CN107811669B - 用于神经介入手术的微导管 - Google Patents
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Abstract
本发明涉及一种用于神经介入手术的微导管，所述微导管至少包含同轴设置的中心通道和外围通道，中心通道为可显影液体栓塞剂通路，外围通道为有粘度的水溶液通道，以实现可显影液体栓塞剂在微导管内的螺旋化和固化。该技术将微流控技术、液体栓塞剂技术以及微导管技术相结合，该技术可实现液体栓塞剂于微导管内固化，形成螺旋米线状的可显影的填塞“聚合物弹簧圈”。该聚合物“弹簧圈”可应用于颅内动脉瘤填塞手术。
Description
技术领域
本发明涉及神经介入手术器械领域，更具体地说，涉及一种将微流控技术、液体栓塞剂技术以及微导管技术相结合的新技术，该技术可实现液体栓塞剂于微导管内固化，形成螺旋米线状的可显影的填塞“聚合物弹簧圈”。
背景技术
由于机械损伤、血管硬化、高血压、血管平滑肌细胞的增生、细菌或病毒感染、静脉瓣疾病的诱导或血流冲击等内外因素的作用，在动静脉血管中会形成血管瘤。血管瘤分为动脉瘤和静脉瘤，其中，产生在颅内的具有圆凸壁的动脉瘤，被称作大脑动脉瘤。大脑动脉瘤在破裂时极易诱发蛛网膜下出血，从而导致病患中风；甚至，80％或者更多的病人在复发大脑动脉瘤破裂后会死亡。因此，尽可能的在大脑动脉瘤出现的较早阶段进行栓塞或者封堵成为最佳的治愈手段。
在栓塞大脑动脉瘤的方法中，一般采用外科手术对已经形成的动脉瘤进行封堵，包括针对动脉瘤母动脉的剪断、结扎和采用动脉瘤夹将动脉瘤颈夹住，从而阻断血液对动脉瘤的冲击。但是，这种方法耗时较长且有可能造成动脉瘤的破损。近年来，随着血管影像学的发展，采用介入手术方法，通过将各种栓塞材料输送至大脑动脉瘤内以封堵、栓塞动脉瘤已经渐渐代替了传统的外科手术。然而，采用贵金属弹簧圈的方法的栓塞率较低、容易形成大范围的血栓而引起大脑梗塞等。并且通常来说，一台动脉瘤填塞手术，平均需要4-5个弹簧圈。弹簧圈费用几万到十几万不等。对于病人和病人家庭无疑是一个巨大的负担。
目前已经公开了多种动脉瘤填塞材料，主要分为固体栓塞材料如贵金属弹簧圈和液体栓塞材料两类。液体栓塞材料可以直接注入动脉瘤瘤腔内，适应不同形状和大小的动脉瘤腔，使瘤壁和栓塞材料之间不留任何空隙，从而达到永久性闭塞。如EV3公司的OnyxHD500就是一款专门针对动脉瘤填塞的液体栓塞剂。Onyx胶组成非常简单，它由聚乙烯醇聚乙烯共聚物EVOH，二甲基亚砜DMSO溶剂和微米级钽粉Ta组成。其中Onyx18和Onyx34在脑动静脉畸形(AVM)的栓塞中普遍被使用。因为它允许医生长时间注射,具有更好的弥散性和更高的栓塞率,自显影性，且具有非粘附的特点。然而Onyx HD500应用于颅内动脉瘤填塞的液体栓塞材料却因为其使用复杂，操作繁琐。需要用球囊对载瘤动脉的瘤口进行保护，防止液体胶跑到动脉瘤外。且要多次的充盈和收缩的操作。即便如此依然有可能会存在液体胶跑出动脉瘤的危险发生。所以该款产品基本已经停止销售。
微流控(Microfluidics)指的是使用微管道(尺寸为数十到数百微米)处理或操纵微小流体(体积为纳升到阿升)的系统所涉及的科学和技术，是一门涉及化学、流体物理、微电子、新材料、生物学和生物医学工程的新兴交叉学科。微流控的重要特征之一是微尺度环境下具有独特的流体性质，如层流和液滴等。借助这些独特的流体现象，微流控可以实现一系列常规方法所难以完成的微加工和微操作。主要的流体现象有液滴和层流。
1，微流控技术之液滴
当两相不互溶的液体(油和水)在微流控通道中流动时，在液/液界面张力和剪切力的作用下，其中一相流体会形成高度均一的间断流，即液滴。在乳液制备的方法中，如果说基于搅拌的方法是自上而下的，那么微流控则是自下而上的方法。微流控能够以非常高的通量制备高度单分散性的液滴乳液。常见的微通道结构为T型和ψ型。在某些情况下，含有不同高分子聚合物的水相液体在微流控通道中也会形成不互溶的液滴。基于这一方法，华中科技大学的刘珊珊等人制备了介入治疗用自显影血管栓塞聚合物微球。她们以海藻酸钠水溶液为分散相、以含有原位生成的CaCl2纳米粒的液体石蜡为连续相,基于液滴型微流控技术结合预交联法,制得了粒径可控且单分散、球形度好的海藻酸钙凝胶微球。方法可通过改变微流控装置构造尺寸和连续相与分散相的流速比,调控凝胶微球尺寸在40μm～700μm间。所得到的微球粒径分布均一,且具有很好的X-射线显影性。
2，微流控技术之层流
层流与湍流相对应，是指流体的层状流动，其流线与管壁相互平行。在粘性力远远大于惯性力，或雷诺数(Reynold number)小于3000时，层流就会出现。当几相不同颜色的流体从不同的入口进入同一个微通道时，即使它们互溶，也会形成层次分明的多相平行流动。利用层流的这种几何规律性，可以实现材料、化学环境和细胞在微通道中的有序排布。
发明内容
本发明有如下技术要点和要素：
此用于神经介入治疗的微导管为两段式设计。如图3所示，其近端段具有同轴双腔结构，有外腔3-1和内腔3-2。而在远端段为单腔体结构，聚合物“弹簧圈(3-3)可以再这一段固化，或者螺旋化。
要形成X显影可见的“聚合物弹簧圈”内腔溶液必须为本身具有显影性的液体栓塞剂。
外腔溶液为有一点剪切粘度的水溶液，外腔溶液和内腔溶液在远端单腔段形成层流流体，并且使内腔溶液的液体栓塞剂逐渐固化。
近端段具有同轴双腔结构，根据经验，优选设计为外腔(1-1和4-1)为正方形结构，优选内腔(1-2和4-2)为圆形结构。如图1和图4所示。
本发明将微流控技术，液体栓塞剂技术和微导管技术相结合，优选液体栓塞剂为可显影液体栓塞剂，更优选非粘性可显影液体栓塞剂。由此实现了将液体栓塞剂直接转变为X显影可见“聚合物弹簧圈”。该“聚合物弹簧圈”可针对颅内动脉瘤实现密堆积的填塞。
在填塞过程中可随时停止内腔溶液的注射，保留外腔溶液的注射流速，实现类似贵金属弹簧圈解脱过程。操作简单，过程可控性好。
附图说明
下面将结合附图及实施例对本发明作进一步说明，附图中：
图1，微导管横切面示意图；
图2：微流控纵切面照片；
图3：微导管纵切面及“聚合物弹簧圈”形成示意图；
图4微流控制备螺旋型聚合物“弹簧圈”示意图；
图5：聚合物“弹簧圈”显微镜照片。
具体实施方式
以下结合具体实施例的具体实施方式
对本发明的上述内容作进一步的详细说明。
本发明正是基于微流控之层流流体形态，将液体栓塞剂技术于之相结合。由此，可以形成一种可注射的“聚合物弹簧圈”。我们对于微导管结构，依照微流控形成层流形态所需的特征进行设计，该设计的微导管有两路进液通道(外腔内腔双腔结构)：中心圆形通道为液体栓塞剂通路，外围方形通道为有粘度的水溶液通道(请参阅图2)。结构的横截面图如图1所示。
可显影液体栓塞剂可由聚乙烯醇聚乙烯共聚物(EVOH)，二甲基亚砜(DMSO)溶剂和微米级钽粉组成。钽粉为显影剂，也可是其它贵金属微米级粉末。聚合物EVOH溶解于DMSO中，但它却不溶解于水。所以当EVOH的DMSO溶液遇到水或者血液时，聚合物就会从DMSO溶剂中沉淀出来。聚合物EVOH沉淀过程会将Ta粉包埋在其形成的胶体固化物中。因其包埋了Ta粉粒子，所以其在X光下可以显影。液体栓塞剂在通过该微导管内就会逐渐固化为聚合物的米线状“填塞弹簧圈”。而且我们可以通过调整微导管的层流段的长度，让其在微导管出来进入人体动脉瘤内时已经充分固化。当动脉瘤填塞完全后，医生只需将内腔通道溶液停止注射，而保留外腔通道的溶液注射。此过程即可视之为弹簧圈的解脱过程。通过这个过程，医生即可用一个液体栓塞剂所形成的“聚合物弹簧圈”达到之前填塞多个贵金属弹簧圈的效果。且填塞更致密，过程更可靠。而且可以很大程度上降低病人的经济负担，因为“聚合物弹簧圈”的成本远低于贵金属弹簧圈。
此外，此用于神经介入治疗的微导管为两段式设计。如图3所示，其近端段具有同轴双腔结构，有外腔3-1和内腔3-2。而在远端段为单腔体结构，聚合物“弹簧圈(3-3)可以再这一段固化，或者螺旋化。
以下对列举例子，对本发明进一步具体描述。1，实验原料与试剂
聚乙烯吡咯烷酮(Mn＝500,0g/mol，分析纯，国药集团化学试剂有限公司)；二甲亚砜(DMSO，分析纯，国药集团化学试剂有限公司)；聚乙二醇(PEG400，Mn＝400g/mol，分析纯，国药集团化学试剂有限公司)；Ta粉(微米-纳米级)(宁夏东方钽业)；EVOH聚合物(台湾长春公司)
2，微流控装置的搭建
单乳液毛细管微流控装置的搭建：将两根圆管分别从方管的两侧插入方管，成一直线排列，并将组装后的管子固定在载玻片上。如图4所示，左侧的圆管作为内相通道，方管左侧作为外相通道，右侧的圆管作为收集区一段(4-3)。圆管子的内径和外径分别是600μm和1.0mm，方管的内径是1.0mm。进口管的末端经拉针器烧细后，再由烧针器将直径截到30μm左右。收集区一段的末端连接一个内径更大的收集区二段(4-4)(具有不同内径的聚四氟乙烯管或者是内径为1mm的方管)。
如图4所示，将EVOH/DMSO/Ta粉的混合溶液和PEG水溶液分别作为内相和外相溶液。两相分别由注射泵注入微流控装置的内外通道中，在收集区一段中形成两相平行的流体。接着两相平行的流体进入一个更宽的收集区二段，在收集区二段中会自发生成螺旋型纤维。其中，图中dj为初始流体的直径；df为收集到的固体纤维的直径；d1为毛细管的内径；d2为收集区二段的内径；λ为螺旋型纤维的波长，l为进口管末端与收集区一段末端之间的距离。在这个过程中，分散相进入收集区一段后，流体中的DMSO开始向连续相液态PEG相迁移。随着DMSO的迁移，内相流体的粘度增大，并且开始收缩。这会导致弹性能和应力的积累，只能通过折叠可以将其释放。同时，通道变宽导致内外相产生速度差，这会对内相流体产生粘性阻力，从而引起卷曲。另外，随着EVOH/DMSO/Ta粉的混合溶液中的DMSO快速向液态PEG相中扩散，内相液体会逐步固化，固化后将维持螺旋的形状。直的流体/纤维转变为螺旋型纤维是由内相的水向外相迁移和通道变宽(收集区一段到收集区二段)的协同作用引起的。需要说明的是，这和之前基于两相水体系，微流控制备微球或者微纤维的报道不同。在这些报道中，他们用的是PEG的水溶液和原位快速交联实现固化。
通过简单地调节内外相的流速、l值及EVOH/DMSO溶液的浓度等，可以制得不同形貌的纤维，包括螺旋型、波浪状和无序卷曲的纤维。对于所有的这些纤维，df/dj均控制在0.5左右(表1)。说明在这一制备过程中，由于水的扩散，液体栓塞剂相的直径减少了～50％。因此，我们可以简单地通过改变内外相的流速来调节流体的初始直径，从而控制最终纤维的直径(表1)。
实施例1-4如表1所示：
表1内外相流速对dj、df和df/dj的影响
实施例5，Qin＝200μL/h，Qout＝5mL/h，d1＝600μm,EVOH/DMSO＝6wt％)，l＝3cm装置。
实施例6，Qin＝200μL/h，Qout＝5mL/h，d1＝600μm,EVOH/DMSO＝6wt％)，l＝6cm装置。
实施例7，Qin＝200μL/h，Qout＝5mL/h，d1＝600μm,EVOH/DMSO＝6wt％)，l＝9cm装置。
实施例8，Qin＝200μL/h，Qout＝5mL/h，d1＝600μm,EVOH/DMSO＝8wt％)，l＝9cm装置。
实施例9，Qin＝200μL/h，Qout＝5mL/h，d1＝600μm,EVOH/DMSO＝10wt％)，l＝9cm装置。
通过以上实施例，微流控所得到的聚合物“弹簧圈”如图5所示。1-9例分别对应5-a到5-i。
Claims (7)
1.一种用于神经介入手术的微导管，其特征在于，所述微导管至少包含同轴设置的中心通道和外围通道，中心通道为可显影液体栓塞剂通路，外围通道为有粘度的水溶液通道，以实现可显影液体栓塞剂在微导管内的螺旋化和固化。
2.根据权利要求1所述的微导管，其特征在于：所述微导管分两段式设计，近端段形成所述中心通道和外围通道，且该外围通道为正方形结构，中心通道为圆形结构；而远端段为单腔导管结构。
3.根据权利要求1所述的微导管，其特征在于：所述可显影液体栓塞剂至少包含水不溶解的聚合物、可显影液体栓塞剂对应的溶剂以及微米化的贵金属粉末三个成分。
4.根据权利要求3所述的微导管，其特征在于：所述液体栓塞剂中还含聚乙烯-聚乙烯醇重复单元的共聚物EVOH。
5.根据权利要求3所述的微导管，其特征在于：所述溶剂是N-甲基吡咯烷酮，或者是N-甲基吡咯烷酮和DMSO的混合溶剂，或者是N-甲基吡咯烷酮、DMSO和无水乙醇的混合溶剂，或者是N-甲基吡咯烷酮和无水乙醇的混合溶剂。
6.根据权利要求3所述的微导管，其特征在于：所述可显影液体栓塞剂进一步包含显影剂，该显影剂是微米化的金属钽粉，或者是微米化的铂金粉末，或者是微米化的铂钨合金粉末。
7.根据权利要求1所述的微导管，其特征在于：该水溶液为聚乙二醇PEG或者是聚乙烯基吡咯烷酮PVP的水溶液。
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