Lemarchand Mathias, Thouin Kiefer, De Serres-Bérard Thiéry, Bellenfant Sabrina, Cadau Sébastien, Berthod François
LOEX, Centre de recherche du CHU de Québec-Université Laval, Québec, Canada.
Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, Canada.
Biotechnol Bioeng. 2023 Jun;120(6):1657-1666. doi: 10.1002/bit.28359. Epub 2023 Feb 27.
Diabetic foot ulcers are a major complication of diabetes that occurs following minor trauma. Diabetes-induced hyperglycemia is a leading factor inducing ulcer formation and manifests notably through the accumulation of advanced glycation end-products (AGEs) such as N-carboxymethyl-lysin. AGEs have a negative impact on angiogenesis, innervation, and reepithelialization causing minor wounds to evolve into chronic ulcers which increases the risks of lower limb amputation. However, the impact of AGEs on wound healing is difficult to model (both in vitro on cells, and in vivo in animals) because it involves a long-term toxic effect. We have developed a tissue-engineered wound healing model made of human keratinocytes, fibroblasts, and endothelial cells cultured in a collagen sponge biomaterial. To mimic the deleterious effects induced by glycation on skin wound healing, the model was treated with 300 µM of glyoxal for 15 days to promote AGEs formation. Glyoxal treatment induced carboxymethyl-lysin accumulation and delayed wound closure in the skin mimicking diabetic ulcers. Moreover, this effect was reversed by the addition of aminoguanidine, an inhibitor of AGEs formation. This in vitro diabetic wound healing model could be a great tool for the screening of new molecules to improve the treatment of diabetic ulcers by preventing glycation.
糖尿病足溃疡是糖尿病的一种主要并发症，发生于轻微创伤之后。糖尿病引发的高血糖是导致溃疡形成的主要因素，尤其通过诸如N-羧甲基赖氨酸等晚期糖基化终产物（AGEs）的积累得以体现。AGEs对血管生成、神经支配和再上皮化均有负面影响，致使微小伤口演变为慢性溃疡，进而增加下肢截肢的风险。然而，AGEs对伤口愈合的影响难以建模（无论是在体外细胞实验还是在体内动物实验中），因为这涉及长期毒性作用。我们构建了一种组织工程化伤口愈合模型，由在胶原海绵生物材料中培养的人角质形成细胞、成纤维细胞和内皮细胞组成。为模拟糖基化对皮肤伤口愈合产生的有害影响，该模型用300 μM乙二醛处理15天以促进AGEs形成。乙二醛处理导致羧甲基赖氨酸积累，并延迟了模拟糖尿病溃疡的皮肤伤口闭合。此外，添加AGEs形成抑制剂氨基胍可逆转这种效应。这种体外糖尿病伤口愈合模型可能是一种用于筛选新分子的理想工具，通过预防糖基化来改善糖尿病溃疡的治疗。
