Reactive Nitrogen–Dominant Plasma Accelerates Diabetic Wound Healing Through Regulated Angiogenesis and TGF‐β Normalisation

ABSTRACT

Chronic diabetic wounds persist because of impaired angiogenesis, dysregulated transforming growth factor beta activity and delayed matrix remodelling. Non-thermal atmospheric pressure plasma therapy represents a potential non-pharmacologic approach to overcome these barriers. This study compared reactive nitrogen–dominant and reactive oxygen–dominant plasma exposures under identical apparatus conditions in a diabetic wound model. A universal plasma jet operated with nitrogen or argon gas was applied to streptozotocin-induced diabetic rats. Wound area reduction and time to 90% closure were quantified. Histological evaluation assessed re-epithelialisation and collagen deposition and immunohistochemistry measured angiogenesis using cluster of differentiation 31 staining and transforming growth factor beta expression. Nitrogen plasma treatment demonstrated sustained improvement in wound reduction relative to diabetic controls and reached 90% closure on day 19, whereas argon plasma reached this threshold on day 24 and diabetic controls exceeded 30 days. Nitrogen plasma was also associated with an earlier, self-limited angiogenic response characterised by an early cluster of differentiation 31 peak on day 6, together with patterns consistent with enhanced collagen maturation and earlier normalisation of transforming growth factor beta expression. Overall, these findings suggest mechanistic differences between reactive nitrogen–dominant and reactive oxygen–dominant plasma exposures in regulating angiogenesis and matrix remodelling during diabetic wound repair. These results indicate that plasma gas chemistry may influence wound-healing trajectories, supporting the potential of plasma therapy as a translational adjunct approach for difficult-to-heal wounds.