CN116920162A - 水凝胶组合物、水凝胶及其制备方法和用途 - Google Patents
水凝胶组合物、水凝胶及其制备方法和用途 Download PDFInfo
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- CN116920162A CN116920162A CN202210343783.8A CN202210343783A CN116920162A CN 116920162 A CN116920162 A CN 116920162A CN 202210343783 A CN202210343783 A CN 202210343783A CN 116920162 A CN116920162 A CN 116920162A
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- fatty acid
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- plant polyphenol
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
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Abstract
本发明提供一种水凝胶组合物、水凝胶及其制备方法和用途。所述水凝胶组合物包括:缓冲体系,所述缓冲体系包括多元酸和生物缓冲剂;以及,成胶组分,所述成胶组分包括植物多酚和含硫脂肪酸类化合物;其中,所述植物多酚和含硫脂肪酸类化合物的质量比为1:2‑10,优选为1:2.5~5。本发明的水凝胶组合物能够用于制备水凝胶,该水凝胶具有抗菌、抗氧化、抗自由基等性能。并且,该水凝胶还具有良好的自修复性能、组织黏附性和生物相容性,适用于细菌感染型伤口、局部出血和开放性伤口愈合。
Description
技术领域
本发明属于生物材料领域,具体涉及一种水凝胶组合物、水凝胶及其制备方法和用途,特别涉及一种医用水凝胶组合物、医用水凝胶及其制备方法、用途和制备医用水凝胶的试剂盒等。
背景技术
由意外创伤或细菌感染引起的伤口是日常生活中不可避免的问题,常伴有出血和脓液。常用的临床方法包括缝线、吻合器和金属丝,用于修复大型皮肤缺损,在没有消毒剂或抗生素的帮助下,会给患者带来不愉快的治疗体验,并增加继发感染的风险。现阶段,研究人员发现水凝胶是伤口愈合的最佳选择。
水凝胶是一种当组织受创、出血、流体(组织液、气体)渗漏时用于密封和封堵的组织密封材料。由于亲水网络中保留了大量的水,水凝胶可以为伤口床提供湿润的环境,提取伤口分泌物并促进伤口愈合。其次,与橡胶、塑料树脂或生物大分子不同,水凝胶通常具有许多独特的特性,例如压力诱导的形状调节、可控的机械强度、理想的生物模拟特性以及药物/纳米材料负载的可及性。第三,水凝胶的交联网络足够坚固,可以避免在实际伤口愈合过程中在水条件下过度膨胀或溶解。
到目前为止,各种研究报告了用于伤口敷料的多功能聚乙二醇基、丙烯酸基、碳水化合物基、多肽基和聚乙烯醇基粘合剂凝胶。然而,上述水凝胶大多需要复杂的制备过程、单体、有毒交联剂或重金属的精确化学设计以及繁琐的合成后处理。虽然许多生物大分子被认为是潜在的绿色原材料,而不是用于粘合水凝胶的合成聚合物,但由于生产地点不同、分子量可变和提取方法不同,它们通常在制定相应产品的标准时面临困难
目前主流的水凝胶可分为生物稳定型、生物降解型、合成稳定型、合成降解型四类。此外,基于抗菌肽的水凝胶由于其昂贵的成本以及蛋白质水解降解和细胞毒性导致的低稳定性限制了其广泛应用。
生物稳定型组织医用胶是以生物基原料,辅以化学试剂交联的材料,如Cryolife的BioGlue即为以生物源白蛋白和戊二醛为主要成分的组织密封材料;生物降解型组织医用胶是全部以生物基原料,可生物降解吸收的材料,如Baxter的Tisseel即为纤维蛋白源的生物可降解的组织胶水;合成稳定型组织医用胶是以高分子自聚合的材料,以α-氰基丙烯酸酯为主,通过在组织界面以阴离子聚合形成组织黏附,但是其聚合物不具有生物降解性;合成降解型组织医用胶主要以化学改性的聚乙二醇为主,随着交联键的断裂,聚乙二醇通过细胞膜渗透、内吞被代谢出体外。
因此,研究一种生产方法简单、资源可持续的水凝胶组合物及水凝胶,成为亟待解决的技术问题。
发明内容
发明要解决的问题
鉴于现有技术中存在的技术问题,本发明首先提供一种水凝胶组合物,本发明的水凝胶组合物能够用于制备水凝胶,该水凝胶具有抗菌、抗氧化、抗自由基等性能。并且,该水凝胶还具有良好的自修复性能、组织黏附性和生物相容性,适用于细菌感染型伤口、局部出血和开放性伤口愈合。
进一步地,本发明还提供一种水凝胶的制备方法,该制备方法简单易行,且绿色无污染,不添加金属离子及有害化合物,成本较低。
用于解决问题的方案
本发明首选提供一种水凝胶组合物,其包括:
缓冲体系,所述缓冲体系包括多元酸和生物缓冲剂;以及,
成胶组分,所述成胶组分包括植物多酚和含硫脂肪酸类化合物;其中,
所述植物多酚和含硫脂肪酸类化合物的质量比为1:2-10,优选为1:2.5~5。
根据本发明所述的水凝胶组合物,其中,所述多元酸与生物缓冲剂的质量比为1:4-10,所述多元酸和含硫脂肪酸类化合物的质量比为1:5-60。
根据本发明所述的水凝胶组合物,其中,所述多元酸包括乙二胺四乙酸、柠檬酸、酒石酸、植酸中的一种或两种以上的组合;所述生物缓冲剂包括三羟甲基氨基甲烷、磷酸盐、氯化盐中的一种或两种以上的组合;
所述植物多酚包括黄酮类、单宁类、花色苷类、酚酸类中的一种或两种以上的组合;优选包括茶褐素、单宁酸、原花青素中的一种或两种以上的组合;所述含硫脂肪酸类化合物包括α-硫辛酸。
本发明还提供一种水凝胶,其在缓冲体系存在的前提下,其由本发明所述的成胶组分的植物多酚和含硫脂肪酸类化合物反应后形成。
根据本发明所述的水凝胶,其中,所述水凝胶的组织黏附强度为2-12KPa;所述水凝胶的最大溶胀率为200-250%;所述水凝胶的断裂伸长率为350-550%,最大拉伸强度为3.5-5.5KPa。
本发明还提供一种根据本发明所述的水凝胶的制备方法,其包括将所述水凝胶组合物的各组分在溶剂中混合的步骤;
优选地,所述制备方法包括以下步骤:
步骤1)使多元酸和生物缓冲剂溶于溶剂中,得到缓冲体系;
步骤2)将植物多酚溶于所述缓冲体系中,得到预混物;
步骤3)将含硫脂肪酸类化合物溶于预混物中后,注入模具后冷却,得到水凝胶。
根据本发明所述的制备方法,其中,所述步骤1)中,所述多元酸、所述生物缓冲剂与所述溶剂的质量比为1:4-10:25-50;溶解所述多元酸和生物缓冲剂的温度为10-60℃;
所述步骤2)中,所述植物多酚与所述溶剂的质量比为1:5-10;溶解所述植物多酚的温度为40~60℃,溶解的时间为3-5min;
所述步骤3)中,所述含硫脂肪酸类化合物与所述溶剂的质量比为1:2-3;溶解所述含硫脂肪酸类化合物的温度为40~60℃;所述冷却的温度为0~25℃,冷却的时间为6-12h。
本发明还提供一种水凝胶贴片,其包括根据本发明所述的水凝胶或者根据本发明所述的水凝胶的制备方法制备得到的水凝胶。
本发明还提供一种水凝胶粉剂,其包括根据本发明所述的水凝胶或者根据本发明所述的水凝胶的制备方法制备得到的水凝胶。
本发明又提供一种根据本发明所述的水凝胶或者根据本发明所述的水凝胶的制备方法制备得到的水凝胶在制备伤口愈合制品、内脏或软组织伤口闭合制品、组织液封堵制品、止血辅助物以及软组织修复补片中的用途。
发明的效果
本发明的水凝胶组合物能够用于制备水凝胶,该水凝胶具有抗菌、抗氧化、抗自由基等性能。并且,该水凝胶还具有良好的自修复性能、组织黏附性和生物相容性,适用于细菌感染型伤口、局部出血和开放性伤口愈合。
进一步地,本发明的水凝胶的制备方法简单易行,且绿色无污染,不添加金属离子及有害化合物,成本较低,适合大批量生产。
附图说明
图1示出了本发明的水凝胶的外观示意图。
图2示出了本发明水凝胶的红外谱图。
图3示出了本发明实施例1中水凝胶的溶胀率。
图4示出了本发明实施例1中水凝胶对不同材料的黏附力曲线(a)和黏合强度(b)。
图5示出了本发明实施例1中水凝胶的抗1,1-二苯基-2-三硝基苯肼(DPPH)自由基的紫外-可见光分光光度计谱图。
图6示出了本发明实施例1中水凝胶用于金黄色葡萄球菌感染的BALC/c小鼠伤口愈合示意图(a),伤口组织HE染色切片(b)。
图7示出了本发明实施例1中水凝胶用于大鼠肝脏止血,其止血照片(a)和出血量统计(b)。
具体实施方式
以下将详细说明本发明的各种示例性实施例、特征和方面。在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
另外,为了更好地说明本发明,在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解,没有某些具体细节,本发明同样可以实施。在另外一些实例中,对于本领域技术人员熟知的方法、手段、器材和步骤未作详细描述,以便于凸显本发明的主旨。
如无特殊声明,本说明书中所使用的单位均为国际标准单位,并且本发明中出现的数值,数值范围,均应当理解为包含了工业生产中所不可避免的系统性误差。
本说明书中,如没有特别说明,则“%”均表示质量百分数。
本说明书中,使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。
本说明书中,所提及的“一些具体/优选的实施方案”、“另一些具体/优选的实施方案”、“实施方案”等是指所描述的与该实施方案有关的特定要素(例如,特征、结构、性质和/或特性)包括在此处所述的至少一种实施方案中,并且可存在于其它实施方案中或者可不存在于其它实施方案中。另外,应理解,所述要素可以任何合适的方式组合在各种实施方案中。
本说明书中,使用“数值A~数值B”表示的数值范围是指包含端点数值A、B的范围。
另外,本说明书中,所述“水”包含去离子水、蒸馏水、离子交换水、双蒸水、高纯水、纯净水等能够使用的任何可行的水。
本说明书中,使用“常温”、“室温”时,其温度可以是10-40℃。
<第一方面>
本发明首先提供一种水凝胶组合物,特别是一种医用水凝胶组合物,其包括:
缓冲体系,所述缓冲体系包括多元酸和生物缓冲剂;以及,
成胶组分,所述成胶组分包括植物多酚和含硫脂肪酸类化合物;其中,
所述植物多酚和含硫脂肪酸类化合物的质量比为1:2-10,优选为1:2.5-5。
其中,所述成胶组分和缓冲体系可以是分离的,在使用前几个小时(例如:6-12小时)将成胶组分和缓冲体系组分混合。优选地,所述缓冲体系中的多元酸和生物缓冲剂可以是分离的,在使用之前几个小时(例如:6-12小时)将多元酸和生物缓冲剂进行混合。所述成胶组分中的植物多酚和含硫脂肪酸类化合物也可以是分离的,在使用之前几个小时(例如:6-12小时)将植物多酚和含硫脂肪酸类化合物进行混合,一般而言,所述缓冲体系可以与植物多酚混合后,再与含硫脂肪酸类化合物混合成胶,制备完成之后,在室温下放置6-12小时后即可使用,可以将制品塑料密封作为创可贴使用。
在实际应用过程中,成胶组分和缓冲体系可以分别单独储存,使用前再将两者进行混合。举例而言,可以是缓冲体系的多元酸和生物缓冲剂溶于溶剂中后,再与植物多酚和含硫脂肪酸类化合物进行混合成胶。本发明对所述的组织医用胶组合物中的各组分的储存方式没有限制,所属技术领域人员可以根据需要,选择具体的储存方式,均在本发明的范围之内。
在本发明中,以含硫脂肪酸类化合物为聚合单体,植物多酚作为化学交联剂,植物多酚可以和含硫脂肪酸类化合物发生迈克尔加成反应,从而形成凝胶网络。缓冲体系中的多元酸可以作为超分子交联剂,其能够与含硫脂肪酸类化合物的羧基发生氢键作用,进而提升水凝胶力学性能。另外,通过使用上述植物多酚,可以在确保安全性的同时,还能够使制备得到的水凝胶具有一定的抗菌性能。
本发明的水凝胶组合物制备得到的水凝胶的化学结构中具有多酚基团、羧基等官能团,对皮肤等蛋白质丰富的组织具有良好的黏附能力。
在本发明中,所述植物多酚和含硫脂肪酸类化合物的质量比为1:2-10,优选为1:2.5-5,例如:1:3、1:4、1:5、1:6、1:7、1:8、1:9等。本发明人发现,当植物多酚和含硫脂肪酸类化合物的质量比为1:2~10时,制备得到的水凝胶的断裂伸长率可以为350-550%,最大拉伸强度可以为3.5-5.5KPa,力学性能优异。进一步,为了有利于形成凝胶,所述植物多酚和含硫脂肪酸类化合物的质量比优选为1:2.5-5。
在一些具体的实施方案中,所述多元酸与生物缓冲剂的质量比为1:4-10,例如:1:5、1:6、1:7、1:8、1:9等,当多元酸与生物缓冲剂的质量比为1:4-10时,所得水凝胶透明,并且不易随水分流失显著降低黏性。
进一步,在本发明中,考虑到力学性能,所述多元酸和含硫脂肪酸类化合物的质量比可以为1:5-60,优选1:10-50;例如:1:10、1:20、1:25、1:30、1:35、1:40、1:45、1:50、1:55等。当多元酸与含硫脂肪酸类化合物的质量比为1:5-60时,所得水凝胶的力学性能优异。
具体地,在本发明中,所述多元酸包括乙二胺四乙酸、柠檬酸、酒石酸、植酸中的一种或两种以上的组合;所述植物多酚包括黄酮类、单宁类、花色苷类、酚酸类中的一种或两种以上的组合;优选包括茶褐素、单宁酸、原花青素中的一种或两种以上的组合;所述含硫脂肪酸类化合物包括α-硫辛酸。对于多元酸,本发明优选使用乙二胺四乙酸、柠檬酸、酒石酸中的一种或两种以上的组合。
另外,对于生物缓冲剂,本发明不作特别限定,可以是本领域常用的一些生物缓冲剂。具体地,所述生物缓冲剂可以包括三羟甲基氨基甲烷、磷酸盐、氯化盐中的一种或两种以上的组合;所述磷酸盐可以是磷酸二氢钾、磷酸氢二钠等,所述氯化盐可以是氯化钠、氯化钾等。通过使用生物缓冲剂,可以获得pH值为8-9的缓冲体系,有利于成胶。
其中,乙二胺四乙酸是一种有机化合物,其化学式为C10H16N2O8,结构式为常温常压下为白色粉末。它是一种能与Mg2+、Ca2+、Mn2+、Fe2+等二价金属离子结合的螯合剂。由于多数核酸酶类和有些蛋白酶类的作用需要Mg2+,故常用做核酸酶、蛋白酶的抑制剂;也可用于去除重金属离子对酶的抑制作用。
柠檬酸,又名枸橼酸,分子式为C6H8O7,是一种重要的有机酸,为无色晶体,无臭,有很强的酸味,易溶于水,是天然防腐剂和食品添加剂。酒石酸,即2,3-二羟基丁二酸,是一种羧酸,化学式为C4H6O6。存在于多种植物中﹐如葡萄和罗望子。也是葡萄酒中主要的有机酸之一。
本发明人发现,乙二胺四乙酸、柠檬酸、酒石酸均为多元酸,具有更强的酸性,可以作为超分子交联剂使用。从而能够与含硫脂肪酸类化合物的羧基发生氢键作用,进而提升水凝胶力学性能。
在一些具体的实施方案中,本发明优选使用黄酮类的植物多酚,例如茶褐素等。茶褐素是茶叶中多种酚类化合物的总称,是茶树鲜叶的主要组成成分,其中以儿茶素为其主体成分,占多酚类物质总量的60%~80%,与茶的汤色、滋味和香气都有着密切的关系。进一步,本发明人发现,单宁酸制品容易随着贮存时间延长而氧化变性,而茶褐素在空气中很稳定。另外,茶褐素的化学反应位点、苯环数量多于单宁酸,能够有效提升水凝胶凝胶网络强度,成胶速度更快。
进一步,对于α-硫辛酸,可以作为性能最优的聚合单体使用。α-硫辛酸会因加而热发生开环聚合反应,产生硫自由基。而植物多酚的多酚基团与硫自由基发生迈克尔加成反应,从而形成交联凝胶网络。
<第二方面>
本发明的第二方面提供一种水凝胶,其在缓冲体系存在的前提下,由本发明第一方面所述的成胶组分的植物多酚和含硫脂肪酸类化合物反应后形成。
进一步所述水凝胶还具有抗菌、抗氧化、抗自由基等性能,且具有良好的自修复性能、组织黏性和生物相容性,适用于细菌感染型伤口、局部出血和开放性伤口愈合。
本发明的水凝胶具有多酚基团、羧基等基团,对组织具有良好的粘附能力。具体地,在本发明中,所述水凝胶的组织黏附强度为2-12KPa,例如:3KPa、4KPa、5KPa、6KPa、7KPa、8KPa、9KPa、10KPa、11KPa等。
水凝胶是具有三维空间网络结构,其不能在水中溶解,能够在水中溶胀,吸收大量的水分,使水凝胶体积增大。而人体内的一些狭小部位,高溶胀性的水凝胶可能会对周围神经造成压迫,而可能干扰机体的正常功能,严重时周围组织可能出现压迫性坏死。而本发明的水凝胶的最大溶胀率较低,仅为200-250%,例如:210%、220%、230%、240%等,其不会对周围神经造成压迫,从而基本不会干扰机体的正常功能。由于本申请的水凝胶具有较低的溶胀率和可自修复性能,可适应复杂多变的佩戴环境,从而作为可长期佩戴的凝胶贴片使用。
<第三方面>
本发明的第三方面提供一种根据本发明第三方面所述的水凝胶的制备方法,其包括将所述水凝胶组合物的各组分在溶剂中混合的步骤,优选地,所述溶剂为水。
本发明的水凝胶的制备方法简单易行,且绿色无污染,不添加金属离子及有害化合物,成本较低,适合大批量生产。
在一些具体的实施方案中,所述制备方法包括以下步骤:
步骤1)使多元酸和生物缓冲剂溶于溶剂中,得到缓冲体系;
步骤2)将植物多酚溶于所述缓冲体系中,得到预混物;
步骤3)将含硫脂肪酸类化合物溶于预混物中后,注入模具后冷却,得到水凝胶。
本发明的含硫脂肪酸类化合物溶于预混物中后,含硫脂肪酸类化合物与植物多酚发生迈克尔加成反应,可快速成胶;同时多元酸与含硫脂肪酸类化合物的羧基发生氢键作用,以提升水凝胶力学性能。该水凝胶具有抗菌、抗氧化、抗自由基等性能,且具有良好的自修复性能、组织黏性和生物相容性,适用于细菌感染型伤口、局部出血和开放性伤口愈合。
在一些具体的实施方案中,所述步骤1)中,所述多元酸、所述生物缓冲剂与所述溶剂的质量比为1:4-10:25-50,例如:1:5-9:30-45、1:6-8:35-40、1:7:38等;溶解所述多元酸和生物缓冲剂的温度为10-60℃,例如:20℃、30℃、40℃、50℃等。优选地,所述缓冲体系的pH值可以是8-9。
当所述多元酸、所述生物缓冲剂与所述溶剂的质量比为1:4-10:25-50时,所制备得到的水凝胶的断裂伸长率可以为350-550%,最大拉伸强度可以为3.5-5.5KPa,并且,所得到的水凝胶呈透明状,并且不易随水分流失显著降低黏性。当溶解所述多元酸和生物缓冲剂的温度为10-60℃时,在加速溶溶解的基础上,不会导致多元酸和生物缓冲剂变质,且不影响后续迈克尔加成反应的进行。
进一步,在本发明中,所述步骤2)中,所述植物多酚与所述溶剂的质量比为1:5-10,例如:1:6、1:7、1:8、1:9等;当植物多酚与所述溶剂的质量比为1:5-10时,成胶速度可以有效控制,可以有效避免成胶速度过快无法注入模具的问题;溶解所述植物多酚的温度为40~60℃,例如:45℃、50℃、55℃、60℃等;溶解的时间为3-5min,例如3.5min、4min、4.5min等。当溶解所述植物多酚的温度为40-60℃时,在加速溶溶解的基础上,不会导致植物多酚失去活性,且不影响后续迈克尔加成反应的进行。
进一步,在本发明中,所述步骤3)中,所述含硫脂肪酸类化合物与所述溶剂的质量比为1:2-3,例如:1:2.2、1:2.4、1:2.6、1:2.8等;所述含硫脂肪酸类化合物与所述溶剂的质量比为1:2-3时,溶液粘度有效提升,有利于植物多酚交联后形成凝胶;溶解所述含硫脂肪酸类化合物的温度为40~60℃例如:45℃、50℃、55℃、60℃等。当溶解所述植物多酚的温度为40-60℃时,在加速溶溶解的基础上,不会导致含硫脂肪酸类化合物失去活性,且不影响后续迈克尔加成反应的进行。
另外,为了获得成型的水凝胶,可以将其置模具中进行冷却。具体地,所述冷却的温度为0~25℃,例如:5℃、10℃、15℃、20℃等;冷却的时间为6-12h,例如:7h、8h、9h、10h、11h等。当冷却的温度为0~25℃,冷却的时间为6-12h时,能够获得凝固的水凝胶,且该水凝胶的力学性能合适。
<第四方面>
本发明的第四方面提供几种常用的水凝胶制品或试剂盒及水凝胶的用途。本发明的水凝胶制品黏附组织,提供一种抗菌、生物相容的微环境从而实现组织修复。
具体地,本发明的本发明的第二方面的水凝胶或者第三方面制备得到的水凝胶可以制成水凝胶贴片,例如通过切片的方式获得水凝胶贴片。本发明的水凝胶贴片具有较低的溶胀率和可自修复性能,可适应复杂多变的佩戴环境,从而能够作为可长期佩戴的凝胶贴片使用。
进一步地,本发明的第二方面的水凝胶或者第三方面制备得到的水凝胶还可以经过粉碎(例如研磨)制备得到水凝胶粉剂,在使用时可以直接将其喷洒至伤口,使用简单方便。
进一步地,本发明还可以提供一种水凝胶试剂盒,其包括本发明第一方面所述的水凝胶组合物以及任选存在的溶剂;优选地,所述水凝胶组合物的缓冲体系和成胶组分是分开储存的,在使用前将缓冲体系和成胶组分混合。
进一步地,所述缓冲体系的多元酸和生物缓冲剂是分开储存的,在使用前将多元酸和生物缓冲剂溶于溶剂中,从而得到缓冲体系。所述成胶组分的植物多酚和含硫脂肪酸类化合物是分开储存的,在使用前依次将植物多酚和含硫脂肪酸类化合物溶于缓冲体系中进行化学反应,最终得到水凝胶。
本发明所述的水凝胶可用于制备伤口愈合制品(特别是细菌感染型伤口)、内脏或软组织伤口闭合制品(特虽是开放性伤口愈合等)、组织液封堵制品、止血辅助物以及软组织修复补片等。作为优选,本发明的水凝胶可以通过组织黏附密封出血的伤口,可作为止血辅助物,例如:出血密封剂,适用于局部出血,例如:毛细血管、静脉和肌性动脉快速止血。
实施例
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1
将1份乙二胺四乙酸,5份三羟甲基氨基甲烷溶解于25份去离子水中,25℃条件下搅拌溶解。随后加入3份茶褐素,60℃条件下搅拌3min进行溶解。首先加入5份α-硫辛酸,60℃条件下搅拌溶解后,再次加入5份α-硫辛酸,60℃条件下进行搅拌溶解。最后将所得液体注入到模具中,25℃条件下冷却12h得到水凝胶。
实施例2
将1份柠檬酸,7.5份三羟甲基氨基甲烷溶解于25份去离子水中,60℃条件下搅拌溶解。随后加入5份茶褐素,60℃条件下搅拌3min进行溶解。首先加入6.25份α-硫辛酸,60℃条件下搅拌溶解后,再次加入6.25份α-硫辛酸,60℃条件下进行搅拌溶解。最后将所得液体注入到模具中,0℃条件下冷却6h得到水凝胶。
实施例3
将1份酒石酸,10份三羟甲基氨基甲烷溶解于50份去离子水中,40℃条件下搅拌溶解。随后加入10份茶褐素,60℃条件下搅拌5min进行溶解。首先加入10份α-硫辛酸,40℃条件下搅拌溶解后,再次加入10份α-硫辛酸,40℃条件下进行搅拌溶解。最后将所得液体注入到模具中,25℃条件下冷却12h得到水凝胶。
实施例4
将1份乙二胺四乙酸,5份三羟甲基氨基甲烷溶解于30份去离子水中,60℃条件下搅拌溶解。随后加入5份茶褐素,60℃条件下搅拌4min进行溶解。首先加入25份α-硫辛酸,60℃条件下搅拌溶解后,再次加入25份α-硫辛酸,60℃条件下进行搅拌溶解。最后将所得液体注入到模具中,4℃条件下冷却6h得到水凝胶。
实施例5
将1份柠檬酸,8份三羟甲基氨基甲烷溶解于45份去离子水中,25℃条件下搅拌溶解。随后加入4.5份茶褐素,50℃条件下搅拌3min进行溶解。首先加入7.5份α-硫辛酸,60℃条件下搅拌溶解后,再次加入7.5份α-硫辛酸,60℃条件下进行搅拌溶解。最后将所得液体注入到模具中,25℃条件下冷却8h得到水凝胶。
实施例6
将1份乙二胺四乙酸,4份三羟甲基氨基甲烷溶解于30份去离子水中,40℃条件下搅拌溶解。随后加入3份茶褐素,40℃条件下搅拌3min进行溶解。首先加入5份α-硫辛酸,50℃条件下搅拌溶解后,再次加入5份α-硫辛酸,50℃条件下进行搅拌溶解。最后将所得液体注入到模具中,10℃条件下冷却9h得到水凝胶。
对比例1
将实施例1中的茶褐素替换为去离子水,其它按照与实施例1完全相同的方法制备得到不含茶褐素的水凝胶。
性能测试实验
(1)红外测试
将干燥的KBr与冻干水凝胶粉末共同研磨,放入金属模具当中施加压力形成KBr研片,随后置于Frontier红外光谱仪中进行测量。如图2所示,水凝胶中含有硫-苯环化学键(S-Ar,1057cm-1),证明茶褐素与α-硫辛酸发生交联化学反应。
(2)水凝胶的溶胀率
将实施例1的水凝胶冻干后浸泡于水中,每隔一段时间将水凝胶取出,沥干表面水分进行称重。水凝胶的溶胀率由以下公式进行计算:
其中,md为水凝胶初始质量,ms为水凝胶发生溶胀后的质量。如图3所示,水凝胶的最大溶胀率为200-250%,为低溶胀率的水凝胶。
另外,本申请的实施例2-6的水凝胶的最大溶胀率同样为200-250%,为低溶胀率的水凝胶。
(3)水凝胶的黏附性
用于黏附性测试的样品(铝片、木片、陶瓷片、聚四氟乙烯、聚氯乙烯、硅橡胶和玻璃片)长度为10cm,宽度为2.5cm,两片样品之间采用实施例1制备得到的水凝胶正方形贴片(厚度1mm,边长25mm)进行黏合,黏合面积为25mm×25mm,随后室温干燥24h或者60℃烘干8h,采用力学拉伸仪将粘合后的样品轴向拉伸测试黏附力,黏附力可由以下公式进行计算:
其中F为粘合样品发生分离时的拉伸强度(N),而A为两片样品之间的接触面积(m2)。如图4所示,烘干后的水凝胶对于木片的黏附力达到了250KPa,而对于其它材料的黏附力为20-25KPa。相对于室温缓慢干燥的水凝胶样品,在60℃下烘干8小时的水凝胶的黏附力明显提升。以上结果说明水凝胶随着水分的流失黏附力可提升2-5倍。
(4)抗自由基能力测试
将凝固后的实施例1制备得到的水凝胶正方形薄片(边长25mm,厚度为1mm)浸泡在0.15mM的DPPH乙醇溶液10min后,用紫外-可见光分光光度计观察517nm处吸光度的大小,通过以下公式计算自由基捕捉率:
其中Ac为对照组DPPH乙醇溶液在517nm处的吸光度,而As为样品组溶液(DPPH乙醇溶液+水凝胶)在517nm的吸光度。如图5所示,水凝胶的DPPH自由基的捕捉率达到了90%。以上结果说明水凝胶对DPPH具有良好的抗氧化、抗自由基能力。
(5)烫伤愈合实验
BALB/c雄性小鼠(年龄为6±20周)在恒定的温度(21±1℃)和相对湿度(60±5%)培养在至少7天。所有小鼠都经历12小时光照-12小时黑暗循环,并且可以自由饮水和进食。在烫伤治疗之前,通过腹腔注射剂量为30mg/kg的10%水合氯醛对小鼠进行麻醉。在此之后,剃掉背部毛发。黄铜圆柱(直径15mm)在90℃热水中预加热10分钟后,按压在小鼠背部皮肤上6s形成烫伤。然后,将10μL的MRSA悬浮液(细菌浓度1×108CFU-mL-1)均匀涂抹烫伤表面。10分钟后,使用实施例1所得水凝胶贴片(直径24mm)覆盖烧伤创面(每组包含6只小鼠)。对照组用生理盐水处理烧伤创面。第1天和第3天,处死小鼠,收集伤口组织样本进行组织学分析。皮肤组织样本在1毫升磷酸盐缓冲盐水(PBS)中均质,并连续稀释。通过在LB琼脂平板上电镀稀释液来评估细菌浓度,并在过夜培养后计数菌落数。
如图6所示,相对不含茶褐素的水凝胶(对比例1)和生理盐水组,实施例1所得水凝胶具有明显的抗菌和促愈效果,伤口愈合后皮肤组织连贯,无明显的红肿现象。
(6)大鼠肝脏止血
对于SD大鼠的肝脏止血模型,肝叶的四分之一被切除后,就将实施例1所得水凝胶贴片(直径24mm,厚度2mm)粘贴到切割表面上。然后在肝脏下方放置一张已知质量(M1)的干净滤纸。未经任何治疗的出血部位作为阴性对照,而纱布按压作为阳性对照。血流3分钟后,滤纸被血液染色并重新称重(M2)。失血量通过滤纸在血液染色前后的质量差来计算:M2-M1,(n=4)。
如图7所示,水凝胶贴片可以有效黏附肝脏切面,抑制出血,相对空白组,止血效率约为75%。以上结果说明本发明所得水凝胶贴片有潜力用于外科手术止血。
(7)力学性能测试
断裂伸长率和最大拉伸强度的测试方法:将实施例1-6的水凝胶样品裁切为长度10cm,厚度0.6cm,宽度1cm的标准样品,然后将其分别置于力学拉伸仪上进行拉力测试,水凝胶拉伸断裂后,记录最大拉伸力和断裂伸长率。最大拉伸力/横截面积即为最大拉伸强度,结果如表1所示。
组织黏附力的检测方法:将实施例1-6的水凝胶样品(厚1mm,长和宽为25mm)粘在两块猪皮之间,用力学拉伸仪将猪皮拉开,组织黏附力即为拉伸力/凝胶接触面积,结果如下表1所示。
表1
由表1可以看出,本发明的水凝胶的力学性能优异,能够作为水凝胶使用。
本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明权利要求的保护范围之内。
Claims (10)
1.一种水凝胶组合物,其特征在于,包括:
缓冲体系,所述缓冲体系包括多元酸和生物缓冲剂;以及,
成胶组分,所述成胶组分包括植物多酚和含硫脂肪酸类化合物;其中,
所述植物多酚和含硫脂肪酸类化合物的质量比为1:2-10,优选为1:2.5~5。
2.根据权利要求1所述的水凝胶组合物,其特征在于,所述多元酸与生物缓冲剂的质量比为1:4-10,所述多元酸和含硫脂肪酸类化合物的质量比为1:5-60。
3.根据权利要求1或2所述的水凝胶组合物,其特征在于,所述多元酸包括乙二胺四乙酸、柠檬酸、酒石酸、植酸中的一种或两种以上的组合;所述生物缓冲剂包括三羟甲基氨基甲烷、磷酸盐、氯化盐中的一种或两种以上的组合;
所述植物多酚包括黄酮类、单宁类、花色苷类、酚酸类中的一种或两种以上的组合;优选包括茶褐素、单宁酸、原花青素中的一种或两种以上的组合;所述含硫脂肪酸类化合物包括α-硫辛酸。
4.一种水凝胶,其特征在于,在缓冲体系存在的前提下,其由权利要求1-3任一项所述的成胶组分的植物多酚和含硫脂肪酸类化合物反应后形成。
5.根据权利要求4所述的水凝胶,其特征在于,所述水凝胶的组织黏附强度为2-12KPa;所述水凝胶的最大溶胀率为200-250%;所述水凝胶的断裂伸长率为350-550%,最大拉伸强度为3.5-5.5KPa。
6.一种根据权利要求4或5所述的水凝胶的制备方法,其特征在于,包括将所述水凝胶组合物的各组分在溶剂中混合的步骤;
优选地,所述制备方法包括以下步骤:
步骤1)使多元酸和生物缓冲剂溶于溶剂中,得到缓冲体系;
步骤2)将植物多酚溶于所述缓冲体系中,得到预混物;
步骤3)将含硫脂肪酸类化合物溶于预混物中后,注入模具后冷却,得到水凝胶。
7.根据权利要求6所述的制备方法,其特征在于,所述步骤1)中,所述多元酸、所述生物缓冲剂与所述溶剂的质量比为1:4-10:25-50;溶解所述多元酸和生物缓冲剂的温度为10-60℃;
所述步骤2)中,所述植物多酚与所述溶剂的质量比为1:5-10;溶解所述植物多酚的温度为40~60℃,溶解的时间为3-5min;
所述步骤3)中,所述含硫脂肪酸类化合物与所述溶剂的质量比为1:2-3;溶解所述含硫脂肪酸类化合物的温度为40~60℃;所述冷却的温度为0~25℃,冷却的时间为6-12h。
8.一种水凝胶贴片,其特征在于,包括根据权利要求4或5所述的水凝胶或者根据权利要求6或7所述的水凝胶的制备方法制备得到的水凝胶。
9.一种水凝胶粉剂,其特征在于,包括对根据权利要求4或5所述的水凝胶或者根据权利要求6或7所述的水凝胶的制备方法制备得到的水凝胶进行粉碎后得到。
10.一种根据权利要求4或5所述的水凝胶或者根据权利要求6或7所述的水凝胶的制备方法制备得到的水凝胶在制备伤口愈合制品、内脏或软组织伤口闭合制品、组织液封堵制品、止血辅助物以及软组织修复补片中的用途。
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