CN108864494B - 一种动态交联双网络水凝胶及其制备方法与应用 - Google Patents
一种动态交联双网络水凝胶及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种动态交联双网络水凝胶及其制备方法与应用。所述动态交联双网络水凝胶由主网络和次网络于水性介质中经穿插缠结形成;主网络为动态的共价键交联聚合物;次网络为离子键交联聚合物;共价键交联聚合物由聚合物A与聚合物B经共价键交联形成;离子键交联聚合物由聚合物C与离子化合物经离子键交联形成。本发明制备方法简单,可原位注射成型,即可在复合凝胶几种成分复合后迅速原位形成水凝胶,常温即可进行,用此种方法制备出的水凝胶可以在所需部位快速形成所需形状,无需提前制备模型,极为快速方便,同时考虑到它所具备的优良的力学性能,使其在组织修复中的应用具备广阔前景。
Description
技术领域
本发明涉及一种双网络水凝胶,具体涉及一种动态交联双网络水凝胶及其制备方法与应用。
背景技术
水凝胶是一种网络交联三维结构的高分子材料,它以水为分散介质,水凝胶的优点是含水量极高,和人体组织相似,并且可以通过改性获得很好的组织相容性、可降解性和较低的细胞毒性,使其在药物输送和组织修复中应用广泛。
常用水凝胶材料可以分为天然高分子和人工合成高分子。其中天然高分子材料包括蛋白:胶原、蚕丝蛋白、纤维蛋白等;多糖:壳聚糖及衍生物、透明质酸酶、海藻酸、淀粉基材料、纤维素、右旋糖苷等。它们的优点是:低毒性、生物降解性,比较低的加工处理费用,再生能力,有利于细胞依附和再生。缺点是:较低的机械、热、化学稳定性,有可能引发排斥反应和有疾病传播的风险。制备过程中有可能失去生物活性。人工合成高分子材料发展比较成熟的有PLGA、PCL、PLA、POE、PPF、PUAs、PURs以及它们的共聚物,可以通过改变它们的分子量、共聚比,在较大范围内改变它们的机械性能、降解性能等。例如PLA等的降解速率受很多因素形象,如移植物尺寸、化学组成、晶区和非晶区形态比例、多分散性、环境因素等,改变这些条件则有可能改变材料的可降解性。然而人工合成高分子面临细胞毒性、生物相容性等一系列问题。
发明内容
本发明的目的是提供一种动态交联双网络水凝胶及其制备方法与应用,本发明利用了天然高分子的低毒性、优良的生物相容性和较低廉的加工成本,制备出了一种动态交联的双网络水凝胶,通过主次网络之间的相互配合,得到了力学性能优异的水凝胶材料,为其实现对软骨等对力学性能要求较高的组织材料的修复提供了可能性,同时此种水凝胶具备可注射性能。
本发明所提供的动态交联双网络水凝胶,由主网络和次网络于水性介质中穿插缠结形成;
所述主网络为动态的共价键交联聚合物;
所述次网络为离子键交联聚合物。
本发明动态交联双网络水凝胶中所述主网络与所述次网络之间没有任何的相互作用。
本发明动态交联双网络水凝胶中的“动态”指的是成键不稳定,断裂后具备一定可恢复能力的键合方式,如在酸性条件下。
上述的动态交联双网络水凝胶中,所述共价键交联聚合物由聚合物A与聚合物B经共价键交联形成;
所述聚合物A可为聚乙烯胺、聚丙烯酰胺、羧甲基壳聚糖、羟乙基壳聚糖、PEG接枝多巴胺和PEG接枝苯硼酸中至少一种;
所述PEG接枝多巴胺指的是一个PEG分子链两端分别接枝一个多巴胺分子,其中多巴胺的接枝率可为50~100%,所述接枝率指的是PEG分子链两端成功接枝上多巴胺分子的摩尔比;
所述PEG接枝苯硼酸指的是一个PEG分子链两端分别接枝一个苯硼酸分子,其中苯硼酸的接枝率可为50~100%,所述接枝率指的是PEG分子链两端成功接枝上苯硼酸分子的摩尔比;
所述聚合物A的分子量可为5~5000kDa。
上述的动态交联双网络水凝胶中,所述聚合物B可为聚乙烯醇和/或PEG接枝醛基;
所述PEG接枝醛基指的是一个PEG分子链两端分别接枝一个苯甲醛分子,其中醛基的接枝率可为50~100%,所述接枝率指的是PEG分子链两端成功接枝上苯甲醛分子的摩尔比;
所述聚合物B的分子量可为5~5000kDa。
上述的动态交联双网络水凝胶中,所述离子键交联聚合物由聚合物C与离子化合物经离子键交联形成;
所述聚合物C为聚丙烯酸、聚甲基丙烯酸、聚氨基酸、聚乳酸、海藻酸和透明质酸中至少一种;
所述聚合物C的分子量可为5~5000kDa。
述的动态交联双网络水凝胶中,所述离子化合物可为氯化镁、氯化钙、氯化铁、氯化锌、磷酸钡、氯化钡和氯化铝中至少一种。
上述的动态交联双网络水凝胶中,所述水性介质没有特殊要求,可选择水、生理盐水、缓冲溶液、乙酸溶液、组织培养液或体液。
本发明还提供了所述动态交联双网络水凝胶的制备方法,包括如下步骤:
将所述主网络和所述次网络的组分均溶于所述水性介质中,然后混合后经搅拌即得。
具体地,可按照下述1)或2)的方式混合:
1)将所述聚合物A、所述聚合物B、所述聚合物C和所述离子化合物分别溶于所述水性介质中,然后将得到的4种溶液混合;
2)将所述聚合物A和所述离子化合物溶于所述水性介质中得到混合溶液1,将所述聚合物B和所述聚合物C溶于所述水性介质中得到混合溶液2,再将混合溶液1和混合溶液2混合。
对于混合搅拌的温度没有特殊限制,室温即可,便于原位包封如蛋白、多肽、药物或细胞等生物活性物质。
优选的将各组分分别溶解后混合;
各溶液中,各组分的浓度可为5~200mg/mL,具体可为20~40mg/mL、20mg/mL或40mg/mL。
本发明所述动态交联双网络水凝胶可用于组织工程或组织修复中,特别是软骨组织的修复。
与现有技术相比,本发明所述的双网络水凝胶,主网络以共价键形式交联,次网络以离子键形式交联,动态交联双网络的形成使水凝胶具备了优良的力学性能,同时,本发明制备方法简单,可原位注射成型,即可在复合凝胶几种成分复合后迅速原位形成水凝胶,常温即可进行,用此种方法制备出的水凝胶可以在所需部位快速形成所需形状,无需提前制备模型,极为快速方便,同时考虑到它所具备的优良的力学性能,使其在组织修复中的应用具备广阔前景。
附图说明
图1为实施例1制备的壳聚糖单网络水凝胶的扫描电镜图片。
图2为实施例1制备的海藻酸钙单网络水凝胶的扫描电镜图片。
图3为实施例1制备的双网络水凝胶的扫描电镜图。
图4为实施例1制备的双网络水凝胶分别降解其中一种网络后与其对应的单网络力学性能对比图。
图5为实施例1制备的双网络水凝胶的动态键可自修复演示。
图6为实施例5制备的单双网络水凝胶的压缩应力-应变曲线。
图7为实施例7制备的双网络水凝胶注射演示示意图。
图8为实施例12中小鼠皮下包埋水凝胶4周和8周的H&E组织切片。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
以下实施例涉及的RPMI1640、DMEM培养基为Gibco公司生产的市售产品。
以下实施例中使用的PEG接枝醛基(CHO-PEG-CHO)是按照下述方法制备的:
将4-羧基苯甲醛2.4g、二环己基碳二亚胺3.3g和4-二甲氨基吡啶0.122g用二氯甲烷溶解后加入用二氯甲烷溶解的聚乙二醇(2000Da)4g,37℃反应24小时后用乙酸乙酯200μL终止反应,半小时后过滤,将滤出液旋蒸,抽滤,加入异丙醇70℃溶解,冷却后放入-20℃冰箱重结晶,结晶产物过滤,将固体用乙醚和异丙醇各冲洗两次,离心3次,取上清液,冻干得最终产物。所制备的CHO-PEG-CHO中,醛基的接枝率为80%。
以下实施例中使用的PEG接枝苯硼酸是按照下述方法制备的:
HO-PEG-OH3g、对羧基苯硼酸2.656g、DCC3.7g和DMAP0.1757g一次性加入100mlDCM中,常温搅拌反应48h,过滤,旋蒸除去DCM,产物用水溶解,离心三次除去不溶物,冷冻干燥得最终产物。所制备的PEG接枝苯硼酸中,苯硼酸的接枝率为85%。
以下实施例中未特殊说明的所使用的水性介质皆为去离子水。
实施例1、羟乙基壳聚糖/海藻酸钙动态交联双网络水凝胶的制备
配制20mg/ml羟乙基壳聚糖和20mg/ml氯化钙的混合溶液1,配制20mg/mlCHO-PEG-CHO和20mg/ml海藻酸钠的混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,即为羟乙基壳聚糖/海藻酸钙动态交联双网络水凝胶,在万能试验机上进行力学压缩实验,得到压缩应力为0.12MPa,断裂形变率为52%。
制备20mg/ml的羟乙基壳聚糖溶液和20mg/ml的CHO-PEG-CHO溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,即为壳聚糖单网络水凝胶,在万能试验机上进行力学压缩实验,得到压缩应力为0.01MPa,断裂形变率为45%。
制备20mg/ml的海藻酸溶液和20mg/ml氯化钙溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体即为海藻酸钙单网络水凝胶,在万能试验机上进行力学压缩实验,海藻酸钙水凝胶由于没有断裂点,取形变为52%处的压缩应力为0.015MPa。
由上述对单双网络水凝胶的力学压缩实验可以看出,相比于单网络水凝胶,双网络水凝胶的压缩模量(压缩应力)、压缩断裂能(断裂形变率)均有大幅度提高;这是因为双网络水凝胶由于有主网络作为刚性网络,能够维持水凝胶基本形态,次网络作为柔性网络,能够分散外界应力,因此获得了优良的力学性能,可见主网络和次网络之间的配合,协同促进了双网络水凝胶的力学性能提升。
本实施例制备的壳聚糖单网络水凝胶、海藻酸钙单网络水凝胶和双网络水凝胶的扫描电镜图片分别如图1、图2和图3所示,由上述各图可以看出,壳聚糖单网络水凝胶孔洞形状较为圆滑,孔洞尺寸较小;海藻酸钙单网络水凝胶孔洞形状则有一些棱角,孔洞尺寸相对较大,双网络水凝胶切面图中既有小而圆滑的孔洞,又有大而有一定棱角的孔洞,因而兼具两种单网络水凝胶的特点。
将本实施例制备的的双网络水凝胶分为两组,其中一组使用pH=5的醋酸溶液破坏掉席夫碱反应形成的亚胺键,去除第一层网络(壳聚糖单网络水凝胶),得到残余的海藻酸钙单网络水凝胶,记为Alg residue,测定其力学性能,如图4所示,得到形变量为52%处的压缩应力为0.016MPa,性能接近于第二层网络(海藻酸钙单网络水凝胶),证明第一层网络被完全去除。
另一组使用EDTA螯合钙离子以去除第二层网络(海藻酸钙单网络水凝胶),得到残余的壳聚糖单网络水凝胶,记为GC residue,测定其力学性能,如图4所示,得到压缩应力为0.01MPa,断裂形变率47%,性能接近于第一层网络(壳聚糖单网络水凝胶),证明第二层网络被完全去除。
图4中Alg和GC分别表示本实施例单独制备的海藻酸钙单网络水凝胶和壳聚糖单网络水凝胶,由图4可以看出,本发明双网络水凝胶中两种单网络水凝胶相互独立,并没有如氢键等的相互作用。
将本实施例制备的水凝胶分成两组,加入不同颜色的染料,分别将混合溶液注入五角星形模具,脱模后将两个五角星形水凝胶切下五角并互换,使用醋酸调节pH=5,几分钟后,水凝胶重新连接成了五角星形,如图5所示。这是因为双网络水凝胶中的第一重网络具有动态共价键,即被破坏的亚胺键,在一定条件下具备自修复能力。
实施例2、羟乙基壳聚糖/海藻酸钙动态交联双网络水凝胶的制备
配制40mg/ml羟乙基壳聚糖和20mg/ml氯化钙的混合溶液1,配制40mg/mlCHO-PEO-CHO和20mg/ml海藻酸钠的混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.23MPa,断裂形变率为54%。
实施例3、聚乙烯胺/聚丙烯酸铁动态交联双网络水凝胶的制备
配制20mg/ml的聚乙烯胺和20mg/ml氯化铁的混合溶液1,配制20mg/mlCHO-PEG-CHO和20mg/ml聚丙烯酸的混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.08MPa,断裂形变率为75%。
制备20mg/ml聚乙烯胺溶液和20mg/ml的CHO-PEG-CHO溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.02MPa,断裂形变率为45%。
制备20mg/ml的聚丙烯酸溶液和20mg/ml氯化铁溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.03MPa,断裂形变率为82%。
实施例4、聚乙烯胺/聚丙烯酸铁动态交联双网络水凝胶的制备
配制40mg/ml的聚乙烯胺和20mg/ml氯化铁混合溶液1,配制40mg/ml的CHO-PEG-CHO和20mg/ml的聚丙烯酸钠混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.12MPa,断裂形变率为79%。
实施例5、羟乙基壳聚糖/聚丙烯酸钙动态交联双网络水凝胶的制备
配制20mg/ml的羟乙基壳聚糖溶液和20mg/ml氯化镁混合溶液1,配制20mg/ml的CHO-PEG-CHO和20mg/ml的聚丙烯酸混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.06MPa,断裂形变率为87%。
制备20mg/ml的羟乙基壳聚糖溶液和20mg/ml的CHO-PEG-CHO溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.01MPa,断裂形变率45%。
制备20mg/ml的聚丙烯酸钠水溶液和20mg/ml氯化镁溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.02MPa,断裂形变率73%。
本实施例制备的单双网络水凝胶的压缩应力-应变曲线如图6所示,其中,gel 1表示羟乙基壳聚糖凝胶,gel 2表示聚丙烯酸钙凝胶,DN gel表示羟乙基壳聚糖/聚丙烯酸钙交联双网络水凝胶,由该图可以看出,相较于两种单网络水凝胶,双网络水凝胶压缩模量和断裂能均获得较大提升。
实施例6、羟乙基壳聚糖/聚丙烯酸钙动态交联双网络水凝胶的制备
配制40mg/ml的羟乙基壳聚糖溶液和20mg/ml氯化镁混合溶液1,配制40mg/ml的CHO-PEG-CHO和20mg/ml的聚丙烯酸钠混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.1MPa,断裂形变率为79%。
实施例7、PEG接枝苯硼酸/透明质酸钙动态交联双网络水凝胶的制备
配制20mg/ml的PEG接枝苯硼酸和20mg/ml氯化钙混合溶液1,配制20mg/ml的PVA和20mg/ml的透明质酸钠混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.11MPa,断裂形变率为85%。
制备20mg/ml的PEG接枝苯硼酸溶液和20mg/ml的PVA溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.02MPa,断裂形变率为91%。
制备20mg/ml的透明质酸钠溶液和100mg/ml氯化钙溶液,混合后注入模具,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.03MPa,断裂形变率为53%。
图7为PEG接枝苯硼酸/透明质酸钙动态交联双网络水凝胶的可注射性能演示,如图7所示,双网络水凝胶由针头挤出后迅速成型,可挤出成特定形状,说明此双网络水凝胶具备可注射性能。
实施例8、PEG接枝苯硼酸/透明质酸钙动态交联双网络水凝胶的制备
配制40mg/ml的PEG接枝苯硼酸和20mg/ml氯化钙混合溶液1,配制40mg/ml的PVA和20mg/ml的透明质酸钠混合溶液2,将混合溶液1和混合溶液2混合并室温搅拌,混合注入特殊模具,得到动态交联双网络水凝胶,5分钟后从模具中脱模,得到规则柱状体,在万能试验机上进行力学压缩实验,得到压缩应力为0.25MPa,断裂形变率为81%。
实施例9、
将聚乙烯胺、氯化铁、CHO-PEG-CHO和聚丙烯酸钠分别高压蒸汽灭菌,按照实施例3所述方法在超净台上制备单双网络水凝胶,溶剂使用RPMI1640培养基溶液,将制备好的水凝胶浸泡于RPMI1640培养基中24h制备单双网络水凝胶的浸提液。
24小时后,将正常培养的贴壁L929细胞使用胰酶消化,转移入加入浸提液的96孔板中,使用RPMI1640培养基正常培养的L929作为对照组。
24小时后,使用CCK-8试剂盒测定单双网络水凝胶对于L929细胞的毒性,聚乙烯胺水凝胶浸提液、聚丙烯酸铁凝胶浸提液和双网络水凝胶浸提液的细胞活力分别为92%、87%和85%,表明单双网络水凝胶浸提液对细胞生长均无毒性。
实施例10、
将成纤维细胞L929分散于葡聚糖RPM1640溶液,混合于海藻酸溶液中,按实施例1的方法形成双网络凝胶。将凝胶置于RPMI 1640培养基中进行培养,培养基中另外加入10%胎牛血清(FBS)、1%青霉素和1%链霉素。CCK-8试剂盒测定L929细胞在凝胶中的增殖情况为:细胞在4天内增殖初始细胞量的252%,第7天增殖478%,由此可以看出,所制备的凝胶具有很好的生物相容性,并能促进L929细胞的增殖。
实施例11、
将成软骨细胞ATDC5分散于葡聚糖DMEM溶液,混合于海藻酸溶液中,按实施例7方法形成的双网络凝胶。将凝胶置于DMEM培养基中进行培养,培养基中另外加入10%胎牛血清(FBS)、1%青霉素和1%链霉素。CCK-8试剂盒测定L929细胞在凝胶中的增殖情况为:细胞在4天内增殖初始细胞量的204%,第7天增殖356%,由此可以看出,所制备的凝胶具有很好的生物相容性,并能促进ATDC5细胞的增殖。
实施例12、
动物实验:取成年Balb/c小鼠(六周,体重20-25g),分为三组,分别为实验组,壳聚糖对照组和海藻酸对照组。实验组小鼠注射实施例9的双网络水凝胶,壳聚糖对照组注射浓度为实施例1的壳聚糖水凝胶,海藻酸对照组注射浓度为实施例1的海藻酸水凝胶。分别于2周、4周和6周后处死小鼠。取出包含凝胶的组织,10%福尔马林溶液固定,石蜡包埋切片,HE染色观察。
图8为小鼠4周、8周后双网络及两种单网络HE染色切片,单双网络水凝胶在小鼠皮下均无明显炎症反应,说明凝胶生物相容性良好。两种单网络水凝胶降解速率较快,8周后基本降解完全,而双网络水凝胶8周后仍有部分未降解,说明双网络水凝胶在降解速率上有较大提升,有助于包载细胞的增殖及分化。
Claims (1)
1.一种动态交联双网络水凝胶,其特征在于:所述动态交联双网络水凝胶由主网络和次网络于水性介质中经穿插缠结形成,所述主网络与所述次网络之间没有任何的相互作用;
所述主网络为动态的共价键交联聚合物;
所述次网络为离子键交联聚合物;
所述共价键交联聚合物由聚合物A与聚合物B经共价键交联形成;
所述聚合物A为聚乙烯胺、聚丙烯酰胺、羧甲基壳聚糖、羟乙基壳聚糖、PEG接枝多巴胺和PEG接枝苯硼酸中至少一种;
所述聚合物B为聚乙烯醇和/或PEG接枝醛基;
所述离子键交联聚合物由聚合物C与离子化合物经离子键交联形成;
所述聚合物C为聚丙烯酸、聚甲基丙烯酸、聚氨基酸、聚乳酸、海藻酸和透明质酸中至少一种;
所述离子化合物为氯化镁、氯化钙、氯化铁、氯化锌、磷酸钡、氯化钡和氯化铝中至少一种;
所述水性介质为水、生理盐水、缓冲溶液、乙酸溶液、组织培养液或体液。
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