CN116570752A - 一种功能性创面修复膜及其制备方法和应用 - Google Patents
一种功能性创面修复膜及其制备方法和应用 Download PDFInfo
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- CN116570752A CN116570752A CN202310536869.7A CN202310536869A CN116570752A CN 116570752 A CN116570752 A CN 116570752A CN 202310536869 A CN202310536869 A CN 202310536869A CN 116570752 A CN116570752 A CN 116570752A
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- film
- solution
- chitosan
- sodium hyaluronate
- membrane
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Abstract
本发明提供了一种功能性创面修复膜及其制备方法和应用,属于生物医用材料技术领域。本发明首先将壳聚糖溶液进行冷冻干燥,得到壳聚糖膜,然后将硫酸铜溶液喷洒于壳聚糖膜上,之后进行冷冻干燥,得到CS‑Cu2+膜;将透明质酸钠、EDC·HCl、DMAP顺次分散于甲酰胺中,之后进行活化处理,得到活化的透明质酸钠溶液,然后将黄芩素溶液与活化的透明质酸钠溶液混合后进行反应,最后经冷冻干燥得到HA‑BAI薄膜;最后将CS‑Cu2+膜和HA‑BAI薄膜进行复合,得到功能性创面修复膜。本发明的功能性创面修复膜中四种成分间协同作用促进了伤口愈合。修复膜具有良好的力学性能、抗菌与抗氧化性,具有良好创面修复的应用前景。
Description
技术领域
本发明涉及生物医用材料技术领域,尤其涉及一种功能性创面修复膜及其制备方法和应用。
背景技术
皮肤是人体最大的器官,是保护内部组织免受机械损伤、微生物感染、紫外线辐射和极端温度影响的关键结构。皮肤损伤是日常生活中的常见事件,很多人都可能因自然灾害、事故等因素造成皮肤损伤。众所周知,伤口愈合是一个复杂的过程,涉及实现组织再生的几种相互关联的生物和分子活动。主要的生理性伤口愈合过程包括凝血、炎症、去除受损基质成分、细胞增殖和迁移、血管生成、基质合成和沉积、再上皮化和重塑。优异的伤口敷料应为愈合过程提供最佳参数,例如预防感染、清除碎屑和废物、适当的氧合、潮湿的环境、促进细胞迁移和伤口闭合。
多糖及其衍生物作为人工细胞外基质(ECM)的理想候选材料,在再生医学领域备受关注。特别是壳聚糖和透明质酸常被用作制备创面愈合膜的主要材料。壳聚糖具有成本低、生物相容性好、可生物降解、止血活性、抗菌、促进伤口愈合等特点和优势。透明质酸由D-葡萄糖醛酸和N-乙酰基-D-氨基葡萄糖组成,是细胞外基质的关键成分,已被广泛用于再生医学的发展,通过与壳聚糖结合,透明质酸可改善组织再生的微环境。吴益栋等报道甲基丙烯酰化壳聚糖(CHMA)和醛基化透明质酸(ALHA)水凝胶,动物实验证明了该水凝胶协同利用壳聚糖与透明质酸的优异性能,促进伤口修复(吴益栋,洪丹,郝文娟,等.超快动态交联的可注射壳聚糖-透明质酸水凝胶及促创伤愈合研究.中国生物医学工程学报,2021,40(5):590-596.)。
黄芩素(BAI)是一种黄酮类化合物,最初从黄芩的根中分离出来,以5,6,7-三羟基黄酮命名。它已被证明具有多种生物学特性,包括抗氧化能力、抗炎作用、抗菌与肿瘤生长抑制,尤其是由于BAI对成纤维细胞TGF-β/Smad2/3信号通路的抑制作用,可抑制瘢痕的形成。BAI的上述优点在伤口愈合中显示出潜在的价值。
微量金属元素在伤口愈合过程中的细胞生长过程中发挥着重要作用。金属铜是日常生活中最常接触的金属之一,也是维持人体生命活动的重要微量元素,功能铜离子(Cu2+)可作为抗菌剂,通过维持血管内皮生长因子(VEGF)和缺氧诱导因子(HIF-1α)的表达促进血管生成,受损组织的微血管修复在难治性伤口的愈合中起着重要作用。文献报道,壳聚糖-铜纳米复合材料(CCNC),可促进了皮肤创伤愈合(A.Gopal,V.Kant,A.Gopalakrishnan,S.K.Tandan,D.Kumar,Chitosan-based copper nanocomposite accelerates healing inexcision wound model in rats,European Journal ofPharmacology.2014,731(1)8–19.)。
综上,壳聚糖与透明质酸多糖、Cu2+离子与中药小分子黄芩素在创面修复领域显示出良好应用前景,将多糖材料、铜离子和黄芩素有机组合,设计出新型伤口敷料,充分发挥各组分的优异性能,是制备CS-Cu2+/HA-BAI膜的出发点,本设计中HA-BAI膜合成与制备未见报道,此外壳聚糖冻干膜喷涂铜离子膜制备方法,未见专利报道。
发明内容
本发明的目的在于提供一种功能性创面修复膜及其制备方法和应用,以解决现有技术中伤口敷料抗菌、抗氧化性差,伤口愈合慢的技术问题。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种功能性创面修复膜的制备方法,包括以下步骤:
(1)将壳聚糖溶液进行冷冻干燥,得到壳聚糖膜;
(2)将硫酸铜溶液喷洒于壳聚糖膜上,之后进行冷冻干燥,得到CS-Cu2+膜;
(3)将透明质酸钠、EDC·HCl、DMAP顺次分散于甲酰胺中,之后进行活化处理,得到活化的透明质酸钠溶液;
(4)将黄芩素溶液与活化的透明质酸钠溶液混合后进行反应,最后经冷冻干燥得到HA-BAI薄膜;
(5)将CS-Cu2+膜和HA-BAI薄膜进行复合,得到功能性创面修复膜。
作为优选,所述步骤(1)中,壳聚糖溶液的浓度为1~5wt%;所述壳聚糖溶液中壳聚糖的分子量为5~500KDa。
作为优选,所述步骤(2)中,硫酸铜溶液的浓度为15~20mg/mL;
所述壳聚糖溶液中的壳聚糖和硫酸铜溶液中的硫酸铜的质量比为0.3~0.6g:30~60mg。
作为优选,所述步骤(3)中,透明质酸钠、EDC·HCl、DMAP和甲酰胺的摩尔体积比为1~2mmol:1~2mmol:0.1~0.3mmol:10~50mL;所述透明质酸钠的分子量为3~1000KDa。
作为优选,所述步骤(3)中,活化处理的温度为20~30℃,时间为1~3h。
作为优选,所述步骤(3)中,黄芩素溶液由黄芩素和二甲基亚砜配制而成,其中黄芩素溶液的浓度为1.5~4mmol/mL;
所述透明质酸钠和黄芩素溶液中的黄芩素的摩尔比为1~2:1。
作为优选,所述步骤(4)中,反应的温度为40~60℃,反应的时间为18~28h。
作为优选,所述步骤(1)、(2)和(4)中,冷冻干燥的温度独立的为-70~-60℃,冷冻干燥的真空度独立的为1~5Pa,冷冻干燥的时间独立的为20~24h。
本发明提供了一种功能性创面修复膜。
本发明提供了一种功能性创面修复膜在制备促进皮肤愈合敷料中的应用。
本发明的有益效果:
本发明制备功能性创面修复膜的原料壳聚糖,具有成本低、生物相容性好、可生物降解、止血活性、抗菌、促进伤口愈合的优势,透明质酸钠是细胞外基质的关键成分,已被广泛用于再生医学的发展,壳聚糖与透明质酸钠均可创造出改善组织再生特性的良好微环境。Cu2+离子与黄芩素功能显示,均可引入促进伤口愈合。本发明将Cu2+离子喷涂于壳聚糖膜上,黄芩素通过酯化反应接枝于透明质酸钠上,最终制成功能性创面修复膜,这是一种复合膜,复合膜保留了四种成分的各自特性,此外,四种成分间的协同作用促进了伤口愈合。该复合膜具有良好的力学性能、抗菌与抗氧化性,作为一种新型的功能敷料,具有良好创面修复的应用前景。
附图说明
图1为实施例1制备的HA-BAI薄膜以及原料黄芩素、原料透明质酸钠的红外图谱,其中a为BAI,b为HA,c为HA-BAI;
图2为实施例1制备的HA-BAI薄膜以及原料透明质酸钠的核磁图谱,其中a为HA,b为HA-BAI;
图3为实施例1制得的壳聚糖膜、对比例1制得的CS/HA膜、对比例2制得的CS-Cu2+/HA膜和实施例1制得的CS-Cu2+/HA-BAI膜的体外抗菌实验结果,其中a为壳聚糖膜,b为CS/HA膜,c为CS-Cu2+/HA膜,(d~f)为CS-Cu2+/HA-BAI膜;
图4为实施例1制得的CS膜(壳聚糖膜)、对比例3制得HA膜、对比例1制得的CS/HA膜、对比例2制得的CS-Cu2+/HA膜、实施例1制得的CS-Cu2+/HA-BAI膜的抗氧化实验结果;
图5为实施例1的壳聚糖膜(CS膜)、对比例3的HA膜、对比例1的CS/HA膜、对比例2的CS-Cu2+/HA膜、实施例1的CS-Cu2+/HA-BAI膜对大鼠创面修复的实验结果。
具体实施方式
本发明提供了一种功能性创面修复膜的制备方法,包括以下步骤:
(1)将壳聚糖溶液进行冷冻干燥,得到壳聚糖膜;
(2)将硫酸铜溶液喷洒于壳聚糖膜上,之后进行冷冻干燥,得到CS-Cu2+膜;
(3)将透明质酸钠、EDC·HCl、DMAP顺次分散于甲酰胺中,之后进行活化处理,得到活化的透明质酸钠溶液;
(4)将黄芩素溶液与活化的透明质酸钠溶液混合后进行反应,最后经冷冻干燥得到HA-BAI薄膜;
(5)将CS-Cu2+膜和HA-BAI薄膜进行复合,得到功能性创面修复膜。
在本发明中,所述步骤(1)中,壳聚糖溶液的浓度为1~5wt%,优选为1.5~4.5wt%,进一步优选为2~4wt%;所述壳聚糖溶液中壳聚糖的分子量为5~500KDa,优选为10~450KDa,进一步优选为100~400KDa。
在本发明中,所述壳聚糖溶液的制备方法优选为:将壳聚糖溶于乙酸溶液中,然后用去离子水透析除去乙酸,其中乙酸溶液的浓度为0.5~3wt%,优选为1.0~2.5wt%,进一步优选为1.5~2.0wt%;透析时间为24~72h,优选为30~65h,进一步优选为35~60h。
在本发明中,所述步骤(2)中,硫酸铜溶液的浓度为15~20mg/mL,优选为16~19mg/mL,进一步优选为17~18mg/mL;
所述壳聚糖溶液中的壳聚糖和硫酸铜溶液中的硫酸铜的质量比为0.3~0.6g:30~60mg,优选为0.4~0.5g:35~55mg,进一步优选为0.45g:40~50mg。
在本发明中,所述步骤(3)中,透明质酸钠、EDC·HCl、DMAP和甲酰胺的摩尔体积比为1~2mmol:1~2mmol:0.1~0.3mmol:10~50mL,优选为1.2~1.8mmol:1.2~1.8mmol:0.15~0.25mmol:15~45mL,进一步优选为1.4~1.6mmol:1.4~1.6mmol:0.2mmol:20~40mL;所述透明质酸钠的分子量为3~1000KDa,优选为100~900KDa,进一步优选为200~800KDa。
在本发明中,所述步骤(3)中,活化处理的温度为20~30℃,优选为22~28℃,进一步优选为25℃;时间为1~3h,优选为1.5~2.5h,进一步优选为2h。
在本发明中,所述步骤(3)中,黄芩素溶液由黄芩素和二甲基亚砜配制而成,其中黄芩素溶液的浓度为1.5~4mmol/mL,优选为2~3.5mmol/mL,进一步优选为2.5~3mmol/mL。
在本发明中,所述透明质酸钠和黄芩素溶液中的黄芩素的摩尔比为1~2:1,优选为1.2~1.8:1,进一步优选为1.4~1.6:1。
在本发明中,所述步骤(4)中,反应的温度为40~60℃,优选为45~55℃,进一步优选为50℃;反应的时间为18~28h,优选为20~26h,进一步优选为22~24h。
在本发明中,所述步骤(1)、(2)和(4)中,冷冻干燥的温度独立的为-70~-60℃,优选为-68~-62℃,进一步优选为-65℃;冷冻干燥的真空度独立的为1~5Pa,优选为2~4Pa,进一步优选为3Pa;冷冻干燥的时间独立的为20~24h,优选为21~23h,进一步优选为22h。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
将0.5g壳聚糖(分子量为5KDa)溶于浓度为3wt%的乙酸溶液中,然后用去离子水透析除去乙酸,其中透析的时间为72h,得到浓度为1wt%的壳聚糖溶液;将壳聚糖溶液转移至12cm×7.5cm×2cm的模具中,在温度为-60℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为1Pa,冷冻干燥的时间为20h,得到壳聚糖膜。
将50mg五水合硫酸铜溶于水中,得到浓度为15mg/mL的硫酸铜溶液,之后将硫酸铜溶液喷洒于壳聚糖膜上,在温度为-60℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为1Pa,冷冻干燥的时间为20h,得到CS-Cu2+膜。
将1.998mmol透明质酸钠(HA)(分子量为500KDa)、1.332mmol的EDC·HCl、0.2mmol的DMAP分散于30mL甲酰胺中,在25℃条件下活化1.5h,得到活化的透明质酸钠溶液;然后将1.332mmol的黄芩素(BAI)溶解于DMSO中,得到浓度为1.5mmol/mL的黄芩素溶液;之后将活化的透明质酸钠溶液和黄芩素溶液混合,在50℃条件下反应24h,反应结束后顺次进行醇沉、抽滤、洗涤,洗涤时直到洗涤液不再出现黄色为止,再将得到的沉淀溶于少量纯净水中透析,最后将透析得到的溶液转移至12cm×7.5cm×2cm的模具中,在-65℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为2Pa,冷冻干燥的时间为20h,得到黄白色海绵状固体HA-BAI薄膜。
最后将CS-Cu2+膜和HA-BAI薄膜复合,即可得到功能性创面修复膜(CS-Cu2+/HA-BAI膜)。
实施例2
将0.6g壳聚糖(分子量为200KDa)溶于浓度为2wt%的乙酸溶液中,然后用去离子水透析除去乙酸,其中透析的时间为24h,得到浓度为5wt%的壳聚糖溶液;将壳聚糖溶液转移至12cm×7.5cm×2cm的模具中,在温度为-70℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为4Pa,冷冻干燥的时间为22h,得到壳聚糖膜。
将60mg五水合硫酸铜溶于水中,得到浓度为17mg/mL的硫酸铜溶液,之后将硫酸铜溶液喷洒于壳聚糖膜上,在温度为-70℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为4Pa,冷冻干燥的时间为22h,得到CS-Cu2+膜。
将1.776mmol透明质酸钠(HA)(分子量为3KDa)、2mmol的EDC·HCl、0.3mmol的DMAP分散于10mL甲酰胺中,在30℃条件下活化1h,得到活化的透明质酸钠溶液;然后将0.888mmol的黄芩素(BAI)溶解于DMSO中,得到浓度为3mmol/mL的黄芩素溶液;之后将活化的透明质酸钠溶液和黄芩素溶液混合,在60℃条件下反应18h,反应结束后顺次进行醇沉、抽滤、洗涤,洗涤时直到洗涤液不再出现黄色为止,再将得到的沉淀溶于少量纯净水中透析,最后将透析得到的溶液转移至12cm×7.5cm×2cm的模具中,在-60℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为3Pa,冷冻干燥的时间为24h,得到黄白色海绵状固体HA-BAI薄膜。
最后将CS-Cu2+膜和HA-BAI薄膜复合,即可得到功能性创面修复膜(CS-Cu2+/HA-BAI膜)。
实施例3
将0.3g壳聚糖(CS)(分子量为500KDa)溶于浓度为0.5wt%的乙酸溶液中,然后用去离子水透析除去乙酸,其中透析的时间为45h,得到浓度为3wt%的壳聚糖溶液;将壳聚糖溶液转移至12cm×7.5cm×2cm的模具中,在温度为-63℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为1Pa,冷冻干燥的时间为23h,得到壳聚糖膜。
将70mg五水合硫酸铜溶于水中,得到浓度为20mg/mL的硫酸铜溶液,之后将硫酸铜溶液喷洒于壳聚糖膜上,在温度为-63℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为1Pa,冷冻干燥的时间为23h,得到CS-Cu2+膜。
将1.852mmol透明质酸钠(HA)(分子量为1000KDa)、1mmol的EDC·HCl、0.1mmol的DMAP分散于50mL甲酰胺中,在20℃条件下活化3h,得到活化的透明质酸钠溶液;然后将1.852mmol的黄芩素(BAI)溶解于DMSO中,得到浓度为4mmol/mL的黄芩素溶液;之后将活化的透明质酸钠溶液和黄芩素溶液混合,在40℃条件下反应28h,反应结束后顺次进行醇沉、抽滤、洗涤,洗涤时直到洗涤液不再出现黄色为止,再将得到的沉淀溶于少量纯净水中透析,最后将透析得到的溶液转移至12cm×7.5cm×2cm的模具中,在-68℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为2Pa,冷冻干燥的时间为23h,得到黄白色海绵状固体HA-BAI薄膜。
最后将CS-Cu2+膜和HA-BAI薄膜复合,即可得到功能性创面修复膜(CS-Cu2+/HA-BAI膜)。
对比例1
将0.6g壳聚糖(CS)(分子量为5KDa)溶于浓度为2wt%的乙酸溶液中,然后用去离子水透析除去乙酸,其中透析的时间为24h,得到浓度为5wt%的壳聚糖溶液;将壳聚糖溶液转移至12cm×7.5cm×2cm的模具中,在温度为-70℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为4Pa,冷冻干燥的时间为22h,得到壳聚糖膜。
将1.998mmol透明质酸钠(HA)(分子量为500KDa)、1.332mmol的EDC·HCl、0.2mmol的DMAP分散于20mL甲酰胺中,在25℃条件下活化1.5h,得到活化的透明质酸钠溶液,然后将活化的透明质酸钠溶液转移至12cm×7.5cm×2cm的模具中,在-65℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为2Pa,冷冻干燥的时间为20h,得到HA薄膜。
然后将壳聚糖膜和HA薄膜薄膜复合,即可得到CS/HA膜。
对比例2
将0.5g壳聚糖(CS)(分子量为5KDa)溶于浓度为3wt%的乙酸溶液中,然后用去离子水透析除去乙酸,其中透析的时间为72h,得到浓度为1wt%的壳聚糖溶液;将壳聚糖溶液转移至12cm×7.5cm×2cm的模具中,在温度为-60℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为1Pa,冷冻干燥的时间为20h,得到壳聚糖膜。
将50mg五水合硫酸铜溶于水中,得到浓度为15mg/mL的硫酸铜溶液,之后将硫酸铜溶液喷洒于壳聚糖膜上,在温度为-60℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为1Pa,冷冻干燥的时间为20h,得到CS-Cu2+膜。
将1.998mmol透明质酸钠(HA)(分子量为500KDa)、1.332mmol的EDC·HCl、0.2mmol的DMAP分散于20mL甲酰胺中,在25℃条件下活化1.5h,得到活化的透明质酸钠溶液,然后将活化的透明质酸钠溶液转移至12cm×7.5cm×2cm的模具中,在-65℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为2Pa,冷冻干燥的时间为20h,得到HA薄膜。
然后将CS-Cu2+膜和HA薄膜薄膜复合,即可得到CS-Cu2+/HA膜。
对比例3
将1.998mmol透明质酸钠(HA)(分子量为500KDa)、1.332mmol的EDC·HCl、0.2mmol的DMAP分散于20mL甲酰胺中,在25℃条件下活化1.5h,得到活化的透明质酸钠溶液,然后将活化的透明质酸钠溶液转移至12cm×7.5cm×2cm的模具中,在-65℃的条件下进行冷冻干燥,其中冷冻干燥的真空度为2Pa,冷冻干燥的时间为20h,得到HA薄膜。
性能检测:
1.对实施例1制得的HA-BAI薄膜、原料黄芩素和原料透明质酸钠进行红外光谱检测,采用KBr压片法,40~4000cm-1波数扫描。测定黄芩素、透明质酸钠以及实施例1制得的HA-BAI薄膜的红外图谱。检测结果如图1所示,图中显示实施例1制备的样品在1705cm-1出现酯键羰基峰,说明黄芩素接枝到透明质酸钠上。
2.取实施例1制得的HA-BAI薄膜10mg溶于D2O中600MHz核磁检测,并测定透明质酸钠氢核磁图谱。检测结果如图2所示,实施例1制得的HA-BAI薄膜具备透明质酸钠和黄芩素特征峰。
3.使用抑菌圈法测定膜的抗菌性能。将实施例1制得的壳聚糖膜、对比例1制得的CS/HA膜、对比例2制得的CS-Cu2+/HA膜,实施例1制得的CS-Cu2+/HA-BAI膜均切成圆片(d=8mm),用紫外线照射30min。分别将大肠杆菌与金黄色葡萄球菌的细菌悬浮液(1×108cfu/mL)涂在两个琼脂板上,然后分别将4种切好的膜均匀地放在盘子上,以上操作均在超净工作台内进行,37℃培养24h后测定抑菌圈直径。
通过抑菌环实验测定壳聚糖膜、CS/HA膜、CS-Cu2+/HA膜、CS-Cu2+/HA-BAI膜均具有抗菌性,均显示出不同大小的抑菌圈;对于E.coli(大肠杆菌),壳聚糖膜、CS/HA膜、CS-Cu2+/HA膜、CS-Cu2+/HA-BAI功能性创面修复膜抑菌圈大小分别为13.8±0.6mm、13.8±0.6mm、17.7±0.6mm、18.3±0.6mm;对于S.aureus(金黄色葡萄球菌),壳聚糖膜、CS/HA膜、CS-Cu2+/HA膜、CS-Cu2+/HA-BAI膜的抑菌圈大小分别为13.6±0.4mm、13.6±0.4mm、17.0±0.4mm、17.5±0.4mm。以上数据得出,各膜材料对两种菌均具有抗菌效果,随着Cu2+和BAI的引入,其抗菌效果逐步增强,同样说明了材料间的抗菌效果协同增强。
4.使用DPPH方法测定材料的抗氧化性:实施例1制得的CS膜(壳聚糖膜)、对比例3制得的HA膜、对比例1制得的CS/HA膜、对比例2制得的CS-Cu2+/HA膜、实施例1制得的CS-Cu2 +/HA-BAI膜。首先取相同大小的CS膜(壳聚糖膜)、HA膜、CS/HA膜、CS-Cu2+/HA膜和CS-Cu2+/HA-BAI膜,分别加入等体积的DPPH溶液(浓度为0.02mg/mL),混匀,室温下避光反应放置30min,在517nm处测定吸光度,敷料对DPPH自由基清除活率由下式确定。
使用DPPH测定研究了不同膜清除反应性自由基的抗氧化能力。作为天然多糖,HA和CS具有抗氧化特性。与CS/HA膜相比,CS-Cu2+/HA膜的氧化性能略有提高,CS-Cu2+/HA-BAI膜与CS-Cu2+/HA膜相比,其抗氧化性能显著提高,黄芩素作为黄酮类化合物的代表,其C6-OH是抗氧化性能提高的主要原因,因此可以看出,本发明所选用的材料具有协同改善的氧化性能,最终达到想要的效果。
清除反应性自由基能力(DPPH)=[1-(Abs1-Abs2)/Abs0]×100%
517nm处测定样品和DPPH溶液吸光度为Abs1,测定样品和无水乙醇的吸光度Abs2,测定DPPH的水溶液吸光度为Abs0。
5.伤口愈合实验
验证实施例1的壳聚糖膜(CS膜)、对比例3的HA膜、对比例1的CS/HA膜、对比例2的CS-Cu2+/HA膜、实施例1的CS-Cu2+/HA-BAI膜的创伤愈合作用。
建立大鼠全层皮肤切除模型以研究功能性创面修复膜的创伤愈合作用。选取170~200g左右的大鼠进行实验,将其分为9组,每组3只。用乙醚进行全身麻醉,大鼠背部脱毛后用酒精将其消毒,在背部用直径15mm的打孔器标记伤口位置,去除该位置全层皮肤。分别使用同等大小的CS膜、HA膜、CS/HA膜、CS-Cu2+/HA膜、CS-Cu2+/HA-BAI膜敷于伤口上,并用医用纱布和医用胶带固定,各组材料使用前经紫外照射消毒,市售创可贴与空白组作为对照组。将大鼠分开喂养在消毒的笼中,每3天用PBS缓冲液清洁伤口并更换敷料,在1、3、7、11和14d对伤口进行观察并拍照记录并计算创口面积。创伤的愈合程度通过皮肤创口的收缩率来表示。
伤口修复率(%)=[(S0-Sn)/S0]×100%
S0代表创伤初始面积;Sn代表修复第n天的创面未闭合面积。
观察不同膜对大鼠创面的愈合效果,当用15mm打孔器在皮肤组织上制备创面模型时,创面部位在5~10min均存在不同程度渗液。第3天,空白组和创可贴组有较多的组织渗液并有炎症发生。CS组、HA组与CS/HA组,伤口均存在不同程度的收缩,CS-Cu2+/HA-BAI组的创伤愈合率达到55%。第7天,CS-Cu2+/HA组创面收缩较CS/HA组明显,CS-Cu2+/HA组和CS-Cu2 +/HA-BAI组全部结痂。第14天,空白创可贴组的伤口未完全修复,CS组、HA组、CS/HA组与CS-Cu2+/HA组形成长而窄的疤痕,CS-Cu2+/HA-BAI组,修复完成,疤痕不明显。从以上结果看,CS-Cu2+/HA-BAI膜伤口修复快,这主要是因Cu2+具有促进血管作用,BAI有抗疤痕作用,所以,CS-Cu2+/HA-BAI伤口修复光滑,伤口愈合率基本达到100%。
由以上实施例可知,本发明提供了一种功能性创面修复膜的制备方法,首先将壳聚糖溶液进行冷冻干燥,得到壳聚糖膜,然后将硫酸铜溶液喷洒于壳聚糖膜上,之后进行冷冻干燥,得到CS-Cu2+膜;将透明质酸钠、EDC·HCl、DMAP顺次分散于甲酰胺中,之后进行活化处理,得到活化的透明质酸钠溶液,然后将黄芩素溶液与活化的透明质酸钠溶液混合后进行反应,最后经冷冻干燥得到HA-BAI薄膜;最后将CS-Cu2+膜和HA-BAI薄膜进行复合,得到功能性创面修复膜。本发明所制得的功能性创面修复膜是一种复合膜。保留了四种成分的各自特性,并且四种成分间协同作用促进了伤口愈合。该功能性创面修复膜具有良好的力学性能、抗菌与抗氧化性,作为一种新型的功能敷料,具有良好创面修复的应用前景。
以上所述仅是本发明的优选实施方式,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,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种功能性创面修复膜的制备方法,其特征在于,包括以下步骤:
(1)将壳聚糖溶液进行冷冻干燥,得到壳聚糖膜;
(2)将硫酸铜溶液喷洒于壳聚糖膜上,之后进行冷冻干燥,得到CS-Cu2+膜;
(3)将透明质酸钠、EDC·HCl、DMAP顺次分散于甲酰胺中,之后进行活化处理,得到活化的透明质酸钠溶液;
(4)将黄芩素溶液与活化的透明质酸钠溶液混合后进行反应,最后经冷冻干燥得到HA-BAI薄膜;
(5)将CS-Cu2+膜和HA-BAI薄膜进行复合,得到功能性创面修复膜。
2.根据权利要求1所述的制备方法,其特征在于,所述步骤(1)中,壳聚糖溶液的浓度为1~5wt%;所述壳聚糖溶液中壳聚糖的分子量为5~500KDa。
3.根据权利要求1或2所述的制备方法,其特征在于,所述步骤(2)中,硫酸铜溶液的浓度为15~20mg/mL;
所述壳聚糖溶液中的壳聚糖和硫酸铜溶液中的硫酸铜的质量比为0.3~0.6g:30~60mg。
4.根据权利要求3所述的制备方法,其特征在于,所述步骤(3)中,透明质酸钠、EDC·HCl、DMAP和甲酰胺的摩尔体积比为1~2mmol:1~2mmol:0.1~0.3mmol:10~50mL;所述透明质酸钠的分子量为3~1000KDa。
5.根据权利要求2或4所述的制备方法,其特征在于,所述步骤(3)中,活化处理的温度为20~30℃,时间为1~3h。
6.根据权利要求5所述的制备方法,其特征在于,所述步骤(3)中,黄芩素溶液由黄芩素和二甲基亚砜配制而成,其中黄芩素溶液的浓度为1.5~4mmol/mL;
所述透明质酸钠和黄芩素溶液中的黄芩素的摩尔比为1~2:1。
7.根据权利要求2或4或6所述的制备方法,其特征在于,所述步骤(4)中,反应的温度为40~60℃,反应的时间为18~28h。
8.根据权利要求7所述的制备方法,其特征在于,所述步骤(1)、(2)和(4)中,冷冻干燥的温度独立的为-70~-60℃,冷冻干燥的真空度独立的为1~5Pa,冷冻干燥的时间独立的为20~24h。
9.权利要求1~8任意一项所述的制备方法制得的功能性创面修复膜。
10.权利要求9所述的功能性创面修复膜在制备促进皮肤愈合敷料中的应用。
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