CN108853588A - 含中药治疗骨坏死的异体骨支架 - Google Patents
含中药治疗骨坏死的异体骨支架 Download PDFInfo
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- CN108853588A CN108853588A CN201810895538.1A CN201810895538A CN108853588A CN 108853588 A CN108853588 A CN 108853588A CN 201810895538 A CN201810895538 A CN 201810895538A CN 108853588 A CN108853588 A CN 108853588A
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Abstract
含中药治疗骨坏死的异体骨支架，本发明属于生物医药、生物材料领域。涉及一种以动物异体松质骨、淫羊藿苷和羧甲基纤维为基础制作的异体骨支架，其中动物异体松质骨经脱细胞处理保留了原有松质骨微观结构，高孔隙率并且孔隙的相互贯通程度高，有利于成骨细胞黏附、增殖，同时方便蛋白质、水分等营养成分通过。淫羊藿苷既能够促进骨髓间充质干细胞及前成骨细胞增殖，又能够增加两种细胞的碱性磷酸酶活性及矿化率，增加骨缺损区成骨骨量，提高愈合质量，加快骨缺损的愈合速度，利于骨坏死的修复。异体骨支架中羧甲基纤维素利于骨组织坏死修复，可作为骨坏死修复促进剂。本发明用于治疗骨坏死相关疾病。
Description
技术领域
本发明属于生物医药、生物材料领域，具体涉及一种含中药治疗骨坏死的异体骨支架。
背景技术
骨坏死是指人体骨骼活组织坏死，祖国医学把骨坏死称之为骨蚀症。人体很多部位，仅就缺血性坏死已经发现40余处。骨坏死的原因很多，如长期使用激素、酗酒、吸烟、创伤和手术，其他可能的病因包括：青少年骺滑移、深海潜水或高气压疾病、系统性红斑狼疮和其他结缔组织疾病、自身免疫性疾病导致的血管炎、镰状细胞贫血、凝血病(易栓症和弥散性血管内凝血)、HIV感染、高脂血症、脂肪栓塞综合征、化疗和放疗、器官移植、慢性肝病、高雪氏症、痛风和代谢性骨病等。在临床常以股骨头坏死最多见。膝关节自发性骨坏死是指构成膝关节的骨性结构(股骨内、外髁，胫骨平台和髌骨)坏死，是仅次于股骨头坏死之后的最常见的骨坏死疾病。近年来，有关双膦酸盐相关性骨坏死(BRONJ)的报道日渐增多，与双膦酸盐类(BPs)药物(强有力的骨吸收抑制剂)广泛应用于临床治疗有关。临床研究证实，髋、膝关节骨坏死均呈阳性者，不论其他关节是否存在临床症状，均有肩、踝、腕、肘一个至数个关节多灶性骨坏死的风险。
淫羊藿(Herba epimedii)是一种传统的补益中药，临床上用来治疗骨折及与骨代谢有关的许多疾病，并取得了良好的效果。淫羊藿具有增强机体免疫功能，抗肿瘤，影响内分泌加强性腺功能、延缓衰老和影响心血管系统等多种重要的药理活性。淫羊藿的有效活性成分淫羊藿苷(icariin，C33H40O15，分子量：676.67)，属黄酮类化合物。淫羊藿苷对股骨头缺血性坏死的有一定的预防和治疗作用。淫羊藿苷既能够促进骨髓间充质干细胞(bonemarrow mesenchymal stem cells，BMMSCs，简称MSCs)及前成骨细胞增殖，又能够促进两种细胞的碱性磷酸酶活性及矿化，利于骨坏死的修复。淫羊藿苷可促使卵泡颗粒细胞分泌雌二醇，高浓度时还可促进肾上腺皮质细胞分泌皮质类固醇，提示淫羊藿补肾壮阳功效。淫羊藿苷在骨创愈合修复中起到积极的作用，淫羊藿苷能够增加骨缺损区成骨骨量，提高愈合质量，加快骨缺损的愈合速度。淫羊藿苷在成骨过程中，发挥雌激素样作用，通过下调Rankl基因，减少破骨细胞的活化，抑制破骨细胞的功能，增加成骨；上调成骨基因Runx2，通过经典Wnt/β-catenin途径，有效地促进骨愈合骨修复；促进骨缺损区成骨细胞成骨蛋白骨钙素的分泌，增加新骨形成的骨量，促进骨组织的愈合；促进成骨细胞成骨蛋白骨桥素的分泌，抑制破骨细胞的活性，增加骨量，加速骨组织愈合修复。
天然纤维素广泛存在，含量较多，在生产上多以纤维素钠盐存在。带负电的聚电解质的水溶性羧甲基纤维素(CMC)(C6H7O2(OH)2CH2COONa)是一种由天然纤维素通过化学改良后得到的重要的纤维素衍生品。由于CMC无毒性和具有粘结性、成膜性、生物相容性等特性，因而可用之于各种片剂、丸剂、散剂、注射剂、悬浮剂和乳剂等，作为粘合剂、涂膜、药囊、缓释剂、稳定剂、分散剂和乳化剂等之用。对CMC的毒性试验表明，口服和皮肤接触完全没有生理活性，即使小鼠口服10g/kg的剂量也未发现毒性。由于CMC具有独特的特性如粘性，稠化，成膜能力，悬架性能和水稳定性，CMC在骨再生及骨组织修复支架领域研究日渐增多。令人鼓舞的是羧甲基纤维素钠作为一种脱钙骨基质载体在体内应用部位可能形成凝胶，利于骨坏死修复。
本发明提供了一种以动物异体松质骨、淫羊藿苷和羧甲基纤维为基础制作的治疗骨坏死的异体骨支架，为病变骨组织提供有效的显微生物力学结构支撑，调节坏死骨局部的成骨和破骨活动，恢复正常的骨代谢平衡。
发明内容
本发明公开了含中药治疗骨坏死的异体骨支架的制备和使用方法。涉及一种以动物异体松质骨、淫羊藿苷和羧甲基纤维为基础制作的治疗骨坏死的异体骨支架，其中动物异体松质骨经脱细胞处理保留了原有松质骨微观结构，利于诱导骨坏死处羟基磷灰石晶体形成，高孔隙率并且孔隙的相互贯通程度高，有利于成骨细胞黏附、增殖，同时方便蛋白质、水分等营养成分通过。淫羊藿苷既能够促进骨髓间充质干细胞及前成骨细胞增殖，又能够促进两种细胞的碱性磷酸酶活性及矿化，增加骨缺损区成骨骨量，提高愈合质量，加快骨缺损的愈合速度，利于骨坏死的修复。异体骨支架中羧甲基纤维素利于骨组织坏死修复，可作为骨坏死修复促进剂。
本发明公开了含中药治疗骨坏死的异体骨支架的制备方法，其流程包括：
(一)异体松质骨的制备：取新鲜动物骨组织，用空心环钻，钻取松质骨柱→无菌去离子水高压冲洗→双氧水振荡浸泡→在超声清洗机内以氯仿、甲醇、水溶液清洗→用无菌去离子水反复冲洗，加入十二烷基硫酸钠液振荡浸泡→用无菌去离子水反复冲洗加入6％Triton X-100振荡浸泡→用无菌去离子水反复冲洗，置于冷冻干燥机中冷冻干燥→冻干结束后，立即用双层血浆袋封装，Gamma射线辐照灭菌。
(二)含中药异体松质骨支架的制备：用无菌去离子水配置羧甲基纤维素溶液→取(一)中制备好的异种骨柱，在无菌条件下浸泡在羧甲基纤维素溶液，室温振荡→冷冻干燥机中冷冻干燥→用无菌去离子水配置淫羊藿苷溶液，将羧甲基纤维素溶液浸泡过的异种骨柱浸泡在淫羊藿苷溶液，室温振荡浸泡→冷冻干燥机中冷冻干燥→冻干结束后，立即用双层血浆袋封装，Gamma射线辐照灭菌。
作为优选的技术方案：
其中，如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述的新鲜动物骨组织来源于猪、牛、羊、猴等动物股骨的远端、胫骨的近端、尺骨近端、桡骨远端。
如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述的振荡浸泡双氧水浓度为3％，浸泡2～3次，每次2～3h。
如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述含氯仿、甲醇、水溶液的体积之比为氯仿∶甲醇∶水＝1∶1∶2。
如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述十二烷基硫酸钠液浓度为2％，振荡浸泡24～36h。
如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述冷冻干燥机冷冻干燥温度为-50～-60度，干燥时间48～72h，工作压强为1×10-4mmHg。
如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述羧甲基纤维素溶液质量分数为0.95～1.05％。
如上所述含中药治疗骨坏死的异体骨支架的制备方法，其特征是所述淫羊藿苷溶液浓度为10-5～10-8mol/L。
与现有技术相比，本发明的有益效果是：采用动物异体松质骨、淫羊藿苷和羧甲基纤维为基础制作的治疗骨坏死的异体骨支架，其中动物异体松质骨保留了原有松质骨微观结构，高孔隙率并且孔隙的相互贯通程度高，为骨坏死修复提供微观结构支撑；淫羊藿苷既能够促进骨髓间充质干细胞及前成骨细胞增殖，又能够促进两种细胞的碱性磷酸酶活性及矿化，增加骨缺损区成骨骨量，提高愈合质量，加快骨缺损的愈合速度，利于骨坏死的修复；羧甲基纤维素利于骨组织坏死修复，可作为骨坏死修复促进剂。三者结合各取其长、优势互补，利于骨坏死的修复。
附图说明
图1是植入含中药治疗骨坏死的异体骨支架治疗的胫骨X-RAY图。
图2是植入单纯异体骨柱治疗的胫骨X-RAY图。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例：
(一)异体骨柱的制备：取新鲜猪股骨远端骨组织，用内径1.5mm空心环钻，钻取直径1.5mm，长度约5mm松质骨柱→无菌去离子水高压冲洗获得的松质骨柱，去组织中的骨髓、血液与脂肪→3％双氧水振荡浸泡3次，每次2h→在超声清洗机内以氯仿、甲醇、水溶液(V氯仿∶V甲醇∶V水＝1∶1∶2)不间断脱脂4天→用无菌去离子水反复冲洗3次，每次15min，加入2％十二烷基硫酸钠液振荡浸泡24h→用无菌去离子水反复冲洗3次，每次20min，加入6％Triton X-100振荡浸泡2次，每次24h→用无菌去离子水反复冲洗3次，每次15min，置于冷冻干燥机中冷冻干燥48h，工作压强为1×10-4mm Hg→冻干结束后，立即用双层血浆袋封装，Gamma射线辐照灭菌，辐照剂量为25k Gy。
(二)含中药异体骨柱的制备：用无菌去离子水配置质量分数为0.95％的羧甲基纤维素溶液→取制备好的异种骨柱，在无菌条件下浸泡在羧甲基纤维素溶液，室温振荡24h→置于冷冻干燥机中冷冻干燥48h，工作压强为1×10-4mmHg→用无菌去离子水配置浓度为10-6mol/L淫羊藿苷溶液，将羧甲基纤维素溶液浸泡过的异种骨柱浸泡在淫羊藿苷溶液，室温振荡浸泡24h→置于冷冻干燥机中冷冻干燥48h，工作压强为1×10-4mmHg→冻干结束后，立即用双层血浆袋封装，Gamma射线辐照灭菌，辐照剂量为25k Gy。
为进一步说明含中药治疗骨坏死的异体骨支架具有促进骨组织形成作用及具体使用方法，现以SD大鼠胫骨缺损为例加以说明。吸入麻醉满意后术区脱毛，清洗备皮后碘伏消毒，铺无菌巾单。取双侧膝关节正中纵行切口，切开皮肤及皮下组织，暴露胫骨平台内侧，钝性分离胫骨结节内侧面附着肌肉，暴露骨面，用直径3mm电钻，钻取直径3mm，深度3mm骨隧道，左侧植入含中药治疗骨坏死的异体骨支架，右侧植入单纯异体骨柱(不含淫羊藿苷和羧甲基纤维素)。逐层关闭切口，碘伏消毒术区，术后允许实验动物自由活动，继续正常饮食和饮水。术后9周，所有实验动物过量麻醉处死，分别取双侧胫骨近端并标记，行骨小梁的微观力学测定分析(见表1)及X-RAY检查(见图1，2)。
表1 植入物周围骨小梁微观力学参数
| 弹性模量 | 刚度 | |
| 含药异体骨支架 | 13.568±1.451# | 0.662±0.077* |
| 单纯异体骨支架 | 11.241±2.145 | 0.602±0.054 |
| 正常组 | 21.101±3.881 | 0.985±0.085 |
注“#，*”表示含药异体骨支架与单纯异体骨支架和正常组相比，差异具有统计学意义。骨小梁微观力学参分析结果表明含中药治疗骨坏死的异体骨支架具有促进骨组织形成作用，但是其新生骨的微观力学性能与正常对照组相比弹性模量和刚度均较低，考虑为不成熟骨组织。
X-RAY检查从图1，可见植入物呈高密度表现，骨柱外形规则，周围可见少量高密度影形成，在胫骨骨骺与植入部位之间髓腔中可见中等量高密度影形成。从图2，可见植入物部分密度减低，骨柱形状欠清晰，骨柱远端可见少量高密度影形成，在胫骨骨骺与植入部位之间髓腔中可见少量高密度影形成。
Claims (5)
1.含中药治疗骨坏死的异体骨支架，其特征在于：所述异体骨支架由动物异体松质骨、淫羊藿苷溶液和羧甲基纤维溶液为基础制成。
2.根据权利要求1所述含中药治疗骨坏死的异体骨支架，其特征在于：所述动物异体松质骨的制备过程为，取新鲜动物骨组织，用空心环钻，钻取松质骨柱→无菌去离子水高压冲洗→双氧水振荡浸泡→在超声清洗机内以氯仿、甲醇、水溶液清洗→用无菌去离子水反复冲洗，加入十二烷基硫酸钠液振荡浸泡→用无菌去离子水反复冲洗加入6％Triton X-100振荡浸泡→用无菌去离子水反复冲洗，置于冷冻干燥机中冷冻干燥→冻干结束后，立即用双层血浆袋封装，Gamma射线辐照灭菌。
3.根据权利要求1所述含中药治疗骨坏死的异体骨支架，其特征在于：所述淫羊藿苷溶液浓度为10-5～10-8mol/L。
4.根据权利要求1所述含中药治疗骨坏死的异体骨支架，其特征在于：所述羧甲基纤维溶液浓度为10-5～10-8mol/L。
5.根据权利要求2所述含中药治疗骨坏死的异体骨支架，其特征在于：所述异体骨支架制备过程为，无菌去离子水配置羧甲基纤维素溶液→取制备好的动物异体松质骨，在无菌条件下浸泡在羧甲基纤维素溶液，室温振荡→冷冻干燥机中冷冻干燥→用无菌去离子水配置淫羊藿苷溶液，将羧甲基纤维素溶液浸泡过的异种骨柱浸泡在淫羊藿苷溶液，室温振荡浸泡→冷冻干燥机中冷冻干燥→冻干结束后，立即用双层血浆袋封装，Gamma射线辐照灭菌。
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