摘要
研究背景：近十多年来，镍钛合金室间隔缺损封堵器已广泛应用于先心病室间隔缺损（Ventricular Septal Defect, VSD）的介入治疗。因其创伤小、安全性高、疗效确切，对于具有适应证的患者介入治疗已为首选的治疗方案。但是目前应用的镍钛合金VSD封堵器仍然存在缺陷：一是镍钛合金丝的金属成分外露，放置在室间隔缺损部位后，较硬的镍钛合金与局部组织直接接触，产生挤压和摩擦作用，造成与其接触的传导系统组织和瓣膜损伤；二是市售镍钛合金封堵器血流阻隔涤纶膜缝合在其中，放置后可留有裂隙，高速血流中的红细胞通过裂隙和撞击到右心室侧的合金丝，发生溶血；三是镍钛丝表面光滑，不易内皮化。国内外学者为了预防介入封堵VSD后的相关并发症，做了较多的努力。在保持镍铁合金封堵器双盘状结构的基础上，对编制材料或结构进行改进，如针对靠近主动脉瓣的室间隔缺损设计的零边的偏心型封堵器；针对膜部瘤和多孔型室间隔缺损的设计的左右侧不对称型的细腰型室间隔缺损封堵器，降低了封堵器导致的完全房室传导阻滞等并发症的发生；为了减少或延缓封堵器中镍离子的释放，研制了烤瓷封堵器；镍钛合金封堵器有不锈钢和镍钛合金两种金属成分组成，放置体内后在两种金属间产生电位差，影响封堵器表面的内皮化，为了克服此种缺陷，发明了单铆和双侧无铆的全镍钛合金封堵器；室间隔缺损中膜部瘤样改变较常见，其左右心室间的间距较大，目前应用的封堵器腰部长度3-4mm，封堵器放置产生两侧相对的挤压作用，为了减少封堵器对缺损周围组织的压迫，国外研究人员发明了腰部长度可调节的封堵器。以上封堵器的研制，进一步减少了VSD封堵器结构缺陷导致的一些并发症的发生，但仍不能避免镍钛合金封堵器直接与血液、组织接触，导致的完全性房室传导阻滞、主动脉瓣磨损、血栓形成、溶血等严重并发症的发生。
为此，我们设计涤纶膜外套式镍钛合金VSD封堵器，外包膜在心肌组织和较硬的镍钛合金之间起到缓冲作用，避免较硬的镍钛合金与心脏软组织直接接触，减少张力，减轻炎症反应，从而减少封堵术后传导阻滞的发生；防止镍钛合金丝对心肌组织的长期直接摩擦，而引起的损伤；此外，外套膜在封堵器的外表面，可能有利内皮细胞爬附，缩短内皮化的时间；外套膜完全覆盖镍钛合金的编织网，有可能避免发生溶血并发症。
研究目的：研制涤纶外套式室间隔缺损封堵器，经体外测试和动物体内植入评价新型室间隔封堵器的性能和安全性，并以市售封堵器为对照，评价其疗效和生物相容性，为临床应用提供实验依据。
研究方法：1、涤纶膜外套式镍钛合金室间隔封堵器的研制：按照市售常规VSD封堵器稍微牵拉的形状制作腊模型，在编网机上使用医用4个0缝合线在腊模型上进行经编，制作成腊模-涤纶外包膜复合体。然后脱蜡和脱脂，制成纯涤纶外套，将市售VSD封堵器置入涤纶外套内，两端缝合在铆钉上，高温刀切割多余部分。2、涤纶膜外套式室间隔缺损封堵器的体外性能测试：取8只涤纶外包膜封堵器用于体外测试，另取8只市售封堵器作为对照组。测量两组封堵器的直径和体外输送鞘管的最小直径；测试两组封堵器的拉力-拉距之间的关系；体外在鞘管内反复回收-释放50次以后，观察涤纶外包膜VSD封堵器表面磨损情况；试管内生理盐水内反复回收释放50次，显微镜下观察包膜有无细微脱屑，利用细胞计数板在显微镜下观察两组封堵器沉渣数量；3、涤纶外包膜室间隔封堵器的植入犬体内实验：使用房间隔穿刺针穿刺犬室间隔和球囊扩张穿刺点制作犬VSD模型；并使用涤纶膜外套式室间隔缺损封堵器和市售VSD封堵器经导管介入的方法封堵犬VSD；并定期观察和记录(1)、动物的一般状态；（2）经胸壁行心脏多谱勒超声观察封堵器位置有无附壁血栓、及其对三尖瓣、主动脉瓣的影响；心电图观察心律失常发生情况。（3）、于不同实验点1周、1、3、6个月分批处死实验犬，取出心脏，切开心脏观察封堵器和邻近结构的大体解剖，封堵器的位置，以及心脏、肺脏、肝、脾、双肾等器官的形态有无异常；（4）、取在不同时间点获取犬心脏内的封堵器标本，将覆盖在封堵器表面的组织剥离，进行组织病理学检查；（5）、取不同时间点封堵器的表面组织进行扫描电镜检查。
结果：1、使用编网机可以成功编织出涤纶外包膜。外包膜的主要参数为腰部直径8mm，两端盘片直径12mm。并且能和直径8mm市售镍钛合金VSD封堵器腰部和盘片完全匹配。应用缝合的方法，可以将涤纶外包膜紧密地缝合在一起。高温刀切割使两端多余涤纶线平齐，凝固，无散丝，脱线。2、（1）、涤纶外包膜VSD封堵器的直径较常规封堵器大0.5mm，需要最小10F鞘管方能输送，而常规VSD封堵器需要8F鞘管输送；（2）、两组封堵器在1.25、2.5、3.75、5.0、6.25、7.5、8.75、10.0、11.25、12.5、13.75和15mm的形变过程中，其两组拉距-拉力之间没有统计学差异；（3）、体外释放回收50次后，肉眼观察涤纶外包膜封堵器表明没有明显磨损，体视显微镜下观察，包膜表面在牵拉前后没有明显差异；（4）、试管内生理盐水牵拉实验，离心液显微镜下观察，细胞计数板计数两组封堵器的离心液的沉渣数，两组无统计学意义，p=0.889。3、18只犬中15只成功制作VSD模型，2只因心包压塞救治无效死亡，1只因伴发IIIo房室传导阻滞死亡，其中8只成功植入涤纶膜外套式VSD封堵器，7只植入市售VSD封堵器。两组动物植入封堵器后均未发生并发症，长期存活。术后1个月经胸超声检查，封堵器位置良好，无移位、附壁血栓，对心脏瓣膜无影响；术后肉眼、扫描电镜、病理组织学观察封堵器表面覆盖组织，植入7天包膜封堵器已经覆盖纤维蛋白包膜，1个月内皮化完全，而市售封堵器7天未见任何包膜形成，1个月纤维蛋白覆盖完全，而3个月后内皮化完全，且在3个月和6个月植入封堵器周围的纤维瘢痕组织在涤纶外包膜组明显减少，两组生物相容性均良好。
结论：1、使用涤纶线经编的方法，可以编织与镍铁合金封堵器相匹配的涤纶膜外套，通过缝制和热切割等工艺，可以成功制作出涤纶膜外套式室间隔封堵器。2、涤纶膜外套式室间隔封堵器各项物理参数与常规VSD封堵器没有明显差别，植入鞘管的直径相对较粗。3、涤纶膜外套式室间隔封堵器可以经导管输送，可以通过介入的方法对犬VSD进行封堵，操作方法简便，安全，疗效可靠。4、涤纶膜外套式室间隔封堵器在体内内皮化所需的时间较市售封堵器短，且带膜封堵器心肌周围纤维结缔组织增生也明显较市售封堵器减少，提示新型封堵器具有良好的生物相容性。5、实验结果表明涤纶膜外套式镍钛合金室间隔封堵器其性能与市售封堵器的无明显差异，且在减少封堵器器周围纤维组织增生、内皮化时间方面明显优于市售的封堵器，提示外套式室间隔封堵器可应用于临床。
Background: Amplatzer ventricular septal defect（VSD） closure devices have beenwidely used in recent years, and transcatheter device closure of VSD has become aoptimal treatment of selected patients because of its slight trauma, high safety andideal efficiency. But at present, the nitinol wire VSD occluder still exists defects. It canresult in the conduction system block, valvular damage because of hard nitinol directcontact with local organizations, and in addition, the time of VSD occluder （VSDO）endothelialization of requires2-3months, or longer. To maintain the same dual-diskstructure of the Amplatzer occluder, domestic and foreign scholars have improved thematerials or waist structure in order to prevent intervention-related complications afterclosure VSD. There are five types of these occluders:1zero rim, symmetric orsmall waist large rim VSDO;2porcelain coated VSDO;3pan-nitinol stainless steelbuttom-removed VSDO;4bioabsorbable vsdo;5waist length adjustableVSDO.However, These occluders can not fundamentally solve the nitinol occluderdirectly with the contact of blood and tissue, leading to edema, scar formation, thrombusattached set of defects caused by complete atrioventricular block, aortic rupture,thromboembolism, hemolysis, and other serious complications.
For the above purposes, we designed the medical polyester thread woven coatednitinol VSDO. Fist, the aim of the design is to reduce the VSD after transcatheter closureof conduction block, because the polyester overcoat cushion between the myocardial tissueand hard nitinol, to reduce tissue tension, reduce inflammation, reduce scarring; Second,polyester overcoat can prevent long-term direct friction of the nitinol wire on themyocardial tissue, destruction of normal myocardial tissue; The last, polyester overcoat canshorten VSDO endothelial cells time.Objective: To design medical polyester thread woven coated VSDO, Evaluation of thephysical properties of the polyester coated VSDO, To evaluate the safety, efficacy andfeasibility of transcatheter closure of VSD with the polyester coated VSDOs in a caninemodel. Comparison of myocardial tissue reaction, endothelialization process andbiocompatibility at different time points in the polyester coated VSDOs goup andconventional VSDOs in canines.
Method:1Design of medical polyester coated ventricular septal defect occluder:The shape wax model was made in accordance with the conventional VSD occluder slightlystretch the shape. After the wax model fixed on the weaving machine, the weavingmachine axle travel speed were set to pitch0.2mm, walking speed0.2mm/s respectively,to make into a wax model-polyester envelope compomer using the medical4-0suturesto the warp knitting on the wax model. The final steps of in this procedure ware to usevegetable oil dewaxing, alkyl sulfonate off grease, then the Polyester envelope wasproduced successfully. Conventional nitinol VSD occluder were delivered to theenvelope by the the sheath. It should be the match between the polyester envelope waistand disc position and the occluder, then and polyester external envelope both ends of thesuture on the VSD both ends of the rivets, the high temperature knife cuttingend ofsurplus part. Two sides of the polyester envelope was sutured at the VSD stainless steelrivets, and both ends of the surplus part cut by high-temperature knife.2Testing thephysical parameters of medical polyester coated ventricular septal defect occluder:16conventional VSDOs were randomly assigned to two groups, which one group(n=8)was made into polyester coated VSDOs, as polyester coated VSDOs group, anothergroup as a conventional occluder group.①Measuring the two groups VSDOs diameter,minimum diameter of the the delivery sheath;②Testing tension of the two groupsVSDOs under different deformation state, to wonder polyester envelope whether theimpact of the the VSDOs hyperelastic;③Observing polyester coated VSDOs surfacewear status by the eyes and microscope after withdrawal-release of50in the sheath invitro;④Taking the lowest centrifugal liquid to observe whether the tiny desquamationby microscope after withdrawal-release of50in tube saline liquid.3Transcatheterclosure of ventricular septal defect in a canine model:①The creation of VSD in acanine model.18dogs underwent transcatheter ventricular septal puncture withBrockenbrough puncture needle via right jugular vein under fluoroscopy,and dilated thedefect with8mm balloon catheter.Left ventricular(LV) angiography was performed withpigtail catheter by transaortic access.②Experimental study of the polyester coatedVSDOs：VSDs were closed by the polyester coated VSDOs via10F delivery sheathunder fluoroscopy in the catheterization laboratory，and by conventional VSDOs via8Fdelivery sheath.The location of device and function of tricuspid valve(TV) and aorticvalve(AV) were observed by ventricular angiography and echocardiography.①TTE observed occluder position estimate mural thrombus, tricuspid valve, aortic valve.②Dogs were administrated with aspirin and sacrificed in1week，1,3,6monthsrespectively after devie implantation， while tissue samples were obtained forhistopathology examination.
Result:1. The use of the weaving machine and warp knitting method can successfullymake polyester envelope of VSDO. Its waist diameter of8mm and disc diameter of12mm can completely fit with the diameter of8mm conventional nitinol VSDO. Thepolyester envelope was sutured tightly with the VSDO with suture method, and usinghigh-temperature knife enable surplus part of two sides of the VSDO smooth，solidification, no loose wire.2.①The diameters of polyester coated VSDOs are largerthan conventional VSDOs by0.5mm, required a minimum of10F sheath to delivery, ascompared with the conventional VSD occluder requires8F sheath.②The tensions oftwo groups of occluder have no statistically significant difference in the deformationprocess of1.25,2.5,3.75,5,6.25,7.5,8.75,10,11.25,12.5,13.75and15mm.③Thepolyester coated VSDOs were showed no obvious wear and tear by eyes, and thesurfaces not significantly different by stereomicroscope before and after the release–delivery.④There were no tiny desquamation in Saline stretch in lowest centrifugalliquid of both of two groups.3.18dogs underwent transcatheter ventricular septalpuncture with Brockenbrough puncture needle via right jugular vein underfluoroscopy,and dilated the defect with8mm balloon catheter.Left ventricular(LV)angiography was performed with pigtail catheter by transaortic access after puncture.2of18dogs died because pericardial tamponade during the procedure and1died becauseIII o atrioventricular block.8of15dogs implanted of polyester coated VSDOssuccessfully, and7dogs of conventional VSDOs. There were no complicationslong-term survival. TTE found occluders in good position, no shift, mural thrombus, noeffect on the heart valves after intervention one month. Postoperative naked eyesobserved, scanning electron microscopy, and histopathological examination occluder.Dogs were sacrificed at the diferent time points.The occluders had been covered by thefibrin membranes after postprocedure the first week, and endothelialization completely inthe first month in the the polyester coated VSDOs goup by eyes observed, scanningelectron microscopy, and histopathological examination. Nevertheless, the conventional occluders had no any membranes formation, been covered by the fibrin membranesafter the first month, and endothelialization completely in the third month. Fibrous scartissue reduced significantly in the polyester coated VSDOs in the third month and sixthmonth. The VSDOs in two groups had good biocompatibility.
Conclusion:1. The polyester envelope of VSDO can be weaved by the weaving machineand warp knitting method, then the polyester coated VSDO can be successfully made bysuture.2. Various physical parameters are not significantly different in comparison ofpolyester coated and conventional VSDOs, so the polyester coated VSDOs can besafely to implant in animals.3. The polyester coated VSDOs closure device can be usedto closure canine VSD model using method of transcatheter intervention.4. Theendothelialization time of polyester coated VSDOs is shorter compared withconventional occluder in a canine model in vivo, and myocardial scar formation aroundthe polyester coated VSDOs is also significantly reduced.So this new occluder haspotential application.
引文
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