完全生物可吸收聚乳酸—三亚甲基碳酸酯—乙交酯共聚物心血管支架的研究

发布时间：2018-03-13 03:25

本文选题：聚乳酸　切入点：聚三亚甲基碳酸酯　出处：《复旦大学》2014年博士论文　论文类型：学位论文

【摘要】：本论文合成了高分子量的PLLA-TMC-GA三元共聚物,并以对应的PLLA-TMC二元共聚物及PLLA和PTMC均聚物作为参比样,研究了热性能、力学性能、酶、水降解行为及生物相容性等基本应用性能；采用微雕刻法,设计并制作了PLLA-TMC-GA三元共聚物血管支架样品。主要研究内容如下：(1)以辛酸亚锡为催化剂,开环聚合合成了不同序列结构的PLLA-TMC-GA三元共聚物及对应的PLLA-TMC二元共聚物和PLLA、PTMC均聚物。研究了PLLA-TMC-GA三元共聚物的分子链结构。采用1H NMR和13C NMR对PLLA-TMC-GA三元共聚物的分子链序列结构进行了表征,并计算了平均序列长度和序列分布。结果表明,TMC或GA单元的加入,使得LLA平均序列长度降低；且GA单元替换等量的TMC单元后,LLA平均序列长度更短。分析发现,LLA平均序列长度与TMC或GA含量之间均存在指数相关性。(2)详细研究了PLLA-TMC-GA三元共聚物分子链微结构与性能之间的关系。实验发现,单体组成对PLLA-TMC-GA三元共聚物热性能和力学性能有明显的影响。TMC和GA单元的引入破坏了PLLA链段的规整度,使得PLLA-TMC-GA三元共聚物的结晶能力大幅降低。共聚物的结晶能力由LLA平均序列长度lLLe值决定。在材料的力学性能方面,GA组分的加入,使得PLLA-TMC-GA三元共聚物的韧性较之PLLA和PLLA-TMC二元共聚物显著提高,而拉伸强度仅有轻微下降。该结果对通过单体配比进行共聚物链结构的调控,进而对材料的性能进行控制有很大的参考价值。(3)研究了PLLA-TMC-GA三元共聚物在蛋白酶K水溶液中的降解行为。实验揭示了PLLA-TMC-GA三元共聚物的酶降解速率是由LLA平均序列长度和结晶度共同决定的。较短的LLA平均序列长度导致共聚物的结晶度较低,从而对加快降解速率有利。但是,当LLA平均序列长度小于4.0时,共聚物的降解反而会受到抑制。降解过程中,聚合物的LLA含量几乎不发生变化,分子量有一定程度的下降。表明在蛋白酶K降解过程中,亦同时存在水解过程。在水分子的增塑和分子量下降的双重作用下,降解材料的结晶能力提高,样品的Tm和△Hm值略有上升。SEM观察发现材料主要以表面溶蚀方式降解。(4)研究了PLLA-TMC-GA三元共聚物在PBS缓冲溶液中的降解行为。与PLLA-TMC二元共聚物和PLLA均聚物相比,PLLA-TMC-GA三元共聚物的降解速率更快。样品的结晶能力在水分子的增塑和分子量下降等原因下,初始阶段出现结晶度上升；但当分子量下降到10,000时,过短的链段,使得降解产物结晶困难。进一步研究发现,PLLA-TMC-GA三元共聚物的水解过程主要分为三个阶段：首先是处于无定形区的GA组分快速降解；随后,无定形和结晶不完善区域LLA的降解开始成为主要因素；最后,降解进一步加剧,晶区开始瓦解,晶区中的LLA和裸露出来的GA单元得以继续降解。(5)从细胞相容性、血液相容性及免疫相容性角度出发,对PLLA-TMC-GA三元共聚物的生物相容性进行了评价。结果显示,PLLA-TMC-GA三元共聚物的细胞毒性小,溶血率较低,具有较好的抗凝血性质,且刺激细胞释放细胞因子的浓度较低,表现出良好的生物相容性。(6)采用完全生物可吸收的PLGA纤维增强了PLLA-TMC-GA三元共聚物。结果表明,氧气等离子体处理过的PLGA纤维使得PLLA-TMC-GA三元共聚物的力学强度得到了进一步提升。PLGA纤维不能在蛋白酶K的作用下降解,因此酶解时,PLGA纤维增强复合材料的失重速率低于PLLA-TMC-GA三元共聚物基体。但由于PLGA纤维具有较快的水解速率,其产生的酸性降解产物催化加速了基体聚合物的降解,使得酶解或水解时基体聚合物的分子量下降速度更快。(7)选取PLLA-TMC-GA三元共聚物为原料,先通过单螺杆挤出机挤出成型具有一定外径和壁厚的管材。然后,采用微雕刻法,成功制作出血管支架样品。该支架有望在为血管提供6-9个月的径向支撑作用后,1-2年内完全降解并被人体吸收,避免传统金属药物洗脱支架对血管的长期刺激、以及由此引发的血管晚期炎症和再狭窄等问题。因此,本论文开发的PLLA-TMC-GA三元共聚物具有较高的强度与韧性、合适的降解速率、良好的生物相容性及成型加工性,在血管支架等生物医用材料领域具有良好的应用前景。
[Abstract]:The molecular weight of three PLLA-TMC-GA copolymer were synthesized in this paper, and the corresponding PLLA-TMC to two yuan PLLA and PTMC copolymer and homopolymer as a reference sample, studied the thermal properties, mechanical properties, enzyme, compatibility and other basic application performance degradation in water and biological behavior; using micro engraving method, design and production of PLLA-TMC-GA three copolymer stent samples. The main contents are as follows: (1) using stannous octoate as catalyst, ring opening of different sequence structure of three PLLA-TMC-GA polymer and the corresponding PLLA-TMC and PLLA two copolymer was synthesized, PTMC homopolymer. The molecular chain structure of PLLA-TMC-GA three. The copolymer molecular chain 1H NMR and 13C NMR sequence structure of PLLA-TMC-GA three copolymer were characterized. The average sequence length and sequence distribution were calculated. The results show that the addition of TMC or GA unit, the LLA average sequence length The degree of reduction; and the GA unit to replace the TMC unit with LLA, the average sequence length shorter. Analysis shows that there were correlation between LLA index and the average sequence length of TMC or GA content. (2) a detailed study of the relationship between three yuan PLLA-TMC-GA copolymer chain microstructure and properties. It was found that the monomer composition the obvious influence of introducing.TMC and GA units to destroy the PLLA segment of three PLLA-TMC-GA polymer tacticity of thermal and mechanical properties, the crystallization ability of PLLA-TMC-GA three copolymer is significantly reduced. The crystallization ability of copolymer LLA value determined by the average sequence length of lLLe. The mechanical properties of materials, component GA added that makes the PLLA-TMC-GA three copolymer toughness compared to PLLA and PLLA-TMC two copolymer significantly increased, while the tensile strength decreased slightly. The only results of the monomer ratio of copolymer chain structure The regulation of material performance control has great reference value. (3) the degradation behaviors of PLLA-TMC-GA copolymer in three proteinase K in aqueous solution. The experiment reveals the enzymatic degradation rate of PLLA-TMC-GA three yuan of copolymer is determined by LLA average sequence length and crystallinity. The average length of sequence is LLA short lead to copolymers of low crystallinity, so as to accelerate the degradation rate advantage. However, when the LLA average sequence length is less than 4, the degradation of the copolymers may be inhibited. The degradation process, the content of LLA polymer almost did not change, the molecular weight decreased to some extent. Show that in the degradation process of K protease at the same time, also exist the hydrolysis process. The dual role of decrease in water molecules plasticization and molecular weight, improve the crystallization ability of degradable materials, samples of Tm and delta Hm value increased slightly the.SEM observation material The main material to surface erosion degradation. (4) the degradation behaviors of PLLA-TMC-GA three copolymer in PBS buffer solution. Compared with PLLA-TMC and PLLA two copolymer homopolymer, copolymer of PLLA-TMC-GA degradation rate three yuan faster. Reason of crystallization capacity of the samples in plastic and molecular weight decreased under water molecules the initial stage, the crystallinity increased; but when the molecular weight decreased to 10000 when the chain is too short, the degradation products of crystallization difficult. Further studies showed that the hydrolysis process of PLLA-TMC-GA three copolymer is mainly divided into three stages: the first is the GA group in the amorphous region of rapid degradation; subsequently, amorphous and the crystallization degradation area of LLA became the main factors; finally, the degradation further intensified, crystal area began to collapse, the GA unit in the crystal region of LLA and exposed to degradation. (5) from the Bao Xiangrong fine Sex, blood compatibility and immunocompatibility perspective on PLLA-TMC-GA three copolymer biocompatibility was evaluated. The results showed that the cytotoxicity of PLLA-TMC-GA three copolymer of small, low hemolytic rate, has good anticoagulant properties, concentration and release of cytokine stimulated cells showed low compatibility good. (6) the bioabsorbable PLGA fiber reinforced PLLA-TMC-GA three copolymer. The results show that the oxygen plasma treated PLGA fiber makes the mechanical strength of PLLA-TMC-GA three copolymer has been further enhance.PLGA fibers do not degrade in the protease K under the action of the enzyme therefore, fiber reinforced PLGA the composite weight loss rate is lower than PLLA-TMC-GA three yuan. But due to the PLGA copolymer matrix fiber has a faster hydrolysis rate, its acidic degradation products with catalytic velocity matrix The degradation of polymers, the enzyme hydrolysis solution or polymer matrix decreased faster. (7) a total of three PLLA-TMC-GA copolymer as raw material, through extrusion molding with a certain diameter and wall thickness of the pipe single screw extruder. Then, using Python Cephas, successfully developed vascular stent the stent is expected to sample. In the 6-9 months to provide radial supporting role for vascular after 1-2 years completely degraded and absorbed by the body, to avoid the traditional metal drug-eluting stent long-term stimulation on blood vessels, and blood vessels caused by late inflammation and restenosis. Therefore, this thesis develops the strength and toughness of PLLA-TMC-GA copolymer with high of three yuan right, the degradation rate, biocompatibility and processability good biological, and has good application prospect in the field of vascular stents and other biomedical materials.

【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R318.08

【参考文献】