*2.2. Tissue Regeneration*

When the wound healing reaction is well organized and controlled, the inflammatory response is quickly resolved and normal tissue structure is restored [57]. However, if the wound healing response is chronic or becomes dysregulated, it can lead to the development of pathological fibrosis or scars, which impair normal tissue function and may ultimately lead to organ failure and death [56]. Therefore, the wound-healing reaction must be strictly regulated. Biological processes involved in cutaneous wound healing include infiltration of inflammatory cells, fibroblast repopulation and new vessel formation, keratinocyte migration, and proliferation [54,58,59]. Although many cells are involved in tissue repair, macrophages exhibit significant regulatory activity at all repair and fibrosis stages and are critically involved in normal tissue homeostasis [60]. It is clear that monocytes and macrophages play more complex roles in tissue repair and in contributing to fibrosis and tissue regeneration [8]. Macrophages are an important source of chemokines, matrix metalloproteinases (MMPs), and other inflammatory mediators that induce early cellular response after injury [61]. Indeed, when macrophages are depleted soon after injury, the inflammatory response is often greatly reduced [8]. However, their removal can also reduce wound debris and cause less efficient repair and regeneration [56]. After the initial inflammatory phase subsides, the main macrophage population develops a wound healing phenotype characterized by the production of numerous growth factors, such as transforming growth factor beta 1 (TGF-β1), platelet-derived growth factor (PDGF), vascular endothelial growth factor alpha (VEGF-α), and insulin-like growth factor 1 (IGF-1) [5].

## **3. Specialized Pro-Resolving Mediators (SPMs)**
