摘要
随着人口老龄化和饮食结构的改变,动脉硬化闭塞性疾病的发病率逐年升高,临床上对中小口径人工血管的需求量很大。目前在临床上使用血管移植物主要有两类:1)自体血管移植物如内乳动脉、桡动脉和大隐静脉:但是来源有限;2)人工合成材料血管:目前临床上使用最广泛的血管替代物仍旧是人工血管。因此,通过对人工材料血管进行改性与修饰,进一步提高其远期通畅率成为研究重点。本实验通过对针织涤纶人工血管进行肝素和壳聚糖自组装表面修饰和生物相容性测试,并将该人工血管按照国标进行力学性能测试,最后将人工血管置换实验犬腹主动脉,术后行彩色多普勒超声和MRI血管造影(MR angiography,MRA)随访移植血管血流通畅度和吻合口内膜增生程度,并于术后分节点取出移植的血管行扫描电镜、组织学和免疫组织化学检测以了解置换的小口径血管移植物在体内的情况,来评价肝素壳聚糖表面修饰小口径人工血管的运用可行性。
第一部分肝素壳聚糖层层自组装涤纶人工血管的制备及生物相容性测试
目的:制备肝素壳聚糖表面修饰小口径涤纶人工血管,并对该表面修饰后的人工血管进行生物相容性测试。
方法:采用层层自组装技术对涤纶人工血管进行肝素壳聚糖表面修饰。参照GB/T16886.4/ISO 10993—4,GB/T 16886.5/ISO 10993-5对修饰后的涤纶人工血管进行细胞粘附试验、MTS细胞毒性试验、LDH释放试验、急性毒性试验、短期皮下植入实验、直接接触溶血试验、间接接触溶血试验、血小板粘附试验。
结果:利用层层自组装技术成功制备肝素壳聚糖表面修饰涤纶人工血管。扫描电镜显示其微观结构没有在表面处理中受到破坏。细胞粘附试验提示人脐静脉内皮细胞株ECV304和小鼠成纤维细胞株L929在修饰后涤纶人工血管表面粘附生长良好;MTS细胞毒性试验和LDH释放试验提示肝素壳聚糖层层自组装涤纶人工血管较阴性对照无明显差异(P＞0.05);急性毒性试验实验组无小鼠死亡,较阴性对照组无明显差异:短期皮下植入实验提示修饰后人工血管周围组织炎症反应较未处理涤纶人工血管无明显区别;直接和间接接触溶血试验提示修饰后涤纶人工血管无明显破坏红细胞作用;血小板粘附提示肝素壳聚糖层层自组装人工血管抗血小板粘附、抗凝血性能优于未处理涤纶血管。
结论:肝素壳聚糖层层自组装技术对涤纶人工血管进行表面处理切实可行,并且对涤纶人工血管的生物相容性未产生不良的影响。
第二部分肝素壳聚糖自组装表面修饰小口径涤纶人工血管的力学性能测试
目的:评估肝素壳聚糖自组装表面修饰对涤纶人工血管力学性能的影响。
方法:根据中国医药行业标准YY0550—2004/IS0 7198:1998对其壁厚、自然状态下内径、加压后内径、轴向拉伸强度、最大缝持张力、吻合口爆破压、人工血管孔隙率、水渗透性进行测试。
结果:肝素壳聚糖自组装表面修饰对涤纶人工血管力学性能符合人体使用标准。对比未修饰人工血管,肝素壳聚糖自组装表面修饰对涤纶人工血管壁厚、自然状态下内径、加压后内径、轴向拉伸强度、最大缝持张力、吻合口爆破压、人工血管孔隙率、水渗透性无显著差异。
结论:肝素壳聚糖自组装表面修饰对涤纶人工血管力学性能无明显影响,肝素壳聚糖自组装表面修饰涤纶人工血管力学性能符合人体使用标准。
第三部分肝素壳聚糖自组装表面修饰小口径涤纶人工血管的动物实验
目的:肝素壳聚糖层层自组装表面修饰小口径涤纶人工血管在体内血流动力条件下血管壁组织结构重塑过程。
方法:将肝素壳聚糖层层自组装表面修饰小口径涤纶人工血管置换6只实验犬自体腹主动脉,对照组为未经表面处理的同口径人工血管手术置换6只实验犬。于术后4w、8w、12w行影像学检查、组织学和免疫组织化学检测,以及扫描电镜检查以评价移植物血管在体内重塑情况。
结果:6根肝素壳聚糖层层自组装表面修饰小口径涤纶人工血均通畅;对照组1只实验犬死亡,术后4w彩超和MRA提示1根人工血管阻塞。6根实验组通畅的血管在术后不同时点取出发现内表面菲薄、光滑。血管壁内表面覆盖一连续、鹅卵石样单层细胞,该细胞Ⅷ因子相关抗原抗体染色阳性。这种移植于体内的小口径血管移植物于术后4w时新生动脉壁厚度约为900μm,并于管壁中层可见较多血管SMC和外膜层主要为成纤维细胞,而且最早于术后4w时在血管壁中层就可见弹力纤维。
结论:肝素壳聚糖层层自组装表面修饰中小口径涤纶人工血管在体内血流动力条件下能在体内完成内皮化,具有较高的近中期通畅率,并参与透壁性内皮化的进程。
全文结论:
1.肝素壳聚糖层层自组装能够用来对涤纶人工血管进行表面修饰。
2.肝素壳聚糖层层自组装表面修饰的涤纶人工血管具有良好的生物相容性(细胞相容性、组织相容性和血液相容性)。
3.肝素壳聚糖层层自组装表面修饰的涤纶人工血管的力学性能符合ISO和GB/T的标准。
4.肝素壳聚糖层层自组装表面修饰的涤纶人工血管能够在体内完成内皮化进程,具有较高的近中期通畅率。
The requirements of Moderate-Caliber Dacron Vascular Graft have been manifolded throughout these years,due to the increasing morbidity and mortality of atherosclerotic diseases.The major vascular grafts applied in the clinical pracice have two kinds:1) autologous vessels,such as radial artery,internal mammary artery,and saphenous vein, which was restricted by the limited source;2) synthetic grafts,such as expanded polytetrafluorethylene(ePTFE) and Polyethylene terephthalate(Dacron or PET) grafts, which are the most widely used in the clinical use.Thus,surface modification of synthetic vascular grafts to improve the short-term and long-term patency is the one of the most pratical methods in the present situation.In this study,we get the moderate-caliber Dacron vascular graft surface modified via layer-by-layer assembly of heparin/chitosan,and study the biocompatibility and mechanical properties according to the GB standards.After that, we evaluate he modified vascular grafts in the animal experiments by the means of B-ultrasonograft,MRA,scanning electron microscope,histochemistry and immunohistology.
PartⅠThe biocompatible tests of the heparin/chitosan modified Dacron vascular graft
Objective:preparation and biocompatible evaluation of the heparin/chitosan modified Dacron vascular grafts.
Methods:preparation of the heparin/chitosan modified Dacron vascular grafts by layer-by-layer assembly.Evaluation of the biocompatibility of the modified grafts according to the GB/T 16886.4 and ISO 10993-4,GB/T 16886.5 and ISO 10993-5,cell adhesion,MTS assay,LDH release assay,acute toxicity tests,subcutaneous implantation,direct hemolysis, indirect hemolysis,and boold platelet adhesion tests.
Results:The micro-structure of the modified grafts maintained after the layer-by-layer assembly.Good cell adhesion of the modified Dacron grafts approved by the cell strain of ECV304 and fibroblast L929.The modified grafts were innoxious in the cytotoxity tests by the MTS assay and LDH release tests(P＞0.05);No significant difference was found both in the acute toxicity test and the inflammation the modified grafts after subcutaneous implantation comparing to the negative control.The red blood cell destruction was found in the direct and indirect hemolytic tests.The anticoagulate effects of the modified grafts were better than the unmodified grafts.
Conclusion:The Dacron vascular grafts could be modified by the layer-by-layer assembly of heparin/chitosan,and the modified grafts maintain good biocompatibility.
PartⅡ
Mechanical properties of the heparin/chitosan modified vascular graft
Objective:Evaluation of the mechanical properties of the heparin/chitosan modified vascular graft.
Methods:The wall thickness,inner diameter,diameter under pressure,axial extends intensity,max suture intension,anastomosis explodes pressure,porosity,integral water permeability was examined according to industry standards.(YY 0500-2004)
Results:Mechanical properties of the heparin/chitosan modified vascular graft met the standards of the YY 0500-2004 in the wall thickness,inner diameter,diameter under pressure,axial extend intensity,max suture intension,anastomosis explode pressure, porosity,integral water permeability.
Concluation:Mechanical properties of the heparin/chitosan modified vascular graft did not undermined in the layer-by-layer assembly,and met the national standards YY 0500-2004.
PartⅢ
The animal experiment of the heparin/chitosan modified Dacron vascular graft
Objective:Evaluation of the heparin/chitosan modified Dacron vascular graft in the animal experiments.
Methods:12 beagles were devided into 2 groups,in which modified vascular grafts and unmodified vascular grafts with the length of 6 cm,was implanted in the beageles abdominal aortic artery.Histology,immunohistochemistry,MRA and ultrasonography was examined 4 weeks and 12 weeks after operation.
Results:Six heparin/chitosan modified vascular grafts maintain the patency after 4w and 12w;one of unmodified grafts in the control group clogged in the forth month.The histology showed that endothelialization of the modified grafts was completed in 4 weeks after operation.
Conclusion:The endothelialization was not disturbed by the heparin/chitosan modified Dacron vascular grafts,and the well patency of short-term and medium-term was found in the modified grafts.
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