CN110342482A - 一种抗菌性银掺杂羟基磷灰石微球的制备方法 - Google Patents
一种抗菌性银掺杂羟基磷灰石微球的制备方法 Download PDFInfo
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Abstract
本发明公开了一种抗菌性银掺杂羟基磷灰石微球的制备方法，其是以贝壳为主要原料，利用水热合成技术结合螯合模板剂制备所述抗菌性银掺杂羟基磷灰石微球。本发明制备方法简单，原料来源广泛，成本低廉，易于推广，所得微球具有很好的球形结构，尺寸为10μm，同时具有良好的抗菌性能，抑菌时效持久，有望成为一种有效的骨、齿填充修复材料。
Description
技术领域
本发明属于材料制备与生物医学领域，具体涉及一种抗菌性银掺杂羟基磷灰石微球的制备方法。
背景技术
作为哺乳动物体内牙齿、骨骼等坚硬部位的主要无机质成分，羟基磷灰石(Cal0(P04)6(OH)2，HAP)由于其优异的生物相容性、骨传导性和生物活性及与宿主骨组织直接结合的能力，广泛应用于骨组织工程领域。然而，随着对其研究及应用的深入，单纯的羟基磷灰石在一些方面已经难达要求，比如抗菌性。羟基磷灰石虽然是其他磷酸钙中最具骨传导性和生物相容性的材料，但其抗菌性有限，而细菌感染是植入体失败的主要原因，因此急需对羟基磷灰石进行抗菌功能改性。
银（Ag）是人体组织内的微量元素之一，具有良好的热稳定性、低挥发性及生物相容性好、低浓度对人体细胞无毒等特点，此外Ag可以强烈地吸引细菌体中蛋白酶上的巯基(-SH)，迅速与其结合在一起，使蛋白酶丧失活性，导致细菌死亡。当细菌被Ag杀死后，Ag又由细菌尸体中游离出来，再与其它菌落接触，周而复始地进行上述过程，因此银离子具有持久的杀菌性，已广泛应用于净水、杀菌日用品等领域。虽然目前已有报道将银掺入羟基磷灰石当中，但其多为二维结构羟基磷灰石，将银离子掺入三维球形羟基磷灰石当中则可拓展其在生物医药领域的应用。
鲍鱼、贻贝、牡蛎、珍珠贝等均为海洋贝类，其壳体占整体的绝大部分质量。现阶段在其肉被食用或加工利用后占绝大体重比的壳体却多被丢弃，这造成了极大的资源浪费。鲍鱼、贻贝、牡蛎、珍珠贝等贝类壳体成分95%以上为碳酸钙，为丰富的钙源材料，利用这一特性将其转化为羟基磷灰石、骨水泥等生物材料可大大增高其价值，变废为宝。
本发明从贝壳资源高值化角度出发，以贝壳为主要钙源，采用柠檬酸钠作为模板剂，水热合成银掺杂羟基磷灰石微球，其整体制备过程简单，制得的银掺杂羟基磷灰石微球保持稳定的三维球形结构并具有良好、持久的抗菌性能，有望成为一种新型、高效的生物材料，应用于药物载体、促骨修复治疗。
发明内容
本发明致力于解决贝类水产经加工后空壳被大量废弃、利用率低下等问题，提供了一种以贝壳为主要钙源制备抗菌性银掺杂羟基磷灰石微球的方法，该方法操作简单，原料来源广泛，成本低廉，易于推广。
为实现上述目的，本发明采用如下技术方案：
一种抗菌性银掺杂羟基磷灰石微球的制备方法，其是以贝壳为主要原料，利用鳌合模板剂及水热合成技术制备所述抗菌性银掺杂羟基磷灰石微球，所得微球尺寸为10μm。其具体包括以下步骤：
（1）将贝壳粉碎，研磨，用200目滤网进行筛选，获得贝壳粉末；
（2）将贝壳粉末溶于醋酸溶液中，不断搅拌至不产生气泡后，离心，得到上清液；
（3）用醋酸溶液将步骤（2）得到的上清液定容至50ml，而后在搅拌条件下以1mL/min的速率在其中滴加50mL磷酸溶液；
（4）待磷酸溶液滴加结束，向混合液中添加硝酸银、柠檬酸钠、尿素并持续搅拌0.5h，得到澄清的前驱体反应液；
（5）将步骤（4）制得的前驱体反应液进行水热反应；
（6）反应结束后，自然冷却至室温，离心，去离子水洗离三遍，无水乙醇洗涤一次，干燥，得到所述抗菌性银掺杂羟基磷灰石微球。
步骤（1）中所述贝壳为鲍鱼壳、贻贝贝壳、牡蛎壳、珍珠贝中的一种或几种。
步骤（2）中贝壳粉末与醋酸溶液的质量体积比为1g:(30-70)mL；其中醋酸溶液的浓度为5～20vol.％。
步骤（2）中离心转数为9000rpm，离心时间为5～10min，离心温度4℃。
步骤（4）中柠檬酸钠用量为0.2352g～2.3528g，尿素用量为6g，硝酸银用量为0.085g～0.338g；
所得前驱体反应液中n(Ca2++Ag+):n(PO4 3-)=1.67:1。
步骤（5）中水热反应的温度为60～90℃，时间为36-48h。
步骤（6）中离心转数为8000rpm，离心时间为10～15min，离心温度为4℃；所述干燥的温度为60℃。
本发明利用柠檬酸根对钙离子及银离子起到共鳌合作用，且鳌合后的螯合物在水热环境下可作为成核位点吸引磷酸根离子富集，原位自组装形成三维羟基磷灰石微球，可良好实现在将银离子掺入羟基磷灰石当中的同时保持其良好的球形结构。此外，尿素在高温条件下分解可保证反应液的pH为碱性，减少调节反应前驱体溶液pH这一过程，方便快捷。
本发明相对于其他羟基磷灰石微球的制备方法有以下优点：
（1）原料来源广泛，成本低廉。利用贝壳为钙源将其转化为羟基磷灰石微球，可在增加其价值的同时减轻其对环境的污染；
（2）使用水热合成法得到的羟基磷灰石微球结晶性好，反应过程无团聚，无需高温灼烧处理，通过改变水热条件（水热时间、水热温度等）及柠檬酸钠添加量、银掺杂比例，可调控羟基磷灰石微球的尺寸及形成率；
（3）本发明所得羟基磷灰石微球生物相容性好，具有良好抗菌性能，方便于实际应用，可长效抑菌，减轻感染风险；
（4）本发明由于形成的是三维结构羟基磷灰石微球，其比表面积大（最高可达110.3387m2/g），故可实现更多银的负载，从而与现有银掺杂纳米羟基磷灰石材料相比具有较高的抑菌性能（可对比文献《沉淀法与水热法合成载银羟基磷灰石及其抗菌性能》,2017,45(4):113-120；《银掺杂纳米羟基磷灰石抗菌粉体的水热合成及结构表征》,2012,70(2):1362-1366；武汉理工大学硕士论文《载银羟基磷灰石粉体和抗菌釉的制备及抗菌性能研究》，2017）。
（5）本发明以贝壳为主要原料，利用水热合成法成功将银掺入羟基磷灰石微球中，使其具有良好的抗菌性能，且其制备工艺较简单，操作方便，易于推广。
附图说明
图1为实施例1-3制得的不同银掺杂量的羟基磷灰石的扫描电子显微图。
图2为实施例3制得的银掺杂羟基磷灰石微球的X射线衍射图谱。
图3为实施例3制得的银掺杂羟基磷灰石微球的EDS能谱图。
图4为实施例3制得的银掺杂羟基磷灰石微球的降解元素释放图。
图5为实施例3制得的银掺杂羟基磷灰石微球在不同添加浓度下的抑菌效果对比图。
图6为实施例3制得的银掺杂羟基磷灰石微球在8mg/L浓度下的抑菌圈实验图。
具体实施方式
为了使本发明所述的内容更加便于理解，下面结合具体实施方式对本发明所述的技术方案做进一步的说明，但是本发明不仅限于此。
实施例1
1）将洗净烘干后的牡蛎壳粉碎，研磨，用200目滤网进行筛选，获得牡蛎壳粉末；
2）取牡蛎壳粉末0.45g（Ca2+ 0.0045mol），使用30ml的10 vol.％的醋酸溶液溶解，持续搅拌至不产生气泡后，于4℃、9000rpm条件下离心5min，取上清液；
3）用去离子水将上清液定容至50ml，在持续搅拌条件下以1ml/min的速率向其中滴加50ml磷酸溶液（0.06M）；
4）待磷酸溶液滴加结束后，向混合液中加入0.2352g柠檬酸钠、0.085g硝酸银（Ag+0.0005mol）及6g尿素，持续搅拌0.5h，得到澄清的前驱体反应液；
5）将步骤4）所得前驱体反应液转移至反应釜中，放入烘箱，90℃水热反应48h；
6）反应结束后，从高压反应釜取出，自然冷却至室温后，于4℃、8000rpm条件下离心10min，用去离子水洗离三遍，无水乙醇洗涤一遍，洗涤后的样品抽气过滤，60℃干燥4h，得到10%银掺杂羟基磷灰石样品。
实施例2
1）将洗净烘干后的贻贝壳粉碎，研磨，用200目滤网进行筛选，获得贻贝壳粉末；
2）取贻贝壳粉末0.4g（Ca2+ 0.004mol），使用20ml的10 vol.％的醋酸溶液溶解，持续搅拌至不产生气泡后，于4℃、9000rpm条件下离心5min，取上清液；
3）用去离子水将上清液定容至50ml，在持续搅拌条件下以1ml/min的速率向其中滴加50ml磷酸溶液（0.06M）；
4）待磷酸溶液滴加结束后，向混合液中加入0.2352g柠檬酸钠、0.169g硝酸银（Ag+0.001mol）及6g尿素，持续搅拌0.5h，得到澄清的前驱体反应液；
5）将步骤4）所得前驱体反应液转移至反应釜中，放入烘箱，90℃水热反应36h；
6）反应结束后，从高压反应釜取出，自然冷却至室温后，于4℃、8000rpm条件下离心10min，用去离子水洗离三遍，无水乙醇洗涤一遍，洗涤后的样品抽气过滤，60℃干燥4h，得到20%银掺杂羟基磷灰石样品。
实施例3
1）将洗净烘干后的鲍鱼壳粉碎，研磨，用200目滤网进行筛选，获得鲍鱼壳粉末；
2）取鲍鱼壳粉末0.3g（Ca2+ 0.003mol），使用10ml的10 vol.％的醋酸溶液溶解，持续搅拌至不产生气泡后，于4℃、9000rpm条件下离心5min，取上清液；
3）用去离子水将上清液定容至50ml，在持续搅拌条件下以1ml/min的速率向其中滴加50ml磷酸溶液（0.06M）；
4）待磷酸溶液滴加结束后，向混合液中加入0.2352g柠檬酸钠、0.338g硝酸银（Ag+0.002mol）及6g尿素，持续搅拌0.5h，得到澄清的前驱体反应液；
5）将步骤4）所得前驱体反应液转移至反应釜中，放入烘箱，90℃水热反应48h；
6）反应结束后，从高压反应釜取出，自然冷却至室温后，于4℃、8000rpm条件下离心10min，用去离子水洗离三遍，无水乙醇洗涤一遍，洗涤后的样品抽气过滤，60℃干燥4h，得到40%银掺杂羟基磷灰石微球。
图1为实施例1-3制得的不同银掺杂量的羟基磷灰石的扫描电子显微图。从图中可以看出，随着银掺杂量的增加，所得羟基磷灰石呈花瓣状到棒状再到球状的转变，当银掺杂量为40%时羟基磷灰石球形规整，其由片状组装而成。
图2为实施例3制得的银掺杂羟基磷灰石微球的X射线衍射图谱。从图中可以看出所制得样品具有羟基磷灰石的特征衍射峰（带星号）。
图3为实施例3制得的银掺杂羟基磷灰石微球的EDS能谱图。图中Ag峰的存在表明银离子成功掺入羟基磷灰石微球当中。
图4为实施例3制得的银掺杂羟基磷灰石微球的降解元素释放图。从图中可以看出在第一天即可释放大量的Ag+，而起到其杀菌作用，后续则呈现一个缓慢释放效应。
将细菌活化、培养、稀释至1×105/ml，吸取1ml菌群液分别加入不同浓度实施例3制得的银掺杂羟基磷灰石微球，每组3个平行组，37℃共培养24h后紫外600nm处检测其吸光度(OD值)来观察抑菌效果。图5为实施例3制得的银掺杂羟基磷灰石微球对大肠杆菌与金黄色葡萄球菌的抑菌效果对比图。图中可见，在共培养24h的情况下，各浓度银掺杂羟基磷灰石微球均对大肠杆菌与金黄色葡萄球菌具有良好的抑制作用。
将菌群液均匀涂覆于固体培养基平板中，选取8mg/L实施例3制得的银掺杂羟基磷灰石微球压制成小片，贴于涂覆有菌群液的固体培养板中，37℃共培养24h后观察抑菌圈大小。图6为实施例3制得的银掺杂羟基磷灰石微球对大肠杆菌与金黄色葡萄球菌的抑菌圈实验图。由图中可见，在8mg/L的浓度下有较为明显的抑菌圈，显示该银掺杂羟基磷灰石微球具有良好的抑菌效果。
以上所述仅为本发明的较佳实施例，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。
Claims (8)
1.一种抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：以贝壳为主要原料，利用鳌合模板剂及水热合成技术制备所述抗菌性银掺杂羟基磷灰石微球；所得微球尺寸为10μm。
2.根据权利要求1所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：包括以下步骤：
（1）将贝壳粉碎，研磨，用200目滤网进行筛选，获得贝壳粉末；
（2）将贝壳粉末溶于醋酸溶液中，并不断搅拌至不产生气泡后，离心，得到上清液；
（3）用去离子水将步骤（2）得到的上清液定容至50ml，而后在搅拌条件下以1mL/min的速率向其中滴加50mL磷酸溶液；
（4）待磷酸溶液滴加结束，向混合液中添加硝酸银、柠檬酸钠、尿素并持续搅拌0.5h，得到澄清的前驱体反应液；
（5）将步骤（4）制得的前驱体反应液进行水热反应；
（6）反应结束后，自然冷却至室温，离心，水洗，无水乙醇洗涤，干燥，得到所述抗菌性银掺杂羟基磷灰石微球。
3.根据权利要求2所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：步骤（1）中所述贝壳为鲍鱼壳、贻贝贝壳、牡蛎壳、珍珠贝中的一种或几种。
4.根据权利要求2所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：步骤（2）中贝壳粉末与醋酸溶液的质量体积比为1g:(30-70)mL；其中醋酸溶液的浓度为5～20vol.％。
5.根据权利要求2所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：步骤（2）中离心转数为9000rpm，离心时间为5～10min，离心温度4℃。
6.根据权利要求2所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：步骤（4）中柠檬酸钠用量为0.2352g～2.3528g，尿素用量为6g，硝酸银用量为0.085g～0.338g；
所得前驱体反应液中（Ca+Ag）的总摩尔量与P的摩尔量之比为1.67:1。
7.根据权利要求2所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：步骤（5）中水热反应的温度为60～90℃，时间为36-48h。
8.根据权利要求2所述的抗菌性银掺杂羟基磷灰石微球的制备方法，其特征在于：步骤（6）中离心转数为8000rpm，离心时间为10～15min，离心温度为4℃；
所述水洗是用去离子水洗离三遍；
所述干燥的温度为60℃。
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