CN107335100A - 一种冠状动脉旁路移植术预防桥血管再狭窄系统 - Google Patents
一种冠状动脉旁路移植术预防桥血管再狭窄系统 Download PDFInfo
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Abstract
本发明提出一种冠状动脉旁路移植术预防桥血管再狭窄系统，包括球囊和球囊内装载的带有氟伐他汀的聚乳酸‑聚乙醇酸共聚物纳米粒子，所述球囊表面上涂布有紫杉醇涂层，球囊的侧壁上开有微孔。针对冠状动脉旁路移植术术后远期影响通畅率的主要因素，即术后中期内膜增生与远期内皮粥样硬化等问题，本发明设计一种冠状动脉旁路移植术预防桥血管再狭窄系统，根据静脉管径选取不同直径的球囊，然后从注射器推入PLGA微球，使肝素、紫杉醇、氟伐他汀复合药物进入动脉血管，提高术后的远期通畅率。
Description
技术领域
本发明属于医疗器械领域，具体涉及一种冠状动脉旁路移植术使用的手术器械。
背景技术
静脉桥作为主要的移植材料被广泛应用于临床，但是其远期通畅率严重影响了CABG(冠状动脉旁路移植术)的远期疗效。对于大隐静脉术后再狭窄的病理基础研究结果显示，其早中晚期再狭窄有不同的表现，具体包括：
(1)早期表现，早期(术后1个月)主要是因为血栓形成，取材、血管吻合过程中的牵拉、夹持等操作不当、用力过大可导致静脉内皮损伤，15％～18％的移植静脉血栓形成可归因于此。同时在刚刚完成血管吻合时大隐静脉内压力的骤然增加会导致静脉内膜损伤，使组织纤维蛋白溶酶原激活剂减少，血栓调节蛋白作用减弱，硫酸乙酰肝素表达减少，这些都能促进血栓形成。
(2)中期表现，中期(术后1个月一1年)纤维增生是主要病理特征。一般内膜增生不会引起显著的狭窄，但是会为血管平滑肌细胞(VSMC)提供增殖条件。在损伤内皮分泌的一系列生长因子、细胞因子的刺激下，巨噬细胞活化，内皮分泌一氧化氮减少，VSMC开始迁移和增殖。其次，移植静脉长期暴露在lO倍压力的动脉环境下，这会持续刺激VSMC增殖。
(3)晚期表现，晚期静脉桥在增生的纤维组织基础上形成粥样斑块，有数据显示静脉桥粥样硬化的速度比自然动脉还要快，斑块也更集中。另外，钙离子也逐渐在斑块内沉积。随着斑块的发展，最后破裂进一步形成血栓，堵塞静脉桥。
目前搭桥术后静脉桥血管再狭窄一直是困扰心脏外科医生的难题，也是影响冠心病患者术后远期生存率的主要因素。目前常用的防止术后静脉再狭窄的方法有以下几种：
1、口服及静脉用药，目前搭桥术后病人口服阿司匹林+替格瑞洛双抗凝可以有效的提高搭桥术后通畅率，但静脉桥再狭窄的发生率依然高达10％以上，且无法正对再狭窄的病因进行针对性治疗。对于血管条件较差或术中行冠脉内膜剥脱的病人，术后可以静脉注射肝素抑制桥血管内血栓形成，但术后静脉应用肝素只能抑制围术期血栓形成而无法抑制远期桥血管粥样硬化，且易导致术后出血性并发症。
2、改良扩张液，隐静脉离取后的扩张已经成为CABG术中的一项常规操作，目前常用的大隐静脉扩张液多为简单的肝素生理盐水，仅有简单的扩张作用。改良扩张液为GV扩张液，其主要的成分是三硝酸甘油和维拉帕米。该扩张液能更好的保护血管内皮细胞的功能，明显减少单位面积死亡的数量，从而在一定程度上提高静脉桥的远期通畅率，但同样GV扩张液的作用原理使其保护效果局限于术后短期，且扩张液无法避免使用者注射量过大引起的机械扩张损伤。
3、基因治疗，基因治疗是指将目的基因导入到载体内制成复合体，再通过载体将目的基因准确地转移至靶组织的细胞内，并使其有效表达，从而达到防治或减轻疾病的目的。随着人类基因图谱的揭示，基因治疗CABG术后静脉移植物再狭窄成了一个炙手可热的话题，有研究也证实了其可行性，但其仍面临着如何选择适当的基因载体和具有治疗价值的基因两大难题。
发明内容
由于术后病人常规应用抗凝药物(肝素或口服抗凝药)，故围术期血栓形成已在很大程度上被抑制。而影响远期通畅率的主要因素即为术后中期内膜增生与远期内皮粥样硬化。本技术旨在设计一种预防术后中远期再狭窄的系统，以提高远期通畅率。
本发明的第一个目的是提出一种冠状动脉旁路移植术预防桥血管再狭窄系统，
本发明的第二个目的是提出所述系统的制备方法。
本发明的第三个目的是提出所述系统的应用。
实现本发明上述目的的技术方案为：
一种冠状动脉旁路移植术预防桥血管再狭窄系统，包括球囊和球囊内装载的带有氟伐他汀的聚乳酸-聚乙醇酸共聚物(PLGA)纳米粒子，所述球囊表面上涂布有紫杉醇涂层，球囊的侧壁上开有微孔。
其中，所述球囊的侧壁的开孔间隔为(0.8～1.2)×(0.8～1.2)mm。
所述的冠状动脉旁路移植术预防桥血管再狭窄系统的制备方法，包括以下步骤：
1)聚乳酸-聚乙醇酸共聚物PLGA纳米微球、氟伐他汀共同溶于有机溶剂，所得混合液再通过蒸发去除有机溶剂，得到复合药物微球；所述有机溶剂为二氯甲烷、乙二醇、丙酮、四氯甲烷中的一种或多种；
2)复合药物微球分散于氯化钠溶液中，形成胶体溶液；
3)用针头在球囊侧壁开孔，球囊侧壁孔制作完成后，将球囊置于紫杉醇溶液中浸泡，然后取出烘干。
4)用注射器把胶体溶液注入球囊中。
上述方法中，球囊的制作和PLGA微球的制作不分先后，为了描述方便，以序号标记。
进一步地，步骤1)中，聚乳酸-聚乙醇酸共聚物PLGA纳米微球、氟伐他汀共同溶于有机溶剂后，超声乳化2min，常压下搅拌挥发12h，再在表压-0.1Mpa条件下减压挥发2h，最后在50℃烤箱中烘干1h，得到带有氟伐他汀的复合药物微球(PLGA微球)。
优选地，步骤1)中，聚乳酸-聚乙醇酸共聚物PLGA纳米微球和氟伐他汀的质量比为1：0.5～0.8。
其中，步骤2)中复合药物微球按照质量比1:(100～500)分散于0.9％氯化钠溶液中，形成胶体溶液。
其中，所述球囊的长度为2～8cm，直径为20、25、30、35mm(根据大隐静脉管径分为四种规格)；侧壁的开孔间隔为(0.8～1.2)×(0.8～1.2)mm。
其中，步骤3)中，将球囊用2～4atm压力扩张，然后用24G针头开孔，再将球囊放气。
更优选地，步骤3)中，将球囊置于紫杉醇溶液中5～15min，取出后40～60℃烘干；所述紫杉醇溶液是质量浓度为10～20％的水溶液。
本发明所述冠状动脉旁路移植术预防桥血管再狭窄系统、所述的制备方法在制备冠脉搭桥手术器械中的应用。
本发明的有益效果在于：
针对冠状动脉旁路移植术术后远期影响通畅率的主要因素，即术后中期内膜增生与远期内皮粥样硬化等问题，本发明设计一种冠状动脉旁路移植术预防桥血管再狭窄系统，根据静脉管径选取不同直径的球囊，然后从注射器推入PLGA微球，使紫杉醇、氟伐他汀复合药物进入动脉血管，抑制血栓形成，提高术后的远期通畅率。
附图说明
图1为所述冠状动脉旁路移植术预防桥血管再狭窄系统的结构示意图；图中右上角小图示出了侧壁上微孔的布置。
图中，1为球囊，2为注射器；
图2为新西兰白兔验证本系统效果的病理切片照片。
具体实施方式
现以以下最佳实施例来说明本发明，但不用来限制本发明的范围。
实施例中，如无特别说明，所采用的技术手段均为本领域常规的技术手段。
本发明方法中，球囊的制作和PLGA微球的制作不分先后，为了描述方便，以序号标记。
实施例1：
本系统由自制带侧孔的涂紫杉醇球囊与载氟伐他汀的PLGA粒子组成，工作原理为利用PLGA粒子溶液充盈球囊，利用充盈的球囊扩张取下的大隐静脉，紫杉醇通过与静脉内皮细胞的接触发挥其细胞毒作用，抑制内皮细胞增生，PLGA粒子由于球囊充盈压力被压入细胞间隙，缓慢释放药物成分，抑制远期粥样硬化。
1、PLGA纳米微球制备
选用聚乳酸-聚乙醇酸共聚物(PLGA，50：50，特性粘度1.13dl/g)(市购，西安瑞禧生物科技有限公司)，此种纳米微粒直径10～500nm，其高分子基质可控制药物缓慢释放，它的超微小体积使其非常容易进入组织间隙，并驻留在组织局部。采用紫杉醇与氟伐他汀两种药物制成复方成分药物，同时抑制术后血管内皮增生和远期粥样硬化。
用电子天平按照1:0.6的质量比称取PLGA纳米微球、氟伐他汀固体药物，混匀后将其按照1:2比例(PLGA和氟伐他汀总质量：溶剂质量)溶于二氯甲烷，快速搅拌(1800r/min转速)5min，使其充分混匀；超声乳化2min，常压下搅拌挥发12h，再在表压-0.1Mpa条件下减压挥发2h，最后在50℃烤箱中烘干1h，得到带有氟伐他汀的PLGA微粒。
按照质量比1:200将干燥后的PLGA微球溶解于0.9％氯化钠溶液，超声震荡1min制成胶体溶液。
2、制备涂有紫杉醇的带侧孔球囊
医用球囊为市购，依据大隐静脉管径分为4型，本实施例选用为5cm×20mm(长度×管径)球囊，首先预扩张球囊，给予2atm(1atm＝101.325KPa)压力扩张。使用24G针头于球囊表面按照1×1mm(长、宽间隔)的密度扎出侧孔。球囊示意图参见图1，球囊侧壁开有微孔。
球囊侧壁孔制作完成后，将球囊放气，将球囊置于16.7ml：100mg的紫杉醇溶液中10min，取出后50℃烘干。
紫杉醇和短时间细胞接触，起轻微抑制作用；紫杉醇溶液中浸泡10min的时间即可达到需要的效果。
实施例2
本实施例中，球囊的尺寸为5cm×25mm(长度×管径)。制备方法同实施例1。
实施例3
本实施例中，球囊的尺寸为5cm×30mm(长度×管径)。制备方法同实施例1。
实施例4
本实施例中，球囊的尺寸为5cm×35mm(长度×管径)。制备方法同实施例1。
试验例
本系统在使用时方法如下，在完成大隐静脉取材后，根据静脉管径选取直径不同的球囊，将球囊从大隐静脉远端送入管腔；从注射器推入PLGA微球的胶体溶液，停留30s。按此步骤扩张大隐静脉全长。参见图1，球囊1连接于注射器2，注射器内灌注PLGA复合药物的胶体溶液，构成冠状动脉旁路移植术预防桥血管再狭窄系统。
下图为前期利用新西兰白兔验证本发明效果时的病理切片。实验将白兔一侧颈总静脉吻合于兔颈动脉，28天后取出。B组为正常的白兔颈静脉切片，A为对照组，采用传统的肝素盐水扩张，可见静脉内皮明显增生，C组为实验组，可见内皮增生程度明显小于A组。
本技术领域内的一般技术人员应当认识到，上述实施例仅是用来说明本发明，而并非用作对本发明的限定，只要在本发明的实质精神范围内，对上述实施例的变换、变型都将落在本发明权利要求的范围内。
Claims (10)
1.一种冠状动脉旁路移植术预防桥血管再狭窄系统，其特征在于，包括球囊和球囊内装载的带有氟伐他汀的聚乳酸-聚乙醇酸共聚物纳米粒子，所述球囊表面上涂布有紫杉醇涂层，球囊的侧壁上开有微孔。
2.根据权利要求1所述的冠状动脉旁路移植术预防桥血管再狭窄系统，其特征在于，所述球囊的侧壁的开孔间隔为(0.8～1.2)×(0.8～1.2)mm。
3.权利要求1或2所述的冠状动脉旁路移植术预防桥血管再狭窄系统的制备方法，其特征在于，包括步骤：
1)聚乳酸-聚乙醇酸共聚物PLGA纳米微球、氟伐他汀共同溶于有机溶剂，所得混合液再通过蒸发去除有机溶剂，得到复合药物微球；所述有机溶剂为二氯甲烷、乙二醇、丙酮、四氯甲烷中的一种或多种；
2)复合药物微球分散于氯化钠溶液中，形成胶体溶液；
3)用针头在球囊侧壁开孔，球囊侧壁孔制作完成后，将球囊置于紫杉醇溶液中浸泡，然后取出烘干；
4)用注射器把胶体溶液注入球囊中。
4.根据权利要求3所述的制备方法，其特征在于，步骤1)中，聚乳酸-聚乙醇酸共聚物纳米微球、氟伐他汀共同溶于有机溶剂后，超声乳化2min，常压下搅拌挥发12h，再在表压-0.1Mpa条件下减压挥发2h，最后在50℃烤箱中烘干1h，得到带有氟伐他汀的复合药物微球。
5.根据权利要求3所述的制备方法，其特征在于，步骤1)中，聚乳酸-聚乙醇酸共聚物纳米微球和氟伐他汀的质量比为1：0.5～0.8。
6.根据权利要求3所述的制备方法，其特征在于，步骤2)中复合药物微球按照质量比1：(100～500)分散于0.9％氯化钠溶液中，形成胶体溶液。
7.根据权利要求3～6任一项所述的制备方法，其特征在于，所述球囊的长度为2～8cm，直径为20、25、30或35mm；侧壁的开孔间隔为(0.8～1.2)×(0.8～1.2)mm。
8.根据权利要求3～6任一项所述的制备方法，其特征在于，步骤3)中，将球囊用2～4atm压力扩张，然后用24G针头开孔，再将球囊放气。
9.根据权利要求3～6任一项所述的制备方法，其特征在于，步骤3)中，将球囊置于紫杉醇溶液中5～15min，取出后40～60℃烘干；所述紫杉醇溶液是质量浓度为10～20％的水溶液。
10.权利要求1或2所述冠状动脉旁路移植术预防桥血管再狭窄系统或权利要求3～9任一项所述的制备方法在制备冠脉搭桥手术器械中的应用。
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Application publication date: 20171110 |