孔径可控pH敏感双层互穿网络水凝胶敷料的分子设计及构建策略

Wound dressing has been an important part of the global medical devices. The wound dressing hydrogel has been widely concerned for its advantages of softness, water absorption and pain relief. However, hydrogel dressings prepared by chemical crosslinking often have chemical residue and polymer chain flexibility, which leads to poor biocompatibility, high brittleness. To solve these problems, simulating the skin outer layer and dermal structure, double pH sensitive hydrogel dressing is designed to improve the biocompatibility and mechanical properties of the hydrogel using the freezing and thawing method to produce physical crosslinking. In the study, the effect of different molecular weight, viscosity and concentrations of PEG, PVA and CMC on the construction of double hydrogels morphology would be explored. Also, freezing temperature, annealing temperature, freezing time and freezing times of engineering control conditions would be investigated to evaluate whether these factors have impacts on the mechanical properties and interface elimination between inner and outer layer. Furthermore, a full-thickness skin defect and diabetic skin injury model would be made to assess the repairing effect of double network hydrogel for wound. Thereby, the purpose of this research is to reveal the correlation between polymer properties, engineering control factors, pore size, and hydrogel morphology, mechanical properties and biological functions, clarify the law of polymer freeze-thaw method to build the hydrogel.

创面敷料在全球医疗器械中一直占有很重要的份额，以水凝胶为代表的创面敷料由于其柔软、吸水性强、缓解疼痛等优点而被广泛关注。但用化学交联制备的水凝胶常存在化学物质残留、高分子柔性链韧性难以发挥，从而导致水凝胶生物相容性差、脆性大等问题。鉴于此，本项目拟对高分子聚合物进行分子设计，采用反复冻融法产生物理交联，模拟皮肤表皮层和真皮层构建双层pH敏感水凝胶敷料，提高水凝胶的生物相容性及力学性能，兼具有pH敏感性。研究聚合物PEG、PVA及CMC的不同分子量、黏度及浓度对双层水凝胶内外层孔径、微观形貌的影响；研究冷冻温度、退火温度、冷冻时间及冷冻次数等工程控制条件对内外层孔径分布、力学性能及内外层界面消除的影响；建立全层皮肤缺损和糖尿病皮肤损伤模型，考察双层络水凝胶对不同创面的修复效果，进而将聚合物性质、工程控制因素与水凝胶的孔径、力学性能及生物学功效相关联，阐明聚合物反复冻融法构建水凝胶敷料的规律。

水凝胶为代表的创面敷料由于其柔软、吸水性强、缓解疼痛等优点，但用化学交联制备的水凝胶常存在化学物质残留、高分子柔性链韧性难以发挥，从而导致水凝胶生物相容性差、脆性大等问题，针对此，本项目构建了4种不同类型的水凝胶，考察了其物理化学、机械性能、生物相容性及对不同创面的修复效果。主要研究成果如下：.1、.构建了PVA/CMC/PEG双层水凝胶，该水凝胶上层孔径较小结构致密，下层孔径较大结构疏松，厚度方向水凝胶孔径从上至下呈现逐渐增大的趋势，两层之间紧密结合。双层水凝胶具有合适的水蒸气透过率、优异的持水能力和阻菌能力，而且不会与伤口黏连。双层水凝胶生物相容性均满足生物材料标准。该水凝胶组能够更快加速创面恢复。.2、.构建了用鞣酸修饰的TA-PVA/PEG/HA双层水凝胶，TA引入水凝胶中以形成双交联网络，并赋予水凝胶粘附性、抗菌性和抗氧化性。该双层水凝胶表现出形状记忆行为和自愈能力，并通过加速胶原沉积、降低肿瘤坏死因子-α（TNF-α）水平和促进血管内皮生长因子（VEGF）的表达，显著促进伤口闭合。.3、.构建了贻贝启发的、基于银纳米酶PDA-PVA/PEG/SA双层水凝胶。受益于聚多巴胺（PDA）涂层还原的Ag纳米颗粒（AgNPs），水凝胶在808nm处表现出高的近红外（NIR）吸收，以产生高温和NIR增强的过氧化物酶活性和产生羟基自由基（•OH）的抗菌性能。该双层水凝胶可以通过促进胶原沉积、减少肿瘤坏死因子-α分泌和促进血管内皮生长因子表达来加速感染皮肤的生成。.4、.构建了葡萄糖/MMP-9双响应水凝胶（CGCI）。该水凝胶具有温度敏感的形状自适应性，能以类固体的弹性保护不规则伤口（25℃），以类液体的流动性自适应深层伤口（37℃）；具有葡萄糖/MMP-9双响应释药系统，可按需释放胰岛素与塞莱昔布，解决慢性糖尿病伤口的高糖、高MMP-9与长期炎症。

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