CN116813370B - 一种生物陶瓷棒及其制备方法和应用 - Google Patents
一种生物陶瓷棒及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于医疗器械技术及增材制造领域,具体涉及一种生物陶瓷棒及其制备方法和应用。本发明提供的生物陶瓷棒,包括以下重量百分比含量的组分:100wt%>Ca3(PO4)2≥70wt%,0<SiO2≤13.5wt%,0<Na2O≤7.35wt%,0<CaO≤7.35wt%,0<P2O5≤1.8wt%,0<SrO≤3wt%;生物陶瓷棒具有三维贯通的孔道,孔道的平均孔径为300~600μm,生物陶瓷棒的孔隙率为35~85%;所述陶瓷棒的孔壁上分布<10μm的开孔且表面分布有诱导沉积类骨羟基磷灰石刺激位点。生物陶瓷棒具有良好的力学性能、沉积类骨羟基磷灰石及抗菌能力、利于成骨及血管化。
Description
技术领域
本发明属于医疗器械技术领域,具体涉及一种生物陶瓷棒及其制备方法和应用。
背景技术
股骨头坏死是骨科的三大顽症之一,甚至股骨头坏死被称为不死的癌症。目前临床上用于治疗股骨头坏死,有以医用钛合金、钽金属等制备的金属支撑棒;以磷酸三钙制备的生物陶瓷棒。由金属制作的支撑棒具有良好的力学性能、生物相容性和生物活性,但是由金属制作的支撑棒具有诸多弊端,例如不能进行生物降解,对处于生长期的青少年型股骨头坏死患者来说不宜使用;再例如进行医学影响检查时由于金属的植入可能会引入图像伪影,从而影响医学检查结果,进而影响周围组织的观察;再再例如,金属离子释放会成为潜在的长期危险;不能适用于对金属过敏的人群;金属导热系数与骨组织导热系数差异较大,会引起患者修复部位的不适。
目前市售的磷酸三钙生物陶瓷棒针对于金属支撑棒上述的诸多弊端,表现良好,但前者力学性能差,孔道结构不可控、孔道连通性差,另外磷酸三钙材料本身缺乏诱导沉积类骨羟基磷灰石能力,且降解速度与新生骨再生速度不匹配,不利于成骨及血管化。
发明内容
有鉴于此,本发明提供了一种生物陶瓷棒及其制备方法和应用,本发明提供的生物陶瓷棒具有贯通的孔道、高连通性、优异力学性能的同时具有沉积类骨羟基磷灰石以及抗菌的能力利于成骨及血管化。
为了解决上述技术问题,本发明提供了一种生物陶瓷棒,包括以下重量百分比含量的组分:100wt%>Ca3(PO4)2≥70wt%,0<SiO2≤13.5wt%,0<Na2O≤7.35wt%,0<CaO≤7.35wt%,0<P2O5≤1.8wt%,0<SrO≤3wt%,各组分的重量百分比之和为100%;
所述生物陶瓷棒具有三维贯通的孔道,所述孔道的平均孔径为300~600μm,所述生物陶瓷棒的孔隙率为35~85%;
所述孔道的孔壁表面分布有不规则形状的凸起,所述凸起高于孔壁平滑面的高度大于0μm小于等于50μm。
优选的,所述孔道的孔壁上分布有开孔,所述开孔的孔径小于10μm。
本发明还提供了上述技术方案所述生物陶瓷棒的制备方法,包括以下步骤:
将第一固相和第二固相混合,得到固相混合物;所述第一固相为低温相的Ca3(PO4)2粉体,所述第一固相的平均粒径<20μm;所述第二固相为包括以下重量百分比含量的组分:43wt%<SiO2<47wt%,22.5wt%<Na2O<26.5wt%,14.5wt%<CaO<26.5wt%,5wt%<P2O5<7wt%,0<SrO<10wt%,所述第二固相的平均粒径<50μm;所述第二固相的中位粒径大于所述第一固相中位粒径的1.5倍;
将所述固相混合物、光敏树脂预混液和分散剂混合,过滤得到打印浆料;所述光敏树脂预混液包括光敏树脂预聚体、活性单体和光引发剂;
将所述打印浆料依次进行光固化3D打印和热处理,得到所述生物陶瓷棒。
优选的,所述热处理包括依次进行低温热处理和高温热处理。
优选的,所述低温热处理为程序升温后终温保温,所述程序升温为:按照0.1~1℃/min的升温速率匀速升温至终温,每升温50~100℃保温1~4h;所述终温为480~520℃,在终温下保温时间为1~3h。
优选的,所述高温热处理的温度为950~1120℃,所述高温热处理的时间为1~6h,升温至高温热处理温度的升温速率为5~10℃/min。
优选的,所述光敏树脂预聚体为环氧丙烯酸酯、聚氨酯丙烯酸酯、脂肪族聚氨酯丙烯酸树脂、聚酯丙烯酸酯和聚醚丙烯酸酯中的一种或多种;
所述活性单体为甲基丙烯酸羟乙酯、1,6己二醇二丙烯酸酯、三丙二醇二丙烯酸酯、三羟甲基丙烷三丙烯酸酯、聚乙二醇二丙烯酸酯和二甲基丙烯酸乙二醇酯中的一种或多种;
所述光引发剂包括苯基双(2,4,6-三甲基苯甲酰基)氧化膦、(2,4,6-三甲基苯甲酰基)二苯基氧化膦和1-羟基环己基苯基甲酮中的一种或多种。
优选的,所述光敏树脂预混液的粘度为100~500mPa·s;
所述打印浆料的粘度为3500~6000mPa·s。
优选的,所述光固化打印为紫外光固化打印;所述光固化打印的曝光强度为2~50mw/cm2,曝光时间为1~10s。
本发明还提供了上述技术方案所述生物陶瓷棒或上述技术方案所述制备方法制备得到的生物陶瓷棒在制备医用植入体中的应用。
本发明提供了一种生物陶瓷棒,包括以下重量百分比含量的组分:100wt%>Ca3(PO4)2≥70wt%,0<SiO2≤13.5wt%,0<Na2O≤7.35wt%,0<CaO≤7.35wt%,0<P2O5≤1.8wt%,0<SrO≤3wt%,各组分的重量百分比之和为100%;所述生物陶瓷棒具有三维贯通的孔道,所述孔道的平均孔径为300~600μm;所述生物陶瓷棒的孔隙率为35~85%;所述孔道的孔壁表面分布有不规则形状的凸起,所述凸起高于孔壁平滑面的高度大于0μm小于等于50μm。利用上述材料制备得到的生物陶瓷棒具有的材料组成以及三维贯通孔道提高了生物陶瓷棒的力学性能。本发明提供的生物陶瓷棒具有与人体骨骼基本相近的无机物(磷酸钙、碳酸盐和微量元素)成分以及优异的微结构。将所述生物陶瓷棒植入损伤部位后,释放的硅离子、钙离子、钠离子、磷离子、锶离子与组织液进行离子交换,改善局部pH值,减少细菌滋生提高抗菌性能;孔壁上孔径<10μm的开孔增大陶瓷棒的比表面积,利于体液浸润、材料溶解以及细胞的黏附;同时在生物陶瓷棒中诱导沉积类骨羟基磷灰石刺激位点形成碳酸羟基磷灰石网络以及Ca-P无定型相层后吸附、聚集组织再生所需的物质,如纤维蛋白、胶原纤维以及各种生长因子及骨诱导蛋白(BMP)等,刺激成骨细胞繁殖,促进血管再生,加速缺损部位愈合。
本发明提供了上述技术方案所述生物陶瓷棒的制备方法,包括以下步骤:将第一固相和第二固相混合,得到固相混合物;所述第一固相为低温相的Ca3(PO4)2粉体,所述第一固相的粒径<20μm;所述第二固相为包括以下重量百分比含量的组分:43wt%<SiO2<47wt%,22.5wt%<Na2O<26.5wt%,14.5wt%<CaO<26.5wt%,5wt%<P2O5<7wt%,0<SrO<10wt%,所述第二固相的粒径<50μm;所述第二固相的中位粒径大于所述第一固相中位粒径的1.5倍;将所述固相混合物、光敏树脂预混液和分散剂混合,得到打印浆料;所述光敏树脂预混液包括光敏树脂预聚体、活性单体和光引发剂;将支撑棒三维模型数据进行处理并导入电脑待用;将所述打印浆料依次进行光固化3D打印和热处理,得到所述生物陶瓷棒。本发明通过光固化3D打印技术以及材料组成、特定的热处理技术能够精确控制生物陶瓷棒的孔道结构利于提高生物陶瓷棒的力学性能和成骨及血管化性能。本发明提供的制备方法能够精确控制生物陶瓷棒的结构利于将生物陶瓷棒用于制备骨缺损或骨股头坏死重建棒。
附图说明
图1为实施例1模型图和实施例1制备得到材料的实物图;
图2为实施例2模型图和实施例2制备得到材料的实物图;
图3为实施例2制备得到的通体骨小梁结构生物陶瓷棒放大实物图;
图4为实施例1制备得到的材料的应力应变曲线图;
图5为实施例2制备得到的材料的应力应变曲线图;
图6为实施例1制备得到的材料的SEM图;
图7为实施例2制备得到的材料的SEM图;
图8为利用实施例1制备得到的材料与小鼠胚胎成纤维细胞体外培养8天的荧光显微图;
图9为利用实施例2制备得到的材料与人脐静脉血管内皮细胞体外培养8天的荧光显微图。
具体实施方式
本发明提供了一种生物陶瓷棒,包括以下重量百分比含量的组分:100wt%>Ca3(PO4)2≥70wt%,0<SiO2≤13.5wt%,0<Na2O≤7.35wt%,0<CaO≤7.35wt%,0<P2O5≤1.8wt%,0<SrO≤3wt%,各组分的重量百分比之和为100%;
所述生物陶瓷棒具有三维贯通的孔道,所述孔道的平均孔径为300~600μm;所述生物陶瓷棒的孔隙率为35~85%;
所述孔道的孔壁上分布<10μm开孔,且表面分布有不规则形状的凸起,所述凸起高于孔壁平滑面的高度大于0μm小于等于50μm。
在本发明中,如果没有特殊说明全部组分为本领域常规市售产品即可。
在本发明中,以质量百分含量计,所述生物陶瓷棒包括大于等于70%小于100%的磷酸三钙,优选为75~95%,更优选为80~90%。在本发明中,所述磷酸三钙的作用是为新骨形成提供营养支持,促进骨细胞的增殖和分化。
在本发明中,以质量百分含量计,所述生物陶瓷材料优选包括大于0小于等于13.5%的二氧化硅,优选为3~12%,更优选为5~9%。在本发明中,所述二氧化硅的作用是促进血管化能力。
在本发明中,以质量百分含量计,所述生物陶瓷材料包括大于0小于等于7.35%的氧化钠,优选为0.5~6%,更优选为2~5%。在本发明中,所述氧化钠的作用为加快离子释放速度,促进羟基磷灰石沉积。
在本发明中,以质量百分含量计,所述生物陶瓷材料优选包括大于0小于等于7.35%的氧化钙,优选为0.5~6%,更优选为2~5%。在本发明中,所述氧化钙的作用为为新骨形成提供营养支持。
在本发明中,以质量百分含量计,所述生物陶瓷材料包括大于0小于等于1.8%的五氧化二磷,优选为0.2~1.6%,更优选为0.4~1.2%。在本发明中,所述五氧化二磷的作用是为新骨形成提供营养支持。
在本发明中,以质量百分含量计,所述生物陶瓷材料包括大于0小于等于3%氧化锶,优选为0.1~2.5%,更优选为0.3~2%。在本发明中,所述氧化锶的作用为促进新骨形成。
在本发明中,所述生物陶瓷棒具有三维贯通的孔道,所述孔道的平均孔径为300~600μm,优选为350~500μm。在本发明中,所述生物陶瓷棒的孔隙率为35~85%,优选为40~82%,更优选为50~80%。在本发明中,所述孔道的孔壁上优选分布有开孔,所述开孔的孔径优选小于10μm。在本发明中,所述生物陶瓷棒的长度优选为10~120mm,优选为30~100mm;
在本发明中,所述孔道的孔壁表面分布有不规则形状的凸起,所述凸起高于孔壁平滑面的高度大于0μm小于等于50μm,凸起平均高度优选为10~30μm。在本发明中,所述凸起的作用优选为提供诱导沉积类骨羟基磷灰石刺激位点。在本发明中,三维贯通的孔道为营养物质的运输提供通道,为血管提供生长空间;孔壁上<10um的开孔增大陶瓷棒的比表面积,利于体液浸润、材料溶解以及细胞的黏附;孔壁上略凸的诱导沉积类骨羟基磷灰石刺激位点优先与体液反应,初步改善骨缺损微环境,起到抗菌作用,进一步刺激生成类骨羟基磷灰石。
本发明提供的生物陶瓷棒的孔道贯通、连通性高、力学性能优异、降解速率可控、具有良好的诱导沉积类骨羟基磷灰石能力及抗菌功能,利于成骨及血管化,用于股骨头坏死或骨缺损修复,大大地提高了手术成功率。
本发明提供了上述技术方案所述生物陶瓷棒的制备方法,包括以下步骤:
将第一固相和第二固相混合,得到固相混合物;所述第一固相为低温相的Ca3(PO4)2粉体,所述第一固相的粒径<20μm;所述第二固相为包括以下重量百分比含量的组分:43wt%<SiO2<47wt%,22.5wt%<Na2O<26.5wt%,14.5wt%<CaO<26.5wt%,5wt%<P2O5<7wt%,0<SrO<10wt%,所述第二固相的粒径<50μm;所述第二固相的中位粒径大于所述第一固相中位粒径的1.5倍;
将所述固相混合物、光敏树脂预混液和分散剂混合,过滤得到打印浆料;所述光敏树脂预混液包括光敏树脂预聚体、活性单体和光引发剂;
将支撑棒三维模型数据进行处理并导入电脑待用;将所述打印浆料依次进行光固化3D打印和热处理,得到所述生物陶瓷棒。
本发明将第一固相和第二固相混合,得到固相混合物。在本发明中,所述第一固相为低温相的Ca3(PO4)2粉体,所述第一固相的粒径<20μm,优选为<15μm。在本发明中,所述第一固相的D50粒径优选小于5μm,更优选为3~4.2μm;所述第一固相的D90粒径优选小于10μm,更优选为8.3~9.6μm。在本发明中,所述Ca3(PO4)2粉体的纯度优选大于等于98%,更优选大于等于99%。
在本发明中,所述第二固相为包括以下重量百分比含量的组分:43wt%<SiO2<47wt%,22.5wt%<Na2O<26.5wt%,14.5wt%<CaO<26.5wt%,5wt%<P2O5<7wt%,0<SrO<10wt%,优选为43.9wt%≤SiO2≤44.5wt%,24.1wt%≤Na2O≤24.6wt%,18.7wt%≤CaO≤19.7wt%,5.5wt%≤P2O5≤6.1wt%,5.7≤SrO≤7.2wt%。
在本发明中,所述第二固相的粒径<50μm,优选<30μm;在本发明中,所述第二固相的D50粒径优选<15μm,更优选为7.4~9.2μm;所述第二固相的D90粒径优选<30μm,更优选为15.3~25.1μm。在本发明中,所述第二固相的纯度优选大于等于98%,更优选大于等于98.5%。
在本发明中,所述第二固相的中位粒径大于所述第一固相中位粒径的1.5倍;
在本发明中,所述第一固相和第二固相的质量比优选大于等于7:3更优选为为2.4~6:1。
在本发明中,所述混合优选为机械混合,所述机械混合优选为湿法混合或干法混合。在本发明中,所述湿法混合用溶剂优选包括无水乙醇或水,更优选为无水乙醇。在本发明中,所述混合的时间优选为0.5~4h,更优选为1~3h,更进一步优选为1.5~2h。
得到固相混合物后,本发明将所述固相混合物、光敏树脂预混液和分散剂混合,过滤得到打印浆料。在本发明中,所述光敏树脂预混液包括光敏树脂预聚体、活性单体和光引发剂。在本发明中,所述光敏树脂预聚体优选为环氧丙烯酸酯、聚氨酯丙烯酸酯、脂肪族聚氨酯丙烯酸树脂、聚酯丙烯酸酯和聚醚丙烯酸酯中的一种或多种,更优选为脂肪族聚氨酯丙烯酸树脂和/或聚氨酯丙烯酸酯;当所述光敏树脂预聚体为两种以上上述具体物质时,本发明对具体物质的配比无特殊限定,采用任意配比即可。在本发明中,所述光敏树脂预聚体占光敏树脂预混液的质量百分含量优选为40~70%,更优选为45~65%。
在本发明中,所述活性单体优选为甲基丙烯酸羟乙酯、1,6己二醇二丙烯酸酯、三丙二醇二丙烯酸酯、三羟甲基丙烷三丙烯酸酯、聚乙二醇二丙烯酸酯和二甲基丙烯酸乙二醇酯中的一种或多种,更优选为1,6己二醇二丙烯酸酯和/或三丙二醇二丙烯酸酯。在本发明中,当所述活性单体为两种以上上述具体物质时,本发明对具体物质的配比无特殊限定,采用任意配比即可。在本发明中,所述活性单体占光敏树脂预混液的质量百分含量优选为30~60%,更优选为35~55%。
在本发明中,所述光引发剂优选包括苯基双(2,4,6-三甲基苯甲酰基)氧化膦、(2,4,6-三甲基苯甲酰基)二苯基氧化膦和1-羟基环己基苯基甲酮中的一种或多种,更优选为苯基双(2,4,6-三甲基苯甲酰基)氧化膦或(2,4,6-三甲基苯甲酰基)二苯基氧化膦。在本发明中,当光引发剂包括两种以上上述具体物质时,本发明对具体物质的配比无特殊要求,采用任意配比即可。在本发明中,所述光引发剂占光敏树脂预混液的质量百分含量优选为0.3~5%,更优选为1~3%。
在本发明中,所述分散剂优选为BYK110、BYK118、BYK160、BYK167、BYK168、路博润32500、路博润AC7590和路博润AC7160中的一种或几种,更优选为BYK110或路博润AC7160。当所述分散剂为两种以上上述具体物质时,本发明对具体物质的配比没有任何特殊的限定,按任意配比进行混合即可。在本发明中,所述分散剂能够改善打印料浆的表面张力,使固相混合物均匀地分布于光敏树脂中。
在本发明中,所述分散剂占打印浆料的质量百分含量优选为0.1~3%,更优选为0.5~2.5%,更进一步优选为0.8~2%。在本发明中,所述固相混合物占打印浆料的质量百分含量优选大于40%,更优选为50~80%,更进一步优选为55~75%。在本发明中,所述光敏树脂预混液占打印浆料的质量百分含量优选小于60%,更优选为20~50%,更进一步优选为25~45%。
本发明对所述混合的顺序没有任何特殊的限定,采用按任意混合顺序进行混合即可。在本发明中,所述混合的方式优选为机械混合,所述机械混合的时间优选为1~8h,更优选为1.5~3h。
得到打印浆料后,本发明将所述打印浆料依次进行光固化3D打印和热处理,得到所述生物陶瓷棒。在本发明中,所述光固化打印前优选还包括:将所述生物陶瓷材料模型的数据处理后导入电脑。在本发明中,所述模型优选为需要制备得到的材料的模型。在本发明中,所述模型优选为三维模型,所述三维模型优选利用三维软件建模得到;所述三维软件优选包括CAD、Rhino、Maya、Solidworks、3DS MAX或UG,更优选为CAD或UG。在本发明中,所述模型数据优选包括形状、尺寸、孔径和孔隙率。在本发明中,所述三维模型所需数据来源于患者骨坏死区域的医学影像数据,如CT、MRI等,根据坏死区域的大小及医生的建议,确定生物陶瓷棒直径、长度。陶瓷棒孔道结构原则上可为任意结构。
在本发明中,以制备骨股头坏死重建棒为例,所述模型的数据来源于患者骨坏死区域的医学影像数据,如CT或MRI的医学影像数据,根据坏死区域的大小及医生的建议,确定骨股头坏死重建棒的直径、长度,按功能所需可进一步优化其外部附加结构;所述附加结构包括:端部螺纹或楔形件。
在本发明中,所述光固化打印优选为紫外光固化打印,所述紫外光的波长优选为300~420nm。在本发明中,所述光固化打印的曝光强度优选为2~50mw/cm2,更优选为5~40mw/cm2,更进一步优选为10~30mw/cm2;所述光固化打印的曝光时间优选为1~10s,更优选为3~8s。
在本发明中,所述光固化打印优选包括立体光刻(SLA)和数字光处理(DLP),具体过程优选为:将模型分层处理,产生构成每层的特定形状或图案,然后在紫外光下曝光,打印浆料按照每层的特定形状逐层叠加进行聚合和硬化,构建成需要的陶瓷生坯。
在本发明中,所述光固化打印后优选还包括:将光固化打印的产品进行清洗。在本发明中,所述清洗优选包括依次进行的喷吹和洗涤。在本发明中,所述喷吹优选采用气流进行喷吹;本发明对所述气流的种类和压力没有特殊的限定,采用本领域技术人员熟知的气流喷吹即可。在本发明的实施例中采用压力为0.5MPa的空气进行喷吹。本发明通过喷吹能够除去未固化的打印浆料。
在本发明中,所述洗涤优选包括在洗涤剂溶液、无水乙醇或异丙醇中进行的超声清洗处理。在本发明中,所述洗涤剂溶液优选包括洗洁精溶液或洗衣液溶液,更优选为洗洁精溶液;所述洗涤剂溶液的质量浓度优选为10~20%,更优选为13~18%。在本发明中,所述超声清洗处理的功率优选为30~180W,更优选为60~150W;所述超声清洗处理的时间优选为3~10min,更优选为4~6min。本发明通过清洗能够除去光固化打印陶瓷棒孔道中残留的打印浆料。
在本发明中,所述热处理优选包括依次进行低温热处理和高温热处理。在本发明中,所述低温热处理优选为程序升温后终温保温,所述程序升温优选为:按照0.1~1℃/min的升温速率匀速升温至终温,每升温50~100℃保温1~4h,在终温下保温时间为1~3h;更优选为按照0.3~0.8℃/min的升温速率匀速升温至终温,每升温80~100℃保温1~2h,在终温保温1~2h。在发明中,所述终温优选为480~520℃,更优选为500℃。在本发明中,所述高温热处理的温度优选为950~1120℃,更优选为1000~1100℃;所述高温热处理的时间优选为1~6h,更优选为2~4h;升温至高温热处理温度的升温速率优选为5~10℃/min,更优选为6~8℃/min。
在本发明中,所述高温热处理后优选还包括:将高温热处理的产物冷却至室温。在本发明中,所述室温优选为20~30℃,更优选为23~28℃。在本发明中,所述冷却优选包括随炉冷却。
本发明分段升温保温的目的是使有机物更好的排出,生物陶瓷棒成品率高;另外适宜的高温热处理升温速率及保温时间,增加生物陶瓷棒的活性。
本发明以粒径小于20μm的第一固相搭配粒径小于50μm的第二固相,且第二固相中位粒径大于第一固相中位粒径的1.5倍,有利于诱导沉积类骨羟基磷灰石刺激位点的形成以及利于提高生物陶瓷棒的力学性能,并且通过调整第二固相的含量、第一固相和第二固相的总含量、热处理温度,可以调控生物陶瓷棒的抗菌及沉积类骨羟基磷灰石能力、降解速率、以及血管化能力。
本发明还提供了上述技术方案所述生物陶瓷棒或上述技术方案所述制备方法制备得到的生物陶瓷棒在制备医用植入体中的应用。在本发明中,所述一种植入体优选包括骨缺损修复重建棒或骨股头坏死重建棒。本发明对所述应用的方法没有任何特殊的限定,采用本领域技术人员熟知的过程进行即可。
为了进一步说明本发明,下面结合实施例对本发明提供的技术方案进行详细地描述,但不能将它们理解为对本发明保护范围的限定。
注:实施例1、2中所述质量比可以理解为原料的用量不受单位级别的限制,可以为“g”、“kg”或“t”等。
实施例1
第一固相,低温相的Ca3(PO4)2粉体,纯度99%,D50=4.2μm,D90=9.6μm;
第二固相,其化学组成按质量百分含量计如下:44.5wt%SiO2、24.1wt%Na2O、18.7wt%CaO、5.5wt%P2O5和7.2wt%SrO,粉体,纯度98.5%,D50=7.4μm,D90=15.3μm;
将第一固相和第二固相粉体质量按照3:1的质量比进行机械湿法混合2h,得到固相混合物;
按照65:35:1的质量比,将固相混合物、液相(脂肪族聚氨酯丙烯酸树脂57wt%,1,6己二醇二丙烯酸酯41wt%,苯基双(2,4,6-三甲基苯甲酰基)氧化膦2wt%)和分散剂(BYK110)进行机械混合1.5h,过滤得到3D打印浆料;
以图1中a为本实施例的3D模型图,3D模型为骨小梁结构,尾部带有楔形,起到固定的作用,3D模型的长度L=88mm、直径d=10mm、平均孔径为618μm,孔隙率为:82%;将3D模型分层处理,产生构成每层的特定形状或图案,然后在波长为380~420nm的紫外光下曝光,3D打印浆料按照每层的特定形状逐层叠加进行聚合和硬化,所述光固化3D打印的曝光强度为12mw/cm2,曝光时间为4s,得到生物陶瓷棒生坯;
采用压力为0.5MPa的空气气流喷吹所述生物陶瓷棒生坯后,放入无水乙醇中超声清洗3min,再用高压气流喷吹,以除去陶瓷棒生坯上黏附的无水乙醇或料浆残留物;
接着进行热处理,首先以0.5℃/min的升温速率升温至500℃保温2h,升温过程中每升温100℃保温1h;然后以5℃/min的升温速率升至1050℃保温2h,然后随炉冷却降温至室温,得到生物陶瓷棒。图1中b为本实施例的生物陶瓷棒。
实施例2
第一固相,低温相的Ca3(PO4)2粉体,纯度99%,D50=3.1um,D90=8.3um;
第二固相,其化学组成按质量百分含量计如下:43.9wt%SiO2、24.6wt%Na2O、19.7wt%CaO、6.1wt%P2O5和5.7wt%SrO,粉体,纯度98.5%,D50=9.2um,D90=18.4um;
将第一固相和第二固相粉体质量按照71:29的质量比进行机械湿法混合1.5h,得到固相混合物;
按照68:32:1的质量比,将固相混合物、液相(聚氨酯丙烯酸酯23wt%,脂肪族聚氨酯丙烯酸树脂39wt%,1,6己二醇二丙烯酸酯24wt%,三丙二醇二丙烯酸酯12wt%,(2,4,6-三甲基苯甲酰基)二苯基氧化膦2wt%)和分散剂(路博润AC7160)进行机械混合2h,过滤得到3D打印浆料;
以图2中c为本实施例的3D模型,3D模型通体为骨小梁结构,3D模型的长度L=80mm、直径d=10mm,平均孔径为591um,孔隙率为:80%;将3D模型分层处理,产生构成每层的特定形状或图案,然后在波长为380~420nm的紫外光下曝光,3D打印浆料按照每层的特定形状逐层叠加进行聚合和硬化,所述光固化3D打印的曝光强度为18mw/cm2,曝光时间为3s,得到生物陶瓷棒生坯;
采用压力为0.5MPa的空气气流喷吹所述生物陶瓷棒生坯后,放入异丙醇中超声清洗2min,再用高压气流喷吹,以除去陶瓷棒生坯上黏附的无水乙醇或料浆残留物;
接着进行热处理,首先以0.7℃/min的升温速率升温至500℃保温2.5h,升温过程中每升温100℃保温1.2h;然后以5℃/min的升温速率升至1020℃保温2.5h,然后随炉冷却降温至室温,得到生物陶瓷棒,图2中d为本实施例制备得到的通体骨小梁结构生物陶瓷棒实物图。图3为实施例2制备得到的通体骨小梁结构生物陶瓷棒更近距实物图。
按照以下方法对实施例1、2制备得到的生物陶瓷棒进行结构和性能测试,其中,按照煮沸法测试孔道连通性;采用压汞仪测试检测孔径及孔隙率;按照国标GB/T1964-1996检测耐压强度和弹性模量;将以上检测结果列于表1中。
表1实施例1、2制备得到的材料的结构和性能参数
由表1可知本发明提供的材料中的孔道具有良好的连通性;同时材料的孔径与孔隙率可调,可根据需要进行调整,制备得到仿生结构的材料。由于陶瓷烧结收缩影响,模型的平均孔径和孔隙率和制备得到的生物陶瓷棒的平均孔径和孔隙率不一致。
对实施例1制备得到的材料进行耐压强度和弹性模量检测时的应力应变曲线图如图4所示对实施例2制备得到的材料进行耐压强度和弹性模量检测时的应力应变曲线图如图5所示。
结合表1和图4、5可知,本发明提供的材料具有良好的力学性能,本发明提供的生物陶瓷支撑棒满足松质骨的抗压强度要求。
对实施例1制备得到的材料进行扫描电子显微镜的观察,得到SEM图,如图6所示;对实施例2制备得到的材料进行扫描电子显微镜的观察,得到SEM图,如图7所示。由图6和图7可知,本发明提供的生物陶瓷棒中,孔壁开孔分布均匀,大量均匀的连通气孔,颗粒间为颈部连接,晶体发育均匀,另外诱导沉积类骨羟基磷灰石刺激位点无规则分布于孔壁表面,位点明显高于底材,生物陶瓷棒的微观形貌为细胞的粘附、攀爬提供了条件。
将实施例1、2制备得到的材料灭菌后于37℃恒温条件下浸泡于SBF缓冲液中24h后,提取浸提液,用pH计测量浸提液pH值,通过数据统计,pH值在8~10之间,呈一定弱碱性;另外分别将实施例1、2的3mL浸提液加入到含有大肠杆菌的不同培养皿中,培养3h后,在发现细菌数量均呈下降趋势,证明生物陶瓷棒有一定的抗菌能力;在37℃恒温条件下于SBF缓冲液中浸泡48h后滤出水合粉体,进行傅里叶红外光谱和X射线衍射光谱检测,测试发现水合反应后,形成了磷酸根,有羟基磷灰石生成,说明生物陶瓷棒生物活性良好,有沉积类骨羟基磷灰石的能力。
将实施例1制备的生物陶瓷棒灭菌后与小鼠胚胎成纤维细胞(NIH3T3)在体外培养第8天时,采用碘化丙啶(PI)对细胞进行染色,然后采用荧光显微镜观察并拍照,得到的图片如图8所示。由图8可以看出细胞贴附于多孔陶瓷孔内壁生长,在该材料上分化、增殖明显,证明生物陶瓷棒具有诱导骨组织再生和增快骨缺损修补重建的功能。
将实施例2制备的生物陶瓷棒灭菌后与人脐静脉血管内皮细胞(HUVEC)在体外培养第8天时,采用碘化丙啶(PI)对细胞进行染色,然后采用荧光显微镜观察并拍照,得到图9,由图9可以看出细胞贴附于多孔陶瓷孔内壁生长,在该材料上分化、增殖明显,证明生物陶瓷棒具有诱导骨组织再生和增快骨缺损修补重建的功能。
将实施例1制备的材料截取一节(直径5.0mm,厚度2mm)灭菌后植入新西兰大白兔颅顶骨缺损处。在植入4个月后取出带有部分周围骨组织的样品,固定于4%多聚甲醛固定液中24h,0.01M PBS漂洗后用15%EDTA(pH7.2~7.4)室温下摇床震荡脱钙14天,常规石蜡包埋、切片(厚度5um)。最后对切片进行苏木精-伊红(HE)染色、Masson三色染色,发现支架内部有血管以及新骨组织生成并且支架部分出现降解。
将实施例2制备的材料截取一节(直径2.5mm,厚度2mm)灭菌后植入大白鼠颅顶骨缺损处。在植入4个月后取出带有部分周围骨组织的样品,固定于4%多聚甲醛固定液中24h,0.01M PBS漂洗后用15%EDTA(pH7.2~7.4)室温下摇床震荡脱钙14天,常规石蜡包埋、切片(厚度5um)。最后对切片进行苏木精-伊红(HE)染色、Masson三色染色,发现支架内部有血管以及新骨组织生成并且支架部分出现降解,降解范围较实施例1大,说明降解速率较实施例1快,起到了调节降解速率的目的。
尽管上述实施例对本发明做出了详尽的描述,但它仅仅是本发明一部分实施例,而不是全部实施例,人们还可以根据本实施例在不经创造性前提下获得其他实施例,这些实施例都属于本发明保护范围。
Claims (10)
1.一种生物陶瓷棒,包括以下重量百分比含量的组分:100wt%>Ca3(PO4)2≥70wt%,0<SiO2≤13.5wt%,0<Na2O≤7.35wt%,0<CaO≤7.35wt%,0<P2O5≤1.8wt%,0<SrO≤3wt%,各组分的重量百分比之和为100%;
所述生物陶瓷棒具有三维贯通的孔道,所述孔道的平均孔径为300~600μm,所述生物陶瓷棒的孔隙率为35~85%;
所述孔道的孔壁表面分布有不规则形状的凸起,所述凸起高于孔壁平滑面的高度大于0μm小于等于50μm。
2.根据权利要求1所述生物陶瓷棒,其特征在于,所述孔道的孔壁上分布有开孔,所述开孔的孔径小于10μm。
3.权利要求1或2所述生物陶瓷棒的制备方法,包括以下步骤:
将第一固相和第二固相混合,得到固相混合物;所述第一固相为低温相的Ca3(PO4)2粉体,所述第一固相的平均粒径<20μm;所述第二固相为包括以下重量百分比含量的组分:43wt%<SiO2<47wt%,22.5wt%<Na2O<26.5wt%,14.5wt%<CaO<26.5wt%,5wt%<P2O5<7wt%,0<SrO<10wt%,所述第二固相的平均粒径<50μm;所述第二固相的中位粒径大于所述第一固相中位粒径的1.5倍;
将所述固相混合物、光敏树脂预混液和分散剂混合,过滤得到打印浆料;所述光敏树脂预混液包括光敏树脂预聚体、活性单体和光引发剂;
将所述打印浆料依次进行光固化3D打印和热处理,得到所述生物陶瓷棒。
4.根据权利要求3所述制备方法,其特征在于,所述热处理包括依次进行低温热处理和高温热处理。
5.根据权利要求4所述制备方法,其特征在于,所述低温热处理为程序升温后终温保温,所述程序升温为:按照0.1~1℃/min的升温速率匀速升温至终温,每升温50~100℃保温1~4h;所述终温为480~520℃,在终温下保温时间为1~3h。
6.根据权利要求4所述制备方法,其特征在于,所述高温热处理的温度为950~1120℃,所述高温热处理的时间为1~6h,升温至高温热处理温度的升温速率为5~10℃/min。
7.根据权利要求3所述制备方法,其特征在于,所述光敏树脂预聚体为环氧丙烯酸酯、聚氨酯丙烯酸酯、脂肪族聚氨酯丙烯酸树脂、聚酯丙烯酸酯和聚醚丙烯酸酯中的一种或多种;
所述活性单体为甲基丙烯酸羟乙酯、1,6己二醇二丙烯酸酯、三丙二醇二丙烯酸酯、三羟甲基丙烷三丙烯酸酯、聚乙二醇二丙烯酸酯和二甲基丙烯酸乙二醇酯中的一种或多种;
所述光引发剂包括苯基双(2,4,6-三甲基苯甲酰基)氧化膦、(2,4,6-三甲基苯甲酰基)二苯基氧化膦和1-羟基环己基苯基甲酮中的一种或多种。
8.根据权利要求3所述制备方法,其特征在于,所述光敏树脂预混液的粘度为100~500mPa·s;
所述打印浆料的粘度为3500~6000mPa·s。
9.根据权利要求3所述制备方法,其特征在于,所述光固化打印为紫外光固化打印;所述光固化打印的曝光强度为2~50mw/cm2,曝光时间为1~10s。
10.权利要求1或2所述生物陶瓷棒或权利要求3~9任一项所述制备方法制备得到的生物陶瓷棒在制备医用植入体中的应用。
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