低分子肝素缓释系统防治兔后发性白内障的实验研究

Experimental study of low molecular weight heparin drug delivery system for prevention of posterior capsular opacification in rabbit eyes

目的探讨低分子肝素缓释系统防治兔后发性白内障的有效性和安全性。方法采用前瞻性随机分组对照研究。以乳酸-羟基乙酸共聚物（PLGA）为载体采用冻干法制备低分子肝素缓释系统（LMWHDDS）并体外评价其缓释特性。将50只（50只眼）新西兰白兔分别行超声乳化透明晶状体吸除术，并随机均分为5组：A组术后生理盐水滴眼，B、C、D组术毕后房分别植入载药量为1．00mg、0．50mg、0．25mg的LMWHDDS，E组植入不含药物的空白缓释系统；术后12周对术眼行裂隙灯显微镜、组织病理学以及电镜检查，并检测房水药物浓度和晶状体后囊膜湿重。术后房水闪光、房水细胞分级以及后囊膜混浊分级资料采用Kruskal—Wallis检验，房水药物浓度采用具有一个重复测量因素的两因素方差分析。结果采用冻干法制备的LMWHDDS包封率为98．2％，体外释药方程拟合以零级方程为佳。术后B、C、D组炎症反应较A、E组显著减轻；术后12周A、B、C、D、E各组后囊膜混浊发生率分别为100％（10／10）、20％（2／10）、30％（3／10）、90％（9／10）、100％（10／10），后囊膜混浊分级评分组间比较差异均具有统计学意义（χ^2=31．637，P=0．000），后囊膜湿重分别为（114．59±14．58）mg、（24．14±6．08）mg、（39．23±17．13）mg、（99．35±29．37）mg、（115．29±19．87）mg，组间比较差异均具有统计学意义（F=42．149，P=0．000）；术后4周内B、C组房水中低分子肝素一直维持较高浓度（大于20mg／L），D组浓度较低且不稳定；光镜和电镜下B、C组后囊细胞增生不活跃，未发现眼内毒性反应；术后均未见眼内出血现象。结论以PLGA为载体采用冻干法制备的LMWHDDS具有良好的缓释性和组织相容性；其后房植入能明显减轻术后炎症反应，能安全、有效抑制后发性白内障的发生，且存在一定量效关系。

Objective To investigate the safety and efficacy of low-molecular-weight heparin drug delivery system （LMWH DDS） for prevention of posterior capsular opacification （PCO） in rabbit eyes. Methods （ 1 ） To prepare the LMWH DDS by freeze-drying way with Polylactic-co-glycolic acid （PLGA） as the carrier, and evaluate its release properties in vitro. （2） Fifty New Zealand albino rabbits （50 eyes） undergoing phacoemulsification were equally divided into five groups： receiving normal saline eye drops （group A） , 3 different dose （ 1 mg, 0. 5 mg and 0. 25 mg） of LMWH DDS respectively implanted into the posterior chamber （group B, C and D）, and a carrier DDS implanted into the posterior chamber （group E）. All the 50 eyes were examined by slit-lamp microscopy. The low-molecular-weight heparin levels in aqueous humor were measured, and the wet posterior capsules were weighed. Results The LMWH DDS prepared with a freeze-dried way has high encapsulation efficiency, and the equation of 49-day release curve fitting in vitro were were similar to zero order. The fibrin exudation in group B, C and D were lower than in Group A and E during the first postoperative day. There were 10, 2, 3, 9 and 10 eyes that developing PCO in the group A, B, C, D and E, respectively. The mean wet-weight of the posterior capsule were （114. 59 ±14.58） mg,（24. 14±6.08） mg,（39.23±17.13） mg, （99.35±29.37） mg,（115.29 ±19.87） mg respectively in 5 trial groups. There were stable and high concentration of low molecular weight heparin in aqueous of group B and C during the 4 weeks （ 〉 20 mg/L）, while a instable and lower concentrations in group D. The result of optical microscopy and electron microscopy examination indicated that fibroblast proliferation was quite active in groups A, D and E, but inactive in group B and C. Neither infiltration of inflammatory cells at the cornea, iris, trabecular meshwork and ciliary body nor retinal degeneration or necrosis was found in any group at 12 weeks. There was no introcular bleeding in all the five groups in the following 12 weeks. Conclusions The LMWH DDS prepared by freeze-drying way with PLGA as the carrier has good slow-release and biological tolerance. Implantion of LMWH DDS into the posterior chamber of experimental animals can significantly reduce postoperative fibrin exudation, and can safe and effective prevent the occurrence of PCO, and also there were some dose-effect relationship.