基于双药分级控释的可降解镁合金支架治疗犬食管良性狭窄模型的实验研究

Esophagus is one of the most important non-vascular channels in human body. Many kinds of diseases, such as esophagus damage, surgery, endoscopic mucosal resection, radiation therapy, achalasia and gastroesophageal reflux, could result in benign esophageal stricture and cause dysphagia, which has already become a thorny issue in clinical. Presently, there is still lack of satisfied treatment for benign esophageal stricture: traditional surgery often has big trauma and high rate of complications, pneumatic dilation is prone to recur after treatment, and permanent metallic stent placement would result in stent migration and late in-stent re-occlusion, plus that the patients are often young, consequently they are all not suitable methods. In this study, we are trying to develop a new kind of biodegradable magnesium stent with dual-drug separate release, in which the stent frame would degrade after providing good support, while the anti-inflammatory (dexamethasone) and anti-proliferating (paclitaxel) drugs could be released separately at the stent surface during its placement. In our drug eluting system, the anti-inflammatory drug would be released at the early stage to inhibit the inflammatory reaction induced by stent injury, and the anti-proliferating drug was then slowly released to inhibit the fibroblasts proliferation to reduce collagen fiber deposition (or scar formation), which may of great help to improve clinical treatment outcome, and reduce the resource rate by stent implantation, which would be a very important and meaningful study.

食管是人体重要的非血管腔道之一，各种良性疾病（包括外源性的食管损伤、外科术后、内镜下粘膜切除术后、放疗后、贲门失弛缓症、胃食管返流病等）所引起的食管狭窄是临床常见的棘手问题，均可造成患者进食困难。食管良性狭窄目前还缺乏很好的治疗手段，传统的外科手术创伤大、并发症率高，球囊扩张术易于复发，永久性金属支架植入具有高移位率和迟发再闭塞率高的特点，加之发病人群通常年龄较轻，因而均不适用于食管良性狭窄病变的治疗。我们课题组拟研发一种基于两种药物分级控释的生物可降解镁合金支架，支架骨架在一定的时间内提供良好的支撑后完全自行降解，同时支架表面分级缓释抗炎(地塞米松)和抗增殖（紫杉醇）药物，实现抗炎药物初期释放，抗增生药物长期缓慢释放，抑制支架植入损伤所引起的初期炎性反应和降低后期成纤维细胞增殖造成的胶原纤维沉积（瘢痕形成），达到提高临床疗效、减少复发的目的，将是具有重要临床意义的课题。

各种食管良性疾病和术后引起的食管狭窄是临床常见的棘手问题，造成患者吞咽困难，影响患者生活质量及预后。食管良性狭窄缺乏有效的治疗方法，外科手术创伤大、并发症高，球囊扩张后易于复发，永久性金属支架植入后移位率高、支架再狭窄及胸部不适等，效果均不甚满意。本课题研发了一种地塞米松和紫杉醇两种药物分级控释的生物可降解支架治疗食管良性狭窄。主要研究内容：1、成功制备了新型食管支架，包括高分子聚丙烯支架和可降解镁合金支架，支架骨架采用拉丝编织结构形成支撑网管，支架外表面覆盖硅胶膜材或者其他可降解的高分子膜材，降低了镁合金支架的降解率：PH4.0、2周时90.2%±3.2%比13.6%±3.1%和4周时73.4%±4.7% 比0；完成了生物可降解镁合金支架的体内外实验，正常食管内能提供至少2周的支撑力，在此期间食管重建基本完成；2、实现了具有紫杉醇药控释功能的纳米纤维膜的制备，该纳米纤维膜在4.0的特定酸性条件下仍可以保持持续稳定缓释约1月，该纳米纤维体外细胞培养实验可以有效抑制平滑肌细胞的增殖；地塞米松于16天内累积释放98.2%，紫杉醇持续缓慢释放，25天内累积释放98.4%。3、地塞米松和紫杉醇分级控释支架植入食管狭窄兔模型实验结束，初步数据表明：植入前食管直径为4.9±0.3 mm，支架植入即时造影支架直径为9.8±0.3 mm， 1W，2W和3W分别为9.7±0.7 mm，9.4±0.8 mm和9.2±0.5 mm。病理结果表明，2周时管壁基本重塑完成，炎症反应和瘢痕形成较轻：支架组1W，2W和3W时食管炎症得分分别为0.25 ± 0.4, 0.4 ± 0.5 和 0.22 ± 0.4，上皮层与狭窄兔变薄：141.2 ± 30.5 μm 比 261.5 ± 17.5 μm，中层平滑肌层较狭窄兔变薄：129.0 ± 9.5 μm 比 193.1 ± 17.0 μm，较正常兔变略厚，129.0 ± 9.5 μm 比90.5± 17.0 μm。该新型食管支架植入后支架表面缓释地塞米松和紫杉醇，抑制支架植入后引起的初期炎症反应和降低修复期成纤维细胞增殖造成的瘢痕形成，食管壁重塑完成后（2周）支架降解，食管狭窄解除。为临床治疗食管良性狭窄提供了一种有效的治疗途径和方法，有明显的经济和社会价值。