CN106609327B - 一种Zn-HAP系锌合金及其制备方法与应用 - Google Patents
一种Zn-HAP系锌合金及其制备方法与应用 Download PDFInfo
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- CN106609327B CN106609327B CN201510689358.4A CN201510689358A CN106609327B CN 106609327 B CN106609327 B CN 106609327B CN 201510689358 A CN201510689358 A CN 201510689358A CN 106609327 B CN106609327 B CN 106609327B
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Abstract
本发明公开了一种Zn‑HAP系锌合金及其制备方法与应用。本发明锌合金中包括Zn和HAP,所述锌合金中HAP的质量百分数为0~10%,但不包括0。所述锌合金中还包括微量元素,所述微量元素为硅、磷、锂、银、锡和稀土元素中的至少一种;所述微量元素的质量百分含量为0~3%,但不包括0。本发明Zn‑HAP系锌合金的力学性质符合医用植入体材料的强度和韧性的要求、对内皮细胞和成骨细胞无细胞毒性且能抑制平滑肌细胞增殖、具备良好的组织相容性和血液相容性,同时又可调控被体液降解,溶出的金属离子能被生物体吸收利用或代谢排除体外,还具备优异的抗菌性能,可应用于医用植入体的制备。
Description
技术领域
本发明属于医用金属材料制备技术领域,涉及一种Zn-HAP系锌合金及其制备方法与应用,具体涉及一种Zn-HAP系锌合金及其制备方法与在制备可体液降解医用植入体中的应用。
背景技术
生物医用材料是用来对生物体进行诊断,治疗,修复或替换其病损组织、器官或增进其功能的材料。它是研究人工器官和医疗器械的基础,按用途可分为修复材料,心血管系统材料,医用膜材料,药物释放载体材料,生物传感器材料,齿科材料等。按组成和性质主要有生物医用金属材料,生物陶瓷,生物医用高分子,生物医用复合材料和生物衍生材料。生物医用金属材料具有高的机械强度和抗疲劳性能,是临床应用最广泛的承力植入材料,其应用遍及硬组织,软组织,人工器官和外壳辅助器材等各个方面。目前临床应用的金属材料主要有纯钛,钽,铌,锆,不锈钢,钴基合金和钛基合金等,多为惰性材料。这些材料在人体内不可降解,为永久性植入,当植入体在人体内的服役期满后,必须通过二次手术取出,从而给患者带来不必要的生理痛苦及经济负担。
生物医用可降解金属就是能够在体内缓慢降解,其降解产物与机体组织和器官有良性的反应,在帮助组织完全恢复之后能够被机体吸收而无残留的一种金属材料。这样就能够尽可能减少材料对机体的长期影响,材料在帮助机体恢复的过程中也在逐渐被机体吸收,其降解产物可以通过新陈代谢被吸收或者排出体外,组织恢复后无需二次手术。由于可降解金属材料的设计更具人性化和功能性,所以成为当今国际材料领域的研究热点。
可降解的医用镁合金一直是几年来的研究热点,不同的合金体系和新型的结构以及表面改性都层出不穷,比如Mg-Ca,Mg-Sr,Mg-Zn以及对工业合金AZ31和WE43 的改良和新型的多孔,纳米晶以及非晶结构都使得镁合金越来越接近应用。尽管镁合金有一系列的优点,降解过快以及析氢过多一直是镁合金难以克服的一个瓶颈。相比于镁合金,铁基合金有着稳定但是过慢的降解速度,其腐蚀产物会引发炎症反应,所以开发一种具有合适的降解速度且与组织能够良性反应的可降解金属材料成为一种需求。
从腐蚀上来看,锌及其合金相比于镁有更正的腐蚀电位,相比于铁又更活泼,可以作为牺牲阳极材料。所以其腐蚀速度应该介于两者之间,可能具备有更合适的体内降解速度。从锌对人体的作用来看,锌是人和动物正常生长,生殖和延长寿命所必需的元素,参与许多酶的合成,发挥调控作用,一个成年人每天需要10-15mg的锌,哺乳期妇女每日需要30-40mg的锌,正常成人体含锌2-4g,其中60%存在于肌肉,30%存在于骨骼。与人体有关的的含锌酶大约在100种,包括乙醇脱氢酶,碱性磷酸酶,碳酸酐酶,羧基肽酶原和胞液的超氧化物歧化酶。锌参与控制蛋白质合成,控制机体的生长发育。锌与核酸,氨基酸代谢及蛋白质合成有密切关系,实验证明缺锌导致氨基酸氧化作用增强,甲硫氨酸结合到组织蛋白减少,胱氨酸参与皮肤蛋白合成减少,引起甘氨酸及脯氨酸合成胶质障碍,还可引起肝脏精氨酸酶活力增高。锌参与蛋白质与核酸的代谢,调节细胞的合成和功能。锌是必需微量元素中作用最多,毒性最小的一种微量元素,是构成多种蛋白质分子所必需的元素,98%的锌都分布在细胞之内,锌在细胞中的含量比其他微量元素都多,脑中红的锌含量是铜的5倍,锰的8倍。锌还参与许多生物膜的形成,有降低脂质过氧化的作用,能改善粘膜上皮的营养代谢和抵抗力,稳定并保护细胞膜。锌对胰岛素生成有重要的作用,与生长激素和性激素也有紧密的联系。锌在维持人体的免疫功能方面具有重要作用,它在细胞分裂活酶,维持T细胞的增殖和分化,促进抗体生成中起重要作用。无论是人和动物,体内含锌量的减少均可引起细胞免疫功能下降,对疾病的易感性增加。锌能通过干扰抑制病毒 DNA的复制产生抗病毒作用。骨骼含有人体中一大部分的锌,骨骼中的锌主要集中在钙化的类骨质层中,骨骼生长缓慢是日常饮食中缺锌的常见症状。研究发现锌对成骨性骨修复和矿物化有促进作用,锌能刺激转录因子Runx2的基因表达,而这种转录因子与成骨细胞分化有关。锌还能通过抑制破骨细胞样细胞从骨髓干细胞的分化和促进成熟破骨细胞的凋亡来抑制破骨性再吸收。锌还对破骨细胞分化因子诱导的破骨细胞生成有抑制作用。锌的转运体在成骨细胞和破骨细胞中都有表达,日常饮食中摄入锌有利于骨质量增长。锌在体内各种蛋白质和酶中的作用决定了锌对心血管健康的重要影响。锌在细胞内氧化还原信号通路内扮演着重要的角色,局部缺血和梗死会引发蛋白质释放锌造成心肌症。补充锌可以增强心肌功能,预防冠状动脉疾病和心肌症。补充足够的锌可以保护心肌细胞免受氧化应激,还能预防心肌受损时并发的炎症反应。锌有愈伤作用,有利于在心脏恢复期间促进起愈伤作用的心肌干细胞的存活。缺锌的病理学表现包括生长缓慢,分娩困难,神经病,周期型厌食,腹泻,皮炎,脱发,失血,低血压低体温症。缺锌还会影响表皮,肠道,中枢神经,免疫系统,骨骼和生殖系统。锌缺乏可以降低成骨细胞活性,影响胶原和蛋白多糖的合成和碱性磷酸酶的活性。所以锌具有良好的生物相容性和合适的降解性能。
羟基磷灰石(Ca10(PO4)6(OH)2、HAP)是脊椎动物骨骼和牙齿的主要无机组成部分,人的牙釉质中羟基磷灰石含量约96wt.%,骨骼中也占到69wt.%。羟基磷灰石具有优良的生物相容性和生物活性,可作为一种骨骼和牙齿的诱导因子,在口腔保健领取中对牙齿具有较好的再矿化,脱敏以及美白作用。实验证明HAP粒子与牙釉质生物相容性好,亲和性高,其矿化液能够有效形成再矿化沉积,阻止钙离子流失,解决牙釉质脱矿问题,从根本上预防龋齿病。羟基磷灰石植入体内后,钙和磷会游离出材料表面被身体组织吸收,并生长出新的组织。有研究证明羟磷灰石的晶粒越细,生物活性越高。羟基磷灰石与锌复合主要用来提高材料的生物活性,同时也可调节降解速度。
目前乐普(北京)医疗器械股份有限公司有关于可降解新基合金支架的专利,西安爱德万思医疗科技有限公司有关于医用生物可降解锌合金毛细管材的制备方法以及耐蚀高强韧锌合金植入材料的专利,国内外还没有文献和专利报道Zn-HAP系锌合金的制备及性能,并提出将Zn-HAP系锌合金用作可降解生物医用材料使用。
发明内容
本发明的目的是提供一种Zn-HAP系锌合金及其制备方法与应用。本发明制备的Zn-HAP系锌合金具有合适的机械性能、可调节的腐蚀速率和良好的细胞相容性、血液相容性,还具备优异的抗菌性能,可用于生物医用植入的制备。
本发明所提供的Zn-HAP系锌合金,包括Zn和羟基磷灰石(Ca10(PO4)6(OH)2,缩写HAP);
所述Zn-HAP系锌合金中HAP的质量百分数为0~10%,但不包括0。
上述Zn-HAP系锌合金中,还可包括微量元素,所述微量元素为硅、磷、锂、银、锡和稀土元素中的至少一种;所述微量元素的质量百分含量为0~3%,但不包括0。
上述Zn-HAP系锌合金的表面还可涂覆有可降解高分子涂层、陶瓷涂层或药物涂层;
所述可降解高分子涂层、所述陶瓷涂层和所述药物涂层的厚度均可为0.01~5mm。
所述可降解高分子涂层的制备材料可为下述1)和2)中的至少一种:
1)聚己酸内酯(PCL)、聚乳酸(PLA)、聚羟基乙酸(PGA)、L-聚乳酸(PLLA)、聚氰基丙烯酸酯(PACA)、聚酸酐、聚膦腈、聚对二氧杂环己烷酮、聚-羟基丁酸酯或聚羟基戊酸酯中的任一种;
2)聚乳酸(PLA)、聚己酸内酯(PCL)、聚羟基乙酸(PGA)、L-聚乳酸(PLLA)、聚氰基丙烯酸酯(PACA)和聚对二氧杂环己烷酮中的至少两种的共聚物;;进一步地,聚乳酸(PLA)、聚己酸内酯(PCL)、聚羟基乙酸(PGA)、L-聚乳酸(PLLA)、聚氰基丙烯酸酯(PACA)和聚对二氧杂环己烷酮中的任意两种的共聚物,任意两者的比例可制备过程中的具体需要进行配比,比如:PLLA和PCL两者的质量比可为(1-9): 1。
所述陶瓷涂层的制备材料可为羟基磷灰石、磷酸三钙和磷酸氧四钙中的至少一种;
所述药物涂层可为雷帕霉素及其衍生物涂层、紫杉醇涂层、依维莫司涂层、西罗莫司涂层、丝裂霉素涂层和抗菌涂层中的至少一种。
本发明提供的Zn-HAP系锌合金具体为下述1)-5)中任一种,为重量百分比:
1)由90~99%的Zn和1%~10%的HAP组成;
2)由99%的Zn和1%的HAP组成;
3)由95%的Zn和5%的HAP组成;
4)由90%的Zn和10%的HAP组成。
本发明所提供的Zn-HAP系锌合金具备可调节的降解速度和良好的生物相容性,血液相容性以及优异的抗菌性能,是一种可靠的生物医用植入材料。
本发明进一步提供了上述Zn-HAP系锌合金的制备方法,包括如下步骤:
将Zn、HAP和所述微量元素按照下述1)和2)中的任一种方式(以粉末形式) 进行混合得到(均匀)混合物;
1)Zn和HAP;
2)Zn、HAP和微量元素;
按照下述a)或b)的步骤即得所述Zn-HAP系锌合金;
a)在真空或惰性气氛下,将所述均匀混合物进行烧结,经冷却后即得所述Zn-HAP系锌合金;
b)在真空或惰性气氛下,将所述均匀混合物进行烧结,经冷却后涂覆所述可降解高分子涂层、所述陶瓷涂层或所述药物涂层即得所述Zn-HAP系锌合金。
上述制备方法,所述混合具体是将Zn、HAP和所述微量元素,在氩气保护气氛下加入真空球磨罐中,于球磨速度180~250rpm、球料比(10-20):1(如:10:1或20:1) 下球磨15~60min,得到均匀混合物,于氩气中保存,防止氧化。
和/或,所述烧结具体为放电等离子烧结(Spark Plasma Sintering)。
和/或,具体的,所述放电等离子烧结为将所述混合物加入石墨磨具中,轴向加压并真空烧结,所述放电等离子烧结的具体参数控制如下:起始烧结压力1MPa,保温烧结压力30~60MPa,先以100℃/min升温到150~300℃,再以50℃/min升温到 200~350℃,最后以25℃/min升温到250~400℃,保温时间3~6min,炉冷降温,得到所述Zn-HAP系锌合金。
为适应不同临床需求,上述Zn-HAP系锌合金的制备方法还包括涂覆涂层的步骤。
所述涂覆可生物降解高分子涂层的方法是将所述Zn-HAP系锌合金进行酸洗,然后将其在所述生物降解高分子涂层的制备材料溶于三氯乙烷制备的胶体中浸涂 10~30min后,匀速拉出进行离心处理得到涂覆有可生物降解高分子涂层的Zn-HAP系锌合金;
所述涂覆陶瓷涂层的方法可为等离子喷涂、电泳沉积、阳极氧化或水热合成中的任一种;
所述等离子体喷涂所用的等离子气体主气为Ar,流量为30~100scfh,等离子气体次气为H2,流量为5~20scfh,喷涂电流为400~800A,喷涂电压为40~80V,喷涂距离为100~500mm;
所述电沉积可降解陶瓷涂层的方法为以Zn-HAP系锌合金为阴极在含钙、磷盐的电解液中,电流密度为2~10mA/cm2,处理10~60min后,清洗干燥得到所述Zn-HAP 系锌合金;
所述阳极氧化和水热合成结合的方法为将所述Zn-HAP系锌合金在含有 0.01~0.5mol/Lβ-甘油磷酸钠和0.1~2mol/L醋酸钙的电解液中,在200~500V下氧化 10~30min,然后将所述锌基复合材料或锌合金在200~400℃下处理1~4h。
所述涂覆药物涂层的方法为物理和化学方法;
所述物理方法涂层工艺主要采用浸泡、喷涂方法;所述化学方法主要运用电化学原理进行电镀;
所述浸泡方法为将活性药物与控释载体(或单独的活性药物)配制成溶液,具体浓度可因溶液粘度和所需药物剂量不同而不同,然后将所述医用植入体浸泡入溶液中,然后经过必要的后处理过程,如交联、干燥、固化等步骤,制成药物涂层;
所述喷涂方法为将活性药物与控释载体(或单独的活性药物)配制成溶液,然后通过喷洒工具或特制的喷涂设备将溶液均匀涂布于所述医用植入体表面,经干燥、固化等后处理步骤之后即制成药物涂层;
所述化学方法是利用活性药物和(或)控释载体在由所述医用植入制作的电极上发生电氧化还原反应,使所述医用植入表面形成稳定的由化学键联接的药物涂层。
本发明利用Zn-HAP系锌合金降解速度和生物功能性均可调控,Zn为人体必须的微量元素,能够促进成骨细胞增殖分化,抑制破骨细胞生长,而羟基磷灰石是骨的主要无机组成部分。锌对心血管健康也有重要作用,能够保护心肌细胞,预防炎症,选择Zn-HAP系锌合金作为可降解医用植入物。本发明的Zn-HAP系锌合金的压缩强度符合医用植入材料的强度要求,同时也可以具备足够的韧性,在体内降解速度可调控,对内皮细胞和成骨细胞无毒性且能抑制平滑肌细胞增殖,血液相容性良好且可调控,还具备优异的抗菌性能,所以Zn-HAP系锌合金是一种综合性能优异的医用植入物。
本发明提供的Zn-HAP系锌合金可应用于制备如下医用植入体:骨修复器械、齿科修复器械;
所述骨修复器械可为骨组织修复支架、接骨器、固定线、固定螺丝、固定铆钉、固定针、夹骨板、髓内针或接骨套;
所述齿科修复器械可为牙髓针或牙齿充填材料。
进一步的,所述Zn-HAP系锌合金可应用于制备具有如下1)-6)中任一种性质的医用植入体中的应用。
1)所述Zn-HAP系锌合金的力学性能;
2)所述Zn-HAP系锌合金可调控的降解性能
3)所述Zn-HAP系锌合金的血液相容性;
4)所述Zn-HAP系锌合金的细胞相容性;
5)所述Zn-HAP系锌合金的抗菌性;
6)所述Zn-HAP系锌合金抑制平滑肌细胞增殖。
本发明具有如下优点:
(1)本发明制备的Zn-HAP系锌合金力学性能符合医用植入体材料的强度和韧性的要求,同时又可体内降解,具有“可体内降解吸收”和“可提供有效力学支撑”的特性。
(2)本发明Zn-HAP系锌合金用于可降解医用植入体时,其体内降解速度可以通过加入不同含量的羟基磷灰石进行调节,从而达到针对体内不同部位植入物降解速度不同的要求,达到可调节的腐蚀速率的目的。
(3)本发明提供的可降解医用植入体对内皮细胞和成骨细胞无毒性且能抑制平滑肌细胞增殖,生物相容性良好,具备良好的细胞相容性和血液相容性以及优异的抗菌能力,同时,通过加入不同成分可以对Zn-HAP系锌合金的生物功能性(细胞相容性,血液相容性,抗菌能力)进行调节从而达到设计其生物功能性的目的。
(4)本发明制备的Zn-HAP系锌合金中组成元素Zn具有促成骨和抑制破骨吸收的作用,羟基磷灰石也时骨的无机组成部分,所以是针对骨科植入物的一种材料。
附图说明
图1为实施例3中的Zn-HAP系锌合金金相。
图2为实施例3中的Zn-HAP系锌合金X射线衍射分析图。
图3为实施例4中的Zn-HAP系锌合金的压缩曲线。
图4为实施例5中的Zn-HAP系锌合金在Hank ’ s 模拟体液中浸泡3个月的宏观腐蚀表面。
图5为实施例5中的Zn-HAP系锌合金浸泡腐蚀表面的扫描电子显微镜图。
图6为实施例5中的Zn-HAP系锌合金浸泡腐蚀产物的EDS能谱元素分析图。
图7为实施例5中的Zn-HAP系锌合金在Hank ’ s 模拟体液中浸泡3个月的pH变化图。
图8为实施例5中的Zn-HAP系锌合金在Hank ’ s 模拟体液中浸泡3个月的失重腐蚀速率和溶液离子浓度(*p<0.05)。
图9为实施例5中的Zn-HAP系锌合金在Hank ’ s 模拟体液中的电化学腐蚀极化曲线。
图10为实施例6中的Zn-HAP系锌合金的溶血率(*p<0.05)。
图11为实施例6中的Zn-HAP系锌合金表面粘附的血小板形貌和数量(*p<0.05)。
图12为实施例6中的Zn-HAP系锌合金在贫血小板血浆中的Zn离子浓度 (*p<0.05)。
图13为实施例7中的Zn-HAP系锌合金的接触角(*p<0.05)。
图14为实施例7中的Zn-HAP系锌合金的细胞存活率(*p<0.05)。
图15为实施例7中的Zn-HAP系锌合金浸提液的锌离子浓度(*p<0.05)。
图16为实施例8中的Zn-HAP系锌合金的抗菌率(*p<0.05)。
图17为实施例8中的Zn-HAP系锌合金在细菌悬液中的Zn离子浓度以及pH值 (*p<0.05)。
具体实施方式
下面通过具体实施例对本发明进行说明,但本发明并不局限于此。
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
下述实施例中所用的百分含量,如无特别说明,均为质量百分含量。
实施例1、制备Zn-HAP系锌合金:
1)以纯Zn粉末(纯度99.9%,粒径45~109μm)(购自Alfa Aesar)、HAP粉末 (纯度99%,长150nm)(购自北京德科岛金有限公司)作为原料,按不同的质量比 (Zn与HAP的质量比分别为99:1,95:5,90:10)于真空手套箱中,在氩气保护下加入真空球磨罐中,通过行星球磨机球磨混匀,球磨速度250rpm,球料比10:1,球磨时间40min,得到不同Zn与HAP质量比的均匀混合物,于氩气保护气氛中保存,防止氧化;
2)将步骤1)中的均匀混合物加入石墨磨具中,轴向加压并通过放电等离子真空烧结:起始烧结压力1MPa,保温烧结压力60MPa,先以100℃/min升温到250℃,再以50℃/min升温到350℃,最后以25℃/min升温到380℃,保温时间6min,得到不同 Zn与HAP质量比的Zn-HAP系锌合金,其中,Zn与HAP质量比为99:1命名为Zn/1HAP;Zn与HAP质量比为99:5命名为Zn/5HAP;Zn与HAP质量比为99:10 命名为Zn/10HAP。
实施例2、制备涂覆陶瓷涂层的Zn-HAP系锌合金:
1)以纯Zn粉末(纯度99.9%,粒径45~109μm)(购自Alfa Aesar)、HAP粉末 (纯度99%,长150nm)(购自北京德科岛金有限公司)作为原料,按不同的质量比 (Zn与HAP的质量比分别为99:1,95:5,90:10)于真空手套箱中,在氩气保护下加入真空球磨罐中,通过行星球磨机球磨混匀,球磨速度200rpm,球料比20:1,球磨时间60min,得到不同Zn与HAP质量比的均匀混合物,于氩气保护气氛中保存,防止氧化;
2)将步骤1)中的均匀混合物加入石墨磨具中,轴向加压并通过放电等离子真空烧结:起始烧结压力1MPa,保温烧结压力50MPa,先以100℃/min升温到250℃,再以50℃/min升温到350℃,最后以25℃/min升温到380℃,保温时间5min,得到不同 Zn与HAP质量比的Zn-HAP系锌合金,其中,Zn与HAP质量比为99:1命名为 Zn/1HAP;Zn与HAP质量比为99:5命名为Zn/5HAP;Zn与HAP质量比为99:10 命名为Zn/10HAP。
3)在步骤2)中得到的Zn-HAP系锌合金表面涂覆陶瓷涂层-磷酸三钙,具体步骤如下:采用离子体喷涂,所用的等离子气体主气为Ar,流量为60scfh,等离子气体次气为H2,流量为15scfh,喷涂电流为600A,喷涂电压为60V,喷涂距离为250mm;喷涂得0.59mm的陶瓷涂层的Zn-HAP系锌合金。
本实施例所制备得到的Zn-HAP系锌合金的腐蚀性能、血液相容性、细胞相容性和抗菌性与实施例1中的相关性能相同或相近。
实施例3、Zn-HAP系锌合金显微组织分析
将实施例1中的Zn-HAP系锌合金,通过线切割制备10×10×1mm试样,依次经400#、800#、1200#和2000#SiC砂纸系列打磨抛光。在丙酮、无水乙醇和去离子水中分别超声清洗15min后,25℃下干燥。将试样进行X射线衍射分析,并用4%硝酸酒精浸蚀试样5~30s后用去离子水清洗,吹干后,在金相显微镜观察,取试样通过密度计测试致密度。
图1为Zn-HAP系锌合金金相,从图1中可以看出HAP均匀分布在纯Zn颗粒的边界上,随着HAP含量的增加,在边界上的HAP开始聚集,割裂了纯锌颗粒之间的结合,纯Zn颗粒与HAP之间主要是物理结合并未发生化学反应。
图2为Zn-HAP系锌合金X射线衍射分析图,发现单质锌和氧化锌,不过能谱显示材料中第二相部分的Ca:P比为1.68,与羟基磷灰石中的Ca:P相同,说明材料中第二相为羟基磷灰石。
表1为Zn-HAP系锌合金致密度,致密度随羟基磷灰石含量增大而降低,羟基磷灰石的团聚增加了材料的孔隙率。
表1、Zn-HAP系锌合金致密度
实施例4、Zn-HAP系锌合金力学性能测试:
将按照实施例1的方法制备的Zn-HAP系锌合金,分别按照ASTM-E9-89a压缩测试标准和ASTM-E10-01硬度测试标准制备样品,依次经400#、800#、1200#和2000#SiC 砂纸系列打磨抛光。在丙酮、无水乙醇和去离子水中分别超声清洗15min后,采用显微硬度计和万能材料力学试验机在室温下进行试验,载荷0.1kN,保压15s,压缩速度为0.2mm/min。
图3为Zn-HAP系锌合金的压缩曲线,从曲线上可以看出该复合材料的压缩塑性随羟基磷灰石含量增加而降低,Zn/10HAP压缩到30%应变产生裂纹失效。
Zn-HAP系锌合金各试样的室温力学性能如表2所示,其中,由表2可知,随HAP 含量的增加,材料强度和硬度逐渐降低。由于羟基磷灰石的加入割裂了基体的结合强度,而且第二相本身无增强作用,所以压缩强度随第二相含量提高而降低。
表2、Zn-HAP系锌合金力学实验结果
*表示与纯锌对比有显著性差异(p<0.05)
实施例5、Zn-HAP系锌合金腐蚀性能测试:
将实施例1中的Zn-HAP系锌合金,通过线切割制备φ6x1mm浸泡试样,依次经400#、800#、1200#和2000#SiC砂纸系列打磨抛光。在丙酮、无水乙醇和去离子水中分别超声清洗15min后,25℃下干燥。之后浸泡在Hank ’ s 模拟体液(NaCl 8.0g,CaCl2 0.14g,KCl0.4g,NaHCO3 0.35g,葡萄糖1.0g,MgCl2·6H2O 0.1g,Na2HPO4·2H2O 0.06g, KH2PO4 0.06g,MgSO4·7H2O 0.06g溶解于1L去离子水中)中,浸泡不同时间间隔并在相应时间点测试溶液pH值,在三个月后取出样品用去离子水清洗,在空气中干燥,通过2.5次元影像仪和扫描电子显微镜(S-4800,Hitachi,日本)观察样品表面,并通过能谱仪检测腐蚀产物成分。取浸泡后的Hank ’ s 模拟体液通过电感耦合等离子体发射光谱仪测试溶液中的各离子浓度。最后用氨基乙酸清洗液(250g/1000ml)清洗腐蚀产物并通过失重法计算腐蚀速率。
电化学测试是将上述处理好的试样通过Autolab电化学工作站,在Hank ’ s 模拟体液中进行电化学测试。
图4为Zn-HAP系锌合金在Hank ’ s 模拟体液中浸泡3个月的宏观腐蚀表面,结果表明:随着羟基磷灰石含量增加,材料的腐蚀加重,Zn/1HAP表面光亮完整,而 Zn/10HAP表面在羟基磷灰石聚集处有大量腐蚀坑,材料边缘腐蚀尤为严重。
图5为Zn/1HAP系锌基复合材料浸泡腐蚀表面的扫描电子显微镜图,微观腐蚀形貌与宏观腐蚀形貌结果一致,Zn/1HAP表面只有少量腐蚀产物,存在一些腐蚀微裂纹,随羟基磷灰石含量增加,腐蚀产物也增加,材料表面裂纹扩大,腐蚀表面部分剥落, Zn/10HAP材料的表面完全被球状白色腐蚀产物覆盖。
图6为Zn-HAP系锌合金浸泡腐蚀产物的EDS能谱元素分析图。可以看出腐蚀产物含有Zn,O,C,Ca,P,Mg,可能为含钙磷盐和Zn,Mg的碳酸盐的复合腐蚀产物。
图7为Zn-HAP系锌合金在Hank ’ s 溶液中浸泡3个月的pH变化图,从图7中可以看出,该复合材料相比于纯锌和Hank ’ s 溶液有更高的pH值,说明其降解速度相对于纯锌是明显加快的。前7天在相同时间点pH值大小Zn/10HAP>Zn/5HAP>Zn/1HAP, 之后Zn/10HAP和Zn/5HAP的pH变化趋于接近但还是明显高于Zn/1HAP,总体来说随羟基磷灰石含量增加,pH值也在升高,复合材料的降解在加快。该复合材料整体上 pH变化趋势与Hank ’ s 溶液本身变化趋势相近,所以该变化趋势并不由材料导致,材料本身的pH值变化趋势相对稳定,所以Zn-HAP系锌合金的腐蚀层能够起到防止进一步腐蚀的作用。
图8为Zn-HAP系锌合金在Hank ’ s 溶液中浸泡3个月后根据失重计算的腐蚀速率和溶液中的离子浓度,从腐蚀速率来看,Zn/1HAP的腐蚀速率比纯锌略慢,但随羟基磷灰石含量增加,复合材料的腐蚀速率显著加快,Zn/10HAP的降解速度大概是纯锌的5倍。离子浓度的趋势与失重一致,随羟基磷灰石含量增加,Hank ’ s 溶液中Zn离子浓度也显著增加。而浸泡溶液中Ca、P含量相对于Hank ’ s 溶液本身却有所降低,说明一部分Ca、P变成钙磷盐沉积到材料表面。
图9为Zn-HAP系锌合金在Hank ’ s 溶液中的电化学腐蚀极化曲线,表3为Zn-HAP系锌合金在Hank ’ s 溶液中的电化学腐蚀速率,从表3中可以看出该复合材料的电化学腐蚀速率随羟基磷灰石含量增加而显著增大,与失重得出的结果一致,羟基磷灰石在纯锌颗粒边界聚集,产生大量缺陷和空位,加速了材料的腐蚀。
表3、Zn-HAP系锌合金电化学腐蚀速率
括号内为标准差,*表示与纯锌相比p<0.005
实施例6、Zn-HAP系锌合金血液相容性测试:
将实施例1中的Zn-HAP系锌合金通过线切割制备φ10x1mm试样片,经400#、 800#、1200#和2000#SiC砂纸系列打磨抛光。在丙酮、无水乙醇和去离子水中分别超声清洗15min后,25℃下干燥。采集健康志愿者身上新鲜血液,置于内含3.8wt.%柠檬酸钠作为抗凝剂的抗凝管保存。用0.9%生理盐水按4:5的比例稀释制成稀释血液样本。将试样浸泡在10mL生理盐水,37±0.5℃保温30min,加入0.2mL稀释血液样本,37±0.5℃保温60min。采用10mL生理盐水作为阴性对照组,10mL去离子水作为阳性对照组。经3000rpm离心5min,取上清液用Unic-7200紫外可见分光光度计 545nm测量吸光度OD值,设置三组平行样以进行统计学分析。
用以下公式计算溶血率:
溶血率=(实验组OD值-阴性组OD值)/(阳性组OD值-阴性组OD值)×100%。
全血采集后,一部分在1000rpm离心10min制备富血小板血浆。将富血小板血浆滴于试样表面,37±0.5℃保温60min,每组3个平行样。取出试样,PBS缓冲液(pH 值为7.2)冲洗3遍以除去未黏附血小板。固定血小板方法为:每孔加入500μL浓度为2.5%的戊二醛固定液,室温下固定两小时,然后将固定液吸出,使用PBS清洗3 遍,使用浓度为50%,60%,70%,80%,90%,95%,100%酒精进行梯度脱水,每个浓度梯度脱水10min,真空干燥后使用扫描电子显微镜(S-4800,Hitachi,日本)观察血小板黏附数量及形态,每个试样随机选择10个区域进行血小板计数和统计学分析。另一部分在3000rpm下离心15min,取上层贫血小板血浆,按500ul/cm2比例将试样放在装有贫血小板血浆的玻璃管中37℃水浴孵育30min,取反应完的贫血小板血浆500ul 进行凝血四项检测。取反应后的贫血小板血浆用电感耦合等离子体发射光谱仪测试浸提原液中的各离子浓度。
图10为Zn-HAP系锌合金的溶血率,实验结果表明:Zn-HAP系锌合金的溶血率均远小于临床使用要求的安全阈值5%,随羟基磷灰石含量增加,溶血率下降,表现出良好的红细胞和血红蛋白相容性。
图11为Zn-HAP系锌合金表面粘附的血小板形貌和数量,从图11中可以看出,该复合材料表面的血小板大多为多边形且伸展出少量伪足,Zn/1HAP和Zn/5HAP材料表面血小板较为圆润饱满而Zn/10HAP表面血小板伪足较长,形态皱缩。从数量上来看,随羟基磷灰石含量增加,粘附的血小板数量显著减少。材料表面的血小板都处于激活的初期阶段,通过增加羟基磷灰石的量可以显著抑制血小板的粘附。
表4为Zn-HAP系锌合金凝血四项结果,图12为Zn-HAP系锌合金的贫血小板血浆以及空白对照的贫血小板血浆(PPP)中Zn离子和Ca离子浓度,从表4可以看到该复合材料的凝血酶原时间(PT)与健康组相比明显延长且随羟基磷灰石含量增加而增加,相比纯锌也有明显延长。活化部分凝血活酶时间(APTT)相比纯锌和健康组以及参考组也都显著延长,趋势与PT变化趋势一致。凝血酶时间(TT)相比健康组、纯锌、参考值都显著的缩短。该复合材料使凝血酶原时间(PT)和活化部分凝血活酶时间(APTT)显著延长,使凝血酶时间(TT)显著缩短,这与贫血小板血浆中Zn离子浓度升高,Ca离子浓度降低作用于凝血系统有关。
表4、Zn-HAP系锌合金凝血四项结果
*表示与健康对照组有显著性差异(p<0.05);#表示与纯锌有显著性差异(p<0.05)
实施例7、Zn-HAP系锌合金的细胞相容性实验:
按实施例1的方法制备Zn-HAP系锌合金,通过线切割制备φ10x1mm试样片,经400#、800#、1200#和2000#SiC砂纸系列打磨抛光。在丙酮、无水乙醇和去离子水中分别超声清洗15min后,25℃下干燥。通过去离子水对试样进行接触角测试,试样经紫外线消毒灭菌,置于无菌孔板中,按试样表面积与含10%血清和1%双抗(青霉素加链霉素混合溶液)的DMEM细胞培养基按体积之比为1.25cm2/mL的比例加入 DMEM细胞培养基,置于37℃、95%相对湿度、5%CO2培养箱中24h,得到锌基复合材料浸提液原液,密封,4℃冰箱保存备用。
浸提液与细胞接种培养及结果观察:将HUVEC,VSMC,细胞复苏、传代后,悬浮于DMEM细胞培养基中,接种于96孔培养板上,阴性对照组加入DMEM细胞培养基,锌基复合材料浸提液原液组加入上述得到的锌基复合材料浸提液原液,使最终细胞浓度为2~5×104/mL。置于37℃、5%CO2培养箱中培养,1,2,4天后分别取出培养板,在倒置相差显微镜下观察活细胞的形态并通过CCK8试剂盒进行细胞存活率的测试,取锌基复合材料浸提液原液用电感耦合等离子体发射光谱仪测试浸提原液中的各离子浓度。
图13为Zn-HAP系锌合金的接触角,随羟基磷灰石含量增加,材料表面接触角增大,从亲水向疏水转变。
图14为Zn-HAP系锌合金的细胞存活率,结果表明:该复合材料相对于纯锌,细胞毒性有显著改善,对内皮细胞和成骨细胞有优异的细胞相容性,不同成分之间没有明显差异,而对于平滑肌细胞,都有明显抑制作用。
图15为Zn-HAP系锌合金浸提液的离子浓度。从锌离子浓度来看,复合材料锌离子浓度相比纯锌明显下降,细胞毒性的降低与锌离子浓度下降有显著关系。
实施例8、Zn-HAP系锌合金的抗菌性试验:
按实施例1的方法制备Zn-HAP系锌合金,通过线切割制备φ10x1mm试样片,经400#、800#、1200#和2000#SiC砂纸系列打磨抛光。在丙酮、无水乙醇和去离子水中分别超声清洗15min后,25℃下干燥后在紫外线下消毒。取1ml冻存的金黄色葡萄球菌(Staphylococcus aureus)(菌种保藏编号为ATCC 29213)于20ml LB液体培养基中180rpm活化12h,再取活化后的1ml菌液于40ml LB液体培养基中200rpm继续活化1小时,取活化后的菌液1ml每孔加入到放有试样的24孔板中,在37℃培养24h 后,取100ul菌液在PBS缓冲液中稀释105倍后涂在LB固体培养基上,计数。将试样取出,用PBS缓冲液冲洗三次,轻轻洗去试样表面粘附不牢的细菌,放入离心管中,加入1ml PBS缓冲液,超声震荡10min将试样表面的细菌震入PBS缓冲液中,取 10mlPBS缓冲液稀释1000倍,涂在LB固体培养基上,计数。取细均悬液用电感耦合等离子体发射光谱仪测试悬液中的锌离子浓度,并测试pH值。
图16为Zn-HAP系锌合金相对于无抗菌作用的Ti6Al4V的抗菌率,该复合材料悬液中的抗菌率随羟基磷灰石含量增加而增加,材料表面的抗菌率也显示出相同的趋势,这与培养液中的离子浓度趋势一致。
图17为Zn-HAP系锌合金的细菌悬以及空白LB培养基和Ti6Al4V培养基的Zn 离子浓度以及pH值,从图中可以看出,锌离子浓度变化与材料抗菌率变化一致,而 pH值变化很小,不能起到抗菌作用,所以主要是降解出来的锌离子对金黄色葡萄球菌(Staphylococcus aureus)有显著地抑制作用。所以,Zn-HAP系锌合金具备有优异的抗菌效果。
Claims (8)
1.一种Zn-HAP系锌合金,由Zn和HAP组成,或由Zn、HAP和微量元素组成;
所述Zn-HAP系锌合金中HAP的质量百分数为0~10%,但不包括0;
所述微量元素为硅、磷、锂、银、锡和稀土元素中的至少一种;
所述Zn-HAP系锌合金中,所述微量元素的质量百分含量为0~3%,但不包括0。
2.如权利要求1所述的Zn-HAP系锌合金,其特征在于:所述Zn-HAP系锌合金的表面涂覆有可降解高分子涂层、陶瓷涂层或药物涂层;
所述可降解高分子涂层、所述陶瓷涂层和所述药物涂层的厚度均为0.01~5mm。
3.如权利要求2所述的Zn-HAP系锌合金,其特征在于:所述可降解高分子涂层的制备材料具体为下述1)和2)中的至少一种:
1)聚己酸内酯、聚乳酸、聚羟基乙酸、L-聚乳酸、聚氰基丙烯酸酯、聚酸酐、聚膦腈、聚对二氧杂环己烷酮、聚-羟基丁酸酯或聚羟基戊酸酯中的任一种;
2)聚乳酸、聚己酸内酯、聚羟基乙酸、L-聚乳酸、聚氰基丙烯酸酯和聚对二氧杂环己烷酮中的至少两种的共聚物;
所述陶瓷涂层的制备材料具体为羟基磷灰石、磷酸三钙和磷酸氧四钙中的至少一种;
所述药物涂层具体为雷帕霉素及其衍生物涂层、紫杉醇涂层、依维莫司涂层、西罗莫司涂层、丝裂霉素涂层和抗菌涂层中的至少一种。
4.一种权利要求1-3中任一项所述的Zn-HAP系锌合金的制备方法,包括如下步骤:将Zn和HAP进行混合,或将Zn、HAP和微量元素进行混合,得到混合物;
按照下述a)或b)的步骤即得所述Zn-HAP系锌合金;
a)在真空或惰性气氛下,将所述混合物进行烧结,经冷却后即得所述Zn-HAP系锌合金;
b)在真空或惰性气氛下,将所述混合物进行烧结,经冷却后涂覆所述可降解高分子涂层、所述陶瓷涂层或所述药物涂层即得所述Zn-HAP系锌合金。
5.如权利要求4所述的制备方法,其特征在于:所述混合为将Zn、HAP和所述微量元素,在氩气保护气氛下加入真空球磨罐中,于球磨速度180~250rpm、球料比(10-20):1下球磨15~60min,得到混合物;
和/或,所述烧结为放电等离子烧结;
所述Zn-HAP系锌合金中HAP的质量百分数为0~10%,但不包括0。
6.如权利要求5所述的制备方法,其特征在于:所述放电等离子烧结为将所述混合物加入石墨模具中,轴向加压并真空烧结,所述放电等离子烧结的具体参数控制如下:起始烧结压力1MPa,保温烧结压力30~60MPa,先以100℃/min升温到150~300℃,再以50℃/min升温到200~350℃,最后以25℃/min升温到250~400℃,保温时间3~6min,炉冷降温,得到所述Zn-HAP系锌合金。
7.权利要求1-3中任一项所述的Zn-HAP系锌合金在制备可体液降解医用植入体中的应用。
8.一种可体液降解医用植入体,其由权利要求1-3中任一项所述Zn-HAP系锌合金制备得到。
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