Nitric oxide (NO) plays a pivotal role in the wound healing process and promotes the generation of healthy endothelium. In this work, a simple method has been developed for fabricating a diselenide grafted gelatin gel, which reduces NO donors such as S-nitroso-N-acetylpenicillamine (SNAP) by glutathione peroxidase-like mechanism to produce NO. Briefly, the process involved covalently conjugating 3,3′-diselenodipropionic acid (DSePA) with gelatin via carbodiimide coupling. The resulting gelatin–DSePA conjugate (G–Se–Se–G) demonstrated NO production upon incubation with SNAP and glutathione (GSH) with the flux of 4.8 ± 0.6 nmol cm−2 min−1 and 1.6 ± 0.1 nmol cm−2 min−1 at 10 min and 40 min, respectively. The G–Se–Se–G recovered even after 5 days of incubation with the reaction mixture retaining catalytic activity up to 74. Subsequently, G–Se–Se–G was suspended (5 w/v) in water with lecithin (6 w/w of gelatin) and F127 (3 w/w of gelatin) to prepare gel through temperature dependant gelation method. The fabricated G–Se–Se–G gel exhibited desirable rheological characteristics and excellent mechanical stability under storage conditions and did not cause any significant toxicity in normal human keratinocytes (HaCaT) and fibroblast cells (WI38) up to 50 μg ml−1 of selenium equivalent. Finally, mice studies confirmed that topically applied G–Se–Se–G gel and SNAP promoted faster epithelization and collagen deposition at the wound site. In conclusion, the development of a biomimetic NO generating gel with sustained activity and biocompatibility was achieved.
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