CN116178751A - 一种自愈性水凝胶及其制备方法 - Google Patents
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Abstract
本发明涉及一种自愈性水凝胶及其制备方法,属于生物医用水凝胶技术领域。一种自愈性水凝胶,所述水凝胶是以聚丙烯酰胺和盐酸多巴胺改性的透明质酸为凝胶基质,多酚化合物通过氢键和共轭作用使两种基质交联形成的水凝胶。本发明提供了一种条件温和,制备方法简单的促进伤口愈合的多酚可注射的自愈性水凝胶制备方法。本发明提供的伤口粘合水凝胶材料具有抗菌性能。当采用大肠杆菌和金黄色葡萄球菌作为致病菌时,该水凝胶表现出优异的抗菌能力。同时还具有抗氧化性能和抗菌性能,能够抑制创面感染,清除自由基,限制创面的炎症反应。
Description
技术领域
本发明涉及一种自愈性水凝胶及其制备方法,属于生物医用水凝胶技术领域。
背景技术
水凝胶是一种具有三维网状结构的大分子聚合物材料,是一种新型的创面敷料材料,能够进行快速止血,促进组织修复,减少疤痕的产生。和传统的敷料相比,水凝胶透气性能优良,不仅能够保证创面湿度还能吸收创面渗出液。湿润开放的环境容易让创面组织遭受细菌的侵袭,因此赋予水凝胶优秀的抗菌能力是非常必要的。可注射水凝胶是指具有一定流动性,能够通过注射的方式应用的水凝胶,具有组织粘附性的注射水凝胶能够贴合不同状态的创面,达到更好的治疗效果。
作为构成人体细胞间质、眼玻璃体、关节滑液等***的主要成分之一的透明质酸,具有生物相容性好,可生物降解等众多优点。除此之外,透明质酸还具有调节血管壁的通透性,调节蛋白质,水电解质扩散及运转,促进创伤愈合等功能。但是透明质酸的组织粘附性较差,脆性大,当用作敷料时,容易造成药物流失和伤口感染,使用邻苯二酚改性能够提高透明质酸水凝胶的组织粘附性和韧性。
发明内容
本发明旨在提供一种促进伤口愈合的多酚可注射的自愈性水凝胶及其制备方法和应用。
一种自愈性水凝胶,所述水凝胶是以聚丙烯酰胺和盐酸多巴胺改性的透明质酸为凝胶基质,多酚化合物通过氢键和共轭作用使两种基质交联形成的水凝胶。
本发明自愈性水凝胶具有可注射性。该水凝胶可通过注射器注射从而能够更好的全方位贴合不规则创面达到更好的愈合效果。
本发明所述自愈性水凝胶,可包含水。在制备过程中,将聚丙烯酰胺、盐酸多巴胺改性和多酚化合物于水中混合均匀。
优选地,所述多酚化合物为单宁酸或没食子酸。
优选地,所述聚丙烯酰胺、盐酸多巴胺改性的透明质酸、多酚化合物的质量比为1:1~5:0.001~0.01。
优选地,所述盐酸多巴胺改性的透明质酸按下述方法制得:将透明质酸溶于吗啉乙磺酸缓冲溶液中,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基丁二酰亚胺,完全溶解后,搅拌状态下进行活化羧基反应,反应温度为20~35℃,反应时间为20~40min;反应结束后,在上述溶液中加入盐酸多巴胺,在氮气保护的氛围下进行接枝反应,反应温度为20~35℃,反应时间为12~72h,透析,冷冻干燥,即为盐酸多巴胺改性的透明质酸,
其中,透明质酸:盐酸多巴胺:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺:N-羟基丁二酰亚胺的质量比为2:2:1:2;透明质酸的分子量为90000~400000。
优选地,所述聚丙烯酰胺按下述方法制得:按1g:10~50mL,将丙烯酰胺溶于水中,加入甲叉双丙烯酰胺及过硫酸铵反应15~20分钟;反应结束后,透析除去未反应的丙烯酰胺、催化剂及副产物,将透析完成的溶液进行冷冻干燥并密封保存,其中,甲叉双丙烯酰胺、过硫酸铵和丙烯酰胺的质量比为0.001:0.01:1。
进一步地,透析的截留分子量为3500~14000。
优选地,室温下,将聚丙烯酰胺和盐酸多巴胺改性的透明质酸混合后,加入多酚化合物,加入一定量的水,反应得到自愈性水凝胶。
进一步地,盐酸多巴胺改性的透明质酸的浓度为0.03~0.15g/mL,聚丙烯酰胺的浓度为0.03~0.15g/mL,多酚化合物的质量浓度为1~20mg/mL。
本发明的有益效果为:本发明提供了一种条件温和,制备方法简单的促进伤口愈合的多酚可注射的自愈性水凝胶制备方法。本发明提供的伤口粘合水凝胶材料具有抗菌性能。当采用大肠杆菌(E.coli)和金黄色葡萄球菌(S.aureus)作为致病菌时,该水凝胶表现出优异的抗菌能力。同时还具有抗氧化性能和抗菌性能,能够抑制创面感染,清除自由基,限制创面的炎症反应。
本发明提供的伤口粘合水凝胶材料具有较高的黏附效率,能够提供自愈合性、可重复粘合性。经过纯化处理后水凝胶基质安全性更高,制作简便,可控性高。本发明提供的伤口粘合多酚水凝胶材料可形变能力强,具有可注射性,可以通过注射器注射从而能够更好的全方位贴合不规则创面达到更好的愈合效果。
天然存在的、价格便宜的单宁酸作为一种有效的凝胶粘附单元能够通过氢键、离子键来抓取高分子链,将高分子链交联起来。基于单宁酸的水凝胶显示出多样化的功能,力学性能可调性,快速自愈合性等。除此之外,单宁酸因其联苯结构具有更强的共轭作用,作为交联剂能够赋予水凝胶更高的粘附性。并且单宁酸具有一定的抗氧化性能和抗菌性能,能够抑制创面感染,清除自由基,限制创面的炎症反应,从而更有效的促进伤口愈合。
附图说明
图1为依照本发明实例的促进伤口愈合的多酚可注射的自愈性水凝胶的合成示意图。
图2为制备的邻苯二酚化透明质酸的H1NMR图。
图3为制备的多酚可注射的自愈性水凝胶的IR图。
图4(a)和(b)为制备的多酚可注射的自愈性水凝胶的扫描电镜图。
图5为实施例3~5制备得到多酚水凝胶的流变力学性能图。
图6为制备的多酚可注射的自愈性水凝胶的组织粘附性和可注射性图。
图7为制备的多酚可注射的自愈性水凝胶抑菌效果图。
图8为所制备多酚可注射的自愈性水凝胶促大鼠伤口愈合效果图。
图9(a)和(b)为实施例3和对比实施例细胞存活和生存率数据。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
下述实施例中所述试验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
具体实施方式之一:
一种促进伤口愈合的多酚可注射的自愈性水凝胶及其制备方法,包括以下步骤:
步骤1,取透明质酸或其钠盐和改性剂,反应得到透明质酸衍生物,所述透明质酸衍生物为邻苯二酚改性透明质酸;
步骤2,取丙烯酰胺、甲叉双丙烯酰胺及过硫酸铵制备聚丙烯酰胺;
步骤3,取所述透明质酸衍生物和聚丙烯酰胺,加入多酚化合物,加入一定量的水,反应得到自愈性水凝胶。
根据本发明的部分实例的自愈性水凝胶及其制备方法,所述改性剂为盐酸多巴胺。
根据本发明的部分实例的自愈性水凝胶及其制备方法,步骤(1)具体为:将透明质酸(HA)溶于吗啉乙磺酸缓冲溶液(0.05M,pH=5.5)中,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)和N-羟基丁二酰亚胺(NHS),完全溶解后,搅拌状态下进行活化羧基反应,反应温度为20-35℃,反应时间为20-40min。反应结束后,在上述溶液中加入盐酸多巴胺(DA),在氮气保护的氛围下进行接枝反应,反应温度为20-35℃,反应时间为12-72h。反应结束后,透析除去杂质。将透析完成的溶液进行冷冻干燥,并避光密封保存即为邻苯二酚接枝透明质酸。
根据本发明部分实例的自愈性水凝胶的制备方法,步骤(1)中透明质酸:盐酸多巴胺:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺:N-羟基丁二酰亚胺的质量比为2:2:1:2。
根据本发明部分实例的自愈性水凝胶的制备方法,步骤(1)中透明质酸的分子量为90000-400000。
根据本发明的部分实例的自愈性水凝胶的制备方法,步骤(2)具体为:将丙烯酰胺溶于水中,得到质量分数为1g:10~50mL溶液,加入甲叉双丙烯酰胺及过硫酸铵反应15~20分钟。反应结束后,透析除去未反应的丙烯酰胺、催化剂及副产物,将透析完成的溶液进行冷冻干燥并密封保存。
根据本发明部分实例的自愈性水凝胶的制备方法,步骤(1)、(2)中使用的透析用品为透析袋或透析管,截留分子量(MWCO)为3500-14000。
根据本发明的部分实例的自愈性水凝胶的制备方法步骤(2)中甲叉双丙烯酰胺、过硫酸铵和丙烯酰胺的质量比为0.001:0.01:1。
根据本发明部分实例的自愈性水凝胶的制备方法,步骤(3)中多酚化合物为单宁酸、没食子酸等其中之一。
根据本发明部分实例的自愈性水凝胶的制备方法,步骤(3)中透明质酸衍生物的浓度为0.03-0.15g/mL,聚丙烯酰胺的浓度为0.03-0.15g/mL。
根据本发明部分实例的自愈性水凝胶的制备方法,步骤(3)中单宁酸的质量浓度为1~20mg/mL。
通过上述方法制得的促进伤口愈合的多酚可注射的自愈性水凝胶。
实施例1
称取透明质酸(HA)0.5g溶于吗啉乙磺酸缓冲溶液(0.05M,pH=5.5)中,加入0.5g1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(EDC)和0.25gN-羟基丁二酰亚胺(NHS),完全溶解后,搅拌状态下反应20min。反应结束后,在上述溶液中加入0.5g盐酸多巴胺(DA),在氮气保护的氛围下反应12h。反应结束后,得到产物用8000-14000Da的透析袋透析72h除去杂质。将透析完成的溶液进行冷冻干燥,得到邻苯二酚接枝透明质酸并避光密封保存。
实施例2
称量0.5g的丙烯酰胺,加入1%甲叉双丙烯酰胺150μL及2%过硫酸铵100μL,加入去离子水使成2mL,混合均匀后反应30分钟后得到聚丙烯酰胺。反应结束后,得到产物用8000-14000Da的透析袋透析48h除去杂质。将透析完成的溶液进行冷冻干燥,得到聚丙烯酰胺并避光密封保存。
实施例3
称量0.1g由实施例1制备得到的透明质酸衍生物及0.1g由实施例2制备得到的聚丙烯酰胺再加入1mg的单宁酸,加入余量水制成2ml水凝胶溶液,搅拌均匀后静置即得促进伤口愈合的多酚可注射的自愈性水凝胶。
实施例4
称量1g由实施例1制备得到的透明质酸衍生物及1g由实施例2制备得到的聚丙烯酰胺再加入30mg的单宁酸,加入余量水制成20ml水凝胶溶液,搅拌均匀后静置即得促进伤口愈合的多酚可注射的自愈性水凝胶。
实施例5
称量2g由实例1制备得到的透明质酸衍生物及1g由实施例2制备得到的丙烯酰胺,加入50mg的单宁酸,加入余量水制成20ml水凝胶溶液,搅拌均匀后静置即得促进伤口愈合的多酚可注射的自愈性水凝胶。
对比例1
称量0.1g的丙烯酰胺,加入1%甲叉双丙烯酰胺30μL及1%过硫酸铵100μL,加入去离子水使成2mL,称量0.1g由实施例1制备得到的透明质酸衍生物加入其中,混合均匀后反应40分钟后得到聚丙烯酰胺。加入1mg的单宁酸,搅拌均匀后静置即得促进伤口愈合的多酚可注射的自愈性水凝胶。
性能测试
实施例1中合成的邻苯二酚接枝透明质酸使用核磁共振氢谱(1H核磁共振)如图2所示。
使用傅里叶变换红外光谱(FTIR)表征了实施例3所制备的可注射的自愈性水凝胶的结构,结果如图3所示。
将多酚可注射的自愈性水凝胶进行冷冻干燥后,使用扫描电镜(ZEISSMERLINCompact,Oxfordx-max)对其进行形貌观察,SEM电镜图如图4所示。
使用TA流变仪(AR2000ex)对实施例3~5制备得到的自愈性水凝胶进行测试,测试温度为25℃,模具板间距为1000μm,在恒定应变为1%的条件下,在0.1~100rad/s范围内获得了存储模量(G’)和损耗模量(G”),结果如图5。
使用猪皮来检测自愈性水凝胶的粘附性。将自愈性水凝胶从注射器注射出粘在干净的猪皮上,猪皮也被弯曲和扭曲来模拟身体运动来检测水凝胶是否有裂口。进而,在手指关节处注射凝胶以模拟在关节处的创伤,通过转动关节来检测水凝胶是否能够完全黏附在人体皮肤上,结果如图6。
将实施例3和对比例1所制备得到的水凝胶分别和L929细胞进行共培养三天,利用DAPI和PI染料对共孵育的细胞进行染色,并在倒置荧光显微镜下观察其状态。结果如图9,细胞数量差别不大,但是从荧光染色图中可以看出实施例3共培养的细胞呈现不规则梭型,而对比例呈现圆球形,发育有一定受损。
Claims (9)
1.一种自愈性水凝胶,其特征在于:所述水凝胶是以聚丙烯酰胺和盐酸多巴胺改性的透明质酸为凝胶基质,多酚化合物通过氢键和共轭作用使两种基质交联形成的水凝胶。
2.根据权利要求1所述的自愈性水凝胶,其特征在于:所述多酚化合物为单宁酸或没食子酸。
3.根据权利要求1所述的自愈性水凝胶,其特征在于:所述聚丙烯酰胺、盐酸多巴胺改性的透明质酸、多酚化合物的质量比为1:1~5:0.001~0.01。
4.根据权利要求1所述的自愈性水凝胶,其特征在于:所述盐酸多巴胺改性的透明质酸按下述方法制得:将透明质酸溶于吗啉乙磺酸缓冲溶液中,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和N-羟基丁二酰亚胺,完全溶解后,搅拌状态下进行活化羧基反应,反应温度为20~35℃,反应时间为20~40min;反应结束后,在上述溶液中加入盐酸多巴胺,在氮气保护的氛围下进行接枝反应,反应温度为20~35℃,反应时间为12~72h,透析,冷冻干燥,即为盐酸多巴胺改性的透明质酸,
其中,透明质酸:盐酸多巴胺:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺:N-羟基丁二酰亚胺的质量比为2:2:1:2;透明质酸的分子量为90000~400000。
5.根据权利要求1所述的自愈性水凝胶,其特征在于:所述聚丙烯酰胺按下述方法制得:按1g:10~50mL,将丙烯酰胺溶于水中,加入甲叉双丙烯酰胺及过硫酸铵反应15~20分钟;反应结束后,透析除去未反应的丙烯酰胺、催化剂及副产物,将透析完成的溶液进行冷冻干燥并密封保存,其中,甲叉双丙烯酰胺、过硫酸铵和丙烯酰胺的质量比为0.001:0.01:1。
6.根据权利要求5所述的自愈性水凝胶,其特征在于:透析的截留分子量为3500~14000。
7.根据权利要求1所述的自愈性水凝胶,其特征在于:所得水凝胶具有可注射性。
8.权利要求1所述自愈性水凝胶的制备方法,其特征在于:室温下,将聚丙烯酰胺和盐酸多巴胺改性的透明质酸混合后,加入多酚化合物,加入一定量的水,反应得到自愈性水凝胶。
9.根据权利要求8所述的方法,其特征在于:盐酸多巴胺改性的透明质酸的浓度为0.03~0.15g/mL,聚丙烯酰胺的浓度为0.03~0.15g/mL,多酚化合物的质量浓度为1~20mg/mL。
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