Role of Nitric Oxide-Releasing Glycosaminoglycans in Wound Healing.
Role of Nitric Oxide-Releasing Glycosaminoglycans in Wound Healing.
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DOI：
10.1021/acsbiomaterials.2c00392
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发表时间：
2022-05
影响因子：
5.8
通讯作者：
Sara E. Maloney;Christopher A. Broberg;Quincy E Grayton;Samantha L Picciotti;Hannah R Hall;S. Wallet;R. Maile;M. Schoenfisch
中科院分区：
文献类型：
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作者：
Sara E. Maloney;Christopher A. Broberg;Quincy E Grayton;Samantha L Picciotti;Hannah R Hall;S. Wallet;R. Maile;M. Schoenfisch
采用碳化二亚胺化学方法对透明质酸(HA)和硫酸软骨素(CS)两种糖胺聚糖(GAG)生物聚合物进行化学修饰，以促进一氧化氮(NO)的负载和释放，从而开发出一种多功能创面愈合剂。所得NO释放GAG向模拟创面液中释放0.2~0.9mmolNO mg-1，半衰期为2 0~110min。含有端伯胺的烷基胺的GAG表现出中间的NO释放动力学，对3株铜绿假单胞菌和金黄色葡萄球菌都有很强的广谱杀菌作用。NO负荷量还可降低小鼠TLR4的活性，提示其治疗作用具有抗炎机制。利用人真皮成纤维细胞和人表皮角质形成细胞进行的体外黏附和增殖分析显示，不同的GAG骨架、烷基胺特性和NO释放特性不同。与抗菌性能相结合，GAG衍生物的粘附性和增殖性使其能够为后续的体内研究选择最有希望的伤口愈合候选者。铜绿假单胞菌感染的小鼠伤口模型显示，CS作为促进伤口愈合的NO供体支架优于HA，其优点是加速伤口闭合，减少细菌负荷，这可归因于活性NO释放和生物聚合物骨架。
Two glycosaminoglycan (GAG) biopolymers, hyaluronic acid (HA) and chondroitin sulfate (CS), were chemically modified via carbodiimide chemistry to facilitate the loading and release of nitric oxide (NO) to develop a multi-action wound healing agent. The resulting NO-releasing GAGs released 0.2-0.9 μmol NO mg-1 GAG into simulated wound fluid with NO-release half-lives ranging from 20 to 110 min. GAGs containing alkylamines with terminal primary amines and displaying intermediate NO-release kinetics exhibited potent, broad spectrum bactericidal action against three strains each of Pseudomonas aeruginosa and Staphylococcus aureus ranging in antibiotic resistance profile. NO loading of the GAGs was also found to decrease murine TLR4 activation, suggesting that the therapeutic exhibits anti-inflammatory mechanisms. In vitro adhesion and proliferation assays utilizing human dermal fibroblasts and human epidermal keratinocytes displayed differences as a function of the GAG backbone, alkylamine identity, and NO-release properties. In combination with antibacterial properties, the adhesion and proliferation profiles of the GAG derivatives enabled the selection of the most promising wound healing candidates for subsequent in vivo studies. A P. aeruginosa-infected murine wound model revealed the benefits of CS over HA as a pro-wound healing NO donor scaffold, with benefits of accelerated wound closure and decreased bacterial burden attributable to both active NO release and the biopolymer backbone.