CN112480434B - 一种铜离子抗菌水凝胶及制备方法和应用 - Google Patents

一种铜离子抗菌水凝胶及制备方法和应用 Download PDF

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CN112480434B
CN112480434B CN202011380606.4A CN202011380606A CN112480434B CN 112480434 B CN112480434 B CN 112480434B CN 202011380606 A CN202011380606 A CN 202011380606A CN 112480434 B CN112480434 B CN 112480434B
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钱军民
纪利杰
胥伟军
侯光晖
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Xian Jiaotong University
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Abstract

本发明公开了一种铜离子抗菌水凝胶及制备方法，首先利用碳二亚胺法将含二个酰肼基团的小分子接枝于含羧基的水溶性高分子上，然后再与铜盐溶液混合均匀，即得到铜离子抗菌水凝胶。本发明的优点是制备方法简单高效、工艺条件温和，铜离子既是交联剂又是抗菌剂，制得水凝胶具有力学性能好、可注射性、自修复性、优异抗菌性和生物相容性等优点，可广泛用于皮肤创面保护及感染治疗和妇科炎症治疗等。

Description

一种铜离子抗菌水凝胶及制备方法和应用
技术领域
本发明属于医用水凝胶技术领域，具体涉及一种铜离子抗菌水凝胶及制备方法和应用。
背景技术
皮肤是人体最大的组织和器官，同时也是人体的第一道防线，它能保护人体免受外界物理和化学刺激以及细菌和病毒侵袭。但当皮肤受到损伤和外界伤害时，创面会面临感染风险，严重时还会危害患者的生命安全。目前临床上多采用纱布、绷带等敷料配合抗生素预防伤口感染，但纱布、绷带等传统敷料因处于干燥状态，容易粘连伤口，更换时容易造成伤口二次损伤，给患者带来更大痛苦。抗生素的大量使用不仅会损害人体健康，还会导致细菌耐药性，长期使用将会对人体健康构成严重威胁。因此需要开发本身具有抗菌功能的新型材料。
水凝胶是近年来发展起来的一种新型现代敷料，它是一种含有大量水分、具有三维网络交联结构的聚合物。与传统敷料相比，水凝胶具有以下优势：(1)水凝胶中含有大量水分，为伤口组织提供湿润的接触环境，利于伤口愈合；(2)水凝胶可以吸收伤口组织渗出液，不与组织粘连，可避免更换时带来的二次损伤；(3)独特的多孔结构赋予其优异的渗透性，便于药物和营养物质的运输；(4)水凝胶形成方法多种多样，大都具有良好的生物相容性，被广泛应用于水凝胶材料。
然而，水凝胶自身通常不具有抗菌性。为赋予水凝胶良好的抗菌性能，通常需要将抗菌剂添加进水凝胶材料中。常见抗菌剂有抗生素、抗菌肽、抗菌性金属离子等。其中，使用抗生素不仅会损害人体健康，还会导致细菌耐药性；抗菌肽合成过程复杂且会引起溶血现象；而抗菌性金属离子如银离子，具有广谱抗菌性，可在极低浓度下对细菌产生杀伤效果，但银离子不属于人体必需元素，在人体中累积终会带来不利影响。相比而言，铜离子是机体内多种酶和蛋白质发挥作用不可缺少的催化剂，参与人体众多生理过程，同时，铜离子作为抗菌剂已有很长历史。但是，其应用形式主要是将其掺杂于合金、无机非金属材料和高分子基体中，难以实现控制释放。
发明内容
本发明的目的在于提供了一种铜离子抗菌水凝胶及制备方法和应用，解决了现有含铜抗菌材料制备方法复杂、难以有效实现铜离子控制释放、生物相容性不够理想的问题。
为实现上述目的，本发明采用的技术方案如下：
一种铜离子抗菌水凝胶的制备方法，包括以下步骤：
(1)利用碳二亚胺法将含两个酰肼基团的有机小分子接枝于含羧基的水溶性高分子上，室温反应12小时～36小时后经透析和冷冻干燥，得到改性度为2％～100％的酰肼化高分子；
(2)将改性度为2％～100％的酰肼化高分子水溶液与可溶性铜盐混合均匀，静置，制成铜离子抗菌水凝胶。
本发明进一步的改进在于：步骤(1)的具体过程为：将含羧基的水溶性高分子溶于水中制成质量浓度为0.5％～10％的溶液，调节pH值至4.5～6.5；然后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，再加入含两个酰肼基团的有机小分子，于室温反应12小时～36小时后，透析，冷冻干燥，得到改性度为2％～100％的酰肼化高分子。
本发明进一步的改进在于：步骤(1)所述的透析采用截留分子量为3000Da的透析袋，透析时间为2-3天，所述的冷冻干燥的温度为零下20℃，冷冻干燥的时间为24小时～72小时。
本发明进一步的改进在于：步骤(1)所述的含两个酰肼基团的有机小分子为3,3'-二硫代二丙酰肼、2,2'-二硫代二乙酰肼、4,4'-二硫代二丁酰肼、己二酸二酰肼、丙二酸二酰肼、丁二酸二酰肼或癸二酸二酰肼。
本发明进一步的改进在于：步骤(1)所述的含羧基的水溶性高分子为透明质酸钠、海藻酸钠、聚谷氨酸、聚天冬氨酸、羧甲基纤维素钠、羧甲基甲壳素或羧甲基壳聚糖。
本发明进一步的改进在于：步骤(1)所述的含羧基的水溶性高分子的分子量为20kDa～3000kDa。
本发明进一步的改进在于：步骤(2)所述的改性度为2％～100％的酰肼化高分子水溶液的质量浓度为0.2％～30％；静置时间为1分钟～30分钟。
本发明进一步的改进在于：步骤(2)所述的可溶性铜盐为氯化铜、醋酸铜、硝酸铜、硫酸铜、铜-赖氨酸配位物、铜-甘氨酸配位物或铜-丙氨酸配位物。
一种根据上述的方法制备的铜离子抗菌水凝胶，该铜离子抗菌水凝胶中铜的质量含量为0.01％～5％。
一种如上述的铜离子抗菌水凝胶在制备用于保护皮肤伤口、治疗伤口感染及治疗妇科炎症药物中的应用。
与现有技术相比，本发明具有以下有益效果：(1)本发明的铜离子抗菌水凝胶是由抗菌性铜离子和高分子上功能基团经配位作用形成的，其中铜离子兼具交联剂和抗菌剂双重功能，避免了其他交联剂加入造成的杂质或残余问题；(2)本发明的抗菌水凝胶具有刺激响应性特征，铜离子释放速度可控，从凝胶中不断释放出来的铜离子发挥抗菌作用，克服了现有含铜抗菌材料多以铜合金或化合物形式发挥抗菌作用存在释放慢、释放速率不可控以及不可避免存在杂质的问题；(3)本发明的抗菌水凝胶在常温和中性pH条件下制备，无需加热并避免了有机溶剂、强酸或强碱的使用，工艺条件温和、过程简单，该水凝胶的原料组成属机体中正常化学成分，生物相容性好；(4)本发明的抗菌水凝胶微观上呈现可逆的三维网络结构，不仅具有良好的力学性能，还具有可注射性能和自修复性能；(5)本发明的抗菌水凝胶避免了抗生素长期使用造成的耐药性问题，以及纳米银抗菌剂着色皮肤的潜在问题。
附图说明
图1为实施例1中铜离子抗菌水凝胶的光学照片和扫描电子显微镜照片。其中，(a)为光学照片，(b)为扫描电子显微镜照片。
图2为实施例1中铜离子抗菌水凝胶的可注射性能示意图。
图3为实施例1中铜离子抗菌水凝胶对金黄色葡萄球菌和大肠杆菌的抑菌效果。其中，(a)为PBS与金黄色葡萄球菌共培养后的照片；(b)为铜离子抗菌水凝胶与金黄色葡萄球菌共培养的照片；(c)为PBS与大肠杆菌共培养的照片；(d)为铜离子抗菌水凝胶与大肠杆菌共培养的照片。
具体实施方式
下面将结合具体实施例对本发明进行进一步阐述，显然，所描述的实施例仅仅是本发明的一部分，而不是本发明的全部实施例，所描述的实施例用于说明本发明而不用于限制本发明的范围。
一种铜离子抗菌水凝胶的制备方法，包括以下步骤：
(1)将分子量为20kDa～3000kDa的含羧基的水溶性高分子，如透明质酸钠、海藻酸钠、聚谷氨酸、聚天冬氨酸，以及羧甲基化多糖如羧甲基纤维素钠、羧甲基甲壳素、羧甲基壳聚糖等中的一种，溶于水中制成质量浓度为0.5％～10％的溶液，接着将pH值调至4.5～6.5；随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，并维持pH值不变；再加入含两个酰肼基团的有机小分子，即3,3'-二硫代二丙酰肼、2,2'-二硫代二乙酰肼、4,4'-二硫代二丁酰肼、己二酸二酰肼、丙二酸二酰肼、丁二酸二酰肼、癸二酸二酰肼中的一种；经室温反应12小时～36小时后，在截留分子量为3000Da的透析袋对水透析2～3天，最后在零下20℃冷冻干燥24小时～72小时，得到改性度为2％～100％的酰肼化高分子。其中，有机中小分子中酰肼基团的物质的量和含羧基的水溶性高分子中待改性羧基的物质的量的摩尔比为(5～30)：1；1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺用量分别为待改性羧基物质的量1～1.2倍和1.1～1.5倍。
(2)将酰肼化高分子溶于水中制成浓度为0.2％-30％的溶液，然后加入氯化铜、醋酸铜、硝酸铜、硫酸铜、铜-赖氨酸配位物、铜-甘氨酸配位物、铜-丙氨酸配位物等的溶液，混合均匀后静置1分钟～30分钟，得到所述抗菌水凝胶，该水凝胶中铜质量百分比为0.01％-5％。
所述的铜离子抗菌水凝胶可在皮肤伤口保护、伤口感染治疗及妇科炎症治疗等中应用。
下面为具体实施例。
实施例1
(1)将分子量为200kDa的1克透明质酸钠溶于100mL水中，制成质量百分比浓度为1％的溶液；接着加入0.05克的N-羟基琥珀酰亚胺和0.6克的3,3'-二硫代二丙酰肼，并将pH值调至5.5；然后，加入含0.072克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的5mL水溶液，期间维持pH值为5.5；室温反应36小时后用截留分子量为3000Da的透析袋对水透析2天；最后在零下20摄氏度冷冻干燥36小时，得到改性度为10％的酰肼化透明质酸。
(2)将酰肼化透明质酸溶于水中制成质量百分比浓度为3％的溶液，然后加入铜-赖氨酸配位物，静置1分钟，得到铜质量百分比为0.1％的铜离子抗菌水凝胶。
图1是实施例1制成的铜离子抗菌水凝胶的宏观和微观结构形貌照片。从图1中(a)和(b)可以看出，该水凝胶呈现均匀的淡蓝色，说明铜离子交联反应均一，对应冻干试样呈现比较均匀的多孔结构，孔径约为100～260微米。
图2是实施例1制成的铜离子抗菌水凝胶的可注射性图片。从图2中可以看出，该水凝胶可通过注射针头进行注射，这表明该水凝胶适用于不同结构和不同部位伤口或炎症的治疗。
图3展示了实施例1制备的铜离子抗菌水凝胶对金黄色葡萄球菌和大肠杆菌的抑菌效果。图3中(a)、(b)、(c)和(d)结果表明，所得水凝胶对金黄色葡萄球菌和大肠杆菌的抑菌率超过96％，抗菌抑菌效果优异。
实施例2
(1)将分子量为2000kDa的1克透明质酸钠溶于200mL水中，制成质量百分比浓度为0.5％的溶液；接着加入0.15克的N-羟基琥珀酰亚胺和1.32克的己二酸二酰肼，并将pH值调至5.5；然后，加入含0.22克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的5mL水溶液，期间维持pH值为5.5；室温反应36小时后用截留分子量为3000Da的透析袋对水透析2天；最后在零下20摄氏度冷冻干燥36小时，得到改性度为30％的酰肼化透明质酸。
(2)将酰肼化透明质酸溶于水中制成质量百分比浓度为0.5％的溶液，然后加入氯化铜溶液，静置30分钟，得到铜质量百分比为1％的铜离子抗菌水凝胶。
实施例3
(1)将分子量为1000kDa的1克羧甲基纤维素钠溶于200mL水中，制成质量百分比浓度为0.5％的溶液；接着加0.17克N-羟基琥珀酰亚胺和3.8克的3,3'-二硫代二丙酰肼，并将pH值调至5.5；然后，加入含0.28克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的5mL水溶液，期间维持pH值为5.5；室温反应36小时后用截留分子量为3000Da的透析袋对水透析2天；最后在零下20摄氏度冷冻干燥36小时，得到改性度为30％的酰肼化羧甲基纤维素。
(2)将酰肼化羧甲基纤维素溶于水中制成质量百分比浓度为1％的溶液，然后加入硝酸铜溶液，静置10分钟，得到铜质量百分比为0.3％的铜离子抗菌水凝胶。
实施例4
(1)将分子量为20kDa的1克海藻酸钠溶于水中，制成质量百分比浓度为10％的溶液；接着加0.09克N-羟基琥珀酰亚胺和0.180克己二酸二酰肼，并将pH值调至4.5；然后，加入含0.012克的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的5mL水溶液，期间维持pH值为4.5；室温反应24小时后用截留分子量为3000Da的透析袋对水透析3天；最后在零下20摄氏度冷冻干燥72小时，得到改性度为2％的酰肼化海藻酸。
(2)将酰肼化海藻酸溶于水中制成质量百分比浓度为0.2％的溶液，然后加入醋酸铜溶液，静置20分钟，得到铜质量百分比为0.01％的铜离子抗菌水凝胶。
实施例5
(1)将分子量为3000kDa的1克聚谷氨酸溶于水中，制成质量百分比浓度为5％的溶液；接着加0.98克N-羟基琥珀酰亚胺和8.1克4,4'-二硫代二丁酰肼，并将pH值调至6.5；然后，加入含1.39克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的5mL水溶液，期间维持pH值为6.5；室温反应30小时后用截留分子量为3000Da的透析袋对水透析2天；最后在零下20摄氏度冷冻干燥24小时，得到改性度为100％的酰肼化聚谷氨酸。
(2)将酰肼化聚谷氨酸溶于水中制成质量百分比浓度为30％的溶液，然后加入铜-甘氨酸配合物溶液，静置20分钟，得到铜质量百分比为3％的铜离子抗菌水凝胶。
实施例6
(1)将分子量为200kDa的1克羧甲基甲壳素溶于水中，制成质量百分比浓度为3％的溶液；接着加0.27克N-羟基琥珀酰亚胺和2.1克癸二酸二酰肼，并将pH值调至5；然后，加入含0.42克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的5mL水溶液，期间维持pH值为5；室温反应36小时后用截留分子量为3000Da的透析袋对水透析3天；最后在零下20摄氏度冷冻干燥50小时，得到改性度为50％的酰肼化羧甲基甲壳素。
(2)将酰肼化羧甲基甲壳素溶于水中制成质量百分比浓度为10％的溶液，然后加入硫酸铜溶液，静置20分钟，得到铜质量百分比为5％的铜离子抗菌水凝胶。

Claims (8)

1.一种铜离子抗菌水凝胶的制备方法，其特征在于，包括以下步骤：
（1）利用碳二亚胺法将含两个酰肼基团的有机小分子接枝于含羧基的水溶性高分子上，室温反应12小时~36小时后经透析和冷冻干燥，得到改性度为2%~100%的酰肼化高分子；具体过程为：将含羧基的水溶性高分子溶于水中制成质量浓度为0.5%~10%的溶液，调节pH值至4.5~6.5；然后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，再加入含两个酰肼基团的有机小分子，于室温反应12小时~36小时后，透析，冷冻干燥，得到改性度为2%~100%的酰肼化高分子；所述的含两个酰肼基团的有机小分子为3,3'-二硫代二丙酰肼、2,2'-二硫代二乙酰肼、4,4'-二硫代二丁酰肼、己二酸二酰肼、丙二酸二酰肼、丁二酸二酰肼或癸二酸二酰肼；
（2）将改性度为2%~100%的酰肼化高分子水溶液与可溶性铜盐混合均匀，静置，制成铜离子抗菌水凝胶。
2.根据权利要求1所述的一种铜离子抗菌水凝胶的制备方法，其特征在于：步骤（1）所述的透析采用截留分子量为3000 Da的透析袋，透析时间为2-3天，所述的冷冻干燥的温度为零下20℃，冷冻干燥的时间为24小时~72小时。
3.根据权利要求1所述的一种铜离子抗菌水凝胶的制备方法，其特征在于：步骤（1）所述的含羧基的水溶性高分子为透明质酸钠、海藻酸钠、聚谷氨酸、聚天冬氨酸、羧甲基纤维素钠、羧甲基甲壳素或羧甲基壳聚糖。
4.根据权利要求1所述的一种铜离子抗菌水凝胶的制备方法，其特征在于：步骤（1）所述的含羧基的水溶性高分子的分子量为20 kDa~3000 kDa。
5.根据权利要求1所述的一种铜离子抗菌水凝胶的制备方法，其特征在于：步骤（2）所述的改性度为2%~100%的酰肼化高分子水溶液的质量浓度为0.2%~30%；静置时间为1分钟~30分钟。
6.根据权利要求1所述的一种铜离子抗菌水凝胶的制备方法，其特征在于：步骤（2）所述的可溶性铜盐为氯化铜、醋酸铜、硝酸铜、硫酸铜、铜-赖氨酸配位物、铜-甘氨酸配位物或铜-丙氨酸配位物。
7.一种根据权利要求1-6中任意一项所述的方法制备的铜离子抗菌水凝胶，其特征在于：该铜离子抗菌水凝胶中铜的质量含量为0.01%~5%。
8.一种如权利要求7所述的铜离子抗菌水凝胶在制备用于保护皮肤伤口、治疗伤口感染及治疗妇科炎症药物中的应用。
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