CN111359003A - 一种骨科创口抗菌防护膜及其制备方法 - Google Patents
一种骨科创口抗菌防护膜及其制备方法 Download PDFInfo
- Publication number
- CN111359003A CN111359003A CN202010236748.7A CN202010236748A CN111359003A CN 111359003 A CN111359003 A CN 111359003A CN 202010236748 A CN202010236748 A CN 202010236748A CN 111359003 A CN111359003 A CN 111359003A
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- Prior art keywords
- chitosan
- protective film
- antibacterial
- antibacterial protective
- sensitive
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Abstract
本发明提供了一种骨科创口抗菌防护膜及其制备方法。该抗菌防护膜包括相互粘结的与创口接触的内源抗菌防护膜以及与外界环境接触的外源抗菌防护膜。所述内源抗菌防护膜为负载抗菌剂的PH敏感型可降解高分子聚合物膜,所述PH敏感型可降解高分子聚合物包括酸敏感化学键,当创口由于内源细菌感染产生炎症时,创口处PH值降低,使得酸敏感化学键断裂,缓释出负载的抗菌剂以抑制内源细菌感染。所述外源抗菌防护膜为接枝有石墨烯的壳聚糖膜,用于阻隔和抑制外源细菌感染。石墨烯通过化学键与壳聚糖相连,不会进入人体内,能够有效抑制外源细菌,因此仅在发生内源感染时,内源抗菌防护膜才会释放抗菌剂,显著减少了进入人体的抗菌剂。
Description
技术领域
本发明属于生物医学材料技术领域,涉及一种骨科创口抗菌防护膜及其制备方法。
背景技术
皮肤是抵御外界环境免受侵害的重要屏障和保护层,日常生活中,不可避免的会因创伤、烧伤等外力因素或人体病变等自身因素造成皮肤的缺损从而形成伤口。在伤口愈合过程中,细菌入侵受伤部位且增殖密度达到105CFU/mL,会引发炎症及感染,阻碍伤口愈合。伤口的细菌感染一般包括内源性感染和外源性感染,内源性感染是指免疫机能低下的病人由自身正常菌群引起的感染,即病人本身是病原携带者,当机体抵抗力降低时引起自身伤口感染;外源性感染是指由外界环境带来的外袭菌群引起的伤口感染。伤口护理膜对损伤部分起临时屏障作用,因此,有效防止内源及外源细菌感染是伤口护理膜的潜在要求之一。
目前临床解决办法是在伤口部位覆盖抑菌性伤口护理膜,通过抑菌剂的抑菌杀菌作用来避免伤口感染同时促进伤口愈合。目前用于伤口护理膜的抑菌剂主要为抗生素、纳米银和有机硅季铵盐等,这些抑菌剂大多都需通过与伤口处的细菌有效接触才能实现抑菌功能,在此过程中,抑菌剂不可避免的会向人体内释放。其中,抗生素的不可控释放会引起人体对细菌的耐药性,影响伤口的愈合;纳米银不断溶出向人体内释放,在体内不断累积会引起生理毒性;有机硅季铵盐多为非溶出型抗菌剂,虽然不易向人体释放累积,但其抑菌率不够高,由于难以与之有效接触,导致对内源性感染的细菌的抑菌率较低。申请号为201810417353.X的中国发明专利公开了一种慢性伤口用PH敏感型长效修复医用敷膜,是在外层纺丝液中添加抗菌剂,内层纺丝液中同时添加抗菌剂和酸敏感型物质,通过同轴静电纺丝,得到外层具有速释功能、内层具有缓释功能的超细纤维膜。该发明虽然利用伤口炎症期的PH值变化,控制抗菌剂的阶段性释放,实现伤口的长效修复,但无论是外源或内源感染,抗菌剂都不可避免的会释放进入人体。
现有技术很少有针对伤口的内源性感染和外源性感染,对护理膜的结构进行设计,以提高抑菌率,并减少抗菌剂对人体的危害。因此,本发明设置内外两层防护膜,通过外层防护膜阻隔和抑制外部细菌的侵入;只有当发生内源感染时,利用伤口感染后PH值的变化,通过PH敏感型防护膜,缓释出抗菌剂实现对内源细菌的抑制,从而有效抑制伤口细菌感染,并显著降低进入人体的抗菌剂的量。
发明内容
针对上述现有技术存在的缺陷,本发明的目的在于提供一种骨科创口抗菌防护膜及其制备方法,通过设置具有PH敏感型缓释功能的内源抗菌防护膜和具有阻隔和抑制外源抗菌剂功能的外源抗菌防护膜,石墨烯通过化学键与壳聚糖相连,不会进入人体内,能够有效抑制外源细菌,因此仅在发生内源感染时,内源抗菌防护膜才会释放抗菌剂,显著减少了进入人体的抗菌剂,进而减少药物累积性伤害。
一种骨科创口抗菌防护膜,包括相互粘结的与创口接触的内源抗菌防护膜以及与外界环境接触的外源抗菌防护膜,所述内源抗菌防护膜为负载抗菌剂的PH敏感型可降解高分子聚合物膜,用于在酸性条件下缓释出所述抗菌剂以抑制内源细菌感染;所述外源抗菌防护膜为接枝有石墨烯的壳聚糖膜,用于阻隔和抑制外源细菌感染。
进一步的,所述PH敏感型可降解高分子聚合物为基于酸敏感化学键的壳聚糖、透明质酸或羧甲基纤维素中的一种。
进一步的,所述酸敏感化学键包括原酸酯、缩醛、缩酮。
进一步的,所述抗菌剂为抗生素、纳米银、有机硅季铵盐中的一种或多种。
一种以上所述骨科创口抗菌防护膜的制备方法,包括以下步骤:
S1.将所述PH敏感型可降解高分子聚合物和抗菌剂溶于有机溶剂中,将PH调节至7.5-8.5,得到聚合物质量分数为1-10%的纺丝液A;
S2.将接枝有石墨烯的壳聚糖溶于有机溶剂中,得到质量分数为1-10%的纺丝液B;
S3.将纺丝液A进行静电纺丝,得到PH敏感型可降解高分子聚合物纤维膜,以所述PH敏感型可降解高分子聚合物纤维膜为接收基底,将纺丝液B进行静电纺丝,得到相互粘结的PH敏感型可降解高分子聚合物纤维膜和接枝有石墨烯的壳聚糖纤维膜,即为所述骨科创口抗菌防护膜。
进一步的,步骤S1中,所述抗菌剂的质量为所述PH敏感型可降解高分子聚合物的质量的2-10%。
进一步的,步骤S3中,所述PH敏感型可降解高分子聚合物纤维膜的厚度为50-200μm,所述接枝有石墨烯的壳聚糖纤维膜的厚度为200-500μm。
进一步的,步骤S1中,所述PH敏感型可降解高分子聚合物的制备方法包括以下步骤:
S101.将二氨基原酸酯单体和三乙胺加入到反应容器中,然后将甲基丙烯酸酐溶于二氯甲烷中,并逐滴加入到反应容器中,在氮气条件下室温反应完全后,依次进行减压蒸馏、萃取,得到甲基丙烯酰胺原酸酯单体;
S102.将壳聚糖加入到蒸馏水中,室温搅拌使其溶胀,然后加入丁二酸酐和碳酸钠,反应3-5h,碱性条件下去除未反应的壳聚糖;接着加入甲基丙烯酸酐,将PH调至8-9,在0℃下反应10-20h,用乙醇洗涤除去未反应的甲基丙烯酸酐,最后真空干燥得到双键功能化的丁二酰胺化壳聚糖;
S103.将步骤S101所述甲基丙烯酰胺原酸酯单体和步骤S102所述双键功能化的丁二酰胺化壳聚糖加入到反应容器中;然后加入磷酸缓冲液,搅拌使其充分溶解;接着在氮气氛围下加入过硫酸钾,于80-90℃下引发自由基共聚反应;最后依次经透析、冷冻干燥,得到所述PH敏感型可降解高分子聚合物。
进一步的,步骤S2中,所述接枝有石墨烯的壳聚糖的制备方法包括以下步骤:
S201.将氧化石墨烯加入至去离子水中,超声分散,得到浓度为0.5-3mg/ml的分散液;
S202.向步骤S201所述分散液中加入冰醋酸,然后加入壳聚糖,在20-40℃下反应2-6h,然后升温至80-90℃,加入水合肼还原,得到接枝有石墨烯的壳聚糖,所述壳聚糖的浓度为2.5-20mg/ml;
S203.将步骤S202所述接枝有石墨烯的壳聚糖抽滤、洗涤至中性,然后冷冻干燥得到接枝有石墨烯的壳聚糖。
进一步的,所述有机溶剂为六氟异丙醇、三氟乙醇、三氯甲烷、甲醇、二氯甲烷、N,N-二甲基甲酰胺中的一种或多种。
有益效果
与现有技术相比,本发明提供的骨科创口抗菌防护膜及其制备方法具有如下有益效果:
(1)本发明提供的骨科创口抗菌防护膜,包括相互粘结的与创口接触的、具有PH敏感型缓释功能的内源抗菌防护膜以及与外界环境接触的、具有阻隔和抑制外源抗菌剂功能的外源抗菌防护膜。PH敏感型缓释功能的内源抗菌防护膜包括酸敏感化学键,当创口由于内源细菌感染产生炎症时,创口处PH值降低,使得酸敏感化学键断裂,缓释出负载的抗菌剂以抑制内源细菌感染。外源抗菌防护膜的石墨烯通过化学键与壳聚糖相连,不会进入人体内,且能够有效阻隔和抑制外源细菌,因此仅在发生内源感染时,内源抗菌防护膜才会释放抗菌剂,显著减少了进入人体的抗菌剂,进而减少药物累积性伤害。
(2)本发明提供的具有PH敏感型缓释功能的内源抗菌防护膜为负载抗菌剂的PH敏感型可降解高分子聚合物膜,优选以含双键的原酸酯类单体为酸敏感部位,以双键功能化的壳聚糖为聚合物主体,通过自由基聚合引发交联,当伤口感染处理炎症期时,伤口处PH值降低,原酸酯键断裂,释放出包裹的抗菌剂。具有阻隔和抑制外源抗菌剂功能的外源抗菌防护膜为接枝有石墨烯的壳聚糖膜,纳米级的石墨烯片具有锋利的边缘能够对细菌细胞膜进行物理切割,并能够将细菌包裹起来,使其与外界环境隔离无法吸取营养而达到抑菌效果。因此,该外源抗菌防护膜能够有效阻隔和抑制外源细菌的侵入。
(3)本发明提供的具有PH敏感型缓释功能的内源抗菌防护膜,优选为通过交联形成三维网络结构的壳聚糖,一方面是具备较好的机械强度,可以吸收伤口处的渗透液。另一方它可以维持湿润的环境,能够阻止病原体的进入,并且没有炎症反应,从而可以促进伤口部位的无痂皮愈合。此外,伤口始终处于湿润的环境一方面可以促进表皮细胞的迁移,增强组织中白细胞的功能。另一方面,湿润的环境有助于生长因子的释放和细胞的增殖。
具体实施方式
以下将对本发明各实施例的技术方案进行清楚、完整的描述,显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例;基于本发明的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施例,都属于本发明所保护的范围。
本发明提供的骨科创口抗菌防护膜,包括相互粘结的与创口接触的内源抗菌防护膜以及与外界环境接触的外源抗菌防护膜,所述内源抗菌防护膜为负载抗菌剂的PH敏感型可降解高分子聚合物膜,用于在酸性条件下缓释出所述抗菌剂以抑制内源细菌感染;所述外源抗菌防护膜为接枝有石墨烯的壳聚糖膜,用于阻隔和抑制外源细菌感染。
优选地,所述PH敏感型可降解高分子聚合物为基于酸敏感化学键的壳聚糖、透明质酸或羧甲基纤维素中的一种。所述酸敏感化学键包括原酸酯、缩醛、缩酮。
更优选地,所述PH敏感型可降解高分子聚合物为基于原酸酯的壳聚糖。
所述基于原酸酯的壳聚糖,为以甲基丙烯酰胺原酸酯单体为酸敏感部位,以双键功能化的丁二酰胺化壳聚糖为聚合物主体,通过自由基聚合引发交联得到PH敏感型的壳聚糖凝胶。当伤口感染处理炎症期时,伤口处PH值降低,原酸酯键断裂,释放出包裹的抗菌剂。
实施例1
一种骨科创口抗菌防护膜,包括相互粘结的与创口接触的、具有PH敏感型缓释功能的内源抗菌防护膜以及与外界环境接触的、具有阻隔和抑制外源抗菌剂功能的外源抗菌防护膜。制备方法包括以下步骤:
S1.将PH敏感型壳聚糖和纳米银溶于三氟乙醇中,将PH调节至8,得到聚合物质量分数为4%的纺丝液A;所述纳米银的质量为所述PH敏感型壳聚糖的质量的8%;
所述PH敏感型壳聚糖制备方法如下:
S101.将二氨基原酸酯单体和适量的三乙胺加入到反应容器中,然后将甲基丙烯酸酐溶于二氯甲烷中(二氨基原酸酯单体和甲基丙烯酸酐的摩尔比为1:3),并逐滴加入到反应容器中,在氮气条件下室温反应完全后,减压除去溶剂,乙酸乙醋溶解产物,用10%的K2CO3溶液及饱和NaCl溶液各萃取一次,收集有机相,然后干燥过滤,减压旋蒸,除去有机相,得到甲基丙烯酰胺原酸酯单体;
S102.将壳聚糖加入到蒸馏水中,室温搅拌使其溶胀,然后加入丁二酸酐和碳酸钠,反应3-5h,用NaOH将溶液PH调至10,离心去除未反应的壳聚糖,得到丁二酰化壳聚糖;将丁二酰化壳聚糖溶于蒸馏水后,加入甲基丙烯酸酐,用NaOH将溶液PH调至8-9,在0℃下反应15h,用乙醇洗涤除去未反应的甲基丙烯酸酐,最后真空干燥得到双键功能化的丁二酰胺化壳聚糖;
S103.将步骤S101所述甲基丙烯酰胺原酸酯单体和步骤S102所述双键功能化的丁二酰胺化壳聚糖(甲基丙烯酰胺原酸酯单体与双键功能化的丁二酰胺化壳聚糖摩尔比为1:3)加入到反应容器中;然后加入0.01M的磷酸缓冲液,搅拌使其充分溶解;接着在氮气氛围下加入过硫酸钾,于85℃下引发自由基共聚反应;最后依次经透析、冷冻干燥,得到所述PH敏感型可降解高分子聚合物。
S2.将接枝有石墨烯的壳聚糖溶于三氟乙醇中,得到质量分数为8%的纺丝液B;
所述接枝有石墨烯的壳聚糖制备方法如下:
S201.将氧化石墨烯加入至去离子水中,超声分散,得到浓度为2mg/ml的分散液;
S202.向步骤S201所述分散液中加入适量的冰醋酸,然后加入壳聚糖,在25℃下反应4h,然后升温至80-90℃,加入水合肼还原,得到接枝有石墨烯的壳聚糖,所述壳聚糖的浓度为10mg/ml;
S203.将步骤S202所述接枝有石墨烯的壳聚糖抽滤、洗涤至中性,然后冷冻干燥得到接枝有石墨烯的壳聚糖。
S3.将纺丝液A进行静电纺丝,以不锈钢滚筒为接收装置,纺丝液流动速率为1.5mL/h,电压18kV,接收距离15cm,得到厚度为100μm的PH敏感型壳聚糖纤维膜,以所述PH敏感型壳聚糖纤维膜为接收基底,将纺丝液B进行静电纺丝,得到相互粘结的PH敏感型壳聚糖纤维膜和接枝有石墨烯的壳聚糖纤维膜(厚度为300μm),即为所述骨科创口抗菌防护膜。
对比例1
一种骨科创口抗菌防护膜,包括具有PH敏感型缓释功能的内源抗菌防护膜,其制备方法与实施例1中PH敏感型壳聚糖纤维膜的制备方法基本相同,在此不再赘述。
对比例2
一种骨科创口抗菌防护膜,包括具有阻隔和抑制外源抗菌剂功能的外源抗菌防护膜,其制备方法与实施例1中接枝有石墨烯的壳聚糖纤维膜的制备方法基本相同,在此不再赘述。
对比例3
一种骨科创口抗菌防护膜,与实施例1相比,不同之处在于,内源抗菌防护膜为负载抗菌剂的壳聚糖膜,即步骤S1如下:
将壳聚糖和纳米银溶于三氟乙醇中,将PH调节至8,得到聚合物质量分数为4%的纺丝液A;所述纳米银的质量为所述壳聚糖的质量的8%。
其他与实施例1基本相同,在此不再赘述。
表1实施例1及对比例1至3抗菌剂释放率
从表1可以看出,实施例1制备的骨科创口抗菌防护膜,在中性条件下抗菌剂的释放率较小,在酸性条件下,40h后释放率可达到81.0%,说明该骨科创口抗菌防护膜具有酸敏感性。当伤口处于酸性条件时,PH敏感型壳聚糖纤维膜中的原酸酯键逐渐降解,使得交联网络解开,内部包裹的抗菌剂逐渐缓释出来,实现内源感染的抗菌功能。对比例1仅包括PH敏感型壳聚糖纤维膜,其释放率与实施例1相差不大,但由于缺乏外源抗菌防护膜,在用于伤口防护时,外源细菌也会逐步侵入伤口,当伤口发炎使得PH值降低时,才会引发PH敏感型壳聚糖纤维膜释放出抗菌剂进行抗菌,显然延缓了抗菌效率,也增加了抗菌剂缓释概率,抗菌剂进入人体的量也随之增多。对比例2仅包括接枝有石墨烯的壳聚糖外源抗菌膜,抗菌剂释放率为0,虽然能够阻隔和抑制外源细菌,但对内源感染的抑制作用很低。对比例3的内源抗菌防护膜为普通的负载抗菌剂的壳聚糖膜,因此不具有酸敏感型,在不同PH值下,释放率变化不大。因此针对内源感染的特异性释放功能较低。
实施例2-3
实施例2-3提供的骨科创口抗菌防护膜与实施例1相比,不同之处在于,在步骤S1中,所述纳米银的质量分别为所述PH敏感型壳聚糖的质量的2%和10%,其他与实施例1基本相同,在此不再赘述。
表2实施例2和3抗菌剂释放率
从表2可以看出,随着PH敏感型壳聚糖中包裹的纳米银的量的增加,抗菌剂的释放率逐渐增加,因此可以通过调节抗菌剂的添加量,调节其缓释速率和缓释量,从而调节抗菌性能。
综述所述,本发明提供的骨科创口抗菌防护膜,包括相互粘结的与创口接触的、具有PH敏感型缓释功能的内源抗菌防护膜以及与外界环境接触的、具有阻隔和抑制外源抗菌剂功能的外源抗菌防护膜。PH敏感型缓释功能的内源抗菌防护膜包括酸敏感化学键,当创口由于内源细菌感染产生炎症时,创口处PH值降低,使得酸敏感化学键断裂,缓释出负载的抗菌剂以抑制内源细菌感染。外源抗菌防护膜的石墨烯通过化学键与壳聚糖相连,不会进入人体内,且能够有效阻隔和抑制外源细菌,因此仅在发生内源感染时,内源抗菌防护膜才会释放抗菌剂,显著减少了进入人体的抗菌剂,进而减少药物累积性伤害。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种骨科创口抗菌防护膜,其特征在于,包括相互粘结的与创口接触的内源抗菌防护膜以及与外界环境接触的外源抗菌防护膜,所述内源抗菌防护膜为负载抗菌剂的PH敏感型可降解高分子聚合物膜,用于在酸性条件下缓释出所述抗菌剂以抑制内源细菌感染;所述外源抗菌防护膜为接枝有石墨烯的壳聚糖膜,用于阻隔和抑制外源细菌感染。
2.根据权利要求1所述骨科创口抗菌防护膜,其特征在于,所述PH敏感型可降解高分子聚合物为基于酸敏感化学键的壳聚糖、透明质酸或羧甲基纤维素中的一种。
3.根据权利要求2所述骨科创口抗菌防护膜,其特征在于,所述酸敏感化学键包括原酸酯、缩醛、缩酮。
4.根据权利要求1所述骨科创口抗菌防护膜,其特征在于,所述抗菌剂为抗生素、纳米银、有机硅季铵盐中的一种或多种。
5.一种权利要求1至4中任一项所述的骨科创口抗菌防护膜的制备方法,其特征在于,包括以下步骤:
S1.将所述PH敏感型可降解高分子聚合物和抗菌剂溶于有机溶剂中,将PH调节至7.5-8.5,得到聚合物质量分数为1-10%的纺丝液A;
S2.将接枝有石墨烯的壳聚糖溶于有机溶剂中,得到质量分数为1-10%的纺丝液B;
S3.将纺丝液A进行静电纺丝,得到PH敏感型可降解高分子聚合物纤维膜,以所述PH敏感型可降解高分子聚合物纤维膜为接收基底,将纺丝液B进行静电纺丝,得到相互粘结的PH敏感型可降解高分子聚合物纤维膜和接枝有石墨烯的壳聚糖纤维膜,即为所述骨科创口抗菌防护膜。
6.根据权利要求5所述的骨科创口抗菌防护膜的制备方法,其特征在于,步骤S1中,所述抗菌剂的质量为所述PH敏感型可降解高分子聚合物的质量的2-10%。
7.根据权利要求5所述的骨科创口抗菌防护膜的制备方法,其特征在于,步骤S3中,所述PH敏感型可降解高分子聚合物纤维膜的厚度为50-200μm,所述接枝有石墨烯的壳聚糖纤维膜的厚度为200-500μm。
8.根据权利要求5所述的骨科创口抗菌防护膜的制备方法,其特征在于,步骤S1中,所述PH敏感型可降解高分子聚合物的制备方法包括以下步骤:
S101.将二氨基原酸酯单体和三乙胺加入到反应容器中,然后将甲基丙烯酸酐溶于二氯甲烷中,并逐滴加入到反应容器中,在氮气条件下室温反应完全后,依次进行减压蒸馏、萃取,得到甲基丙烯酰胺原酸酯单体;
S102.将壳聚糖加入到蒸馏水中,室温搅拌使其溶胀,然后加入丁二酸酐和碳酸钠,反应3-5h,碱性条件下去除未反应的壳聚糖;接着加入甲基丙烯酸酐,将PH调至8-9,在0℃下反应10-20h,用乙醇洗涤除去未反应的甲基丙烯酸酐,最后真空干燥得到双键功能化的丁二酰胺化壳聚糖;
S103.将步骤S101所述甲基丙烯酰胺原酸酯单体和步骤S102所述双键功能化的丁二酰胺化壳聚糖加入到反应容器中;然后加入磷酸缓冲液,搅拌使其充分溶解;接着在氮气氛围下加入过硫酸钾,于80-90℃下引发自由基共聚反应;最后依次经透析、冷冻干燥,得到所述PH敏感型可降解高分子聚合物。
9.根据权利要求5所述的骨科创口抗菌防护膜的制备方法,其特征在于,步骤S2中,所述接枝有石墨烯的壳聚糖的制备方法包括以下步骤:
S201.将氧化石墨烯加入至去离子水中,超声分散,得到浓度为0.5-3mg/ml的分散液;
S202.向步骤S201所述分散液中加入冰醋酸,然后加入壳聚糖,在20-40℃下反应2-6h,然后升温至80-90℃,加入水合肼还原,得到接枝有石墨烯的壳聚糖,所述壳聚糖的浓度为2.5-20mg/ml;
S203.将步骤S202所述接枝有石墨烯的壳聚糖抽滤、洗涤至中性,然后冷冻干燥得到接枝有石墨烯的壳聚糖。
10.根据权利要求5所述的骨科创口抗菌防护膜的制备方法,其特征在于,所述有机溶剂为六氟异丙醇、三氟乙醇、三氯甲烷、甲醇、二氯甲烷、N,N-二甲基甲酰胺中的一种或多种。
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