CN108434518B - 中药单体序列缓释成骨成血管钙磷支架材料的制备方法 - Google Patents
中药单体序列缓释成骨成血管钙磷支架材料的制备方法 Download PDFInfo
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Abstract
本发明涉及中药单体序列缓释成骨成血管钙磷支架材料的制备方法，包括步骤：1)钙磷晶体支架制备；2)缓释成骨涂层；3)缓释成血管涂层；4)将功能颗粒重复2‑5个循环，结晶冻干后备用，所有的操作在无菌环境中进行；根据不同的临床需要制备所需大小和形状的钙磷支架。本发明的有益效果是：用低温微纳米微沉积技术，有序循环搭载中药单体成分丹酚酸B和三七皂苷R1，构建可同时促成骨成血管的复合仿生钙磷支架材料；低温微纳米微沉积技术是利用低温微纳米微沉积技术制备的仿生涂层，在缓冲体系中形成钙磷微纳米晶体，该晶体能够在常温下凝结成具有一定强度的支架。
Description
技术领域
本发明涉及一种中药单体序列缓释成骨成血管钙磷支架材料的制备方法，可制成广泛应用于整形外科、创伤骨科及口腔种植的修复重建手术的钙磷支架材料，属于医疗器械技术领域。
背景技术
外伤、肿瘤、炎症等导致的长节段骨缺损的修复是临床医师面临的最棘手难题之一。长段骨缺损修复难度大，主要是由于骨缺损部位血供差，新生血管长入困难，营养不能及时供给进而影响成骨效果。目前，促进血管化工程骨主要通过联合显微外科技术，但该方法主要通过外源性途径来为移植物提供血运，其效果难以满足临床需要。联合生长因子(如VEGF、BMP)可诱导新生血管形成，但生长因子价格贵和使用剂量较高所导致一些副作用限制了其在临床上的应用。
理想的骨修复支架材料的降解性应与新骨形成速度相一致，同时新生血管可以及时提供其成骨过程中所需要的养分及干细胞等，因此成骨成血管并进是修复大段骨缺损的关键。中药单体丹酚酸B(SALB)具有良好的成血管活性，三七皂苷R1(NGR1)具有良好的成骨活性，中药单体成分明确，价格低廉，因而临床上使用能显著降低临床治疗成本，减轻患者经济负担，现在临床上使用的骨充填材料主要来自于国外，价格昂贵且成骨效果不理想，吸收缓慢临床上不易愈合，延长临床作用时间。
发明内容
本发明的目的是克服现有技术中的不足，提供一种中药单体序列缓释成骨成血管钙磷支架材料的制备方法。
中药单体序列缓释成骨成血管钙磷支架材料的制备方法，包括如下步骤：
1)钙磷晶体支架制备：
1.1)取40.1-42.5g NaCL，0.8-1.2g KCL，1.2-1.5g CaCL22H2O，0.8-1.2gMgCL26H2O，将上述4份材料同时溶解于超纯水中并搅拌，加入15-20毫升浓度为1mM的1mMHCL，PH降为1.8-2，此为溶液一；
1.2)取0.3-0.4g Na2HPO42H2O溶于超纯水中，此为溶液二，将溶液二倒入溶液一中；
1.3)取4.5-5.5g碳酸氢钠缓慢倒入溶液一中，同时滴加1mM的1mM HCL监测溶液PH值使之始终保持在5.8-6.2之间；
1.4)最终加入超纯水，温度控制在36.5-37.5度同时监测PH值12-14小时；
1.5)沉淀生成，去除上清液，沉淀用超纯水重悬，离心机上离心，以上清洗步骤重复4-5次；
1.6)用无菌过滤器真空过滤，将过滤器中得到的磷酸钙收集于成型器中，放于烘箱，支架材料干燥后磷酸钙支架材料成乳白色；
2)缓释成骨涂层：
2.1)将钙磷晶体支架放入含无菌NGR1的超饱和钙磷溶液中，配比为：7-9g HCl；0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O；5-7g；三羟甲基氨基甲烷TRIS base，加入35-45毫升1M HCL调节PH值7.35-7.45；
2.2)无菌过滤器过滤此超饱和溶液，搅拌36-48小时，冷却至室温，收集支架材料超声5-10秒，超纯水冲洗，真空干燥后形成NGR1-钙磷支架；
3)缓释成血管涂层：
3.1)将NGR1-钙磷支架放入含无菌SalB的超饱和钙磷溶液中，配比为：7-9g HCl；0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O；5-7g三羟甲基氨基甲烷TRIS base，加入35-45毫升1M HCL调节PH值7.35-7.45；
3.2)无菌过滤器过滤此超饱和溶液，搅拌36-48小时，冷却至室温，收集支架材料超声5-10秒，超纯水冲洗，真空干燥后形成SalB-NGR1-钙磷支架；
4)将上述功能颗粒重复2-5个循环，结晶冻干后备用，所有的操作在无菌环境中进行；根据不同的临床需要制备所需大小和形状的钙磷支架。
这种中药单体序列缓释成骨成血管钙磷支架材料的使用方法，包括如下步骤：
1)将支架材料充填入骨缺损部位时，血液中的巨噬细胞吞噬材料表面的涂层，同时缓释出丹酚酸B和钙磷成分，丹酚酸B激活血液中的干细胞，快速诱导成血管的发生，在骨缺损处形成血管***，血液循环给骨缺损处补给营养成分及原料；
2)涂层继续降解的同时缓释三七皂苷R1，其高效诱导血液循环带来的干细胞向成骨细胞分化，并利用降解的钙磷成分，在缺损处矿化成新生骨，新生骨骨小梁等结构可比拟生理骨结构。
本发明的有益效果是:用低温微纳米微沉积技术，有序循环搭载中药单体成分丹酚酸B和三七皂苷R1，构建可同时促成骨成血管的复合仿生钙磷支架材料。低温微纳米微沉积技术是利用低温微纳米微沉积技术制备的仿生涂层，在缓冲体系中形成钙磷微纳米晶体，该晶体能够在常温下凝结成具有一定强度的支架。该支架可实现有序搭载中药单体成分，与传统的支架烧结形成技术不同，低温微沉积技术可更好的保持中药单体的活性。在形成缓释涂层的同时循环加载三七皂苷R1和丹酚酸B，形成花瓣状循环交互的中药单体结构，在钙磷涂层溶解的同时缓释丹酚酸B，促进新生血管形成，同时血运带来干细胞和成骨过程必须的因子和养分。钙磷涂层进一步溶解缓释三七皂苷R1，其能更好的利用血运来源的干细胞，高效诱导干细胞向成骨细胞转换，并促进成骨矿化及新生骨的形成。近年来临床上使用的是骨形成蛋白BMP，但其价格昂贵，副作用如过量成骨形成骨赘(缺乏成血管性)，过量激活破骨细胞造成溶骨等而影响其临床应用。中药单体序列缓释能很好的解决这个问题，丹酚酸B具有很好的成血管活性提供新生骨能量和干细胞源，三七皂苷R1是传统中药被用于治疗骨缺损已有几千年的历史，其几乎无副作用，不仅可以持续成骨而且可以防止溶骨等副作用。此支架材料的局部缓释可使完成成骨成血管的序列发生，获得最佳的成骨诱导效果，其形成的新生骨可比拟正常骨结构，此外支架材料复合的中药单体源于中国，来源广泛，价格低廉，此低成本高骨诱导性的临床骨修复支架材料是我国修复大段骨缺损的迫切需要。
附图说明
图1是合成过程示意图；
图2是扫描电镜图(SEM)，可见珊瑚状中药单体层；
图3是成血管图(左：对照组。右：材料组)；
图4是成骨矿化图(左：对照组。右：材料组)；
图5是体内成骨实验MicroCT图，显示新生骨形貌；
图6是扫描电镜图(SEM)，可见较均匀珊瑚状中药单体层；
图7是成血管图(左：对照组。右：材料组)；
图8是成骨矿化图(左：对照组。右：材料组)；
图9是体内成骨实验MicroCT图，显示新生骨形貌。
具体实施方式
下面结合实施例对本发明做进一步描述。下述实施例的说明只是用于帮助理解本发明。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，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
本发明分为钙磷晶体和缓释涂层，在生物体内破骨细胞的作用下，缓释涂层中的钙磷在降解的同时释放出中药单体丹酚酸B，作用于骨缺损处首先促进成血管的发生，新生血管形成后将血液中的干细胞和营养成分带到骨缺损处。下一步钙磷涂层继续降解，缓释出三七皂苷R1，其能高效诱导血液中的干细胞向成骨方向分化，并利用降解的钙磷作为原材料，血液中的微量成分和因子提供营养，最终高效完成整个骨缺损的仿生理修复。
本发明所采用的技术方案是：中药单体序列缓释成骨成血管钙磷支架材料的制备方法，特征步骤如下：
钙磷晶体支架制备：操作在无菌超净工作台中进行。取40.1-42.5g氯化钠(NaCL)，0.8-1.2g氯化钾(KCL)，1.2-1.5g水合氯化钙(CaCL22H2O)，0.8-1.2g水合氯化镁(MgCL26H2O)，将上述4份材料同时溶解于超纯水中(MillQ water)并搅拌，加入15-20毫升浓度为1mM的氯化氢(1mM HCL)，PH降为1.8-2，此为溶液一。取0.3-0.4g水合磷酸氢二钠(Na2HPO42H2O)溶于5毫升超纯水(MillQ water)中，此为溶液二，将溶液二倒入溶液一中。取4.5-5.5g碳酸氢钠缓慢倒入溶液一中，同时滴加1mM的氯化氢(1mM HCL)监测溶液PH值使之始终保持在5.8-6.2之间。最终加入超纯水使得液体总量在1000毫升，在磁力搅拌器上转速(260r/min)，温度控制在36.5-37.5度同时监测PH值12-14小时。沉淀生成，去除上清液，沉淀用超纯水重悬5分钟，离心机上5000r/min离心5分钟，以上清洗步骤重复4-5次，用0.22微米的无菌过滤器真空过滤，将过滤器中得到的磷酸钙收集于成型器中(以自主制作的直径5mm圆形成型器为例)，放于37度烘箱12小时，支架材料干燥后磷酸钙支架材料成乳白色。
缓释成骨涂层：将钙磷晶体支架分别放入含无菌的1mg,10mg,100mg,1g的NGR1(单体成分明确可购买)的1000ml超饱和钙磷溶液中(7-9g HCl；0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O；5-7g三羟甲基氨基甲烷TRIS base[Sigma]，加入35-45毫升1M HCL调节PH值7.35-7.45。0.2μm无菌过滤器过滤此超饱和溶液)恒温37℃转速为50转/分搅拌36-48小时，冷却至室温，收集支架材料超声5-10秒，超纯水冲洗，真空干燥后形成NGR1-钙磷支架。
缓释成血管涂层：将NGR1-钙磷支架分别放入含无菌的0.1mg,1mg,10mg,100mg的SalB(单体成分明确可购买)的1000ml超饱和钙磷溶液中(7-9g HCl；0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O；5-7g三羟甲基氨基甲烷TRIS base[Sigma]，加入35-45毫升1MHCL调节PH值7.35-7.45。0.2μm无菌过滤器过滤此超饱和溶液)恒温37℃转速为50转/分搅拌36-48小时，冷却至室温，收集支架材料超声5-10秒，超纯水冲洗，真空干燥后形成SalB-NGR1-钙磷支架。
将上述功能颗粒重复2-5个循环，结晶冻干后备用，所有的操作在无菌环境中进行(合成过程示意图1)。可根据不同的临床需要制备所需大小和形状的钙磷支架。
将支架材料充填入骨缺损部位时，血液中的巨噬细胞吞噬材料表面的涂层，同时缓释出丹酚酸B和钙磷成分，丹酚酸B激活血液中的干细胞，快速诱导成血管的发生，在骨缺损处形成血管***，血液循环给骨缺损处补给营养成分及原料。涂层继续降解的同时缓释三七皂苷R1，其高效诱导血液循环带来的干细胞向成骨细胞分化，并利用降解的钙磷成分，在缺损处矿化成新生骨，新生骨骨小梁等结构可比拟生理骨结构。
实施例一：
钙磷晶体支架制备：操作在无菌超净工作台中进行。取42g氯化钠(NaCL)，1g氯化钾(KCL)，1.4g水合氯化钙(CaCL22H2O)，1g水合氯化镁(MgCL26H2O)，将上述4份材料同时溶解于超纯水中(MillQ water)并搅拌，加入18毫升浓度为1mM的氯化氢(1mM HCL)，PH降为2，此为溶液一。取0.35g水合磷酸氢二钠(Na2HPO42H2O)溶于5毫升超纯水(MillQ water)中，此为溶液二，将溶液二倒入溶液一中。取5g碳酸氢钠缓慢倒入溶液一中，同时滴加1mM的氯化氢(1mM HCL)监测溶液PH值使之始终保持在6。最终加入超纯水使得液体总量在1000毫升，在磁力搅拌器上转速(260r/min)，温度控制在37度同时监测PH值14小时。沉淀生成，去除上清液，沉淀用超纯水重悬5分钟，离心机上5000r/min离心5分钟，以上清洗步骤重复5次，用0.22微米的无菌过滤器真空过滤，将过滤器中得到的磷酸钙收集于成型器中(以自主制作的直径5mm圆形成型器为例)，放于37度烘箱12小时，支架材料干燥后磷酸钙支架材料成乳白色。
缓释成骨涂层：将钙磷晶体支架放入含无菌的100mg的NGR1(单体成分明确可购买)的1000ml超饱和钙磷溶液中(8g HCl；0.38g Na2HPO4·2H2O；0.6g CaCl2·2H2O；6g三羟甲基氨基甲烷TRIS base[Sigma]，加入40毫升1M HCL调节PH值7.4。0.2μm无菌过滤器过滤此超饱和溶液)恒温37℃转速为50转/分搅拌48小时，冷却至室温，收集支架材料超声5秒，超纯水冲洗，真空干燥后形成NGR1-钙磷支架。
缓释成血管涂层：将NGR1-钙磷支架放入含无菌的10mg的SalB(单体成分明确可购买)的1000ml超饱和钙磷溶液中(8g HCl；0.38g Na2HPO4·2H2O；0.6g CaCl2·2H2O；6g三羟甲基氨基甲烷TRIS base[Sigma]，加入40毫升1M HCL调节PH值7.4。0.2μm无菌过滤器过滤此超饱和溶液)恒温37℃转速为50转/分搅拌48小时，冷却至室温，收集支架材料超声5秒，超纯水冲洗，真空干燥后形成SalB-NGR1-钙磷支架。
将上述功能颗粒重复四个循环，结晶冻干后备用，所有的操作在无菌环境中进行。
实施例一扫描电镜下可见支架表面均匀分布珊瑚状的中药单体涂层(图2)。将此缓释钙磷支架材料用于脐静脉内皮细胞-材料共培养和间充质干细胞-材料共培养体系中发现，此材料成骨成血管效果较单一钙磷支架材料好且有明显差异(图3,4)。用于动物体内诱导成骨实验发现，成骨量明显优于临床使用的成骨材料，六周后成骨效果更为显著，且MicroCT发现新生骨的骨小梁距离较近，其结构更接近于正常骨结构(图5)。
实施例二：
钙磷晶体支架制备：操作在无菌超净工作台中进行。取40g氯化钠(NaCL)，0.8g氯化钾(KCL)，1.2g水合氯化钙(CaCL22H2O)，0.8g水合氯化镁(MgCL26H2O)，将上述4份材料同时溶解于超纯水中(MillQ water)并搅拌，加入16毫升浓度为1mM的氯化氢(1mM HCL)，PH降为1.8，此为溶液一。取0.3g水合磷酸氢二钠(Na2HPO42H2O)溶于5毫升超纯水(MillQ water)中，此为溶液二，将溶液二倒入溶液一中。取4.5g碳酸氢钠缓慢倒入溶液一中，同时滴加1mM的氯化氢(1mM HCL)监测溶液PH值使之始终保持在5.8。最终加入超纯水使得液体总量在1000毫升，在磁力搅拌器上转速(260r/min)，温度控制在36.5度同时监测PH值12小时。沉淀生成，去除上清液，沉淀用超纯水重悬5分钟，离心机上5000r/min离心5分钟，以上清洗步骤重复5次，用0.22微米的无菌过滤器真空过滤，将过滤器中得到的磷酸钙收集于成型器中(以自主制作的直径5mm圆形成型器为例)，放于37度烘箱12小时，支架材料干燥后磷酸钙支架材料成乳白色。
缓释成骨涂层：将钙磷晶体支架放入含无菌的1mg的NGR1(单体成分明确可购买)的1000ml超饱和钙磷溶液中(7g HCl；0.34g Na2HPO4·2H2O；0.55g CaCl2·2H2O；5g三羟甲基氨基甲烷TRIS base[Sigma]，加入38毫升1M HCL调节PH值7.35。0.2μm无菌过滤器过滤此超饱和溶液)恒温37℃转速为50转/分搅拌48小时，冷却至室温，收集支架材料超声5秒，超纯水冲洗，真空干燥后形成NGR1-钙磷支架。
缓释成血管涂层：将NGR1-钙磷支架放入含无菌的0.1mg的SalB(单体成分明确可购买)的1000ml超饱和钙磷溶液中(7g HCl；0.34g Na2HPO4·2H2O；0.55g CaCl2·2H2O；5g三羟甲基氨基甲烷TRIS base[Sigma]，加入38毫升1M HCL调节PH值7.35。0.2μm无菌过滤器过滤此超饱和溶液)恒温37℃转速为50转/分搅拌48小时，冷却至室温，收集支架材料超声5秒，超纯水冲洗，真空干燥后形成SalB-NGR1-钙磷支架。
将上述功能颗粒重复两个循环，结晶冻干后备用，所有的操作在无菌环境中进行。
实施例二扫描电镜下可见支架表面较均匀分布珊瑚状的中药单体涂层(图6)。将此缓释钙磷支架材料用于脐静脉内皮细胞-材料共培养和间充质干细胞-材料共培养体系中发现，此材料成骨成血管效果较好(图7,8)。用于动物体内诱导成骨实验发现，成骨量较多，六周后成骨效果更为显著，MicroCT发现新生骨的骨小梁结构类似于生理骨结构(图9)。
Claims (2)
1.一种中药单体序列缓释成骨成血管钙磷支架材料的制备方法，其特征在于：包括如下步骤：
1)钙磷晶体支架制备：
1.1)取40.1-42.5g NaCL，0.8-1.2g KCL，1.2-1.5g CaCL22H2O，0.8-1.2g MgCL26H2O，将上述4份材料同时溶解于超纯水中并搅拌，加入15-20毫升浓度为1mM的1mM HCL，pH降为1.8-2，此为溶液一；
1.2)取0.3-0.4g Na2HPO42H2O溶于超纯水中，此为溶液二，将溶液二倒入溶液一中；
1.3)取4.5-5.5g碳酸氢钠缓慢倒入溶液一中，同时滴加1mM的1mM HCL监测溶液pH值使之始终保持在5.8-6.2之间；
1.4)最终加入超纯水，温度控制在36.5-37.5度同时监测pH值12-14小时；
1.5)沉淀生成，去除上清液，沉淀用超纯水重悬，离心机上离心，以上清洗步骤重复4-5次；
1.6)用无菌过滤器真空过滤，将过滤器中得到的磷酸钙收集于成型器中，放于烘箱，支架材料干燥后磷酸钙支架材料成乳白色；
2)缓释成骨涂层：
2.1)将钙磷晶体支架放入含无菌NGR1的超饱和钙磷溶液中，配比为：7-9g HCl；0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O；5-7g；三羟甲基氨基甲烷TRIS base，加入35-45毫升1M HCL调节pH值7.35-7.45；
2.2)无菌过滤器过滤此超饱和溶液，搅拌36-48小时，冷却至室温，收集支架材料超声5-10秒，超纯水冲洗，真空干燥后形成NGR1-钙磷支架；
3)缓释成血管涂层：
3.1)将NGR1-钙磷支架放入含无菌SalB的超饱和钙磷溶液中，配比为：7-9g HCl；0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O；5-7g三羟甲基氨基甲烷TRIS base，加入35-45毫升1M HCL调节pH值7.35-7.45；
3.2)无菌过滤器过滤此超饱和溶液，搅拌36-48小时，冷却至室温，收集支架材料超声5-10秒，超纯水冲洗，真空干燥后形成SalB-NGR1-钙磷支架；
4)将上述功能颗粒重复2-5个循环，结晶冻干后备用，所有的操作在无菌环境中进行；根据不同的临床需要制备所需大小和形状的钙磷支架。
2.根据权利要求1所述的中药单体序列缓释成骨成血管钙磷支架材料的制备方法，其特征在于：步骤2.1)中将钙磷晶体支架分别放入含无菌的1mg,10mg,100mg,1g的NGR1的1000ml超饱和钙磷溶液中；步骤3.1)中将NGR1-钙磷支架分别放入含无菌的0.1mg,1mg,10mg,100mg的SalB的1000ml超饱和钙磷溶液中。
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