CN115463252A - 一种用于感染性骨缺损治疗的磁性骨水泥及其制备方法与应用 - Google Patents
一种用于感染性骨缺损治疗的磁性骨水泥及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供一种用于感染性骨缺损治疗的磁性骨水泥及其制备方法与应用，所述磁性骨水泥包括磷酸钙镁骨水泥和明胶包覆的Fe3O4微球，所述明胶包覆的Fe3O4微球完全干燥状态下粒径范围为10‑100μm，所述明胶包覆的Fe3O4微球的复合量为所述磷酸钙镁骨水泥粉体质量的8‑50％。通过将明胶包覆的四氧化三铁微球复合入磷酸钙镁骨水泥，制备出的磁性骨水泥具有优异的生物相容性、促成骨能力与可降解性。
Description
技术领域
本发明涉及生物医用材料技术领域，具体涉及一种用于感染性骨缺损治疗的磁性骨水泥及其制备方法与应用。
背景技术
由于人口老龄化速度加快及不良的生活方式，我国每年的骨折人数显著增长，且常伴随骨与软组织的多重损伤，尤其是严重污染的开放性骨折，更易引起创伤后感染性骨缺损。目前，临床上针对感染性骨缺损的传统治疗方式仍然是全身应用抗生素或药物，且往往需要多期移植手术才能达到清创彻底、伤口愈合的目的，但其长期使用抗生素极易引起人体正常菌群失调，甚至产生耐药菌，治疗周期过长，给患者带来极大痛苦，甚至危及生命。
近年来，由交变磁场介导的磁热治疗作为一种新兴的治疗手段，在促成骨和耐药细菌感染治疗等方面引起研究学者的极大兴趣。
发明内容
本发明的目的是提供一种用于感染性骨缺损治疗的磁性骨水泥及其制备方法和应用。所述的磁性骨水泥具有良好的生物相容性和促成骨能力，在交变磁场作用下有灵敏的磁性响应性，能杀灭金黄色葡萄球菌(S.aureus)和大肠杆菌(E.coli)，提高了感染性骨缺损的治疗效率。
本发明解决上述技术问题所采用的方案是：
一种用于感染性骨缺损治疗的磁性骨水泥，包括磷酸钙镁骨水泥和明胶包覆的Fe3O4微球，所述明胶包覆的Fe3O4微球完全干燥状态下粒径范围为10-100μm。
优选地，所述明胶包覆的Fe3O4微球的复合量为所述磷酸钙镁骨水泥粉体质量的8-50％。
优选地，所述微球的包覆率不低于70％。
优选地，所述磷酸钙镁骨水泥中纳米氧化镁的用量占粉体总量的20-40％。
优选地，所述磷酸钙镁骨水泥包括纳米氧化镁粉体、β-TCP、磷酸二氢钙、固化液。
进一步优选地，所述纳米氧化镁粉体的直径为20～90nm。
优选地，β-TCP、磷酸二氢钙、固化液的质量比为(3-7)：(15-18)：(9-18)。
进一步优选地，所述纳米氧化镁粉体、β-TCP、磷酸二氢钙的质量份数比例为8：(5.5-7)：(15-16.5)。
优选地，所述固化液为去离子水、PBS、柠檬酸、柠檬酸盐、磷酸盐、植酸、壳聚糖、氯化钙溶液中的任一种或几种。
优选地，所述明胶包覆的Fe3O4微球的制备方法包括如下步骤：
(1)将FeCl3·6H2O、柠檬酸钠、尿素、聚丙烯酰胺加入到去离子水中，搅拌至溶解，将所得混合物在160-250℃条件下反应10-24h，脱去溶液，干燥，得到介孔Fe3O4纳米微球；
(2)将所得介孔Fe3O4纳米微球超声分散在明胶溶液中，将所得明胶溶液滴加到液体石蜡和司班80的混合乳液中，再滴加碳二亚胺盐酸盐，冰水浴条件下，150-600r/min搅拌0.5-4h，产物清洗干燥，得到明胶包覆的Fe3O4微球。
进一步优选地，步骤(1)中，FeCl3·6H2O、柠檬酸钠、尿素、聚丙烯酰胺的质量份数之比为(0.3-0.5)：(0.6-1.5)：(0.1-0.5)：(0.01～0.1g)。
进一步优选地，步骤(2)中，Fe3O4纳米微球与明胶溶液的比例为(0.25-0.45)g：5ml，其中明胶溶液中明胶的质量浓度为5％-50％。
进一步优选地，步骤(2)中，液体石蜡和司班80的质量比为(5-15)：1；碳二亚胺盐酸盐的加入量为明胶质量的0.1％-0.5％。
优选地，所述磁性骨水泥在交变磁场作用下可升温至50～55℃。
本发明还提供上述磁性骨水泥的制备方法，包括如下步骤：
(1)获得明胶包覆的Fe3O4微球；
(2)将所得明胶包覆的Fe3O4微球与纳米氧化镁粉体、β-TCP、磷酸二氢钙混合均匀，与固化液在-20℃～10℃的低温条件下充分混合后注模成型，即得到所述磁性骨水泥。
本发明还提供上述的磁性骨水泥作为感染性骨缺损治疗所用的骨修复材料的应用。
磷酸钙镁骨水泥具有良好的生物相容性和骨传导性，可用作药物或抗生素载体，在填充骨缺损的同时释放活性药物、抗生素或离子以达到治疗目的。钙(Ca)是人体中最丰富的金属元素，是矿化组织的主要成分，对骨的再生和愈合至关重要；磷(P)是骨骼中第二大矿物质元素，参与多种生物过程，如细胞生理和骨骼矿化；镁(Mg)是人体必需的矿物元素，能增强骨组织的矿物质密度，降低骨骼脆性，在骨稳态和代谢中发挥重要作用，此外，镁离子还具有高效的抗菌效应，可通过影响细胞极化状态、生化反应、核酸结构及酶活性进而抑制细菌的生长。此外，本发明所设计的原料纳米氧化镁在骨水泥的水化反应过程中是过量的，剩余的纳米氧化镁可通过活性氧氧化损伤和吸附作用引起的机械损伤达到杀菌效果，且其极易与水反应生成氢氧化镁(Mg(OH)2)及过氧离子(O2–)，营造局部碱性微环境并提高O2–稳定性及活性。
本发明通过将明胶包覆的四氧化三铁微球复合入磷酸钙镁骨水泥，制备出的磁性骨水泥具有优异的生物相容性、促成骨能力与可降解性。通过复合明胶包覆四氧化三铁纳米粒子，相对于单一四氧化三铁纳米粒子具有在交变磁场下可调可控的精准升温效果(50～55℃)，可有效杀灭细菌，在兼顾抗菌效果的同时，具有促成骨效应且对正常细胞的影响小。水化反应过程中剩余的纳米氧化镁具有显著的抑菌效果；降解过程中释放出的钙、镁、磷等生物活性离子可显著促进成骨。制备工艺简单，亦可根据需要在明胶包覆的四氧化三铁微球中负载药物、抗生素、生长因子等提高治疗效果，在生物医用材料领域具有良好的应用前景。
附图说明
图1是实施例1和实施例2所得磁性骨水泥的磁热升温图像；
图2是实施例1制备的磁性骨水泥在H＝220Oe，f＝495kHz正弦交变磁场下作用5min的升降温曲线；
图3是实施例1～4所得磁性骨水泥在磁场作用下对金黄色葡萄球菌的抑菌效果，磁场条件为正弦交变磁场(H＝220Oe，f＝495kHz)作用15min；
图4是实施例2制备的磁性骨水泥在磁场作用下对大肠杆菌的抑制效果，为所述磁性骨水泥与大肠杆菌共培养，在正弦交变磁场(H＝220Oe，f＝495kHz)作用15min的涂布平板效果；
图5是实施例2和6所得磁性骨水泥在磁场作用下镁离子的释放曲线，为所得磁性骨水泥按0.2g/ml比例浸提于PBS培养液(pH＝7.4)，在正弦交变磁场(H＝220Oe，f＝495kHz)作用20min后的镁离子的释放效果；
图6是实施例7和8所得磁性骨水泥在磁场作用下碱性磷酸酶染色图片，为所得磁性骨水泥与骨髓间充质干细胞共培养后，在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后的碱性磷酸酶染色效果。
具体实施方式
为更好的理解本发明，下面的实施例是对本发明的进一步说明，但本发明的内容不仅仅局限于下面的实施例。
实施例1
本实施例的制备过程包括：
(1)将0.38g FeCl3·6H2O、0.7g柠檬酸钠、0.3g尿素、0.05g聚丙烯酰胺溶解于40ml去离子水中，在180℃条件下水热反应12h，清洗干燥后得到介孔Fe3O4纳米微球。
(2)将步骤(1)制备好的0.3g Fe3O4纳米微球分散在5ml、明胶质量分数40％的明胶溶液中，滴加到40ml液体石蜡和司班80(体积比为12：1)的混合乳液中，再滴加1ml、0.05M的碳二亚胺盐酸盐，冰水浴搅拌1h，清洗干燥得明胶包覆的四氧化三铁磁性微球。
(3)将步骤(2)制备好的0.6g明胶包覆的四氧化三铁磁性微球、0.8g纳米氧化镁粉体、0.4gβ-TCP、1.8g磷酸二氢钙混合均匀，在0℃条件下与1.5g去离子水充分混合搅拌，注模成型后于37℃、100％相对湿度环境中养护48小时，即得到所述用于感染性骨缺损治疗的磁性骨水泥。
所得明胶包覆的四氧化三铁微球通过胶原酶在37℃下反应2h将明胶分解后，测得其包覆率为78％，其中：包覆率＝酶溶解明胶后分离出的四氧化三铁质量/明胶包覆的四氧化三铁微球总质量。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至50.2℃(图1)，且随磁场开关，磁热升/降温效果循环可控(图2)，对金黄色葡萄球菌的抑菌率为85％(图3)。
实施例2
本实施例的制备过程与实施例1的区别在于：步骤(3)制备好的明胶包覆的四氧化三铁磁性微球掺量为1.2g。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至52.5℃(图1)，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为95％(图3)，对大肠杆菌有显著的抑制效果(图4)，在磁场作用下镁离子缓慢释放(图5)。
实施例3
本实施例的制备过程与实施例2的区别在于：步骤(3)所述纳米氧化镁粉体为1.0g、磷酸二氢钙为1.6g。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至52.1℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为98％(图3)。
实施例4
本实施例的制备过程与实施例1的区别在于：步骤(3)是将制备好的1.0g明胶包覆的四氧化三铁磁性微球、0.9g纳米氧化镁粉体、0.3gβ-TCP、1.8g磷酸二氢钙混合均匀，在-5℃条件下与1.5g柠檬酸溶液充分混合搅拌，注模成型后于37℃、100％相对湿度环境中养护48小时，即得到所述用于感染性骨缺损治疗的磁性骨水泥。
该骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至51.7℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为96.1％(图3)。
实施例5
本实施例的制备过程与实施例1的区别在于：步骤(3)制备好的明胶包覆的四氧化三铁磁性微球掺量为1.5g。
该骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至54.7℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为99％。
实施例6
本实施例的制备过程与实施例1的区别在于：
步骤(3)将步骤(2)制备好的0.9g明胶包覆的四氧化三铁磁性微球、0.8g纳米氧化镁粉体、0.7gβ-TCP、1.5g磷酸二氢钙混合均匀，在0℃条件下与1.5g磷酸盐溶液充分混合搅拌，注模成型后于37℃、100％相对湿度环境中养护48小时，即得到所述用于感染性骨缺损治疗的磁性骨水泥。
该骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至51.6℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为98％，在磁场作用下镁离子释放速率高于实施例2(图5)。可知，相对于实施例2，即使本实施例的升温较低，但由于镁离子作用，抑菌率反而更高。
实施例7
本实施例的制备过程与实施例1的区别在于：步骤(3)是将制备好的0.6g明胶包覆的四氧化三铁磁性微球、1.2g纳米氧化镁粉体、0.3gβ-TCP、1.5g磷酸二氢钙混合均匀，在-10℃条件下与1.5g PBS充分混合搅拌，注模成型后于37℃、100％相对湿度环境中养护48小时，即得到所述用于感染性骨缺损治疗的磁性骨水泥。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至50.4℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为98％。根据与实施例1的对比可知，在磁性微球用量相同的情况下，氧化镁增加对磁热升温效果影响不大，但是抑菌效果更显著。值得注意的是，本实施例相比于空白对照组可显著促进骨髓间充质干细胞碱性磷酸酶的表达(图6)。
实施例8
本实施例的制备过程与实施例1的区别在于：步骤(3)是将制备好的1.5g明胶包覆的四氧化三铁磁性微球、1.2g纳米氧化镁粉体、0.3gβ-TCP、1.5g磷酸二氢钙混合均匀，在-10℃条件下与1.5g PBS充分混合搅拌，注模成型后于37℃、100％相对湿度环境中养护48小时，即得到所述用于感染性骨缺损治疗的磁性骨水泥。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至54.8℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为99.7％，但相比于空白对照组和实施例7，其骨髓间充质干细胞碱性磷酸酶的表达更低(图6)。
对比例1
本实施例的制备过程与实施例1的区别在于：步骤(3)制备好的明胶包覆的四氧化三铁磁性微球掺量为1.8g。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至58.5℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为100％，但将其与骨髓间充质干共培养后，近50％细胞死亡，施加磁场后，死亡率达85％。
对比例2
本实施例的制备过程与实施例1的区别在于：步骤(3)所述的纳米氧化镁粉体质量为1.5g，β-TCP与磷酸二氢钙的总用量为1.5g。
所得骨水泥在正弦交变磁场(H＝220Oe，f＝495kHz)作用5min后，可升温至50.1℃，且随磁场开关，磁热升/降温效果循环可控，对金黄色葡萄球菌的抑菌率为89％，但将其与骨髓间充质干共培养后，近20％细胞死亡，施加磁场后，死亡率达34％。
以上所述是本发明的优选实施方式而已，当然不能以此来限定本发明之权利范围，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和变动，这些改进和变动也视为本发明的保护范围。
Claims (10)
1.一种用于感染性骨缺损治疗的磁性骨水泥，其特征在于，包括磷酸钙镁骨水泥和明胶包覆的Fe3O4微球，所述明胶包覆的Fe3O4微球完全干燥状态下粒径范围为10-100μm，其中所述明胶包覆的Fe3O4微球的复合量为所述磷酸钙镁骨水泥粉体质量的8-50％。
2.根据权利要求1所述的磁性骨水泥，其特征在于，所述微球的包覆率不低于70％。
3.根据权利要求1所述的磁性骨水泥，其特征在于，所述磷酸钙镁骨水泥粉体中纳米氧化镁的用量占粉体总量的20-40％。
4.根据权利要求1所述的磁性骨水泥，其特征在于，所述磷酸钙镁骨水泥包括纳米氧化镁粉体、β-TCP、磷酸二氢钙、固化液。
5.根据权利要求4所述的磁性骨水泥，其特征在于，β-TCP、磷酸二氢钙的质量比为(3-7)：(15-18)。
6.根据权利要求4所述的磁性骨水泥，其特征在于，所述固化液为去离子水、PBS、柠檬酸、柠檬酸盐、磷酸盐、植酸、壳聚糖、氯化钙溶液中的任一种或几种。
7.根据权利要求1所述的磁性骨水泥，其特征在于，所述明胶包覆的Fe3O4微球的制备方法包括如下步骤：
(1)将FeCl3·6H2O、柠檬酸钠、尿素、聚丙烯酰胺加入到去离子水中，搅拌至溶解，将所得混合物在160-250℃条件下反应10-24h，脱去溶液，干燥，得到介孔Fe3O4纳米微球；
(2)将所得介孔Fe3O4纳米微球超声分散在明胶溶液中，将所得明胶溶液滴加到液体石蜡和司班80的混合乳液中，再滴加碳二亚胺盐酸盐，冰水浴条件下，150-600r/min搅拌0.5-4h，产物清洗干燥，得到明胶包覆的Fe3O4微球。
8.根据权利要求1所述的磁性骨水泥，其特征在于，所述磁性骨水泥在交变磁场作用下可升温至50～55℃。
9.如权利要求1～7任一项所述磁性骨水泥的制备方法，其特征在于，包括如下步骤：
(1)获得明胶包覆的Fe3O4微球；
(2)将所得明胶包覆的Fe3O4微球与纳米氧化镁粉体、β-TCP、磷酸二氢钙混合均匀，与固化液在-20℃～10℃的低温条件下充分混合后注模成型，即得到所述磁性骨水泥。
10.根据权利要求1-8所述的磁性骨水泥或者权利要求9所述制备方法所得磁性骨水泥的应用，其特征在于，作为感染性骨缺损治疗所用的骨修复材料。
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Citations (5)
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| CN101256871A (zh) * | 2007-12-26 | 2008-09-03 | 嘉应学院 | 明胶包覆水基磁流体及其制备方法 |
| CN101564556A (zh) * | 2009-05-15 | 2009-10-28 | 天津大学 | 明胶微球/磷酸钙骨水泥复合的多级释药载体的制备方法 |
| CN105903063A (zh) * | 2016-05-16 | 2016-08-31 | 武汉理工大学 | 一种镁基医用骨粘结剂材料及其制备方法 |
| CN108379666A (zh) * | 2018-03-05 | 2018-08-10 | 武汉理工大学 | 一种明胶微球/磷酸镁基骨水泥药物缓释载体及其制备方法 |
| CN112245656A (zh) * | 2019-11-20 | 2021-01-22 | 武汉理工大学 | 一种磷酸钙镁骨水泥复合支架的制备方法 |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101256871A (zh) * | 2007-12-26 | 2008-09-03 | 嘉应学院 | 明胶包覆水基磁流体及其制备方法 |
| CN101564556A (zh) * | 2009-05-15 | 2009-10-28 | 天津大学 | 明胶微球/磷酸钙骨水泥复合的多级释药载体的制备方法 |
| CN105903063A (zh) * | 2016-05-16 | 2016-08-31 | 武汉理工大学 | 一种镁基医用骨粘结剂材料及其制备方法 |
| CN108379666A (zh) * | 2018-03-05 | 2018-08-10 | 武汉理工大学 | 一种明胶微球/磷酸镁基骨水泥药物缓释载体及其制备方法 |
| CN112245656A (zh) * | 2019-11-20 | 2021-01-22 | 武汉理工大学 | 一种磷酸钙镁骨水泥复合支架的制备方法 |
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