CN111978588A - 一种大孔水凝胶及其制备方法和应用 - Google Patents
一种大孔水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种大孔水凝胶及其制备方法和应用，其制备方法中采用水溶性明胶微球作为致孔剂，采用加热的方式使得明胶微球界面处相互粘接，交联成胶后去除明胶微球模板，最终形成孔隙直径可控、相互连通的大孔水凝胶。有利于细胞的粘附、迁移、增殖以及氧气和营养物质等运输，有望进一步开发促血管化的凝胶支架，扩大水凝胶在组织工程和再生医学中的应用。与传统方法所制备大孔水凝胶相比，本发明制备的大孔水凝胶，成胶时间短，几秒可成胶，孔隙结构可控、均匀且相互连通，孔径范围为30μm‑600μm。
Description
技术领域
本发明属于生物材料技术领域，尤其涉及一种大孔水凝胶及其制备方法和应用。
背景技术
组织工程和再生医学是通过构建组织工程支架模拟细胞外基质和种子细胞一起形成复合体来实现组织修复或再生。为了更好地修复不同的受损组织，通过仿生设计，构建具有细胞外基质类似物理和化学性能的组织工程支架至关重要。水凝胶因其具有与天然细胞外基质高度相似的仿生结构，良好的力学性能、生物相容性、易于制备等优点，在组织工程和再生医学领域中得到了广泛的应用，常作为活细胞三维培养及运载系统。
然而，负载的细胞通常被包覆和限制在亚微米级或纳米级聚合物凝胶网络中，不利于细胞在凝胶内部的铺展、迁移与增殖，严重限制了细胞的生长和组织形成，成为扩大水凝胶组织再生应用的一大障碍。这可以通过设计具有大孔结构的凝胶支架来实现。与成分类似的无孔支架相比，孔隙有利于细胞的渗透、迁移和增殖，能够促进氧气和营养物质的运输，利于新组织的形成和血管的长入。
近年来，大孔水凝胶作为细胞载体和组织工程支架越来越受到人们的关注。水凝胶支架中引入的大孔不仅提高了支架的渗透性，有利于营养物质的运输，还为细胞粘附、增殖和细胞外基质沉积创造了空间/界面。
一般将有效孔径在10nm～10μm范围内的水凝胶称为微孔水凝胶，有效孔径大于10μm的水凝胶称为大孔水凝胶。目前常见的制备生物大孔水凝胶的方法主要有盐浸出法、相分离法、冻干法、气体发泡法等，但这些方法往往缺乏均匀的、相互连通的孔隙结构和孔径，难以制备具有超大孔径的水凝胶，或是制备过程中需要引入额外化学品增加毒性，不利于材料的生物相容性。
发明内容
本发明的目的在于提供一种具有孔隙均匀且相互连通的大孔水凝胶及其制备方法和应用。
本发明所采取的技术方案为：
本发明的第一个方面，提供：
一种大孔水凝胶的制备方法，包括如下步骤：
(1)明胶微球置于模具中，注入含易挥发溶剂的水溶液；
(2)加热；
(3)干燥，得到明胶微球模板；
(4)将明胶微球模板置于水凝胶溶液中，保持负压真空，至水凝胶溶液交联；保持负压真空，能使得水凝胶溶液更好进入明胶微球模板的内部，围绕明胶微球模板形成大孔水凝胶。
(5)去除明胶微球模板，得到大孔水凝胶。
优选的，上述步骤(1)中明胶微球的粒径为30μm～600μm。
优选的，上述步骤(1)中易挥发溶剂为选自乙醇、甲醇、异丙醇、丙酮中的至少一种；采用含易挥发溶剂的水溶液，能使得明胶微球在步骤(2)加热时只在微球表面处产生轻微溶解。
优选的，上述步骤(2)中加热至明胶微球界面相互粘接；采用加热的方法使得紧密堆积的明胶微球在其界面处轻微溶解后相互粘接，形成整齐排列的、相互粘接的明胶微球模板。
优选的，上述步骤(2)加热的温度为50℃～80℃，所述加热的时间为5min～10min。
优选的，上述步骤(3)中干燥为选自冷冻干燥、超临界干燥、风干中的至少一种。
优选的，上述步骤(4)中水凝胶溶液为凝胶前驱体溶液与引发剂的混合溶液。
优选的，上述凝胶前驱体溶液为选自改性透明质酸、改性明胶、肝素、海藻酸钠、硫酸软骨素、胶原、RGD多肽、丝素蛋白及它们的衍生物中的至少一种。这些凝胶前驱体溶液所形成的水凝胶具有良好的生物性能和降解性能。
优选的，上述凝胶前驱体溶液为选自改性透明质酸、改性明胶中的至少一种。
优选的，上述改性透明质酸是指含有双键的改性透明质酸，上述改性明胶是指含有双键的改性明胶，这些含双键的改性材料均为细胞外基质中的主要成分，具有良好的生物相容性。
优选的，上述引发剂为选自2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮、1-羟基环己基-苯基甲酮、苯基-2,4,6-三甲基苯甲酰基次膦酸锂、2,2-二甲氧基-苯基乙酮中的至少一种。
优选的，上述步骤(4)中负压为-0.04MPa～-0.1MPa。
优选的，上述步骤(4)中交联为紫外光交联，所述交联的时间为1s～20s。
优选的，上述紫外光交联紫外光的光照强度为30～90mW/cm2。
优选的，上述步骤(5)中去除明胶微球模板是用33℃～40℃的PBS溶液或去离子水溶解该明胶微球模板去除。
本发明的第二个方面，提供：
一种大孔水凝胶，由上述大孔水凝胶的制备方法制得。
优选的，上述大孔水凝胶的孔隙相互连通。
优选的，上述大孔水凝胶的孔隙直径为30μm～600μm。
本发明的第三个方面，提供：
一种大孔水凝胶在用于制备组织工程材料上的应用，该大孔水凝胶为上述大孔水凝胶的制备方法制得，或者为上述的大孔水凝胶。
本发明的有益效果是：
(1)采用水溶性明胶微球作为致孔剂，生物相容性好，制孔条件温和，未引入额外有机溶剂增加毒性，模板去除过程不影响凝胶性能。
(2)制备相互粘接的明胶微球为致孔剂模板，使得最终形成的大孔水凝胶孔隙相互连通，有利于细胞的粘附、迁移、增殖，氧气和营养物质等运输。
(3)与传统方法所制备大孔水凝胶相比，本发明制备的大孔水凝胶，成胶时间短，几秒可成胶，孔隙结构可控、均匀且相互连通，孔径范围为30μm-600μm。
(4)水凝胶在组成上与天然细胞外基质相似，具有优异的生物相容性和降解性能。本发明中的大孔水凝胶在组织修复和再生中具有良好的应用前景。
附图说明
图1为双乳液法制得的不同粒径的明胶微球的SEM图，其中，A为粒径约为737μm明胶微球的SEM图；B为粒径约为275μm明胶微球的SEM图；C为粒径约为117μm明胶微球的SEM图；D为粒径约为42μm明胶微球的SEM图。
图2为实施例1步骤(4)中制得的相互粘接的明胶微球模板SEM图。
图3为实施例1中大孔水凝胶内部孔隙结构的SEM图。
图4为实施例2中大孔水凝胶内部孔隙结构的SEM图。
图5为对比例1中大孔水凝胶内部孔隙结构的SEM图。
图6为对比例2中大孔水凝胶内部孔隙结构的SEM图。
具体实施方式
为了使本发明的发明目的、技术方案及其技术效果更加清晰，以下结合具体实施方式，对本发明进行进一步详细说明。应当理解的是，本说明书中描述的具体实施方式仅仅是为了解释本发明，并非为了限定本发明。
以下实施例或对比例中，明胶微球的制备方法为双乳液法，具体为：
将10mL乙酸乙酯混入30mL明胶溶液(0.1g/mL)中，搅拌，将混合液与60mL大豆油混合，搅拌，在300mL预冷(-20℃)乙醇中可自发形成明胶微球。依次用1,4-二氧六环/丙酮冲洗。风干后，通过标准筛收集微球。对所制得的明胶微球SEM观察得图1所示。
实施例1：一种水凝胶及其制备方法：
(1)取0.3g粒径为230μm左右的明胶微球置于聚四氟乙烯模具中，轻轻敲打模具使明胶微球紧密堆积，表面平整；
(2)将乙醇溶液注入堆积的明胶微球中，每克明胶微球注入约1mL体积浓度为80％的乙醇溶液；
(3)将模具移至70℃烘箱中保持8min；
(4)取出模具，冻干，得到相互粘接的明胶微球模板，其SEM图如图2所示，相互临近的微球在界面处产生轻微粘接，形成相互粘接的明胶微球模板；
(5)将步骤(4)的明胶微球模板放入1mL的质量浓度为2％的含有0.2％2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮的双键透明质酸溶液中，-0.08MPa条件下，使得混合溶液进入明胶微球内部，光照强度为60mW/cm2的紫外光下光照10s，使混合溶液交联成胶；
(6)将步骤(5)所得的模板放入37℃的去离子水中，溶解去除明胶微球模板，得到大孔水凝胶。
实施例2：一种水凝胶及其制备方法：
(1)筛分出粒径为100μm左右的明胶微球，取0.2g粒径为100μm左右的明胶微球置于聚四氟乙烯模具中，轻轻敲打模具使明胶微球紧密堆积，表面平整；
(2)将乙醇溶液注入堆积的明胶微球中，每克明胶微球注入约1mL体积浓度为80％的乙醇溶液；
(3)将模具移至80℃烘箱中保持5min；
(4)取出模具，冻干，得到相互连接的明胶微球模板；
(5)将1％双键透明质酸溶液，10％双键明胶溶液，以体积比10:1混合，加入0.1％的苯基-2,4,6-三甲基苯甲酰基次膦酸锂，得到混合液；将步骤(4)的明胶微球模板放入1mL前述混合溶液中，-0.1MPa条件下，使得混合溶液进入明胶微球内部，取出明胶微球模板，在光照强度为70mW/cm2的紫外光下光照5s，使混合溶液交联成胶；
(6)将步骤(5)所得的模板放入37℃的PBS中，溶解去除明胶微球模板，得到大孔水凝胶。
对比例1：一种水凝胶及其制备方法：
(1)配置1mL质量浓度为2％含有0.2％2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮的双键透明质酸溶液；
(2)在光照强度为70mW/cm2的紫外光下光照3s，使混合溶液交联后成胶。
对比例2：一种水凝胶及其制备方法：
(1)取0.3g粒径为230μm左右的明胶微球置于聚四氟乙烯模具中，轻轻敲打模具使明胶微球紧密堆积，表面平整；
(2)将乙醇溶液注入堆积的明胶微球中，每克明胶微球注入约1mL体积浓度为80％的乙醇溶液；
(3)取出模具，冻干，得到明胶微球模板；
(4)将步骤(3)的明胶微球模板放入1mL质量浓度为2％含有0.2％2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮的双键透明质酸溶液中，-0.08MPa条件下，使得混合溶液进入明胶微球内部，在光照强度为70mW/cm2的紫外光下光照3s，使混合溶液交联成胶；
(5)将步骤(4)所得的模板放入37℃的去离子水中，溶解去除明胶微球模板，得到大孔水凝胶。
测试例：
将实施例1、2与对比例1制得的水凝胶冻干后切片，SEM观察水凝胶支架的微观结构，结果分别对应如图3、图4、图5、图6所示。
从图3、图4、图5、图6可看出，对比例1～2中水凝胶孔隙多为闭孔，孔隙间不连通。而实施例1～2中大孔凝胶孔隙结构均匀，且孔隙相互连通。其提高了水凝胶支架的渗透性，为后续细胞粘附、增殖和细胞外基质沉积提供空间/界面，利于新组织的形成和血管的长入。有望进一步开发促血管化的凝胶支架，扩大水凝胶在组织工程和再生医学中的应用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种大孔水凝胶的制备方法，其特征在于：包括如下步骤：
(1)明胶微球置于模具中，注入含易挥发溶剂的水溶液；
(2)加热；
(3)干燥，得到明胶微球模板；
(4)负压下，往明胶微球模板注入水凝胶溶液后，取出，水凝胶溶液交联；
(5)去除明胶微球模板，得到大孔水凝胶。
2.根据权利要求1所述的大孔水凝胶的制备方法，其特征在于：步骤(2)所述加热为加热至明胶微球界面相互粘接；优选的，所述加热的温度为50℃～80℃，所述加热的时间为5min～10min。
3.根据权利要求1所述的大孔水凝胶的制备方法，其特征在于：步骤(4)中所述水凝胶溶液为凝胶前驱体溶液与引发剂的混合溶液。
4.根据权利要求3所述的大孔水凝胶的制备方法，其特征在于：所述凝胶前驱体溶液为选自改性透明质酸、改性明胶、肝素、海藻酸钠、硫酸软骨素、胶原、RGD多肽、丝素蛋白及它们的衍生物中的至少一种。
5.根据权利要求1所述的大孔水凝胶的制备方法，其特征在于：步骤(4)中所述负压为-0.04MPa～-0.1MPa。
6.根据权利要求1所述的大孔水凝胶的制备方法，其特征在于：步骤(4)中所述交联为紫外光交联，所述交联的时间为1s～20s。
7.一种大孔水凝胶，其特征在于：所述大孔水凝胶由权利要求1～6任一项所述的大孔水凝胶的制备方法制得。
8.根据权利要求7所述的大孔水凝胶，其特征在于：所述大孔水凝胶的孔隙相互连通。
9.根据权利要求7所述的大孔水凝胶，其特征在于：所述大孔水凝胶的孔隙直径为30μm～600μm。
10.一种大孔水凝胶在用于制备组织工程材料上的应用，其特征在于：所述大孔水凝胶为权利要求1～6任一项所述的大孔水凝胶的制备方法制得，或者为权利要求7～9任一项所述的大孔水凝胶。
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| CN113861448A (zh) * | 2021-09-13 | 2021-12-31 | 广东省科学院健康医学研究所 | 一种肝素化透明质酸水凝胶及其制备方法和应用 |
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