CN103877624B - 一种可降解聚酯支架及其制备方法 - Google Patents
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Abstract
本发明属于医疗器械领域,具体涉及一种可降解聚酯支架及其制备方法。本发明的可降解聚酯支架包括聚酯复合材料,其中聚酯复合材料由生物可降解聚酯材料和金属基材料制成。本发明方法提高了可降解聚酯支架的力学性能,并且实现了支架主体及整体的显影。
Description
技术领域
本发明属于医疗器械领域,具体涉及一种可降解聚酯支架及其制备方法。
背景技术
支架作为治疗血管狭窄的重要器械已经在心血管疾病领域得到了越来越广泛的应用。目前临床上的金属支架,由于其在完成治疗任务后将永久存留于人体,存在削弱冠状动脉的MRI或CT影像、干扰外科血运重建、阻碍侧枝循环的形成、抑制血管正性重塑等缺陷。生物可降解支架作为可能的一种替代解决方案引起了人们的普遍关注。
生物可降解支架由可降解的聚合物材料或金属材料制成,在植入病变位置后可以在短期内起到支撑血管的作用,实现血运重建。在治疗完成以后,生物可降解支架在人体环境内会降解成为可被人体吸收、代谢的有机物,最终该支架会消失。
常见的可用于支架制备的可降解聚合物材料有聚乳酸、聚乙醇酸、聚己内酯等;可降解金属材料有镁合金、铁基合金等。镁和铁均是生物体中不可缺少的微量元素,具有良好的生物相容性、独特的降解吸收功能、优异的综合力学性能及加工成形性能。
但是,应用过程中发现,聚合物支架的力学性能普遍低于金属支架,支架尺寸较大,且具有较金属支架明显的血管内管腔丢失、局部炎症反应和内膜增生现象,同时支架不具有显影性。而镁合金支架的降解速度太高,导致镁支架在体内的力学强度衰减速率过快,影响治疗效果;铁基合金支架虽然力学性能满足支架要求,但铁支架的腐蚀速度难以控制,同时在模拟体液下和人体环境中的降解腐蚀机理不明,从而限制了铁基支架作为心血管支架的应用。
为了解决镁支架过快降解的问题,美国专利申请US2009240323A1公开了一种在镁支架表面进行可降解聚合物涂层的方法,能够实现镁支架的可控降解。但是需要实现致密的聚合物涂层,以避免体液从可降解聚合物涂层渗透进入镁支架导致镁支架内部发生降解。
为了解决可降解聚合物支架力学性能较弱的问题,美国专利申请US20110015726公开了一种将陶瓷材料作为增强剂,加入可降解材料中,提高可降解支架的力学性能。但陶瓷材料在血液中的降解机理不甚清楚,同时材料的韧性会有显著下降。另一美国专利申请US2009248147A1公开了一种将均聚物和无机盐作为成核剂,加入可降解共聚材料中,提高可降解共聚物支架的力学性能。但共聚物本身的结晶速率就低于均聚物,加入成核剂对支架的力学强度提高并不显著。
为了解决显影问题,美国专利申请US2009149940A1公开了一种在支架表面覆盖一层带有显影微粒的显影层,实现支架整体显影。但显影层的力学强度较低,且显影效率较差,且可能存在与支架主体层的结合紧密等缺陷。
此外,中国专利申请CN102532835A公开了一种通过溶液共混制备聚乳酸/镁复合材料,进而浇注成型制备支架。该方法利用镁作为无机增强介质,提高聚乳酸支架力学性能,并中和聚乳酸降解产生的酸性物质。但是,由于镁的强度并不比聚乳酸高很多,且两者界面相容性不佳,因而力学性能提高有限,并且没有有效利用聚乳酸的结晶性能,导致支架的力学强度偏低。
由此可见,现有技术对性能更佳的可降解支架仍有需求。
发明内容
本发明提供一种可降解聚酯支架及其制备方法,将可降解金属基粉末材料分散于聚酯基体中,从而提高了聚酯材料的结晶性能,并作为增强剂提高了支架的力学性能。可降解金属释放产生的金属离子能预防或抑制血管再狭窄的发生,同时有些可降解金属还具有显影能力,从而改善了聚酯支架的显影性。
具体而言,本发明涉及一种可降解聚酯支架,包括聚酯复合材料,其中聚酯复合材料由生物可降解聚酯材料和金属基材料制成。
根据本发明,生物可降解聚酯材料包括但不限于如下材料中的一种或多种:聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸-乙醇酸共聚物(PLGA)、聚己内酯(PCL)、聚三亚甲基碳酸酯(PTMC)、聚酯酰胺、聚丁二酸丁二醇酯(PBS)、聚羟基丁酸戊酯(PHBV)、聚乙酰谷氨酸和聚正酯(POE)等聚酯材料;
根据本发明,金属基材料包括但不限于如下材料中的一种或多种:纯镁,纯铁,镁基合金,镁盐化合物,铁基合金等;其中铁基材料可以提高支架的显影能力。
根据本发明,金属基材料在支架中的比例按重量百分比计为0.1~20%,其余为生物可降解聚酯材料。
根据本发明,金属基材料的形状为粉末,其粒径介于10nm-10μm之间。
本发明还涉及可降解聚酯支架的制备方法,其特征在于将金属基材料分散于聚酯基体中,制备成聚酯复合材料,经过挤出成型、后处理和切割制备成支架,包括下列步骤:
将金属基粉末材料通过溶液共混、熔融共混或机械共混等方式加入至聚酯基体中,制备成聚酯复合材料;
为使金属基粉末材料能均匀分散在聚酯基体中,提高粉末和聚酯基体的相容性,优选可对金属粉末进行表面改性,如羟基改性,有机官能团接枝等;
形成的聚酯复合材料在高于该材料熔点以上的温度通过螺杆挤出加工成管材形状,其中金属基材料作为增强介质,提高聚酯材料的力学强度;
管材切割成支架,或者管材经过处理后再切割成支架,其中所述管材处理包括退火、吹胀、拉伸等管材处理方式中的一种或多种的组合,其目的是进一步提高管材的强度、韧性、结晶度等性能。
为提高管材的结晶度,管材处理的温度优先选择在聚酯的玻璃化转变温度-熔点之间。
本发明与现有技术的区别在于聚酯复合材料的组成、支架的制备方法以及支架的性能。本发明方法可以提高可降解聚酯的结晶能力,进而提高聚酯及支架的力学性能;本发明方法提供的支架成型工艺简单,可操作性强,可实现产量化生产。本发明支架具有优异的生物相容性,有些支架具有较好的显影效果,可以实现支架主体及整体显影。
附图说明
为了更清楚地描述本发明的技术方案,下面将结合附图作简要介绍。显而易见,这些附图仅是本申请记载的一些具体实施方式。本发明包括但不限于这些附图。
图1示出了本发明最终得到的支架的结构图;以及
图2示出了金属基颗粒均匀分布在聚酯基体中示意图,其中1代表金属颗粒,2代表聚酯基体。
具体实施方式
为了进一步理解本发明,下面将结合实施例对本发明的优选方案进行描述。这些描述只是举例说明本发明可降解聚酯支架的特征和优点,而非限制本发明的保护范围。
实施例1
将一定量的纳米铁粉(4-8g,粒径小于10μm)加入至500~1000ml的二氯甲烷溶液中,溶液搅拌并超声使得纳米铁粉均匀分散在溶液中,继续加入重均分子量30万的聚左旋乳酸粒子96~192g,完全溶解并搅拌均匀,经过冷冻干燥后粉碎成粒子,得到聚乳酸/铁复合材料,其中纳米铁粉占复合材料的重量百分比为4%。
将聚乳酸/铁复合材料进行单螺杆挤出加工成管材,管材的外径1.8mm,内径0.5mm。得到的管材拉伸强度70MPa,弹性模量2.5GPa,高于同样尺寸的聚乳酸管材。
将得到的管材在70°C吹塑成管材,管材外径3.30mm,内径3.05mm。
将得到的管材通过激光切割成支架并压握在输送系统的球囊上。得到的支架径向抗挤压强度150kPa,结晶度54%,高于同样尺寸的聚乳酸支架。
将支架包装后灭菌,手术时通过输送系统将支架送到血管的狭窄病变位置,对球囊进行充盈加压,扩张支架,从而撑开狭窄的血管。植入后没有观察到明显炎症反应,植入6个月后,观察到血管内皮化,植入2年后支架完全降解。
在整个手术过程中,通过X光机可看到整个支架的清晰轮廓。植入1周天后,发现支架在X光下的显影性明显降低,支架在X光下变得模糊。植入1个月后,支架在X光下不显影,说明支架内的显影材料已经代谢完毕。在此一个月中,未发现明显的炎症反应。支架植入6个月后,观察到血管内皮化,部分支架波杆被血管内皮包裹,此时支架内层已经降解完毕,没有对内皮细胞产生不良影响。
实施例2
将100g氧化镁粉末(粒径≤100nm)和900g聚乙醇酸(重均分子量40万)在180-220°C通过双螺杆挤出机共混并加工,得到聚乙醇酸/氧化镁复合材料管材,其中镁合金在复合材料中的重量百分比为10%。管材外径2.8mm,内径2.5mm。将管材在120°C下退火1小时,得到的管材拉伸强度70MPa,弹性模量3.5GPa,高于同样尺寸的聚乙醇酸管材。
将得到的管材通过激光切割成支架并压握在输送系统的球囊上,得到的支架径向抗挤压强度120kPa,结晶度63%,高于同样尺寸的聚乙醇酸支架。
将支架包装后灭菌,手术时通过输送系统将支架送到血管的狭窄病变位置,对球囊进行充盈加压,扩张支架,从而撑开狭窄的血管。植入后没有观察到明显炎症反应,植入6个月后,观察到血管内皮化,植入1年后支架完全降解。
本发明与现有技术相比,具有以下优点和效果:
(1)金属基材料分散于聚酯基体中,提高了聚酯材料的力学性能,进而提高了聚酯支架的力学强度;
(2)金属基材料均匀分散于聚酯基体中,在聚酯管材吹塑过程中作为成核剂,提高了聚酯材料的结晶能力,延长了聚酯材料的降解时间和提高聚酯材料的力学性能;
(3)在聚酯支架的降解过程中,镁降解产生的镁离子能抑制聚酯降解过程中产生的炎症反应,进一步预防血管再狭窄;
(4)在聚酯支架的降解过程中,释放的铁离子通过影响相关基因表达减小血管平滑肌细胞的增殖,进一步对抗血管再狭窄;
(5)铁合金材料在聚酯支架中,提高了聚酯支架的显影能力,聚酯支架在X下具有显影性;
(6)金属颗粒可以分散支架中的应力,提高支架的疲劳寿命。增强后的聚酯具有较高的模量和较低的柔量,有效降低了支架植入血管后的蠕变形变。
以上实施例的说明只是用于帮助理解本发明的核心思想。应当指出,对于本领域的普通技术人员而言,在不脱离本发明原理的前提下,还可以对本发明方法进行若干改进和修饰,但这些改进和修饰也落入本发明权利要求请求保护的范围内。
Claims (8)
1.一种可降解聚酯支架,包括聚酯复合材料,其中聚酯复合材料由生物可降解聚酯材料和金属基粉末材料制成,金属基粉末材料选自纯铁和铁基合金,其中所述支架通过包括下列步骤的方法制备:
将金属基粉末材料通过溶液共混、熔融共混或机械共混方式加入至聚酯基体中,制备成聚酯复合材料;
上述聚酯复合材料在高于其熔点以上的温度通过螺杆挤出加工成管材;
管材经处理后再切割成支架,其中管材处理包括退火、吹胀、拉伸方式中的一种或多种的组合。
2.权利要求1的可降解聚酯支架,其中生物可降解聚酯材料选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸-乙醇酸共聚物(PLGA)、聚己内酯(PCL)、聚三亚甲基碳酸酯(PTMC)、聚酯酰胺、聚丁二酸丁二醇酯(PBS)、聚羟基丁酸戊酯(PHBV)、聚乙酰谷氨酸和聚正酯(POE)。
3.权利要求1或2的可降解聚酯支架,其中金属基粉末材料在聚酯复合材料中的比例按重量百分比计为0.1~20%,其余为生物可降解聚酯材料。
4.权利要求1或2的可降解聚酯支架,其中金属基粉末材料的粒径介于10nm-10μm之间。
5.权利要求1-4任一项的可降解聚酯支架的制备方法,包括下列步骤:
将金属基粉末材料通过溶液共混、熔融共混或机械共混方式加入至聚酯基体中,制备成聚酯复合材料;
上述聚酯复合材料在高于其熔点以上的温度通过螺杆挤出加工成管材;
管材经处理后再切割成支架,其中管材处理包括退火、吹胀、拉伸方式中的一种或多种的组合。
6.权利要求5的制备方法,其中对金属基粉末材料进行表面改性。
7.权利要求6的制备方法,其中对金属基粉末材料进行表面改性是羟基改性和/或有机官能团接枝。
8.权利要求5-7任一项的制备方法,其中管材处理的温度在聚酯的玻璃化转变温度-熔点之间。
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CN108453927A (zh) * | 2018-02-08 | 2018-08-28 | 西安交通大学 | 一种可生物降解PCL/Mg复合材料FDM耗材的制备工艺 |
CN108939164A (zh) * | 2018-06-15 | 2018-12-07 | 南京冬尚生物科技有限公司 | 3D打印PCL-Mg骨组织工程支架及其制备方法 |
CN109567990B (zh) * | 2018-12-07 | 2023-07-21 | 上海百心安生物技术股份有限公司 | 一种可降解支架及其制造方法 |
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