## 2 Physiology and Pathology of Cutaneous-Wound Healing  
In the skin, tissue damage is repaired through complex biological processes, involving extensive cooperation of various cell types, growth factors and cytokines [19]. Restoring the integrity of all the layers of the skin (epidermis, dermis and hypodermis) are essential for its function, as a protective barrier against the damaging effects of abiotic external factors, as well as to prevent dehydration of the body, and to protect wounds from biotic aggressions (infections) [20]. A normal scar will form with loose fibrous connective tissue in a slow healing process, which consists of several phases. However, the damaged tissue will remain weaker and functionally deficient for at least some time, compared to uninjured tissue [19]. Thus, healing is a dynamic progression comprising four phases: hemostasis, inflammation, proliferation and maturation/remodeling. These phases may overlap, and even different areas of wounds may be in different stages of healing [17]. Within seconds or minutes after the wound originates, hemostasis begins with the action of platelets. The latter produces a blood clot that stops bleeding, further protecting the wound area from microbial invasion [21]. In addition, the formed fibrin network serves as a platform for the migration of vascular cells, leukocytes and fibroblasts [20]. Different cytokines, hormones and chemokines, necessary for the activation of subsequent healing phases, are also released [17]. In the second phase, an inflammatory reaction is induced in the area of ulceration, which aim is cleansing the damaged area of the skin. Within the first 24 h after the wound is produced, neutrophils synthesize proteases and antimicrobial compounds [2]. They kill microorganisms that are trapped after violation of the skin barrier [22]. At 48 h of wounding, the damaged zone gets cleaned by macrophages and lymphocytes, that engulf and digest the remains of the matrix and existing microorganisms. Then, they change phenotype, participating in the production of anti-inflammatory cytokines and extracellular matrix (ECM) [23]. These cytokines and chemokines activate the proliferation phase [24]. Therefore, after 48 h, the inflammatory process must be turned off to prevent the development of a pathological process. The third phase comprises re-epithelialization, neovascularization and granulation tissue formation [21], which take place up to two to three weeks after injury. Re-epithelialization of the damaged skin occurs due to the differentiation and proliferation of keratinocytes, as well as regenerative epidermal stem cells. They originate from the interflollicular epidermis, hair follicles and sebaceous glands at the wound edge [25]. Cytokines and vascular growth factors, such as vascular endothelial growth factors (VEGF) and basic fibroblast growth factor (bFGF), induce angiogenesis, and thus the formation of new blood vessels [17]. This process is important for the progression of healing in the face of hypoxia and nutrient deprivation, occurring at the wound site [19]. Fibroblasts also proliferate and produce large amounts of ECM components. Some fibroblasts, under the action of transforming growth factor beta (TGF-\(\beta\)) differentiate into myofibblasts. They have a contractile function: attach to the extracellular matrix via integrins, and contract via alpha smooth-muscle actin (\(\alpha\)-SMA) [20]. Therefore, the size of the wound is reduced, contributing to its closure [19]. Finally, in the last and longer maturation/remodeling phase (for up to a year after skin injury), the tissue reaches its final appearance of healing [2]. After the closure of the skin wound, the ratio of fibrillar collagen I to collagen III in the temporal wound matrix (2:1) returns to the level of normal skin (5:1) [19]. This phase is characterized by the restructuring of the entire unorganized ECM [26], and the reduction of both dermis cellularity and blood-vessel density [17].