Acta Biomaterialia ( IF 9.4 ) Pub Date : 2023-10-10 , DOI: 10.1016/j.actbio.2023.10.009 Jiyuan Hu 1 , Zhenyu Wang 2 , Hao Hu 3 , Jing Zhao 4 , Hongwei Li 2 , Xinyu Zhang 2 , Jianbin Bi 5 , Jianzhong Li 1
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Ureteral stricture caused by holmium: YAG laser lithotripsy is one of the most challenging issues for urologists. Currently, evidence for rapamycin application in reducing ureterostenosis is not sufficient. This study aimed to assess the inhibition of ureteral stricture of rapamycin-eluting stents in vitro and in vivo. A bilayered drug-eluting ureteral stent consisted of drug blending with poly (lactic-co-glycolic acid) (PU/drug stent), which was over-layered by polycaprolactone (PCL) by ultrasonic atomizing spraying. Stent morphology was observed by scanning electron microscope. A kidney-ureter-bladder model was established to simulate the stents-releasing condition, and high-performance liquid chromatography was used to measure the drug release rate. The inhibitory proliferation was detected by CCK-8. The bladder of rats was injured through electro tome, and stents were implanted for 7, 14, and 28 days. The effects of drug-eluting stents was investigated by hematoxylin-eosin staining, immunofluorescence staining, real-time quantitative polymerase chain reaction and western blot. The bilayered stents could block the burst loss of the drug and maintained a sustained delivery period because of the 5.3 μm thickness of the PCL layer. The relative growth rates of cells plotted inhibitory effect on the proliferation of human urethral scar fibroblast cells. For in vivo results of 28 days, the bilayered stent maintained structural integrity and induced less deposition of crystals, thinner and less lamina propria connective tissues were formed, and α-SMA and TGF-β1 were downregulated. Bilayered rapamycin-eluting stent is significantly effective in alleviating fibrosis in in vitro and in vivo models.
Statement of significance
The occurrence of ureteral stricture resulting from holmium: YAG laser lithotripsy presents a significant challenge for urologists. Traditional double J stents have not been proven to offer a shorter indwelling time or improved inhibition of tissue blocking. While drug-eluting stents containing rapamycin, paclitaxel, and other substances have been extensively used in treating artery stenosis, there is insufficient evidence supporting their application in reducing ureterostenosis. Consequently, a biodegradable polymer ureteric scaffold incorporating rapamycin was fabricated in this study, employing ultrasonic atomization spraying technology to optimize the bilayers composed of 75/25 poly (lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL). The efficacy of the scaffold was subsequently confirmed through in vitro and in vivo experiments.
中文翻译：
双层可降解雷帕霉素洗脱支架治疗钬引起的输尿管狭窄的体内外评估：YAG激光碎石术
钬引起的输尿管狭窄：YAG激光碎石术是泌尿外科医生最具挑战性的问题之一。目前，应用雷帕霉素减少输尿管狭窄的证据尚不充分。本研究旨在评估雷帕霉素洗脱支架在体外和体内对输尿管狭窄的抑制作用。双层药物洗脱输尿管支架由药物与聚乳酸-乙醇酸共混物（PU/药物支架）组成，通过超声雾化喷涂在其上覆盖聚己内酯（PCL）。通过扫描电镜观察支架形貌。建立肾-输尿管-膀胱模型模拟支架释放情况，采用高效液相色谱法测定药物释放率。通过CCK-8检测抑制增殖。电刀损伤大鼠膀胱，植入支架7、14、28天。通过苏木精-伊红染色、免疫荧光染色、实时定量聚合酶链反应和蛋白质印迹研究药物洗脱支架的效果。由于PCL层厚度为5.3μm，双层支架可以阻止药物的突发损失并维持持续的递送时间。以细胞相对生长速率绘制对人尿道疤痕成纤维细胞增殖的抑制作用。 28天的体内结果显示，双层支架保持了结构完整性，并减少了晶体沉积，形成了更薄且更少的固有层结缔组织，α-SMA和TGF-β1下调。在体外和体内模型中，双层雷帕霉素洗脱支架对于减轻纤维化具有显着效果。
重要性声明
钬：YAG激光碎石术引起的输尿管狭窄的发生对泌尿科医生提出了重大挑战。传统双 J 支架尚未被证明可以提供更短的留置时间或改善对组织阻塞的抑制。虽然含有雷帕霉素、紫杉醇等物质的药物洗脱支架已广泛用于治疗动脉狭窄，但尚无足够的证据支持其在减少输尿管狭窄方面的应用。因此，本研究制备了掺有雷帕霉素的可生物降解聚合物输尿管支架，采用超声雾化喷涂技术来优化由75/25聚乳酸-乙醇酸（PLGA）和聚己内酯（PCL）组成的双层。随后通过体外和体内实验证实了支架的功效。
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