CN114762737A - 高强度天然高分子水凝胶及其制备方法和应用 - Google Patents
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Abstract
本发明提供高强度天然高分子水凝胶及其制备方法和应用,在35‑40℃下,将待增强强度的水凝胶浸泡在茶多酚(TP)溶液中5‑50h后,即得到高强度天然高分子水凝胶,其中,茶多酚(TP)溶液的质量百分数为15‑25%。以明胶为基底的高强度天然高分子水凝胶(GelMA‑TP)与原始的水凝胶相比,经茶多酚(TP)处理的代表性天然高分子(NP)由于茶多酚(TP)和天然高分子(NP)链之间的氢键相互作用,使其拉伸/压缩强度、杨氏模量、断裂伸长率和断裂韧性分别具有明显的提高;在大鼠全层皮肤损伤模型中进行了体内的生物学实验,以明胶为基底的高强度天然高分子水凝胶(GelMA‑TP)能够更好的促进伤口愈合。
Description
技术领域
本发明涉及生物医用材料技术领域,更具体地说涉及高强度天然高分子水凝胶及其制备方法和应用。
背景技术
天然高分子(NP)水凝胶具有良好的生物相容性和生物降解性,是生物医学领域中一类重要的生物材料。然而,传统的天然高分子(NP)水凝胶由于力学性能弱、功能单一,严重限制了其在组织工程方面的应用。过去十年中,高强度水凝胶在设计原则上有了巨大的发展;然而,以前的研究主要集中在合成聚合物水凝胶上。尽管人们已经投入了大量的精力来提高天然聚合物水凝胶的机械强度,但其策略主要依赖于引入合成聚合物,这不可避免地影响其生物降解性和生物相容性。
茶叶蛋是中国著名的小吃之一,普通的蛋白凝胶是脆的,但是茶叶蛋的蛋白凝胶的强度显著增强,这是由于茶叶中的活性物质与蛋白之间的氢键相互作用导致网络密度增强所致。先前的分析测试已经确定,茶多酚(TP)是从绿茶中提取的一组多酚化合物。此外单宁酸已被用于增强水凝胶的机械强度,其增强机理可能来源于酚与聚合物之间的氢键作用。例如,将甲基丙烯酸化水凝胶(GelMA)水凝胶浸泡在单宁酸(TA)溶液中可以分别提高凝胶的拉伸强度和断裂伸长率。一些研究还表明,将聚乙烯醇(PVA)或聚丙烯酰胺(PAAm)凝胶浸泡在单宁酸(TA)溶液中可以提高它们的机械性能,然而,根据世界卫生组织的报告,高浓度单宁酸(TA)可能对人类构成致癌风险。而茶多酚(TP)具有抗氧化、伤口愈合、抗菌等作用,因此使用茶多酚(TP)来增强天然高分子水凝胶的强度。
发明内容
本发明克服了现有技术中的不足,传统的天然高分子(NP)水凝胶由于力学性能弱、功能单一,严重限制了其在组织工程方面的应用,人们通过引入合成聚合物提高天然聚合物水凝胶的机械强度,但是这会影响其生物降解性和生物相容性,提供了高强度天然高分子水凝胶及其制备方法和应用,以明胶为例,首先对明胶进行甲基丙烯酸酐改性接枝双键得到甲基丙烯酸化水凝胶(GelMA),将甲基丙烯酸化水凝胶(GelMA)浸泡在茶多酚(TP)溶液中得到以明胶为基底的高强度天然高分子水凝胶(GelMA-TP),对制得的凝胶的机械力学性能,抗氧化性能,抗菌性能进行了测试,并且进行了体内的生物学实验。
本发明的目的通过下述技术方案予以实现。
高强度天然高分子水凝胶及其制备方法,在35-40℃下,将待增强强度的水凝胶浸泡在茶多酚(TP)溶液中5-50h后,即得到高强度天然高分子水凝胶,其中,茶多酚(TP)溶液的质量百分数为15-25%。
待增强强度的水凝胶包括甲基丙烯酸化水凝胶(GelMA)、增强琼脂糖(AG)水凝胶和甲基丙烯酰化的海藻酸钠(Alg-MA)-Ca2+水凝胶。
浸泡温度为36-38℃,浸泡时间为6-48h。
茶多酚(TP)溶液的质量百分数为20%。
甲基丙烯酸化水凝胶(GelMA)的制备,按照下述步骤进行:
步骤1,将明胶置于40℃的水浴中充分溶解于去离子水中,然后,向上述溶液中加入溶剂体积2/3的N,N-二甲基甲酰胺(DMF),待溶液澄清后,再加入甲基丙烯酸酐,置于40℃下反应2h沉降后,即得到产物,将所得产物溶于去离子水中再冻干后,即得到甲基丙烯酸化明胶;
步骤2,将步骤1制备得到的甲基丙烯酸化明胶溶解于去离子水中,并向上述溶液中加入光引发剂后,将其注入密闭容器内,将上述密闭容器置于紫外线下进行固化反应30-50min后,即得到甲基丙烯酸化水凝胶(GelMA)。
在步骤1中,明胶来源于猪皮,属于A类明胶。
在步骤2中,甲基丙烯酸化明胶溶液的质量浓度为15-25%,优选20%,光引发剂采用IRGACURE 1173,固化反应为40min。
高强度天然高分子水凝胶在生物医用材料上的应用,经过茶多酚(TP)增强的甲基丙烯酸化水凝胶(GelMA)的拉伸/压缩强度、杨氏模量、断裂伸长率和断裂韧性相较于原始的水凝胶分别提高(18-20)-/(28-32)-、(8.0-8.5)-、(4.0-4.5)-、(70-75)倍;经过茶多酚(TP)增强的增强琼脂糖(AG)水凝胶的拉伸强度、断裂伸长率相较于原始的水凝胶分别提高(4.0-4.5)、(7.0-7.5)倍;经过茶多酚(TP)增强的甲基丙烯酰化的海藻酸钠(Alg-MA)-Ca2+水凝胶的拉伸/压缩强度、杨氏模量、断裂伸长率和断裂韧性相较于原始的水凝胶分别提高(3.5-4.0)/(5.0-5.5)、(2.0-2.5)、(7.0-7.5)倍。
本发明的有益效果为:本发明制备得到的以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)与原始水凝胶相比,经茶多酚(TP)处理的代表性天然高分子(NP)由于茶多酚(TP)和天然高分子(NP)链之间的氢键相互作用,其拉伸/压缩强度、杨氏模量、断裂伸长率和断裂韧性分别提高了19-/30-、8.4-、4.4-、72倍;在PBS缓冲液中,经茶多酚(TP)处理的天然高分子(NP)仍能保持良好的力学性能,并且随着茶多酚(TP)的释放其含水量升高、并且具有抗菌和抗氧化活性;在大鼠全层皮肤损伤模型中进行了体内的生物学实验,以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)组的伤口明显闭合,愈合率达到96%,而对照组和丙烯酰化水凝胶(GelMA)组的愈合率分别只有86%和91%,即说明以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)能够更好的促进伤口愈合;本发明的制备方法简单,材料来源广泛,实用性强。
附图说明
图1是茶多酚(TP)、甲基丙烯酸化水凝胶(GelMA)和以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)的红外谱图;
图2是茶多酚(TP)对甲基丙烯酸化水凝胶(GelMA)的力学性能的影响图以及以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)在生理环境中的力学性能图,其中,A-C)为GelMA-TP-x水凝胶的拉伸性能;D-F)为GelMA-TP-48h水凝胶在PBS缓冲液中浸泡12-72h后拉伸性能的变化;G)为GelMA、GelMA-TP-PBS和GelMA-TP-尿素水凝胶的拉伸应力-应变曲线;
图3是验证茶多酚(TP)对天然高分子水凝胶强度增强的普适性能图,其中,A-B)为AG-TP-x水凝胶的拉伸性能;C-D)为AG-TP-6h水凝胶在PBS缓冲液中浸泡12-72h后拉伸性能的变化;
图4是测定茶多酚(TP)对3D打印的生物支架的增强作用示意图,其中,A)为3D打印六边形、三角形和正方形水凝胶图片;B)为三维打印的六边形、三角形和正方形水凝胶经TP处理后的照片;C)为TP增强的矩形凝胶网格可以抵抗弯曲,卷曲和500克的重量负荷;D)为TP处理后的网状结构水凝胶可提起100g的重量;E)为3D打印水凝胶的拉伸应力-应变曲线;
图5是对以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)清除自由基能力和抗菌性能的测试图,其中,A)为GelMA-TP水凝胶处理DPPH溶液随时间变化的照片;B)为GelMA-TP水凝胶处理DPPH溶液的紫外-可见吸收光谱;C)为GelMA-TP水凝胶对DPPH的清除率随时间的变化;D)为GelMA水凝胶和GelMA-TP水凝胶对大肠杆菌和金黄色葡萄球菌的抑菌环测定;
图6是采用全层皮肤缺损模型图,其中,A)为伤口愈合评估,在第0、3、6、9和12天进行各种治疗后的伤口闭合率的代表性照片,B)为伤口愈合率。
具体实施方式
下面通过具体的实施例对本发明的技术方案作进一步的说明。
实施例1
用托盘天平称取0.2g GelMA于10mL的离心管中,然后加入1mL去离子水将其溶解,最后加入4uL的1173于离心管中并将其混匀。将其密封后放入紫外交联仪中进行紫外光照40min。将制备的凝胶于37℃下浸泡在浓度为20%的TP溶液中48小时得到GelMA-TP水凝胶。
实施例2
用托盘天平称取0.2g GelMA于10mL的离心管中,然后加入1mL去离子水将其溶解,最后加入4uL的1173于离心管中并将其混匀。将其密封后放入紫外交联仪中进行紫外光照40min。将制备的凝胶于38℃下浸泡在浓度为25%的TP溶液中5小时,得到GelMA-TP水凝胶。
实施例3
用托盘天平称取0.3g AG于100mL的烧杯中,然后加入10mL去离子水将其加热至90℃溶解,将其趁热放入模具中制成片状凝胶。将制备的凝胶于37℃下浸泡在浓度为20%的TP溶液中6小时得到AG-TP水凝胶。
实施例4
用托盘天平称取0.3g AG于100mL的烧杯中,然后加入10mL去离子水将其加热至90℃溶解,将其趁热放入模具中制成片状凝胶。将制备的凝胶于36℃下浸泡在浓度为15%的TP溶液中50小时得到AG-TP水凝胶。
实施例5
用托盘天平称取0.08g AlgMA于10mL的离心管中,然后加入1mL去离子去离子水将其溶解,最后加入1.6uL的1173于离心管中并将其混匀。将其放入模具中在紫外交联仪中进行紫外光照40min。将制备的AlgMA水凝胶,在0.5mol L-1氯化钙溶液中浸泡1h,得到AlgMA-Ca2+水凝胶,再在20%的TP溶液中浸泡2h,得到AlgMA-Ca2+-TP水凝胶。
实施例6
用托盘天平称取0.08g AlgMA于10mL的离心管中,然后加入1mL去离子去离子水将其溶解,最后加入1.6uL的1173于离心管中并将其混匀。将其放入模具中在紫外交联仪中进行紫外光照40min。将制备的AlgMA水凝胶,在0.5mol L-1氯化钙溶液中浸泡1h,得到AlgMA-Ca2+水凝胶,39℃下浸泡在浓度为22%的TP溶液中36小时,得到AlgMA-Ca2+-TP水凝胶。
如图1所示,茶多酚(TP)在3384cm-1处的峰值属于羟基的伸缩振动峰;在甲基丙烯酸化水凝胶(GelMA)谱图中1642和1526cm-1处的峰值属于明胶主链的特征峰,3326cm-1处的峰归属于甲基丙烯酸化水凝胶(GelMA)中的N-H振动,而在以明胶为基底的高强度天然高分子水凝胶(GelMA-TP)的红外谱图中该峰值蓝移至3309cm-1,表明甲基丙烯酸化水凝胶(GelMA)和茶多酚(TP)之间形成了氢键。
如图2所示,图2A,2B,2C表明,茶多酚(TP)的处理有助于增强水凝胶的力学性能。GelMA水凝胶在较小的拉伸应力(50kPa)/应变(55%)和压缩应力(150kPa)/应变(42%)下破裂。相比之下,GelMA-TP-x水凝胶表现出很好的机械性能,拉伸强度(从0.06到1.14MPa)、杨氏模量(从0.09MPa到0.76MPa)和断裂应变(从55%到276%)分别增加了19倍、8.4倍和5倍。并且GelMA-TP-48h水凝胶的断裂韧性可达1.13MJ/m3,是GelMA凝胶的72倍,说明茶多酚(TP)增强了水凝胶的韧性。图2D,2E,2F是测定了GelMA-TP水凝胶在37℃PBS中的力学性能。在PBS中浸泡72h后,水凝胶的拉伸强度、杨氏模量、断裂伸长率和韧性分别保持在0.39MPa、0.36MPa和200%和0.35MJ/m3。这表明,GelMA-TP水凝胶即使在37℃下浸泡72h也能保持良好的力学性能。为了进一步验证茶多酚(TP)与甲基丙烯酸化水凝胶(GelMA)之间的氢键相互作用,将GelMA-TP-48h水凝胶浸泡在5mol/L的尿素溶液(氢键破坏剂)中,24h后进行拉伸力学测试,如图2G所示,GelMA-TP-48h水凝胶在PBS中浸泡24h后的拉伸应力可以达到0.45MPa,但在尿素溶液中浸泡后,拉伸强度急剧下降到80kPa,与原GelMA水凝胶的力学性能相似。这说明尿素导致了甲基丙烯酸化水凝胶(GelMA)和茶多酚(TP)之间氢键的断裂,间接证明茶多酚(TP)的增强机制主要是茶多酚(TP)与甲基丙烯酸化水凝胶(GelMA)之间的氢键相互作用。
如图3所示,将琼脂糖水溶液(3%m/v)冷却至室温形成琼脂糖(AG)水凝胶,然后用茶多酚(TP)处理琼脂糖(AG)水凝胶;图3A和3B给出了力学性能测试结果,琼脂糖(AG)水凝胶在茶多酚(TP)中浸泡6h后,拉伸强度和断裂伸长率分别达到0.52MPa和153%,是琼脂糖(AG)水凝胶的4.3倍和6.1倍。图3C和3D是测定了它们在PBS中的稳定性,AG-TP水凝胶在PBS中浸泡72h后可保持0.3MPa的拉伸强度和50%的断裂应变,表明在盐溶液中也具有一定的力学稳定性。
如图4所示,采用海藻酸钠(Alg)与甲基丙烯酸化水凝胶(GelMA)混合溶液作为生物墨水进行打印然后在紫外光下聚合形成GelMA/Alg水凝胶,然后在茶多酚(TP)溶液中浸泡。GelMA/Alg混合溶液表现出极好的印刷适性,并被印刷成六边形、三角形和正方形结构,在茶多酚(TP)溶液中浸泡12h后其结构大大缩小并保持高打印保真度(图4A和4B)。图4C显示TP增强的矩形凝胶网格可以抵抗弯曲、卷曲,甚至可以举起500g的重量。经TP处理的GelMA/Alg水凝胶渔网可承受100g重量(图4D)。此外还测定了打印凝胶的拉伸性能,如图4E所示,3D打印GelMA/Alg原始水凝胶的拉伸应力和断裂伸长率分别为0.12MPa和42%;而GelMA/Alg-TP的拉伸强度和断裂应变可以达到0.72MPa和102%。
如图5所示,通过1,1-二苯基-2-三硝基苯肼(DPPH)法研究了GelMA-TP水凝胶对自由基的清除能力,将2.5mg GelMA-TP-48h水凝胶置于25mL DPPH溶液中,每5min进行拍照。如图5A所示,随着时间的推移,DPPH溶液从紫色变为黄色,这意味着GelMA-TP水凝胶可以有效去除DPPH自由基(图5A)。此外,我们还测定了其在520nm处的吸光度,并计算了DPPH自由基的清除率。如图5B和5C所示,经GelMA-TP处理后的DPPH溶液其在520nm处的吸光度随着孵育时间的延长而降低,20min时其在520nm处的吸收峰几乎消失,并且ROS清除率在15min时可达到67.5%,这表明GelMA-TP水凝胶具有良好的自由基清除活性。此外,对GelMA-TP水凝胶对金黄色葡萄球菌和大肠杆菌的体外抗菌性能也进行了测定。如图5D所示,GelMA-TP水凝胶对大肠杆菌和金黄色葡萄球菌具有明显的抑菌环,而在空白组和GelMA水凝胶组没有出现抑菌环,表明茶多酚(TP)赋予了水凝胶抗菌性能。
如图6所示,在不同的时间段追踪GelMA和GelMA-TP-48h水凝胶处理的伤口闭合情况,并将未处理的缺损皮肤作为对照组。从图6A中可以看出,治疗3天后,GelMA-TP-48h组、GelMA组和对照组的伤口大小开始出现差异。第12天,与对照组和GelMA组相比,GelMA-TP组的伤口明显闭合,愈合率达到96%,而对照组和GelMA组的愈合率分别只有86%和91%(图6B),说明GelMA-TP凝胶能够更好的促进伤口愈合。
以上对本发明做了示例性的描述,应该说明的是,在不脱离本发明的核心的情况下,任何简单的变形、修改或者其他本领域技术人员能够不花费创造性劳动的等同替换均落入本发明的保护范围。
Claims (10)
1.高强度天然高分子水凝胶,其特征在于:在35-40℃下,将待增强强度的水凝胶浸泡在茶多酚(TP)溶液中5-50h后,即得到高强度天然高分子水凝胶,其中,茶多酚(TP)溶液的质量百分数为15-25%。
2.根据权利要求1所述的高强度天然高分子水凝胶,其特征在于:待增强强度的水凝胶包括甲基丙烯酸化水凝胶(GelMA)、增强琼脂糖(AG)水凝胶和甲基丙烯酰化的海藻酸钠(Alg-MA)-Ca2+水凝胶。
3.根据权利要求1所述的高强度天然高分子水凝胶,其特征在于:浸泡温度为36-38℃,浸泡时间为6-48h。
4.根据权利要求1所述的高强度天然高分子水凝胶,其特征在于:茶多酚(TP)溶液的质量百分数为20%。
5.高强度天然高分子水凝胶的制备方法,其特征在于:在35-40℃下,将待增强强度的水凝胶浸泡在茶多酚(TP)溶液中5-50h后,即得到高强度天然高分子水凝胶,其中,茶多酚(TP)溶液的质量百分数为15-25%。
6.根据权利要求5所述的高强度天然高分子水凝胶的制备方法,其特征在于:待增强强度的水凝胶包括甲基丙烯酸化水凝胶(GelMA)、增强琼脂糖(AG)水凝胶和甲基丙烯酰化的海藻酸钠(Alg-MA)-Ca2+水凝胶。
7.根据权利要求5所述的高强度天然高分子水凝胶的制备方法,其特征在于:浸泡温度为36-38℃,浸泡时间为6-48h。
8.根据权利要求5所述的高强度天然高分子水凝胶的制备方法,其特征在于:茶多酚(TP)溶液的质量百分数为20%。
9.如权利要求1-4任一所述的高强度天然高分子水凝胶在生物医用材料中的应用,其特征在于:经茶多酚(TP)处理的天然高分子(NP),使得茶多酚(TP)和天然高分子(NP)链之间存在氢键的相互作用,使得其拉伸/压缩强度、杨氏模量、断裂伸长率和断裂韧性分别有了明显的提高,且高强度天然高分子水凝胶能够更好的促进伤口愈合。
10.根据权利要求9所述的应用,其特征在于:高强度天然高分子水凝胶的ROS清除率为65-70%,与未增强的水凝胶相比,高强度天然高分子水凝胶的愈合率为95-97%。
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CN111286045A (zh) * | 2020-03-11 | 2020-06-16 | 广东省医疗器械研究所 | 一种多酚类物质氢键增强水凝胶 |
CN111518290A (zh) * | 2020-06-28 | 2020-08-11 | 河南省科学院同位素研究所有限责任公司 | 一种高透明度高韧性抗菌型聚乙烯醇水凝胶及其制备方法 |
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