新型“纤—膜”可降解输尿管支架管的制备、结构及其降解行为

发布时间：2018-05-06 21:37

本文选题：可降解输尿管支架管 + PGLA　；参考：《东华大学》2015年博士论文

【摘要】：输尿管支架管是置放在患者输尿管管腔面的特殊设计的中空管状支架，是泌尿外科常用的器械之一。它主要起到支撑和引流作用，保证输尿管的通畅。可降解输尿管支架管在置入体内一段时间后会降解并随尿液排出体外，避免了二次手术拔出造成的损伤和相应的并发症，因而在国内外得到了广泛地开发和研究，但由于复杂的制备工艺，降解过程无规律，降解过程中易堵塞等缺点仍未得到临床应用，因此需要设计一种新型的输尿管支架管，在特定时间内起到良好引流支撑作用，随后在体内程序性降解，随尿液顺利排出体外，并同时具备临床可操作性及易加工成型性，以改善现有可降解支架管的不足，推进其在临床上的早日应用。本文针对现有可降解支架管存在的问题，采用微型编织及后处理工艺制备一种“纤-膜”双组份可降解输尿管支架管，建立制备工艺与支架管的结构之间的关系，比较不同结构支架管之间的力学性能的特点，并多方位评价其体内外降解性能及生物相容性。基于临床使用要求，从结构设计、原料选择、编织工艺、热处理工艺和涂层处理四个方面，阐述了可降解输尿管支架管的设计依据，系统探讨了制备过程及其成型工艺与管壁结构的关系。基于输尿管支架管的性能要求，设计一定规格、形状及双组份结构的支架管，选择聚乙交酯（PGA）和聚乙交酯-丙交酯（PGLA（910））作为纤维支架管的基本原料。根据输尿管支架管的结构及性能特点，选用编织工艺作为支架管原型的制备工艺，并探索编织机齿轮比、锭子排布与支架管管壁结构参数之间的关联。其中齿数比为14:140时可制备出编织密度最大的支架管结构。设计并通过配置不同纱线组合的锭子来实现两种纤维材料在管壁上的三种不同分布结构。使用高温热处理方式实现管壁结构中膜与纤维均匀相互交织的新型“纤-膜”双组份结构，探索并选用的最佳热处理温度和时间为210℃，46s。相比于商用支架管，热处理后的“纤-膜”支架管从薄壁和轻质上都有明显的优势。不同支架管间甚至是支架管内外表面间的膜相对覆盖率都大于理论值的50%。不同双组份排布支架管热处理后支架管的长度、管壁厚度和质量损失及单位面积重量增长不同，双组份排布更加分散的支架管热处理后尺寸变化较大。基于编织和热处理工艺，探索并实现支架管的环状末端结构的制备工艺。为实现可降解支架管的可显影性，尝试了两种显影材料和涂层方法，探索最佳显影效果及可能对其他性能造成的影响。硫酸钡涂层支架管具有良好的显影效果，材料易得且工艺简单可行，同时初步尝试一种新型点状涂层方法，优化了硫酸钡涂层的不足，但有待继续探索。从轴向拉伸性能和径向压缩性能两个角度对可降解输尿管支架管进行力学性能评价，系统研究了不同“纤-膜”分布结构对支架管主要力学性能的构效关系。“纤-膜”支架管中的膜组分的相对覆盖率直接与支架管的径向压缩强力相关，而支架管中纤维含量则直接影响支架管的轴向拉伸强度，因此膜和纤维组分分别增强支架管的抗压缩和拉伸性能，可通过调控双组份的比例和含量来进一步优化结构和力学性能。三种双组份结构中，支架管C具有较好的抗压缩和回弹性能以及拉伸性能，属于最佳结构。相比于商用不可降解支架管，可降解支架管具有更高的压缩强力和拉伸强度，能够在体内更持久地保持支撑效果，且不易断裂。可降解支架管的弹性为商用支架管的90%。构建不同的降解环境，研究支架管的“纤-膜”组分，及经过不同工艺条件处理后支架管的体外降解行为，全面揭示了“纤-膜”支架管的降解特性。可降解支架管在人体尿液、模拟尿液及三种pH的PBS中的降解有较大差异，在碱性降解液里降解速度更快，人体尿液中的降解明显最快，在第18天时降解成碎段，21天时呈粉末状，模拟尿液和人体尿液较大的降解差异不仅受到了降解液pH的影响，还受到人体尿液中其他组分如微量元素和酶的影响；支架管的膜和纤维组分在模拟和人体尿液中的降解分别呈现不同的力学性能及形态变化。两种组分在力学性能上的不同作用保证了双组份支架管在降解第10天内有足够的综合力学性能。纤维组分在两种降解液中分别出现环状裂纹和整体降解两种模式，而在双组份支架管上的膜组分由于被纤维组分分割成小块，比纯膜支架管降解更快，膜组分在降解中出现规则的裂纹形态。降解过程中压缩曲线的变化反映出膜组分的降解程度，膜组分碎裂的程度同样也能从支架管拉伸曲线的前端的波动程度体现，而曲线的后段则几乎完全反映了支架管中纤维组分的拉伸状态。人体尿液中的纯纤维支架管在降解后期表面上出现结壳现象，主要是由生物膜而形成的钙盐；热处理温度越高，支架管降解越快，两种组分的结晶度值差异越大，因而双组份具有越大的降解差异；经过涂层的支架管降解性能明显加快，且涂层显影剂的支架管在降解过程中显影效果可维持1周时间；设计的一种体外动态模拟降解仪为进一步的支架管降解性能的优化和评价提供一个良好的平台。对“纤-膜”可降解输尿管支架管的生物相容性及体内降解行为进行研究，证实了本实验支架管具有优良的生物相容性，发现了体内外降解行为的差异及其可能影响因素。通过体外细胞毒性和大鼠肌肉填埋实验对硫酸钡涂层处理后的可降解支架管材料进行生物相容性评价，结果表明支架管材料细胞及组织相容性良好。后处理和灭菌过程并未对相容性良好的原材料造成影响；体内降解实验中双侧放置输尿管支架管的手术过程安全可行，未对体内降解结果造成影响。病理学分析得出植入期间可降解与商用支架管具有相近的生物相容性；综合B超检测图像，标本内支架管样品的观测及取出的支架管样的形态学和力学评价确定可降解支架管在体内的降解过程和特点。植入7天后，支架管保持管状和环状弯头形状，双组份中的膜组分碎裂成小块，仍有良好的力学性能；植入14天后，，膜组分大多已脱落，由于纤维网状结构存在仍保持管状结构及一定的抗压缩和拉伸强度；植入21天后支架管大多完全降解，剩余少量碎片；植入28天支架管材料降解完全。降解过程中也有出现在第14天时出现折痕、膜结构较快脱落及第21天出现断裂的现象；体内降解环境有复杂的力学作用，在支架管降解前期加速其降解过程，与体外降解有较大差异，针对这些特点改进支架管的结构和力学性能，减少体内降解中出现的提前断裂现象，同时完善体外动态模拟降解装置，以便于更准确地模拟并评价可降解支架管的降解性能。综上所述，本文以PGA和PGLA复丝为原料，采用微型编织及后处理工艺制备一种新型“纤-膜”可降解输尿管支架管，建立制备工艺与支架管的结构之间的关系，比较不同结构支架管之间的力学性能的特点，并多方位评价和验证了其良好的体内外降解性能及生物相容性。改善了已有可降解输尿管支架管的不足，充实了可降解支架管性能评价体系，为进一步支架管的研究及结构性能优化甚至是推向临床试验奠定基础。
[Abstract]:The ureteral stent tube is a specially designed hollow tubular stent placed on the patient ' s ureter lumen surface , which is one of the commonly used devices in the urology . It mainly plays the role of supporting and drainage to ensure the smooth smooth of the ureter . The degradable ureteral stent tube can degrade and discharge with the urine after being placed in the body for a certain period of time , thus avoiding the damage caused by the extraction of the secondary operation and the corresponding complication .

In view of the problems existing in the existing degradable stent tubes , a kind of " fiber - membrane " dual - component degradable ureteral stent was prepared by micro - weaving and post - treatment process . The relationship between the preparation process and the structure of scaffold tube was established . The mechanical properties of scaffold tubes with different structures were compared .

Based on the requirements of clinical use , the design basis of degradable ureteral stent was discussed from four aspects : structural design , raw material selection , braiding process , heat treatment process and coating treatment .

The mechanical properties of degradable ureteral stent were evaluated from two angles of axial tension and radial compression . The relative coverage rate of membrane components in " fiber - membrane " stent was directly related to the radial compression strength of stent tube .

The degradable stent tube was degraded in human urine , simulated urine and three kinds of pH in vitro . The degradation rate of degradable scaffold tube in human urine , simulated urine and three pH PBS was faster .
The membrane and fiber components of the scaffold tube exhibited different mechanical properties and morphological changes in the simulated and human urine respectively . The different effects of the two components on the mechanical properties ensured that the two groups of scaffold tubes had sufficient comprehensive mechanical properties in the 10 days of degradation .
The higher the heat treatment temperature , the faster the degradation of the stent tube , the greater the difference between the crystallinity values of the two components , and thus the greater the degradation difference of the two components .
the degradation performance of the coated stent tube is obviously accelerated , and the developing effect of the scaffold tube of the coating developer can be maintained for 1 week in the degradation process ;
An in vitro dynamic simulation degradation instrument is designed to provide a good platform for further optimization and evaluation of degradation performance of stent tube .

The biocompatibility and the in vivo degradation behavior of the " fiber - membrane " degradable ureteral stent were studied . The biocompatibility of the scaffold tube was confirmed . The biocompatibility evaluation of degradable stent tube material after the treatment of barium sulfate coating was carried out through in vitro cytotoxicity and muscle filling experiment .
In vivo degradation experiment , the procedure of bilateral placement of ureteral stent tube was safe and feasible , which did not affect the result of in vivo degradation . The pathological analysis showed that the degradable and commercial stent tube had similar biocompatibility during implantation .
The degradation process and the characteristics of degradable stent tube in vivo were determined by the observation and mechanical evaluation of the stent tube samples . After 7 days of implantation , the stent tube remained tubular and annular , and the membrane components in the two components were fragmented into small pieces , still having good mechanical properties .
After 14 days of implantation , most of the membrane components have fallen off , and because of the existence of the fiber net structure , the tubular structure and certain compressive and tensile strength remain .
Most of the stent tubes were completely degraded after 21 days of implantation , and a small amount of debris remained ;
There were folds on the 14th day in the course of degradation , and the membrane structure was faster and the rupture occurred in 21 days .
In order to improve the structure and the mechanical property of the scaffold tube and reduce the early fracture phenomenon occurring in the in vivo degradation , the in vitro dynamic simulation and degradation device is improved , so that the degradation performance of the degradable stent tube can be simulated and evaluated more accurately .

In conclusion , using PGA and PGLA multifilament as raw materials , a novel " fiber - membrane " degradable ureteral stent was prepared by micro - weaving and post - treatment process . The relationship between the preparation process and the structure of stent was established . The properties and biocompatibility of biodegradable stent were compared .

【学位授予单位】：东华大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R699

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