CN108478872A - 一种复合型医用生物骨水泥及其制备方法及应用 - Google Patents
一种复合型医用生物骨水泥及其制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种复合型医用生物骨水泥,包括重量比为1:1~1.5的粉末部分和液体部分,所述的粉末部分,按重量份计,包括阿仑膦酸钠‑纳米羟基磷灰石粉末40‑45份、数均分子量为50‑70万的聚甲基丙烯酸甲酯粉末45‑60份、过氧化二苯甲酰3‑4份;阿仑膦酸钠‑纳米羟基磷灰石粉末大大提高了PMMA骨水泥的生物相容性,促进骨水泥的矿化作用,能与骨骼很好的结合,其骨传导作用和骨诱导作用亦可有效地促进骨骼的生长,同时含有的阿仑膦酸钠有效抗骨质疏松,抑制破骨细胞活性,减少骨吸收。
Description
技术领域:
本发明涉及生物材料技术领域,具体涉及一种复合型医用生物骨水泥及其制备方法及应用。
背景技术:
目前聚甲基丙烯酸甲酯(PMMA)骨水泥,因具有其良好的可操作性、生物相容性、化学稳定性及良好的力学性能而广泛运用于临床,但聚甲基丙烯酸甲酯(PMMA)骨水泥功能单一,只是依靠其力学强度发挥支撑作用,并且聚甲基丙烯酸甲酯骨水泥弹性模量较高,而且在体内不可降解吸收,同时在临床应用时产热作用及可能出现的骨水泥渗漏造成损伤部位周围的神经组织损伤。
发明内容:
本发明的目的是提供一种复合型医用生物骨水泥,在减少骨水泥总用量的前提下实现自膨胀的功能,有较好的组织相容性,能够在体内逐渐降解被自身组织替代,不在体内残留终身异物;同时促进新骨形成、抑制骨吸收,增加骨质疏松骨骨量、改善骨质酥松骨骨骼状态增强骨强度。
本发明是通过以下技术方案予以实现的:
一种复合型医用生物骨水泥,包括重量比为1:1~1.5的粉末部分和液体部分,所述的粉末部分,按重量份计,包括阿仑膦酸钠-纳米羟基磷灰石(ALN-HA)粉末40-45份、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末(PMMA)45-60份、过氧化二苯甲酰(BPO)3-4份;所述阿仑膦酸钠-纳米羟基磷灰石粉末(ALN-HA)的制备方法如下:将溶解于超纯水的阿仑膦酸钠(ALN)加入纳米羟基磷灰石(nHA),阿仑膦酸钠与纳米羟基磷灰石的质量比为0.01-0.2,90℃搅拌5h,冷冻干燥72h,研磨得到目标产品;所述的液体部分包括对苯二甲酸二甲酯(DMT)溶液和甲基苯烯酸甲酯(MMA)溶液,其中,对苯二甲酸二甲酯(DMT)溶液和甲基苯烯酸甲酯(MMA)溶液的重量比为1:210-220,对苯二甲酸二甲酯溶液中对苯二甲酸二甲酯的质量分数为4wt‰~6wt‰,甲基丙烯酸甲酯溶液中甲基丙烯酸甲酯的质量分数为99.4wt%~99.6wt%。
所述复合型医用生物骨水泥的制备方法包括以下步骤,将阿仑膦酸钠-纳米羟基磷灰石(ALN-HA)粉末、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末搅拌均匀,加入过氧化二苯甲酰,加入对苯二甲酸二甲酯溶液和甲基苯烯酸甲酯溶液,搅拌至粘稠状,吸进注射器内,缓慢推动除去气泡,然后缓慢注入圆柱形玻璃模具中,室温下固化24h,即得。
纳米羟基磷灰石的合成(参见申请号为201310545809.8,发明名称为一种可注射复合型骨水泥及其制备方法和应用):称取(CaNO3)2·4H2O和(NH4)2HPO4粉末溶解于水中,在超声搅拌的条件下,将(NH4)2HPO4溶液滴加到(CaNO3)2·4H2O溶液中,加入分散剂,调节pH,陈化,离心,水洗,即得。
数均分子量为50-70万的PMMA粉末的合成(参见申请号为201310545809.8,发明名称为一种可注射复合型骨水泥及其制备方法和应用):将聚乙烯醇溶于蒸馏水中,搅拌下充分溶解后,加入甲基丙烯酸甲酯及过氧化二苯甲酰,升温至60~100℃,反应5~6h后,将所得的产物用蒸馏水洗3~5次,置于70~90℃烘箱中干燥4~8h,即得,将所得的高分子量PMMA碾磨成颗粒,待用。
本发明还保护所述复合型医用生物骨水泥的应用。
本发明的有益效果如下:
1)聚甲基丙烯酸甲酯作为骨组织的填充材料具有优异的力学性能,阿仑膦酸钠-纳米羟基磷灰石粉末大大提高了PMMA骨水泥的生物相容性,促进骨水泥的矿化作用,能与骨骼很好的结合,其骨传导作用和骨诱导作用亦可有效地促进骨骼的生长,同时含有的阿仑膦酸钠有效抗骨质疏松,抑制破骨细胞活性,减少骨吸收。
2)本发明阿仑膦酸钠-纳米羟基磷灰石粉末含有米阿伦磷酸钠在损伤部位形成阿仑膦酸钠有效浓度,抑制骨吸收,有效抗骨质疏松增强骨强度,同时避免阿伦磷酸钠全身用药所产生的不良反应。
3)阿仑膦酸钠-纳米羟基磷灰石粉末与聚甲基丙烯酸甲酯粉末结合形成的复合型医用骨水泥具有用量少、促成骨、抗骨吸收的优点,在减少骨水泥总用量的前提下实现自膨胀的功能,有较好的组织相容性,能够在体内逐渐降解被自身组织替代,不在体内残留终身异物;同时促进新骨形成、抑制骨吸收,增加骨质疏松骨骨量、改善骨质酥松骨骨骼状态增强骨强度。
4)本发明复合型医用骨水泥制备方法快速简便,并且所得的骨水泥力学性能达标,且无毒性。同时,溶血实验结果显示其并与血液有良好的相容性。
附图说明:
图1是本发明阿仑膦酸钠-纳米羟基磷灰石的红外图谱;
其中,ALN-HA为阿仑膦酸钠-纳米羟基磷灰石。
图2是本发明阿仑膦酸钠-纳米羟基磷灰石的热重分析图,其中20%指ALN-HA中ALN的修饰度。
图3是本发明实施例1和对照例1的体外矿化SEM图。其中1%ALN,5%ALN,10%ALN,15%ALN,20%ALN指ALN-HA中ALN的修饰度。
图4是本发明骨水泥的细胞毒性结果图。其中,1%,5%,10%,15%,20%指ALN-HA中ALN的修饰度。
图5为本发明骨水泥的血液相容性结果图。其中1%ALN,5%ALN,10%ALN,15%ALN,20%ALN指ALN-HA中ALN的修饰度。
具体实施方式:
以下是对本发明的进一步说明,而不是对本发明的限制。
实施例1:
一种复合型医用生物骨水泥,包括重量比为1:1的粉末部分和液体部分,所述的粉末部分,按重量份计,包括阿仑膦酸钠-纳米羟基磷灰石(ALN-HA)粉末0.4g、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末(PMMA)0.6g、过氧化二苯甲酰(BPO)0.03g;所述阿仑膦酸钠-纳米羟基磷灰石粉末(ALN-HA)的制备方法如下:将溶解于超纯水的阿仑膦酸钠(ALN)加入纳米羟基磷灰石(nHA),阿仑膦酸钠与纳米羟基磷灰石的质量比为0.01-0.2,90℃搅拌5h,冷冻干燥72h,研磨得到目标产品,其红外图谱参见图1;当阿仑膦酸钠与纳米羟基磷灰石的质量比为0.2,即ALN-HA中ALN的修饰度为20%时,实验热重分析结果如图2所示;所述的液体部分包括0.0048g对苯二甲酸二甲酯(DMT)溶液和1.0252g甲基苯烯酸甲酯(MMA)溶液,其中,对苯二甲酸二甲酯溶液中对苯二甲酸二甲酯的质量分数为4wt‰~6wt‰,甲基丙烯酸甲酯溶液中甲基丙烯酸甲酯的质量分数为99.4wt%~99.6wt%。
所述复合型医用生物骨水泥的制备方法包括以下步骤,将阿仑膦酸钠-纳米羟基磷灰石(ALN-HA)粉末、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末搅拌均匀,加入过氧化二苯甲酰,加入对苯二甲酸二甲酯溶液和甲基苯烯酸甲酯溶液,搅拌至粘稠状,吸进注射器内,缓慢推动除去气泡,然后缓慢注入圆柱形玻璃模具中,室温下固化24h,即得。
对照例1:
参考实施例1,不同之处在于用纳米羟基磷灰石代替阿仑膦酸钠-纳米羟基磷灰石(ALN-HA)粉末。
实施例2:
参考实施例1,不同之处在于:粉末部分和液体部分重量比为1:1.5,阿仑膦酸钠-纳米羟基磷灰石(ALN-HA)粉末0.45g、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末(PMMA)0.45g、过氧化二苯甲酰(BPO)0.04g。
压缩强度:按照ISO5833骨水泥标准,制备12mm×6mm圆柱体标本,在37℃恒温下固化24h后,用AGS-10KN万能材料试验机(AGS-10KN,Universal Testing Machines,Shimadzu,Japan)测定压缩强度。结果表明本发明所得的骨水泥力学性能达标。
骨水泥的体外矿化实验:参考CN107041970A,实施例1和对照例1的体外生物矿化SEM结果如图3所示。
由图3可知阿仑膦酸钠-纳米羟基磷灰石粉末促进骨水泥的矿化作用。
MTT测试:细胞毒性实验样品尺寸为:高6mm,直径6.5mm的圆柱体。使用的骨水泥样品为实施例1所述的骨水泥。
第一步,浸提液的制备:各骨水泥样品分别使用酒精,磷酸缓冲液(PBS)泡24小时后,使用完全培养基浸泡24小时得到对照组和实验组骨水泥的两组浸提液。
第二步,细胞的接种:以完全培养基为空白组,每孔接种5000-10000个人成骨细胞(HFOB),于37℃,5%CO2环境下培养24小时和48小时后,测得细胞存活率(MTT)。实验结果如图4所示,说明材料是无毒性的。
溶血实验测试:选用人抗凝全血进行溶血实验测试。
制备长为10mm,直径6mm的圆柱体骨水泥样品,每组设置5个平行样。样品预处理方式与浸提液制备方法同MTT测试第一步。
溶血试验采用人全血(含acid-citrate-dextrose,ACD)进行。将0.5mL ACD血加入到盛有1mL骨水泥浸提液的试管中,在37℃恒温水浴中孵育1h,然后1000rpm/min离心5min。取200μL的上清液于96孔板中测量光密度。用1mLPBS作为阴性对照,1mL去离子水作为阳性对照。扫描波长为545nm。溶血百分数通过下式计算:
溶血率=(实验组吸光度-阴性对照组吸光度)/(阳性对照组吸光度-阴性对照组吸光度)x100%。本发明骨水泥的血液相容性结果图如图5所示。溶血实验结果显示本发明与血液有良好的相容性。
Claims (3)
1.一种复合型医用生物骨水泥,其特征在于,包括重量比为1:1~1.5的粉末部分和液体部分,所述的粉末部分,按重量份计,包括阿仑膦酸钠-纳米羟基磷灰石粉末40-45份、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末45-60份、过氧化二苯甲酰3-4份;所述阿仑膦酸钠-纳米羟基磷灰石粉末的制备方法如下:将溶解于超纯水的阿仑膦酸钠加入纳米羟基磷灰石,阿仑膦酸钠与纳米羟基磷灰石的质量比为0.01-0.2,90℃搅拌5h,冷冻干燥72h,研磨得到目标产品;所述的液体部分包括对苯二甲酸二甲酯溶液和甲基苯烯酸甲酯溶液,其中,对苯二甲酸二甲酯溶液和甲基苯烯酸甲酯溶液的重量比为1:210-220,对苯二甲酸二甲酯溶液中对苯二甲酸二甲酯的质量分数为4wt‰~6wt‰,甲基丙烯酸甲酯溶液中甲基丙烯酸甲酯的质量分数为99.4wt%~99.6wt%。
2.权利要求1所述的复合型医用生物骨水泥的制备方法,其特征在于,该方法包括以下步骤,将阿仑膦酸钠-纳米羟基磷灰石粉末、数均分子量为50-70万的聚甲基丙烯酸甲酯粉末搅拌均匀,加入过氧化二苯甲酰,加入对苯二甲酸二甲酯溶液和甲基苯烯酸甲酯溶液,搅拌至粘稠状,吸进注射器内,缓慢推动除去气泡,然后缓慢注入圆柱形玻璃模具中,室温下固化24h,即得。
3.权利要求1所述的复合型医用生物骨水泥的应用。
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