生物可降解胆管覆膜支架的制备及其压缩性能数值模拟

发布时间：2018-01-08 14:23

本文关键词：生物可降解胆管覆膜支架的制备及其压缩性能数值模拟　出处：《东华大学》2017年博士论文　论文类型：学位论文

【摘要】：肝胆类疾病以发病率和死亡率高、并发症多等特点成为当今威胁人类生命健康的疾病之一,其中最为常见的是良恶性肝胆管疾病引起的胆管狭窄阻塞,导致梗阻性黄疸、胆管炎、胰腺炎、胆管结石等并发症的产生,严重威胁人类生活质量。目前治疗良恶性胆管狭窄的主要手段是借助放射介入技术胆管支架植入:内镜下胆管支架植入和经皮肝穿刺胆管支架植入,该方法能够很大程度改善胆管引流,缓解患者病情,并且创伤及痛苦小。胆管支架安放成功率超过90%,已经得到医生及患者的肯定。目前临床上,常用的胆管支架有塑料胆管支架和金属胆管支架,随着临床实践的积累,塑料支架与金属支架远期疗效存在缺陷,并发症(支架狭窄、堵塞、移位等)发生率较高,需要反复取出更换,增加患者治疗风险与经济负担。因此,研究完全可降解的生物可降解胆管覆膜支架(FCBBS)具有重要意义。FCBBS是一种能有效对胆管狭窄部位进行一定时间持续扩张,并能自行降解,反应产物对人体无毒副作用,还可依托覆膜结构能够防止支架再狭窄,减少了支架植入并发症产生的风险。本文根据纺织技术,设计并制备了一系列不同结构参数的FCBBS,通过压缩测试与有限元方法,阐述了结构参数与覆膜结构对支架压缩性能、应力应变的影响。主要研究内容如下:本文首先设计了fcbbs,该支架由生物可降解胆管裸支架(ncbbs)与覆膜部分组成。ncbbs是菱形网状结构,具有一定孔隙率、交织点多、结构平整稳定的特点;采用静电纺技术对ncbbs进行覆膜得到fcbbs,覆膜层具有纤维直径小、比表面积大、高孔隙率的特点。本文选用具有良好生物相容性的可降解材料聚对二氧环己酮(pdo)单丝作为ncbbs用材料,首先研究pdo单丝力学性能和体外降解性能,研究结果显示:pdo单丝具有较好力学性能,其中,pdo单丝拉伸断裂强度随单丝直径增大而减小,抗弯刚度随单丝直径增加而增加;体外降解试验显示:pdo单丝在整个降解过程中的前8周,表面形态保持较好,质量变化很小,质量保持率维持在97.5%以上,在降解过程后期12-16周,pdo单丝表面出现裂纹,并有片状脱落现象发生,pdo单丝试样在16周后的质量保持率为80.42%;pdo单丝拉伸断裂强度、抗弯刚度测试能够维持12周,在降解过程末期,pdo单丝变得脆弱易碎,容易被拉伸测试仪的夹头夹碎,导致测试无法继续进行。在整个降解过程中,pdo单丝拉伸断裂强度保持率逐渐降低,降解过程进行到10周时,强度保持率仅为16.39%。pdo单丝抗弯刚度随降解时间的增长而增加,12周时,抗弯刚度增加了45.45%;采用可降解聚己内酯材料(pcl),利用正交试验研究了不同静电纺工艺参数对pcl薄膜中纤维形态、纤维直径、孔隙率、表面积-体积比以及力学性能指标的影响,确定了适合制备fcbbs覆膜材料的最优静电纺工艺参数:pcl浓度:18.0g/100ml,聚二甲基甲酰胺(dmf)百分比:43%,电压:15kv。利用不同直径pdo单丝,制备了12种不同结构参数ncbbs,利用优选的静电纺方法对网状菱形结构ncbbs和商用mtn-da型镍钛合金胆管支架(mtn-da)进行覆膜,制备了12种不同结构参数fcbbs和1种mtn-da型镍钛合金胆管覆膜支架(fcm),通过压缩测试,对比分析两种覆膜支架以及生物可降解胆管支架覆膜前后的压缩性能。研究结果显示:fcbbs和fcm的压缩回复曲线基本相同,均表现出一定程度的塑性变形;同种直径不同编织头数的fcbbs的最大压缩力随编织头数的增大而增大,相同编织头数的fcbbs的最大压缩力随pdo单丝直径增大同样增大;在压缩过程中,对fcbbs与fcm出现的最大压缩力进行比较,结果表明:单丝直径为0.29mm时,12头fcbbs的最大压缩力较大一些,而10头fcbbs接近于fcm最大压缩力。单丝直径为0.36mm时,8头、10和12头fcbbs最大压缩力均大于fcm,由此可知,上述结构参数fcbbs力学性能够达到临床要求;比较生物可降解胆管支架覆膜前后最大压缩力可知,fcbbs最大压缩力大于对应结构参数ncbbs。本文根据实测用fcbbs与ncbbs,利用solidworks和abaqus软件,设计不同编织头数、pdo单丝直径的ncbbs和fcbbs数值模型,并对上述支架数值模型进行线弹性和弹塑性压缩数值模拟分析,研究支架结构在压缩过程中对其应力应变的影响,以及覆膜结构对支架应力应变的影响。研究结果显示:对单丝直径(0.36mm)4种编织头数ncbbs进行线弹性压缩数值模拟预分析,比较压缩数值模拟结果与对应支架试样压缩试验结果,压缩数值模拟结果与试样压缩试验结果表现出很高一致性。从压缩数值模型中提取压缩力,4种不同编织头数ncbbs压缩力均随压缩位移的增加而增加,其中12头ncbbs压缩力最大,其次是10头和8头,最小的是6头ncbbs;ncbbs中应力集中部位主要分布在支架头端“拱形结构”和单丝交织点处。比较4种编织头数ncbbs在压缩过程中出现的最大应力值,编织头数越大的ncbbs出现的最大应力值越大,说明越容易发生损害。对9种不同编织头数、单丝直径的fcbbs进行弹塑性压缩数值模拟分析,提取fcbbs压缩数值模型中压缩力,fcbbs压缩力大小随支架单丝直径增加而增加,同样随支架编织头数增加而增加,比较压缩力的压缩数值模拟结果与试样压缩试验结果,两者表现出较高一致性;fcbbs中裸支架应力集中较高区域主要分布在支架头端、支架两侧和支架中心部分,且应力大小变化剧烈,分布不均匀,fcbbs覆膜部分应力集中区域主要分布在薄膜头端和中间部位,应力大小变化平缓,分布比较均匀;比较不同结构参数fcbbs最大应力值,单丝直径相同时,fcbbs最大应力值随编织头数增大而增大,当编织头数相同时,fcbbs最大应力值随单丝直径增加而增大;fcbbs塑性耗散能随压缩时间增长而增加,其中,pdo单丝直径0.29mm(12头)与0.36mm(12头)2种fcbbs塑性耗散能大于其它7种fcbbs塑性耗散能,说明上述结构参数fcbbs较难发生塑性变形;9种fcbbs在压缩过程中均产生塑性形变,其中5种fcbbs塑性应变仅发生在薄膜部分,分别是:pdo单丝直径0.29mmm(8头、10头)2种fcbbs与pdo单丝直径0.23mmm(8头、10头、12头)3种fcbbs。比较fcbbs与ncbbs弹塑性压缩数值模拟结果可知,从压缩数模模型中提取压缩力,fcbbs压缩力大于对应结构参数ncbbs压缩力值;fcbbs最大应力值大于对应结构参数ncbbs最大应力;对比不同结构参数fcbbs与ncbbs塑性耗散能,fcbbs塑性耗散能大于对应结构参数ncbbs产生的塑性耗散能;9种结构参数fcbbs最大塑性应变值均大于零,已经发生塑性应变,而ncbbs仅单丝直径0.36mm3种编织头数(8头、10头、12头)类型支架的最大塑性应变大于零,发生塑性应变;比较fcbbs中裸支架与ncbbs最大塑性应变变化规律,pdo单丝直径0.36mm3种编织头数(8头、10头、12头)与pdo单丝直径0.29mm(12头)fcbbs模型中裸支架部分发生塑性应变,而ncbbs模型中,只有pdo单丝直径0.36mm,3种编织头数(8头、10头、12头)ncbbs发生塑性应变。本文将fcbbs放置到无菌人体胆汁环境中,研究其体外降解规律,与细胞共同培养,了解其生物相容性情况,研究结果显示:fcbbs在降解前后,结构发生显著变化,在降解前,fcbbs结构完整,支架中pdo单丝颜色为蓝色,pcl薄膜完整无破裂,且与fcbbs中裸支架粘附较好。随降解过程逐步进行,pdo单丝颜色逐渐消失变为半透明状,pcl薄膜与fcbbs中裸支架粘附作用减弱,甚至发生脱落。降解过程后期,fcbbs中pdo单丝出现断裂,支架发生坍塌,失去支撑能力;9种FCBBS在降解过程前2周,其最大压缩力值明显下降,降解过程2-10周,FCBBS最大压缩力呈不稳定态势增加,在降解过程中后期,FCBBS最大压缩力又开始下降,直到支架发生坍塌无法测量,其中,单丝直径0.36mm(8头、10头、12头)FCBBS压缩力保持时间最长,约为24周。其次是单丝直径0.29mm(8头、10头、12头)FCBBS,压缩力保持时间为22周,压缩力保持时间最短的是单丝直径0.23mm(8头、10头、12头)FCBBS,保持时间为16周;9种FCBBS质量变化趋势基本相同,在降解过程前8周,质量变化不明显,在降解过程中后期,FCBBS质量加快减小;将脐带静脉内皮细胞种植到FCBBS中PDO单丝和覆膜PCL材料上面共同培养,经过七天时间生长后,细胞数量明显增多,细胞骨架和细胞核完全伸展,生存状态良好,说明FCBBS具有良好生物相容性。综上所述,本文在纺织结构FCBBS的设计、选材、制备、性能测试以及有限元方法模拟分析方面进行了系统研究,为支架结构优化以及临床应用提供参考依据。
[Abstract]:Hepatobiliary disease with high morbidity and mortality, complications and other characteristics has become one of the most life-threatening disease today, which is the most common benign and malignant bile duct stricture of bile duct obstruction caused by disease, cause obstructive jaundice, cholangitis, pancreatitis, biliary stone and other complications, a serious threat to human life quality. Is the use of interventional biliary stent implantation mainly means the treatment of benign and malignant biliary stenosis: endoscopic biliary stenting and percutaneous transhepatic biliary stent implantation, this method can greatly improve the biliary drainage, alleviate the patient's condition, and little trauma and pain. Biliary stent placement success rate of over 90%, has been doctors and patients sure. The current clinical, biliary stents are commonly used plastic biliary stent and metal stent, with the clinical practice and the accumulation of plastic stents and gold The long-term curative effect of stent is defective, complications (stent blockage, displacement) occurred at a higher rate, the need to repeatedly removed, increasing the risk of patient treatment and economic burden. Therefore, the research of bile duct stent biodegradable completely biodegradable (FCBBS) has the important significance of.FCBBS is an effective for stenosis of bile duct was the duration of expansion, and self degradation reaction product of toxic side effects on the human body can also rely on the structure of film can prevent the stent restenosis, reduce the risk of stent implantation complications. According to the textile technology, and design a series of different structural parameters were prepared by FCBBS, by the compression test and the finite element method, elaborated the structure parameters and the structure of film on the compression performance of stents, the influence of stress and strain. The main research contents are as follows: firstly, the design of the fcbbs, the stent is made of biodegradable Bile duct stent (ncbbs) is composed of.Ncbbs and coated diamond mesh structure has certain porosity, interlacing points, structure formation and stability characteristics of ncbbs film; fcbbs by electrostatic spinning technology, coating layer has small fiber diameter, large surface area, high porosity. The selection of good biocompatibility biodegradable material poly two oxygen cyclohexanone (PDO) monofilament as ncbbs material, first study the properties and in vitro degradation of PDO monofilament mechanics, the results showed that PDO monofilament had good mechanical properties, the tensile strength of PDO monofilament with monofilament diameter increases, the flexural stiffness with fiber diameter increased increase; display in vitro degradation test: PDO monofilament during the whole degradation process in the first 8 weeks, the surface morphology is very good, the quality change is very small, the quality of maintenance in more than 97.5%, in the degradation process During the period of 12-16 weeks, PDO filament surface cracks and flaking phenomenon, PDO monofilament sample retention rate was 80.42% in quality after 16 weeks; PDO monofilament tensile strength test, flexural stiffness can be maintained for 12 weeks in the degradation process of the late PDO monofilament crumbly easily, tensile tester the chuck is broken, causing the test to continue. During the whole degradation process, PDO monofilament tensile strength retention rate decreased gradually, the degradation process of the 10 week, the strength retention rate of only 16.39%.pdo monofilament bending stiffness degradation with the increase of time increased at 12 weeks, the bending stiffness increased 45.45%; the use of degradable polycaprolactone materials (PCL), the orthogonal experiment was conducted to study the effects of electrospinning parameters on PCL thin film fiber morphology, fiber diameter, porosity, surface effect volume ratio and mechanical properties were determined for the area. Preparation of fcbbs coated material optimal electrospinning parameters: PCL concentration: 18.0g/100ml, poly two methyl formamide (DMF) percentage: 43%, voltage: 15kv. with different diameters of PDO monofilament, 12 different structural parameters of ncbbs were prepared on diamond mesh structure ncbbs and commercial mtn-da type nickel titanium alloy stent by electrostatic the preferred method of spinning (mtn-da) coated with 12 different structural parameters, fcbbs and 1 mtn-da nickel titanium alloy stent was prepared by bile duct (FCM), through compression test, comparative analysis of two kinds of biodegradable stent and bile duct stent coating before and after compression performance. The results showed that fcbbs and FCM compression response curve is basically the same, showed a certain plastic deformation degree; the maximum compressive force with different diameter knitting head number fcbbs with the increase of the number of knitting head increases, the maximum compression force the same knitting head number fcbbs The same with the increase of PDO filament diameter increased; in the compression process, the fcbbs and FCM of the maximum compression stress were compared. The results show that the fiber diameter is 0.29mm, 12 fcbbs of the maximum compression stress is larger, and the 10 head fcbbs is close to FCM maximum compression force. The filament diameter is 0.36mm, 8. 10 and 12 fcbbs maximum compression force was greater than FCM, therefore, the structure parameters of fcbbs mechanical properties can meet the clinical requirement; comparison of biodegradable stent coating before and after the maximum pressure of the fcbbs maximum compression force is greater than the corresponding ncbbs. structural parameters according to the measured by fcbbs and ncbbs, using SolidWorks and ABAQUS software, the design of different braiding head the number of ncbbs and fcbbs numerical model of PDO filament diameter, and the support of numerical model of linear elastic and elastic-plastic compression numerical simulation analysis of support structure in the compression process of the The influence of stress and strain, and the structure of film to support the influence of stress and strain. The results showed that the fiber diameter (0.36mm) of 4 kinds of numerical simulation analysis of linear elastic knitting head pre compression ncbbs, compression numerical simulation results and experimental results corresponding to support sample compression, compression and compression test specimens numerical simulation results the results show high consistency. The extraction of compression force from compression numerical model, 4 different braiding head number ncbbs compression force were increasing with the compression displacement, the maximum compression force of 12 ncbbs, followed by 10 and 8, the minimum is 6 ncbbs; the main distribution concentrated part of interlacing point at the end of "arch support structure" and the single stress ncbbs. Comparison of 4 kinds of knitting head number ncbbs in the compression process of the maximum stress, maximum knitting head the greater the number of ncbbs stress value is bigger, that is to The occurrence of the damage. On 9 different braiding head number, filament diameter fcbbs elastic plastic compression numerical simulation analysis, extraction pressure fcbbs compression numerical model of compression, fcbbs compression force increases with the increase of fiber diameter increased with the same bracket, bracket knitting head number increased, compared the simulation results with the compression compression force sample numerical compression test results, which showed high consistency; stent fcbbs stress concentration area mainly distributed in the higher end bracket, and the support bracket on both sides of the central part, and the stress size change, uneven distribution, fcbbs covered part of the stress concentration area is mainly distributed in the head end and the middle part of the film. Stress changes smoothly and evenly distributed; comparison of different structure parameters fcbbs the maximum stress value, the filament diameter is fcbbs at the same time, the maximum stress value increases with the knitting head number increases, when the knitting head number At the same time, the maximum stress value of fcbbs with the fiber diameter increased; fcbbs plastic dissipation energy increases with the compression time growth of which PDO filament diameter 0.29mm (12 head) and 0.36mm (12) of 2 kinds of fcbbs plastic dissipation energy is greater than the other 7 kinds of fcbbs plastic dissipation energy, the structure parameters fcbbs is difficult to occur plastic deformation; 9 kinds of fcbbs produce plastic deformation in the compression process, including 5 kinds of fcbbs plastic strain occurs only in the films, which are PDO 0.29mmm filament diameter (8 head, 10 head) 2 fcbbs and PDO 0.23mmm filament diameter (8 head, 10 head, 12 head) 3 fcbbs. fcbbs compared with ncbbs elastic-plastic compression numerical simulation results show that the compression force from the compression modulus extraction model, fcbbs compression force is greater than the corresponding structural parameters of ncbbs compression force; fcbbs maximum stress value is greater than the corresponding structural parameters of ncbbs maximum stress; comparison of different structural parameters fcbbs and ncbbs plastic dissipation Fcbbs energy, plastic dissipation energy is greater than the corresponding structural parameters of ncbbs produced by the plastic dissipation energy; 9 kinds of structure parameters of fcbbs the maximum plastic strain values are greater than zero, have plastic strain, while the ncbbs only 0.36mm3 filament diameter knitting head (8 head, 10 head, 12 head) the type of stent the plastic strain is greater than zero, the plastic strain; fcbbs stent and ncbbs law of plastic strain change, PDO monofilament diameter 0.36mm3 braided head number (8 head, 10 head, 12 head) and PDO (12) 0.29mm monofilament diameter stents of fcbbs model plastic strain. While the ncbbs model, only PDO filament diameter 0.36mm, 3 knitting head number (8 head, 10 head, 12 head) plastic strain ncbbs. The fcbbs is placed into a sterile environment in human bile, study the degradation in vitro, co cultured with cells, understanding its biological compatibility condition, study shows in: fcbbs degradation Before and after, significant changes have taken place in the structure, before degradation, fcbbs structure, PDO monofilament stent for the color blue, PCL film complete rupture, and fcbbs stent with good adhesion. The degradation process step by step, PDO monofilament becomes translucent color gradually disappear, weaken the bare stent adhesion of PCL thin films and fcbbs and even drop. The degradation process of the late fcbbs PDO monofilament breakage, stent collapse, loss of support ability; 9 kinds of degradation of FCBBS in the first 2 weeks, the maximum compressive force value decreased, the degradation process of 2-10 weeks, FCBBS maximum compression force was not steady increase late during the degradation. FCBBS maximum compression force began to decline, until the stent collapse cannot be measured, the filament diameter 0.36mm (8 head, 10 head, 12 head) FCBBS compression force remains the longest time for about 24 weeks. Then the filament diameter 0.29mm (8 head, 10 head, 12 head) F CBBS, the compressive force is maintained for 22 weeks, the compressive force holding time is the shortest fiber diameter 0.23mm (8 head, 10 head, 12 head) FCBBS, keep time for 16 weeks; 9 FCBBS quality is basically the same trend, 8 weeks before the degradation process, the quality did not change significantly, late in the degradation process. In FCBBS, the quality of speed will decrease; human umbilical vein endothelial cells seeded onto the FCBBS PDO and PCL coated monofilament material co culture, after seven days of growth, the number of cells increased significantly, cytoskeleton and nucleus fully extended, survive in good condition, indicating that FCBBS has good biocompatibility. In summary, this paper design in textile the structure of the FCBBS material, preparation, simulation and analysis of aspects of the system performance test and the finite element method, provides the reference for the optimization of frame structure and clinical application.

【学位授予单位】：东华大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R657.3;R318.08

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