A continuous mode of action of nitric oxide in hard-to-heal wound healing

Nitric oxide (NO) is one of the most studied molecules in medical science. The role of NO as an endogenous regulator of inflammation, as an antibacterial agent and as an endogenous gasotransmitter is well established. Even so, despite a plethora of excellent wound healing data, hard-to-heal (chronic) wounds are of epidemic proportions, and still growing in number. However, yet to be established and sorely needed is the identification of a single, continuous NO mechanism of action (MoA), where phase-to-phase variance in the complex sequence of cellular and molecular wound healing may elucidate the potential for placing hard-to-heal wounds on positive healing trajectories. Hence, the objectives of this review were to: identify salient MoAs for NO in each phase of skin wound healing; and to select and validate a single MoA that is both ubiquitous and continuous in NO across acute and hard-to-heal wound sequences, and which potentiates the ability to supplementally motivate and guide the recovery of a hard-to-heal wound onto a positive healing trajectory. The search began by selecting a detailed, multipart wound healing model. Next, as guided by the literature, was the identification of salient NO functionalities for each model segment. These modes of action were then be used to identify and validate a single NO MoA that is continuous across the healing spectrum. Finally, by using the principle of 'super position' of two continuous functions, this acute healing NO MoA solution was compared to a similar solution set describing a hard-to-heal or chronic wound. As both solution sets are continuous in a NO function, the resultant 'overlay' then helped to identify and guide the use of a NO MoA capable of placing any hard-to-heal wound on a positive healing trajectory.