CN117503990A - 一种复合双网络水凝胶敷料及其制备方法与应用 - Google Patents
一种复合双网络水凝胶敷料及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医药材料技术领域，涉及一种复合双网络水凝胶敷料及其制备方法与应用。本发明提供了一种复合双网络水凝胶敷料的制备方法，将多巴胺溶液和硅酸亚铁陶瓷粉体混合，得到混合溶液；在混合溶液中加入明胶，多巴胺与明胶的质量比为8‑32：100，溶解之后，加入京尼平、丙烯酰胺和N‑N亚甲基双丙烯酰胺，N‑N亚甲基双丙烯酰胺与丙烯酰胺的质量比为1.3‑1.8:1000，搅拌，加入引发剂，固化得到水凝胶敷料。本发明制备的水凝胶敷料具有稳定附着在皮肤组织及心脏组织的良好生物湿粘附性能和促血管再生能力。
Description
技术领域
本发明属于生物医药材料技术领域，涉及一种复合双网络水凝胶敷料及其制备方法与应用。
背景技术
皮肤创伤组织的修复涉及血液凝固、炎症的发生与进展、基质的合成、血管再生、纤维组织增生、再上皮化、创口收缩及组织重构等过程。传统伤口敷料存在止血效果差、伤口干燥、置换过程中粘附在伤口上导致二次损伤、感染等缺陷。水凝胶由于其高含水量，能够模仿ECM环境作为细胞移植的载体，促进细胞存活、增殖、分化和迁移，因此在组织工程应用中具有巨大的潜力。
生物玻璃和硅酸盐生物陶瓷等生物材料已被证明能够影响细胞行为和组织再生，如促进干细胞分化和血管形成，这表明硅酸盐生物材料可以通过激活细胞增殖、迁移、分化和细胞外基质合成在原位组织工程过程中发挥生物活性作用。生物陶瓷本身由于其结构稳定，活性离子释放量低，导致材料生物活性低，无法直接用于组织缺损治疗。而离子掺杂可以导致材料结构改变，降解性增强，活性离子释放增多，生物活性增加。某些特定的具有治疗作用的金属离子，如锶、锰、铜、锌离子等，已被纳入生物陶瓷的化学结构中，赋予材料新的功能性，扩展其在不同生物医学中应用。但是，实现生物陶瓷离子稳定释放一直是科研工作者的一项工作难点。铁作为人体离子中最丰富的微量元素，在人体中以Fe2+和Fe3+离子的形式存在，已被证明，在调控VEGF、HIF-1α等血管生成相关基因表达方面具有良好的血管生成活性。但是Fe3+离子在浓度较高时可能会引起细胞毒性，而Fe2+离子由于其化学稳定性较低，在实际应用时具有一定局限性。现有研究多采用加入抗氧化剂抑制Fe2+离子的氧化，此外，基于陶瓷粉体的水凝胶敷料的湿态粘附性能较差，针对有大量组织渗出液的创面而言，无法有效包覆伤口，无法满足不规则伤口的应用需求。因此，设计一种具有良好湿粘附性能和稳定释放加速血管生成活性离子的水凝胶伤口敷料具有非常重要应用前景。
发明内容
本发明的目的在于提供一种复合双网络水凝胶敷料及其制备方法与应用，具有稳定附着在皮肤组织及心脏组织的良好生物湿粘附性能、抑制Fe2+的氧化而显示出的稳定生物活性离子释放性能、机械性能、止血性能、生物相容性和促血管再生能力的多功能明胶/硅酸盐陶瓷复合双网络水凝胶伤口敷料。
基于上述目的，本申请通过提供一种复合双网络水凝胶敷料的制备方法来解决该领域中的这种需要。
一方面，本发明涉及一种复合双网络水凝胶敷料的制备方法，包括：
将多巴胺溶液和硅酸亚铁陶瓷粉体混合，得到混合溶液；在混合溶液中加入明胶，多巴胺与明胶的质量比为8-32：100，溶解之后，加入京尼平、丙烯酰胺和N-N亚甲基双丙烯酰胺，N-N亚甲基双丙烯酰胺与丙烯酰胺的质量比为1.3-1.8:1000，搅拌，加入引发剂，固化得到水凝胶敷料。
进一步地，本发明提供的复合双网络水凝胶敷料的制备方法，所述多巴胺溶液和硅酸亚铁陶瓷粉体混合之前，将多巴胺溶液采用1mol/L NaOH溶液调节pH至10。
进一步地，本发明提供的复合双网络水凝胶敷料的制备方法，所述多巴胺溶液中多巴胺的质量浓度为4-17mg/mL。
进一步地，本发明提供的复合双网络水凝胶敷料的制备方法，所述多巴胺与硅酸亚铁陶瓷粉体的质量比为0.5-2:60。
进一步地，本发明提供的复合双网络水凝胶敷料的制备方法，所述在混合溶液中加入明胶，在40-47℃下溶解完全。
进一步地，本发明提供的复合双网络水凝胶敷料的制备方法，所述加入引发剂之后，放置在55-65℃的烘箱中固化0.5-1.5h。
进一步地，本发明提供的复合双网络水凝胶敷料的制备方法，所述所述京尼平与明胶的质量比为2.8-3.2:100。
另一方面，本发明涉及一种水凝胶敷料由上述水凝胶制备方法制备得到，使基于陶瓷粉体的水凝胶敷料的湿态粘附性能较好，能够有效包覆伤口，且抑制了陶瓷粉体中Fe2+的氧化，具有良好的促血管再生能力。
另一方面，本发明制备的水凝胶敷料可粘附在湿态皮肤组织上，并通过稳定释放Fe2+和SiO4 4-等生物活性离子促进血管形成，加速创面愈合，由此本发明请求保护水凝胶敷料在制备促进创面新血管生成药物中的应用。
本发明与现有技术相比具有以下有益效果或者优点：
本发明所得水凝胶敷料通过加入多巴胺，聚多巴胺包覆在陶瓷粉体表面后，与明胶分子交联，与聚丙烯酰胺形成双网络结构后，由于强氢键相互作用，不仅提高了体系的湿粘附性能，还抑制了陶瓷粉体中Fe2+的氧化，实现了体系中Fe2+和SiO4 4-的稳定释放，使其具有良好的促血管再生能力。同时引入了甘油，破坏了材料与组织之间的水合层，使体系中的邻苯二酚基团直接与组织接触，极大的提高了材料的湿粘附性能。体内实验证实，该复合水凝胶可粘附在湿态皮肤组织上，并通过稳定释放Fe2+和SiO4 4-等生物活性离子促进血管形成，加速创面愈合。
附图说明
图1为水凝胶敷料的结构红外图。
图2为水凝胶敷料的微观形貌图。
图3为水凝胶敷料的湿粘附性能图。
图4为水凝胶敷料的离子释放速率图。
图5为水凝胶敷料细胞存活率的效果图。
图6为全皮层缺损小鼠模型水凝胶的伤口愈合图。
具体实施方式
下面，结合实施例对本发明的技术方案进行说明，但是，本发明并不限于下述的实施例。
为了使本领域技术人员更好地理解本发明的技术方案能予以实施，下面结合具体实施例和附图对本发明作进一步说明，但所举实施例不作为对本发明的限定。
下述各实施例中所述实验方法和检测方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可在市场上购买得到。
实施例
实施例1
本实施例提供了一种复合双网络水凝胶敷料的制备方法。
将多巴胺溶于水和甘油质量比为1:1的混合溶液中，配制成质量浓度为16mg/mL的多巴胺溶液，加入1mol/L NaOH溶液调节pH至10，在100ml的多巴胺溶液中加入与多巴胺质量比为1:60的硅酸亚铁陶瓷粉体，超声分散30min，得到混合溶液。
在上述混合溶液中加入15g明胶于45℃下溶解，加入0.45g京尼平，再加入60g丙烯酰胺和0.09g交联剂N-N亚甲基双丙烯酰胺，搅拌30min后，加入6g过硫酸铵做引发剂，将产品放置在60℃的烘箱中进行固化1h，得到水凝胶敷料。
实施例2
本实施例提供了一种复合双网络水凝胶敷料的制备方法。
将多巴胺溶于水和甘油质量比为1:1的混合溶液中，配制成质量浓度为4mg/mL的多巴胺溶液，加入1mol/L NaOH溶液调节pH至10，在100ml的多巴胺溶液中加入与多巴胺质量比为0.5:60的硅酸亚铁陶瓷粉体，超声分散30min，得到混合溶液。
在上述混合溶液中加入5g明胶于40℃下溶解，加入0.14g京尼平，再加入20g丙烯酰胺和0.026g交联剂N-N亚甲基双丙烯酰胺，搅拌30min后，加入2g过硫酸铵做引发剂，将产品放置在55℃的烘箱中进行固化0.5h，得到水凝胶敷料。
实施例3
本实施例提供了一种复合双网络水凝胶敷料的制备方法。
将多巴胺溶于水和甘油质量比为1:1的混合溶液中，配制成质量浓度为17mg/mL的多巴胺溶液，加入1mol/L NaOH溶液调节pH至10，在100ml的多巴胺溶液中加入与多巴胺质量比为2:60的硅酸亚铁陶瓷粉体，超声分散30min，得到混合溶液。
在上述混合溶液中加入5.32g明胶于47℃下溶解，加入0.17g京尼平，再加入21.28g丙烯酰胺和0.038g交联剂N-N亚甲基双丙烯酰胺，搅拌30min后，加入0.532g过硫酸铵做引发剂，将产品放置在60℃的烘箱中进行固化1.5h，得到水凝胶敷料。
实施例4
本实施例提供制备得到的水凝胶敷料的测试性能。
(1)VECTOR-22FT-IR光谱仪上记录了复合双网络水凝胶敷料在4000-400cm-1范围内的FT-IR光谱，测试制样时，在40℃真空烘箱中，-0.08MPa下干燥KBr，将样品在玛瑙研钵中混合研磨，随后取少量进行压片。所有样品经冷冻处理消除水分后滴在KBr压片上，在红外光谱仪上对所有样品分别进行FT-IR测试。实施例1制备的复合双网络水凝胶敷料的结构红外图如图1所示。1050cm-1处为SiO4 2-的特征吸收峰。在3287cm-1处出现的宽吸收峰是水凝胶中明胶的-OH和-NH键的特征吸收峰的重叠(由氢键和酰胺键形成)，当氢键强度增加时，吸收带可能向低频迁移。1633cm-1、1538cm-1、1236cm-1处的峰分别对应酰胺Ⅰ带的-C＝O伸缩振动峰，酰胺Ⅱ带的-NH弯曲振动峰和酰胺Ⅲ带的-CN伸缩振动峰。1610cm-1处的峰为水凝胶中多巴胺上苯环中C＝C的特征吸收峰，1280cm-1处出现的峰为多巴胺上邻苯二酚结构的特征吸收峰，3000cm-1-3500cm-1和1645cm-1处分别为-NH伸缩振动特征峰和C＝O伸缩振动特征峰。
(2)利用中科院仪器厂的1000B型扫描电子显微镜对实施例3提供的水凝胶敷料的表面形貌进行观察。将实施例3提供的水凝胶敷料样品冷冻干燥，用液氮脆断，在凝胶样品进行喷金处理后测试。样品观察在10kV的加速电压下进行，对样品的形貌进行观察并拍照。水凝胶敷料的微观形态如图2所示。通过京尼平交联多巴胺并引入硅酸亚铁陶瓷粉体后，水凝胶截面处孔洞变得非常致密，但可以观察到明显的粉体颗粒。这是由于聚多巴胺包覆在粉体表面后，与明胶分子交联，导致交联密度较高，与聚丙烯酰胺形成双网络结构后，由于强氢键相互作用，孔洞结构变得致密，无法观察到明显孔洞结构。
(3)使用搭接剪切测试方法测量样品在不同组织(新鲜猪皮、PBS浸泡30min的猪皮和新鲜猪心肌组织)上的湿粘附性能。取适量实施例1-3水凝胶敷料(10mm*10mm*2mm)置于组织表面(实施例1-3水凝胶敷料分别对应标记为图3中的实例1、实例2和实例3)，覆盖另一层组织，按压30s，使用通用材料试验机以5mm/min的速度拉组织两端。每组实验测量三次。通过使用最大载荷除以重叠面积来获得粘合强度。
试验结果如图3所示，表明本发明提供的水凝胶敷料湿粘附性能为21.78kPa，符合国标中伤口敷料的使用标准，在经过弯曲、扭曲、水浸泡、拉伸一系列操作后，依然可以稳定粘附在猪心肌组织上，说明其具有优异的湿粘附性能。
(4)取实施例3水凝胶敷料于50mlPBS溶液中，在37℃振荡器中震荡24h，离心后取30ml上清液，用王水溶解样品，将溶液加热至1ml，用纯水稀释至30ml后过滤膜(0.22μm)，采用电感耦合等离子体原子发射光谱法(ICP-OES：710-ES，Varian，USA)测定样品中Fe和Si离子的浓度。
水凝胶敷料的离子释放行为如图4所示，本发明水凝胶敷料在PBS溶液中浸泡24h后，Fe和Si离子含量分别为0.154和0.608ppm，符合国标中对于伤口敷料所含重金属离子的规定。通过测量其在1、3、5、7、9、12、14天Fe和Si离子的释放量，可以看到水凝胶敷料可以达到稳定可持续的离子释放，并且在14天后Fe和Si离子释放量为4.473和10.595ppm，不会有重金属中毒的风险。
(5)实验前，将实施例1-3水凝胶敷料置于无菌培养皿中，加入75％酒精浸泡灭菌2h，加入PBS缓冲液交换2次，每次5min(目的洗去残留酒精)，后分别按照0.2g/ml标准于RPMI1640培养基中浸提，置于37℃，5％CO2培养箱中培养24h，得到样品浸提液。将细胞接种到密度为5000细胞/孔的96孔板中，并在37℃，5％CO2培养箱中孵育24h，待细胞完全贴壁后，弃掉原培养基，对照组每孔加入200μLRPMI 1640培养基，试验组每孔加入100μL样品浸提液和100μL RPMI 1640培养基。在第1、3、5天时，用分光光度酶标仪在450nm处测量板的吸光度。
水凝胶敷料的细胞存活率的效果试验结果如图5所示。与纯CHL细胞生长的空白对照相比，本发明提供的水凝胶敷料上的CHL细胞培养5天后，与对照组相比，OD值无显著差异，说明其细胞活性相似，且细胞存活率均超过100％，证明其具有优异的生物相容性，并且均具有促进细胞生长和繁殖的性能。
(6)采用来自于购自斯贝福(北京)生物技术有限公司，许可证号SCXK(京)2019-0010的无特征性病原体(SPF)常规大鼠(6-8周龄，200-220g)的全层皮肤缺陷模型评估水凝胶对体内伤口愈合的影响。保持18-26℃，12h的光/暗循环条件下，大鼠能够自由获取水及颗粒食品。此外，动物福利和实验程序严格按照《实验动物护理和使用指南》(中国陕西省科学技术厅，2016年)和兵器工业卫生研究所的相关伦理规定执行。水凝胶在植入前用紫外线消毒24h。手术前，用2％戊巴比妥钠腹腔注射麻醉，剂量为50mg/kg。在去毛皮肤左右两侧分别用手术剪刀剪出两个直径为1cm的圆形创口。左侧为自身对照，右侧为干预组，干预组在创口处覆盖等面积的实施例1-3水凝胶敷料。之后，两侧创口均用碘伏均匀涂抹。最后，依次在创口上覆盖一层玻璃纸、两层医用纱布、一层无刺激医用胶布固定，将大鼠至于37℃恒温台上直至大鼠苏醒，苏醒后，将大鼠单笼饲养。
水凝胶敷料的全皮层缺损小鼠模型水凝胶的伤口愈合情况如图6所示，(a1)、(a2)、(a3)、(a4)、(a5)、(a6)为空白对照组在0、3、7、9、12、14天时的伤口愈合情况，(b1)、(b2)、(b3)、(b4)、(b5)、(b6)为实施例1制备水凝胶敷料在0、3、7、9、12、14天时的伤口愈合情况，(c1)、(c2)、(c3)、(c4)、(c5)、(c6)为实施例2制备水凝胶敷料在0、3、7、9、12、14天时的伤口愈合情况，(d1)、(d2)、(d3)、(d4)、(d5)、(d6)为实施例3制备水凝胶敷料在0、3、7、9、12、14天时的伤口愈合情况与空白对照组相比，(实施例1-3水凝胶敷料分别对应标记为图6中的实例1、实例2和实例3)，本发明提供的水凝胶敷料分别在0、3、7、9、12、14天时的伤口面积均小于空白组，伤口愈合情况均优于空白对照组，证实本发明提供的水凝胶敷料具有促进伤口愈合的功能。
如上所述，即可较好地实现本发明，上述的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案做出的各种改变和改进，均应落入本发明确定的保护范围内。
Claims (9)
1.一种复合双网络水凝胶敷料的制备方法，其特征在于，包括：
将多巴胺溶液和硅酸亚铁陶瓷粉体混合，得到混合溶液；在混合溶液中加入明胶，多巴胺与明胶的质量比为8-32：100，溶解之后，加入京尼平、丙烯酰胺和N-N亚甲基双丙烯酰胺，N-N亚甲基双丙烯酰胺与丙烯酰胺的质量比为1.3-1.8:1000，搅拌，加入引发剂，固化得到水凝胶敷料。
2.根据权利要求1所述的复合双网络水凝胶敷料的制备方法，其特征在于，所述将多巴胺溶液和硅酸亚铁陶瓷粉体混合之前，将多巴胺溶液采用1mol/L NaOH溶液调节pH至10。
3.根据权利要求1所述的复合双网络水凝胶敷料的制备方法，其特征在于，所述多巴胺溶液中多巴胺的质量浓度为4-17mg/mL。
4.根据权利要求1所述的复合双网络水凝胶敷料的制备方法，其特征在于，所述多巴胺与硅酸亚铁陶瓷粉体的质量比为0.5-2:60。
5.根据权利要求1所述的复合双网络水凝胶敷料的制备方法，其特征在于，所述在混合溶液中加入明胶之后，在40-47℃下溶解完全。
6.根据权利要求1所述的复合双网络水凝胶敷料的制备方法，其特征在于，所述加入引发剂之后，放置在55-65℃的烘箱中固化0.5-1.5h。
7.根据权利要求1所述的复合双网络水凝胶敷料的制备方法，其特征在于，所述京尼平与明胶的质量比为2.8-3.2:100。
8.一种水凝胶敷料，由权利要求1-7任一项所述的复合双网络水凝胶敷料的制备方法制备得到。
9.权利要求8所述的水凝胶敷料在制备促进创面新血管生成药物中的应用。
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