## 2 Physiology and Pathology of Cutaneous-Wound Healing
In general, after superficial injury, the scar is barely (or may not even be) visible to the naked eye. In the case of a deeper wound, the scar is often visible, but is seen as a smooth, pale and flattened area known as a normotrophic scar. As a result of this final stage, barely visible scars are generated for superficial injuries. They are usually visible as smooth, pale and flattened in deep trauma [27]. An incorrect sequence and timing of these phases could potentially result in abnormal healing [2]. This failure of tissue-repair processes can be associated with vascular diseases, diabetes mellitus, or aging. It can be also caused by genetic variations in genes responsible for such processes [20]. Ulcers may become chronic if the inflammatory phase takes more than three weeks [28]. On the other hand, an excess of fibrosis during the proliferation phase may generate hypertrophic scarring or keloids [29] (Figure 1). Inflammatory responses are essential during wound-healing processes. Yet, a prolonged acute-inflammation phase may impair the proliferation of keratinocytes and recruitment of profibrotic macrophages [30]. An imbalance may occur between inflammatory and anti-inflammatory signals, and chronic inflammation may develop. Appropriate steps may not progress, leading to an imbalance in the environment, and disrupting wound healing [31]. Failure to proceed through the normal phases of healing generates chronic wounds [11]. This prolonged inflammation stage is caused by a local increase in levels of pro-inflammatory cytokines, like interleukin-1 beta (IL-18) and tumor necrosis-factor alpha (TNF-\(\alpha\)). All that delays wound healing [29]. In this scenario, the levels of matrix metalloproteinases (MMP) and serine proteases are significantly increased. They are capable of destroying components of the extracellular matrix, and worsening the migration of cells [32] (Figure 1b). Chronic inflammation is one of the causes of poor healing in patients with diabetes. This pathology is responsible for the majority of non-traumatic lower-limb amputations. In fact, 15-20% of diabetic foot ulcers may require amputation [33]. Diabetes decreases the immune response, which facilitates infections. It also produces defects in microcirculation which, together with peripheral neuropathy and peripheral arterial disease, favor the appearance of skin ulcers. The healing of these ulcers is aggravated by hyperglycemia, which leads to the formation of advanced glycation end-products (AGE). They favor the chronification of inflammation. That is characterized by an increased presence of pro-inflammatory M1 macrophages, in relation to anti-inflammatory M2 ones, and increased levels of pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) [33]. Age is also a risk factor that slows the rate of healing of skin wounds. With age, there are changes in the conformation of skin, that affect both the epidermis and dermis, making it more vulnerable to different types of damage. For example, the number of dermal-epidermal junctions in the epidermis decreases, as does the speed of keratinocyte migration. Additionally, in the dermis, there are fewer fibroblasts, macrophages, vessels and extracellular matrix components, such as collagen [34]. In addition, age may be also associated with increased malnutrition, sedentary lifestyle, decreased steroid hormones and increased medication, as a consequence of the appearance of pathologies associated with aging. All these factors also have a negative influence on healing capacity [34]. Defects in scar formation can lead to excessive accumulation of ECM in tissues (fibrosis) and cause pathological scarring, with loss of skin function. The most significant components of such process are TGF-\(\beta\), connective tissue growth factor (CTGF), interleukin-4, 13 (IL-4, 13), platelet-derived growth factor (PDGF) and osteopontin [35]. Such abnormal scar overgrowth can lead to two different types of fibrotic-skin disorders: hypertrophic scars and keloids [19].