CN108392670A - 一种抗血栓骨水泥 - Google Patents
一种抗血栓骨水泥 Download PDFInfo
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- CN108392670A CN108392670A CN201810467622.3A CN201810467622A CN108392670A CN 108392670 A CN108392670 A CN 108392670A CN 201810467622 A CN201810467622 A CN 201810467622A CN 108392670 A CN108392670 A CN 108392670A
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- bone cement
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- mma
- bone
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Abstract
本发明公开了一种抗血栓的骨水泥,所述骨水泥为双组份系统的PMMA骨水泥,所述双组份系统由粉体组分和液体组分构成,在所述粉体组分中,每40g粉体中含有4000‑24000AxaU的依诺肝素钠。本发明的骨水泥可以在术前暂停皮下注射低分子肝素钠的情况下保证手术过程中骨水泥使用部位不会形成血栓,降低骨水泥肺栓塞的风险,既能够避免皮下注射肝素抗凝出现的全身凝血系统低凝状态,又能够有效地防止手术局部以及传统骨水泥植入周围部位形成血栓,并且不影响患者术后12小时常规使用抗凝药物,具有很高的临床应用价值。另外,本发明的骨水泥在保证了相对于现有骨水泥的生物力学性质不变的前提下,可缓慢释放依诺肝素钠,对于患者全身凝血系统影响小,安全性更高。
Description
技术领域
本发明涉及一种医用骨水泥复合材料,具体的说是一种抗血栓骨水泥。
背景技术
骨水泥是骨科手术中常用的关节假体固定材料,手术后经过短期康复,换上的关节即可发挥作用,而且这种固定相当牢靠,可保持十几年,乃至二十几年。骨水泥在发展过程中形成了两大体系,一类是磷酸钙骨水泥,一类是聚甲基丙烯酸甲酯骨水泥。聚甲基丙烯酸甲酯(PMMA)骨水泥一般为双组分系统(液体组分和粉体组分),使用时,只要按一定比例混合,即可在室温下发生聚合反应,逐步固化,整个过程只需十几分钟。
PMMA骨水泥的液体组分主要包括甲基丙烯酸甲酯(MMA)、N,N-二甲基对甲苯胺(DmpT)和邻苯二酚。MMA是甲基丙烯酸的一种酯类,它是一种无色、透明、有强烈气味、易燃的液体,MMA分子结构中含有一个可聚合的碳碳双键(C=C)。DmpT是作为自由基聚合的活化剂或共引发剂,在骨水泥的液体组分中,MMA与DmpT的比例通常为98:2。骨水泥液体组分中还含有少量的邻苯二酚,其作用是防止单体的过早聚合。
PMMA骨水泥的粉体组分是骨水泥性能的关键,其主要由聚合物、过氧化苯甲酰(BPO)、显影剂和着色剂。其中聚合物占粉体组分的约80%以上,目前市场上不同品牌的骨水泥的粉体组分,特别是聚合物组分,成分均不一样。比如,C-ment®骨水泥粉体中除了含有MMA外,甚至含有两种共聚单体:丙烯酸甲酯(MA)和丙烯酸乙酯(EA)。Durus®骨水泥粉体中含有甲基丙烯酸乙基乙基酯。Boneloc®骨水泥粉体中仅含有甲基丙烯酸丁酯(BuMA)和甲基丙烯酸甲酯的共聚物。另外,骨水泥粉体中,尽管聚合物或共聚物在化学构成可能相同,但他们可能拥有完全不同的性质,其主要是由于聚合物或共聚物的加工方法(额外的添加剂,所使用聚合物和粉体的制作规格不同)通常并不是通用的。因此市场上大多数骨水泥供应商所使用聚合物是专门为特定品牌制造而生产的,因此也就防止了他们品牌被复制。另外,聚合组分的差异会影响到骨水泥的性能,因此粉体组分是大多数骨水泥性能的关键。
PMMA骨水泥虽然有诸多优点,但其同时也存在一些无法避免的副作用。骨水泥植入后,会引发血压下降、呼吸困难、深静脉血栓形成、肺栓塞等一系列并发症,严重的甚至会导致心脏骤停、猝死,统称为骨水泥植入综合征。骨水泥主要通过以下几种方式引起栓塞:①骨水泥单体诱导单核细胞释放组织因子,引起内皮细胞的变形和分离,导致血管内皮表面覆盖纤维蛋白原,继而活化为纤维蛋白,促使血小板因子 A 的释放,诱使血栓的形成。②骨水泥单体的化学毒性作用,阻断血管平滑肌钙通道,导致血管松弛、血压下降、血流速度下降,血液淤积容易引起血栓,同时骨水泥单体聚合反应产热,该聚合热可能超过组织蛋白的凝固温度,损伤血管内皮,进一步引发血栓形成。③骨水泥单体进入血液后激活补体系统,增加细胞因子的产生和释放,从而增加肺血管通透性,产生较长时间凝血活动增强,引起血栓。④骨折椎体血窦被破坏,注入骨水泥后,椎体腔内压力升高,导致更多的血栓栓子通过血窦进入血循环形成血栓。⑤在关节置换术中,因手术操作凝血途径被激活致手术区局部处于高凝状态,同时当向髓腔内填塞骨水泥时,髓内压迅速增大,将形成的微小血栓挤压入小静脉循环系统,形成栓塞。研究结果表明,骨水泥通过多种机制会在骨科手术过程中引起血栓栓塞,需要引起我们的高度重视。因此,在骨科手术应用骨水泥的过程中,骨科医师迫切需要一个方案来解决骨水泥相关的血栓栓塞。目前临床上预防血栓发生的手段是皮下注射低分子肝素钠,但是为了避免低分子肝素引起出血的风险,在外科手术前12小时低分子肝素的使用会被暂停,在手术后12小时才能继续使用,从而造成了24小时的“空窗期”,在这一时期患者进行手术,加上骨水泥的刺激,会造成手术操作局部和骨水泥植入周围部位形成血栓,对患者生命健康造成危害。
发明内容
本发明的目的是提供一种抗血栓骨水泥,以解决现有PMMA骨水泥应用中存在的植入后易引发血压下降、呼吸困难、深静脉血栓形成、肺栓塞等一系列并发症的问题。
本发明的目的是这样实现的:
一种抗血栓骨水泥,所述骨水泥为双组份系统的PMMA骨水泥,所述双组份系统由粉体组分和液体组分构成,其中,在所述粉体组分中,每40g粉体中含有4000-24000AxaU的依诺肝素钠。
本发明所述的抗血栓骨水泥,所述粉体组分中含有MA/MMA共聚物80-88 wt %、二氧化锆11-18 wt %、引发剂0.5-2.5 wt %。
本发明所述的抗血栓骨水泥,所述MA/MMA共聚物由MMA单体和MA单体按摩尔比MMA∶MA=2-4∶1聚合而成,分子量为60万~100万Da。
本发明所述的抗血栓骨水泥,所述粉体组分中含有MA/MMA共聚物83-85 wt %、二氧化锆14-16 wt %、引发剂1-2 wt %。
本发明所述的抗血栓骨水泥,所述引发剂为过氧化苯甲酰。
本发明所述的抗血栓骨水泥,每40克多聚体粉末中含有10000~24000 AxaIU依诺肝素钠。
本发明所述的抗血栓骨水泥,所述液体组分中含MMA单体、DmpT和邻苯二酚,其中,所含MMA单体与DmpT体积比为15~25∶0.3~0.5,所含邻苯二酚的浓度为25~100ppm。
本发明的骨水泥可以在术前暂停皮下注射低分子肝素钠的情况下保证手术过程中骨水泥使用部位不会形成血栓,降低骨水泥肺栓塞的风险,既能够避免皮下注射肝素抗凝出现的全身凝血系统低凝状态,又能够有效地防止手术局部以及传统骨水泥植入周围部位形成血栓,并且不影响患者术后12小时常规使用抗凝药物,具有很高的临床应用价值。另外,本发明的骨水泥在保证了相对于现有骨水泥的生物力学性质不变的前提下,可缓慢释放依诺肝素钠,对于患者全身凝血系统影响小,安全性更高,是一种全新的优良的复合型骨水泥。
附图说明
图1是兔髋关节骨水泥植入后活体兔肺部99Tcm-SZ-51放免显像图。
图1中A是实施例2的放射免疫显像结果,B是对比例1的放射免疫显像结果。
图2是将动物处死获取的离体新鲜肺组织照片。
图2中A是离体的肺组织照片,B是离体的肺组织充气照片。
图3是离体的新鲜肺组织平面显像图。
图3中A是术后1h对比例1的肺血栓情况,B是术后1h实施例4的肺血栓情况。
图4是术后1h实施例1、实施例2、实施例3的新鲜离体肺组织血栓显影。
图4中A是实施例1、B是实施例2、C是实施例3。
具体实施方式
实施例1
粉体组分40g,其中:
MA/MMA共聚物33.6g、二氧化锆6g、过氧化苯甲酰(BPO)0.4g、依诺肝素钠4000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。
实施例2
粉体组分40g,其中:
MA/MMA共聚物35.2g、二氧化锆4.6g、过氧化苯甲酰(BPO)0.2g、依诺肝素钠8000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚30ppm。
实施例3
粉体组分40g,其中:
MA/MMA共聚物32g、二氧化锆7.2g、过氧化苯甲酰(BPO)0.8g、依诺肝素钠12000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚100ppm。
实施例4
粉体组分40g,其中:
MA/MMA共聚物33.2g、二氧化锆6.4g、过氧化苯甲酰(BPO)0.4g、依诺肝素钠16000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。
实施例5
粉体组分40g,其中:
MA/MMA共聚物34g、二氧化锆5.6g、过氧化苯甲酰(BPO)0.4g、依诺肝素钠20000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。
实施例6
粉体组分40g,其中:
MA/MMA共聚物33.6g、二氧化锆6g、过氧化苯甲酰(BPO)0.4g、依诺肝素钠24000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。
对比例1
与实施例1相比,依诺肝素钠添加量2000AxaIU,即:
粉体组分40g,其中:
MA/MMA共聚物33.6g二氧化锆6g、过氧化苯甲酰(BPO)0.4g、依诺肝素钠2000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。
对比例2
与实施例1相比,依诺肝素钠添加量26000AxaIU,即:
粉体组分40g,其中:
MA/MMA共聚物33.6g二氧化锆6g、过氧化苯甲酰(BPO)0.4g、依诺肝素钠26000AxaIU。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。。
对比例3
市购普通骨水泥,品牌是Cemex®,依诺肝素钠添加量与实施例1相同。
对照例
未添加依诺肝素钠,其它组分与实施例1相同,即:
粉体组分40g,其中:
MA/MMA共聚物33.6g二氧化锆6g、过氧化苯甲酰(BPO)0.4g。
液体组分20mL,其中:
MMA单体19.6mL、N,N-二甲基对甲苯胺(DmpT)0.4mL、对苯二酚50ppm。
对实施例1~6、对比例1~2、对比例3、对照例的骨水泥的抗血栓效果进行动物实验和对其生物力学性能进行检测。
一、动物实验
实验方案:新西兰大耳白兔60只,雌雄不拘,体重约2.5-3.0kg,随机分为10组(分别对应实施例1-6、对比例1-3、对照例),每组6只,均建立兔关节置换骨水泥植入模型。
建立模型方法:①用3%戊巴比妥钠,按10mL/kg耳缘静脉注射麻醉家兔,用戊巴比妥钠维持麻醉。②左侧颈动脉插管,监测动脉压;右侧颈外静脉插管监测中心静脉压;气管插管监测呼吸;直接法监测心电图。③分离股骨上段肌肉,暴露大转子,在此与股骨纵轴成45°截骨(髋关节保持完好,不暴露),使用直径4mm的硬钻扩髓,深度为股骨全长的2/3,清理股骨髓腔,大量生理盐水冲洗髓腔,干燥后待用。④使用注射器向各组家兔髓腔内灌注等量混合后的骨水泥,置入自制的兔髋关节假体模型,压实骨水泥。
以上10组均进行关节假体周围以及肺部血栓形成的99Tcm-SZ-51放射免疫显像研究。
实验方法:
各组动物耳缘静脉注入99Tcm-SZ-51液2mL。
①将实验动物于骨水泥灌注后10min、20min、30min、40min、50min、60min观察记录生命体征,抽取血样,并做放射免疫显像。
如图1是兔髋关节骨水泥植入99Tcm-SZ-51放免显像图,图1中A是实施例2的放射免疫显像结果,B是对比例1的放射免疫显像结果,可见骨水泥植入周围有新鲜血栓形成。
但由于血池影和肝影长时间存在,在活体显像中对肺脏显像遮挡很大,所以我们要在下一步进行离体肺平面显像。
②分别于术后1h、3h、6h各处死各组的2只实验动物,将动物处死后,立即完整取出肺组织(如图2中A),去除表面血迹,充气使肺组织充分膨胀与活体肺体积大小相当时(如图2中B),夹闭气管进行平面显像(如图3中A和B),检测计算整个离体肺组织放射性活度,并以像素数进行修正,求出平均值,以排除肺体积大小不同的干扰。
骨水泥灌注并加压后,肺部新鲜血栓全部显影,并逐渐浓聚,放射活性随术后时间延长而增加。图3中,A表示术后1h经99Tcm-SZ-51标记后对比例1兔肺血栓情况;B表示术后1h实施例4兔肺血栓情况。图3中的高亮部分为99Tcm-SZ-51的浓集的表现,亮度越高,则肺组织血栓数量越多,可以看出对比例1的血栓明显高于对比例4。
图4中A是实施例1、B是实施例2、C是实施例3的新鲜离体肺组织血栓显影(术后1h)比较。由图4可以看出,随依诺肝素钠添加量增加,肺组织血栓数量明显降低。
③放射显像检测结束后,左侧肺组织立即使用福尔马林溶液固定肺组织,隔日取肺组织,石蜡包埋切片,HE染色后进行病理学检查。
结果如表1所示:
表1:动物实验抗血栓效果。
由表1中结果可以看出,4000-24000 AxaIU的依诺肝素钠添加量可有效预防手术操作局部血栓形成以及骨水泥相关的肺栓塞的发生。
二、力学实验
试验方法:据国际标准ISO5833:2002《外科植入物--丙烯酸类树脂骨水泥》规定,设计并制出骨水泥标准试件模具草图,制成直径(6±0.1)mm、高(12±0.1)mm的骨水泥圆柱体模具10个,长(75±0.1)mm、宽(10±0.1)mm、高(3.3±0.1)mm的骨水泥长方体模具10个。骨水泥圆柱体试件要求在室温,无菌条件下,打入模具后保持(24±0.1)h 取出。24h后将试件垂直放在万用压力测试仪上测定其压缩强度。按相同方法制成骨水泥板条。24h后用万用压力测试仪做骨水泥板条的四点弯曲实验,计算弯曲模量和弯曲强度。用spss统计学软件分析处理数据。
结果如表2所示:
表2:生物力学性能检测结果
由表2可以看出相对于未添加依诺肝素钠的骨水泥(即对照例),实施例1和对比例1的骨水泥抗压强度和抗弯强度也均超过了ISO5833国际标准,而对比例2的骨水泥可能是由于依诺肝素钠的添加量过多而导致抗压强度和抗弯强度大大下降,低于ISO5833国际标准。同时,对比例3的骨水泥虽然添加了与实施例1等量的依诺肝素钠,但其抗压强度和抗弯强度却大大下降,这可能是由于对比例3品牌骨水泥与本申请骨水泥组分上的差异导致的。
本发明在原有传统PMMA骨水泥的粉体组分的基础上,对骨水泥组分进行了改进,并采用真空混合的方法加入依诺肝素钠,制成新型抗血栓骨水泥。
Claims (7)
1.一种抗血栓骨水泥,其特征是,所述骨水泥为双组份系统的PMMA骨水泥,所述双组份系统由粉体组分和液体组分构成,其中,在所述粉体组分中,每40g粉体中含有4000-24000AxaU的依诺肝素钠。
2.根据权利要求1所述的抗血栓骨水泥,其特征是,所述粉体组分中含有MA/MMA共聚物80-88 wt %、二氧化锆11-18 wt %、引发剂0.5-2.5 wt %。
3.根据权利要求2所述的抗血栓骨水泥,其特征是,所述MA/MMA共聚物由MMA单体和MA单体按摩尔比MMA∶MA=2-4∶1聚合而成,分子量为60万~100万Da。
4.根据权利要求2所述的抗血栓骨水泥,其特征是,所述粉体组分中含有MA/MMA共聚物83-85 wt %、二氧化锆14-16 wt %、引发剂1-2 wt %。
5.根据权利要求2所述的抗血栓骨水泥,其特征是,所述引发剂为过氧化苯甲酰。
6.根据权利要求1或2所述的抗血栓骨水泥,其特征是,每40克多聚体粉末中含有10000~24000 AxaIU依诺肝素钠。
7.根据权利要求1或2所述的抗血栓骨水泥,其特征是,所述液体组分中含MMA单体、DmpT和邻苯二酚,其中,所含MMA单体与DmpT体积比为15~25∶0.3~0.5,所含邻苯二酚的浓度为25~100ppm。
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US20130259911A1 (en) * | 2003-11-26 | 2013-10-03 | Advanced Cardiovascular Systems, Inc. | Biobeneficial coating compositions and methods of making and using thereof |
CN104906632A (zh) * | 2015-06-19 | 2015-09-16 | 上海凯利泰医疗科技股份有限公司 | 一种骨水泥及其制备方法和应用 |
CN107412850A (zh) * | 2017-09-01 | 2017-12-01 | 苏州大学 | 一种表面降解的可注射骨填充材料及其制备方法 |
CN107614026A (zh) * | 2015-05-27 | 2018-01-19 | 东丽株式会社 | 抗血栓性材料 |
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2018
- 2018-05-16 CN CN201810467622.3A patent/CN108392670A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1592463B1 (en) * | 2003-02-13 | 2006-08-16 | SYNTHES AG Chur | Injectable bone-replacement mixture |
US20130259911A1 (en) * | 2003-11-26 | 2013-10-03 | Advanced Cardiovascular Systems, Inc. | Biobeneficial coating compositions and methods of making and using thereof |
CN107614026A (zh) * | 2015-05-27 | 2018-01-19 | 东丽株式会社 | 抗血栓性材料 |
CN104906632A (zh) * | 2015-06-19 | 2015-09-16 | 上海凯利泰医疗科技股份有限公司 | 一种骨水泥及其制备方法和应用 |
CN107412850A (zh) * | 2017-09-01 | 2017-12-01 | 苏州大学 | 一种表面降解的可注射骨填充材料及其制备方法 |
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