CN110251279B - 一种磷酸钙骨水泥涂覆的3d打印plga椎间融合器的制备方法 - Google Patents
一种磷酸钙骨水泥涂覆的3d打印plga椎间融合器的制备方法 Download PDFInfo
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Abstract
本发明涉及一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法,通过3D打印技术制备可降解聚酯PLGA椎间融合器,再利用磷酸钙骨水泥涂覆聚合物表面,并填充打印间隙,磷酸钙骨水泥固化后形成羟基磷灰石涂层。本发明有望克服可降解类材料在椎间融合器领域应用时面临的体内降解过快、降解产物酸性较大、力学性能不足等问题,同时3D打印技术为临床个性化制备符合人体解剖学形态的椎间融合器提供了新的途径,具有广阔的临床应用前景。
Description
技术领域
本发明涉及一种生物医用材料技术领域的方法,特别是涉及一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法。
背景技术
随着脊柱椎间融合技术不断发展与完善,椎间融合术成为治疗涉及脊柱退行性变、畸形、骨折、肿瘤、结核等脊柱相关疾病的主流手术模式和金标准。然而,随着脊柱椎间融合手术的不断增多,近年来发生椎间融合器下沉等术后长期并发症的报道也逐渐增加[王鹏,孙桂森,李红旗等,中国组织工程研究,2018],造成这一现象的因素较多,如患者骨质疏松、老龄等[Brunello G, Sivolella S, Meneghello R, Biotechnology Advances,2016]。
目前临床常用的椎间融合器材料主要为不可降解和可降解两类。可降解融合器因其生物相容性好、体内可吸收、力学性能与自体骨相近等优点,受到了广泛的关注。但这类材料在体内降解速度过快,不足以维持到椎体骨性融合,因此术后易出现融合器塌陷、椎间隙高度丢失、椎体不稳等现象。同时,聚酯类可降解材料还存在降解产物酸性较大的问题,可能引发无菌性炎症、骨质溶解等并发症。
椎间融合器的尺寸和形状也是影响治疗效果的因素之一。理想的椎间融合器的形状应最大限度的与椎间隙形状、大小和上下终板实现完美契合,进而实现良好的骨融合。临床上,可以通过CT数据重建,构建符合病患人体解剖学的椎间融合器模型,并通过3D打印技术个性化制备可降解椎间融合器。但3D打印融合器仍面临体内降解过快、力学强度无法维持至骨性融合等难题,且打印间隙也会放大这类缺陷。
基于以上背景,本发明利用磷酸钙骨水泥具有可塑性的特点,使其填充至3D打印椎间融合器的打印间隙中,并涂覆PLGA表面,降低其与降解介质的接触,碱性的骨水泥固化产物能中和酸性降解产物,降低PLGA的降解速率;另一方面,固化后的磷酸钙骨水泥填充打印间隙,提高了椎间融合器的骨传导性和力学性能,满足临床应用的需求。
发明内容
针对现有技术的不足,本发明的目的在于提供一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法,一种3D打印技术制备的具有良好力学性能和生物相容性的磷酸钙骨水泥涂覆PLGA椎间融合器的制备方法。
本发明目的通过以下技术方案来实现:一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法,通过3D打印技术制备可降解聚酯PLGA椎间融合器,再利用磷酸钙骨水泥涂覆聚合物表面,并填充打印间隙,磷酸钙骨水泥固化后形成羟基磷灰石涂层,包括以下步骤:
(1)制备PLGA椎间融合器
以PLGA为3D打印“墨水”,打印针头选用170μm,设置打印参数:每层采用平行式打印,间隙为0.2-0.3mm,Z轴逐层升高0.15mm,打印温度170-190℃,基础速率为1.5-2mm/s,打印平台温度为30℃,使用生物3D打印机进行3D打印,制备PLGA椎间融合器;
(2)制备明胶改性α-TCP粉末
将磷酸氢钙与碳酸钙按摩尔比2:1湿法球磨混合,干燥后用马弗炉在1250-1400℃煅烧2-4h后取出,在鼓风环境下急速冷却,之后用氧化锆球磨罐450rpm湿法球磨6h,得到粒径均一的α-TCP粉末,将上述α-TCP粉末按0.5g/mL加入0.5%(w/v)的明胶溶液中,高速磁力搅拌0.5h后置于-80℃冰箱中冰冻,进行冷冻干燥48h,得到明胶改性α-TCP粉末;
(3)制备磷酸钙骨水泥涂覆PLGA椎间融合器
配制质量分数为2.5%的Na2HPO4溶液作为骨水泥固化液,与明胶改性α-TCP粉末按液固比0.5-1mL/g混合成调和浆,涂覆至PLGA椎间融合器表面并填充打印间隙,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min,使PLGA玻璃化转变、与固化产物羟基磷灰石两相进一步融合,得到磷酸钙骨水泥涂覆PLGA椎间融合器。
其中,步骤(1)中,所述的PLGA分子量为10W-40W,LA/GA为75/25,分子链两端可为酯基、羟基或羧基封端。
步骤(2)中,所述的磷酸氢钙与碳酸钙湿法球磨为使用无水乙醇作为混合介质的玛瑙球磨,转速400rpm,球磨时间为1-4h,球磨后悬浊液通过旋转蒸发除去乙醇后放入60℃烘箱中干燥过夜。
步骤(2)中,所述明胶溶液的配制方式为50℃加热下磁力搅拌助溶。
以PLGA为打印“墨水”,170-190℃进行熔融打印,打印模型、尺寸、打印间隙等参数可按需求调控;制备α-TCP粉末,加入明胶进行改性,改善骨水泥流动性和固化性能,改性后的粉末与固化液Na2HPO4溶液混合成调和浆;将调和浆涂覆至3D打印椎间融合器孔隙内及聚酯表面,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min,使PLGA玻璃化转变、与固化产物羟基磷灰石两相进一步融合,得到磷酸钙骨水泥涂覆PLGA椎间融合器。
本发明方法具体包括以下步骤:
1、以PLGA为打印“墨水”,出料针头选用170μm,采用解剖型椎间融合器模型,设置打印参数:每层平行式打印,打印间隙为0.2-0.3mm,Z轴方向逐层升高0.15mm,层与层之间采用垂直交叉式堆叠,打印温度为170-190℃,挤出速度为1.5-2mm/s,接收平台温度为30℃,打印得到解剖型PLGA椎间融合器;
2、将磷酸氢钙与碳酸钙按摩尔比2:1混合均匀,所述混合方式为使用无水乙醇为混合介质的球磨混合,转速400rpm,球磨时间为1-4h,混合后的悬浊液通过旋转蒸发除去乙醇后放入60℃烘箱中干燥;
3、将干燥后的磷酸氢钙与碳酸钙混合物在1250-1400℃炉中锻烧2-4h后取出,在鼓风环境下急速冷却,之后采用氧化锆球磨罐湿法球磨的方式得到粒径均一的α-TCP粉末。
4、将上述α-TCP粉末按0.5g/mL加入0.5%(w/v)的明胶溶液中,高速磁力搅拌0.5h后置于-80℃冰箱中冰冻,进行冷冻干燥48h,得到明胶改性α-TCP粉末。
5、配制质量分数为2.5%的Na2HPO4溶液作为骨水泥固化液,所述配制方式为常温下磁力搅拌。
6、固化液与明胶改性α-TCP粉末按固液比0.5-1mL/g混合成调和浆,涂覆至PLGA椎间融合器打印间隙中和聚酯表面,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min,使PLGA玻璃化转变、与固化产物羟基磷灰石两相进一步融合,得到磷酸钙骨水泥涂覆PLGA椎间融合器。
具体是通过3D打印技术制备可降解聚酯PLGA椎间融合器,再利用磷酸钙骨水泥涂覆聚合物表面,并填充打印间隙,磷酸钙骨水泥固化后形成羟基磷灰石涂层,能有效提高融合器的生物相容性、骨传导性,中和酸性降解产物、延长降解速率,同时改善融合器的力学性能。
磷酸钙骨水泥固化后在PLGA表面形成羟基磷灰石涂层,并填充3D打印间隙,一方面能有效提高融合器的生物相容性、骨传导性;另一方面,降低PLGA与降解介质的接触,中和酸性降解产物,延长降解速率;同时打印间隙中的骨水泥固化后,进一步提高融合器的力学性能。本发明有望克服可降解类材料在椎间融合器领域应用时面临的体内降解过快、降解产物酸性较大、力学性能不足等问题,同时3D打印技术为临床个性化制备符合人体解剖学形态的椎间融合器提供了新的途径,具有广阔的临床应用前景。
本发明的优点在于:
1、本发明以PLGA为打印“墨水”,通过3D打印技术制备椎间融合器,使融合器具备体内降解能力,同时最大限度与椎间间隙的形状、高度、上下终盘相匹配,适合个性化治疗。
2、利用磷酸钙骨水泥的可塑性和固化特点,以固化产物羟基磷灰石包覆融合器表面、填充打印间隙,降低PLGA与体内降解介质的接触,提高融合器的生物相容性,克服了PLGA体内降解过快、降解酸度较大等缺点,打印间隙的填充也提高了融合器的力学性能。
附图说明
图1是所制备磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的实物图,固化后的磷酸钙骨水泥均匀涂覆在融合器表面;
图2是实施例1试验组与对照组的体外降解试验结果,涂覆后的PLGA椎间融合器能明显延长降解时间。
具体实施方式
以下实施例以发明技术方案为前提进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围并不限于下述的实施例。
对照组为现有市售产品。
实施例1
一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器,通过3D打印技术制备可降解聚酯PLGA椎间融合器,再利用磷酸钙骨水泥涂覆聚合物表面,并填充打印间隙,磷酸钙骨水泥固化后形成羟基磷灰石涂层,按以下步骤制备:
1、3D打印PLGA椎间融合器的制备:
以PLGA(Mw=20W)为打印“墨水”,3D打印机为Bio-Architect ®-WS,材料置于高温喷头料筒中,打印针头为170μm,设置打印参数:每层采用平行式打印,间隙为0.2mm,Z轴方向逐层升高0.15mm,层与层间采用垂直交叉式堆叠,打印温度190℃,挤出速度设为2mm/s,接收平台温度为30℃。打印得到颈椎椎间融合器,将该融合器作为对照组。
2、明胶改性α-TCP的制备:
按摩尔比2:1称量磷酸氢钙粉末和碳酸钙粉末,使用适量无水乙醇为介质湿法球磨,转速400rpm,球磨时间4h,球磨珠与粉末质量比为2:1。原料混合液通过旋转蒸发除去乙醇,置于60℃烘箱中干燥24h;将干燥后的粉末置于马弗炉中,1400℃煅烧2h后取出,在鼓风环境下急速冷却;将冷却后的粉末以无水乙醇为介质湿法球磨,转速450rpm,用氧化锆球磨罐球磨6h,球磨珠与粉末质量比为4:1;粉末悬浊液置于80℃烘箱中充分干燥,制备得到α-TCP粉末。称取α-TCP粉末20g,加入40mL0.5%(w/v)的明胶溶液,1000rpm磁力搅拌0.5h,进行冷冻干燥,得到明胶改性α-TCP粉末。
常温下磁力搅拌配制质量分数为2.5%的Na2HPO4溶液作为骨水泥固化液,称取2g明胶改性α-TCP粉末,按固液比0.8mL/g与固化液混合成调和浆,涂覆至PLGA椎间融合器打印间隙中和表面,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min得到磷酸钙骨水泥涂覆PLGA椎间融合器,产品结构如图1所示。该融合器作为试验组,在弹性形变范围内抗压强度为98.5MPa,对照组抗压强度为80.7MPa;1个月内降解速率与对照组相比明显降低,如附图2所示。
实施例2
一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器,按以下步骤制备:
1、3D打印PLGA椎间融合器的制备:
以PLGA(Mw=20W)为打印“墨水”,3D打印机为Bio-Architect ®-WS,材料置于高温喷头料筒中,打印针头为170μm,设置打印参数:每层采用平行式打印,间隙为0.25mm,Z轴方向逐层升高0.15mm,层与层间采用垂直交叉式堆叠,打印温度190℃,挤出速度设为2mm/s,接收平台温度为30℃。打印得到颈椎椎间融合器,将该融合器作为对照组。
2、明胶改性α-TCP的制备同实施例1。
3、常温下磁力搅拌配制质量分数为2.5%的Na2HPO4溶液作为骨水泥固化液,称取2g明胶改性α-TCP粉末,按固液比0.8mL/g与固化液混合成调和浆,涂覆至PLGA椎间融合器打印间隙中和表面,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min得到磷酸钙骨水泥涂覆PLGA椎间融合器。该融合器在弹性形变范围内抗压强度为82.4MPa,对照组抗压强度为65.4MPa。
实施例3
一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器,按以下步骤制备:
1、3D打印PLGA椎间融合器的制备:
以PLGA(Mw=20W)为打印“墨水”,3D打印机为Bio-Architect ®-WS,材料置于高温喷头料筒中,打印针头为170μm,设置打印参数:每层采用平行式打印,间隙为0.3mm,Z轴方向逐层升高0.15mm,层与层间采用垂直交叉式堆叠,打印温度190℃,挤出速度设为2mm/s,接收平台温度为30℃。打印得到颈椎椎间融合器,将该融合器作为对照组。
2、明胶改性α-TCP的制备同实施例1。
3、常温下磁力搅拌配制质量分数为2.5%的Na2HPO4溶液作为骨水泥固化液,称取2g明胶改性α-TCP粉末,按固液比0.8mL/g与固化液混合成调和浆,涂覆至PLGA椎间融合器打印间隙中和表面,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min得到磷酸钙骨水泥涂覆PLGA椎间融合器。该融合器在弹性形变范围内抗压强度为73.6MPa,对照组抗压强度为42.1MPa。
Claims (3)
1.一种磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法,其特征在于,通过3D打印技术制备可降解聚酯PLGA椎间融合器,再利用磷酸钙骨水泥涂覆聚合物表面,并填充打印间隙,磷酸钙骨水泥固化后形成羟基磷灰石涂层,包括以下步骤:
(1)制备PLGA椎间融合器
以PLGA为3D打印“墨水”,打印针头选用170μm,设置打印参数:每层采用平行式打印,间隙为0.2-0.3mm,Z轴逐层升高0.15mm,打印温度170-190℃,基础速率为1.5-2mm/s,打印平台温度为30℃,使用生物3D打印机进行3D打印,制备PLGA椎间融合器;
(2)明胶改性α-TCP粉末
将磷酸氢钙与碳酸钙按摩尔比2:1湿法球磨混合,干燥后用马弗炉在1250-1400℃煅烧2-4h后取出,在鼓风环境下急速冷却,之后用氧化锆球磨罐450rpm湿法球磨6h,得到粒径均一的α-TCP粉末,将所述α-TCP粉末按0.5g/mL加入0.5%(w/v)的明胶溶液中,高速磁力搅拌0.5h后置于-80℃冰箱中冰冻,进行冷冻干燥48h,得到明胶改性α-TCP粉末;
(3)磷酸钙骨水泥涂覆PLGA椎间融合器
配制质量分数为2.5%的Na2HPO4溶液作为骨水泥固化液,与明胶改性α-TCP粉末按液固比0.5-1mL/g混合成调和浆,涂覆至PLGA椎间融合器表面并填充打印间隙,涂覆完成后置于37℃100%湿度环境中24h使骨水泥完全固化,最后将融合器置于100℃烘箱中10min,使PLGA玻璃化转变、与固化产物羟基磷灰石两相进一步融合,得到磷酸钙骨水泥涂覆PLGA椎间融合器;其中,
步骤(1)所述的PLGA分子量为10W-40W,LA/GA为75/25,分子链两端可为酯基、羟基或羧基封端。
2.根据权利要求1所述磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法,其特征在于,步骤(2)所述的磷酸氢钙与碳酸钙湿法球磨为使用无水乙醇作为混合介质的玛瑙球磨,转速400rpm,球磨时间为1-4h,球磨后悬浊液通过旋转蒸发除去乙醇后放入60℃烘箱中干燥过夜。
3.根据权利要求1所述磷酸钙骨水泥涂覆的3D打印PLGA椎间融合器的制备方法,其特征在于,步骤(2)所述明胶溶液的配制方式为50℃加热下磁力搅拌助溶。
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