Zhang Yuxin, Wang Tianchang, Zhang Dahe, Xia Simo, Jiao Zixian, Cai Bin, Shen Pei, Yang Chi, Deng Yiwen
Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai 200011, China; Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Int J Biol Macromol. 2023 Oct 1;250:126010. doi: 10.1016/j.ijbiomac.2023.126010. Epub 2023 Jul 28.
Oxidative stress microenvironment caused by reactive oxygen species (ROS) accumulation seriously hinders wound healing in diabetes, which brings great burden to global health. Various wound dressings on the market focus on delivering active substances to promote wound healing in diabetes. However, the complex pathological microenvironment of diabetic wounds often leads to the inactivation of delivery factors, which often leads to treatment failure, and thus, emerging therapeutic approaches are urgently needed. In this study, a macromolecular hydrogel synthesized by crosslinking N-carboxyethyl chitosan, hyaluronic acid-aldehyde, and adipic acid dihydrazide, with self-healing and injectable abilities was used to deliver total glycosides of paeony (TGP). The TGP incorporated hydrogel could obviously induce fibroblasts proliferation and secretion of various extracellular matrix proteins and growth factors, induce migration and angiogenesis of vein endothelial cells, and enhance macrophages polarization to M2 phenotype by eliminating accumulated ROS. In diabetic wound models, the ROS-scavenging hydrogel efficiently enhanced proliferation, re-epithelialization, collagen deposition, as well as angiogenesis in the wound area. Besides, the dressing induced the macrophages polarization from M1 phenotype (pro-inflammatory) to M2 phenotype (anti-inflammatory) and decreased the levels of inflammatory cytokines, thereby enhancing the diabetic wound healing. The wounds treated with TGP incorporated hydrogel almost completely healed 16 days after treatment. However, the residual wound areas in the groups of Con, INTRA, and Gel are 55.2 ± 4.6 %, 33.7 ± 6.5 %, and 34.9 ± 6.1 % on the 16th day, respectively. This hydrogel with pathological microenvironment improvement ability affords a novel therapeutic strategy for enhancing healing of chronic diabetic wound.
活性氧（ROS）积累所导致的氧化应激微环境严重阻碍糖尿病患者伤口愈合，给全球健康带来巨大负担。市场上的各种伤口敷料都专注于递送活性物质以促进糖尿病患者的伤口愈合。然而，糖尿病伤口复杂的病理微环境常常导致递送因子失活，进而导致治疗失败，因此迫切需要新的治疗方法。在本研究中，通过N-羧乙基壳聚糖、透明质酸-醛和己二酸二酰肼交联合成的具有自愈和可注射能力的大分子水凝胶被用于递送芍药总苷（TGP）。负载TGP的水凝胶能够明显诱导成纤维细胞增殖以及分泌各种细胞外基质蛋白和生长因子，诱导静脉内皮细胞迁移和血管生成，并通过清除积累的ROS增强巨噬细胞向M2表型极化。在糖尿病伤口模型中，这种清除ROS的水凝胶有效促进了伤口区域的增殖、再上皮化、胶原蛋白沉积以及血管生成。此外，该敷料诱导巨噬细胞从M1表型（促炎）向M2表型（抗炎）极化，并降低炎症细胞因子水平，从而促进糖尿病伤口愈合。用负载TGP的水凝胶治疗的伤口在治疗16天后几乎完全愈合。然而，在第16天，Con组、INTRA组和Gel组的残余伤口面积分别为55.2±4.6%、33.7±6.5%和34.9±6.1%。这种具有改善病理微环境能力的水凝胶为增强慢性糖尿病伤口愈合提供了一种新的治疗策略。
