CN116869925A - 一种可注射水凝胶及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种可注射水凝胶及其制备方法和应用，属于生物医用材料制备技术领域。所述水凝胶为Laponite水凝胶，由laponite在水中自组装形成，其中，所述laponite在水中的浓度为2‑20%。本发明利用Laponite水凝胶结合药物/因子/蛋白等成分，从而使药物/因子/蛋白等成分的释放时间延长，具有良好的临床应用前景。
Description
技术领域
本发明涉及生物医用材料制备技术领域，具体涉及一种可注射水凝胶及其制备方法和应用。
背景技术
药物的特定递送十分重要，但通常情况下，原位注射会使药物在发挥作用之前就迅速分解并在血液中流失。针对这一问题，已有多种药物载体材料被研究开发，例如纳米纤维载体、聚乳酸微球、纤维蛋白凝胶等：纳米纤维具有较大的比表面积，药物能够在其表面缓慢分解，起到较好的治疗效果；聚乳酸微球能够能够提高蛋白质类药物的稳定性；纤维蛋白胶的生物相容性高，对人体的毒副作用小。
Laponite是一种人工合成粘土基材料，结构与天然蒙脱石类似，为2:1层状硅酸盐结构，在镁氧八面体的两边各有一个共用氧原子的硅氧四面体，其中部分二价的镁原子被一价锂原子置换，使粒子表面带有永久负电荷，使其具有能够结合带正电的药物/因子/蛋白等成分的潜力。同时，Lapnoite 因其层状结构，分散在水中能形成直径为25nm，厚度为0.92nm的扁平状晶体。由于片层晶体边缘带的微弱正电荷与相邻晶体表面的负电荷相互作用，最终通过Laponite物理交联的作用而形成了独特三维网络结构，即形成Lapnoite水凝胶。Lapnoite水凝胶由于其高离子性和较大的表面积以及剪切稀化的特性，使其能够通过注射器被轻松注射到特定部位。
专利CN114983972A公开了水凝胶包被miRNA-200s纳米微粒缓释系统可制备视神经炎疾病类药物，该水凝胶是通过Laponite水凝胶中添加猪皮明胶原液制得。专利CN111012947A公开了一种可注射和自愈合淀粉基水凝胶，采用淀粉、聚乙烯醇和Laponite带电纳米粒子作为原料。CN108525017A公开了一种锂藻土与透明质酸原位聚合形成的可注射水凝胶。US20210213181A1公开了一种以Laponite和聚环氧乙烷原料的抗粘性剪切稀化水凝胶。WO2020263398A1公开了以Laponite和阴离子多糖为原料的可注射的剪切稀化水凝胶。
现有技术中，以Laponite为原料制备水凝胶时，均需在其中添加有机聚合物。有机聚合物的添加可以促进Laponite颗粒之间的相互作用，从而增强凝胶的稳定性并构建网络结构。同时可以调节凝胶的性质，例如凝胶的强度、稳定性和流变特性。不同类型和浓度的有机聚合物可以影响凝胶的结构和形态，从而调控凝胶的特性，使其更适合特定的应用需求。但添加的有机聚合物往往会形成具有固定形状且无剪切变稀特性的凝胶，不具备可注射性，也无法更好的适应伤口或缺损部位形状。同时越多的外来物质引入到体内，越有可能引发免疫排斥反应和生物相容性等问题，可能具有一定毒副作用，对人体的生物安全性差，临床应用时需要面临更多的问题。
发明内容
针对现有技术中存在的问题，本发明提供一种可注射水凝胶及其制备方法和应用。本发明利用Laponite水凝胶结合药物/因子/蛋白等成分，从而使药物/因子/蛋白等成分的释放时间延长，具有良好的临床应用前景。
本发明提供的一种可注射水凝胶，所述水凝胶为Laponite水凝胶，由laponite在水中自组装形成。
进一步地，所述laponite在水中的浓度为2-20%，laponite含量太低不成胶，含量太高时会堵塞针头，影响注射效果，并且含量过高会导致细胞毒性增加。
进一步地，所述laponite在水中的浓度为4-6%。
本发明还提供了上述的可注射水凝胶的制备方法，将Laponite分散于超纯水中，静置即得。
Laponite因其由高离子性、大表面积的合成盘状结晶纳米颗粒组成，使生物分子能够嵌入和溶解在Lapnoite药物递送系统中。
本发明还提供了一种上述可注射水凝胶作为载体在药物递送系统中的应用。
本发明还提供了一种可注射水凝胶缓释体系，其包括上述的可注射水凝胶。
进一步地，还包括：负载在可注射水凝胶内部和/或表面的药物、因子或蛋白。药物、因子应当理解为，在生理pH下带正电、电中性或弱负电的药物或因子，药物比如卡马西平、罗哌卡因等，因子如碱性成纤维细胞生长因子 (basic fibroblast growth factor,bFGF)等。
本发明技术方案，具有如下优点：
本发明提供的可注射水凝胶，具有很好的剪切稀化性能，可作为载体运用于药物递送系统。
本发明提供的制备方法简单，具有较高的实用价值和临床应用价值。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1是本发明实施例中不同浓度的Laponite水凝胶实物图；
图2是本发明实施例2中所制备的Laponite水凝胶扫描电镜图；
图3是本发明实施例2中所制备的Laponite水凝胶频率扫描流变图；
图4是本发明实施例2中所制备的Laponite水凝胶时间扫描流变图；
图5是本发明实施例2中所制备的Laponite水凝胶注射示意图；
图6是本发明实施例3-6中所制备的缓释体系中模型蛋白PRTM释放情况；
图7是本发明实施例7中所制备的缓释体系治疗后动物损伤处GFAP和Tuj-1的表达情况；
图8是本发明实施例7中所制备的缓释体系治疗后动物损伤处CS-56的表达情况；
图9是本发明实施例7中所制备的缓释体系治疗后动物损伤处NF的表达情况。
具体实施方式
以下通过具体实施例对本发明的技术方案进一步说明。如无特殊说明，本发明所涉及的原料、试剂、仪器等均为普通市售产品。
实施例1
一种可注射水凝胶，其由浓度为4%的Lapnoite水溶液自组装而成。
制备方法如下：
将4mg的Lapnoite分散于100μl的超纯水中，静置待其自组装形成Lapnoite水凝胶。
实施例2
一种可注射水凝胶，其由浓度为6%的Lapnoite水溶液自组装而成。
制备方法如下：
将6mg的Lapnoite分散于100μl的超纯水中，静置待其自组装形成Lapnoite水凝胶。
实施例3
一种可注射水凝胶缓释体系，其由实施例2所制备的可注射水凝胶和模型蛋白药物鱼精蛋白硫酸盐（PRTM）组成。
制备方法如下：
将Lapnoite 6mg、模型蛋白药物鱼精蛋白硫酸盐0.25 mg分散于100μl的超纯水中，静置待其自组装形成可注射水凝胶缓释体系。
实施例4
一种可注射水凝胶缓释体系，其由实施例2所制备的可注射水凝胶和模型蛋白药物鱼精蛋白硫酸盐（PRTM）组成。
制备方法如下：
将Lapnoite 6mg、模型蛋白药物鱼精蛋白硫酸盐0.5 mg分散于100μl的超纯水中，静置待其自组装形成可注射水凝胶缓释体系。
实施例5
一种可注射水凝胶缓释体系，其由实施例1所制备的可注射水凝胶和模型蛋白药物鱼精蛋白硫酸盐（PRTM）组成。
制备方法如下：
将Lapnoite 4mg、模型蛋白药物鱼精蛋白硫酸盐0.25 mg分散于100μl的超纯水中，静置待其自组装形成可注射水凝胶缓释体系。
实施例6
一种可注射水凝胶缓释体系，其由实施例1所制备的可注射水凝胶和模型蛋白药物鱼精蛋白硫酸盐（PRTM）组成。
制备方法如下：
将Lapnoite 4mg、模型蛋白药物鱼精蛋白硫酸盐0.5 mg分散于100μl的超纯水中，静置待其自组装形成可注射水凝胶缓释体系。
实施例7
一种可注射水凝胶缓释体系，其由实施例1所制备的可注射水凝胶和硫酸软骨素ABC酶组成。
制备方法如下：
将Lapnoite 4mg、硫酸软骨素ABC酶分散于100μl的超纯水中，静置待其自组装形成三维结构，硫酸软骨素ABC酶负载在三维结构上，形成ChABC@Lapnoite水凝胶。
性能表征
Laponite由于片层晶体边缘带的微弱正电荷与相邻晶体表面的负电荷相互作用，最终通过物理交联而形成独特三维网络结构，将Lapnoite按照不同浓度溶解于纯水中静止片刻后即可自组装形成Lapnoite水凝胶(图1)。Laponite因其具有高离子性、大表面积的合成盘状结晶纳米颗粒组成，使生物分子能够嵌入和溶解在Lapnoite药物递送系统中。
如图2所示，使用扫描电镜观察了冻干Lapnoite水凝胶的形貌(图2)。结果显示冻干水凝胶显示出多孔的片状网络结构。
通过流变分析表征Laponite水凝胶的流变行为，如图2所示，在频率扫描模式下观察6%Lapnoite溶液在0.1Hz至1Hz范围内G’（储能模量）和G’’（损耗模量）的变化，其储能模量始终大于损耗模量，表明Lapnoite溶液的浓度为6%时，Lapnoite溶液呈现经典的凝胶流变行为。
为了模拟原位注射的流变行为，测试在低剪切应变（1%，模拟静息状态）和高剪切应变（500%，模拟挤出状态）的情况下G’和G’’随时间变化的数值，结果如图4所示，在低剪切应变下，该水凝胶材料的G’远大于G’’，而在高剪切应变下，该水凝胶材料的G’则小于G’’，以上结果体现了Lapnoite从凝胶到溶胶的转变，表明该水凝胶具有很好的剪切稀化性能。
为了观察该水凝胶是否具有可注射性，使用注射器挤出Lapnoite水凝胶。如图5所示，轻轻推动注射器，Lapnoite水凝胶能够从注射器中流利地注射出并能够写出HNU，表明Lapnoite水凝胶具有很好的可注射性。
为了探究Lapnoite水凝胶能否实现蛋白类药物的持续释放，将带有正电荷的模型蛋白药物鱼精蛋白硫酸盐（PRTM）负载到Lapnoite水凝胶中，检测其蛋白释放情况。体外药物释放结果如图6所示，Lapnoite水凝胶能够持续释放鱼精蛋白硫酸盐5天，表现出Lapnoite水凝胶的持续缓释蛋白性能。
为探究该可注射水凝胶缓释体系的体内治疗效果，本发明使用Laponite水凝胶负载硫酸软骨素ABC酶（ChABC@Lapnoite水凝胶），动物模型采用大鼠脊髓夹伤模型，在损伤处应用ChABC@Lapnoite水凝胶，通过免疫荧光评价，ChABC@Lapnoite水凝胶能够显著降低胶质纤维酸性蛋（GFAP）和硫酸软骨素（CS-56）在脊髓损伤处的表达。硫酸软骨素ABC酶能够降解硫酸软骨素蛋白聚糖，减少硫酸软骨素蛋白聚糖对轴突生长的抑制作用，促进神经轴突的生长。结果如图7和图8所示，证明，ChABC@Lapnoite水凝胶能够减少脊髓损伤后瘢痕组织的产生。同时，如图7和图9所示，ChABC@Lapnoite水凝胶能够显著增加成熟神经元（NF）的保留和促进新生神经元（Tuj-1）的产生，表明ChABC@Lapnoite水凝胶能够促进神经再生，具有良好的体内治疗效果，进一步证明本发明中的可注射Laponite水凝胶缓释体系具有良好的临床应用前景。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (7)
1.一种可注射水凝胶，其特征在于，所述水凝胶为Laponite水凝胶，由laponite在水中自组装形成。
2.根据权利要求1所述的一种可注射水凝胶，其特征在于，所述laponite在水中的浓度为2-20%。
3.根据权利要求1所述的一种可注射水凝胶，其特征在于，所述laponite在水中的浓度为4-6%。
4.一种如权利要求1-3任一项所述的可注射水凝胶的制备方法，其特征在于，将Laponite分散于超纯水中，静置即得。
5.一种如权利要求1-3任一项所述的可注射水凝胶作为载体在药物递送系统中的应用。
6.一种可注射水凝胶缓释体系，其包括如权利要求1-3任一项所述的可注射水凝胶。
7.根据权利要求6所述的一种可注射水凝胶缓释体系，其特征在于，还包括：负载在可注射水凝胶内部和/或表面的药物、因子或蛋白。
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