CN114133593A - 一种纤维素-聚乙二醇-层状二氧化硅复合水凝胶及其应用 - Google Patents

一种纤维素-聚乙二醇-层状二氧化硅复合水凝胶及其应用 Download PDF

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CN114133593A
CN114133593A CN202111405230.2A CN202111405230A CN114133593A CN 114133593 A CN114133593 A CN 114133593A CN 202111405230 A CN202111405230 A CN 202111405230A CN 114133593 A CN114133593 A CN 114133593A
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CN114133593B (zh
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胡怡晨
潘震
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Shanghai Ruining Biotechnology Co ltd
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Abstract

本发明公开了一种纤维素‑聚乙二醇‑层状二氧化硅复合水凝胶，包括改性水溶性纤维素和/或其盐、层状二氧化硅、聚乙二醇、无机盐和水。本发明利用层状二氧化硅提高纤维素水凝胶的稳定性的同时向体系内加入聚乙二醇，显著改善了层状二氧化硅引起体系粘度的大幅增加的问题，适用于注射或者通过细导管介入纤维素水凝胶的治疗。本发明所述复合水凝胶相对于化学交联法具有不引入交联剂和使用简单的优点，具有广阔的应用前景。

Description

一种纤维素-聚乙二醇-层状二氧化硅复合水凝胶及其应用
技术领域
本发明属于生物医用材料领域，特别涉及一种可注射用的纤维素-聚乙二醇-层状二氧化硅复合水凝胶及其应用。
技术背景
纤维素是D-吡喃型葡萄糖单元(AGU)以β-1,4苷键连接形成的线型高分子，是自然界最丰富的有机高分子，具有可再生、绿色和生物相容性，是化学化工的重要基础原材料。纤维素分子中存在大量的氢键,易形成复杂的分子间和分子内氢键作用，结晶度高使其不溶于水及一般有机溶剂。当前纤维素的改性技术主要由醚化和酯化两方面。纤维素醚是纤维素经醚化改性而制得的一类纤维素衍生物，可溶于水和有机溶剂，其水溶液具有增稠、成膜等作用，具有良好的生物相容性和生物可降解性，安全无毒，对皮肤、黏膜无刺激性，无免疫反应，在医学领域应用非常广泛。
然而，尽管改性的纤维素具有良好的生物相容性和生物降解性的优点，作为生物材料而具有极高的应用价值，但其在人体内吸收迅速以及在组织内停留时间短等缺点而限制了其应用，通常以物理交联、化学交联或复合材料的形式提高纤维素水凝胶的降解时间。
专利US10052408B2报道了一种基于羧甲基纤维素的防粘连材料，通过钙离子将羧甲基纤维素和聚乙二醇进行物理交联，可以提高体系的稳定性。专利CN104327307A公布了一种纤维素类的可生物降解水凝胶的制备方法，利用聚乙二醇二缩水甘油醚作为交联剂，得到可生物降解的羧甲基纤维素水凝胶，通过调节羧甲基纤维素和交联剂的比例可以调节水凝胶的降解率。
此外，可以通过加入无机纳米材料调控水凝胶的物理性质。二氧化硅层状材料由于具有独特的静电性质、均一的尺寸和生物活性在药物、化妆品和食物中作为有效成分或者粘度调节剂有广泛应用。例如，在明胶中加入二氧化硅层状材料可以提高水凝胶的稳定性，在48小时内的降解率由50％提高至接近90％。(Biotechnol.J.2020,1900456)将Laponite二氧化硅层状材料加入至海藻酸水凝胶中，制得剪切变稀的非牛顿流体，可以通过针筒注射，在体内形成固体凝胶。(Adv.Sci.2019,6,1901041)
发明内容
本发明针对现有技术纤维素衍生物水凝胶易降解的问题，向纤维素衍生物水凝胶加入层状二氧化硅以提高凝胶的稳定性，又利用聚乙二醇解决层状二氧化硅加入后导致凝胶粘度的大幅增加的问题，得到一种可注射的稳定的纤维素复合水凝胶。
本发明具体技术方案如下：
一种改性纤维素复合水凝胶，包括改性水溶性纤维素和/或其盐、层状二氧化硅、聚乙二醇、无机盐和水。
优选的，所述改性水溶性纤维素为聚阴离子纤维素，进一步优选为醚化的纤维素(纤维素醚)，包括单一醚类和混合醚类。单一醚类包括烷基醚(如乙基纤维素、丙基纤维素、苄基纤维素、苯基纤维素、氰乙基纤维素等)、羟烷基醚(如羟甲基纤维素、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)等)、羧烷基醚(如羧甲基纤维素(CMC)、羧乙基纤维素等。混合醚类是指分子结构中连有两个及以上基团的醚类，如苄基氰乙基纤维素、羧甲基羟乙基纤维素、羧甲基羟丙基纤维素、羟丙基甲基纤维素(HPMC)、2-羟基-3-丁氧基丙基羟乙基纤维素(HBPEC)等。本发明所述醚化纤维素可选自单一醚类和混合醚类纤维素中的一种或几种。优选羟烷基醚、羧烷基醚、羧烷基羟烷基醚类纤维素中的一种或几种。本发明一个具体的示例为羧甲基纤维素(CMC)。
本发明所述改性水溶性纤维素分子量为2000-2000000Da，取代度为0.6-0.9。优选分子量为90000-700000Da，取代度为0.7-0.9。
本发明所述聚乙二醇分子量为300-4000000Da。优选4000-10000Da。
本发明所述层状二氧化硅材料为天然或人工合成，本发明一个具体的示例，层状二氧化硅购自于德国BYK公司的Laponite XLG产品。
本发明所述无机盐为碱金属盐和/或者碱土金属盐。无机盐作为电解质在水溶液中与纤维素分子争夺水分子，达到增稠的作用。优选的，无机盐为钙盐和/或钠盐。一个具体的示例为氯化钙和氯化钠。
优选的，本发明所述的复合水凝胶中改性水溶性纤维素、层状二氧化硅、聚乙二醇的质量比为0.05-5：0.05-5：0.05-10。优选0.5-3：0.5-3：0.5-5。
优选的，本发明所述的复合水凝胶中改性水溶性纤维素、层状二氧化硅、聚乙二醇的质量百分含量分别为0.05-5％，0.05-5％和0.05-10％。优选0.5-3％，0.5-3％和0.5-5％更优选的，本发明所述的复合水凝胶包括羧甲基纤维素/羧甲基纤维素钠、层状二氧化硅、聚乙二醇、氯化钙、氯化钠和水，羧甲基纤维素的分子量为90000-700000Da，取代度为0.7-0.9，聚乙二醇分子量为4000-10000Da，羧甲基纤维素、层状二氧化硅、聚乙二醇的质量比为0.5-3：0.5-3：0.5-5。
本发明一个具体的方案，所述复合水凝胶包括羧甲基纤维素/羧甲基纤维素钠、层状二氧化硅、聚乙二醇、氯化钙、氯化钠和水，羧甲基纤维素/羧甲基纤维素钠的分子量为70000Da0，取代度为0.9，聚乙二醇分子量为6000Da，羧甲基纤维素/羧甲基纤维素钠、层状二氧化硅、聚乙二醇的质量百分含量为1.5％，1.5％，1.5％。
本发明另一目的在于提供本发明所述的复合水凝胶在制备组织填充剂、组织防粘连剂、组织工程支架、封合剂或栓塞剂中的应用。
本发明还提供了所述复合水凝胶的制备方法，将改性水溶性纤维素加入水中搅拌均匀，继续加入层状二氧化硅，搅拌均匀，进一步加入无机盐和聚乙二醇混合粉末，搅拌均匀，得到复合水凝胶。
本发明优点：
本发明利用层状二氧化硅提高纤维素水凝胶的稳定性的过程中，发现虽然层状二氧化硅能够提高纤维素水凝胶的稳定性，但是会引起体系粘度的大幅增加，这给注射或者通过细导管介入纤维素水凝胶带来极大的问题。在解决上述问题过程中，本发明研究意外发现向体系内加入聚乙二醇后，能够显著改善体系粘度大的问题，同时保证纤维素水凝胶的稳定性。本发明技术方案相对于化学交联法具有不引入交联剂和使用简单的优点，具有广阔的应用前景。
具体实施方式
下面结合具体实施例并参照数据进一步详细描述本发明，应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在本发明中使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1CMC复合水凝胶的制备
以分子量为70万，取代率为0.9的CMC为例，考察加入层状二氧化硅和聚乙二醇对水凝胶粘度的影响。
CMC水凝胶1号样品：将0.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀，得到CMC水凝胶1号样品。
CMC水凝胶2号样品：将0.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀，继续加入0.5g层状二氧化硅Laponite，搅拌均匀，得到CMC水凝胶2号样品。
CMC水凝胶3号样品：将0.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀。继续加入0.5g Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和1g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到CMC水凝胶3号样品。
CMC水凝胶4号样品：将1.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀，得到CMC水凝胶4号样品。
CMC水凝胶5号样品：将1.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀，继续加入0.5g层状二氧化硅Laponite搅拌均匀，得到CMC水凝胶5号样品。
CMC水凝胶6号样品：将1.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀。继续加入0.5g Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和0.25g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到CMC水凝胶6号样品。
CMC水凝胶7号样品：将5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀，得到CMC水凝胶7号样品。
CMC水凝胶8号样品：将5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀，继续加入0.25g层状二氧化硅Laponite搅拌均匀，得到CMC水凝胶8号样品。
CMC水凝胶9号样品：将1.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀。继续加入0.25g Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和5g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到CMC水凝胶9号样品。
粘度测定：将得到的水凝胶样品以SNB型旋转粘度测量仪测定粘度。
结果如表1所示，当CMC的质量百分数为0.5％，1.5％，5％时，在CMC水凝胶体系中加入层状二氧化硅Laponite后，其粘度均有大幅上升，而进一步加入PEG则能够显著降低体系粘度。
特别的，CMC的质量百分数为1.5％时，通过对比水凝胶4-6号样品的粘度发现，在CMC水凝胶体系中加入层状二氧化硅Laponite后，其粘度上升幅度巨大(水凝胶5号)，增大了37.97倍，并且形成流动性差的粘稠状体系，而进一步加入PEG能够显著降低体系粘度(水凝胶6号)。
表1层状二氧化硅和聚乙二醇对纤维素水凝胶粘度的影响
Figure BDA0003372554420000041
Figure BDA0003372554420000051
实施例2
以分子量为70万Da，取代率为0.9的CMC为例，考察加入不同分子量的聚乙二醇对水凝胶粘度的影响。
CMC水凝胶10号样品：将1.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀。继续加入1.5g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和0.25g分子量为600Da的聚乙二醇混合粉末，搅拌均匀，得到CMC水凝胶10号样品。
CMC水凝胶11号样品：将1.5g分子量为70万Da，取代率为0.9的CMC加入至100mL去离子水中，机械搅拌均匀。继续加入1.5g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和0.25g分子量为4000000Da的聚乙二醇混合粉末，搅拌均匀，得到CMC水凝胶11号样品。
表2不同分子量的聚乙二醇对纤维素水凝胶粘度的影响
Figure BDA0003372554420000052
结果如表2所示，结果表明分子量在600-4000000范围内的聚乙二醇能够明显降低加入层状二氧化硅的纤维素凝胶的粘度。
实施例3聚乙二醇对不同分子量的纤维素水凝胶粘度调节能力
CMC水凝胶12号样品：将1.5g分子量为9万Da，取代率为0.7的CMC加入至100mL去离子水中，机械搅拌均匀，得到CMC水凝胶12号样品。
CMC水凝胶13号样品：将1.5g分子量为9万Da，取代率为0.7的CMC加入至100mL去离子水中，机械搅拌均匀，继续加入1.5g层状二氧化硅Laponite搅拌均匀，得到CMC水凝胶13号样品。
CMC水凝胶14号样品：将1.5g分子量为9万Da，取代率为0.7的CMC加入至100mL去离子水中，机械搅拌均匀。继续加入1.5g层状二氧化硅Laponite，搅拌均匀。进一步加入0.235gCaCl2·2H2O，0.215gNaCl和1.5g分子量为6000Da的聚乙二醇混合粉末，搅拌均匀，得到CMC水凝胶14号样品。
结果如表3所示，结合表1和表2的结果可知，分子量在9万-70万Da范围内的CMC能够与层状二氧化硅和聚乙二醇形成粘度理想的复合凝胶。
表3质量分数为1.5％的CMC水凝胶样品的粘度
Figure BDA0003372554420000061
实施例4本发明所述纤维素-聚乙二醇-层状二氧化硅复合水凝胶的稳定性称取1g水凝胶样品置于离心管中，加入10mL，pH值为7.4的磷酸盐缓冲盐溶液，于控制在37℃的恒温水浴摇床中进行稳定性实验。每隔一定时间将样品取出观察状态，当无法取出明显的凝胶时即为降解终点。水凝胶1-9号的稳定性考察结果如表4所示，与纯CMC水凝胶相比，加入层状二氧化硅后可以增加稳定性，继续加入聚乙二醇后稳定性不受影响。例如水凝胶1号为0.5％CMC，其降解周期为2小时，加入0.5％层状二氧化硅的水凝胶2号，降解周期延长至20小时，而进一步加入1％聚乙二醇的水凝胶3号以及加入5％聚乙二醇的水凝胶9号，降解周期维持不变，水凝胶6号的降解周期甚至明显延长，表明本发明所述的纤维素-聚乙二醇-层状二氧化硅复合水凝胶具有理想的粘度以及良好的稳定性。
表4CMC水凝胶样品的稳定性
Figure BDA0003372554420000062
Figure BDA0003372554420000071

Claims (10)

1.一种改性纤维素复合水凝胶，其特征在于包括改性水溶性纤维素和/或其盐、层状二氧化硅、聚乙二醇、无机盐和水。
2.根据权利要求1所述的复合水凝胶，其特征在于所述改性水溶性纤维素为聚阴离子纤维素。
3.根据权利要求2所述的复合水凝胶，其特征在于所述聚阴离子纤维素为纤维素醚，选自甲基纤维素、羟乙基甲基纤维素、羧甲基纤维素、乙基纤维素、乙基羟乙基纤维素、羟乙基羧甲基纤维素、羟丙基羧甲基纤维素、苄基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羟丁基纤维素、氰乙基纤维素、苄基氰乙基纤维素、羧甲基羟乙基纤维素、苯基纤维素中的一种或几种。
4.根据权利要求1所述的复合水凝胶，其特征在于所述改性水溶性纤维素分子量为2000-2000000Da，取代度为0.6-0.9。
5.根据权利要求1所述的复合水凝胶，其特征在于所述聚乙二醇分子量为300-4000000Da。
6.根据权利要求1所述的复合水凝胶，其特征在于所述无机盐为碱金属盐和/或者碱土金属盐。
7.根据权利要求1所述的复合水凝胶，其特征在于所述改性水溶性纤维素、层状二氧化硅、聚乙二醇的质量比为0.05-5：0.05-5：0.05-10。
8.根据权利要求7所述的复合水凝胶，其特征在于包括羧甲基纤维素、层状二氧化硅、聚乙二醇、氯化钙、氯化钠和水，羧甲基纤维素的分子量为90000-700000Da，取代度为0.7-0.9，聚乙二醇分子量为4000-10000Da，羧甲基纤维素、层状二氧化硅、聚乙二醇的质量比为0.5-3：0.5-3：0.5-5。
9.根据权利要求1-8任一项所述的复合水凝胶在制备组织填充剂、组织防粘连剂、组织工程支架、封合剂或栓塞剂中的应用。
10.根据权利要求1-8任一项所述的复合水凝胶的制备方法，其特征在于将改性水溶性纤维素加入水中搅拌均匀，继续加入层状二氧化硅，搅拌均匀，进一步加入无机盐和聚乙二醇混合粉末，搅拌均匀，得到复合水凝胶。
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