School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, PR China.
The State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu 610065, PR China.
Acta Biomater. 2022 Jul 15;147:147-157. doi: 10.1016/j.actbio.2022.05.047. Epub 2022 May 29.
Hyaluronic acid (HA)-based antioxidant hydrogels have achieved remarkable results in diabetic wound repair. However, the realization of their glucose-responsive antioxidant functions remains a significant challenge. In this study, we modified hyaluronic acid methacrylate (HAMA) with phenylboronic acid (PBA) and developed a glucose-responsive HA derivative (HAMA-PBA). A glucose-responsive HAMA-PBA/catechin (HMPC) hydrogel platform was then fabricated by forming a borate ester bond between HAMA-PBA and catechin. The results showed that the HMPC hybrid hydrogel not only had a three-dimensional network structure and Young's modulus similar to those of skin tissue, but also possessed biocompatibility. The HMPC hydrogel also showed unique glucose-responsive catechin release behavior and remarkable antioxidant capability, which could effectively eliminate intracellular reactive oxygen species and protect cells from oxidative stress damage (increased superoxide dismutase activity, stabilized reduced glutathione/oxidized glutathione ratio, and reduced malondialdehyde content). Additionally, in vitro and in vivo experimental results showed that the HMPC hydrogel effectively promoted angiogenesis (enhanced VEGF and CD31 expression) and reduced inflammatory responses (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within three weeks). This was a significant improvement as compared to that observed for the untreated control group and the HMP hydrogel group. These results indicated the potential for the application of the HMPC hydrogel for treating diabetic wounds. STATEMENT OF SIGNIFICANCE: At present, the delayed closure rate of diabetic chronic wounds caused by excessive reactive oxygen species (ROS) remains a worldwide challenge. Hyaluronic acid (HA)-based antioxidant hydrogels have made remarkable achievements in diabetic wound repair; however, the realization of their glucose-responsive antioxidant functions is a tough challenge. In this work, we developed a novel HA-based hydrogel platform with glucose-responsive antioxidant activity for rapid repair of diabetic wounds. In vitro and in vivo experimental results showed that the HMPC hydrogel could effectively promote angiogenesis (enhanced VEGF and CD31 expression) and reduce inflammatory response (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within 3 weeks). These results indicated the potential of the HMPC hydrogel for application in diabetic wound treatment.
基于透明质酸（HA）的抗氧化水凝胶在糖尿病伤口修复方面取得了显著成效。然而，实现其葡萄糖响应的抗氧化功能仍然是一个重大挑战。在本研究中，我们用苯硼酸（PBA）对透明质酸甲基丙烯酯（HAMA）进行修饰，得到了一种葡萄糖响应的透明质酸衍生物（HAMA-PBA）。然后通过 HAMA-PBA 与儿茶素之间形成硼酸酯键，构建了一种葡萄糖响应的 HAMA-PBA/儿茶素（HMPC）水凝胶平台。结果表明，HMPC 杂化水凝胶不仅具有与皮肤组织相似的三维网络结构和杨氏模量，而且具有生物相容性。HMPC 水凝胶还表现出独特的葡萄糖响应儿茶素释放行为和显著的抗氧化能力，可有效清除细胞内的活性氧物种，保护细胞免受氧化应激损伤（增加超氧化物歧化酶活性、稳定还原型谷胱甘肽/氧化型谷胱甘肽比值、降低丙二醛含量）。此外，体外和体内实验结果表明，HMPC 水凝胶可有效促进血管生成（增强 VEGF 和 CD31 表达），减少炎症反应（降低 IL-6 水平，增加 IL-10 水平），从而快速修复糖尿病伤口（在 3 周内）。与未处理的对照组和 HMP 水凝胶组相比，这是一个显著的改善。这些结果表明，HMPC 水凝胶在治疗糖尿病伤口方面具有应用潜力。
