摘要
血管内支架置入术已经成为血管阻塞性病变的主要治疗手段。然而，传统支架置入术后再狭窄(in-stent restenosis ISS)率高达40-60％，成为限制其继续发展的“瓶颈”问题。药物洗脱支架(drug-eluting stent DES)的应用开辟了预防ISS的新途径，应用DES治疗动脉阻塞性疾病再狭窄率可降为0-8.0％左右。然而，目前DES研究尚存在缺陷。与冠脉相类似，外周动脉ISS发生率也较高(22％-61％)，DES在外周动脉闭塞性病变中有着广阔的应用前景。但由于解剖结构的不同以及支架结构的不同，外周血管DES研究尚处于尝试阶段，疗效尚不明确；同时，DES的“内皮化延迟(delayed endothelialization)”问题始终是困扰DES研究的普遍难题，相应地引起了血栓形成等严重并发症，影响了DES抑制ISS的中远期疗效。
本研究利用国产外周血管形状记忆合金支架为平台，设计了雷帕霉素-肝素-聚丙交酯乙交酯(polylactide coglycotide PLGA)药膜涂层支架表面，并对该载药涂层支架的表面性能，血液相容性，降解性能及体外药物释放性能及动物体内影像学评价进行了系统的研究，为未来国产外周动脉雷帕霉素-肝素洗脱支架的临床应用奠定基础。本研究分为以下三个部分：
第一部分：国产外周动脉雷帕霉素-PLGA药膜制各及其性能研究。目的：评价国产雷帕霉素-PLGA外周动脉洗脱支架药膜抑制“爆发释放”特性。方法：采用自制PLGA与雷帕霉素制成雷帕霉素-PLGA药膜，并用该药膜涂层12枚自制镍钛合金外周血管支架。观察支架表面药物涂层的宏观形貌，三维形貌和表面粗糙度。并对洗脱支架进行血液相容性，体外降解行为及体外药代动力学研究。结果：12枚支架药膜表面光整，层厚均一，未见皲裂、脱落、翘起现象。涂层表面粘附的血小板数量明显减少，没有变形和聚集，血小板处于未激活状态。PLGA在2周之内降解约20％，在2至6周降解速度逐渐加快直至完全降解。雷帕霉素释放可持续50天，24h突释量11.02％，9天累积释放量41.23％；30天累积释放量79.44％。结论：国产雷帕霉素-PLGA外周动脉洗脱支架药膜涂层均匀光滑，可有效抑制“爆发释放”。
第二部分：国产外周动脉雷帕霉素-肝素洗脱支架制备及其性能研究。目的：评价国产雷帕霉素-肝素洗脱支架物理性能，生物相容性及体外药代动力学特性。方法：利用自制喷涂装置将PLGA与肝素的混合溶液雾化喷出，在涂覆载Sirolimus聚合物涂层的12枚NiTi支架表面形成载肝素聚合物涂层。对载药涂层支架进行物理性能检测，降解特性检测，血液相容性试验及药物释放特性研究。结果：雷帕霉素-肝素支架表面质量良好，与支架有良好的结合力。血液相容性实验结果表明：PLGA涂层与血小板接触，血小板粘附量明显较少，变形较小，未引起大量聚集；载药的PLGA涂层表面粘附的血小板数量更少，没有变形，未引起进一步的聚集。载药涂层的凝血时间长，凝血因子被激活的程度低。体外药物释放结果表明：药物支架在动态介质中释放速率明显快于静态；支架第二层与第三层为载雷帕霉素涂层释放曲线为线性释放，在第9天时有一个斜率的变化，但仍属线性释放。肝素涂层在释放初期存在突释，为60％左右，后期释放较平缓，在一个月左右释放为总量的70％。结论：国产外周动脉雷帕霉素-肝素洗脱支架具有良好的生物相容性，雷帕霉素及肝素能够持续缓慢释放，提高了洗脱支架的抗凝性能。
第三部分：国产外周动脉雷帕霉素-肝素洗脱支架动物体内影像学研究。目的：评价国产雷帕霉素-肝素洗脱支架顺应性，可视性及预防再狭窄性能。方法：12枚雷帕霉素-肝素洗脱支架，8枚雷帕霉素洗脱支架，8枚裸支架分别置入14条犬中。严格抗凝后，30天造影观察后1／2处死，60天造影观察后全部处死。分别观察支架顺应性，可视性；血栓形成；测量支架段直径，参考节段内直径，迟发丢失，支架内再狭窄率，参考节段内再狭窄率。结果进行统计分析。结果：全部28枚支架位置良好，无移位，脱落，不张等发生；支架具有良好的顺应性，X线下可视性较强，标记清楚，释放时无明显回缩或前跳；30天造影复查，无血栓形成或内膜增生发生，支架造影剂通过顺利。60天复查时，2枚雷帕霉素支架血栓性闭塞，其中1枚对侧裸支架内膜增生；1枚雷帕霉素支架-肝素支架和2枚裸支架内膜增生；1枚雷帕霉素支架-肝素支架近端可见血管狭窄性变化。经统计学检验，支架置入30天时，雷帕霉素-肝素支架、雷帕霉素支架和裸支架各项指标均无统计学差异。支架置入30天时，雷帕霉素-肝素支架、雷帕霉素支架和裸支架各项指标均无统计学差异。支架置入60天时，雷帕霉素-肝素支架、雷帕霉素支架、裸支架支架段直径间差别有统计学意义(F：0.049，P＜0.05)；经SNK检验，雷帕霉素-肝素支架与雷帕霉素支架、裸支架间有差别，差别有统计学意义；裸支架与雷帕霉素支架差别无统计学意义。雷帕霉素-肝素支架、雷帕霉素支架、裸支架支架段直径间晚期丢失差别有统计学意义(F：0.047，P＜0.05)；经SNK检验，雷帕霉素-肝素支架与雷帕霉素支架，裸支架间有差别，差别有统计学意义；裸支架与雷帕霉素支架差别无统计学意义。
结论：国产雷帕霉素-肝素洗脱支架具有良好的柔顺性，X线下可视性较强，标记清楚，释放时无明显回缩或前跳；国产雷帕霉素-肝素洗脱支架具有一定的抗凝性能及预防再狭窄能力。
The intravascular stenting has been the main therapeutic tool of vascular obstructive disease.However,the in-stent restenosis rate of traditional intravascular stenting was as high as 15-60% and had been the restrictive factor to the development of intravascular stenting.The success of drug-eluting stent provided a new way to reducing in-stent restenosis rate to 0-3.0%.At present,the studies about coronary drug-eluting stent home and abroad were the main stream,while those of peripheral artery were rarely reported.The drug-eluting stent has gained satisfactory clinical result,but the appearance of "drug burst release" and "delayed endothelialization" impacted its clinical application.Our study designed the drug membrane with sirolimus-heparin-polylactide coglycotide complex on the platform of native peripheral shape memory metal stent,and carried out systemic a series of studies on its surface nature,blood compatibility,degrading process,drug release in vitro and animal imaging evaluation in order to eliminating the "drug burst release" and "delayed endothelialization". Our study might provid some foundation experience to native sirolimus-heparin eluting stent of peripheral artery.The study included three parts:
PartⅠone: the preparation of native sirolimus-PLGA membrane and its pharmacokinetics study.Purpose:to evaluate the "burst release" controlling of native sirolimus-PLGA membrane.Method:coated 12 niccolum-titanium alloy peripheral stents with self-made sirolimus-PLGA membrane and evaluated its surface nature,blood compatibility,degrading process and pharmacokinetics in vitro.Result:the whole 12 stents had smooth surface and uniform membrane thickness,without membrane rhagades and falling off.The platelets were fewer then the control ones and stayed in a stable state.PLGA degraded 20% within 2 weeks and speeded up in 2-6 weeks to complete degradation.The drug release lasted for 50 days.The releasing dose within 1,9,30 days was 11.02%,41.23%,79.44% separately.Conclusion:the native sirolimus-PLGA membrane kept smooth and even and controlled "burst release" effectively.
PartⅡ:the study on making native sirolimus-heparin eluting stent of peripheral artery and its efficiency.Purpose:to evaluate the stent's physical efficiency biocompatibility and pharmacokinetics in vitro.Method:coated PLGA-heparin complex to the Sirolimus-coated stents with selfmade printing equipment to gain the multiple membrane.Ecaluated the physical and degrading efficiency,blood compatibility,drug releasing mode of the stents coated with multiple membrane.Result:the stents had good surface and passed assemblage and dilation test successfully.The degrading test showed that our membrane degraded slower and longer and that the microcrystalline form of the drug in the carrier influenced the following release.The drug releasing test showed that the membrane with different ratio of PLGA had different degrading speed. Exactly,the PLGA of ratio 50/50 had a higher diffusion rate then that of ratio 75/25 or 80/20.The stents carrying different dose of drug showed different releasing speed and the stents coated with 50% drug released faster then the 30% ones though no obvious difference.The drug released faster in dynamic circumstance then in static circumstance.The drug release test of stents with multiple membrane showed that the releasing curve of the stents group with sirolimus in the first and second layer was linear one though the slope rate had a slight change.The heparin layer showed a "burst release" of 60% and slowed down later with a release dose of 70% within 1 month.The blood compatibility test indicated that platelet adhesion on, PLGA membrane was reduced,no generous aggregation.The PLGA membrane with drugs had even less platelet adhesion.The clotting time of drug coating was prolonged and blood coagulation factors were activated in a low level. Blood coagulation factors were least activated by stents carring 50% sirolimus.Conclusion:the stent with multiple membrane had satisfactory biocompatibility,eliminated the "burst release" and drug release lasted for 50 days.
PartⅢ:the imaging evaluation of native sirolimus-heparin eluting stent of peripheral artery.Purpose:to evaluate the compliance,visibility,radial force and restenosis inhibition efficiency.Method:8 sirolimus-heparin eluting stents,8 sirolimus eluting stents and 8 bare stents were implanted into peripheral arteries of 12 dogs.The dogs accepted strictly anticoagulation.1/2 of them were killed 30 days later and the others were killed after 2 months.The condition of implanted nature including plasticity,tenacity,adaptability for curvature,visibility of trace were investigated.The in-stent thrombosis,in-stent diameter,late loss of lumina and in-stent restenosis rate were evaluated mainly.Result:the whole 24 stents were successfully implanted into dogs' peripheral arteries without complication.The stents had satisfactory plasticity and visibility.No recovery and skip was found during in the process of implantation.The imaging following up indicated no thrombosis and intimal hyperplasy.60 days later,one sirolimus stent and one bare stent occurred obstruction due to obvious thrombosis;one opposite sirolimus-heparin stent occurred intimal hyperplasy.One sirolimus-heparin stent and one sirolimus stent had intimal hyperplasy. One case was found stenosis in the segment proximate to sirolimus-heparin stent.Conclusion:the native peripheral sirolimus-heparin eluting stent had good plasticity and visibility to X-ray.There's no recovery and skip during implantation. The native sirolimus-heparin eluting stent of peripheral artery could provid a strong radial force and efficiency of anticoagulation.The in-stent restenosis and thrombosis was reduced to the least degree.
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