CN114796160A - 一种抗菌材料及其应用 - Google Patents
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Abstract
本发明提供了一种抗菌材料,由具有生物相容性的胶原蛋白和壳聚糖制备而成,胶原蛋白和壳聚糖的质量比为2:8至8:2,优选情况下胶原蛋白和壳聚糖的质量比为1:1、3:2或1:2,其中的壳聚糖可以选自普通壳聚糖和羧甲基壳聚糖。本发明提供的抗菌材料,抑菌率达70%以上,且能缩短创口出血时间至3分钟之内,具有良好的创口修复、止血和抑菌效果。
Description
技术领域
本发明涉及医疗技术领域,具体涉及一种抗菌材料及其应用。
背景技术
宫颈炎、阴道炎、子宫颈溃疡是育龄期妇女常见疾病,并且发病率较髙。临床表现主要为白带增多并呈黏液脓性,阴道分泌物刺激引发外阴疼痛,伴有腰酸、下腹部坠痛及性交出血等症状。这些妇科疾病可与子宫内膜炎同时发生,也常有泌尿道症状,如尿急、尿频、尿痛。妇科检查中可见到子宫颈充血、水肿、糜烂,有黏液脓性分泌物流出。患者常常瘙痒难忍、白带多、味臭,并且易复发,忍受较大的痛苦。目前常用的治疗方法有两种,一种是用药水灌洗,另一种是将片剂、栓剂、胶囊等塞入阴道病变位置。但是此类药物难于到达或是停留在病变位置,从而大大影响了药物的疗效。
胶原蛋白在动物体内含量丰富,主要存在于动物的皮、软骨、韧带、肌腱及结缔组织中,起支持和保护作用,是结缔组织重要的结构蛋白。由于其力学性能高、能够促进细胞生长、止血、具有可吸收性、弱抗原性、良好的生物相容性和生物降解性等优点,可作为一种理想的天然大分子医用材料。作为材料,胶原蛋白透水透气性好,润滑性、稳定性好,具有一定的生物可塑性,官能团多,可进行交联,因此生物降解速度和溶解(溶胀)性可以根据需要而进行调节。
壳聚糖是一种天然高分子聚合物。分子中有不饱和的阳离子基团,对带负电荷的各类有害物质如细菌、真菌和病毒等有强大的吸附作用。其机理是氨基带正电荷,能与细菌黏附在一起,干扰细菌外壁的代谢;壳聚糖表面的正电荷和红细胞表面氨基酸残基的受体相互作用而使负电荷减少,通过对红细胞直接的黏附和聚集作用实现良好的止血、镇痛作用;同时可促进巨噬细胞的迁移,促进伤口愈合。例外在伤口处通过促进肉芽组织及上皮的生成,减少伤口的收缩,起到抑制疤痕的功效。由于其生物降解的性能,可以被机体吸收,从而消除了揭除时的流血以及疼痛,此外也不会因为留下碎屑而延缓伤口的愈合,而且不会对周围的组织产生强烈的刺激作用。
发明内容
本发明的目的是提供一种胶原混合壳聚糖的抗菌材料,能够改善创面的微环境、抑制细菌生长,并且能够快速止血、促进伤口更好的愈合。尤其是解决现有妇科疾病宫颈部位用药的缺陷,它既有保护创面、抗菌消炎,又有促进创面愈合的作用。
本发明的又一目的是提供上述抗菌材料的制备方法,使提供的抗菌材料能够生产、并实际应用于临床。
发明人提供的胶原混合壳聚糖抗菌材料包含胶原蛋白和壳聚糖,其中的壳聚糖选自羧甲基壳聚糖(分子量为543.52)或者普通壳聚糖(分总量为3000),胶原蛋白和壳聚糖的比例为2:8至8:2。
本发明中用到的主要试剂购自上海复申生物科技有限公司,产品目录号如下:
胶原蛋白的制备过程如下:
牛蹄筋原料(购自:上海悦羊贸易有限公司)中的脂肪去除后,进行冷冻并用切片机切成薄片(1mm)。取处理好的牛蹄筋100g于氢氧化钠溶液(0.1mol/L)中搅拌(200r/min)3h,搅拌结束后,用40目金属丝网过滤后,用清水清洗;重复此以上操作直到清洗液显示为中性为止。将脱脂后的牛蹄筋剪碎置于乙酸溶液(0.5mol/L)中,分两次加入胃蛋白酶(购自默克西格玛公司,浓度为:0.05%质量体积比),机械搅拌酶解24h,此过程宜在4℃的环境下进行。离心(3000r/min)分离取上层清液。在上层清液中加入NaOH(4mol/L)调节酶解液的PH值至4.2。边搅拌边缓慢加入乙醇直至乙醇终浓度为50%(V:V),4℃静置24h,过滤脱醇(过滤网为60-100目)。把醇沉后的固体胶原蛋白加入到乙酸溶液(0.1mol/L)中进行溶解,溶解过程中要不断搅拌。将复溶后的胶原蛋白溶液置入透析袋中,置于装有乙酸(0.025mol/L)的容器中透析12h。高速冷冻(4℃)离心机8000rpm离心脱泡10min。将脱泡后的胶原蛋白液注入到模具(模具可根据最终产品的形状和大小进行选择,本发明中选用120mm×80mm×7mm的模具)中进行冻干得到胶原蛋白(分子量5000左右)。
冻干程序如下表:
本发明提供的抗菌材料的制备方法,包括以下步骤:
1、胶原蛋白与壳聚糖溶液的配制
首先称取0.5g的胶原蛋白,室温搅拌溶解到0.1M的冰醋酸溶液中,配制质量分数为1%-2%的胶原溶液备用;然后称取一定质量的壳聚糖粉末,配制5%壳聚糖溶液(质量体积比);按照一定质量比例(胶原蛋白:壳聚糖质量比为1:1、3:2、1:2)将二者混合,得到胶原与壳聚糖混合溶液。
2、聚乙二醇溶液的配制
称取一定质量的聚乙二醇固体,室温配制质量分数为50%,pH=3的聚乙二醇溶液(用冰醋酸调节溶液pH)。
3、胶原蛋白与壳聚糖混合溶液的透析浓缩
将步骤1获得的胶原蛋白与壳聚糖混合溶液装入透析袋中,然后把透析袋放入聚乙二醇溶液中,透析一段时间(8-12小时)后,溶液中的胶原蛋白质量分数达到1.5%-2.5%。
4、注模脱泡冻干
使用注射器将浓缩后的胶原蛋白壳聚糖溶液注入定制的模具中,置于4℃的环境下8000rpm离心脱泡12h,然后放入冻干机中干燥成型。
抗菌材料的使用方法就是将抗菌材料制成各种合适的贴片、膜片等贴敷至创口上,如果是用抗菌材料制备成专门用于宫颈等部位使用的宫颈抗菌器材,其使用方法是:由专科医生或妇科医生用专用的长镊子将膜片或贴片(可连有一根棉线)送入子宫颈部位卡住,之后患者可以自行取出。
本发明提供的抗菌材料,还可以作为基材,在其上连接其他抗/抑菌(病毒)剂(是指对霉菌、细菌、病毒等微生物高度敏感的化学物质,它们能通过化学反应或物理作用杀死与其接触的微生物),如可通过物理法(如复合和涂敷)和化学法(键合)将其他抗/抑菌剂连接到抗菌膜上,进一步增强抗/抑菌效果和其他治疗效果。
本发明的有益效果:本发明提供的抗菌材料由生物相容性材料制备,对创口没有二次伤害,而且具有良好的创面修复、止血和抑菌效果,抑菌率高达70%以上。抗菌材料的组分之一---壳聚糖上具有大量的羟基和氨基活性基团,使得抗菌材料可以作为基材,耦连其他抗/抑菌(病毒)剂,进一步拓展了抗菌材料的用途并提高抗/抑菌(病毒)效果。
具体实施方式
实施例1
称取0.5g的胶原蛋白,分步室温搅拌溶解到0.1M的冰醋酸溶液中,配制质量分数为1%的胶原溶液备用。然后称取0.66g的羧甲基壳聚糖粉末制备5%水溶性羧甲基壳聚糖溶液(溶剂为水)。取上述20体积胶原溶液和4体积羧甲基壳聚糖溶液将二者混合,得到胶原羧甲基壳聚糖溶液(质量比例是胶原蛋白:羧甲基壳聚糖为1:1)。
称取50g的聚乙二醇固体,室温配制质量分数为50%,pH=3的聚乙二醇溶液(用冰醋酸调节溶液pH)。将溶液装入透析袋中,然后把透析袋放入聚乙二醇的溶液中,透析10小时后,使用注射器将浓缩后的胶原壳聚糖溶液注入定制的模具中,置于4℃的环境下脱泡12h,然后放入冻干机中干燥成型。
实施例2
与实施例1基本相同,区别仅仅在于胶原蛋白:羧甲基壳聚糖最终的质量比为3:2。
实施例3
与实施例1基本相同,区别仅仅在于胶原蛋白:羧甲基壳聚糖最终的质量比为1:2。
实施例4
称取0.5g的胶原蛋白,分步室温搅拌溶解到0.1M的冰醋酸溶液中,配制质量分数为1%的胶原溶液备用。然后称取0.66g的普通壳聚糖粉末制备5%酸溶性壳聚糖溶液(溶剂为0.1M的冰醋酸)。取上述20体积胶原溶液和4体积酸溶性壳聚糖溶液将二者混合,得到胶原酸溶性壳聚糖溶液(质量比例是胶原蛋白:壳聚糖为1:1)
称取一定质量50g的聚乙二醇固体,室温配制质量分数为50%,pH=3的聚乙二醇溶液(用冰醋酸调节溶液pH)。将溶液装入透析袋中,然后把透析袋放入聚乙二醇的溶液中,透析一段时间后,使用注射器将浓缩后的胶原壳聚糖溶液注入定制的模具中,置于4℃的环境下脱泡12h,然后放入冻干机中干燥成型。
实施例5
与实施例4基本相同,区别仅仅在于胶原蛋白:普通壳聚糖最终质量比为3:2。
实施例6
与实施例4基本相同,区别仅仅在于胶原蛋白:普通壳聚糖最终质量比为1:2。
实施例7胶原壳聚糖宫颈膜创伤修复效果实验
上述所示的实施例得到的抗菌材料分别标记为1-6。取豚鼠27只,分为9组,每组3只,将豚鼠背部剪毛,酒精消毒,在背部切除2X2cm的全层皮肤,抗菌材料膜片(组别1-6),1%胶原蛋白(组别7)和5%普通壳聚糖(组别8)切下2X2cm覆盖在伤口上并用无菌纱布包扎;对照(组别9)直接用无菌纱布包扎创面。于术后1天、3天、5天、7天观察抗菌材料膜片对创面的修复情况,记录创面修复情况(见表1,+越多,表明修复效果越好)。
表1创面修复效果
组别 | 术后1天 | 术后3天 | 术后5天 | 术后7天 |
1 | 无效果 | + | ++ | +++ |
2 | 无效果 | + | ++ | +++ |
3 | 无效果 | + | ++ | +++ |
4 | 无效果 | + | ++ | ++++ |
5 | 无效果 | + | ++ | +++ |
6 | 无效果 | ++ | +++ | +++++ |
7 | 无效果 | 无效果 | + | + |
8 | 无效果 | + | + | ++ |
9 | 无效果 | 无效果 | + | ++ |
使用抗菌材料膜片的动物创口从术后3天开始呈现出被修复的现象,无渗血,到术后5天创口轻微粘合,肿胀、发炎发红等现象变轻微,术后7天实验组豚鼠的创口全部愈合,无肿胀现象。其中第6组的愈合速度和愈合效果较其它组别快。胶原壳聚糖组合使用的效果优于单独胶原蛋白或是单独壳聚糖的使用,而对照组直至术后5天出血才停止,出现轻微修复现象,而到术后7天,仍呈现出轻微发红现象,创口有轻微粘合但仍然未愈合。
实施例8抗菌材料膜片止血效果试验
取家兔21只,随机分为7组,每组3只,左耳缘三分之一处,横切约1cm长的伤口,伤口从耳缘横切家兔耳部,所有耳朵做同样伤口处理。1-8组(分别是实施例1-6获得的抗菌材料膜片,1%胶原蛋白和5%普通壳聚糖)5秒内覆盖2X2cm材料膜片再用无菌纱布按压一分钟,对照(组别9)仅用无菌纱布按压一分钟。一分钟以后开始观察伤口的出血情况,并开始计时到不再渗血、出血为止血时间,记录结果(见表2)。
表2伤口的止血时间
结果显示1-6组均有不同程度的止血作用,效果优于胶原蛋白或是壳聚糖单独使用,其中第6组效果明显,表明抗菌材料膜片有较好的止血性能。
实施例9抗菌材料抑菌试验
将金黄色葡萄球菌(购自环凯微生物公司)24h斜面培养物用PBS洗下,制成菌悬液(浓度为:用100μL滴于对照样片上,回收菌数为1X104-9X104cfu/片)。取被试样片1-6(2cmX3cm)置于灭菌平皿内,7为壳聚糖组别,8为胶原蛋白组别。取上述菌悬液,分别在每个被试样片上滴加100μL,均匀涂布/混合。开始计时,作用20min后,用无菌镊分别将样片投人含5mL PBS的试管内,充分混匀,适当稀释后吸取5ml,置于两个平皿,用凉至40-45℃的营养琼脂培养基(细菌)15mL作倾注,转动平皿,使其充分均匀,琼脂凝固后翻转板。35℃±2℃培养48h,作活菌菌落计数。抑菌率=(对照菌落数-被试菌落数)/对照菌落数*100%
表3抑菌率
结果显示1-7组均有抑菌作用,其中第6组效果明显,表明胶原壳聚糖抗菌材料有良好的抑菌作用,抑菌率高达70%以上,优于壳聚糖和胶原蛋白单独使用时的抑菌效果。
Claims (5)
1.一种抗菌材料,其特征在于包括胶原蛋白和壳聚糖,胶原蛋白和壳聚糖的质量比为2:8至8:2。
2.根据权利要求1所述的抗菌材料,其特征在于其中的壳聚糖可选自普通壳聚糖或者羧甲基壳聚糖。
3.根据权利要求1或2任一项所述的抗菌材料,其特征在于胶原蛋白和壳聚糖的质量比优选为1:1、3:2或1:2。
4.权利要求1-3任一项所述的抗菌材料,其制备方法包括如下步骤:
(1)胶原蛋白与壳聚糖溶液的配制
首先称取0.5g的胶原蛋白,分步室温搅拌溶解到0.1M的冰醋酸溶液中,配制质量分数为1%-2%的胶原溶液备用;然后称取0.66g的壳聚糖粉末,配制5%壳聚糖溶液;按照胶原蛋白:壳聚糖为2:8至8:2的质量比将二者混合,得到胶原与壳聚糖混合溶液;
(2)聚乙二醇溶液的配制
称取50g聚乙二醇固体,室温配制质量分数为50%,pH=3的聚乙二醇溶液(用冰醋酸调节溶液pH);
(3)胶原蛋白与壳聚糖混合溶液的透析浓缩
将步骤(1)获得的胶原蛋白与壳聚糖混合溶液装入透析袋中,然后把透析袋放入聚乙二醇溶液中,透析8-12小时后,溶液中的胶原蛋白质量分数达到1.5%-2.5%;
(4)注模脱泡冻干
将浓缩后的胶原蛋白壳聚糖溶液注入定制的模具中,置于4℃的环境下脱泡12h,然后放入冻干机中干燥成型。
5.权利要求1-3任一项所述的抗菌材料在制备创口修复、止血和抗/抑菌和抗/抑病毒制品中的应用。
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