搅拌状态下(400r/min),将磷酸氢二铵溶液用蠕动泵滴入硝酸钙溶液中(150r/min),用氨水调节反应液的pH至6.8。待磷酸氢二铵滴加完毕后,pH保持6.8继续搅拌2h,然后室温陈化2d,每天换3次去离子水,离心冻干。将冻干后的粉末在900℃下煅烧2h得到β-TCP粉体,过53μm的筛以备打印用。
(3)打印浆料的配制:将0.5g ZS、9.5gβ-TCP与0.3g甲基纤维素粉体混合均匀后倒入10g 8wt.%PVA溶液中,用机械搅拌器调和均匀后将浆料转移至料筒中备用。
(4)陶瓷支架的制备:将solidworks软件设计的10×10×7mm圆柱形模型保存为.stl格式文件,导入打印软件,对打印路径进行编辑,打印速度为12mm/s,层高为340μm,纤维间距为800μm,生成软件可以识别的GCode,平台温度和针头温度根据现场情况实时设置,挤出压力设置为0.35MPa,开启电磁阀,预挤浆料,当浆料呈纤维状垂直挤出且能连续不断出丝,表明浆料的可打印性良好,点击开始打印。将打印得到的支架坯体在室温下干燥1d、60℃干燥1d、120℃干燥1d,脱模后置于马弗炉中煅烧得到磷酸三钙陶瓷支架。烧结制度为先升温至200℃保温1h,然后升温至700℃保温1h,再升温至1100℃保温2h后,降温至室温,升温速率和降温速率均为2℃/min。
实施例2
(1)硅酸锌粉体的制备:将5.895g乙酸锌加入60ml去离子水中,磁力搅拌至溶解,滴加稀氨水将反应液的pH调至7后用注射器将3ml正硅酸乙酯滴入上述溶液中,滴加完毕后继续搅拌10min,然后将带有白色沉淀的反应液转入反应釜中,170℃下反应4.5h,待反应釜冷却后,将产物转移至离心管中,离心水洗4次,无水乙醇洗2次,60℃烘干,过53μm的筛以备打印用。
(2)磷酸三钙粉体的制备:称取79.34g磷酸氢二铵溶于1.2L去离子水中配成0.5mol/L磷酸氢二铵溶液,再称取212.54g四水硝酸钙溶于2L去离子水中配成0.45mol/L溶液。搅拌状态下(400r/min),将磷酸氢二铵溶液用蠕动泵滴入硝酸钙溶液中(150r/min),用氨水调节反应液的pH至6.8。待磷酸氢二铵滴加完毕后,pH保持6.8继续搅拌2h,然后室温陈化2d,每天换3次去离子水,离心冻干。将冻干后的粉末在900℃下煅烧2h得到β-TCP粉体,过53μm的筛以备打印用。
(3)打印浆料的配制:将1g ZS、9gβ-TCP与0.3g羟丙基甲基纤维素粉体混合均匀后倒入10g 8wt.%PVA溶液中,用机械搅拌器调和均匀后将浆料转移至料筒中备用。
(4)陶瓷支架的制备:将solidworks软件设计的10×10×7mm圆柱形模型保存为.stl格式文件,导入打印软件,对打印路径进行编辑,打印速度为12mm/s,层高为340μm,纤维间距为800μm,生成软件可以识别的GCode,平台温度和针头温度根据现场情况实时设置,挤出压力设置为0.35MPa,开启电磁阀,预挤浆料,当浆料呈纤维状垂直挤出且能连续不断出丝,表明浆料的可打印性良好,点击开始打印。将打印得到的支架坯体在室温下干燥1d、60℃干燥1d、120℃干燥1d,脱模后置于马弗炉中煅烧得到磷酸三钙陶瓷支架。烧结制度为先升温至200℃保温1h,然后升温至700℃保温1h,再升温至1100℃保温2h后,降温至室温,升温速率和降温速率均为2℃/min。
实施例3
(1)硅酸锌粉体的制备:将5.895g乙酸锌加入60ml去离子水中,磁力搅拌至溶解,滴加稀氨水将反应液的pH调至7后用注射器将3ml正硅酸乙酯滴入上述溶液中,滴加完毕后继续搅拌10min,然后将带有白色沉淀的反应液转入反应釜中,170℃下反应4.5h,待反应釜冷却后,将产物转移至离心管中,离心水洗4次,无水乙醇洗2次,60℃烘干,过53μm的筛以备打印用。
(2)磷酸三钙粉体的制备:称取79.34g磷酸氢二铵溶于1.2L去离子水中配成0.5mol/L磷酸氢二铵溶液,再称取212.54g四水硝酸钙溶于2L去离子水中配成0.45mol/L溶液。搅拌状态下(400r/min),将磷酸氢二铵溶液用蠕动泵滴入硝酸钙溶液中(150r/min),用氨水调节反应液的pH至6.8。待磷酸氢二铵滴加完毕后,pH保持6.8继续搅拌2h,然后室温陈化2d,每天换3次去离子水,离心冻干。将冻干后的粉末在900℃下煅烧2h得到β-TCP粉体,过53μm的筛以备打印用。
(3)打印浆料的配制:将1.5g ZS、8.5gβ-TCP与0.3g羟乙基纤维素粉体混合均匀后倒入10g 8wt.%PVA溶液中,用机械搅拌器调和均匀后将浆料转移至料筒中备用。
(4)陶瓷支架的制备:将solidworks软件设计的10×10×7mm圆柱形模型保存为.stl格式文件,导入打印软件,对打印路径进行编辑,打印速度为12mm/s,层高为340μm,纤维间距为800μm,生成软件可以识别的GCode,平台温度和针头温度根据现场情况实时设置,挤出压力设置为0.35MPa,开启电磁阀,预挤浆料,当浆料呈纤维状垂直挤出且能连续不断出丝,表明浆料的可打印性良好,点击开始打印。将打印得到的支架坯体在室温下干燥1d、60℃干燥1d、120℃干燥1d,脱模后置于马弗炉中煅烧得到磷酸三钙陶瓷支架。烧结制度为先升温至200℃保温1h,然后升温至700℃保温1h,再升温至1100℃保温2h后,降温至室温,升温速率和降温速率均为2℃/min。
对比例1
为与实施例制备得到的硅酸锌复合磷酸三钙陶瓷支架进行对比,对比例1制备了不含硅酸锌的磷酸三钙陶瓷支架骨修复材料,具体方法如下:
(1)磷酸三钙粉体的制备:称取79.34g磷酸氢二铵溶于1.2L去离子水中配成0.5mol/L磷酸氢二铵溶液,再称取212.54g四水硝酸钙溶于2L去离子水中配成0.45mol/L溶液。搅拌状态下(400r/min),将磷酸氢二铵溶液用蠕动泵滴入硝酸钙溶液中(150r/min),用氨水调节反应液的pH至6.8。待磷酸氢二铵滴加完毕后,pH保持6.8继续搅拌2h,然后室温陈化2d,每天换3次去离子水,离心冻干。将冻干后的粉末在900℃下煅烧2h得到β-TCP粉体,过53μm的筛以备打印用。
(2)打印浆料的配制:将10gβ-TCP与0.3g甲基纤维素粉体混合均匀后倒入10g8wt.%PVA溶液中,用机械搅拌器调和均匀后将浆料转移至料筒中备用。
(3)陶瓷支架的制备:将solidworks软件设计的10×10×7mm圆柱形模型保存为.stl格式文件,导入打印软件,对打印路径进行编辑,打印速度为12mm/s,层高为340μm,纤维间距为800μm,生成软件可以识别的GCode,平台温度和针头温度根据现场情况实时设置,挤出压力设置为0.35MPa,开启电磁阀,预挤浆料,当浆料呈纤维状垂直挤出且能连续不断出丝,表明浆料的可打印性良好,点击开始打印。将打印得到的支架坯体在室温下干燥1d、60℃干燥1d、120℃干燥1d,脱模后置于马弗炉中煅烧得到磷酸三钙陶瓷支架。烧结制度为先升温至200℃保温1h,然后升温至700℃保温1h,再升温至1100℃保温2h后,降温至室温,升温速率和降温速率均为2℃/min。
对对比例1和实施例1~3所得的陶瓷支架用体式显微镜进行拍照和高倍扫描电镜进行表断面形貌表征,结果见图1。对比例1和实施例1~3所得的陶瓷支架纤维保形性良好、侧向孔明显、三维连通程度高。
对对比例1和实施例1~3所得的陶瓷支架采用阿基米德排水法进行开口孔隙率测试,结果见图2。硅酸锌的添加显著降低了磷酸三钙陶瓷支架的开口孔隙率。
对对比例1和实施例1~3所得的陶瓷支架采用万能材料试验机进行抗压强度测试(参考国标GB/T 6569-86),结果见图3。磷酸三钙陶瓷支架的抗压强度平均仅有4.79MPa,硅酸锌复合磷酸三钙陶瓷支架的抗压强度可达到20MPa以上,表明硅酸锌的复合能显著提升磷酸三钙陶瓷支架的抗压强度。
对对比例1和实施例1~3所得的陶瓷支架采用CCK8试剂盒进行细胞增殖实验表征。每组设6个平行样,当细胞在支架上分别培养1、3、7天后,将接种有mBMSCs的支架转移到新的48孔板中,随后加入250μL的CCK8工作液,培养箱中避光孵育1h,取100μL上清液加入到96孔板中,使用酶标仪测其在450nm处的吸光度,结果见图4。结果表明,硅酸锌复合磷酸三钙陶瓷支架上的细胞数量能随着培养时间的延长而增多,增殖趋势优于对比例1所得的磷酸三钙,表明硅酸锌的复合能促进细胞在磷酸三钙陶瓷支架的增殖,且复合量越多,支架的促细胞增殖性能就越显著。
对对比例1和实施例1~3所得的陶瓷支架采用BCA总蛋白试剂盒和碱性磷酸酶定量试剂盒进行细胞碱性磷酸酶活性实验表征。每组设6个平行样,mBMSCs的接种密度为1×105cells/孔,材料接种细胞12小时后,将培养基更换为成骨诱导液后隔天换成骨诱导液,14天后将带细胞的支架转移至新孔板中裂解,收集裂解液离心取上清液,按照试剂盒说明书定量检测总蛋白和碱性磷酸酶活性,结果见图5。碱性磷酸酶活性是细胞成骨分化早期标志之一,细胞在硅酸锌/磷酸三钙陶瓷支架上14天的碱性磷酸酶显著高于对比例1的磷酸三钙陶瓷支架,表明硅酸锌的复合能显著增强细胞在磷酸三钙陶瓷支架的碱性磷酸酶活性。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (8)
1.一种硅酸锌复合磷酸三钙陶瓷支架的制备方法,其特征在于,包括以下步骤:
(1)将固相粉体和增稠剂混合均匀后,加入聚乙烯醇水溶液调和,得到打印浆料;所述固相粉体包括硅酸锌粉体、β-磷酸三钙粉体;
步骤(1)中所述固相粉体包括以下质量百分数的组分:硅酸锌粉体的含量大于等于5wt.%、小于15wt.%,β-磷酸三钙粉体含量大于85wt.%、小于等于95wt.%;或硅酸锌粉体的含量15wt.%,β-磷酸三钙粉体含量85wt.%;
步骤(1)中所述硅酸锌粉体的制备包括以下步骤:搅拌状态下,将正硅酸乙酯加入至乙酸锌溶液中充分反应后,将带有白色沉淀的反应液转入反应釜中,经水热、离心、洗涤、烘干、过筛,得到硅酸锌粉体;
(2)将打印浆料进行3D打印,得到支架坯体,支架坯体经过梯度干燥和烧结,得到所述硅酸锌复合磷酸三钙陶瓷支架。
2.根据权利要求1所述的硅酸锌复合磷酸三钙陶瓷支架的制备方法,其特征在于,步骤(1)中所述增稠剂为甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素中的至少一种,增稠剂的添加量为所述固相粉体的1~5wt.%;所述聚乙烯醇水溶液的浓度为6~10wt.%,聚乙烯醇水溶液的添加量为所述固相粉体的90~110wt.%。
3.根据权利要求1所述的硅酸锌复合磷酸三钙陶瓷支架的制备方法,其特征在于,步骤(1)中所述β-磷酸三钙粉体的制备包括以下步骤:搅拌状态下,将磷酸氢二铵溶液加入到硝酸钙溶液中充分反应后,经陈化、离心、冻干、煅烧、过筛,得到磷酸三钙粉体。
4.根据权利要求1所述的硅酸锌复合磷酸三钙陶瓷支架的制备方法,其特征在于,步骤(2)中,所述3D打印的条件为针头直径260~600μm、层高208~640μm、纤维间距660~1000μm、挤出压力0.1~0.6MPa、打印速度1~25mm/s。
5.根据权利要求1所述的硅酸锌复合磷酸三钙陶瓷支架的制备方法,其特征在于,步骤(2)中,所述梯度干燥为先室温干燥1~2d,然后50~80℃烘干1~2d,最后100~140℃烘干1~2d。
6.根据权利要求1所述的硅酸锌复合磷酸三钙陶瓷支架的制备方法,其特征在于,步骤(2)中,所述烧结为先升温至150~250℃保温1~2h,然后升温至600~800℃保温1~2h,再升温至1050~1150℃保温2~3h后,降温至室温,升温速率和降温速率均为1~10℃/min。
7.根据权利要求1-6任一项所述制备方法制备得到的硅酸锌复合磷酸三钙陶瓷支架。
8.根据权利要求7所述的硅酸锌复合磷酸三钙陶瓷支架在制备骨修复材料中的应用。
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