注射型硼酸盐壳聚糖复合物作为药物载体治疗骨髓炎的实验研究  

INJECTABLE BORATE GLASS/CHITOSAN COMPOSITE AS BRUG CARRIER FOR TREATMENT OF CHRONIC OSTEOMYELITIS

作　　者：赵存举[1] 王信富[1] 张长青[1] 崔旭[2] 贾伟涛[1] 黄文旵[2] 

机构地区：[1]上海交通大学附属第六人民医院骨科,上海200233 [2]同济大学材料科学与工程学院生物工程与信息技术材料研究所

出　　处：《中国修复重建外科杂志》2012年第6期641-646,共6页Chinese Journal of Reparative and Reconstructive Surgery

基　　金：国家自然科学基金青年科学基金资助项目(81000811)~~

摘　　要：目的评价载万古霉素的注射型硼酸盐壳聚糖复合物(vancomycin-loaded borate glass/chitosancomposite,VBC)的体内、外生物活性及治疗骨髓炎效果,探讨其生物降解及抗生素缓释规律,为临床应用奠定基础。方法 VBC固相由硼酸盐玻璃及万古霉素粉剂组成,液相由壳聚糖、柠檬酸和葡萄糖按照质量比1∶10∶20比例混匀制成,固相及液相按质量比2∶1比例混合凝固获得VBC。硫酸钙粉剂代替硼酸盐玻璃,无菌生理盐水代替壳聚糖溶液,同法制备载药硫酸钙(vancomycin-loaded calcium sulfate,VCS),作为对照。采用高效液相色谱法检测VBC及VCS抗生素释放率,抗生素双重管稀释法测定释放抗生素的最低抑菌浓度(minimum inhibitory concentration,MIC);扫描电镜观察浸泡前及D-Hank’s溶液中浸泡2、4、8、16、40 d的VBC、VCS降解情况,X射线衍射仪分析VBC浸泡后40 d物相组成。取33只成年健康新西兰大白兔,雌雄不限,体重2.25～3.10 kg;采用Norden方法制备右胫骨近端骨髓炎模型。4周后将28只骨髓炎模型制备成功的大白兔随机分成4组:A组(n=8)单纯清创,B、C组(n=8)清创后注入VCS及VBC至缺损处,D组(n=4)不作任何处理。术后2个月摄X线片并行Norden评分,取缺损处标本行组织学观察。结果 VBC释药过程持续30 d,药物缓释前8 d释放率达75%,最终释放率达90%以上;VCS释药过程仅持续16 d。VBC、VCS的MIC均为2μg/mL。扫描电镜观察,VCS浸泡前为光滑玻璃晶体表面,4 d后已大部分降解;VBC浸泡前具有典型光滑玻璃表面,8 d后结合相的玻璃部分溶化,40 d后材料表面几乎完全被生成的白色颗粒状沉淀物覆盖,材料结合疏松。VBC浸泡40 dX线衍射分析反应生成物主要物相为羟基磷灰石。术后2个月X线片及组织学观察示C组骨髓炎症状均消失,优于其余各组。A、B、C、D组X线片评分分别为(3.50±0.63)、(2.29±0.39)、(2.00±0.41)、(4.25±0.64)分,Smeltzer评分分别为(6.00±0.89)、(4Objective To evaluate the characterization,biocompatibility in vitro and in vivo,and antimicrobial activity of an injectable vancomycin-loaded borate glass/chitosan composite（VBC） so as to lay the foundation for its further clinical application.Methods The solid phase of VBC was constituted by borate glass and vancomycin,liquid phase was a mixture of chitosan,citric acid,and glucose with the proportion of 1 ∶ 10 ∶ 20.Solid phase and liquid phase was mixed with the ratio of 2 ∶ 1.Vancomycin-loaded calcium sulfate（VCS） was produced by the same method using calcium sulfate instead of borate glass and saline instead of chitosan,as control.High performance liquid chromatography was applied to detect the release rate of antibiotics from VBC and VCS,and minimum inhibitory concentration（MIC） was tested by using an antibiotic tube dilution method.The structure of the VBC and VCS specimens before and 2,4,8,16,and 40 days after immersion in D-Hank’s was examined by scanning electron microscopy,and the phase composition of VBC was analysed by X-ray di raction after soaked for 40 days.Thirty-three healthy adult New Zealand white rabbits（weighing,2.25-3.10 kg;male or female） were used to establish the osteomyelitis models according to Norden method.After 4 weeks,the models of osteomyelitis were successfully established in 28 rabbits,and they were randomly divided into 4 groups（groups A,B,C,and D）.In group A（n=8）,simple debridement was performed;in groups B and C（n=8）,defect was treated by injecting VCS or VBC after debridement;and in group D（n=4）,no treatment was given.The e ectiveness of treatment was assessed using radiological and histological techniques after 2 months.Results The releases of vancomycin from VBC lasted for 30 days;the release rate of vancomycin reached 75% at the rst 8 days,then could reached more than 90%.The releases of vancomycin from VCS lasted only for 16 days.The MIC of VBC and VCS were both 2 μg/mL.The VCS had a smooth glass crystal surface before immersion,ho

关 键 词：注射型硼酸盐壳聚糖复合物 药物载体 万古霉素 骨髓炎 生物活性 兔 

分 类 号：R681.2[医药卫生—骨科学]