CN109568656A - 一种藻酸银水凝胶抗菌微球及其制备方法 - Google Patents
一种藻酸银水凝胶抗菌微球及其制备方法 Download PDFInfo
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Abstract
一种藻酸银水凝胶抗菌微球，该微球以beta‑磷酸三钙为芯体，将海藻酸钠固定在beta‑磷酸三钙微球的多孔结构中，并在银离子存在下交联得到，同时本发明还公开了其制备方法。本发明的藻酸银水凝胶微球对生物体无毒害作用，具有良好的细胞相容性和可降解性，原料方便易得，制备方法简单便捷，可操作性强。
Description
技术领域
本发明属于材料技术领域，具体涉及一种藻酸银水凝胶抗菌微球及其制备方法。
背景技术
海藻酸钠是天然多糖，具有良好的生物相容性和生物降解性，同时价廉易得，作为一类重要的生物材料，已经被广泛的用于修复组织缺损。利用海藻酸钠与磷钙材料进行复合，可以有效负载细胞与药物。因此，天然类高分子，特别是海藻酸钠，在药物控制释放领域更具有优势[中南药学, 2016, 1, 52]。海藻酸钠的分子中含有-COO－ 基团，当向海藻酸钠的水溶液中添加二价阳离子时，G单元中的Na+会与这些二价阳离子发生交换，使海藻酸钠溶液向凝胶转变。当海藻酸钠水凝胶作为药物的释放载体时常选用Ca2+作为交联剂[化学进展, 2013, 25, 1012]。
但是单一使用海藻酸钠时，其载药性能需要进一步提高，此外，作为生物材料，也要求具有良好的抗菌性能。采用模板法制备多功能藻酸凝胶微球，将海藻酸钠固定在磷酸微球的多孔结构中，使海藻酸钠交联[RSC Advances, 2016, 24, 20447]。因为与天然磷酸钙在化学组分上一致，合成的纳米磷酸钙材料被认为具有良好的生物相容性，并且在植入人体后不会被组织识别及发生排斥反应。所以，种类丰富的人工合成磷酸钙类化合物被作为重要的生物材料用于骨修复/组织工程，药物/基因载体、生物成像等众多领域的研究。因其优良的生物相容性和生物降解性，合成的磷酸钙类材料被认为是构建生物材料体系的理想选择之一。合成的磷酸钙类材料可以与海藻酸钠复合，用作药物载体去吸附和装载种类丰富的药物，蛋白质，生长因子，抗生素及其它生物大分子等。基于纳米结构磷酸钙的药物载体系统中，磷酸钙可以起到协助药物分子进入细胞及逃离溶酶体以更好的发挥药效的作用。为了使复合体系具有较好的抗菌性能，需要引入抗菌纳米颗粒。硝酸银作为较好的抗微生物试剂被研究和使用，多种纳米结构的含银磷酸钙复合材料已经被制备出来，但是与磷钙纳米材料、海藻酸钠复合，其细胞毒性仍需要进一步研究。
发明内容
本发明的目的在于提供一种藻酸银水凝胶抗菌微球，同时提供其制备方法是本发明的又一发明目的。
基于上述目的，本发明采取如下技术方案：
一种藻酸银水凝胶抗菌微球，该微球以beta-磷酸三钙为芯体，将海藻酸钠固定在beta-磷酸三钙微球的多孔结构中，在银离子存在下交联得到。
所述的藻酸银水凝胶抗菌微球的制备方法，包括以下步骤：
1） 将beta-磷酸三钙与海藻酸钠水溶液混合，搅拌，离心去除上清液，洗涤沉淀；
2） 将步骤（1）所得沉淀溶于硝酸银水溶液，搅拌，离心去除上清液，洗涤沉淀，即得藻酸银水凝胶抗菌微球。
步骤1）中，所述海藻酸钠水溶液的质量浓度为1%～3%，beta-磷酸三钙与海藻酸钠水溶液的用量比为1g：（60～120）mL。
步骤2）中，硝酸银水溶液的摩尔浓度为0.05M～0.75M，硝酸银溶液和海藻酸钠溶液的体积用量比3:（1～6）。
步骤1）和步骤2）中，搅拌速度为转速为8000～20000 rpm，离心的转速为3000～5000 rpm，离心时间为3～5分钟；其中，步骤1）搅拌时间为9～15分钟；步骤2）搅拌时间为1～5分钟。
与现有技术相比，本发明的技术优势在于：
1、本发明的复合微球具有良好的吸附作用，可有效控制药物释放，可以用于药物装载和释放以及骨修复等领域；且具有良好的细胞相容性，良好的抗菌性能，抗菌范围比较广，且具有可降解性，无毒副作用；
2、采用本发明制备方法获得更加稳定的抗菌微球，可以储存在水溶液中；本发明制备方法未见文献报道，制备过程简单、可操作性强，有利于本发明在生物医用领域的推广。
附图说明
图1为实施例1制得的微球透射电镜（TEM）照片；
图2为实施例1制得的微球装载阿霉素（DOX）的释放曲线；
图3为实施例1制得的微球与293T细胞培养60h的光学显微镜照片；
图4 为实施例1制得的不同浓度的抗菌复合微球与革兰氏阴性细菌（Gram-negativeE. coli ATCC 25922）培养12小时后的抗菌圈照片；
图5 为实施例1制得的抗菌复合微球与革兰氏阳性细菌（Gram-positive S. aureusATCC 6538）培养12小时后的照片，左侧为空白对照，右侧为样品，浓度为50 ug/mL；
图6 为实施例1制得的不同浓度的抗菌复合微球与革兰氏阳性细菌（Gram-positiveS. aureus ATCC 6538）培养12小时后的抗菌圈照片；
图7为实施例1到实施例5制得的抗菌复合微球与革兰氏阴性细菌（Gram-negative E.coli ATCC 25922）培养12小时后的OD600值。
具体实施方式
下面结合具体实施例对本发明做进一步描述。本发明中所述室温是指25~ 30 ℃均可。将一定量的海藻酸钠室温下溶解于超纯水中，制得海藻酸钠水溶液，将一定量的硝酸银在避光情况下配制成硝酸银水溶液。
本发明中，海藻酸钠的分子量为198.11，硝酸银的分子量为169.87，计算时,取小数点后两位，四舍五入。
实施例1
一种藻酸银水凝胶抗菌微球，该微球以beta-磷酸三钙为芯体，将海藻酸钠固定在beta-磷酸三钙微球的多孔结构中，在银离子存在下交联得到。
其制备方法，包括以下步骤：
1）将0.15g beta -磷酸三钙置于50 mL离心管中，加入12 m L的质量浓度为1%的海藻酸钠水溶液，在室温下8000 rpm高速搅拌15分钟，然后在室温下3000 rpm离心3分钟，用超纯水洗涤3次；
2）向步骤1）所得沉淀中加入浓度为0.75M的硝酸银水溶液，硝酸银溶液和海藻酸钠溶液的体积用量比3:1；在室温下8000 rpm高速搅拌1分钟，然后3000 rpm离心3min，超纯水洗涤3次；所得沉淀即得以beta-磷酸三钙为核芯的藻酸银水凝胶微球。
实施例2
一种的藻酸银水凝胶抗菌微球，该微球以beta-磷酸三钙为芯体，将海藻酸钠固定在beta-磷酸三钙微球的多孔结构中，在银离子存在下交联得到。
其制备方法，包括以下步骤：
1）将0.15g beta -磷酸三钙置于50 mL离心管中，加入12 m L的质量浓度为1.5%的海藻酸钠水溶液，在室温下12000 rpm高速搅拌10分钟，然后在室温下4000 rpm离心3分钟，用超纯水洗涤3次；
2）向步骤1）所得沉淀中加入浓度为0.05M的硝酸银水溶液，硝酸银溶液和海藻酸钠溶液的体积用量比3:3；在室温下12000 rpm高速搅拌5分钟，然后4000 rpm离心3min，超纯水洗涤3次；所得沉淀即得以beta-磷酸三钙为核芯的藻酸银水凝胶微球。
实施例3
一种藻酸银水凝胶抗菌微球，该微球以beta-磷酸三钙为芯体，将海藻酸钠固定在beta-磷酸三钙微球的多孔结构中，在银离子存在下交联得到。
其制备方法，包括以下步骤：
1）将0.15g beta -磷酸三钙置于50 mL离心管中，加入12 m L的质量浓度为1.5%的海藻酸钠水溶液，在室温下12000 rpm高速搅拌9分钟，然后在室温下3500 rpm离心5分钟，用超纯水洗涤3次；
2）向步骤1）所得沉淀中加入浓度为0.1M的硝酸银水溶液，硝酸银溶液和海藻酸钠溶液的体积用量比3:6；在室温下12000 rpm高速搅拌4分钟，然后3500 rpm离心5min，超纯水洗涤3次；所得沉淀即得以beta-磷酸三钙为核芯的藻酸银水凝胶微球。
实施例4
一种藻酸银水凝胶抗菌微球及其制备方法，与实施例1不同之处在于，海藻酸钠水溶液的用量为9mL；步骤1）和步骤2）中搅拌速度为20000rpm，离心转速为5000 rpm；其余同实施例1。
实施例5
一种藻酸银水凝胶抗菌微球及其制备方法，与实施例1不同之处在于，海藻酸钠水溶液的用量为18mL；海藻酸钠水溶液的质量浓度为3%，其余同实施例1。
效果实验
为表明本发明效果，以实施例1为例，分别对其制得的微球进行透射电镜观察，载药试验和细胞相容试验，结果如图1-3所示，其中，图1为实施例1制得的微球的透射电镜（TEM）照片；图2为实施例1制得的微球装载阿霉素（DOX）的释放曲线；图3为实施例1制得的微球与293T细胞培养60h的光学显微镜照片。且对其他实施例所得微球进行上述试验，均得到了一致的结果。
图1为采用本发明实施例1获得的微球透射电镜（TEM）照片，可以看出beta-磷酸三钙分散在海藻酸钠网络内，并形成微球。
图2为采用本发明实施例1制得的微球装载阿霉素（DOX）的释放曲线，可以看到DOX总释放量随着时间的增加而增加，在72小时后总释放量可以达到0.8%。
图3为采用本发明实施例1制得的微球与293T细胞培养60h的光学显微镜照片，可以看到293T细胞在60h和120h都呈现了良好的细胞形态，在120h的细胞数量要比60h的细胞数量多。
图4为采用本发明实施例1制得的不同浓度的抗菌复合微球与革兰氏阴性细菌（Gram-negative E. coli ATCC 25922）培养12小时后的抗菌圈照片，可以看出不同浓度条件下都出现了抗菌圈，随着浓度的增加，抗菌圈变大，说明制备的复合微球对革兰氏阴性细菌（Gram-negative E. coli ATCC 25922）具有良好的抗菌性。
图5为采用本发明为实施例1制得的抗菌复合微球与革兰氏阳性细菌（Gram-positive S. aureus ATCC 6538）培养12小时后的照片，左侧为空白对照，右侧为样品，浓度为50 ug/mL，从图中可以看出加入复合微球后，含有细菌的溶液变得透明清晰，证明了复合微球的抗菌效果。
图6为采用本发明实施例1制得的不同浓度的抗菌复合微球与革兰氏阳性细菌（Gram-positive S. aureus ATCC 6538）培养12小时后的抗菌圈照片，可以看出不同浓度条件下都出现了抗菌圈，随着浓度的增加，抗菌圈变大，说明制备的复合微球对革兰氏阳性细菌（Gram-positive S. aureus ATCC 6538）具有良好的抗菌性。
图7为采用本发明实施例1到实施例5制得的抗菌复合微球与革兰氏阴性细菌（Gram-negative E. coli ATCC 25922）培养12小时后的OD600值，OD600值越小，说明细菌数量越少，从图中可以看出实施例1和实施例4的抗菌效果最好。
Claims (5)
1.一种藻酸银水凝胶抗菌微球，其特征在于，该微球以beta-磷酸三钙为芯体，将海藻酸钠固定在beta-磷酸三钙微球的多孔结构中，并在银离子存在下交联得到。
2.权利要求2所述的藻酸银水凝胶抗菌微球的制备方法，其特征在于，包括以下步骤：
1）将beta-磷酸三钙与海藻酸钠水溶液混合，搅拌，离心去除上清液，洗涤沉淀；
2）将步骤（1）所得的沉淀溶于硝酸银溶液，搅拌，离心去除上清液，洗涤沉淀，即得以藻酸银水凝胶抗菌微球。
3.如权利要求2所述的藻酸银水凝胶抗菌微球的制备方法，其特征在于，步骤1）中，所述海藻酸钠水溶液的质量浓度为1%～3%，beta-磷酸三钙与海藻酸钠水溶液的用量比为1g：（60～120）mL。
4.如权利要求2所述的藻酸银水凝胶抗菌微球的制备方法，其特征在于，步骤2）中，硝酸银水溶液的摩尔浓度为0.05M～0.75M，硝酸银溶液和海藻酸钠溶液的体积用量比3:（1～6）。
5.如权利要求2所述的藻酸银水凝胶抗菌微球的制备方法，其特征在于，步骤1）和步骤2）中，搅拌速度为转速为8000～20000 rpm，离心的转速为3000～5000 rpm，离心时间为3～5分钟；其中，步骤1）搅拌时间为9～15分钟；步骤2）搅拌时间为1～5分钟。
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