梯度可降解输尿管支架管的研制及动物实验研究
|
摘要
传统输尿管支架管存在留置后需经膀胱镜取出、膀胱刺激症状、感染、血尿及结石形成等诸多弊端。随着可降解高分子材料在医学领域内的广泛应用，研究者们试图研究可降解输尿管支架管，但目前仍存在降解时间可控性差、材料表面粗糙、组织相容性不良及降解过程中支架管不均一降解致输尿管梗阻等问题。因此，支架管的基质材料的选择、加工工艺及降解模式的设计是目前该领域内需要解决的主要问题。目的：
评价一种新型可由远端向近端降解的输尿管支架管的微观结构、降解时间、力学性能及生物相容性，同时评价该支架管在猪模型中的引流效果及原位组织相容性。方法：
1.将聚己内酯（PCL）与聚乳酸-羟基乙酸（PLGA）按一定的质量比（5%，10%，15%，20%，25%，30%）共溶解于三氯甲烷中，配成5%的溶液，采用单喷头电纺丝法制备PCL/PLGA输尿管支架管。拉伸仪对各种比例支架管的断裂强度进行检测。
2.体外降解研究：将5%，10%，15%三种质量比的支架管截成长约1cm小段，真空干燥，称重；分别浸于人尿液中并置于37℃恒温震荡器内，尿液每日更换一次，按浸泡时间分别于7、14、21、28、35、42、49、56天时取出3个平行样品。观察大体形态并测量残重。
3.在生物相容性研究中，MTT法进行体外细胞毒性检测，采用Hela细胞系，将25%PCL/PLGA支架管截成长约2mm小段，用含血清的细胞培养液作为浸提介质，浸提原液浓度为0.2g/ml，将浸提液用细胞培养液稀释成比例为1：2，1：4，1：8，1：16，1：32五种浓度，采用苯酚做阳性对照，细胞培养液做阴性对照，检测492nm吸光值。组织相容性研究中，将材料埋于兔脊背两侧肌肉内，用6F聚氨酯输尿管支架做为对照，分别于植入后1周、4周、12周处死动物，进行组织学观察。
4.动物实验研究：以15%及25%PCL/PLGA为原料，采用双喷头法制备可由远端向近端降解的输尿管支架。实验动物为长白猪，共10只，实验组6只，输尿管镜下植入可降解支架管；对照组4只，输尿管镜下植入聚氨酯支架。分别于支架植入后第2、4、6、8、10周进行血肌酐、尿液检测，同时行肾盂分泌造影检查评价支架管降解情况、肾脏积水及肾脏功能受损情况。10周后采用麻醉过量处死动物，取出肾脏、输尿管及膀胱，评价支架管的组织相容性。
结果：
1.支架呈白色,长度15～20cm,内径约1.5mm，外径约2.0mm，具有一定的韧性和记忆性，弯曲后不会折断。电镜扫描见支架管由直径不等的纤维丝构成，纤维直径约在60nm～1200nm之间。纤维丝无规则排列，相互交织成网状，网孔直径约在50～180um之间。不同比例PCL/PLGA电镜下结构基本相近。拉伸性能检测结果，随着PCL比例的增加，支架管的断裂强度逐渐增大，且各种比例PCL/PLGA断裂强度的差异具有统计学意义(p<0.05)。
2.体外降解实验证实三种不同质量比PCL/PLGA支架管的降解曲线均近似直线，其中5%PCL/PLGA降解至第28天时崩解成小块；15%PCL/PLGA第42天时崩解成小块，而25%PCL/PLGA第56天时崩解成小块。
3.MTT结果：阴性对照组与各种浓度浸提液组及各种浓度浸提液组之间吸光度无明显差异（P>0.05）,但均显著高于阳性对照组（P<0.05）。实验组中仅1:4组毒性为1级，其余各种比例毒性为0级，苯酚对照组毒性为4级。组织相容性研究显示：术后1周，材料与肌肉交界可见大量炎细胞浸润，并可见较多单核巨细胞，炎细胞厚度约1mm；术后4周，炎细胞明显减少，炎细胞厚度明显变薄，层数变少，仍可见单核巨细胞，交界面可见纤维化；12周时仅见少量炎细胞位于交界处，而纤维化程度较4周时无明显增加；对照组1周、4周时组织学表现与实验组相似，12周时肌肉组织与材料界面纤维化明显，纤维层较实验组厚。
4.动物实验结果：所有支架管植入顺利，位置良好，无输尿管穿孔、剥脱及严重出血等并发症。两组动物血清肌酐变化的差异无统计学意义（p>0.05）。在尿液常规动态观察中，两组动物的尿PH值差异无统计学意义（p>0.05），对照组尿液中白细胞在第8、10周显著高于实验组（p<0.05）。术后2周支架管长度及显影强度未见明显变化；术后6周4例支架管降解长度近原长度二分之一；术后8周4例支架管完全降解，术后10周全部支架降解。对照组1例术后第10周出现支架管表面结石形成。肾盂分泌造影示术后2周实验组5例出现不同程度肾脏积水，至10周末支架降解后仅1例存在轻度肾脏积水，两组动物在第8周及10周积水评分差异有统计学意义（P<0.05）。两组动物肾脏功能损害情况差异仅在第8周有统计学意义（P<0.05）。支架植入10周后，动物处死后，剖开标本见肾盂内、输尿管管腔及膀胱内未见支架管碎块残留。实验组动物肾脏及输尿管组织学改变评分为0-1分，而对照组中有2例动物组织学评分分别为2、3分,对照组动物肾盂及输尿管上段组织学评分明显高于实验组（p<0.05），而输尿管中、下段及膀胱组织学评分在两组动物间无显著差异（p>0.05）。
结论：
电纺丝工艺可制备具有纳米结构的输尿管支架管，PCL/PLGA支架管具有较好的力学性能，且随PCL含量的增高支架管的断裂强度逐渐增强。不同比例PCL/PLGA支架管体外降解时间约4-10周，其中15%及25%PCL/PLGA两种支架管的降解时间分别为6和8周，可满足临床对输尿管支架管引流时间的需求；PCL/PLGA支架管未见细胞毒性，且具有较好的组织相容性；双喷头电纺丝工艺可制备由远端向近端降解的PCL/PLGA支架管，动物实验研究证实了PCL/PLGA支架管的可由远端向近端降解的降解模式，充分引流尿液，较少引起肾脏积水、肾功能改变及尿路上皮组织学改变，可用于替代传统输尿管支架管。
Objective:
This study was designed to investigate the microstructure, degradation time,mechanical property and biocompatibility of a poly (lactic acid-glycolicacid)/polycaprolactone degradable ureteral stent in vitro. We also describe thedegradation mode, and physiological and histological responses in a porcine model.
Methods:
Fabrication and tension test of the stents: PCL and PLGA (80:20) were mixed atspecific mass percentages (5%,10%,15%,20%,25%, and30%PCL with PLGA).The mixtures were dissolved in trichloromethane to prepare a5%solution. Theelectrospinning technique was used to fabricate the ureteral stent. The micro-structureof the stents were investigated by scanning electron microscopy. The tensile propertiesof the scaffolds were determined by tensile testing of scaffold specimens in a tensilefixture of a dynamic mechanical analyzer.
In vitro degradation test: We chose the stents with mass percentages of5%,15%,and25%PCL/PLGA as the samples for testing degradation. The scaffolds was cutinto small pieces (10mm). After recording the weight, the samples were immersed inthe urine to evaluate its degradability at the temperature of37°C. The urine came fromthe healthy volunteers, and was replaced every day. At each observation points (7,14,21,28,42,49, and56days), three parallel samples were removed and the residualweight ratio were investigated.
MTT: The culture medium with serum was used as the extraction vehicle. Theconcentration of the extraction vehicle and material was0.2g/ml. HeLa cells wereused in test. The highest concentration was100%extract, and the other solutions wereextract diluted at ratios of1:2,1:4,1:8, and1:16. Culture medium was used as negative control, and phenol as the positive control. The cell viability (%) wasrecorded.
Tissue compatibility: The15%PCL/PLGA stents were cut into small pieces of1cm. Three samples were implanted into each side of the rabbit muscle separated by aninterval of1cm. The control group received an F6ureteral stent made of polyurethane.1,4, and12weeks after implantation, two rabbits were killed via air embolism at eachobservation points (7,28, and84days). The implanted stents were removed alongwith the surrounding tissues, and samples were fixed in formalin prior to paraffinembedding and hematoxylin and eosin staining.
Animal experiment: The15%PCL/PLGA and25%PCL/PLGA were used tofabricate ureteral stent which can degrade from distal end to the proximal end bydouble-needle electrospinning. A total of10female Changbai pigs were used in thestudy. Six PCL/PLGA stents and4polyurethane stents were ureteroscopically insertedunilaterally in2groups of animals. Excretory urogram, and blood and urine tests wereperformed on different observation points (14,28,42,56and70days). On day70allpigs underwent necropsy by using overdose of anesthesia for microscopic andhistological evaluation.
Results:
Stents were white, with a length of15–20cm, an inner diameter of1.5mm, andan outer diameter of2.0mm. The stent was soft with some toughness and memory,and it did not break after bending. The scanning electron microscopy showed thestents were composed of nano-fibers with a multi-pore structure. The diameters of thefiber were60-1200nm, and the pore size were50-180um, different mass percentagesstents had the same structure. The tension test results showed that with increasingPCL concentration, the tensile strength of the stent gradually increased. ThePCL/PLGA stent with5%PCL exhibited the lowest breaking strength, but thisbreaking strength was still greater than2MPa.
All three curves were almost linear, and the5%PCL/PLGA stent disintegratedinto many segments by day28. The15%PCL/PLGA stent disintegrated into segments by day42, but the25%PCL/PLGA stent did not disintegrate until day56. Theseresults provide strong evidence that the degradation time can be increased by the useof increasing PCL concentration.
The absorbance of the negative control group and samples exposed to theleaching solutions of different concentration were all greater than0.5, whereas theOD492value of the positive phenol-exposed group was less than0.1. There were nosignificant differences between the absorbance values of the negative control groupand cells exposed to the leaching solutions of different concentration (p>0.05), but allof these values were significantly higher than that of positive control group (p<0.05).The results indicate that the scaffolds fabricated by electrospinning are not cytotoxic.
The histological results showed that1week after the operation, manyinflammatory cells were present forming a layer1mm thick at the boundary andmany mononuclear giant cells also were seen. Four weeks later, the number ofinflammatory cells had decreased significantly, but some mononuclear giant cellswere still observed. The boundary became fibrotic. Twelve weeks after the operation,only a few inflammatory cells were located in the boundary; however, the fibrosispresented no apparent increase compared with that of the4th week. The histologicalappearance of the control group showed no differences with the experimental group atthe1st and4th weeks, but at the12th week, we observed significant fibrosis andthicker fibrous layers in the control group.
All10animals were stented successfully. There were no differences in bodyweight and serum creatinean in either group at any time point(p>0.05). Urinalysisshowed that the urine PH had no differences between the two groups(p>0.05), but thewhite blood cells in the polyurethane group was apparently higher after8weeks(p<0.05). Two weeks after the implantation, the PCL/PLGA stents showed nochange in length. All PCL/PLGA stents began to degrade at4weeks, and4stentsdegraded nearly50%in length at six weeks. Four stents were completely degraded byweek8, and all stents were completely degraded by week10. There was no incidentof ureteral obstruction due to degraded stent fragments and no retained pieces in the kidneys of test animals. IVP was done to assess kidney function and hydronephrosis.In PCL/PLGA group, nephrosis was observed after2week, and the nephrosis wasdecreased at4weeks. However, only1case remained mild hydronephrosis at10weeks. On week six, no significant differences were observed in hydronephrosisseverity between PCL/PLGA and polyurethane stented pigs(p>0.05). As indwellingtime increased beyond8weeks, the level of hydronephrosis increased significantly inthe polyurethane group (p<0.05). It remained constant in the PCL/PLGA group.Contrast material entry into the kidney/ureters of polyurethane stented pigs wasdelayed by week8(which approached significance) vs. PCL/PLGA stented pigs,suggesting decreased kidney function in the former.
On day70all pigs underwent necropsy by using overdose of anesthesia. The sizeof stented kidneys in each group was similar to nonstented kidneys. No stents pieceswas observed in the renal pelvic, ureter and bladder. In the polyurethane group, amassively calcified stent was observed. On day70histological findings indicatinginflammation or hydronephrosis were more frequent and severe in stented kidneysthan in nonstented kidneys. Interestingly, bullous edema, an irregular surface andincreased thickness of the urothelia were present only in the polyurethane group. Itappears that the PCL/PLGA stent produced less bladder irritation and inflammation.No difference in histological severity score was observed in the middle and distalureter sections and bladder of PCL/PLGA and polyurethane stented animals (p>0.05).In contrast, PCL/PLGA stented pigs had significantly lower mean severity scores inthe kidney and proximal ureter sections compared to polyurethane stentcontrols(p<0.05).
Conclusions:
The PCL/PLGA ureteral stent can be fabricated by electrospinning technique anddouble-needle electrospinning can fabricate the ureteral stent which can degrade fromdistal end to the proximal end. The PCL/PLGA ureteral stent had excellentmechanical properties, with the increasing of PCL concentration, the mechanicalproperties of the stent gradually increased. The degradation time of15%and25% PCL/PLGA sent was6and8weeks, respectively. The PCL/PLGA stent has nocytotoxicity and has a good histocompatibility. Animal study showed the stent candegrade from the distal end to the proximal end, and the stent had equivalent drainageeffects, less hydronephrosis and more biocompatibility compared to conventionalstents.
评价一种新型可由远端向近端降解的输尿管支架管的微观结构、降解时间、力学性能及生物相容性，同时评价该支架管在猪模型中的引流效果及原位组织相容性。方法：
1.将聚己内酯（PCL）与聚乳酸-羟基乙酸（PLGA）按一定的质量比（5%，10%，15%，20%，25%，30%）共溶解于三氯甲烷中，配成5%的溶液，采用单喷头电纺丝法制备PCL/PLGA输尿管支架管。拉伸仪对各种比例支架管的断裂强度进行检测。
2.体外降解研究：将5%，10%，15%三种质量比的支架管截成长约1cm小段，真空干燥，称重；分别浸于人尿液中并置于37℃恒温震荡器内，尿液每日更换一次，按浸泡时间分别于7、14、21、28、35、42、49、56天时取出3个平行样品。观察大体形态并测量残重。
3.在生物相容性研究中，MTT法进行体外细胞毒性检测，采用Hela细胞系，将25%PCL/PLGA支架管截成长约2mm小段，用含血清的细胞培养液作为浸提介质，浸提原液浓度为0.2g/ml，将浸提液用细胞培养液稀释成比例为1：2，1：4，1：8，1：16，1：32五种浓度，采用苯酚做阳性对照，细胞培养液做阴性对照，检测492nm吸光值。组织相容性研究中，将材料埋于兔脊背两侧肌肉内，用6F聚氨酯输尿管支架做为对照，分别于植入后1周、4周、12周处死动物，进行组织学观察。
4.动物实验研究：以15%及25%PCL/PLGA为原料，采用双喷头法制备可由远端向近端降解的输尿管支架。实验动物为长白猪，共10只，实验组6只，输尿管镜下植入可降解支架管；对照组4只，输尿管镜下植入聚氨酯支架。分别于支架植入后第2、4、6、8、10周进行血肌酐、尿液检测，同时行肾盂分泌造影检查评价支架管降解情况、肾脏积水及肾脏功能受损情况。10周后采用麻醉过量处死动物，取出肾脏、输尿管及膀胱，评价支架管的组织相容性。
结果：
1.支架呈白色,长度15～20cm,内径约1.5mm，外径约2.0mm，具有一定的韧性和记忆性，弯曲后不会折断。电镜扫描见支架管由直径不等的纤维丝构成，纤维直径约在60nm～1200nm之间。纤维丝无规则排列，相互交织成网状，网孔直径约在50～180um之间。不同比例PCL/PLGA电镜下结构基本相近。拉伸性能检测结果，随着PCL比例的增加，支架管的断裂强度逐渐增大，且各种比例PCL/PLGA断裂强度的差异具有统计学意义(p<0.05)。
2.体外降解实验证实三种不同质量比PCL/PLGA支架管的降解曲线均近似直线，其中5%PCL/PLGA降解至第28天时崩解成小块；15%PCL/PLGA第42天时崩解成小块，而25%PCL/PLGA第56天时崩解成小块。
3.MTT结果：阴性对照组与各种浓度浸提液组及各种浓度浸提液组之间吸光度无明显差异（P>0.05）,但均显著高于阳性对照组（P<0.05）。实验组中仅1:4组毒性为1级，其余各种比例毒性为0级，苯酚对照组毒性为4级。组织相容性研究显示：术后1周，材料与肌肉交界可见大量炎细胞浸润，并可见较多单核巨细胞，炎细胞厚度约1mm；术后4周，炎细胞明显减少，炎细胞厚度明显变薄，层数变少，仍可见单核巨细胞，交界面可见纤维化；12周时仅见少量炎细胞位于交界处，而纤维化程度较4周时无明显增加；对照组1周、4周时组织学表现与实验组相似，12周时肌肉组织与材料界面纤维化明显，纤维层较实验组厚。
4.动物实验结果：所有支架管植入顺利，位置良好，无输尿管穿孔、剥脱及严重出血等并发症。两组动物血清肌酐变化的差异无统计学意义（p>0.05）。在尿液常规动态观察中，两组动物的尿PH值差异无统计学意义（p>0.05），对照组尿液中白细胞在第8、10周显著高于实验组（p<0.05）。术后2周支架管长度及显影强度未见明显变化；术后6周4例支架管降解长度近原长度二分之一；术后8周4例支架管完全降解，术后10周全部支架降解。对照组1例术后第10周出现支架管表面结石形成。肾盂分泌造影示术后2周实验组5例出现不同程度肾脏积水，至10周末支架降解后仅1例存在轻度肾脏积水，两组动物在第8周及10周积水评分差异有统计学意义（P<0.05）。两组动物肾脏功能损害情况差异仅在第8周有统计学意义（P<0.05）。支架植入10周后，动物处死后，剖开标本见肾盂内、输尿管管腔及膀胱内未见支架管碎块残留。实验组动物肾脏及输尿管组织学改变评分为0-1分，而对照组中有2例动物组织学评分分别为2、3分,对照组动物肾盂及输尿管上段组织学评分明显高于实验组（p<0.05），而输尿管中、下段及膀胱组织学评分在两组动物间无显著差异（p>0.05）。
结论：
电纺丝工艺可制备具有纳米结构的输尿管支架管，PCL/PLGA支架管具有较好的力学性能，且随PCL含量的增高支架管的断裂强度逐渐增强。不同比例PCL/PLGA支架管体外降解时间约4-10周，其中15%及25%PCL/PLGA两种支架管的降解时间分别为6和8周，可满足临床对输尿管支架管引流时间的需求；PCL/PLGA支架管未见细胞毒性，且具有较好的组织相容性；双喷头电纺丝工艺可制备由远端向近端降解的PCL/PLGA支架管，动物实验研究证实了PCL/PLGA支架管的可由远端向近端降解的降解模式，充分引流尿液，较少引起肾脏积水、肾功能改变及尿路上皮组织学改变，可用于替代传统输尿管支架管。
Objective:
This study was designed to investigate the microstructure, degradation time,mechanical property and biocompatibility of a poly (lactic acid-glycolicacid)/polycaprolactone degradable ureteral stent in vitro. We also describe thedegradation mode, and physiological and histological responses in a porcine model.
Methods:
Fabrication and tension test of the stents: PCL and PLGA (80:20) were mixed atspecific mass percentages (5%,10%,15%,20%,25%, and30%PCL with PLGA).The mixtures were dissolved in trichloromethane to prepare a5%solution. Theelectrospinning technique was used to fabricate the ureteral stent. The micro-structureof the stents were investigated by scanning electron microscopy. The tensile propertiesof the scaffolds were determined by tensile testing of scaffold specimens in a tensilefixture of a dynamic mechanical analyzer.
In vitro degradation test: We chose the stents with mass percentages of5%,15%,and25%PCL/PLGA as the samples for testing degradation. The scaffolds was cutinto small pieces (10mm). After recording the weight, the samples were immersed inthe urine to evaluate its degradability at the temperature of37°C. The urine came fromthe healthy volunteers, and was replaced every day. At each observation points (7,14,21,28,42,49, and56days), three parallel samples were removed and the residualweight ratio were investigated.
MTT: The culture medium with serum was used as the extraction vehicle. Theconcentration of the extraction vehicle and material was0.2g/ml. HeLa cells wereused in test. The highest concentration was100%extract, and the other solutions wereextract diluted at ratios of1:2,1:4,1:8, and1:16. Culture medium was used as negative control, and phenol as the positive control. The cell viability (%) wasrecorded.
Tissue compatibility: The15%PCL/PLGA stents were cut into small pieces of1cm. Three samples were implanted into each side of the rabbit muscle separated by aninterval of1cm. The control group received an F6ureteral stent made of polyurethane.1,4, and12weeks after implantation, two rabbits were killed via air embolism at eachobservation points (7,28, and84days). The implanted stents were removed alongwith the surrounding tissues, and samples were fixed in formalin prior to paraffinembedding and hematoxylin and eosin staining.
Animal experiment: The15%PCL/PLGA and25%PCL/PLGA were used tofabricate ureteral stent which can degrade from distal end to the proximal end bydouble-needle electrospinning. A total of10female Changbai pigs were used in thestudy. Six PCL/PLGA stents and4polyurethane stents were ureteroscopically insertedunilaterally in2groups of animals. Excretory urogram, and blood and urine tests wereperformed on different observation points (14,28,42,56and70days). On day70allpigs underwent necropsy by using overdose of anesthesia for microscopic andhistological evaluation.
Results:
Stents were white, with a length of15–20cm, an inner diameter of1.5mm, andan outer diameter of2.0mm. The stent was soft with some toughness and memory,and it did not break after bending. The scanning electron microscopy showed thestents were composed of nano-fibers with a multi-pore structure. The diameters of thefiber were60-1200nm, and the pore size were50-180um, different mass percentagesstents had the same structure. The tension test results showed that with increasingPCL concentration, the tensile strength of the stent gradually increased. ThePCL/PLGA stent with5%PCL exhibited the lowest breaking strength, but thisbreaking strength was still greater than2MPa.
All three curves were almost linear, and the5%PCL/PLGA stent disintegratedinto many segments by day28. The15%PCL/PLGA stent disintegrated into segments by day42, but the25%PCL/PLGA stent did not disintegrate until day56. Theseresults provide strong evidence that the degradation time can be increased by the useof increasing PCL concentration.
The absorbance of the negative control group and samples exposed to theleaching solutions of different concentration were all greater than0.5, whereas theOD492value of the positive phenol-exposed group was less than0.1. There were nosignificant differences between the absorbance values of the negative control groupand cells exposed to the leaching solutions of different concentration (p>0.05), but allof these values were significantly higher than that of positive control group (p<0.05).The results indicate that the scaffolds fabricated by electrospinning are not cytotoxic.
The histological results showed that1week after the operation, manyinflammatory cells were present forming a layer1mm thick at the boundary andmany mononuclear giant cells also were seen. Four weeks later, the number ofinflammatory cells had decreased significantly, but some mononuclear giant cellswere still observed. The boundary became fibrotic. Twelve weeks after the operation,only a few inflammatory cells were located in the boundary; however, the fibrosispresented no apparent increase compared with that of the4th week. The histologicalappearance of the control group showed no differences with the experimental group atthe1st and4th weeks, but at the12th week, we observed significant fibrosis andthicker fibrous layers in the control group.
All10animals were stented successfully. There were no differences in bodyweight and serum creatinean in either group at any time point(p>0.05). Urinalysisshowed that the urine PH had no differences between the two groups(p>0.05), but thewhite blood cells in the polyurethane group was apparently higher after8weeks(p<0.05). Two weeks after the implantation, the PCL/PLGA stents showed nochange in length. All PCL/PLGA stents began to degrade at4weeks, and4stentsdegraded nearly50%in length at six weeks. Four stents were completely degraded byweek8, and all stents were completely degraded by week10. There was no incidentof ureteral obstruction due to degraded stent fragments and no retained pieces in the kidneys of test animals. IVP was done to assess kidney function and hydronephrosis.In PCL/PLGA group, nephrosis was observed after2week, and the nephrosis wasdecreased at4weeks. However, only1case remained mild hydronephrosis at10weeks. On week six, no significant differences were observed in hydronephrosisseverity between PCL/PLGA and polyurethane stented pigs(p>0.05). As indwellingtime increased beyond8weeks, the level of hydronephrosis increased significantly inthe polyurethane group (p<0.05). It remained constant in the PCL/PLGA group.Contrast material entry into the kidney/ureters of polyurethane stented pigs wasdelayed by week8(which approached significance) vs. PCL/PLGA stented pigs,suggesting decreased kidney function in the former.
On day70all pigs underwent necropsy by using overdose of anesthesia. The sizeof stented kidneys in each group was similar to nonstented kidneys. No stents pieceswas observed in the renal pelvic, ureter and bladder. In the polyurethane group, amassively calcified stent was observed. On day70histological findings indicatinginflammation or hydronephrosis were more frequent and severe in stented kidneysthan in nonstented kidneys. Interestingly, bullous edema, an irregular surface andincreased thickness of the urothelia were present only in the polyurethane group. Itappears that the PCL/PLGA stent produced less bladder irritation and inflammation.No difference in histological severity score was observed in the middle and distalureter sections and bladder of PCL/PLGA and polyurethane stented animals (p>0.05).In contrast, PCL/PLGA stented pigs had significantly lower mean severity scores inthe kidney and proximal ureter sections compared to polyurethane stentcontrols(p<0.05).
Conclusions:
The PCL/PLGA ureteral stent can be fabricated by electrospinning technique anddouble-needle electrospinning can fabricate the ureteral stent which can degrade fromdistal end to the proximal end. The PCL/PLGA ureteral stent had excellentmechanical properties, with the increasing of PCL concentration, the mechanicalproperties of the stent gradually increased. The degradation time of15%and25% PCL/PLGA sent was6and8weeks, respectively. The PCL/PLGA stent has nocytotoxicity and has a good histocompatibility. Animal study showed the stent candegrade from the distal end to the proximal end, and the stent had equivalent drainageeffects, less hydronephrosis and more biocompatibility compared to conventionalstents.
引文
[1] Damiano R, Oliva A, Esposito C, De Sio M, Autorino R, D'Armiento M. Earlyand late complications of double pigtail ureteral stent[J]. Urologiainternationalis,2002,69(2):136-40.
[2] Liatsikos E, Kallidonis P, Stolzenburg JU, Karnabatidis D. Ureteral stents: past,present and future[J]. Expert review of medical devices,2009,6(3):313-24.
[3] Al-Aown A, Kyriazis I, Kallidonis P, Kraniotis P, Rigopoulos C, KarnabatidisD, et al. Ureteral stents: new ideas, new designs[J]. Therapeutic advances inurology,2010,2(2):85-92.
[4] Herman JR. Urology:A View Through the Retrospectroscope.[M]. Hagerstown,Maryland: Harper&Row;1973.
[5] Tulloch WS. Restoration of the continuity of the ureter by means of polythenetubing[J]. British journal of urology,1952,24(1):42-5.
[6] Zimskind PD, Fetter TR, Wilkerson JL. Clinical use of long-term indwellingsilicone rubber ureteral splints inserted cystoscopically[J]. The Journal ofurology,1967,97(5):840-4.
[7] Gibbons RP, Mason JT, Correa RJ, Jr. Experience with indwelling siliconerubber ureteral catheters[J]. The Journal of urology,1974,111(5):594-9.
[8] Hepperlen TW, Mardis HK, Kammandel H. Self-retained internal ureteralstents: a new approach[J]. The Journal of urology,1978,119(6):731-4.
[9] Finney RP. Experience with new double J ureteral catheter stent[J]. TheJournal of urology,1978,120(6):678-81.
[10] Puhse G, Piechota H, Scheffold C, Kloska S, Hertle L, Wulfing C. Multiorganfailure17years after initial stone therapy: forgotten ureteral stent in ahorseshoe kidney[J]. Eur Urol,2007,52(6):1784-7.
[11] Bardapure M, Sharma A, Hammad A. Forgotten ureteric stents in renaltransplant recipients: three case reports[J]. Saudi journal of kidney diseasesand transplantation: an official publication of the Saudi Center for OrganTransplantation, Saudi Arabia,2014,25(1):109-12.
[12] Mardis HK, Kroeger RM, Hepperlen TW, Mazer MJ, Kammandel H.Polyethylene double-pigtail ureteral stents[J]. The Urologic clinics of NorthAmerica,1982,9(1):95-101.
[13] Denstedt JD, Wollin TA, Reid G. Biomaterials used in urology: current issuesof biocompatibility, infection, and encrustation[J]. Journal of endourology/Endourological Society,1998,12(6):493-500.
[14] Beiko DT, Knudsen BE, Denstedt JD. Advances in ureteral stent design[J].Journal of endourology/Endourological Society,2003,17(4):195-9.
[15] Venkatesan N SS, Jayachandran K, Doble M. Polymers as ureteral stents.[J].Journal of endourology/Endourological Society,2010,24(2):191-8.
[16] Cormio L TM, Koivusalo A, M kisalo H, Wolff H, Ruutu M. Biocompatibilityof various indwelling double-J stents.[J]. The Journal of urology,1995,153(2):494-6.
[17] John T, Rajpurkar A, Smith G, Fairfax M, Triest J. Antibiotic pretreatment ofhydrogel ureteral stent[J]. Journal of endourology/Endourological Society,2007,21(10):1211-6.
[18] Christman MS, L'Esperance J O, Choe CH, Stroup SP, Auge BK. Analysis ofureteral stent compression force and its role in malignant obstruction[J]. TheJournal of urology,2009,181(1):392-6.
[19] Pedro RN, Hendlin K, Kriedberg C, Monga M. Wire-based ureteral stents:impact on tensile strength and compression[J]. Urology,2007,70(6):1057-9.
[20] Pauer W, Eckerstorfer GM. Use of self-expanding permanent endoluminalstents for benign ureteral strictures: mid-term results[J]. The Journal of urology,1999,162(2):319-22.
[21] Kulkarni R, Bellamy E. Nickel-titanium shape memory alloy Memokath051ureteral stent for managing long-term ureteral obstruction:4-yearexperience[J]. The Journal of urology,2001,166(5):1750-4.
[22] Leveillee RJ, Pinchuk L, Wilson GJ, Block NL. A new self-expanding linedstent-graft in the dog ureter: radiological, gross, histopathological andscanning electron microscopic findings[J]. The Journal of urology,1998,160(5):1877-82.
[23] Trueba Arguinarena FJ, Fernandez del Busto E. Self-expandingpolytetrafluoroethylene covered nitinol stents for the treatment of ureteralstenosis: preliminary report[J]. The Journal of urology,2004,172(2):620-3.
[24] Kulkarni RK, Pani KC, Neuman C, Leonard F. Polylactic acid for surgicalimplants[J]. Archives of surgery,1966,93(5):839-43.
[25] Lumiaho J, Heino A, Pietilainen T, Ala-Opas M, Talja M, Valimaa T, et al. Themorphological, in situ effects of a self-reinforced bioabsorbable polylactide(SR-PLA96) ureteric stent; an experimental study[J]. The Journal of urology,2000,164(4):1360-3.
[26] Li G, Wang ZX, Fu WJ, Hong BF, Wang XX, Cao L, et al. Introduction tobiodegradable polylactic acid ureteral stent application for treatment ofureteral war injury[J]. BJU international,2011,108(6):901-6.
[27] Fu WJ, Wang ZX, Li G, Cui FZ, Zhang Y, Zhang X. Comparison of abiodegradable ureteral stent versus the traditional double-J stent for thetreatment of ureteral injury: an experimental study[J]. Biomedical materials,2012,7(6):065002.
[28]王炜,李牧,刘绍虔等.消旋聚乳酸输尿管支架管在家犬体内的降解变化及输尿管病理学表现[J].第三军医大学学报,2010,(09):959-62.
[29] Assimos DG, Smith C, Schaeffer AJ, Carone FA, Grayhack JT. Efficacy ofpolyglycolic acid (PGA) tubing stents in ureteroureterostomies[J]. Urologicalresearch,1984,12(6):291-3.
[30] Oosterlinck W, Talja M. Endoscopic urethroplasty with a free graft on abiodegradable polyglycolic acid spiral stent. A new technique[J]. Eur Urol,2000,37(1):112-5.
[31] Chew BH, Paterson RF, Clinkscales KW, Levine BS, Shalaby SW, Lange D. Invivo evaluation of the third generation biodegradable stent: a novel approachto avoiding the forgotten stent syndrome[J]. The Journal of urology,2013,189(2):719-25.
[32] Olweny EO, Landman J, Andreoni C, Collyer W, Kerbl K, Onciu M, et al.Evaluation of the use of a biodegradable ureteral stent after retrogradeendopyelotomy in a porcine model[J]. The Journal of urology,2002,167(5):2198-202.
[33] Talja M, Multanen M, Valimaa T, Tormala P. Bioabsorbable SR-PLGA hornstent after antegrade endopyelotomy: a case report[J]. Journal of endourology/Endourological Society,2002,16(5):299-302.
[34] Hadaschik BA, Paterson RF, Fazli L, Clinkscales KW, Shalaby SW, Chew BH.Investigation of a novel degradable ureteral stent in a porcine model[J]. TheJournal of urology,2008,180(3):1161-6.
[35] Chew BH, Lange D, Paterson RF, Hendlin K, Monga M, Clinkscales KW, et al.Next generation biodegradable ureteral stent in a yucatan pig model[J]. TheJournal of urology,2010,183(2):765-71.
[36] Tamboli V, Mishra GP, Mitra AK. Novel pentablock copolymer(PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery:Effect of copolymer compositions on the crystallinity of copolymers and invitro drug release profile from nanoparticles[J]. Colloid and polymer science,2013,291(5):1235-45.
[37] Erdemli O, Usanmaz A, Keskin D, Tezcaner A. Characteristics and releaseprofiles of MPEG-PCL-MPEG microspheres containing immunoglobulin G[J].Colloids and surfaces B, Biointerfaces,2014.
[38] Khojasteh A, Behnia H, Hosseini FS, Dehghan MM, Abbasnia P, Abbas FM.The effect of PCL-TCP scaffold loaded with mesenchymal stem cells onvertical bone augmentation in dog mandible: a preliminary report[J]. Journalof biomedical materials research Part B, Applied biomaterials,2013,101(5):848-54.
[39] Ba Linh NT, Min YK, Lee BT. Hybrid hydroxyapatite nanoparticles-loadedPCL/GE blend fibers for bone tissue engineering[J]. Journal of biomaterialsscience Polymer edition,2013,24(5):520-38.
[40] Jones DS, Djokic J, McCoy CP, Gorman SP. Poly(epsilon-caprolactone) andpoly(epsilon-caprolactone)-polyvinylpyrrolidone-iodine blends as ureteralbiomaterials: characterisation of mechanical and surface properties,degradation and resistance to encrustation in vitro[J]. Biomaterials,2002,23(23):4449-58.
[41] Olweny EO, Portis AJ, Sundaram CP, Afane JS, Humphrey PA, Ewers R, et al.Evaluation of a chronic indwelling prototype mesh ureteral stent in a porcinemodel[J]. Urology,2000,56(5):857-62.
[42] Patel MJ, Patel SS, Patel NS, Patel NM. Current status and future prospects ofdrug eluting stents for restenosis[J]. Acta pharmaceutica,2012,62(4):473-96.
[43] Waksman R, Maluenda G. Polymer drug-eluting stents: is the futurebiodegradable?[J]. Lancet,2011,378(9807):1900-2.
[44] Bosiers M, Deloose K, Keirse K, Verbist J, Peeters P. Are drug-eluting stentsthe future of SFA treatment?[J]. The Journal of cardiovascular surgery,2010,51(1):115-9.
[45] Dunn MD, Portis AJ, Kahn SA, Yan Y, Shalhav AL, Elbahnasy AM, et al.Clinical effectiveness of new stent design: randomized single-blindcomparison of tail and double-pigtail stents[J]. Journal of endourology/Endourological Society,2000,14(2):195-202.
[46] Liatsikos EN, Hom D, Dinlenc CZ, Kapoor R, Alexianu M, Yohannes P, et al.Tail stent versus re-entry tube: a randomized comparison after percutaneousstone extraction[J]. Urology,2002,59(1):15-9.
[47] Lam JS, Gupta M. Update on ureteral stents[J]. Urology,2004,64(1):9-15.
[48] Ecke TH, Bartel P, Hallmann S, Ruttloff J. Evaluation of symptoms andpatients' comfort for JJ-ureteral stents with and without antireflux-membranevalve[J]. Urology,2010,75(1):212-6.
[49] Rotariu P, Yohannes P, Alexianu M, Rosner D, Lee BR, Lucan M, et al.Management of malignant extrinsic compression of the ureter by simultaneousplacement of two ipsilateral ureteral stents[J]. Journal of endourology/Endourological Society,2001,15(10):979-83.
[50] Hafron J, Ost MC, Tan BJ, Fogarty JD, Hoenig DM, Lee BR, et al. Noveldual-lumen ureteral stents provide better ureteral flow than single ureteral stentin ex vivo porcine kidney model of extrinsic ureteral obstruction[J]. Urology,2006,68(4):911-5.
[51]王春喜,侯宇川,王勇等.漏斗形生物降解材料输尿管支架的动物实验研究[J].中华泌尿外科杂志,2006,(11):738-41.
[52] Macaluso JN, Jr., Deutsch JS, Goodman JR, Appell RA, Prats LJ, Jr., Wahl P.The use of the Magnetip double-J ureteral stent in urological practice[J]. TheJournal of urology,1989,142(3):701-3.
[53] Taylor WN, McDougall IT. Minimally invasive ureteral stent retrieval[J]. TheJournal of urology,2002,168(5):2020-3.
[54] Liatsikos E KP, Kyriazis I, et,al. Ureteral obstruction: is the full metallicdouble-pigtail stent the way to go?[J]. European Urology,2010,57(3):480-6.
[55] Cauda F, Cauda V, Fiori C, et a. Heparin coating on ureteral Double J stentsprevents encrustations: an in vivo case study[J]. Journal of endourology/Endourological Society,2008,22(3):465-72.
[56] Lange D, Elwood CN, Choi K, et a. Uropathogen interaction with the surfaceof urological stents using different surface properties[J]. The Journal ofurology,2009,182(3):1194-200.
[57] Watterson JD, Cadieux PA, Beiko DT, Cook AJ, Burton JP, Harbottle RR, et al.Oxalate-degrading enzymes from Oxalobacter formigenes: a novel devicecoating to reduce urinary tract biomaterial-related encrustation[J]. Journal ofendourology/Endourological Society,2003,17(5):269-74.
[58] Laube N, Kleinen L, Bradenahl J, Meissner A. Diamond-like carbon coatingson ureteral stents--a new strategy for decreasing the formation of crystallinebacterial biofilms?[J]. The Journal of urology,2007,177(5):1923-7.
[59] Chew BH, Denstedt JD. Technology insight: Novel ureteral stent materials anddesigns[J]. Nature clinical practice Urology,2004,1(1):44-8.
[60] Chung HH, Lee SH, Cho SB, Park HS, Kim YS, Kang BC, et al. Comparisonof a new polytetrafluoroethylene-covered metallic stent to a noncovered stentin canine ureters[J]. Cardiovascular and interventional radiology,2008,31(3):619-28.
[61] Liatsikos EN, Karnabatidis D, Kagadis GC, Rokkas K, Constantinides C,Christeas N, et al. Application of paclitaxel-eluting metal mesh stents withinthe pig ureter: an experimental study[J]. Eur Urol,2007,51(1):217-23.
[62] Shin JH, Song HY, Choi CG, Yuk SH, Kim JS, Kim YM, et al. Tissuehyperplasia: influence of a paclitaxel-eluting covered stent--preliminary studyin a canine urethral model[J]. Radiology,2005,234(2):438-44.
[63] Cadieux PA, Chew BH, Nott L, Seney S, Elwood CN, Wignall GR, et al. Useof triclosan-eluting ureteral stents in patients with long-term stents[J]. Journalof endourology/Endourological Society,2009,23(7):1187-94.
[64] Krambeck AE, Walsh RS, Denstedt JD, Preminger GM, Li J, Evans JC, et al. Anovel drug eluting ureteral stent: a prospective, randomized, multicenterclinical trial to evaluate the safety and effectiveness of a ketorolac loadedureteral stent[J]. The Journal of urology,2010,183(3):1037-42.
[65] Yin M, Yuan Y, Liu C, Wang J. Combinatorial coating of adhesive polypeptideand anti-CD34antibody for improved endothelial cell adhesion andproliferation[J]. Journal of materials science Materials in medicine,2009,20(7):1513-23.
[66] Lingeman JE, Preminger GM, Berger Y, Denstedt JD, Goldstone L, Segura JW,et al. Use of a temporary ureteral drainage stent after uncomplicatedureteroscopy: results from a phase II clinical trial[J]. The Journal of urology,2003,169(5):1682-8.
[67]侯宇川,王春喜,安伟等.新型生物降解材料输尿管支架的动物实验研究[J].科学技术与工程,2006,6(17):2738-42.
[68]侯宇川,王春喜,陈学思等.新型生物降解材料输尿管支架的生物相容性研究[J].中华实验外科杂志,2006,(05):571-2.
[69]侯宇川,王春喜,郑佐柱等.生物降解输尿管支架材料丙交酯/乙交酯共聚物的生物相容性及体内外降解特性[J].吉林大学学报(医学版),2005,(04):526-9+480.
[70]赵勇,唐华.输尿管支架管相关症状的防治[J].中华临床医师杂志(电子版),2012,(10):2746-8.
[71]唐维寅,夏术阶.输尿管支架管对上尿路影响的研究进展[J].临床泌尿外科杂志,2012,27(09):711-6.
[72]李双燕,王曙东,张幼珠.静电纺PLGA管状支架的结构与性能[J].苏州大学学报(工科版),2009,29(06):21-5.
[73] Thomas V, Donahoe T, Nyairo E, Dean DR, Vohra YK. Electrospinning ofBiosyn((R))-based tubular conduits: structural, morphological, and mechanicalcharacterizations[J]. Acta biomaterialia,2011,7(5):2070-9.
[74] Iverson N, Plourde N, Chnari E, Nackman GB, Moghe PV. Convergence ofnanotechnology and cardiovascular medicine: progress and emergingprospects[J]. BioDrugs: clinical immunotherapeutics, biopharmaceuticals andgene therapy,2008,22(1):1-10.
[75] Klose D, Laprais M, Leroux V, Siepmann F, Deprez B, Bordet R, et al.Fenofibrate-loaded PLGA microparticles: effects on ischemic stroke[J].European journal of pharmaceutical sciences: official journal of the EuropeanFederation for Pharmaceutical Sciences,2009,37(1):43-52.
[76]李双燕. PLGA组织工程支架材料的研究与展望[J].国外丝绸,2009,24(02):29-31.
[77]申雄军,阮建明,周忠诚等. PLGA的合成、表征及其导管支架的制备[J].长沙理工大学学报(自然科学版),2008,5(02):93-6+102.
[78] Jain RA. The manufacturing techniques of various drug loaded biodegradablepoly(lactide-co-glycolide)(PLGA) devices[J]. Biomaterials,2000,21(23):2475-90.
[79] Athanasiou KA, Niederauer GG, Agrawal CM. Sterilization, toxicity,biocompatibility and clinical applications of polylactic acid/polyglycolic acidcopolymers[J]. Biomaterials,1996,17(2):93-102.
[80]赵莉,何晨光,高永娟等. PLGA的不同组成对支架材料性能的影响研究[J].中国生物工程杂志,2008,28(05):22-8.
[81] Hendlin K, Vedula K, Horn C, Monga M. In vitro evaluation of ureteral stentcompression[J]. Urology,2006,67(4):679-82.
[82] Wang X, Chen, QH, Hou, YC,et,al. Fabrication, crosslinking and in vitrobiocompatibility of a novel degradable nano-structure urethral tubularscaffold[J]. Chem Res Chinese Universities,2012,28(5):912-5.
[83] Lu JM, Wang X, Marin-Muller C, Wang H, Lin PH, Yao Q, et al. Currentadvances in research and clinical applications of PLGA-basednanotechnology[J]. Expert review of molecular diagnostics,2009,9(4):325-41.
[84] Pungkham H, Swatdipakdi N, Theerasilp M, Karnkla S, Chittchang M,Ploypradith P, et al. PEG-b-PCL and PEG-b-PLA polymeric micelles asnanocarrieres for lamellarin N delivery[J]. Conference proceedings: AnnualInternational Conference of the IEEE Engineering in Medicine and BiologySociety IEEE Engineering in Medicine and Biology Society Conference,2011,2011:3245-8.
[85] Shi S, Zhu X, Guo Q, Wang Y, Zuo T, Luo F, et al. Self-assembledmPEG-PCL-g-PEI micelles for simultaneous codelivery of chemotherapeuticdrugs and DNA: synthesis and characterization in vitro[J]. Internationaljournal of nanomedicine,2012,7:1749-59.
[86] Dubey N, Varshney R, Shukla J, Ganeshpurkar A, Hazari PP, BandopadhayaGP, et al. Synthesis and evaluation of biodegradable PCL/PEG nanoparticlesfor neuroendocrine tumor targeted delivery of somatostatin analog[J]. Drugdelivery,2012,19(3):132-42.
[87] Kehoe S, Zhang XF, Lewis L, O'Shea H, Boyd D. Characterization of PLGAbased composite nerve guidance conduits: effect of F127content on modulusover time in simulated physiological conditions[J]. Journal of the mechanicalbehavior of biomedical materials,2012,14:180-5.
[88] Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) asBiodegradable Controlled Drug Delivery Carrier[J]. Polymers,2011,3(3):1377-97.
[89] McCall RL, Sirianni RW. PLGA nanoparticles formed by single-ordouble-emulsion with vitamin E-TPGS[J]. Journal of visualized experiments:JoVE,2013,(82):51015.
[90] Shim JH, Moon TS, Yun MJ, Jeon YC, Jeong CM, Cho DW, et al. Stimulationof healing within a rabbit calvarial defect by a PCL/PLGA scaffold blendedwith TCP using solid freeform fabrication technology[J]. Journal of materialsscience Materials in medicine,2012,23(12):2993-3002.
[91] Johnson HJ, Northup SJ, Seagraves PA, Atallah M, Garvin PJ, Lin L, et al.Biocompatibility test procedures for materials evaluation in vitro. II. Objectivemethods of toxicity assessment[J]. Journal of biomedical materials research,1985,19(5):489-508.
[92] Laschke MW, Strohe A, Scheuer C, Eglin D, Verrier S, Alini M, et al. In vivobiocompatibility and vascularization of biodegradable porous polyurethanescaffolds for tissue engineering[J]. Acta biomaterialia,2009,5(6):1991-2001.
[93] Cu Y, Booth CJ, Saltzman WM. In vivo distribution of surface-modified PLGAnanoparticles following intravaginal delivery[J]. Journal of controlled release: officialjournal of the Controlled Release Society,2011,156(2):258-64.
[94] Faisant N, Akiki J, Siepmann F, Benoit JP, Siepmann J. Effects of the type ofrelease medium on drug release from PLGA-based microparticles: experimentand theory[J]. International journal of pharmaceutics,2006,314(2):189-97.
[95] Dyer RB, Chen MY, Zagoria RJ, Regan JD, Hood CG, Kavanagh PV.Complications of ureteral stent placement[J]. Radiographics: a reviewpublication of the Radiological Society of North America, Inc,2002,22(5):1005-22.
[96] Yossepowitch O, Lifshitz DA, Dekel Y, Gross M, Keidar DM, Neuman M, etal. Predicting the success of retrograde stenting for managing ureteralobstruction[J]. The Journal of urology,2001,166(5):1746-9.
[97] Yoo JY, Kim JM, Seo KS, Jeong YK, Lee HB, Khang G. Characterization ofdegradation behavior for PLGA in various pH condition by simple liquidchromatography method[J]. Bio-medical materials and engineering,2005,15(4):279-88.
[98] Zolnik BS, Burgess DJ. Effect of acidic pH on PLGA microsphere degradationand release[J]. Journal of controlled release: official journal of the ControlledRelease Society,2007,122(3):338-44.
[99] Maheshwari PN, Andankar MG, Khera R, Stone RG. The indwelling uretericstent: a 'friendly' procedure with unfriendly high morbidity[J]. BJUinternational,2000,86(6):757-8.
[100] Richter S, Ringel A, Shalev M, Nissenkorn I. The indwelling ureteric stent: a'friendly' procedure with unfriendly high morbidity[J]. BJU international,2000,85(4):408-11.
[101] Tschada R, Mickisch G, Rassweiler J, Knebel L, Alken P.[Success and failurewith double J ureteral stent. Analysis of107cases][J]. Journal d'urologie,1991,97(2):93-7.
[102] Klis R1K-KE, Denys A, Sosnowski M, Rozanski W. Relationship betweenurinary tract infection and self-retaining Double-J catheter colonization[J].Journal of endourology/Endourological Society,2009,23(6):1015-9.
[103] Glazier DB, Jacobs MG, Lyman NW, Whang MI, Manor E, Mulgaonkar SP.Urinary tract infection associated with ureteral stents in renal transplantation[J].The Canadian journal of urology,1998,5(1):462-6.
[104] el-Faqih SR, Shamsuddin AB, Chakrabarti A, Atassi R, Kardar AH, Osman MK, et al.Polyurethane internal ureteral stents in treatment of stone patients: morbidity relatedto indwelling times[J]. The Journal of urology,1991,146(6):1487-91.
[2] Liatsikos E, Kallidonis P, Stolzenburg JU, Karnabatidis D. Ureteral stents: past,present and future[J]. Expert review of medical devices,2009,6(3):313-24.
[3] Al-Aown A, Kyriazis I, Kallidonis P, Kraniotis P, Rigopoulos C, KarnabatidisD, et al. Ureteral stents: new ideas, new designs[J]. Therapeutic advances inurology,2010,2(2):85-92.
[4] Herman JR. Urology:A View Through the Retrospectroscope.[M]. Hagerstown,Maryland: Harper&Row;1973.
[5] Tulloch WS. Restoration of the continuity of the ureter by means of polythenetubing[J]. British journal of urology,1952,24(1):42-5.
[6] Zimskind PD, Fetter TR, Wilkerson JL. Clinical use of long-term indwellingsilicone rubber ureteral splints inserted cystoscopically[J]. The Journal ofurology,1967,97(5):840-4.
[7] Gibbons RP, Mason JT, Correa RJ, Jr. Experience with indwelling siliconerubber ureteral catheters[J]. The Journal of urology,1974,111(5):594-9.
[8] Hepperlen TW, Mardis HK, Kammandel H. Self-retained internal ureteralstents: a new approach[J]. The Journal of urology,1978,119(6):731-4.
[9] Finney RP. Experience with new double J ureteral catheter stent[J]. TheJournal of urology,1978,120(6):678-81.
[10] Puhse G, Piechota H, Scheffold C, Kloska S, Hertle L, Wulfing C. Multiorganfailure17years after initial stone therapy: forgotten ureteral stent in ahorseshoe kidney[J]. Eur Urol,2007,52(6):1784-7.
[11] Bardapure M, Sharma A, Hammad A. Forgotten ureteric stents in renaltransplant recipients: three case reports[J]. Saudi journal of kidney diseasesand transplantation: an official publication of the Saudi Center for OrganTransplantation, Saudi Arabia,2014,25(1):109-12.
[12] Mardis HK, Kroeger RM, Hepperlen TW, Mazer MJ, Kammandel H.Polyethylene double-pigtail ureteral stents[J]. The Urologic clinics of NorthAmerica,1982,9(1):95-101.
[13] Denstedt JD, Wollin TA, Reid G. Biomaterials used in urology: current issuesof biocompatibility, infection, and encrustation[J]. Journal of endourology/Endourological Society,1998,12(6):493-500.
[14] Beiko DT, Knudsen BE, Denstedt JD. Advances in ureteral stent design[J].Journal of endourology/Endourological Society,2003,17(4):195-9.
[15] Venkatesan N SS, Jayachandran K, Doble M. Polymers as ureteral stents.[J].Journal of endourology/Endourological Society,2010,24(2):191-8.
[16] Cormio L TM, Koivusalo A, M kisalo H, Wolff H, Ruutu M. Biocompatibilityof various indwelling double-J stents.[J]. The Journal of urology,1995,153(2):494-6.
[17] John T, Rajpurkar A, Smith G, Fairfax M, Triest J. Antibiotic pretreatment ofhydrogel ureteral stent[J]. Journal of endourology/Endourological Society,2007,21(10):1211-6.
[18] Christman MS, L'Esperance J O, Choe CH, Stroup SP, Auge BK. Analysis ofureteral stent compression force and its role in malignant obstruction[J]. TheJournal of urology,2009,181(1):392-6.
[19] Pedro RN, Hendlin K, Kriedberg C, Monga M. Wire-based ureteral stents:impact on tensile strength and compression[J]. Urology,2007,70(6):1057-9.
[20] Pauer W, Eckerstorfer GM. Use of self-expanding permanent endoluminalstents for benign ureteral strictures: mid-term results[J]. The Journal of urology,1999,162(2):319-22.
[21] Kulkarni R, Bellamy E. Nickel-titanium shape memory alloy Memokath051ureteral stent for managing long-term ureteral obstruction:4-yearexperience[J]. The Journal of urology,2001,166(5):1750-4.
[22] Leveillee RJ, Pinchuk L, Wilson GJ, Block NL. A new self-expanding linedstent-graft in the dog ureter: radiological, gross, histopathological andscanning electron microscopic findings[J]. The Journal of urology,1998,160(5):1877-82.
[23] Trueba Arguinarena FJ, Fernandez del Busto E. Self-expandingpolytetrafluoroethylene covered nitinol stents for the treatment of ureteralstenosis: preliminary report[J]. The Journal of urology,2004,172(2):620-3.
[24] Kulkarni RK, Pani KC, Neuman C, Leonard F. Polylactic acid for surgicalimplants[J]. Archives of surgery,1966,93(5):839-43.
[25] Lumiaho J, Heino A, Pietilainen T, Ala-Opas M, Talja M, Valimaa T, et al. Themorphological, in situ effects of a self-reinforced bioabsorbable polylactide(SR-PLA96) ureteric stent; an experimental study[J]. The Journal of urology,2000,164(4):1360-3.
[26] Li G, Wang ZX, Fu WJ, Hong BF, Wang XX, Cao L, et al. Introduction tobiodegradable polylactic acid ureteral stent application for treatment ofureteral war injury[J]. BJU international,2011,108(6):901-6.
[27] Fu WJ, Wang ZX, Li G, Cui FZ, Zhang Y, Zhang X. Comparison of abiodegradable ureteral stent versus the traditional double-J stent for thetreatment of ureteral injury: an experimental study[J]. Biomedical materials,2012,7(6):065002.
[28]王炜,李牧,刘绍虔等.消旋聚乳酸输尿管支架管在家犬体内的降解变化及输尿管病理学表现[J].第三军医大学学报,2010,(09):959-62.
[29] Assimos DG, Smith C, Schaeffer AJ, Carone FA, Grayhack JT. Efficacy ofpolyglycolic acid (PGA) tubing stents in ureteroureterostomies[J]. Urologicalresearch,1984,12(6):291-3.
[30] Oosterlinck W, Talja M. Endoscopic urethroplasty with a free graft on abiodegradable polyglycolic acid spiral stent. A new technique[J]. Eur Urol,2000,37(1):112-5.
[31] Chew BH, Paterson RF, Clinkscales KW, Levine BS, Shalaby SW, Lange D. Invivo evaluation of the third generation biodegradable stent: a novel approachto avoiding the forgotten stent syndrome[J]. The Journal of urology,2013,189(2):719-25.
[32] Olweny EO, Landman J, Andreoni C, Collyer W, Kerbl K, Onciu M, et al.Evaluation of the use of a biodegradable ureteral stent after retrogradeendopyelotomy in a porcine model[J]. The Journal of urology,2002,167(5):2198-202.
[33] Talja M, Multanen M, Valimaa T, Tormala P. Bioabsorbable SR-PLGA hornstent after antegrade endopyelotomy: a case report[J]. Journal of endourology/Endourological Society,2002,16(5):299-302.
[34] Hadaschik BA, Paterson RF, Fazli L, Clinkscales KW, Shalaby SW, Chew BH.Investigation of a novel degradable ureteral stent in a porcine model[J]. TheJournal of urology,2008,180(3):1161-6.
[35] Chew BH, Lange D, Paterson RF, Hendlin K, Monga M, Clinkscales KW, et al.Next generation biodegradable ureteral stent in a yucatan pig model[J]. TheJournal of urology,2010,183(2):765-71.
[36] Tamboli V, Mishra GP, Mitra AK. Novel pentablock copolymer(PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery:Effect of copolymer compositions on the crystallinity of copolymers and invitro drug release profile from nanoparticles[J]. Colloid and polymer science,2013,291(5):1235-45.
[37] Erdemli O, Usanmaz A, Keskin D, Tezcaner A. Characteristics and releaseprofiles of MPEG-PCL-MPEG microspheres containing immunoglobulin G[J].Colloids and surfaces B, Biointerfaces,2014.
[38] Khojasteh A, Behnia H, Hosseini FS, Dehghan MM, Abbasnia P, Abbas FM.The effect of PCL-TCP scaffold loaded with mesenchymal stem cells onvertical bone augmentation in dog mandible: a preliminary report[J]. Journalof biomedical materials research Part B, Applied biomaterials,2013,101(5):848-54.
[39] Ba Linh NT, Min YK, Lee BT. Hybrid hydroxyapatite nanoparticles-loadedPCL/GE blend fibers for bone tissue engineering[J]. Journal of biomaterialsscience Polymer edition,2013,24(5):520-38.
[40] Jones DS, Djokic J, McCoy CP, Gorman SP. Poly(epsilon-caprolactone) andpoly(epsilon-caprolactone)-polyvinylpyrrolidone-iodine blends as ureteralbiomaterials: characterisation of mechanical and surface properties,degradation and resistance to encrustation in vitro[J]. Biomaterials,2002,23(23):4449-58.
[41] Olweny EO, Portis AJ, Sundaram CP, Afane JS, Humphrey PA, Ewers R, et al.Evaluation of a chronic indwelling prototype mesh ureteral stent in a porcinemodel[J]. Urology,2000,56(5):857-62.
[42] Patel MJ, Patel SS, Patel NS, Patel NM. Current status and future prospects ofdrug eluting stents for restenosis[J]. Acta pharmaceutica,2012,62(4):473-96.
[43] Waksman R, Maluenda G. Polymer drug-eluting stents: is the futurebiodegradable?[J]. Lancet,2011,378(9807):1900-2.
[44] Bosiers M, Deloose K, Keirse K, Verbist J, Peeters P. Are drug-eluting stentsthe future of SFA treatment?[J]. The Journal of cardiovascular surgery,2010,51(1):115-9.
[45] Dunn MD, Portis AJ, Kahn SA, Yan Y, Shalhav AL, Elbahnasy AM, et al.Clinical effectiveness of new stent design: randomized single-blindcomparison of tail and double-pigtail stents[J]. Journal of endourology/Endourological Society,2000,14(2):195-202.
[46] Liatsikos EN, Hom D, Dinlenc CZ, Kapoor R, Alexianu M, Yohannes P, et al.Tail stent versus re-entry tube: a randomized comparison after percutaneousstone extraction[J]. Urology,2002,59(1):15-9.
[47] Lam JS, Gupta M. Update on ureteral stents[J]. Urology,2004,64(1):9-15.
[48] Ecke TH, Bartel P, Hallmann S, Ruttloff J. Evaluation of symptoms andpatients' comfort for JJ-ureteral stents with and without antireflux-membranevalve[J]. Urology,2010,75(1):212-6.
[49] Rotariu P, Yohannes P, Alexianu M, Rosner D, Lee BR, Lucan M, et al.Management of malignant extrinsic compression of the ureter by simultaneousplacement of two ipsilateral ureteral stents[J]. Journal of endourology/Endourological Society,2001,15(10):979-83.
[50] Hafron J, Ost MC, Tan BJ, Fogarty JD, Hoenig DM, Lee BR, et al. Noveldual-lumen ureteral stents provide better ureteral flow than single ureteral stentin ex vivo porcine kidney model of extrinsic ureteral obstruction[J]. Urology,2006,68(4):911-5.
[51]王春喜,侯宇川,王勇等.漏斗形生物降解材料输尿管支架的动物实验研究[J].中华泌尿外科杂志,2006,(11):738-41.
[52] Macaluso JN, Jr., Deutsch JS, Goodman JR, Appell RA, Prats LJ, Jr., Wahl P.The use of the Magnetip double-J ureteral stent in urological practice[J]. TheJournal of urology,1989,142(3):701-3.
[53] Taylor WN, McDougall IT. Minimally invasive ureteral stent retrieval[J]. TheJournal of urology,2002,168(5):2020-3.
[54] Liatsikos E KP, Kyriazis I, et,al. Ureteral obstruction: is the full metallicdouble-pigtail stent the way to go?[J]. European Urology,2010,57(3):480-6.
[55] Cauda F, Cauda V, Fiori C, et a. Heparin coating on ureteral Double J stentsprevents encrustations: an in vivo case study[J]. Journal of endourology/Endourological Society,2008,22(3):465-72.
[56] Lange D, Elwood CN, Choi K, et a. Uropathogen interaction with the surfaceof urological stents using different surface properties[J]. The Journal ofurology,2009,182(3):1194-200.
[57] Watterson JD, Cadieux PA, Beiko DT, Cook AJ, Burton JP, Harbottle RR, et al.Oxalate-degrading enzymes from Oxalobacter formigenes: a novel devicecoating to reduce urinary tract biomaterial-related encrustation[J]. Journal ofendourology/Endourological Society,2003,17(5):269-74.
[58] Laube N, Kleinen L, Bradenahl J, Meissner A. Diamond-like carbon coatingson ureteral stents--a new strategy for decreasing the formation of crystallinebacterial biofilms?[J]. The Journal of urology,2007,177(5):1923-7.
[59] Chew BH, Denstedt JD. Technology insight: Novel ureteral stent materials anddesigns[J]. Nature clinical practice Urology,2004,1(1):44-8.
[60] Chung HH, Lee SH, Cho SB, Park HS, Kim YS, Kang BC, et al. Comparisonof a new polytetrafluoroethylene-covered metallic stent to a noncovered stentin canine ureters[J]. Cardiovascular and interventional radiology,2008,31(3):619-28.
[61] Liatsikos EN, Karnabatidis D, Kagadis GC, Rokkas K, Constantinides C,Christeas N, et al. Application of paclitaxel-eluting metal mesh stents withinthe pig ureter: an experimental study[J]. Eur Urol,2007,51(1):217-23.
[62] Shin JH, Song HY, Choi CG, Yuk SH, Kim JS, Kim YM, et al. Tissuehyperplasia: influence of a paclitaxel-eluting covered stent--preliminary studyin a canine urethral model[J]. Radiology,2005,234(2):438-44.
[63] Cadieux PA, Chew BH, Nott L, Seney S, Elwood CN, Wignall GR, et al. Useof triclosan-eluting ureteral stents in patients with long-term stents[J]. Journalof endourology/Endourological Society,2009,23(7):1187-94.
[64] Krambeck AE, Walsh RS, Denstedt JD, Preminger GM, Li J, Evans JC, et al. Anovel drug eluting ureteral stent: a prospective, randomized, multicenterclinical trial to evaluate the safety and effectiveness of a ketorolac loadedureteral stent[J]. The Journal of urology,2010,183(3):1037-42.
[65] Yin M, Yuan Y, Liu C, Wang J. Combinatorial coating of adhesive polypeptideand anti-CD34antibody for improved endothelial cell adhesion andproliferation[J]. Journal of materials science Materials in medicine,2009,20(7):1513-23.
[66] Lingeman JE, Preminger GM, Berger Y, Denstedt JD, Goldstone L, Segura JW,et al. Use of a temporary ureteral drainage stent after uncomplicatedureteroscopy: results from a phase II clinical trial[J]. The Journal of urology,2003,169(5):1682-8.
[67]侯宇川,王春喜,安伟等.新型生物降解材料输尿管支架的动物实验研究[J].科学技术与工程,2006,6(17):2738-42.
[68]侯宇川,王春喜,陈学思等.新型生物降解材料输尿管支架的生物相容性研究[J].中华实验外科杂志,2006,(05):571-2.
[69]侯宇川,王春喜,郑佐柱等.生物降解输尿管支架材料丙交酯/乙交酯共聚物的生物相容性及体内外降解特性[J].吉林大学学报(医学版),2005,(04):526-9+480.
[70]赵勇,唐华.输尿管支架管相关症状的防治[J].中华临床医师杂志(电子版),2012,(10):2746-8.
[71]唐维寅,夏术阶.输尿管支架管对上尿路影响的研究进展[J].临床泌尿外科杂志,2012,27(09):711-6.
[72]李双燕,王曙东,张幼珠.静电纺PLGA管状支架的结构与性能[J].苏州大学学报(工科版),2009,29(06):21-5.
[73] Thomas V, Donahoe T, Nyairo E, Dean DR, Vohra YK. Electrospinning ofBiosyn((R))-based tubular conduits: structural, morphological, and mechanicalcharacterizations[J]. Acta biomaterialia,2011,7(5):2070-9.
[74] Iverson N, Plourde N, Chnari E, Nackman GB, Moghe PV. Convergence ofnanotechnology and cardiovascular medicine: progress and emergingprospects[J]. BioDrugs: clinical immunotherapeutics, biopharmaceuticals andgene therapy,2008,22(1):1-10.
[75] Klose D, Laprais M, Leroux V, Siepmann F, Deprez B, Bordet R, et al.Fenofibrate-loaded PLGA microparticles: effects on ischemic stroke[J].European journal of pharmaceutical sciences: official journal of the EuropeanFederation for Pharmaceutical Sciences,2009,37(1):43-52.
[76]李双燕. PLGA组织工程支架材料的研究与展望[J].国外丝绸,2009,24(02):29-31.
[77]申雄军,阮建明,周忠诚等. PLGA的合成、表征及其导管支架的制备[J].长沙理工大学学报(自然科学版),2008,5(02):93-6+102.
[78] Jain RA. The manufacturing techniques of various drug loaded biodegradablepoly(lactide-co-glycolide)(PLGA) devices[J]. Biomaterials,2000,21(23):2475-90.
[79] Athanasiou KA, Niederauer GG, Agrawal CM. Sterilization, toxicity,biocompatibility and clinical applications of polylactic acid/polyglycolic acidcopolymers[J]. Biomaterials,1996,17(2):93-102.
[80]赵莉,何晨光,高永娟等. PLGA的不同组成对支架材料性能的影响研究[J].中国生物工程杂志,2008,28(05):22-8.
[81] Hendlin K, Vedula K, Horn C, Monga M. In vitro evaluation of ureteral stentcompression[J]. Urology,2006,67(4):679-82.
[82] Wang X, Chen, QH, Hou, YC,et,al. Fabrication, crosslinking and in vitrobiocompatibility of a novel degradable nano-structure urethral tubularscaffold[J]. Chem Res Chinese Universities,2012,28(5):912-5.
[83] Lu JM, Wang X, Marin-Muller C, Wang H, Lin PH, Yao Q, et al. Currentadvances in research and clinical applications of PLGA-basednanotechnology[J]. Expert review of molecular diagnostics,2009,9(4):325-41.
[84] Pungkham H, Swatdipakdi N, Theerasilp M, Karnkla S, Chittchang M,Ploypradith P, et al. PEG-b-PCL and PEG-b-PLA polymeric micelles asnanocarrieres for lamellarin N delivery[J]. Conference proceedings: AnnualInternational Conference of the IEEE Engineering in Medicine and BiologySociety IEEE Engineering in Medicine and Biology Society Conference,2011,2011:3245-8.
[85] Shi S, Zhu X, Guo Q, Wang Y, Zuo T, Luo F, et al. Self-assembledmPEG-PCL-g-PEI micelles for simultaneous codelivery of chemotherapeuticdrugs and DNA: synthesis and characterization in vitro[J]. Internationaljournal of nanomedicine,2012,7:1749-59.
[86] Dubey N, Varshney R, Shukla J, Ganeshpurkar A, Hazari PP, BandopadhayaGP, et al. Synthesis and evaluation of biodegradable PCL/PEG nanoparticlesfor neuroendocrine tumor targeted delivery of somatostatin analog[J]. Drugdelivery,2012,19(3):132-42.
[87] Kehoe S, Zhang XF, Lewis L, O'Shea H, Boyd D. Characterization of PLGAbased composite nerve guidance conduits: effect of F127content on modulusover time in simulated physiological conditions[J]. Journal of the mechanicalbehavior of biomedical materials,2012,14:180-5.
[88] Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) asBiodegradable Controlled Drug Delivery Carrier[J]. Polymers,2011,3(3):1377-97.
[89] McCall RL, Sirianni RW. PLGA nanoparticles formed by single-ordouble-emulsion with vitamin E-TPGS[J]. Journal of visualized experiments:JoVE,2013,(82):51015.
[90] Shim JH, Moon TS, Yun MJ, Jeon YC, Jeong CM, Cho DW, et al. Stimulationof healing within a rabbit calvarial defect by a PCL/PLGA scaffold blendedwith TCP using solid freeform fabrication technology[J]. Journal of materialsscience Materials in medicine,2012,23(12):2993-3002.
[91] Johnson HJ, Northup SJ, Seagraves PA, Atallah M, Garvin PJ, Lin L, et al.Biocompatibility test procedures for materials evaluation in vitro. II. Objectivemethods of toxicity assessment[J]. Journal of biomedical materials research,1985,19(5):489-508.
[92] Laschke MW, Strohe A, Scheuer C, Eglin D, Verrier S, Alini M, et al. In vivobiocompatibility and vascularization of biodegradable porous polyurethanescaffolds for tissue engineering[J]. Acta biomaterialia,2009,5(6):1991-2001.
[93] Cu Y, Booth CJ, Saltzman WM. In vivo distribution of surface-modified PLGAnanoparticles following intravaginal delivery[J]. Journal of controlled release: officialjournal of the Controlled Release Society,2011,156(2):258-64.
[94] Faisant N, Akiki J, Siepmann F, Benoit JP, Siepmann J. Effects of the type ofrelease medium on drug release from PLGA-based microparticles: experimentand theory[J]. International journal of pharmaceutics,2006,314(2):189-97.
[95] Dyer RB, Chen MY, Zagoria RJ, Regan JD, Hood CG, Kavanagh PV.Complications of ureteral stent placement[J]. Radiographics: a reviewpublication of the Radiological Society of North America, Inc,2002,22(5):1005-22.
[96] Yossepowitch O, Lifshitz DA, Dekel Y, Gross M, Keidar DM, Neuman M, etal. Predicting the success of retrograde stenting for managing ureteralobstruction[J]. The Journal of urology,2001,166(5):1746-9.
[97] Yoo JY, Kim JM, Seo KS, Jeong YK, Lee HB, Khang G. Characterization ofdegradation behavior for PLGA in various pH condition by simple liquidchromatography method[J]. Bio-medical materials and engineering,2005,15(4):279-88.
[98] Zolnik BS, Burgess DJ. Effect of acidic pH on PLGA microsphere degradationand release[J]. Journal of controlled release: official journal of the ControlledRelease Society,2007,122(3):338-44.
[99] Maheshwari PN, Andankar MG, Khera R, Stone RG. The indwelling uretericstent: a 'friendly' procedure with unfriendly high morbidity[J]. BJUinternational,2000,86(6):757-8.
[100] Richter S, Ringel A, Shalev M, Nissenkorn I. The indwelling ureteric stent: a'friendly' procedure with unfriendly high morbidity[J]. BJU international,2000,85(4):408-11.
[101] Tschada R, Mickisch G, Rassweiler J, Knebel L, Alken P.[Success and failurewith double J ureteral stent. Analysis of107cases][J]. Journal d'urologie,1991,97(2):93-7.
[102] Klis R1K-KE, Denys A, Sosnowski M, Rozanski W. Relationship betweenurinary tract infection and self-retaining Double-J catheter colonization[J].Journal of endourology/Endourological Society,2009,23(6):1015-9.
[103] Glazier DB, Jacobs MG, Lyman NW, Whang MI, Manor E, Mulgaonkar SP.Urinary tract infection associated with ureteral stents in renal transplantation[J].The Canadian journal of urology,1998,5(1):462-6.
[104] el-Faqih SR, Shamsuddin AB, Chakrabarti A, Atassi R, Kardar AH, Osman MK, et al.Polyurethane internal ureteral stents in treatment of stone patients: morbidity relatedto indwelling times[J]. The Journal of urology,1991,146(6):1487-91.