Shen Tong, Dai Kai, Yu Yuanman, Wang Jing, Liu Changsheng
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR. China; Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR. China.
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR. China; Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, PR. China.
Acta Biomater. 2020 Nov;117:192-203. doi: 10.1016/j.actbio.2020.09.035. Epub 2020 Sep 29.
Emerging evidence suggests that dysfunctional macrophages can cause chronic inflammation and impair tissue regeneration in diabetic wounds. Therefore, improving macrophage behaviors and functions may improve therapeutic outcomes of current treatments in diabetic wounds. Herein, we present a sulfated chitosan (SCS)-doped Collagen type I (Col I/SCS) hydrogel as a candidate for diabetic wound treatments, and assess its efficacy using streptozocin (STZ)-induced diabetic wound model. Results showed that Col I/SCS hydrogel significantly improved wound closure rate, collagen deposition, and revascularization in diabetic wounds. Flow cytometry analysis and immunofluorescent staining analysis showed that the Col I/SCS hydrogel accelerated the resolution of excessive inflammation by reducing the polarization of M1-like macrophages in chronic diabetic wounds. In addition, ELISA analysis revealed that the Col I/SCS hydrogel reduced the production of pro-inflammatory interleukin (IL)-6 and increased the production of anti-inflammatory cytokines including IL-4 and transforming growth factor-beta 1 (TGF-β1) during wound healing. Moreover, the Col I/SCS hydrogel enhanced the transdifferentiation of macrophages into fibroblasts, which enhanced the formation of collagen and the extracellular matrix (ECM) in wound tissue. We highlight a potential application of manipulating macrophages behaviors in the pathological microenvironment via materials strategy. STATEMENT OF SIGNIFICANCE: Improving the chronic inflammatory microenvironment of diabetic wounds by regulating macrophage behaviors has been of wide concern in recent years. We designed a Col I/SCS hydrogel based on Collagen type I and sulfated chitosan (SCS) without exogenous cells or cytokines, which could significantly improve angiogenesis and resolve chronic inflammation in diabetic wounds, and hence accelerate diabetic wound healing. The Col I/SCS hydrogel could facilitate the polarization of M1-to-M2 macrophages and activate the transdifferentiation of macrophages to fibroblasts. Additionally, the Col I/SCS hydrogel also equilibrated the content of pro-inflammatory and anti-inflammatory cytokines. This strategy may afford a new avenue to improve macrophage functions and accelerate diabetic chronic wound healing.
新出现的证据表明，功能失调的巨噬细胞可导致慢性炎症并损害糖尿病伤口的组织再生。因此，改善巨噬细胞的行为和功能可能会改善当前糖尿病伤口治疗的效果。在此，我们提出一种硫酸化壳聚糖（SCS）掺杂的I型胶原蛋白（Col I/SCS）水凝胶作为糖尿病伤口治疗的候选材料，并使用链脲佐菌素（STZ）诱导的糖尿病伤口模型评估其疗效。结果表明，Col I/SCS水凝胶显著提高了糖尿病伤口的愈合率、胶原蛋白沉积和血管再生。流式细胞术分析和免疫荧光染色分析表明，Col I/SCS水凝胶通过减少慢性糖尿病伤口中M1样巨噬细胞的极化，加速了过度炎症的消退。此外，酶联免疫吸附测定（ELISA）分析显示，Col I/SCS水凝胶在伤口愈合过程中减少了促炎白细胞介素（IL）-6的产生，并增加了包括IL-4和转化生长因子-β1（TGF-β1）在内的抗炎细胞因子的产生。此外，Col I/SCS水凝胶增强了巨噬细胞向成纤维细胞的转分化，从而增强了伤口组织中胶原蛋白和细胞外基质（ECM）的形成。我们强调了通过材料策略在病理微环境中操纵巨噬细胞行为的潜在应用。重要性声明：近年来，通过调节巨噬细胞行为来改善糖尿病伤口的慢性炎症微环境受到广泛关注。我们设计了一种基于I型胶原蛋白和硫酸化壳聚糖（SCS）的Col I/SCS水凝胶，无需外源性细胞或细胞因子，它可以显著改善糖尿病伤口的血管生成并消除慢性炎症，从而加速糖尿病伤口愈合。Col I/SCS水凝胶可以促进M1向M2巨噬细胞的极化，并激活巨噬细胞向成纤维细胞的转分化。此外，Col I/SCS水凝胶还平衡了促炎和抗炎细胞因子的含量。这一策略可能为改善巨噬细胞功能和加速糖尿病慢性伤口愈合提供一条新途径。
