CN108676178B - 改性多糖水凝胶的制备方法及制备的改性多糖水凝胶 - Google Patents
改性多糖水凝胶的制备方法及制备的改性多糖水凝胶 Download PDFInfo
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Abstract
本发明公开了一种改性多糖水凝胶的制备方法及制备的改性多糖水凝胶，属于凝胶制备技术领域。上述改性多糖水凝胶的制备方法包括以下步骤：(1)双键改性多糖的制备；(2)两性离子巯基聚合物(CB‑SH)制备；(3)“点击”化学水凝胶的制备。本发明的水凝胶在生理条件即可形成，反应条件简单，温和；透明质酸和两性离子聚合物共同作用，提高了材料的生物相容性，使得水凝胶材料具有较高的平衡含水量，具有抗蛋白性能和自愈合性能等。
Description
技术领域
本发明涉及水凝胶制备技术领域，特别是指一种改性多糖水凝胶的制备方法及制备的改性多糖水凝胶。
背景技术
水凝胶是一种三维交联的聚合物网络，性质柔软，在保持其完整性的同时，吸收大量的水而不溶于水。水凝胶因其优异的溶胀-退溶胀特性和刺激反应行为，在软性隐形眼镜、化学传感器、药物控释材料、组织工程、创面敷料和诊断技术等领域得到了广泛的应用。
凡是水溶性或亲水性的高分子，通过一定的化学交联或物理交联，都可以形成水凝胶。这些高分子按其来源可分为天然和合成两大类，天然的亲水性高分子包括多糖类(淀粉、纤维素、海藻酸、透明质酸，壳聚糖等)和多肽类(胶原、聚L-赖氨酸、聚L-谷胺酸等)。合成的亲水高分子包括醇、丙烯酸及其衍生物类(聚丙烯酸，聚甲基丙烯酸，聚丙烯酰胺等)。
随着功能高分子合成技术的迅速发展，高分子材料除了力学性能外，更需要特殊基团和结构以显示化学功能、物理功能等特殊性能。烯类单体和巯基化合物的种类非常多，使得通过巯基-双键“点击”反应制备功能性的聚合物具有良好的分子可设计性。巯基-双键“点击反应”具有反应高效、快速；不需要金属催化剂；产物易分离提纯，后处理简单等优点，可以将不同功能性的材料结合在一起，从而赋予材料特殊的性能，具有很大的发展潜力。
许多化学交联，辐射交联的水凝胶，由于无法自发形成水凝胶，限制了其在生物体内的应用。天然高分子具有良好的生物相容性、对环境的敏感性以及丰富的来源、低廉的价格和可降解等优点。生理条件下可形成水凝胶且具有良好生物相容性材料具有更好的发展前景。
发明内容
为解决现有技术中很多合成材料生物相容性差，合成条件苛刻等缺点，本发明提供一种改性改性多糖水凝胶的制备方法及制备的改性多糖水凝胶，制备的水凝胶具有良好的生物相容性，抗蛋白吸附性能，自愈性能和较高的平衡含水率等。
为解决上述技术问题，本发明提供技术方案如下：
本发明提供一种改性多糖水凝胶的制备方法，包括以下步骤：
(1)双键改性多糖的制备：
将多糖与水按比例混合均匀，在磁力搅拌下，加入三乙胺、四丁基溴化铵、甲基丙烯酸缩水甘油酯，反应结束后，依次在氯化钠水溶液和去离子水中透析，冻干得到双键改性的透明质酸；
(2)两性离子巯基聚合物(CB-SH)制备：
将两性离子单体和双丙烯酰胱胺(BAC)(即N,N'-双(丙烯酰)胱胺)溶于溶剂中，加入引发剂，反应24h，将上述反应产物在去离子水中透析三天除去未反应的单体和引发剂，之后在氮气保护下，转移至含有PBS(PH＝8)缓冲溶液的烧杯中，加入二硫苏糖醇(DTT)，反应6h后，将产物在酸性去离子水(PH＝3)中透析，冻干得到两性离子巯基聚合物(CB-SH)；
(3)“点击”化学水凝胶的制备：
将步骤1和步骤2制备的原料，按照质量比为1-2：1-2的比例，在37℃水浴中，一段时间自发形成水凝胶。
进一步的，所述步骤(1)中，多糖为透明质酸；所述多糖在水中的浓度为3wt％，所述反应为在室温下反应24h。
进一步的，所述步骤(1)中，所述氯化钠水溶液浓度为0.1mol/L；
所述透析袋截留分子量为Mn＝7000Da。
进一步的，所述步骤(1)中，所述多糖、三乙胺、四丁基溴化铵、甲基丙烯酸缩水甘油酯的重量比为1:2:1:8；
所述步骤(1)中制备的双键改性的透明质酸的双键取代度为60％以上。
进一步的，所述步骤(2)中，两性离子单体为羧酸甜菜碱甲基丙烯酸甲酯(CBMA)；
所述的溶剂为水和乙醇的混合溶剂，混合体积比为1:1；所述的引发剂为过硫酸铵(APS)和N,N,N',N'-四甲基乙二胺(TMEDA)。
进一步的，所述步骤(2)中，所述两性离子单体、双丙烯酰胱胺、引发剂的重量比为30:2.5:1；所述的透析袋为截留分子量Mn＝4000Da，所述冻干温度为-60℃冻干24h。
进一步的，所述步骤(2)制备的两性离子巯基聚合物的巯基含量为0.3M/g。
进一步的，所述步骤(3)，反应时间为1h。
本发明还提供一种上述改性多糖水凝胶的制备方法制备的多糖改性的水凝胶，具有不均匀的孔道结构，平均孔径为100nm，平衡含水量为90％以上，所述多糖改性的水凝胶具有抗蛋白吸附的性能和自愈合性能。
本发明具有以下有益效果：
本发明中，所述的水凝胶在生理条件即可形成，反应条件简单，温和；透明质酸和两性离子聚合物共同作用，提高了材料的生物相容性，使得水凝胶材料具有较高的平衡含水量，具有抗蛋白性能和自愈合性能等。
附图说明
图1为本发明实施例1制备的双键改性多糖、两性离子巯基聚合物和“点击”化学水凝胶的红外表征：a，b，c分别为两性离子巯基聚合物，双键改性多糖和“点击”化学水凝胶的红外表征图谱；
图2为本发明实施例1制备的“点击”化学水凝胶的宏观表象和扫描电镜表征：a为宏观图像，b为扫描电镜图像；
图3为本发明实施例1-3制备的“点击”化学水凝胶的平衡含水量图表；
图4为本发明实施例1-3制备的“点击”化学水凝胶的蛋白吸附图表；
图5为本发明实施例1制备的“点击”化学水凝胶的自愈合性能的实物图，a为水凝胶切割前，b为水凝胶切割后，c为水凝胶自愈合后。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚，下面将结合附图及具体实施例进行详细描述。
以下实施例中所用试剂除特殊说明外，均为市售产品。
本发明提供一种改性多糖水凝胶的制备方法及制备的改性多糖水凝胶。具体说明如下。
实施例1
本发明提供一种改性多糖水凝胶的制备方法，包括以下步骤：
(1)双键改性多糖的制备：
将0.5g透明质酸与水按比例混合均匀，其浓度为3wt％，磁力搅拌下，加入100μL三乙胺，0.47g四丁基溴化铵，3.2mL甲基丙烯酸缩水甘油酯，反应24h后，依次在0.1M氯化钠和去离子水中透析12h，冻干得到双键改性的透明质酸(HAGMA)；
(2)两性离子巯基聚合物(CB-SH)的制备：
将0.5g羧酸甜菜碱甲基丙烯酸甲酯(CBMA)和40mgN,N'-双(丙烯酰)胱胺(BAC)溶于4ml水和乙醇的混合溶剂中，之后加入16mg过硫酸铵，20μL N,N,N',N'-四甲基乙二胺，反应24h，将反应产物在去离子水中透析三天除去未反应的单体和引发剂，之后在氮气保护下，将其转移至含有40ml PBS(PH＝8)缓冲溶液的烧杯中，加入0.5g二硫苏糖醇(DTT)，反应6h后，将产物在酸性去离子水(PH＝3)中透析，冻干得到产物；
(3)“点击”化学水凝胶的制备：
取50mg HAGMA溶于1ml PBS(PH＝7.2)缓冲溶液，搅拌均匀，备用；取0.1g CB-SH溶于1ml PBS(PH＝7.2)缓冲溶液，搅拌均匀，备用。分别取一定量的两种母液，按双键-巯基比例为1:1的比例混合均匀，放入37℃恒温水浴中，1h内凝胶可自发形成。
图1中，b为双键改性的透明质酸的红外谱图，可以看出在1620cm-1处为C＝C的吸收峰，说明透明质酸双键改性成功；1591cm-1处为透明质酸上的N-H的吸收峰；图1中，a为CB-SH的红外谱图2500-2700cm-1为SH的吸收峰，说明二硫键成功被DTT还原成SH；1591cm-1处为N-H的吸收峰；图1中，c为制得的水凝胶的红外谱图，从图中可以看出，2500-2700cm-1处SH吸收峰消失，双键吸收峰基本消失，说明巯基和双键基本完全反应。
图2中，a为水凝胶的宏观图像，从图中可以看出已形成块状凝胶状态，说明水凝胶制备成功，b为水凝胶截面的扫描电镜图像，从图中可以看出，水凝胶具有多空的网络结构，这些不均匀的孔道结构使得水凝胶可以吸收大量的水分。
实施例2
本发明提供一种改性多糖水凝胶的制备方法，包括以下步骤：
(1)双键改性多糖的制备同实施例1步骤(1)；
(2)两性离子巯基聚合物(CB-SH)的制备同实施例1步骤(2)；
(3)“点击”化学水凝胶的制备：
取50mg HAGMA溶于1ml PBS(PH＝7.2)缓冲溶液，搅拌均匀，备用；取0.1g CB-SH溶于1ml PBS(PH＝7.2)缓冲溶液，搅拌均匀，备用；分别取一定量的两种母液，按双键-巯基比例为2:1的比例混合均匀，放入37℃恒温水浴中，1h内凝胶可自发形成。
实施例3
本发明提供一种改性多糖水凝胶的制备方法，包括以下步骤：
(1)双键改性多糖的制备同实施例1步骤(1)；
(2)两性离子巯基聚合物(CB-SH)的制备同实施例1步骤(2)；
(3)“点击”化学水凝胶的制备：
取50mg HAGMA溶于1ml PBS(PH＝7.2)缓冲溶液，搅拌均匀，备用；取0.1g CB-SH溶于1ml PBS(PH＝7.2)缓冲溶液，搅拌均匀，备用。分别取一定量的两种母液，按双键-巯基比例为1:2的比例混合均匀，放入37℃恒温水浴中，1h内凝胶可自发形成。
为进一步说明本发明制备的水凝胶的性能，因篇幅有限，仅以实施例1为例构建对比例如下。
对比例1
将实施例1步骤(2)中的双丙烯酰胱胺替换为等量的DTT，其余条件与实施例1相同。
对上述实施例和对比例制备的水凝胶进行性能测试，具体测试方式及结果如下。
水凝胶平衡水含量的测试：
将水凝胶在PBS缓冲溶液中浸泡，达到吸水平衡后，取出，擦去表面的水分后称重，记作(Ws)，水凝胶冻干后称重，记作(Wd)，测试三组数据。平衡水含量(EWC)计算如式(1)所示：
图3为“点击”化学水凝胶的平衡含水量。从图中可以看出所有比例的凝胶平衡含水量均达到90％以上，表明制备的水凝胶材料具有较好的吸水性能。DTT交联的水凝胶平衡含水量约为87％，相比于双丙烯酰胱胺交联的水凝胶平衡含水量略有下降，这是由透明质酸较高的吸水保水性决定的。
抗蛋白吸附实验：
37℃下，将制备的水凝胶浸泡在PBS缓冲溶液中，达到吸水平衡后，将水凝胶培育在含有1.0mg ml-1的牛血清蛋白(BSA)的20ml PBS缓冲溶液中12h，之后将溶液用紫外分光光度仪测试279nm处的吸光度。同时制备5种不同浓度的BSA溶液作为对照样以绘制标准曲线，根据标准曲线计算出对应的提取液浓度从而推算出水凝胶的蛋白吸附量。
蛋白质吸附量(Q)计算如式(2)所示。
Q＝C0V0-C1V1/S (2)
其中：C0，C1分别为水凝胶吸附前后的BSA质量浓度(g/mL)，V0，V1分别为水凝胶吸附前后的BSA溶液体积(mL)；S为样品的总表面积(cm2)。
图4显示水凝胶的蛋白吸附测试结果，从图中可以看出，和DTT交联的水凝胶相比，所有比例的水凝胶蛋白吸附量明显降低，说明制备的水凝胶材料具有抗蛋白吸附的性能。
水凝胶自愈合性能测试：
将制备的水凝胶用小刀切成两半，然后将两部分连接在一起，静置30min，得到自愈合的水凝胶材料。
图5中，a，b，c分别为水凝胶切割前后对比图像，可以看出，将水凝胶切割成两部分后，将其放在一起，静置一段时间后，可以自动恢复原状，且能承受住自身重量，说明水凝胶具有很好的自愈合性能。而DTT交联的水凝胶没有自愈合性能。
综上，本发明的改性多糖水凝胶的制备方法制备的改性多糖水凝胶具有较高的平衡含水量，抗蛋白性能和自愈合性能。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以作出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种改性多糖水凝胶的制备方法，其特征在于，包括以下步骤：
(1)双键改性多糖的制备：
将透明质酸与水按比例混合均匀，透明质酸在水中的浓度为3wt％，在磁力搅拌下，加入三乙胺、四丁基溴化铵、甲基丙烯酸缩水甘油酯，在室温下反应24h，反应结束后，依次在氯化钠水溶液和去离子水中透析，冻干得到双键取代度为60％以上的双键改性的透明质酸；所述透明质酸、三乙胺、四丁基溴化铵、甲基丙烯酸缩水甘油酯的重量比为1:2:1:8；
(2)两性离子巯基聚合物(CB-SH)制备：
将羧酸甜菜碱甲基丙烯酸甲酯(CBMA)和双丙烯酰胱胺(BAC)溶于体积比为1:1水和乙醇的混合溶剂中，加入引发剂过硫酸铵(APS)和N,N,N',N'-四甲基乙二胺(TMEDA)，反应24h，将上述反应产物在去离子水中透析三天除去未反应的单体和引发剂，之后在氮气保护下，转移至含有PBS pH＝8缓冲溶液的烧杯中，加入二硫苏糖醇(DTT)，反应6h后，将产物在酸性去离子水pH＝3中透析，透析袋为截留分子量Mn＝4000Da，-60℃冻干24h得到两性离子巯基聚合物(CB-SH)；所述CBMA、双丙烯酰胱胺、引发剂的重量比为30:2.5:1；
(3)“点击”化学水凝胶的制备：
将步骤1和步骤2制备的原料，按照双键-巯基比为1-2：1-2的比例，在37℃水浴中，反应1h后自发形成水凝胶。
2.根据权利要求1所述的改性多糖水凝胶的制备方法，其特征在于，所述步骤(1)中，所述氯化钠水溶液浓度为0.1mol/L；
所述透析袋截留分子量为Mn＝7000Da。
3.根据权利要求1所述的改性多糖水凝胶的制备方法，其特征在于，所述步骤(2)制备的两性离子巯基聚合物的巯基含量为0.3M/g。
4.权利要求1-3任一所述的改性多糖水凝胶的制备方法制备的多糖改性的水凝胶，其特征在于，具有不均匀的孔道结构，平均孔径为100nm，平衡含水量为90％以上。
5.根据权利要求4所述的多糖改性的水凝胶，其特征在于，所述多糖改性的水凝胶具有抗蛋白吸附的性能和自愈合性能。
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