Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair
Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair
复制标题
载有衣康酸 4-辛酯的多功能水凝胶具有抗菌、抗氧化和血管生成特性，可修复糖尿病伤口
DOI：
10.1016/j.bioadv.2022.212979
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发表时间：
2022-08-01
影响因子：
--
通讯作者：
Guo, Xiaodong
中科院分区：
文献类型：
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作者：
Ding, Qiuyue;Jing, Xirui;Guo, Xiaodong
皮肤创面愈合，尤其是糖尿病创面愈合是临床上常见的问题。活性氧(ROS)和细菌感染是导致氧化应激和炎症的两个主要因素，导致血管生成和伤口愈合受阻。然而，糖尿病创面慢性炎症和过度氧化应激的恶劣微环境仍很难逆转。依他康酸是一种内源性代谢物，近年来作为一种重要的免疫调节剂引起了广泛关注。在这项研究中，我们使用了4-辛基衣康酸酯(4OI)，一种细胞渗透性衣康酸衍生物，具有抗氧化和抗炎作用，用于糖尿病创面再生。同时，通过将四臂聚乙二醇(PEG)与硝酸银结合来传递生物活性分子，制备了一种可注射、自愈和抗菌的动态配位水凝胶。体外实验证实，4OI@PEG水凝胶具有抑制细菌生长、保护人脐静脉内皮细胞免受ROS损伤、促进新生血管形成的作用。此外，水凝胶通过激活Keap1-Nrf2抗氧化防御系统，增加线粒体极化，减少线粒体碎裂。体内实验证明，这种多功能水凝胶通过抑制局部炎症和促进血管生成，促进糖尿病伤口的愈合。总的来说，负载40I的多功能材料可以逆转各种不利的微环境，如过度的氧化应激、炎症和感染，并可以促进新生血管的形成，因此，这类材料在治疗糖尿病溃疡方面显示出巨大的前景。
Cutaneous wound healing, especially diabetic wound healing, is a common clinical problem. Reactive oxygen species (ROS) and bacterial infection are two major factors in the induction of oxidative stress and inflammation, leading to impeded angiogenesis and wound healing. However, it is still very difficult to reverse the harsh microenvironment of chronic inflammation and excessive oxidative stress on diabetic wound. Itaconate, an endogenous metabolite, has recently attracted extensive attention as a critical immune-regulator. In this study, we used 4-octyl itaconate (4OI), a cell-permeable itaconate derivative, to have antioxidative and anti-inflammatory functions for diabetic wound regeneration. Simultaneously, an injectable, self-healing, and anti-bacterial dynamic coordinative hydrogel was manufactured by binding the 4-arm polyethylene glycol (PEG) with silver nitrate to deliver the bioactive molecule. In vitro experiments confirmed that 4OI@PEG hydrogel could inhibit bacterial growth, protect human umbilical vein endothelial cells from ROS damage and enhance neo-vascularization. In addition, the hydrogel increased mitochondrial polarization and reduced mitochondrial fragmentation by activating the Keap1-Nrf2 antioxidant defense system. In vivo experiments proved that this multifunctional hydrogel facilitated diabetic wound healing by inhibiting local inflammation and promoting angiogenesis. Collectively, 4OI-loaded multifunctional materials could reverse various unfavorable microenvi-ronments, such as excessive oxidative stress, inflammation, and infection, and can promote neovascularization; thus, such materials show great promise for the treatment of diabetic ulcers.