CN107744604A - 一种聚乙烯醇/羟基磷灰石复合支架 - Google Patents
一种聚乙烯醇/羟基磷灰石复合支架 Download PDFInfo
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Abstract
一种聚乙烯醇/羟基磷灰石复合支架,其以活性多孔羟基磷灰石载体为核心层,表面交替包覆4层聚乙烯醇涂层,其中,由内至外,聚乙烯醇涂层依次为包含异烟肼的聚乙烯醇涂层、包含利福平的聚乙烯醇涂层、包含异烟肼的聚乙烯醇涂层和包含利福平的聚乙烯醇涂层,或者聚乙烯醇涂层依次为包含利福平的聚乙烯醇涂层、包含异烟肼的聚乙烯醇涂层、包含利福平的聚乙烯醇涂层和包含异烟肼的聚乙烯醇涂层。
Description
技术领域
本发明涉及医用人工骨移植材料的技术领域,具体涉及一种可用于抗结核的术后骨填充缓释复合材料,及其制备方法。
背景技术
骨结核常常来源于肺结核,主要包括脊柱结核和关节结核。大多数患者来自发展中国家的贫困家庭,例如印度、中国和南部非洲等。骨组织的破坏、畸形,以及继发的神经损害将严重影响患者的生活治疗,并造成沉重的经济负担。产生严重并发症的患者需要手术治疗,病灶清除是最关键的手术步骤。然而彻底的清除病灶常常难以实现,从而导致结核复发。
长期口服抗结核药物是治疗骨关节结核的原则,但是由于肝脏的代谢,只有少部分药物可以到达病灶。研究表明局部化疗有利于防止结核的复发,所以手术过程中常常将明胶海绵包裹链霉素粉剂植入病灶清除后的骨缺损区。但这种方式的局部药物释放难以维持很长时间,因此我们设计了负载抗结核药物的多孔HA人工骨来治疗骨关节结核。
由于结核导致的骨破坏,大多数骨结核手术过程需要融合和内固定。骨融合采用的材料包括自体骨、异体骨、同种异体骨、人工骨等,这些材料都有一定的骨传导和骨诱导性。自体骨来源于自体髂骨,会增加创伤和手术时间。异体骨来源于自尸体骨,来源有限。异种骨来源于无活性的牛骨组织,成骨能力差,而且具有抗原性,导致其不能在临床广泛应用。人工骨包括羟基磷灰石和磷酸三钙,煅烧后和人体骨结果类似,具有生物活性和多孔结构。材料的蜂窝状结构有利于毛细血管长入其内部,为内部空隙内的成骨细胞提高营养。
作为成熟的骨替代材料,羟基磷灰石(HA)产品已经商业化,并在临床应用。CN102580161A中以磷酸钙骨水泥为载体附着物,海藻酸钠水溶液和氯化钙水溶液双组份处理形成凝胶将抗结核菌药物负载于磷酸钙骨水泥中得到人工骨填充缓释材料,其药物缓释性能还有改进的空间。CN101862230A公开了利用3D打印技术制备得到了异烟肼-利福平控释型载药人工骨的制备,其制备工艺复杂,药物缓释性和力学性能还有改进的空间。CN102940905A公开了一种具有抗结核活性的多孔骨修复材料,其主要由类骨钙磷材料、有机高分子和抗结核药物组成,材料的缓释性能和力学性能还有待于进一步提高。
上述现有技术中的骨替代材料依然存在缓释性能差和力学强度不够的问题,本发明利用层层覆涂技术,在生物活性多孔羟基磷灰石支架孔隙内交替覆涂了负载异烟肼(INH)与利福平(RMP)的聚乙烯醇(聚乙烯醇)膜各两层,实现了联合负载INH与RMP的聚乙烯醇/HA复合支架的构建,得到了具有优异的缓释性能和力学性能的多孔支架。
发明内容
本发明提供了一种聚乙烯醇/羟基磷灰石复合支架。其以活性多孔羟基磷灰石载体为核心层,表面包覆4层聚乙烯醇涂层。其中,由内至外,聚乙烯醇涂层依次为包含异烟肼的聚乙烯醇涂层、包含利福平的聚乙烯醇涂层、包含异烟肼的聚乙烯醇涂层和包含利福平的聚乙烯醇涂层,或者聚乙烯醇涂层依次为包含利福平的聚乙烯醇涂层、包含异烟肼的聚乙烯醇涂层、包含利福平的聚乙烯醇涂层和包含异烟肼的聚乙烯醇涂层。其中,活性多孔羟基磷灰石、聚乙烯醇、异烟肼和利福平的质量比为80-100:20-32:15-20:15-20。
所述生物活性多孔羟基磷灰石的制备方法为:
(1)将浓度为2%-10%(g/mL)的海藻酸盐溶液通过计量注射针逐滴加入浓度为1-10mol/L的氯化钙溶液中,将得到的海藻酸盐凝胶微珠在2-5小时内充分交联,随后用去离子水清洗除去多余溶液,将湿的微珠浸入乙醇中进行溶剂交换;(2)将羟基磷灰石粉末与浓度为2%-10%(g/mL)的海藻酸盐溶液混合制备羟基磷灰石浆料,将所述进行溶剂交换的微珠与羟基磷灰石浆料转移至圆柱模具中,随后用活塞单轴压缩混合物从而将微珠中的空腔用羟基磷灰石浆料充满,同时,微珠之间形成了桥接,将浆料渗透模板投入到氯化钙溶液中使羟基磷灰石浆料形成凝胶,然后取出模板,在40-50℃干燥获得圆柱形3D支架,并在大气条件下于700-800℃烧结2-4小时除去海藻酸盐,1200-1300℃烧结2-4小时得到生物活性多孔羟基磷灰石。
其中,第(1)步中海藻酸盐溶液与氯化钙溶液的质量比为(4-6):(1-1.5);第(2)步中羟基磷灰石粉末与海藻酸盐溶液的质量比为(1-10):(1-10);海藻酸盐选自海藻酸钠、海藻酸钾中的一种或两种。
聚乙烯醇/羟基磷灰石复合支架的制备方法为:
(1)配制浓度为4%-10%(g/mL)的聚乙烯醇水溶液,加入15-20质量份异烟肼后磁力搅拌2-3小时使之充分溶解得到异烟肼-聚乙烯醇溶液备用;将15-20质量份利福平溶于二甲亚砜溶液,充分搅拌溶解后放入浓度为4-10%(g/mL)的聚乙烯醇水溶液,再次充分搅拌溶解得到利福平-聚乙烯醇溶液;
(2)将生物活性多孔羟基磷灰石放入异烟肼-聚乙烯醇溶液中;
(3)在0.1-0.5Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于800-1000r/min转速下离心10-30min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5-10小时;
(4)将步骤(3)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料;
或者为:
(1)配制浓度为4%-10%(g/mL)的聚乙烯醇水溶液,加入15-20质量份异烟肼后磁力搅拌2-3小时使之充分溶解得到异烟肼-聚乙烯醇溶液备用;将15-20质量份利福平溶于二甲亚砜溶液,充分搅拌溶解后放入浓度为4-10%(g/mL)的聚乙烯醇水溶液,再次充分搅拌溶解得到利福平-聚乙烯醇溶液;
(2)将生物活性多孔羟基磷灰石放入利福平-聚乙烯醇溶液中;
(3)在0.1-0.5Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于800-1000r/min转速下离心10-30min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5-10小时;
(4)将步骤(3)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料。
本发明通过将包含异烟肼和利福平的聚乙烯醇涂层交替包覆于生物活性多孔羟基磷灰石表面,获得了具有优异缓释性能和力学性能的多孔人工骨支架材料。
附图说明
图1为实施例1中得到的多孔人工骨支架材料的扫描电镜照片。
图2为将实施例1中的多孔人工骨支架材料以及未加载任何药物的HA支架植入兔子股骨髁缺损模型6个月时的HE染色切片,其中a中支架为实施例1中载有异烟肼、利福平的多孔HA支架,b中支架为未加载任何药物的HA支架。
具体实施方式
实施例1:
1、生物活性多孔羟基磷灰石的制备方法
将浓度为2.0%(g/mL)海藻酸钠溶液200ml通过计量注射针逐滴加入浓度为1mol/L的氯化钙溶液10ml中,将得到的海藻酸盐凝胶微珠在2小时内充分交联,随后用去离子水清洗三次并除去多余溶液,将湿的微珠浸入乙醇中进行溶剂交换。将羟基磷灰石粉末20g与浓度为2%(g/mL)的海藻酸钠溶液500ml混合制备羟基磷灰石浆料。将所述进行溶剂交换的微珠与羟基磷灰石浆料转移至圆柱模具中,随后用活塞单轴压缩混合物从而将微珠中的空腔用羟基磷灰石浆料充满。同时,微珠之间形成了桥接。将浆料渗透模板投入到氯化钙溶液中使羟基磷灰石浆料形成凝胶。然后取出模板,在40℃干燥获得圆柱形3D支架,并在大气条件下于700℃烧结2小时除去海藻酸盐,1200℃烧结2小时得到多孔羟基磷灰石支架。
2、多孔人工骨支架材料的制备
(1)配制浓度为4%(g/mL)的聚乙烯醇水溶液50ml,加入2g异烟肼后磁力搅拌2小时使之充分溶解得到异烟肼-聚乙烯醇溶液备用。将1.5g利福平溶于20ml二甲亚砜(DMSO)溶液,充分搅拌溶解后放入浓度为4%(g/mL)的聚乙烯醇水溶液30ml,再次充分搅拌溶解得到利福平-聚乙烯醇溶液;
(2)将8g生物活性多孔羟基磷灰石放入异烟肼-聚乙烯醇溶液中;
(3)在0.1Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于1000r/min转速下离心10min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5小时;
(4)将步骤(3)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料。
所得多孔人工骨支架材料的扫描电镜照片如图1所示。
选择新西兰白兔,通过手术在兔左右两侧股骨,制造尺寸为(2×1×1cm)的骨缺损模型,通过手术将载药支架植入所构建的兔股骨缺损模型中(缺损尺寸:2×1×1cm);空白组实验动物植入未加载任何药物的HA支架;在植入6个月后,处死试验模型动物,进行组织学分析,结果见图2。由图2发现可见到明显的幼稚骨组织形成,材料的多孔结构仍然存在,内部被大量的骨髓组织所填充。负载多种抗结核药的多孔HA支架并未对材料的生物活性及骨形成能力构成影响。
实施例2
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了将制备多孔人工骨支架材料的步骤(2)-(5)替换为:
(2)将8g生物活性多孔羟基磷灰石放入利福平-聚乙烯醇溶液中;
(3)在0.1Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于1000r/min转速下离心10min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5小时;
(4)将步骤(3)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料。
实施例3
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了将利福平的用量替换为2g。
实施例4
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了将异烟肼的用量替换为1.5g。
实施例5
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了将生物活性多孔羟基磷灰石的用量替换为10g。
实施例6
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了将配制异烟肼-聚乙烯醇溶液时的聚乙烯醇用量替换为20mL。
对比例1
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了不使用利福平-聚乙烯醇溶液,仅使用异烟肼-聚乙烯醇溶液浸渍生物活性多孔羟基磷灰石。
对比例2
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了不使用异烟肼-聚乙烯醇溶液,仅使用利福平-聚乙烯醇溶液浸渍生物活性多孔羟基磷灰石。
对比例3
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了使用3D打印技术形成含异烟肼的聚乙烯醇层和含利福平的聚乙烯醇层。
对比例4
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了在多孔人工骨支架材料的制备第(1)步中不使用聚乙烯醇溶液,即将2g异烟肼溶解于50ml二甲亚砜后磁力搅拌2小时使之充分溶解备用。将1.5g利福平溶于20ml二甲亚砜(DMSO)溶液后充分搅拌溶解。
对比例5
生物活性多孔羟基磷灰石和多孔人工骨支架材料的制备方法与实施例1相同,除了在多孔人工骨支架材料的制备第(2)步中将8g生物活性多孔羟基磷灰石放入异烟肼-聚乙烯醇溶液以及异烟肼的聚乙烯醇溶液中,0.1Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于1000r/min转速下离心10min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5小时,获得多孔人工骨支架材料。
技术效果:
1.抑菌性能
将去离子水与多孔人工骨支架材料按液/固比0.5m L/g混合均匀制成浆体,分装于玻璃试管(180mm*18mm)中,每管10ml,在12℃高压灭菌20min;刮去生长在改良罗氏培养基的结核杆菌菌苔加入含有0.5%吐温80的生理盐水,配置成1×107CFU/ml,每个试管接种结核杆菌0.1ml置于37℃,培养4周观察结果,用结核杆菌的抑制率作为指标比较治疗效果,其结果如表1所示。
表1材料的抑菌效果
编号 | 抑菌率 |
实施例1 | 99.85% |
实施例2 | 99.53% |
实施例3 | 99.16% |
实施例4 | 99.62% |
实施例5 | 99.30% |
实施例6 | 99.68% |
对比例1 | 30.26% |
对比例2 | 33.69% |
对比例3 | 60.98% |
对比例4 | 53.29% |
对比例5 | 40.36% |
2.缓释性能
将实施例和对比例中的多孔人工骨支架材料放入透析袋中,加入2ml pH为7.4的PBS溶液中,使材料充分浸泡,将透析袋封口后放入盛有5ml PBS的试管中,放入摇床中在37℃的温度下持续摇晃。并定时取出5ml PBS溶液,同时加入5ml PBS溶液,测定缓释时间。
表2材料的缓释效果
3.抗压强度
将实施例和对比例中的多孔人工骨支架材料置入37℃模拟体液中,浸泡24h后置于万能材料试验机(Zwick/roell)下,进行压缩实验,压缩速率为0.5mm/min,测试材料的抗压强度,性能数据列于表3。
表3材料的抗压强度
编号 | 抗压强度(MPa) |
实施例1 | 6.8 |
实施例2 | 6.2 |
实施例3 | 6.4 |
实施例4 | 6.5 |
实施例5 | 6.0 |
实施例6 | 6.3 |
对比例1 | 1.6 |
对比例2 | 1.9 |
对比例3 | 3.1 |
对比例4 | 2.3 |
对比例5 | 2.1 |
Claims (8)
1.一种聚乙烯醇/羟基磷灰石复合支架,其以活性多孔羟基磷灰石载体为核心层,表面交替包覆4层聚乙烯醇涂层,其中,由内至外,聚乙烯醇涂层依次为包含异烟肼的聚乙烯醇涂层、包含利福平的聚乙烯醇涂层、包含异烟肼的聚乙烯醇涂层和包含利福平的聚乙烯醇涂层,或者聚乙烯醇涂层依次为包含利福平的聚乙烯醇涂层、包含异烟肼的聚乙烯醇涂层、包含利福平的聚乙烯醇涂层和包含异烟肼的聚乙烯醇涂层;
聚乙烯醇/羟基磷灰石复合支架的制备方法为:
(1)配制浓度为4%-10%(g/mL)的聚乙烯醇水溶液,加入15-20质量份异烟肼后磁力搅拌2-3小时使之充分溶解得到异烟肼-聚乙烯醇溶液备用;将15-20质量份利福平溶于二甲亚砜溶液,充分搅拌溶解后放入浓度为4-10%(g/mL)的聚乙烯醇水溶液,再次充分搅拌溶解得到利福平-聚乙烯醇溶液;
(2)将生物活性多孔羟基磷灰石放入异烟肼-聚乙烯醇溶液中;
(3)在0.1-0.5Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于800-1000r/min转速下离心10-30min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5-10小时;
(4)将步骤(3)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料。
2.如权利要求1所述的聚乙烯醇/羟基磷灰石复合支架,其中将步骤(2)-(5)替换为:
(2)将生物活性多孔羟基磷灰石放入利福平-聚乙烯醇溶液中;
(3)在0.1-0.5Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于800-1000r/min转速下离心10-30min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5-10小时;
(4)将步骤(3)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料。
3.如权利要求1所述的聚乙烯醇/羟基磷灰石复合支架,所述生物活性多孔羟基磷灰石的制备方法为:(1)将浓度为2%-10%(g/mL)的海藻酸盐溶液通过计量注射针逐滴加入浓度为1-10mol/L的氯化钙溶液中,将得到的海藻酸盐凝胶微珠在2-5小时内充分交联,随后用去离子水清洗除去多余溶液,将湿的微珠浸入乙醇中进行溶剂交换;(2)将羟基磷灰石粉末与浓度为2%-10%(g/mL)的海藻酸盐溶液混合制备羟基磷灰石浆料,将所述进行溶剂交换的微珠与羟基磷灰石浆料转移至圆柱模具中,随后用活塞单轴压缩混合物从而将微珠中的空腔用羟基磷灰石浆料充满,同时,微珠之间形成了桥接,将浆料渗透模板投入到氯化钙溶液中使羟基磷灰石浆料形成凝胶,然后取出模板,在40-50℃干燥获得圆柱形3D支架,并在大气条件下于700-800℃烧结2-4小时除去海藻酸盐,1200-1300℃烧结2-4小时得到生物活性多孔羟基磷灰石。
4.如权利要求1所述的聚乙烯醇/羟基磷灰石复合支架,其中,活性多孔羟基磷灰石、聚乙烯醇、异烟肼和利福平的质量比为80-100:20-32:15-20:15-20。
5.如权利要求3所述的聚乙烯醇/羟基磷灰石复合支架,其中制备生物活性多孔羟基磷灰石的第(1)步中海藻酸盐与氯化钙的质量比为(4-6):(1-1.5)。
6.如权利要求3所述的聚乙烯醇/羟基磷灰石复合支架,其中制备生物活性多孔羟基磷灰石的第(2)步中羟基磷灰石粉末与海藻酸盐溶液的质量比为(1-10):(1-10)。
7.如权利要求3所述的聚乙烯醇/羟基磷灰石复合支架,海藻酸盐选自海藻酸钠、海藻酸钾中的一种或两种。
8.如权利要求1-7中任一项所述的聚乙烯醇/羟基磷灰石复合支架的制备方法,其特征在于:
制备聚乙烯醇/羟基磷灰石复合支架的步骤如下:
(1)配制浓度为4%-10%(g/mL)的聚乙烯醇水溶液,加入15-20质量份异烟肼后磁力搅拌2-3小时使之充分溶解得到异烟肼-聚乙烯醇溶液备用;将15-20质量份利福平溶于二甲亚砜溶液,充分搅拌溶解后放入浓度为4-10%(g/mL)的聚乙烯醇水溶液,再次充分搅拌溶解得到利福平-聚乙烯醇溶液;
(2)将生物活性多孔羟基磷灰石放入异烟肼-聚乙烯醇溶液中;
(3)在0.1-0.5Mpa负压下真空抽吸直至材料周围未见明显气泡渗出,取出材料,于800-1000r/min转速下离心10-30min,去除材料中多余的药物溶液,避免材料内部孔隙堵塞,再次取出材料,置入电热烘干机烘干5-10小时;
(4)将步骤(3)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3);
(5)将步骤(4)中得到的材料置入异烟肼-聚乙烯醇溶液中,并重复步骤(3);
(6)将步骤(5)中得到的材料置入利福平-聚乙烯醇溶液中,并重复步骤(3),获得具有4层药物涂层结构的多孔人工骨支架材料。
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