**2. Pathophysiology**

Following our studies [2] and those by Mirza et al. [4, 5], we started to focus on the role of accumulation and insufficiency of macrophages in wound healing. Macrophage dysfunction has been shown to produce prolonged inflammatory responses in critical wounds, in diabetes through local secretion of proinflammatory cytokines, such as IL‐1β, TNF‐α, MMP‐9, and IL‐6, in particular, lack of switch to a second macrophage phenotype secreting proregenerative factors, such as IL‐10, IGF‐1, and TGF‐β [6].

The result is an important interruption of healing with persistence of inflammation, whether hyperglycemia through cascade of ROS is its cause or not.

This produces critical wounds. Obviously, single biological steps can be analyzed in experi‐ mental studies, whereas in clinical practice this single factor must often be added to other associated diseases, such as reduction of blood supply due to vascular obstruction. In the latter case, translation from experimental to clinical work must also take into account adding proangiogenetic factors even to provide a complete care.

Our clinical experience deals with persistence of inflammation through both monocyte and vascular insufficiency.

### **2.1. Our experimental studies on wound healing**

In this section, we report our experimental evidences leading to the results about the above‐ mentioned inflammasome inhibition [2]. Plastic surgeons together with pharmacologists of the University of Messina have been working on wound healing for more than 15 years developing some models on rodents.

### *2.1.1. Animals*

For these experiments adult male mice have been chosen, caged alone, and maintained under a controlled environment (12‐hour light cycles day/night and 23°C room temperature, food, and water ad libitum) following Helsinki's declaration and European and Italian laws and Guidelines for Animal Laboratory Experiments.

Animals aging 8 weeks and weighing 20–25 g were used.
