CN106913916A - 一种可降解的锌基合金植入材料在制备血管支架中的应用 - Google Patents
一种可降解的锌基合金植入材料在制备血管支架中的应用 Download PDFInfo
- Publication number
- CN106913916A CN106913916A CN201710142675.3A CN201710142675A CN106913916A CN 106913916 A CN106913916 A CN 106913916A CN 201710142675 A CN201710142675 A CN 201710142675A CN 106913916 A CN106913916 A CN 106913916A
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- China
- Prior art keywords
- zinc
- containing alloy
- implantation material
- alloy implantation
- intravascular stent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明公开了一种可降解的锌基合金植入材料在制备血管支架中的应用,按质量百分含量,包括0.01wt%‑14.0wt%Fe和0wt%‑13.0wt%Cu和余量的Zn。制备时将Zn、Fe和Cu混合均匀后置于高纯石墨坩埚中,在SF6和CO2的混合气体气氛下熔炼,即得。该锌基合金植入材料的力学性能得到显著改善,使植入材料易于加工成型且强度、塑性等性能符合血管支架的基本要求。
Description
技术领域
本发明涉及医疗器械技术领域,特别是涉及一种可降解的锌基合金植入材料在制备血管支架中的应用,该血管支架用于经皮血管成型术(Percutaneous TransluminalAngioplasty,PTA)。
背景技术
经皮血管成型术(PTA)是一种经皮穿刺病人外周动脉,插入特制的球囊导管至病人病变血管、扩张狭窄的病变部,或植入支架,使病变血管疏通的微创技术。按照病变部位不同可区分为经皮外周血管成型术、经皮冠脉血管成型术等,其中冠脉的治疗难度更大、风险更高,对植入的支架要求也更严格。1977年,德国医生Gruentzig实施了世界首例经皮冠脉成型术(PTCA)。至上世纪九十年代,第一代心脏支架(BMS)的出现虽然大幅提高了经皮冠脉成型术(PTA)的治疗效果,但血管内再狭窄率仍高达30%。2001-2002年,表面涂覆药物的第二代药物洗脱心脏支架(DES)出现,使血管内再狭窄率降低到约10%;2004-2012年,主要支架生产厂家陆续推出改进的、具有可降解涂层的DES,以进一步减少晚期不良事件(TLF)的发生。但DES以不可降解金属为材质,在治疗后终身留置体内,并伴随患者一生,使用者必须长期服用抗凝剂等,这些特性决定了其使用的局限性和存在的安全隐患。
完全可降解支架能够克服上述缺陷,被公认为血管支架领域(尤其是冠脉支架领域)的下一代产品。2007年第一支完全可降解支架(PLLA外周血管支架)获得CE证书以来,PLLA(聚左旋乳酸)、PLGA(聚已交酯丙交酯)、络氨酸/聚碳酸酯、铁、镁合金等完全可降解支架不断出现。PLLA冠脉支架在欧洲进行的一项二期临床实验中,使得病人血管恢复了病变之前的活性。该产品已经取得欧洲CE认证,国内临床实验已经完成,有望在近期内上市。然而由于高分子材料本身力学性能存在局限,其径向支撑力低、壁厚太厚等缺陷目前仍无法克服,一些手术难度较大的病变仍无法使用。
铁支架、镁合金支架的出现就是对可降解材料力学性能差进行的弥补性尝试。实际开发过程表明,铁基支架力学性能优异但存在周围血管钙化弊病,且植入后降解速度过慢(2-3年)。镁基合金支架力学性能在植入初期能够满足临床需求,但降解速度过快(2-3周,支架结构就降解至不完整或支撑强度下降到较低水平),无法满足临床对支撑力保持时间的要求;且镁基合金降解产物对周围环境pH的影响不利于组织正常功能的恢复。一些降低镁降解速度的尝试(WE43合金、JDBM合金、表面微弧氧化、涂层处理)等,也未能取得理想的改进效果。
实际开发过程表明,镁基合金虽然力学性能在植入初期能够满足临床需求,但降解速度过快,无法满足临床对支撑力保持时间的要求。在力学性能达到加工和使用的前提下,目前对降解速度控制的较为理想的镁合金“JDBM”的耐蚀性接近高纯镁,大约为0.25mm/a(AZ91D 2.64mm/a,99.99%Mg 0.20mm/a;1cm2:30ml,Immersion corrosion rate)。此外,镁基合金降解产物(Mg2+,偏碱性)对周围环境的pH会产生影响,不利于组织正常功能的恢复,甚至可能引发溶血反应,因而限制了其在医疗器械领域的应用。与镁基合金相反,铁基合金作为可降解植入材料,其降解速度过慢(0.012mm/a;1cm2:25ml,Immersion corrosionrate),过慢的降解速度违背了可降解支架设计的初衷,且其降解产物(Fe3O4、Fe3(PO4)2等)会引发的钙化和炎症,因此可降解铁支架在心血管支架领域及其他领域一直也未有成功应用的报道。
锌的降解产物(Zn2+)对人体无毒害,且是人体必需的金属元素(摄入量约为15mg/天)之一,参与构成多种蛋白及300余种酶反应,且Zn2+/Zn标准电极电势为-0.7618V,大于Mg2+/Mg(-2.372V)而小于Fe2+/Fe(-0.447V)和Fe3+/Fe(-0.037V),这意味着锌的化学反应活性介于铁和镁之间。降解实验也表明锌的降解时间位于金属镁和铁之间(99.95%Fe0.105mm/a,99.99%Zn 0.325mm/a,99.9%Mg 1.94mm/a,ASTM_G31-1972方法)。
但是,纯锌的力学强度较低,无法直接应用于植入性医疗器械。公开号为CN104587532A的专利申请中公布了一种含有Mg的锌基合金,该合金成分中含Mg0.002-4wt%,余量为锌,并要严格控制其他金属(如Fe、Al、Mn等)杂质的含量。该专利申请中引入镁的主要目的是为了改善锌的力学性能,但仍未解决镁的降解对植入物周围组织环境pH的影响可能给机体带来的损害。公开号为CN103736152A的专利申请中公布了一种含有Ce、Mg、Ca、Cu的锌基合金,该材料中引入了多种金属元素,也是为了改善锌的力学性能,但这些金属元素会给体内植入带来诸多不确定性和安全隐患。
因此,对于血管支架而言,植入后受损部位的再内皮化进程是否顺利是影响PCI(经皮冠状动脉介入治疗)预后及支架有效性、安全性的重要指标。同时具有内皮促进功能与良好力学性能的可降解金属支架是本领域研究的重点。
发明内容
本发明的目的是针对现有技术中存在的技术缺陷,提供一种可降解的锌基合金植入材料在制备血管支架中的应用,所述锌基合金植入材料按质量百分含量,包括0.01wt%-14.0wt%Fe,0wt%-13.0wt%Cu和余量的Zn;优选的,所述血管支架可作为外周血管支架和/或冠脉血管支架。
所述锌基合金植入材料按质量百分含量,包括0.5wt%-14wt%Fe和余量的Zn。
所述锌基合金植入材料按质量百分含量,包括14wt%Fe,0.01wt%-3.0wt%Cu和余量的Zn。
所述锌基合金植入材料按质量百分含量,包括0.01wt%-2wt%Fe(优选0.1wt%-2wt%),0.01wt%-2wt%的Cu和余量Zn;优选的,包括1wt%Fe、1wt%Cu和余量Zn。
所述锌基合金植入材料中Zn、Fe和Cu的纯度要大于99.99%,杂质总含量≤0.01%。
所述锌基合金植入材料表面涂覆有抗增生药物的药物涂层。
所述抗增生药物为紫杉醇或其衍生物、雷帕霉素或其衍生物。
所述药物涂层为含有抗增生药物的可降解聚合物层;所述可降解聚合物为聚乳酸、聚左旋乳酸、聚内酯、聚碳酸酯、聚氨基酸、壳聚糖、磺化壳聚糖中一种或几种。
所述锌基合金植入材料的制备方法为:按质量百分含量,将Zn,Fe和Cu混合后置于高纯石墨坩埚中,在SF6和CO2的混合气体气氛下熔炼,拉拔、退火,得到所述锌基合金植入材料。
所述血管支架的制备方法为:按质量百分含量,将Zn,Fe和Cu混合后置于高纯石墨坩埚中,在SF6和CO2的混合气体气氛下熔炼,拉拔、退火,得到管状的所述锌基合金植入材料;再经激光雕刻、抛光、喷涂药物涂层、压握,得到所述血管支架。
与现有技术相比,本发明的有益效果是:
(1)本发明将铁作为锌基合金植入材料的主要成分引入,是为了通过在锌-铁之间形成微电极,微电极牺牲阳极保护阴极,铁的活性低,会优先降解锌,即保护铁降解锌从而调节锌组分的降解速率;
(2)铁的引入还能显著改善锌基合金植入材料的力学性能,使植入材料易于加工成型且强度、塑性等性能符合血管支架的基本要求;
(3)本发明中对功能性元素铜的引入,可使锌基合金植入材料具备如下功能:
①铜的降解产物Cu2+具有一定的抗菌作用,能够防止以器械为中心的感染(BCI);
②铜的降解产物Cu2+能够促进内皮型一氧化氮合酶(eNOS)的分泌,维持血管内皮完整和内皮细胞功能;有利于刺激VEGF(血管内皮生长因子)的分泌,促进血管内皮细胞增值和迁移,因此能够促进植入部位的快速再内皮化及血管内皮正常功能的恢复和维持、诱导血管新生。
附图说明
图1所示为实施例1的锌基合金植入材料用于冠脉血管支架时的形状示意图;
图2所示为实施例1的锌基合金植入材料的雕刻花型放大图;
图3所示为实施例1的锌基合金植入材料用作血管支架的冠脉造影图;
图4所示为实施例1的锌基合金植入材料用作血管支架的切片HE染色图。
具体实施方式
本发明提出的可用作血管支架的锌基合金植入材料为可降解材料,按质量百分含量,包括Zn 73wt%-99.99wt%,Fe 0.01wt%-14wt%,和Cu 0wt%-13wt%(优选0wt%-5wt%)。锌基合金植入材料中优选Fe 0.01wt%-2wt%,Cu 0.01wt%-2wt%,余量为Zn;更优选,Fe 1wt%,Cu 1wt%,余量为Zn,杂质总量<0.01wt%。其中,锌、铁和铜的纯度要大于99.99%,杂质的总含量要≤0.01%;尤其要避免杂质Al的混入,因为Al和Fe会形成Fe-Al金属间化合物,影响后续加工(主要是抛光)的进行。
制备本发明可降解的锌基合金植入材料的方法,包括以下过程:
按质量百分含量,将Zn和Fe,或Zn、Fe和Cu混合均匀后置于高纯石墨坩埚中,在SF6和CO2的混合气体气氛下熔炼,拉拔、退火,即得到所述锌基合金植入材料;最后再加工成所需的形状即可使用。
本发明提供的锌基合金植入材料可用作血管支架,尤其是用作外周血管支架和/或冠脉血管支架。制备血管支架的方法为:将上述制备得到的锌基合金植入材料加工成管状,再经激光雕刻、抛光、喷涂药物涂层、压握得到血管支架,如图1所示。
以下结合具体实施例,更具体地说明本发明的内容,并对本发明作进一步阐述,但这些实施例绝非对本发明进行限制。
下述实施例中所用方法如无特别说明均为常规方法。所述百分比如无特别说明均为质量百分比含量。
实施例1:锌-铁-铜合金
本实施例的可降解的锌基合金植入材料为锌-铁-铜合金,制备过程具体包括如下步骤:
1)按质量百分含量,将1wt%的Fe、1wt%的Cu和余量的Zn(杂质总含量<0.001wt%)在保护气体SF6(1vol.%)和CO2氛围中,加入高纯石墨坩埚中混合、熔炼,得到锌基合金。
2)熔炼后,将得到的锌基合金挤压成直径为10mm、长度为50cm的棒材。
3)将所得棒材在经多次退火(温度200℃-500℃,30min)、拉拔成外径为0.15mm±0.013mm、壁厚为0.1mm±0.013mm的管材,设计花型为3.0×20的支架,经飞秒激光雕刻成型(雕刻花型见图1),电化学抛光法去除材料棱角使其光滑,拟用于冠脉血管支架。制备成的支架平台杆宽为0.1mm、空白比表面积为20%,雕刻花型放大图见图2。
4)最后用喷涂或浸渍等方法在支架表面涂覆药物涂层,压握到输送系统、灭菌、包装制成冠脉血管支架;药物可选自雷帕霉素及其衍生物或紫杉醇及其衍生物,涂层选用制备而成。
效果验证:
上述方法制备得到的锌基合金植入材料,其屈服强度约为243MPa,抗拉强度约为264MPa,延伸率达到22%,能够适应支架压卧和撑开的加工和使用过程,是一种力学性能较为理想的冠脉血管支架材料。制备成的冠脉血管支架按标称直径撑开后压缩至90%,支撑力为1.8N,符合临床使用要求;按照ASTM_G31-72方法测得的降解速率为0.23mm/a;依据GB16886系列方法检测血液相容性,溶血率为1%,低于标准规定值5%;细胞毒性反应为Ⅰ级、无皮内刺激,致敏率0%。
按照QB/T2591-2003《抗菌塑料抗菌性能实验方法和抗菌效果》附录A进行抗细菌性能测试,对金黄色葡萄球菌和大肠埃希氏菌的抗细菌率分别为92%和94%,按标准中5.1表1判定为“有抗细菌作用”。
将上述血管支架装载到输送系统后用于动物模型(上海白猪,雄性去势,23kg)中,并观察其冠脉造影和1个月切片HE染色结果,如图3和图4所示。由图可知,本发明的锌基合金植入材料作为血管支架具有良好的显影性、通过性。分析发现,该血管支架植入后未见慢性炎症(间歇性免疫反应的诱因)、支架内血栓和支架杆断裂等问题,因此该锌基合金植入材料可作为一种前景广阔的可降解血管支架材料。
实施例2:锌-铁-铜合金
本实施例的可降解的锌基合金植入材料为锌-铁-铜合金,其中含有铁0.14wt%,铜1.8wt%,余量为锌,杂质总含量<0.001wt%,制备过程同实施例1。
效果验证:
上述方法制备得到的锌基合金植入材料,其屈服强度约为210MPa,抗拉强度约为240MPa,延伸率达到22%,能够适应支架压卧和撑开的加工和使用过程,是一种力学性能较为理想的冠脉血管支架材料。制备成的冠脉血管支架按标称直径撑开后压缩至90%,支撑力为1.8N,符合临床使用要求;按照ASTM_G31-72方法测得的降解速率为0.19mm/a;依据GB16886系列方法检测血液相容性,溶血率为1%,低于标准规定值5%;细胞毒性反应为Ⅰ级、无皮内刺激,致敏率0%。
实施例3:锌-铁-铜合金
本实施例的可降解的锌基合金植入材料为锌-铁-铜合金,其中含有铁2.0wt%,铜0.1wt%,余量为锌,杂质总含量<0.001wt%,制备过程同实施例1。
实施例4:锌-铁-铜合金
本实施例的可降解的锌基合金植入材料为锌-铁-铜合金,其中含有铁10.0wt%,铜2.0wt%,余量为锌,杂质总含量<0.001wt%,制备过程同实施例1。
实施例5:锌-铁-铜合金
本实施例的可降解的锌基合金植入材料为锌-铁-铜合金,其中含有铁12.0wt%,铜3.0wt%,余量为锌,杂质总含量<0.001wt%,制备过程同实施例1。
实施例6:锌-铁-铜合金
本实施例的可降解的锌基合金植入材料为锌-铁-铜合金,其中含有铁5.0wt%,铜3.0wt%,余量为锌,杂质总含量<0.001wt%,制备过程同实施例1。
实施例7:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁1.4wt%,余量为锌,杂质总含量<0.001wt%,制备过程同实施例1。
实施例8:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁0.7wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
实施例9:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁0.35wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
实施例10:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁0.2wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
实施例11:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁14wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
实施例12:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁10wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
实施例13:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁2wt%,铜2wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
实施例14:锌-铁合金
本实施例的可降解的锌基合金植入材料为锌-铁合金,其中含有铁0.5wt%,余量为锌,杂质总含量<0.001%,制备过程同实施例1。
比较例1(Fe高于14%的锌-铁-铜合金):按本发明的制备方法制备得到锌基合金植入材料,其中含有16wt%的铁,1wt%铜,余量为锌。
比较例2(Fe低于0.1%的锌-铜合金):按本发明的制备方法制备得到锌基合金植入材料,其中含有1wt%铜,0.001%铁余量为锌。
比较例3(功能性元素如Cu高于13%的锌-铁-铜合金):按本发明的制备方法制备得到锌基合金植入材料,其中含有14wt%铜,1wt%铁,余量为锌。
比较例4(无Fe的现有技术锌基合金):按照已经公开专利申请CN103736152A中的方法制备得到的锌基合金植入材料,其中含有
0.1wt%Ce,0.5wt%Mg,0.1wt%Ca,1.5wt%Cu,其余为Zn。
比较例5(Fe高于14%的锌-铁合金):按本发明的制备方法制备得到锌基合金植入材料,其中含有17wt%的铁,余量为锌。
比较例6(无Fe的锌材料):按本发明的制备方法制备得到锌基合金植入材料,其中只含有锌,其中含有1wt%的铜,不含有别的元素。
实施例1-14的锌基合金植入材料拟用于血管支架的制备,其力学性能和腐蚀性能((ASTM-G31-72),Hank’s模拟体液,37℃)见表1。比较例1-6的力学性能和腐蚀性能也见表1。
表1实施例1-14的力学性能和腐蚀性能
表1的结果表明,本发明的可降解的锌基合金植入材料无论是力学强度(屈服强度、抗拉强度)还是弹性性能(弹性模量)和延伸性能(延伸率),都满足该材料作为血管支架植入体内作为支撑以及加工性的要求。此外,该材料的降解速度(腐蚀速度)理想(0.16mm/a-0.45mm/a),可以作为可降解的体内植入材料使用。按照ISO10993方法测试,实施例1-14的材料细胞毒性均为2级,为无明显的细胞毒性,无皮内刺激,无致敏和遗传毒性。
与本发明的锌基合金植入材料相比,比较例1-6的材料要么力学强度太低无法起到应有的支撑效果(如比较例2),要么延伸率太小无法适应器械加工及使用过程的形变(如比较例1、比较例2、比较例4和比较例5),要么降解速度过慢无法满足临床对材料降解的要求(如比较例3、比较例5和比较例6)。
以上所述仅是本发明的优选实施方式,应当指出的是,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种可降解的锌基合金植入材料在制备血管支架中的应用,其特征在于,所述锌基合金植入材料按质量百分含量,包括0.01wt%-14.0wt%Fe,0wt%-13.0wt%Cu和余量的Zn;优选的,所述血管支架可作为外周血管支架和/或冠脉血管支架。
2.根据权利要求1所述应用,其特征在于,所述锌基合金植入材料按质量百分含量,包括0.5wt%-14wt%Fe和余量的Zn。
3.根据权利要求1所述应用,其特征在于,所述锌基合金植入材料按质量百分含量,包括14wt%Fe,0.01wt%-3.0wt%Cu和余量的Zn。
4.根据权利要求1所述应用,其特征在于,所述锌基合金植入材料按质量百分含量,包括0.01wt%-2wt%Fe(优选0.1wt%-2wt%),0.01wt%-2wt%的Cu和余量Zn;优选的,包括1wt%Fe、1wt%Cu和余量Zn。
5.根据权利要求1-4任一所述应用,其特征在于,所述锌基合金植入材料中Zn、Fe和Cu的纯度要大于99.99%,杂质总含量≤0.01%。
6.根据权利要求1-5任一所述应用,其特征在于,所述锌基合金植入材料表面涂覆有抗增生药物的药物涂层。
7.根据权利要求6所述应用,其特征在于,所述抗增生药物为紫杉醇或其衍生物、雷帕霉素或其衍生物。
8.根据权利要求6或7所述应用,其特征在于,所述药物涂层为含有抗增生药物的可降解聚合物层;所述可降解聚合物为聚乳酸、聚左旋乳酸、聚内酯、聚碳酸酯、聚氨基酸、壳聚糖、磺化壳聚糖中一种或几种。
9.根据权利要求1-8任一所述应用,其特征在于,所述锌基合金植入材料的制备方法为:按质量百分含量,将Zn,Fe和Cu混合后置于高纯石墨坩埚中,在SF6和CO2的混合气体气氛下熔炼,拉拔、退火,得到所述锌基合金植入材料。
10.根据权利要求1-9任一所述应用,其特征在于,所述血管支架的制备方法为:按质量百分含量,将Zn,Fe和Cu混合后置于高纯石墨坩埚中,在SF6和CO2的混合气体气氛下熔炼,拉拔、退火,得到管状的所述锌基合金植入材料;再经激光雕刻、抛光、喷涂药物涂层、压握,得到所述血管支架。
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CN106913916B (zh) | 2020-08-25 |
EP4079341A3 (en) | 2022-11-23 |
CN106890356B (zh) | 2020-07-24 |
CN106890356A (zh) | 2017-06-27 |
EP4079341A2 (en) | 2022-10-26 |
EP3427763B1 (en) | 2022-08-10 |
CN106955376B (zh) | 2020-07-10 |
CN106955376A (zh) | 2017-07-18 |
WO2017152878A1 (zh) | 2017-09-14 |
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