CN103191468B - 一种人骨替代材料的制备方法 - Google Patents
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Abstract
本发明提供了一种人骨替代材料，以克服现有聚醚醚酮羟基磷灰石复合的人骨替代材料生物活性和机械性能不能够兼具和平衡的缺点，本发明通过在现有聚醚醚酮羟基磷灰石复合材料中添加质量分数为(2-8%)的磺化聚醚醚酮（S-PEEK），以获得人骨替代材料生物活性和机械性能的平衡。
Description
技术领域
本发明涉及人骨替代材料技术领域，具体地涉及以聚醚醚酮羟基磷灰石复合材料为基体的人骨替代材料。
背景技术
聚醚醚酮(PEEK)是一种全芳香半结晶高聚物，它具有良好的物理力学性能，耐高温、耐腐蚀性能和良好的耐蠕变、抗疲劳性能。同时，它有很好的加工性。因此，PEEK是一种很好的修复和替换人体硬组织的生物材料之一。研究表明，PEEK有良好的生物相容性，在生物盐水的作用下，耐磨性、光滑性和刚性等物理性质没有明显的降低。但由于PEEK缺乏生物活性，导致了它在医用方面的使用范围受到限制。羟基磷灰石(HA)是一种有良好的生物相容性和生物活性的无机非金属材料，它能与骨组织形成牢固的键合，但是纯HA的抗弯强度低，脆性大，不能很好地满足临床应用的要求，因此需要有一种基体对HA增韧。
因此聚醚醚酮/羟基磷灰石的复合材料开始受到关注，复合材料通常具有复合体系中各个材料的优良性能，通过熔融共混的方法将HA加入到PEEK中可以制备具有一定生物活性的复合材料，HA加入量与复合材料力学性能存在重要关系，随着HA含量增加，导致复合材料抗拉强度降低。
因此，目前聚醚醚酮羟基磷灰石复合材料存在的问题是：聚醚醚酮的生物活性低，在满足机械强度要求的条件下很难找到替代聚醚醚酮的材料；为获得较好的生物活性，需要加入含量较高的羟基磷灰石，而羟基磷灰石的较高含量使得复合材料的机械性能降低，目前，羟基磷灰石的添加量均为复合材料质量分数的20％以下，20％以上含量很难满足人骨替代材料的机械强度。
发明内容
为此，本发明为解决上述技术问题，提供一种人骨替代材料及其制备方法。
本发明采用的技术方案是：一种人骨替代材料，包含有聚醚醚酮和羟基磷灰石复合材料，还包含有质量分数为2％-8％的磺化聚醚醚酮。
优选地，所述人骨替代材料组分的质量分数为：磺化聚醚醚酮2％-8％、羟基磷灰石10％-30％，余量为聚醚醚酮。
优选地，所述羟基磷灰石的质量分数为20％-30％。
本发明还提供一种人骨替代材料的制备方法，包括以下步骤：
a.以环丁砜为溶剂，加入磺化聚醚醚酮和羟基磷灰石，加热至180-200℃，将磺化聚醚醚酮和羟基磷灰石完全溶解或分散；
b.将等摩尔比的对苯二酚和4,4'-二氟二苯甲酮与溶剂二苯砜在反应器中混合均匀，在氮气保护下加热至混合物熔融，加入无水碳酸钠和无水碳酸钾混合物作为成盐剂，加热至250-320℃，直至缩聚反应完成，得灰色粘稠液体；
c.将步骤a中溶于环丁砜的磺化聚醚醚酮和羟基磷灰石缓慢加入反应器中，维持温度250℃-320℃，冷凝回流并搅拌加热至混合均匀后趁热迅速倾倒至常温蒸馏水中凝结分散，得到固体聚醚醚酮-磺化聚醚醚酮-羟基磷灰石复合材料。
优选地，所述步骤c得到固体聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料后还包括将固体产物经粉碎机捣碎成粉末状，用丙酮和蒸馏水多次反复抽提、过滤，除去未反应的单体、溶剂和盐类杂质，在电热恒温鼓风干燥箱中进行干燥，得到提纯的聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料。
具体地，所述磺化聚醚醚酮的制备方法是：将聚醚醚酮溶于浓硫酸后并进行搅拌，控制磺化度为10-15％，在搅拌过程中加入蒸馏水，至溶液温度降至室温后过滤得到的固体粉末即为磺化聚醚醚酮。
本发明的有益效果是：本发明的人骨替代材料为聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料，通过在现有聚醚醚酮和羟基磷灰石二元复合材料中加入质量分数为2％-8％的磺化聚醚醚酮，能有效地提高人骨替代材料的生物活性，实验表明，加入的磺化聚醚醚酮本身无细胞毒性，并且得到的三组分材料与两组分材料相比，能更好地促进细胞增殖。
另一方面，由于磺化聚醚醚酮与聚醚醚酮和羟基磷灰石形成良好的界面以及自身较好的机械性能，使得人骨替代材料中羟基磷灰石的含量可以适当地得到提升，本发明的聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料中羟基磷灰石的含量达到30％时仍然具有较好的机械强度，能满足人骨替代材料的要求。
附图说明
图1细胞标准生长曲线；
图2SPEEK对细胞形态影响；
图3组份材料随时间变化对细胞增殖影响；
图4二元复合材料随时间变化对细胞增殖影响；
图5三元复合材料随时间变化对细胞增殖影响；
图6SPEEK随时间变化对细胞增殖影响。
具体实施方式
下面，结合具体实施例对本发明进行详细描述。
本发明以含有质量分数为2％-8％的磺化聚醚醚酮的聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料作为人骨替代材料，其制备方法如下：
首先对磺化聚醚醚酮(SPEEK)的制备进行说明，可采用下述具体方法进行制备，称量3g左右的聚醚醚酮溶于一定体积的98％的浓硫酸中配成聚醚醚酮质量分数为1％的溶液后，在50-80oC范围分别用搅拌器搅拌1、3、6个小时，边搅拌边倒入冷水中，待降至室温后过滤得到磺化聚醚醚酮，磺化度在10-15％。用蒸馏水洗涤至PH＝7，烘干，制得磺化聚醚醚酮固体粉末。
下面对聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料的制备进行说明，其中，聚醚醚酮缩写为PEEK，磺化聚醚醚酮缩写为SPEEK，羟基磷灰石缩写为HA；
称量一定质量的环丁砜注入三口烧瓶，加入SPEEK，冷凝回流下搅拌加热至180度保温30分钟后在升温至200左右保温至SPEEK完全溶解。HA搅拌均匀后注入三口烧瓶，冷凝回流下搅拌加热至180度保温30分钟后在升温至200左右保温至HA完全分散，将两者搅拌均匀混合后备用。
称取对苯二酚，4,4'-二氟二苯甲酮(摩尔比1:1)以及二苯砜溶剂，混合均匀后加入500ml的三口烧瓶中。通入氮气10min以排出空气，在氮气保护下加热至混合物熔融，此时呈淡黄色透明液体。缓慢升温后180℃时加入无水碳酸钠和无水碳酸钾混合物作为成盐剂。继续缓慢升温至200℃，稍作停留后升温至320℃恒温反应3h，待恒温反应缩聚反应完成后，得灰色粘稠液体。将预热至250℃的环丁砜/SPEEK/HA材料缓慢加入反应器中，维持温度250℃，充分搅拌均匀，保持温度20min。充分搅拌均匀。冷凝回流搅拌加热至它们搅拌混合均匀后趁热迅速倾倒至常温蒸馏水中凝结分散，得灰白色块状固体.产物经粉碎机捣碎后呈粉末状，用丙酮和蒸馏水多次反复抽提、过滤，除去未反应的单体、溶剂和盐类杂质。在电热恒温鼓风干燥箱中100℃烘干12小时以上，得到提纯后的聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料。
本实施例中，磺化聚醚醚酮在PEEK-SPEEK-HA中的质量分数可在2％-8％范围内选择，羟基磷灰石在PEEK-SPEEK-HA中的质量分数分别选择为10％，20％和30％。
下面对制备的PEEK-SPEEK-HA三元复合材料的性能测试进行详细说明。
将HA、PEEK、SPEEK、PEEK/10％HA、PEEK/20％HA、PEEK/SPEEK/10％HA、PEEK/SPEEK/20％HA、PEEK/SPEEK/30％HA高压灭菌后，每种材料用RPMI1640培养基按4mg/ml、8mg/ml、16mg/ml、32mg/ml、64mg/ml配成不同浓度混悬液。
将对数生长期的MG-63细胞制备成7种不同浓度(2.5×103—1.6×105个/ml)细胞悬液,并依次加入96孔培养(100ｕL/孔，n＝3).置于37℃、5％CO2培养箱中培养72h,再加入5％MTT(20ｕL/孔)继续培养4h。倒掉原培养液,用0.1mmol/L的PBS液清洗后加入DMSO(150ｕL/孔)室温下孵育15～20min,用酶联检测仪,测其570nm处OD值,计算出各浓度组均值，作曲线，得到细胞标准生长曲线图如图1所示。
首先进行细胞毒性试验，以确保磺化聚醚醚酮(SPEEK)的加入不会产生细胞毒性。
在细胞对数生长期时，弃去原培养液，用PBS洗涤2次.用0.25％胰蛋白酶消化贴壁细胞，用含10％牛血清的RPMI1640培养液配成单个细胞悬液，细胞板计数，按每孔2×104个/ml接种在96孔板(n＝3)，每孔体积200ul，24h细胞贴壁后,吸去培养液,换成含有上述各种材料的培养液，将培养板移入CO2孵箱中，在37℃、5％CO2及饱和湿度条件下培养.培养5d.培养细胞用胰液酶消化，在倒置显微镜下观察细胞形态及细胞贴壁情况.在第2、3、4、5天时，每孔加入MTT溶液(5mg/ml)20ul，37℃孵箱中继续孵育4h，终止培养，小心吸弃孔内培养上清液，每孔加入150ul DMSO，振荡10min，使结晶物充分溶解，选择570nm波长，在酶联免疫检测仪上测定各孔光吸收值，记录结果。培养第2d时，用倒置显微镜观察各组材料对细胞形态的影响，经对SPEEK材料组进行观察，观察到的SPEEK对细胞形态影响图如图2所示，可以看到材料周围有细胞粘附生长，细胞呈梭性，折光性强、为正常活细胞，说明SPEEK对细胞无毒性。各组材料毒性级别见表1。
表1各组材料的RGR和毒性级别
下面对生物活性进行测试：
用MTT比色法检测，通过OD值绘制细胞增殖曲线，以浓度4mg/ml条件下实验数据为例进行说明。参看附图3-附图6组份材料、二元复合材料、三元复合材料、SPEEK随时间变化对细胞增殖影响图，图3显示组份材料对细胞增殖影响，HA曲线与空白接近，对细胞增殖有一定促进作用，PEEK和SPEEK曲线与空白组几乎重合，表示这两种材料对细胞增殖作用相近。细胞生长到第4天时，增殖有减缓趋势。
图4显示二元复合材料对细胞增殖影响，随着HA加入，复合材料对细胞增殖增加。细胞生长到第4天时，增殖有减缓趋势，其中PEEK减缓趋势最明显。
图5显示三元复合材料对细胞增殖影响，PEEK/SPEEK/30％HA位于其他曲线上方，与其他两种材料相比，对细胞增殖有明显促进作用。PEEK/SPEEK/20％HA、PEEK/SPEEK/10％HA曲线随时间变化趋势类似。
图6显示SPEEK对细胞增殖影响，PEEK/SPEEK/20％HA高于PEEK/20％HA曲线，表示PEEK/SPEEK/20％HA材料对细胞增殖作用比PEEK/20％HA强。
由此可知，三组分材料与两组分材料相比，加入SPEEK能促进细胞增殖，倒置显微镜观察显示SPEEK对细胞有黏附作用，MG-63细胞是贴壁型生长细胞，所以利于细胞在其生长。
下面对细胞黏附性能进行测试：
将PEEK、SPEEK、PEEK/10％HA、PEEK/20％HA、PEEK/SPEEK/10％HA、PEEK/SPEEK/20％HA、PEEK/SPEEK/30％HA分别制备成5mm×2mm大小圆柱体，经过高温高压灭菌后，置于24孔细胞培养板中，将细胞以2×104个/ml的密度加入到细胞培养板中，每孔0.5ml，于37℃、体积分数为5％CO及饱和湿度条件下培养，培养48小时后，采用细胞计数板计数，具体方法为：将材料取出，培养板残余细胞消化收集、计数，所得结果为未黏附细胞数；材料的细胞黏附率＝(总细胞数－未黏附细胞数)/总细胞数x100％。结果见表2。组份材料SPEEK细胞粘附率高于PEEK；二组份PEEK/HA复合材料随着HA含量的增加，细胞粘附率增加；三组份PEEK/SPEEK/HA复合材料随着HA含量的增加，细胞粘附率增加，并且都高于二组份PEEK/HA复合材料,说明SPEEK，HA加入能改善材料对细胞的粘附性能。
表2各组材料的细胞粘附率
同时，通过加入SPEEK，PEEK-SPEEK-HA三元复合材料中HA的含量达到30％时，PEEK-SPEEK-HA三元复合材料也能满足人骨替代材料的机械强度要求。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (3)
1.一种人骨替代材料的制备方法，包括以下步骤：
a.以环丁砜为溶剂，加入磺化聚醚醚酮和羟基磷灰石，加热至180-200℃，将磺化聚醚醚酮和羟基磷灰石完全溶解或分散；
b.将等摩尔比的对苯二酚和4,4'-二氟二苯甲酮与溶剂二苯砜在反应器中混合均匀，在氮气保护下加热至混合物熔融，加入无水碳酸钠和无水碳酸钾混合物作为成盐剂，加热至250-320℃，直至缩聚反应完成，得灰色粘稠液体；
c.将步骤a中溶于环丁砜的磺化聚醚醚酮和羟基磷灰石缓慢加入反应器中，维持温度250℃-320℃，冷凝回流并搅拌加热至混合均匀后趁热迅速倾倒至常温蒸馏水中凝结分散，得到固体聚醚醚酮-磺化聚醚醚酮-羟基磷灰石复合材料。
2.根据权利要求1所述的人骨替代材料的制备方法，其特征在于，所述步骤c得到固体聚醚醚酮-磺化聚醚醚酮-羟基磷灰石复合材料后还包括将固体产物经粉碎机捣碎成粉末状，用丙酮和蒸馏水多次反复抽提、过滤，除去未反应的单体、溶剂和盐类杂质，在电热恒温鼓风干燥箱中进行干燥，得到提纯的聚醚醚酮-磺化聚醚醚酮-羟基磷灰石三元复合材料。
3.根据权利要求1所述的人骨替代材料的制备方法，其特征在于，所述磺化聚醚醚酮的制备方法是：将聚醚醚酮溶于浓硫酸后并进行搅拌，控制磺化度为10-15％，在搅拌过程中加入蒸馏水，至溶液温度降至室温后过滤得到的固体粉末即为磺化聚醚醚酮。
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| CN110885533A (zh) * | 2019-12-03 | 2020-03-17 | 常州华森医疗器械有限公司 | 一种高生物活性peek复合材料人工关节假体及其制备方法 |
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| CN117624634B (zh) * | 2024-01-25 | 2024-04-12 | 吉林省汇融生物科技有限公司 | 一种聚砜羟基磷灰石聚合物及其制备方法与应用 |
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