CN115010958A - 一种用于促进伤口愈合的水凝胶及其制备方法和应用 - Google Patents
一种用于促进伤口愈合的水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于生物医用材料领域，具体涉及一种用于促进伤口愈合的水凝胶及其制备方法和应用。一种用于促进伤口愈合的水凝胶，该水凝胶的原料组分包含改性党参多糖。本发明的水凝胶通过乙酰化改性修饰党参多糖，又与多巴胺进行共混接枝交联，结果发现该水凝胶不仅具有较高的抗氧化生物活性，还具有较好的黏附性，并在后续测试该水凝胶的抗菌性能实验中发现，相比未加多巴胺的水凝胶，本发明水凝胶的抗菌性大大提升了。
Description
技术领域
本发明属于生物医用材料领域，具体涉及一种用于促进伤口愈合的水凝胶及其制备方法和应用。
背景技术
人体最常见的皮肤损伤修复过程是一个动态过程，包括4个阶段，其中第2阶段开始于蛋白水解酶与促炎因子从侵入的免疫细胞释放到伤口区域，产生炎症免疫反应，这类炎性细胞产生活性氧促进伤口修复进程，但过高浓度的ROS水平可能通过增加氧化应激与脂质过氧化甚至造成严重的细胞损伤而阻止伤口愈合。在这一阶段，所有的异物与组织碎片都被嗜中性粒细胞与巨噬细胞从伤口床清除，此外细胞因子和相应酶的释放刺激成纤维细胞和成肌细胞的生长，在此过程中伤口渗出液为愈合过程提供了必需的水分。
创面敷料能遮盖和保护伤口，促进外伤、烧伤、糖尿病足和术后切口的伤口愈合。理想的伤口敷料可以提供湿润的环境、防止继发性感染、清除多余的组织渗液、促进创面附近组织再生、提高伤口愈合质量并减少瘢痕的产生。水凝胶敷料能够提供湿润的创面环境，防止二次感染，促进坏死创面和肉芽创面的自溶清创，提高创面愈合效率，是一种较为理想的创面敷料。与人工合成聚合物水凝胶相比，天然生物聚合物水凝胶（如多糖水凝胶和多肽水凝胶等）具有生物相容性良好、可降解性、生物特异性、不会引起免疫和毒性反应、降解时间可控、降解产物无毒、无免疫原性且最终代谢产物可以排出体外等优点。自2002年受贻贝启发的多巴（DOPA）改性水凝胶的制备被报道以来，利用DOPA结构单元修饰水凝胶备受关注。DOPA的关键结构单元是邻苯二酚结构，它能够与各种无机/有机/金属表面形成强共价键和非共价键，从而大大提升水凝胶的黏附性与力学性能。同时，大量研究表明，邻苯二酚官能化水凝胶组织黏附性极佳，且抗氧化活性较强。
研究表明，党参含有多糖类、植物甾醇类、萜类、生物碱类、苯丙素苷类等多种化学成分，其中多糖类所占比例最大，是党参具有增强机体免疫力、抗衰老和降血糖等多种作用的主要活性成分。已有研究表明党参多糖（CPP）对超氧阴离子自由基具有清除作用，有一定的抗氧化活性且对机体部分损伤有保护作用。目前，党参多糖的生物活性研究大多局限于其对免疫系统功能的调节方面，这在某种程度上阻碍了药材党参的相关新药资源开发，致使药材党参的附加值不高，制约了党参种植及相关产业的发展。
天然多糖的生物活性和理化性质与其结构密切相关。为了更好地发挥多糖的功效，使其有着更为广泛的应用，研究人员常常对多糖分子进行修饰或改性。多糖的改性可以提高多糖的生物活性和吸收效率，并赋予其新的功效。同时多糖改性技术也能为一些因为结构性质而无法发挥其活性或是无法投入工业化生产的多糖提供新的利用途径。但是，许多改性方法还存在着缺陷，如改性成本高昂、改性条件苛刻、改性工艺危险、改性副产物阻碍改性进行或造成污染等，这些极大地限制了多糖改性技术的大规模应用。
发明内容
为了解决上述的技术问题，同时为党参多糖的进一步系统研究和开发奠定基础，填补现有医用材料中的空白，本发明提供了一种新型天然的水凝胶生物材料。本申请人通过对党参多糖进行乙酰化修饰，以期增大党参多糖的溶解度，从而增强其生物活性，又为进一步提高水凝胶的粘附性和力学性能，将改性后的多糖与多巴胺进行共混接枝交联。对本发明的水凝胶进行性能实验评价，结果发现该水凝胶不仅具有较好的黏附性，还具有较高的抗氧化生物活性，应用于皮肤伤口敷料中可以加快伤口愈合的速度和质量。另外，本申请人在测试该水凝胶的抗菌性能实验中还发现，相比未加多巴胺的水凝胶，本发明水凝胶的抗菌性大大提升了。
为了实现上述的发明目的，本发明采用了以下的技术方案：
一种用于促进伤口愈合的水凝胶，该水凝胶的原料组分包含改性党参多糖。
作为优选，所述改性党参多糖是乙酰化党参多糖。乙酰基能改变多糖分子的定向性和横次序，从而改变多糖的物理性质，乙酰基的引入使分子的伸展变化，最终可导致多糖羧基基团的暴露，增加在水中的溶解性。
作为优选，所述乙酰化党参多糖采用的乙酰化改性剂为冰醋酸或乙酸酐中的一种。
作为优选，所述水凝胶的原料组分还包含多巴胺和交联剂。水凝胶可以通过物理或者化学的方法形成，物理交联的水凝胶往往具有较好的生物相容性但是机械性能较差，化学交联形成的水凝胶则比较稳定，但化学交联剂的引入往往会导致细胞相容性较差从而限制其应用。
作为优选，所述交联剂为京尼平和柠檬酸中的一种或多种组合。京尼平和柠檬酸属于天然生物交联剂，可以与含有氨基的聚合物交联形成生物材料，其毒性远远低于戊二醛和其他化学交联剂。
进一步，本发明提供了所述的水凝胶的制备方法，所述方法包括以下步骤：
1）乙酰化党参多糖的制备：将党参多糖用去离子水充分溶解，加入乙酰化改性试剂，用NaOH溶液控制体系pH8.0-10.0，搅拌反应1-2h，用HCl溶液调节pH至中性，终止反应后透析36-48h，透析液旋转蒸发仪中减压浓缩后加入无水乙醇，4℃醇沉24-48h，冷冻干燥后得乙酰化党参多糖。
2）将步骤1）得到的乙酰化党参多糖加入去离子水中，加热搅拌至溶解，得到乙酰化党参多糖水溶液，加入交联剂水溶液混合，室温下搅拌均匀后静置，然后加入多巴胺水溶液，加热搅拌均匀后静置得到水凝胶。
作为优选，所述乙酰化党参多糖水溶液的质量浓度为5wt%-10wt%。
作为优选，所述多巴胺水溶液的质量浓度为1wt%-8wt%。
作为优选，所述交联剂水溶液的质量浓度为1wt%-2wt%。
进一步，本发明提供了所述的水凝胶和所述的制备方法在医用敷料中的应用。
采用本技术方案的有益效果是：本发明水凝胶制备采用的原料组分均为自然界中本身存在的天然物质，对皮肤和身体无毒且无刺激性，具有良好的生物可降解性。本发明通过多糖改性技术对党参多糖进行乙酰化修饰，提高了其清除自由基的能力，结合多巴胺混合接枝交联后，具有良好的机械性能和生物组织黏附性，同时反应中采用的是天然交联剂，与常用的化学交联剂戊二醛相比，具有生物相容性好的优势。此外，由于伤口修复过程往往伴随细菌感染，因此对本发明水凝胶的抗菌性能进行了测试，结果发现该水凝胶的抗菌性能有较大的提升，最终得到一种具有良好的抗氧化性能和一定的生物组织黏附性，以及抗菌性能优异的新型水凝胶材料，在生物医药材料领域中具有较好的应用前景。
具体实施方式
下面将结合本发明实施例，对本发明实施例中的技术方案进行清查、完整的描述，进而进一步解释发明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部实施例。给予本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
主要实验试剂和材料：
党参多糖、多巴胺、京尼平、柠檬酸和戊二醛均购自市售产品。大肠杆菌和金黄色葡萄球菌购自国家微生物保藏中心。
实施例1水凝胶的配方和制备方法
| 原料组分 | 水凝胶1 | 水凝胶2 | 水凝胶3 | 水凝胶4 | 水凝胶5 | 水凝胶6 | 水凝胶7 | 水凝胶8 |
| 党参多糖 | 7wt% | - | - | - | - | - | - | 7wt% |
| 乙酰化党参多糖 | - | 7wt% | 7wt% | 7wt% | 7wt% | 7wt% | 7wt% | - |
| 多巴胺 | - | - | - | - | - | 1wt% | 6wt% | 6wt% |
| 京尼平 | - | - | 1wt% | - | 0.5wt% | 0.5wt% | 0.5wt% | 0.5wt% |
| 柠檬酸 | - | - | - | 1wt% | 0.5wt% | 0.5wt% | 0.5wt% | 0.5wt% |
| 戊二醛 | 1wt% | 1wt% | - | - | - | - | - | - |
注：“-”表示不含该组分。
本发明水凝胶的制备方法：1）乙酰化党参多糖的制备：将党参多糖用去离子水充分溶解，加入乙酰化改性试剂，用NaOH溶液控制体系pH8.0-10.0，搅拌反应1-2h，用HCl溶液调节pH至中性，终止反应后透析36-48h，透析液旋转蒸发仪中减压浓缩后加入无水乙醇，4℃醇沉24-48h，冷冻干燥后得乙酰化党参多糖。2）将步骤1）得到的乙酰化党参多糖加入去离子水中，加热搅拌至溶解，得到乙酰化党参多糖水溶液，加入交联剂水溶液混合，室温下搅拌均匀后静置，然后加入多巴胺水溶液，加热搅拌均匀后静置得到水凝胶。
实施例中其余水凝胶的制备除配方组分和含量不同，其他方法步骤基本一致。
实施例2水凝胶的体外抗氧化活性测定
对DPPH自由基清除能力的测定：取水凝胶样品用0.05M/L醋酸溶液溶解，分别取2.0mL的样品溶液，加入2.5mL0.1mmol/L的DPPH95%乙醇溶液，充分混匀，室温下震荡，完全反应。避光反应30min，于517nm处测其吸光度。每个样品重复三次。以蒸馏水代替水凝胶样液作空白对照，按下式计算清除率：DPPH自由基清除率/%=（A 2-A 1）/A 2×100。式中，A 1为实验组吸光度；A 2为空白组吸光度。结果如表1所示。从表1数据可以发现，相比未经修饰的党参多糖，采用乙酰化党参多糖制备的水凝胶具有较高的DPPH自由基清除率，说明乙酰化修饰改性党参多糖能够一定程度提高其生物抗氧化活性，且其中采用天然交联剂制备得到的水凝胶抗氧化活性高于采用戊二醛作交联剂得到的水凝胶，DPPH自由基清除率达到了82%以上。
表1
| 样品 | 水凝胶1 | 水凝胶2 | 水凝胶3 | 水凝胶4 | 水凝胶5 | 水凝胶6 | 水凝胶7 | 水凝胶8 |
| DPPH自由基清除率（%） | 51.05 | 73.77 | 81.20 | 82.68 | 82.51 | 82.04 | 81.43 | 50.37 |
实施例3水凝胶的粘性性能表征
采用AG-Xplus万能材料试验机测试的生物粘性。将片状生物粘性水凝胶切成长20mm×宽10mm×厚1mm的试样，与人体手背皮肤在100g的压力下接触1min达到粘接，随后夹住水凝胶没有被粘接的部分，向上拉伸将其从人体表皮处剥离，得到水凝胶生物粘性的剥离应力-应变曲线，取剥离时的平均应力作为水凝胶的粘接强度。从表2的实验数据可以发现，相比未添加多巴胺的水凝胶，采用多巴胺制备的水凝胶具有较高的粘性，说明通过多巴胺的共混接枝交联能够一定程度提升凝胶的生物组织黏附性。
表2
| 样品 | 水凝胶1 | 水凝胶2 | 水凝胶3 | 水凝胶4 | 水凝胶5 | 水凝胶6 | 水凝胶7 | 水凝胶8 |
| 粘接强度（kPa） | 5.29 | 6.03 | 6.15 | 6.07 | 6.10 | 7.35 | 8.50 | 8.31 |
实施例4水凝胶的抑菌活性测试
大肠杆菌和金黄色葡萄球菌菌液配制：用LB液体培养基分别复苏、传代大肠杆菌和金黄色葡萄球菌，用接种环将细菌均匀分散在装有PBS缓冲溶液的离心管中，置于摇床中恒温振荡培养后得到OD600为0.5的细菌悬浮液。实验所用的玻璃仪器，培养基，PBS缓冲液等实验用品均用高压灭菌锅灭菌，水凝胶样品通过紫外消毒杀菌。
抑菌圈法：将直径为9mm、高度为1mm的圆柱形水凝胶样品分别放入涂有金黄色葡萄球菌和大肠杆菌细菌悬浮液的固体培养基中。所有样品在37℃恒温生化培养箱中培养24h，最后测量抑菌圈大小。每个样本的抑制率（PI）标准如下：PI=di/dh×100%；其中di和dh分别表示抑菌区直径（mm）和水凝胶直径。
表3
| 样品 | 水凝胶1 | 水凝胶2 | 水凝胶3 | 水凝胶4 | 水凝胶5 | 水凝胶6 | 水凝胶7 | 水凝胶8 |
| 金黄色葡萄球菌抑制率 | 87% | 90% | 101% | 106% | 125% | 162% | 166% | 150% |
| 大肠杆菌抑制率 | 95% | 97% | 113% | 117% | 131% | 178% | 173% | 154% |
从表3的实验数据可以发现，本发明的水凝胶采用乙酰化党参多糖和多巴胺共混交联后的抗菌性能大大提升，金黄色葡萄球菌抑制率达到162-166%，大肠杆菌抑制率达到了173-178%，未远高于未加多巴胺的水凝胶，且通过数据可以发现采用天然交联剂也能够一定程度上提高水凝胶的抗菌性能，且当京尼平和柠檬酸混合使用时的抑制率较高。
以上为对本发明实施例的描述，通过对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的。本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施列，而是要符合与本文所公开的原理和新颖点相一致的最宽的范围。
Claims (10)
1.一种用于促进伤口愈合的水凝胶，其特征在于，该水凝胶的原料组分包含改性党参多糖。
2.根据权利要求1所述的水凝胶，其特征在于，所述改性党参多糖是乙酰化党参多糖。
3.根据权利要求2所述的水凝胶，其特征在于，所述乙酰化党参多糖采用的乙酰化改性剂为冰醋酸或乙酸酐中的一种。
4.根据权利要求1所述的水凝胶，其特征在于，所述水凝胶的原料组分还包含多巴胺和交联剂。
5.根据权利要求4所述的水凝胶，其特征在于，所述交联剂为京尼平和柠檬酸中的一种或多种组合。
6.权利要求1-5任意一项权利要求所述的水凝胶的制备方法，其特征在于，所述方法包括以下步骤：
1）乙酰化党参多糖的制备：将党参多糖用去离子水充分溶解，加入乙酰化改性试剂，用NaOH溶液控制体系pH8.0-10.0，搅拌反应1-2h，用HCl溶液调节pH至中性，终止反应后透析36-48h，透析液旋转蒸发仪中减压浓缩后加入无水乙醇，4℃醇沉24-48h，冷冻干燥后得乙酰化党参多糖；
2）将步骤1）得到的乙酰化党参多糖加入去离子水中，加热搅拌至溶解，得到乙酰化党参多糖水溶液，加入交联剂水溶液混合，室温下搅拌均匀后静置，然后加入多巴胺水溶液，加热搅拌均匀后静置得到水凝胶。
7.根据权力要求6所述的制备方法，其特征在于，所述乙酰化党参多糖水溶液的质量浓度为5 wt%-10 wt%。
8.根据权利要求6所述的制备方法，其特征在于，所述多巴胺水溶液的质量浓度为1wt%-8 wt%。
9.根据权利要求6所述的制备方法，其特征在于，所述交联剂水溶液的质量浓度为1wt%-2 wt%。
10.权利要求1-5任意一项权利要求所述的水凝胶和权利要求6-9任意一项权利要求所述的制备方法在医用敷料中的应用。
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| CN117143264B (zh) * | 2023-10-30 | 2024-02-20 | 中国医学科学院药用植物研究所 | 乙酰乙酰化黄芪多糖、制备方法及在制备促进伤口愈合水凝胶中的应用 |
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