CN116693885A - 一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法 - Google Patents
一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法 Download PDFInfo
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- CN116693885A CN116693885A CN202310529314.XA CN202310529314A CN116693885A CN 116693885 A CN116693885 A CN 116693885A CN 202310529314 A CN202310529314 A CN 202310529314A CN 116693885 A CN116693885 A CN 116693885A
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- glucomannan
- oxidized
- bletilla striata
- healing
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Abstract
本发明公开了一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,包括:将聚乙烯醇在水浴下溶解在去离子水中,得到聚乙烯醇溶液;将氧化白及葡甘聚糖和氧化白及葡甘聚糖纳米银复合物溶解到聚乙烯醇溶液中获得混合液;向混合液中加入硼砂溶液得到自愈合性氧化白及葡甘聚糖复合水凝胶。本发明制备的水凝胶具有自愈合性、可注射性以及性状适应性,并能够适应关节活动,具有处理关节皮肤创伤以及不规则创面的潜力;此外,该水凝胶生物相容性良好,固有的抗菌性能和止血性能优异,能够促进感染创面愈合。本发明的自愈合性氧化白及葡甘聚糖复合水凝胶在临床创面修复和止血处理方面具有良好的应用前景,有望发展成为一种新型的医用敷料。
Description
技术领域
本发明属于生物医用材料技术领域,更具体地说,本发明涉及一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法。
背景技术
白及为兰科植物白及的干燥块茎,具有收敛止血、消肿生肌之功效,主治肺胃出血、外伤出血、肺结核吐血、消化道溃疡、皮肤皲裂等。白及的药效成分主要含多糖、菲类、蒽醌类、联苄类等。其中白及葡甘聚糖是白及块茎经水提醇沉得到的一种黏性多糖,其主要化学成分为葡萄甘露聚醣,有研究表明白及葡甘聚糖外用对实质性器官、肌肉血管出血等有良好的止血作用,其止血作用机制是增强血小板第Ⅲ因子活性、缩短凝血酶生成时间、抑制纤维蛋白酶的活性,同时促进细胞凝聚,形成人工血栓,从而达到止血之功效,同时白及葡甘聚糖还具有一定的抑菌抗炎与促进伤口愈合的功效。白及葡甘聚糖具有良好的生物降解性、安全、无毒副作用、无致热原性等特性,已作为一种安全可靠的生物医学材料应用于医药、化工行业。
水凝胶(Hydrogel)是一类极为亲水的三维网络结构凝胶,它在水中迅速溶胀并在此溶胀状态可以保持大量体积的水而不溶解。由于存在交联网络,水凝胶可以溶胀和保有大量的水,水的吸收量与交联度密切相关。交联度越高,吸水量越低。这一特性很像一种软组织。水凝胶中的水含量可以低到百分之几,也可以高达99%。凝胶的聚集态既非完全的固体也非完全的液体。固体的行为是一定条件下可维持一定的形状与体积,液体行为是溶质可以从水凝胶中扩散或渗透。
将氧化白及葡甘聚糖、纳米银和水凝胶相结合制备具有自愈合能力的复合水凝胶的技术方案并没有被现有技术所公开,如何结合制备得到具有自愈合性、可注射性以及性状适应性,并能提供适应关节活动,具有处理关节皮肤创伤以及不规则创面的复合水凝胶就成为目前需要解决的问题。
发明内容
本发明的一个目的是解决至少上述问题和/或缺陷,并提供至少后面将说明的优点。
为了实现根据本发明的这些目的和其它优点,提供了一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,包括以下步骤:
步骤一、提取白及葡甘聚糖;
步骤二、制备氧化白及葡甘聚糖;
步骤三、将氧化白及葡甘聚糖溶于去离子水中,水浴搅拌形成氧化白及葡甘聚糖溶液,将AgNO3溶液滴加到氧化白及葡甘聚糖溶液中并搅拌混合均匀,然后在水浴下避光搅拌后自然冷却至室温,离心收集悬浮液,最后经冷冻真空干燥获得氧化白及葡甘聚糖纳米银复合物;
步骤四、先将聚乙烯醇在水浴下溶解在去离子水中,得到聚乙烯醇溶液;然后将的氧化白及葡甘聚糖和氧化白及葡甘聚糖纳米银复合物溶解到聚乙烯醇溶液中获得均匀的混合液;最后,在磁力搅拌状态下,向混合液中加入硼砂溶液得到自愈合性氧化白及葡甘聚糖复合水凝胶。
优选的是,其中,所述步骤一中,提取白及葡甘聚糖的方法包括:将白及块茎粉末加入去离子水中,煎煮法提取,离心,沉淀物重复提取两次,收集上清液,用旋转蒸发器在真空下浓缩,将浓缩得到的浓缩液缓慢倒入无水乙醇中,在冰箱中醇沉过夜,离心收集沉淀物,再经冷冻真空干燥得到白及葡甘聚糖。
优选的是,其中,所述步骤一中,白及块茎粉末与去离子水的质量体积比为1g:40mL;煎煮法提取时间为60min,煎煮后离心转速为5000rpm,离心时间为10min;用旋转蒸发器进行真空浓缩的温度为80℃,浓缩液与无水乙醇的体积比为1:3;冰箱醇沉过夜的温度为4℃。
优选的是,其中,所述步骤二中,制备氧化白及葡甘聚糖的方法包括:向白及葡甘聚糖溶液中加入一定物质量的NaIO4,室温避光下反应,加入与NaIO4等物质量的乙二醇溶液,继续搅拌2h终止反应,离心;上清液经截流量为3kDa的透析袋于蒸馏水中透析48h后进行冷冻真空干燥,获得氧化白及葡甘聚糖。
优选的是,其中,所述步骤二中,白及葡甘聚糖溶液的浓度为2%(w/v);NaIO4与白及葡甘聚糖的摩尔比为0.2:1;室温下避光反应时间为24h,并以300r/min的转速进行搅拌。
优选的是,其中,所述步骤三中,氧化白及葡甘聚糖溶液的浓度为2.5%(w/v),水浴温度为80℃;将AgNO3溶液滴加到氧化白及葡甘聚糖溶液中并搅拌混合均匀,然后在90℃水浴下避光搅拌60min后自然冷却至室温;AgNO3溶液与氧化白及葡甘聚糖溶液的体积比为1:10,反应体系中AgNO3的浓度为0.01~1.0%(w/v);离心收集悬浮液的离心转速为10000rpm,离心时间为15min;冷冻真空干燥的温度为-80℃,真空度小于10Pa,冷冻真空时间为48h。
优选的是,其中,所述步骤四中,聚乙烯醇溶液的水浴温度为90℃,聚乙烯醇溶液的浓度为6.25%(w/v),硼砂溶液的质量分数为0.5%,聚乙烯醇溶液与硼砂溶液的体积比为4:1氧化白及葡甘聚糖与氧化白及葡甘聚糖纳米银复合物的质量比为1:0~1。
优选的是,其中,所述步骤三中,将AgNO3滴加到氧化白及葡甘聚糖溶液中后,先超声分散20~60min,超声频率为30~75kHz;然后以2℃/min的速度升温至90℃,在90℃水浴下避光搅拌60min后,以5℃/min的降温速率降温至25℃。
一种自愈合性氧化白及葡甘聚糖复合水凝胶的应用,所述自愈合性氧化白及葡甘聚糖复合水凝胶应用于抑制大肠杆菌、金黄色葡萄球菌的生长繁殖。
一种自愈合性氧化白及葡甘聚糖复合水凝胶的应用,所述自愈合性氧化白及葡甘聚糖复合水凝胶应用于伤口创面的抗菌、止血、愈合。
本发明至少包括以下有益效果:本发明提供的一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,将氧化白及葡甘聚糖、氧化白及葡甘聚糖纳米银复合物、聚乙烯醇和硼砂溶液混合后经过交联反应而得;所述氧化白及葡甘聚糖是白及葡甘聚糖经高碘酸钠氧化所得,氧化白及葡甘聚糖纳米银复合物是氧化白及葡甘聚糖原位还原硝酸银所得。该水凝胶为三维多孔网状结构,有利于吸收伤口多余渗液,并能提供湿润的创面愈合环境;同时,该水凝胶具有自愈合性、可注射性以及性状适应性,并能够适应关节活动,具有处理关节皮肤创伤以及不规则创面的潜力;此外,该水凝胶生物相容性良好,固有的抗菌性能和止血性能优异,能够促进感染创面愈合。本发明的载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶在临床创面修复和止血处理方面具有良好的应用前景,有望发展成为一种新型的医用敷料。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为PB水凝胶、PBR1.0水凝胶和实施例1制备的PBR1.0@OAg0.25水凝胶的红外图谱;
图2为PB水凝胶、PBR水凝胶和实施例1制备的PBR1.0@OAg0.25水凝胶的扫描电镜图;
图3为实施例1制备的PBR1.0@OAg0.25水凝胶的吸水溶胀曲线;
图4为实施例1制备的PBR1.0@OAg0.25水凝胶的自愈合性测试示意图;
图5为实施例1制备的PBR1.0@OAg0.25水凝胶的可注射性测试示意图;
图6为实施例1制备的PBR1.0@OAg0.25水凝胶的形状适应性测试示意图;
图7为实施例1制备的PBR1.0@OAg0.25水凝胶的关节运动适应性测试示意图;
图8为应变在1%和200%周期交替变化下PBR1.0@OAg0.25水凝胶的模量变化;
图9为实施例1制备的PBR1.0@OAg0.25水凝胶的剪切稀化行为示意图;
图10为实施例1制备的PBR1.0@OAg0.25水凝胶、实施例2制备的PBR1.0@OAg0.25水凝胶、实施例3制备的PBR1.0@OAg0.25水凝胶、PBR1.0和PB水凝胶对大肠杆菌的抗菌活性示意图;
图11为实施例1制备的PBR1.0@OAg0.25水凝胶、实施例2制备的PBR1.0@OAg0.25水凝胶、实施例3制备的PBR1.0@OAg0.25水凝胶、PBR1.0水凝胶和PB水凝胶对金黄色葡萄球菌的抗菌活性示意图;
图12为实施例1制备的PBR1.0@OAg0.25水凝胶、PB水凝胶和PBR1.0水凝胶的肝失血量测试结果示意图;
图13为实施例1制备的PBR1.0@OAg0.25水凝胶、PB水凝胶和PBR1.0水凝胶的肝止血时间测试结果示意图;
图14为PB水凝胶、市售对照组、PBR1.0水凝胶和PBR1.0@OAg0.25水凝胶治疗再生皮肤的组织学分析示意图。
具体实施方式
下面结合附图对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
应当理解,本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它元件或其组合的存在或添加。
实施例1
本实施例提供了一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,包括以下步骤:
步骤一、提取白及葡甘聚糖(RBP):将10g白及块茎粉末加入400mL去离子水中,煎煮法提取60min后5000rpm离心10min,沉淀物重复提取两次。收集上清液,用旋转蒸发器在80℃真空下浓缩。浓缩液缓慢倒入3倍体积的无水乙醇中,在4℃冰箱醇沉过夜。离心收集沉淀物,再经冷冻真空干燥得到白及葡甘聚糖(RBP);
步骤二、制备氧化白及葡甘聚糖(ORBP):准备2%(w/v)浓度的RBP溶液,加入一定物质量的NaIO4,NaIO4与氧化白及葡甘聚糖的摩尔比为0.2:1,室温避光下反应24h,同时以300r/min的转速搅拌,加入与NaIO4等物质量的乙二醇溶液,继续搅拌2h终止反应,离心。上清液经截留分子量为3kDa的透析袋于蒸馏水中透析48h后进行冷冻真空干燥,获得氧化白及葡甘聚糖(ORBP);
步骤三、制备氧化白及葡甘聚糖纳米银复合物(OAg):将适量ORBP溶于去离子水中,80℃水浴下搅拌均匀,形成2.5%(w/v)的ORBP溶液。室温条件下,将2.5mL 5%(w/v)的AgNO3溶液滴加到25mL ORBP溶液中并搅拌混合均匀,并在90℃水浴下避光搅拌60min。结束后,自然冷却至室温,以10000rpm离心15min,收集悬浮液并经冷冻真空干燥获得OAg;冷冻真空干燥的温度为-80℃,真空度小于10Pa,冷冻真空时间为48h。
步骤四、制备载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶(PBR@OAg)即自愈合性氧化白及葡甘聚糖复合水凝胶:先将PVA在90℃水浴下溶解在去离子水中,得到6.25%(w/v)的PVA溶液。然后,将一定量的ORBP和OAg溶解到PVA溶液中获得均匀的混合液。最后,在磁力搅拌状态下,按体积比4:1(6.25% PVA:0.5%硼砂)加入0.5%的硼砂溶液得到自愈合性氧化白及葡甘聚糖复合水凝胶(PBR@OAg)。在PBR@OAg水凝胶配方中,ORBP的添加量1%,OAg的添加量依次为0‰、0.25‰、0.5‰和1.0‰,将本实施例制备的自愈合性氧化白及葡甘聚糖复合水凝胶命名PBR1.0@OAg0.25。
实施例2
本实施例提供的一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其与实施例1不同之处为在步骤四中,OAg的添加量为0.5‰,其与余制备过程与实施例1相同,将本实施例制备的自愈合性氧化白及葡甘聚糖复合水凝胶命名PBR1.0@OAg0.5。
实施例3
本实施例提供的一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其与实施例1不同之处为在步骤四中,OAg的添加量为1.0‰,其余制备过程与实施例1相同,将本实施例制备的自愈合性氧化白及葡甘聚糖复合水凝胶命名PBR1.0@OAg1.0。
实施例4
本实施例提供的一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其与实施例1不同之处为在步骤三中,将AgNO3滴加到氧化白及葡甘聚糖溶液中后,先超声分散20min,超声频率为30kHz;然后以2℃/min的速度升温至90℃,在90℃水浴下避光搅拌60min后,以5℃/min的降温速率降温至25℃,其余制备方法与实施例1相同,将本实施例制备得到的自愈合性氧化白及葡甘聚糖复合水凝胶记为PBR1.0@OAg0.25-1。
实施例5
本实施例提供的一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其与实施例1不同之处为在步骤三中,将AgNO3滴加到氧化白及葡甘聚糖溶液中后,先超声分散60min,超声频率为75kHz;然后以2℃/min的速度升温至90℃,在90℃水浴下避光搅拌60min后,以5℃/min的降温速率降温至25℃,其余制备方法与实施例1相同,将本实施例制备得到的自愈合性氧化白及葡甘聚糖复合水凝胶记为PBR1.0@OAg0.25-2
对比例1
本对比例提供的一种PBR水凝胶的制备方法,其与实施例1不同之处为在步骤四中未添加OAg,其余制备过程与实施例1相同,将本对比例例制备的自愈合性氧化白及葡甘聚糖复合水凝胶命名PBR1.0。
对比例2
本对比例提供了一种不含氧化白及葡甘聚糖(ORBP)和氧化白及葡甘聚糖纳米银复合物(OAg)的PB水凝胶的制备方法,包括:先将聚乙烯醇(PVA)在90℃水浴下溶解在去离子水中,得到6.25%(w/v)的PVA溶液。然后在磁力搅拌状态下,按体积比4:1(6.25% PVA:0.5%硼砂)加入0.5%的硼砂溶液得到PB水凝胶。
(一)红外分析
分析方法:将水凝胶分别采用溴化钾圆盘压片法制样,在傅立叶变换红外光谱仪(Nicolet 6700,Thermo Scientific,USA)上进行扫描获得红外图谱,扫描范围400-4000cm-1,分辨率4cm-1。测试结果如图1所示。
所有水凝胶中都观察到在1425cm-1和1328cm-1处属于B-O-C的不对称伸缩振动峰,表明硼砂与PVA链间形成了硼酸酯键。PB水凝胶在3425cm-1处的吸收峰归属于PVA中的羟基(O-H)拉伸及其参与形成的氢键。将ORBP引入PB体系后,在PBR水凝胶中观察到羟基峰蓝移至3405cm-1处,表明ORBP与PVA之间形成了更强的氢键。而继续引入ORBP-Ag后,羟基峰出现了轻微的红移(3413cm-1),表明ORBP-Ag与PBR体系形成的氢键强度减弱。这些结果表明PBR@OAg复合水凝胶网络是基于硼酸酯键和氢键构建的。
(二)扫描电镜测试
分析方法:将冻干水凝胶样品经液氮脆断后借助双面碳带将其固定在试样架上,并在真空中使用离子溅射系统(SC7620,Emitech,Great Britain)用金溅射180s,然后用扫描电子显微镜(EVO 18,Zeiss,Germany)检查水凝胶的微观形貌特征。测试结果如图2所示。
所有水凝胶都具有明显的蜂窝网状内部网孔,但孔结构差异明显。PB水凝胶主要由含密集小孔的片层状结构组成。当引入ORBP后,PBR水凝胶和PBR@OAg水凝胶呈现出更大孔径的、不规则的开放网孔结构。
(三)吸水溶胀性能
测试方法:将冻干的PBR@OAg水凝胶样品(M0,g)浸入PBS缓冲液中放于37℃下孵育,在不同时间点取出水凝胶样品并去除表面多余的水分,称量记录重量(MS,g)。按下面公式计算溶胀率:溶胀率(%)=(MS-M0)/M0×100%,实验结果如图3所示。PBR@OAg水凝胶在120min内可达到溶胀平衡,溶胀率高达300%,具有良好的吸水溶胀性能,有利于伤口渗出液处理和维持湿润的愈合环境。
(四)自愈合性、可注射性、形状适应性和关节活动适应性
自愈合性测试方法:通过宏观和定量实验来评估了水凝胶的自愈合能力。对于宏观自愈试验,先将直径为1cm的圆盘状水凝胶对半切开,然后将2块半圆水凝胶边缘接触,在无外力作用下自愈合1min后,用镊子夹住水凝胶两端进行拉伸并拍照记录,结果如图4所示。此外,还用流变仪对水凝胶进行了定量测试。在固定的角频率(1Hz)下,通过交替应变扫描研究水凝胶圆盘的自愈行为。将振荡应变从小应变(γ=1.0%,每个间隔60s)切换为大应变(γ=200%,每个间隔60s),进行3个循环。测试结果如图8所示。
可注射性测试方法:先将制备好的PBR@OAg水凝胶装入注射器中,通过注射的方式书写单词“SWUST”并拍照记录,结果如图5所示。此外,还通过流变仪定量分析了水凝胶的剪切稀化行为,结果如图9所示。
形状适应性测试方法:PBR@OAg水凝胶先放入方形模具中成形,然后将方形水凝胶装入注射器中并通过注射到圆形模具中再次成形来验证水凝胶的性状适应性,过程和结果通过拍照记录,结果如图6所示。
关节活动适应性测试方法:通过将PBR@OAg水凝胶敷在指关节和肘关节处,通过不同角度的弯曲变化来验证水凝胶适应关节活动的能力,拍照记录了过程,结果如图7所示。
如图4所示,两块独立凝胶在无任何干扰条件下接触1min后,块体凝胶又成为一体,在重力作用或拉伸情况下仍能保持完整的形状。此外,如图8所示,在1%低应变下水凝胶的G'>G”,表明水凝胶为凝胶态。当应变切换到200%高应变后,水凝胶的G'约从800Pa下降到300Pa左右,且G'<G”,表明凝胶网络被破坏。但应变恢复1%低应变后,G'和G”几乎又能完全恢复到初始的模量,表明水凝胶网络有重新建立。这些结果表明水凝胶具有优异的自愈合/修复能力。
如图5所示,水凝胶通过注射器注射成功书写了单词“SWUST”。此外,如图9所示,水凝胶的表观粘度随着剪切速率的增大而降低,表明剪切破坏了凝胶网络中的动态交联,使其向流体态转变。这些结果表明PBR@OAg水凝胶具有可注射性。
图6显示了方形水凝胶通过注射器注射到圆形模具后,无外界干扰条件下1min内能够重新形成圆形水凝胶,这表明水凝胶具有良好的形状适应性。
如图7所示,将PBR@OAg水凝胶分别应用于在指关节和肘关节,实验者在0-180°间自由弯曲活动,没有任何阻力,这验证了PBR@OAg水凝胶作为关节皮肤伤口敷料的实际用途。
三、载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶的用途
(一)抗菌活性
测试方法:以大肠杆菌(E.coli,ATCC 25922)和金黄色葡萄球菌(S.aureus,ATCC6538)为受试菌,通过直接接触法来测试了水凝胶的表面抗菌活性。将200μL灭菌好的水凝胶前体溶液加入到48孔板中(n=3),待水凝胶完全形成后,将5μL细菌悬液(105-106CFU/mL)加到水凝胶表面,放入37℃培养箱中孵育3h。结束后,每孔加入1mL PBS,使残存细菌重悬形成的菌悬液。将5μL细菌悬液(105-106CFU/mL)加入1mL PBS中获得细菌悬液作为对照组。最后,将每组最终细菌悬液10μL滴在LB固体培养基上,放入37℃培养箱孵育18~24h后,计数各组平板上的菌落数。按下面公式计算杀菌率:杀菌率(%)=(对照组菌落数-水凝胶组菌落数)/对照组菌落数×100%,杀菌率测试结果如图10、图11所示;图10中PBR1.0@OAg0.25对大肠杆菌的杀菌率为95.45%,实施例4制备得到的PBR1.0@OAg0.25-1对大肠杆菌的杀菌率为98.85%。
PB水凝胶对大肠杆菌(E.coli)和金黄色葡萄球菌(S.aureus)均无抗菌活性。添加ORBP后的PBR1.0水凝胶表现出一定的抗菌活性,对E.coli和S.aureus的杀灭率分别为74%和71%。同时添加ORBP和ORBP-Ag后的PBR@OAg复合水凝胶的抗菌活性得到显著提高。ORBP-Ag添加量仅为0.5‰(PBR1.0@OAg0.5)时,PBR@OAg复合水凝胶对E.coli和S.aureus的杀灭率均超过了99.9%。因此,载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶具有优异的抗菌活性,有望在伤口护理过程中防止细菌造成创面感染。
(二)止血性能
肝脏止血试验:将昆明小鼠麻醉后固定在泡沫板上,并倾斜大约45o,剖开小鼠腹部,暴露肝,用滤纸先去除腹腔内多余液体并将含有蜡膜的滤纸放于肝叶下以防止伤口外液体的吸收,然后将预先称重的滤纸置于肝脏下方。先用3mm直径的活检冲头在肝叶中部造成的肝缺损出血模型,出血后开始计时,并用水凝胶填充肝缺损部位进行止血处理,出血后未经处理为对照组。停止出血后暂停计时并通过称重法量化各组失血量。肝失血量和止血时间测试结果见图12和图13:
所有水凝胶组的失血量和止血时间均显著低于对照组。在所有水凝胶组中,PBR1.0组和PBR1.0@OAg0.25组的失血量和止血时间相近,均显著低于PB组,表现出更好的止血能力。含ORBP的水凝胶组(PBR1.0组和PBR1.0@OAg0.25组)的失血量约为对照组的0.25倍,约为PB组的0.43倍。含ORBP的水凝胶组分别比对照组和PB组缩短了近115秒和50秒。这些结果表明载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶具有良好的止血性能,具有作为止血材料的潜力。
(三)促创面愈合性能
1.金黄色葡萄球菌(S.aureus)感染的全层皮肤缺损小鼠模型建立和治疗
用于评估载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶促感染伤口愈合的能力。实验在雌性昆明小鼠中进行,体重约为25g。所有动物实验均经西南科技大学实验动物管理与伦理委员会批准,并按《实验动物护理与使用指南》执行。
所有昆明小鼠(雌性,约25g,达硕)驯化一周后,用剃毛器剃去背部毛发。小鼠随机分为4组,每组9只。小鼠腹腔注射水合氯醛麻醉后,在脊柱一侧制作直径1cm的全层皮肤缺损创面。此后,将100μL S.aureus(108CFU/mL)滴加至伤口处建立感染。感染24h后,小鼠创面分别用市售银离子抗菌凝胶(Ag+crossingTM,对照组)、PB水凝胶、PBR1.0水凝胶、PBR1.0@OAg0.25和PBR1.0@OAg0.25-1水凝胶进行治疗。实验期间间隔2天更换一次敷料,在第0、5、10和14天拍摄伤口部位记录创面愈合情况并用ImageJ软件量化伤口面积。
2.伤口愈合率
按下面公式计算伤口愈合率(%):伤口愈合率(%)=(S0-Sn)/S0×100%
式中,S0表示初始伤口面积,Sn表示不同处理n天后伤口面积(n=5、10或14)。
不同治疗组的伤口愈合率结果见表1:
表1各治疗组伤口愈合率统计
通过各治疗组伤口愈合率的统计结果可以看出,PB水凝胶组的伤口愈合率在整个愈合过程中都落后于Ag+crossingTM组(对照组),伤口愈合速度最慢。只添加ORBP的PBR1.0水凝胶组表现出与对照组相近的伤口愈合率。而同时添加ORBP和ORBP-Ag的PBR1.0@OAg0.25和PBR1.0@OAg0.25-1水凝胶组(载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶组)在整个愈合过程中都处于领先,伤口愈合率显著高于其余组,在治疗14天后伤口就已完全愈合,这说明该复合水凝胶具有良好的促进感染创面愈合能力。
3.新生皮肤的组织学分析
组织学分析:治疗14天后,对小鼠实施安乐死,收集新生皮肤组织并用4%多聚甲醛固定,然后包埋在石蜡中并横切为5μm厚的切片,最后切片分别进行苏木精-伊红(HE)染色和马森三色(Masson)染色。所有切片在显微镜下观察并拍照记录,组织学分析结果见图14。
在治疗14天后,相比于市售敷料对照组(Ag+crossingTM)、PB水凝胶组和PBR1.0水凝胶组,PBR1.0@OAg0.25水凝胶组(载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶组)的表皮最薄且更加规则,表明该组再上皮化更快。此外,PBR1.0@OAg0.25水凝胶组形成了更多的血管和毛囊、汗腺等皮肤附件,以及成熟胶原蛋白的沉积更多,表明该组皮肤的重建质量更高。因此,组织学分析结果表明载银氧化白及葡甘聚糖-聚乙烯醇复合水凝胶能显著促进感染创面愈合和高质量功能性皮肤的重建,具有作为新型伤口敷料的潜力
这里说明的设备数量和处理规模是用来简化本发明的说明的。对本发明的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节和这里示出与描述的图例。
Claims (10)
1.一种自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,包括以下步骤:
步骤一、提取白及葡甘聚糖;
步骤二、制备氧化白及葡甘聚糖;
步骤三、将氧化白及葡甘聚糖溶于去离子水中,水浴搅拌形成氧化白及葡甘聚糖溶液,将AgNO3溶液滴加到氧化白及葡甘聚糖溶液中并搅拌混合均匀,然后在水浴下避光搅拌后自然冷却至室温,离心收集悬浮液,最后经冷冻真空干燥获得氧化白及葡甘聚糖纳米银复合物;
步骤四、先将聚乙烯醇在水浴下溶解在去离子水中,得到聚乙烯醇溶液;然后将的氧化白及葡甘聚糖和氧化白及葡甘聚糖纳米银复合物溶解到聚乙烯醇溶液中获得均匀的混合液;最后,在磁力搅拌状态下,向混合液中加入硼砂溶液得到自愈合性氧化白及葡甘聚糖复合水凝胶。
2.如权利要求1所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤一中,提取白及葡甘聚糖的方法包括:将白及块茎粉末加入去离子水中,煎煮法提取,离心,沉淀物重复提取两次,收集上清液,用旋转蒸发器在真空下浓缩,将浓缩得到的浓缩液缓慢倒入无水乙醇中,在冰箱中醇沉过夜,离心收集沉淀物,再经冷冻真空干燥得到白及葡甘聚糖。
3.如权利要求2所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤一中,白及块茎粉末与去离子水的质量体积比为1g:40mL;煎煮法提取时间为60min,煎煮后离心转速为5000rpm,离心时间为10min;用旋转蒸发器进行真空浓缩的温度为80℃,浓缩液与无水乙醇的体积比为1:3;冰箱醇沉过夜的温度为4℃。
4.如权利要求1所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤二中,制备氧化白及葡甘聚糖的方法包括:向白及葡甘聚糖溶液中加入一定物质量的NaIO4,室温避光下反应,加入与NaIO4等物质量的乙二醇溶液,继续搅拌2h终止反应,离心;上清液经截流量为3kDa的透析袋于蒸馏水中透析48h后进行冷冻真空干燥,获得氧化白及葡甘聚糖。
5.如权利要求4所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤二中,白及葡甘聚糖溶液的浓度为2%(w/v);NaIO4与白及葡甘聚糖的摩尔比为0.2:1;室温下避光反应时间为24h,并以300r/min的转速进行搅拌。
6.如权利要求1所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤三中,氧化白及葡甘聚糖溶液的浓度为5%(w/v),水浴温度为80℃;将AgNO3溶液滴加到氧化白及葡甘聚糖溶液中并搅拌混合均匀,然后在90℃水浴下避光搅拌60min后自然冷却至室温;AgNO3溶液与氧化白及葡甘聚糖溶液的体积比为1:10,反应体系中AgNO3的浓度为0.01~1.0%(w/v);离心收集悬浮液的离心转速为10000rpm,离心时间为15min;冷冻真空干燥的温度为-80℃,真空度小于10Pa,冷冻真空时间为48h。
7.如权利要求1所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤四中,聚乙烯醇溶液的水浴温度为90℃,聚乙烯醇溶液的浓度为6.25%(w/v),硼砂溶液的质量分数为0.5%,聚乙烯醇溶液与硼砂溶液的体积比为4:1氧化白及葡甘聚糖与氧化白及葡甘聚糖纳米银复合物的质量比为1:0~1。
8.如权利要求1所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法,其特征在于,所述步骤三中,所述步骤三中,将AgNO3滴加到氧化白及葡甘聚糖溶液中后,先超声分散20~60min,超声频率为30~75kHz;然后以2℃/min的速度升温至90℃,在90℃水浴下避光搅拌60min后,以5℃/min的降温速率降温至25℃。
9.一种自愈合性氧化白及葡甘聚糖复合水凝胶的应用,所述自愈合性氧化白及葡甘聚糖复合水凝胶由权利要求1-8任一项所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法制备得到,其特征在于,所述自愈合性氧化白及葡甘聚糖复合水凝胶应用于抑制大肠杆菌、金黄色葡萄球菌的生长繁殖。
10.一种自愈合性氧化白及葡甘聚糖复合水凝胶的应用,所述自愈合性氧化白及葡甘聚糖复合水凝胶由权利要求1-8任一项所述的自愈合性氧化白及葡甘聚糖复合水凝胶的制备方法制备得到,其特征在于,所述自愈合性氧化白及葡甘聚糖复合水凝胶应用于伤口创面的抗菌、止血、愈合。
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