一种新型的溶石药物控释金属支架治疗难治性胆总管结石的实验研究

Nowadays, Endoscopic Retrograde Cholangiopancreatography (ERCP) has become the most important therapeutic method for treatment of common bile duct (CBD) stone. However, some CBD stones remain difficult to remove, if they are large or multiple. Our early research has shown that the plastic stent coated with degradable membranes containing ethylene diamine tetraacetic acid ( EDTA) and sodium cholate effectively dissolved CBD stones in vitro, but the effect of the stent in vivo is still unknown. And there are several defects of this stent, for example, plastic stent is prone to be blocked, and coating membrane is easy to fall off. Our project intends to improve the stent, achieve long term and stable release of drugs for dissolving stones, and ensure stent patency and the continuous friction of stone by stent. Thus we can remove difficult CBD stones with ERCP after effectively reducing the size of CBD stone. Our research team plans to use a novel retrievable biliary metal stent, covered with drug loaded poly(L-lactide-co-caprolactone) nanofibers via electrospinning, and do following studies. The optimal drug concentrations and property of stent were defined by studying the curve of drug releasing in vitro, coated membrane degradation time, and weight of stones dissolved. The effect of this stent in various kinds of CBD stones porcine model and the safety in vivo were studied. This study is expected to provide new and effective treatment for difficult CBD stone.

经内镜逆行性胰胆管造影术下取石是目前治疗胆总管结石的主要方法，但仍有部分胆总管难治性结石因巨大、多发等原因而无法经内镜取出。项目组前期研究结果显示，用浸涂法制作的载有胆酸钠和乙二胺四乙酸的药物涂层塑料支架在体外具有明显溶石作用，但其体内作用效果仍未知，且存在塑料支架易堵塞及涂层易脱落等缺点。本项目拟对上述支架进行改良，以实现胆管内溶石药物长期稳定释放，同时保证支架的通畅及对结石的持续压迫、摩擦作用，从而有效减小胆总管难治性结石，达到进一步在内镜下取石目的。项目组拟在新型可回收胆管金属支架中，以生物可降解材料为载体，采用具有药物控释功能的静电纺丝技术载入不同含量的上述溶石药物，通过对支架体外药物释放、涂层降解时间及溶石作用曲线等研究，明确最佳载药含量及支架体外性能，并进一步探讨该支架对猪各种成分胆总管结石模型的治疗作用及体内应用的生物安全性。该研究有望为难治性胆总管结提供新的有效治疗手段。

经内镜逆行性胰胆管造影术下取石是目前治疗胆总管结石的主要方法，但仍有部分胆总管难治性结石因巨大、多发等原因而无法经内镜取出。本项目拟研制一种荷载溶石药物的胆道金属支架，在解除胆道梗阻的同时，实现胆管内溶石药物长期稳定释放，从而有效减小胆总管难治性结石，达到进一步在内镜下取石的目的。.本项目以新型可回收胆管金属支架为支架主体，以胆酸钠及EDTA二钠为溶石药物， 以生物可降解材料为溶石药物载体，采用3种不同载药技术（浸涂法—1号支架，静电纺丝技术—2号支架，浸涂法联合静电纺丝技术—3号支架）载入不同含量的上述溶石药物，通过对支架体外药物释放、涂层降解时间及溶石作用曲线等研究，明确最佳载药方式及载药含量，并进一步探讨溶石支架在体外的溶石作用及体内应用的生物安全性。.在药物缓释方面，3号支架可在30天内可平缓释放药物，1号支架及2号支架的突释现象较为明显。在体外浸泡的溶石效果，3号支架>2号支架>1号支架>裸支架。当支架载药量为50mg时，3种载药支架在体外胆汁灌流条件下均未发挥溶石作用；当支架载药量为200mg时，3种载药支架及裸支架在体外胆汁灌流条件下的溶石效果：3号支架>2号支架=1号支架>裸支架。3号支架（载药量200mg）和裸支架置入猪胆囊后，实验期间未引起肝肾功能及电解质的变化，两者均引起胆囊、CBD不同程度的炎症反应，炎症评级无统计学差异（p>0.05）。.浸涂法联合静电纺丝法制备的载药支架可满足药物缓释的要求，具有一定的溶石作用，生物安全性良好，有望为难治性胆总管结提供新的有效治疗手段。