CN114748685A - 具有促进烫伤和急性创面愈合功能的水凝胶制备方法及其应用 - Google Patents
具有促进烫伤和急性创面愈合功能的水凝胶制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种具有促进烫伤和急性创面愈合功能的水凝胶制备方法及其应用,该方法将卵白蛋白溶于乙二胺四乙酸溶液中,持续搅拌得到反应溶液,搅拌过程中向反应溶液中逐滴滴加2‑亚氨基硫烷盐酸盐,持续搅拌反应,得到均匀的改性OVA溶液,再制备tOVA前体溶液和tGel前体溶液;将tOVA前体溶液和tGel前体溶液混合,搅拌均匀,得到tOVA/tGel混合溶液体系;向混合溶液体系中边搅拌边滴加硝酸银溶液,继续搅拌,得到预凝胶溶液,最后将预凝胶溶液快速倒入模具中放置,即得到水凝胶。本发明的组织粘附水凝胶,原料廉价易得,制作简单且周期短,愈合条件简单、愈合效果好,在用于创面时可直接使用。
Description
技术领域
本发明涉及卵白蛋白水凝胶的制备方法,具体涉及一种具有促进烫伤和急性创面愈合功能的水凝胶制备方法及其应用。
背景技术
水凝胶材料具有类似于细胞外基质的结构、高亲水性、防粘黏等优点。传统的伤口敷料为干燥材质,易粘连伤口,无抗菌抗感染功能,不能够满足理想伤口敷料的标准。水凝胶因其特殊的性能成为现代伤口敷料的理想候选材料。
目前常见的水凝胶敷料以合成聚合物为主,需要额外负载抗生素类药品以达到抗炎抗感染的目的,这可能会导致生物安全性以及抗生素滥用的问题。与合成聚合物水凝胶相比,蛋白质基水凝胶具有出色的功能特性,如两亲性、生物相容性等,可以降低生物医学应用中的毒性风险。银离子具有强大的广谱抗菌性,降低由抗生素滥用导致的多重耐药细菌感染,同时,可以通过金属配位作用与蛋白质交联,形成坚固的水凝胶支架。
发明内容
本发明的目的在于克服现有技术的不足,提供了一种具有促进烫伤和急性创面愈合功能的水凝胶制备方法,该方法能够简单、快速和高效的化学方法提升卵白蛋白的巯基化程度,通过配位作用使银离子与改性蛋白、明胶交联形成-SAg,从而制备水凝胶材料,通过系统对凝胶化性能、银离子缓释效果、抑菌效果进行评价,大大提升水凝胶对急性创面和烫伤的愈合功能。
为实现上述目的,本发明所设计一种具有促进烫伤和急性创面愈合功能的水凝胶制备方法,包括以下步骤:
1)按重量份数比称取100份的卵白蛋白(OVA)和2~25份的2-亚氨基硫烷盐酸盐,备用;
2)将卵白蛋白溶于乙二胺四乙酸溶液中,持续搅拌得到反应溶液,搅拌过程中向反应溶液中逐滴滴加2-亚氨基硫烷盐酸盐,持续搅拌反应,得到均匀的改性OVA溶液,其中,所述乙二胺四乙酸溶液是由将乙二胺四乙酸(EDTA)溶于磷酸盐缓冲液(PBS)制备而成;
3)将改性OVA溶液透析纯化,最后真空冷冻干燥得到改性OVA粉末(即为巯基化卵白蛋白,简称tOVA);
4)按重量份数比称取10~100份的改性OVA粉末(tOVA)、10~100份的巯基化明胶(tGel)和3~8份的硝酸银;
5)将改性OVA粉末和巯基化明胶分别溶于乙酸钠-乙酸缓冲液中,恒温水浴搅拌过夜,分别得到tOVA前体溶液和tGel前体溶液;同时,将硝酸银溶于水中,得到硝酸银溶液;
6)将tOVA前体溶液和tGel前体溶液混合,搅拌均匀,得到tOVA/tGel混合溶液体系;向混合溶液体系中边搅拌边滴加硝酸银溶液,继续搅拌,得到预凝胶溶液,最后将预凝胶溶液快速倒入模具中放置,即得到tOVA/tGel@Ag水凝胶。
进一步地,所述步骤1)中,卵白蛋白和2-亚氨基硫烷盐酸盐重量份数分别为100份和4~20份。
再进一步地,所述步骤1)中,卵白蛋白和2-亚氨基硫烷盐酸盐重量份数分别为100份和20份。
再进一步地,所述步骤2)中,乙二胺四乙酸溶液中,乙二胺四乙酸浓度为3mmol/L~10mmol/L。
再进一步地,所述步骤2)中,搅拌条件为:
温度为4℃,转速为100rpm,总搅拌时间为6h。
再进一步地,所述步骤3)中,透析纯化时间为2~3d。
再进一步地,所述步骤4)中,改性OVA粉末、巯基化明胶和硝酸银的重量份数分别为30~70份、30~70份和5.1份。
再进一步地,所述改性OVA粉末、巯基化明胶和硝酸银的重量份数分别为30份、70份和5.1份。
再进一步地,所述改性OVA粉末、巯基化明胶和硝酸银的重量份数分别为50份、50份和5.1份。
再进一步地,所述步骤5)中,乙酸钠-乙酸缓冲液的pH值为5.0-7.0;
改性OVA粉末溶于乙酸钠-乙酸缓冲液时,恒温水浴温度为4℃;
巯基化明胶tGel分别溶于乙酸钠-乙酸缓冲液时,恒温水浴温度为40~45℃。
本发明还提供了一种上述的方法制备的水凝胶在制备组织工程材料中的应用,所述组织工程材料为医用伤口敷料或细胞支架(该组织工程材料具有促进烫伤和急性创面愈合功能)。
本发明的有益效果:
本发明引入生物相容性高、吸水能力优异的天然生物材料卵白蛋白质和明胶为主体材料,通过巯基化反应提高卵白蛋白和明胶的游离巯基含量。巯基与Ag+通过配位作用构建稳固交联的三维网络;并将功能硝酸银均匀分散在支架中,在低温条件下快速成胶。功能Ag+能有效缓解抑制病原微生物,并控制伤口的氧化应激微环境。同时,交联的天然蛋白质具有良好的凝胶性能,具有较高的机械强度与粘附强度,能提供自愈合性。可模拟组织细胞基质中的蛋白成分构建仿生组织工程多孔支架,能够有效促进损伤后组织的再生与重建。本发明的组织粘附水凝胶,原料廉价易得,制作简单且周期短,愈合条件简单、愈合效果好,在用于创面时可直接使用。
附图说明
图1为OVA和改性OVA的紫外吸收光谱图(A)和游离巯基含量图(B);
图中,control代表未改性的天然OVA,1代表改性OVA粉末1,2代表改性OVA粉末2,3代表改性OVA粉末3;
图2为实施例2~4和对比例1~2制备的水凝胶的对比照片;
图中,A为水凝胶O10的照片、B为水凝胶O7G3的照片、C为水凝胶O5G5的照片、D为水凝胶O3G7的照片、E为水凝胶G10的照片;
图3为实施例2~4和对比例1~2制备的水凝胶的扫描电镜图;
图中,A为水凝胶O10、B为水凝胶O7G3、C为水凝胶O5G5、D为水凝胶O3G7、E为水凝胶G10;
图4为不同水凝胶的T2弛豫曲线图(A)、T2弛豫时间图(B)和T2组分的峰面积图(C);
图5为在37℃条件下,0-7天内从水凝胶中释放银离子的累积释放曲线图;
图6为各组小鼠急性创面不同时间点的代表性照片;
图中,Control为空白对照、YIFU为市售凝胶、O5G5和O3G7为5:5和3:7的水凝胶,比例尺:2mm;
图7为水凝胶促进小鼠烫伤伤口愈合情况图(第0、3、7、14天);
图中,MEBO为市售烫伤膏、Control为空白对照、O3G7为3:7的水凝胶,比例尺:2mm;
图8为水凝胶处理小鼠的主要脏器(心脏、肝脏、脾脏、肺和肾脏)苏木精-伊红染色显微照片(比例尺:100μm)。
具体实施方式
下面结合具体实施例对本发明作进一步的详细描述,以便本领域技术人员理解。
实施例1
一种改性OVA粉末1~3的制备方法,包括以下步骤:
1)按改性OVA粉末的原料比例表1分别称取卵白蛋白OVA和2-亚氨基硫烷盐酸盐,备用;
表1
卵白蛋白(OVA) | 2-亚氨基硫烷盐酸盐 | |
改性OVA粉末1(tOVA1) | 100mg | 4mg |
改性OVA粉末2(tOVA2) | 100mg | 12mg |
改性OVA粉末3(tOVA3) | 100mg | 20mg |
2)将卵白蛋白(OVA)溶于乙二胺四乙酸溶液中,在温度为4℃,转速为100rpm条件下持续搅拌3h,得到反应溶液,搅拌过程中向反应溶液中逐滴滴加2-亚氨基硫烷盐酸盐,持续搅拌3h反应,得到均匀的改性OVA溶液,其中,所述乙二胺四乙酸溶液是将乙二胺四乙酸(EDTA)溶于磷酸盐缓冲液(PBS)制备而成;乙二胺四乙酸溶液中,乙二胺四乙酸浓度为5mmol/L;
3)使用透析系统(MWCO 8000)将改性OVA溶液透析纯化3d,最后真空冷冻干燥得到改性OVA粉末1~3(tOVA1~3);保存在-20℃下,备用。
上述改性OVA粉末1~3(tOVA1~3)进行游离巯基测定:
使用Ellman测定卵白蛋白和改性卵白蛋比的游离巯基含量(Ellman,1959):
1.首先用Tris-glycine缓冲液溶解tOVA1~3(Tris 10.4g/L,glycine6.9g/L,EDTA 1.2g/L,pH为8.0),分别配制浓度为4mg/mL的样品溶液。
2.将不同的2mL样品溶液与100μL Ellman试剂(4mg/mL,溶解于上述Tris-glycine缓冲液中)混合;将混合物在25℃黑暗中孵育0.5小时后,使用紫外/可见分光光度计(Nanodrop-2000C,Thermo Scientific,Waltham,USA)在412nm记录样品溶液的吸光度。
如图1A~B所示:随着改性剂(2-亚氨基硫烷盐酸盐)添加量的增加,tOVA1~3在412nm处的紫外吸收强度显著增强,意味着游离巯基含量显著增加,这有利于形成更多的-SAg配位键,从而构建致密稳定的三维网络结构。但当改性剂添加量超过卵白蛋白质量的1/5时,会对蛋白质结构产生不良影响,因此,tOVA3效果最好。
实施例2
一种具有促进烫伤和急性创面愈合功能的水凝胶1制备方法,包括以下步骤:
1)称取70mg的tOVA3、30mg份的巯基化明胶tGel和5.1mg的硝酸银;
2)将tOVA3溶于乙酸钠-乙酸缓冲液中,在温度为4℃的恒温水浴锅搅拌过夜,得到tOVA前体溶液;巯基化明胶tGel分别溶于乙酸钠-乙酸缓冲液中,在温度为40℃的恒温水浴锅搅拌过夜,得到tGel前体溶液;其中,乙酸钠-乙酸缓冲液的pH值为5.0-7.0;
同时,将硝酸银溶于水中,得到浓度为0.1mol/L的硝酸银溶液;
3)将tOVA前体溶液和tGel前体溶液混合,搅拌5min,得到tOVA/tGel混合溶液体系;向混合溶液体系中边搅拌边滴加硝酸银溶液,继续搅拌,得到预凝胶溶液,最后将预凝胶溶液快速倒入聚四氟乙烯圆盘模具中并在温度为37℃下放置,即得到tOVA/tGel@Ag水凝胶1,即为O7G3。
实施例3
本实施例3制备的水凝胶2(O5G5)与实施例2制备的方法基本相同,不同之处在于:
称取tOVA3、巯基化明胶tGel和硝酸银质量分别为:50mg、50mg和5.1mg。
实施例4
本实施例4制备的水凝胶3(O3G7)与实施例2制备的方法基本相同,不同之处在于:
称取tOVA3、巯基化明胶tGel和硝酸银质量分别为:30mg、70mg和5.1mg。
对比例1
一种水凝胶O10制备方法,包括以下步骤:
1)称取100mg的tOVA3和5.1mg的硝酸银;
2)将tOVA3溶于乙酸钠-乙酸缓冲液中,在温度为4℃的恒温水浴锅搅拌过夜,得到tOVA前体溶液,其中,乙酸钠-乙酸缓冲液的pH值为5.0-7.0;
同时,将硝酸银溶于水中,得到浓度为0.1mol/L的硝酸银溶液;
3)向tOVA前体溶液中边搅拌边滴加硝酸银溶液,继续搅拌,得到预凝胶溶液,最后将预凝胶溶液快速倒入聚四氟乙烯圆盘模具中并在温度为37℃下放置,即得到水凝胶O10。
对比例2
一种水凝胶G10制备方法,包括以下步骤:
1)称取100mg的巯基化明胶tGel和5.1mg的硝酸银;
2)将巯基化明胶tGel溶于乙酸钠-乙酸缓冲液中,在温度为40℃的恒温水浴锅搅拌过夜,得到tGel前体溶液,其中,乙酸钠-乙酸缓冲液的pH值为5.0-7.0;
同时,将硝酸银溶于水中,得到浓度为0.1mol/L的硝酸银溶液;
3)向tGel前体溶液中边搅拌边滴加硝酸银溶液,继续搅拌,得到预凝胶溶液,最后将预凝胶溶液快速倒入聚四氟乙烯圆盘模具中并在温度为37℃下放置,即得到水凝胶G10。
上述实施例2~4和对比例1~2制备得到水凝胶O10、O7G3、O5G5、O3G7和G10进行性能检测:
1.水凝胶的凝胶状态对比
从图2A可以看出,添加银离子之后,O10溶液由原来的半透明状态转变为白色,说明发生了蛋白聚集,但仍处于溶液状态。而O7G3、O5G5、O3G7以及G10溶液迅速由溶液状态转化为凝胶状态(图2B、C、D和E)。从图3A可以看出,O10有一定程度的聚集,但没有形成完整的网络结构。O7G3水凝胶形成粗糙表面的多孔三维结构(图3B),O5G5水凝胶、O3G7和G10水凝胶显示典型的多孔的微观形态学(图3C、D、E),其中,O5G5的结构与O3G7相似,孔径较小且分布均匀。结果表明,O5G5和O3G7水凝胶的凝胶状态最好。
2.低场核磁(LF-NMR)
将水凝胶O10、O7G3、O5G5、O3G7和G10在室温下置于透明色谱瓶中,采用低场核磁的Carr-PurcellMeiboom-Gill(CPMG)脉冲序列测定凝胶样品溶胀过程中的横向弛豫时间(T2)分布,磁体强度为0.5T,质子共振频率为21.56MHz,90°脉冲宽度为2.8μs,180°脉冲宽度为6μs,用仪器自带的MultiExp Inv Analysis软件对CPMG指数衰减曲线进行反演,得到T2分布谱图。
从图4A、B中可以看出,在0.1~10000ms的弛豫时间内,O10、O7G3和G10的T2呈双峰分布。第一个峰在0.1~15ms(T21)对应束缚水,第二个峰在100~1300ms(T22)对应固定水和自由水之间的水状态。O5G5和O3G7水凝胶呈现三个峰,第一个峰(T21)代表结合水,第三个峰(T23)是第二个峰(T22)的肩峰,这两个峰代表了固定水和自由水之间的水态。从图4C中可以看出,水凝胶中T21的含量随着tGel含量的增加而逐渐增加,说明结合水的含量增加表明持水性增强。
3.水凝胶银离子缓释曲线
在PBS(pH=7.4)中检测到Ag+从水凝胶中的释放量。将OVA水凝胶(200μL)浸入37℃的4mL PBS中。在一定的时间间隔(2h、4h、6h、1d、2d、4d和7d),取出2mL溶液,并重新补充等量的新鲜PBS。按照GB11907-89的火焰原子吸收分光光度法测定银离子的释放,测量结果表示为银离子随时间释放的累积浓度,并通过三次测量取平均值得到最终数据。
如图5所示:各组水凝胶在第一天均表现出了快速Ag+的释放行为,并且在随后的2-7天内持续而缓慢释放Ag+。其中,O3G7水凝胶在第7天时Ag+的累积释放浓度达到9.3ppm左右。水凝胶网络受控制的侵蚀和溶解以及Ag+的均匀分布,有利于银从水凝胶网络中持续释放。研究表明,这种类型的缓释行为在短时间内有效地消除病原体,并获得持续稳定的Ag+来源以防止微生物进一步定植方面具有显著的优势。
综上所述:O5G5和O3G7水凝胶的凝胶性能最好,水分分布情况较好,能够释放较多的银离子从而实现优良的抑菌效果。
实施例5上述实施例制备的水凝胶O5G5和O3G7的应用
1.小鼠背部全层皮肤损伤模型
首先,腹腔注射10%水合氯醛(350mg/kg)对小鼠进行麻醉,剃光小鼠背部的毛发并用75%乙醇对背部脱毛区皮肤进行消毒,使用直径为6mm的灭菌皮肤活检打孔器在小鼠背部按出印记,然后使用剪刀按照印记制造全层皮肤损伤的急性创面,其直径为6mm。对小鼠进行称重之后加样:Control组未采取任何治疗措施;YIFU组在创面表面均匀覆盖200μL市售凝胶;O5G5组在创面表面均匀覆盖200μL O5G5水凝胶;O3G7组在创面表面均匀覆盖200μL O3G7水凝胶。最后,将所有创面用3M膜覆盖。在术后的固定时间点进行取样,采集创面皮肤并从创面中心平均分为两份,一份立刻置于液氮中,然后转移至-80℃冰箱保存,另外一份完全浸泡于4%多聚甲醛中固定。上述操作均在小鼠麻醉的情况下进行。
如图6所示:在整个愈合周期内,所有组别小鼠的创面都随时间的延长而逐渐缩小,无感染或其他异常症状。在第2天,与对照组和O5G5组相比,YIFU组和O3G7组的伤口表现出更为明显的缩小,并已经开始结痂。在第5天,对照组、YIFU组和O5G5组均出现结痂现象,而O3G7组小鼠的结痂已开始脱落。在第9天O3G7组和阳性对照组的小鼠伤口已接近愈合或完全愈合,而在对照组和O5G5组中仍可以观察到明显的皮肤缺损。
2.小鼠背部皮肤深Ⅱ度烫伤模型
首先,腹腔注射10%水合氯醛(350mg/kg)对小鼠进行麻醉。剃光小鼠的背部皮肤的毛发并用75%乙醇对背部脱毛区皮肤进行消毒,将直径为5mm的圆柱形铝棒在沸水浴中加热5分钟后取出,用纱布将表面水分擦干,迅速在小鼠背部按压并持续10s,整个过程应确保铝棒不移动,烫伤创面直径为5mm对小鼠进行称重后加样:Control组未接受任何治疗,MEBO组在创面表面涂抹200μL美宝烫伤膏,O3G7组涂抹200μL O3G7水凝胶。实验期间,每天用生理盐水清洗创面后更换敷料。所有上述操作均在小鼠麻醉的情况下进行,分别在烫伤后的第3、7和14天对创面取样。
以深Ⅱ度烧伤创面小鼠模型进一步验证水凝胶的生物相容性和促烫伤创面的愈合效果;由图7可以看出,造模后小鼠背部皮肤局部变为白色,略微肿胀,可以观察到与周围皮肤有明显的分界线。第3天,各组小鼠创面没有明显的好转迹象,创面边缘有红肿现象。此时Control组的创面有肉眼可见的扩大趋势,这可能是由于感染引起的溃疡。O3G7水凝胶组的创面与MEBO组创面表现类似,无明显的扩大,创面基本消肿,说明水凝胶组的炎症周期较短。治疗后第7天,各组均形成加痂皮,O3G7水凝胶组创面较小,部分小鼠痂皮已经脱落。治疗后第14天,对照组伤口仍有硬尚未完全脱落,而MEBO组和O3G7组的伤口结痂已经脱落,其中,O3G7水凝胶组的伤口几乎完全愈合,修复后的皮肤光滑,颜色较浅,瘢痕不明显。
3.水凝胶生物安全性分析
在第9天,收集了Normal、Control、YIFU、O5G5和O3G7组小鼠的主要器官(心脏、肝脏、脾脏、肺和肾)进行H&E染色进行组织学评价。
对于应用于临床治疗的新型生物材料,明确其生物安全性是必要的。在整个研究过程中,所有实验组的小鼠均未出现异常症状或死亡。此外,为了进一步对O5G5和O3G7水凝胶的生物安全性进行评价,我们采集了术后第9天各组小鼠的主要器官(心脏、肝脏、脾脏、肺和肾脏)进行H&E组织染色分析并与正常组进行了对比,结果如图8所示。与正常组小鼠相比,由O5G5和O3G7水凝胶处理的小鼠心脏细胞没有明显的聚集、肝脏没有发现散乱的炎症细胞堆积、肺部细胞形态没有发生明显变化、脾脏和肾脏也没有发现病理性组织。综上所述,所有实验组小鼠的主要器官均未表现出异常或损伤,表明O5G5和O3G7水凝胶在伤口愈合过程中未对生物体产生安全问题。
其它未详细说明的部分均为现有技术。尽管上述实施例对本发明做出了详尽的描述,但它仅仅是本发明一部分实施例,而不是全部实施例,人们还可以根据本实施例在不经创造性前提下获得其他实施例,这些实施例都属于本发明保护范围。
Claims (10)
1.一种具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:包括以下步骤:
1)按重量份数比称取100份的卵白蛋白和2~25份的2-亚氨基硫烷盐酸盐,备用;
2)将卵白蛋白溶于乙二胺四乙酸溶液中,持续搅拌得到反应溶液,搅拌过程中向反应溶液中逐滴滴加2-亚氨基硫烷盐酸盐,持续搅拌反应,得到均匀的改性OVA溶液,其中,所述乙二胺四乙酸溶液是由将乙二胺四乙酸溶于磷酸盐缓冲液制备而成;
3)将改性OVA溶液透析纯化,最后真空冷冻干燥得到改性OVA粉末;
4)按重量份数比称取10~100份的改性OVA粉末、10~100份的巯基化明胶和3~8份的硝酸银;
5)将改性OVA粉末和巯基化明胶分别溶于乙酸钠-乙酸缓冲液中,恒温水浴搅拌过夜,分别得到tOVA前体溶液和tGel前体溶液;同时,将硝酸银溶于水中,得到硝酸银溶液;
6)将tOVA前体溶液和tGel前体溶液混合,搅拌均匀,得到tOVA/tGel混合溶液体系;向混合溶液体系中边搅拌边滴加硝酸银溶液,继续搅拌,得到预凝胶溶液,最后将预凝胶溶液快速倒入模具中放置,即得到tOVA/tGel@Ag水凝胶。
2.根据权利要求1所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述步骤1)中,卵白蛋白和2-亚氨基硫烷盐酸盐重量份数分别为100份和4~20份。
3.根据权利要求2所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述步骤1)中,卵白蛋白和2-亚氨基硫烷盐酸盐重量份数分别为100份和20份。
4.根据权利要求1~3任意一项所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述步骤2)中,乙二胺四乙酸溶液中,乙二胺四乙酸浓度为3mmol/L~10mmol/L。
5.根据权利要求1~3任意一项所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述步骤2)中,搅拌条件为:
温度为4℃,转速为100rpm,总搅拌时间为6h。
6.根据权利要求1所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述步骤4)中,改性OVA粉末、巯基化明胶tGel和硝酸银的重量份数分别为30~70份、30~70份和5.1份。
7.根据权利要求6所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述改性OVA粉末、巯基化明胶和硝酸银的重量份数分别为30份、70份和5.1份。
8.根据权利要求6所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述改性OVA粉末、巯基化明胶和硝酸银的重量份数分别为50份、50份和5.1份。
9.根据权利要1所述具有促进烫伤和急性创面愈合功能的水凝胶制备方法,其特征在于:所述步骤5)中,乙酸钠-乙酸缓冲液的pH值为5.0-7.0;
改性OVA粉末溶于乙酸钠-乙酸缓冲液时,恒温水浴温度为4℃;
巯基化明胶分别溶于乙酸钠-乙酸缓冲液时,恒温水浴温度为40~45℃。
10.一种权利要求1所述的方法制备的水凝胶在制备组织工程材料中的应用,其特征在于:所述组织工程材料为医用伤口敷料或细胞支架。
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