## 2 Wound Healing
### Chronic Wounds: The Impaired Healing  
Chronic wounds are characterized by an impaired healing process caused by different factors, both external and internal. There are different types of chronic wounds, namely, vascular ulcers (venous and arterial). Even though the term \"chronicity\" and the timeframe for the healing process are not clearly pre-established, it is estimated that the impaired physiologic process can take more than six weeks [2; 10; 11]. The long healing process that significantly affects the patient's quality of life is a significant cause of morbidity due to serious infections and ulceration and leads to amputations, such as in the case of diabetic foot ulcers [12]. Nowadays, the issue relative to chronic wounds leads to approximately 40 million chronic wound patients worldwide, causing an enormous economic impact on healthcare systems [8]. An increase of more than 44% is envisaged for 2023, in respect of 2016 [8]. Based on these statistical data, adequate and well-planned management of chronic wounds has achieved increasing importance [2]. In order to improve human quality of life, a deeper knowledge of the healing process and the development of new alternatives for chronic wound treatment have raised great interest in the scientific community [6; 8]. Therefore, it is a priority to understand the normal and insufficient healing process. In healthy people, wound healing is a fascinating biological process, composed of four main basic phases, including hemostasis, inflammatory, proliferative, and remodeling (Figure 1). The hemostasis phase is characterized by current platelet activation, which results in releasing chemokines and growth factors to form the clot [13]. When the coagulation is complete, the platelet is reinforced with a fibrin network acting as a molecular binding agent to form a barrier against microorganisms and organize the matrix for cell migration. In response to inflammatory signs, phagocytes (neutrophils and macrophages) migrate to the wound, facilitating phagocytosis of bacteria and damaged tissue [5; 13]. Both cells are responsible for the production of cytokines and growth factors, which are necessary for an efficient wound healing process [14]. Before the proliferative phase, macrophages are responsible for the release of cytokines and residual neutrophils by apoptosis, which allows the healing process to proceed. In response to growth factors, the wound closure is also characterized by the deposition of collagen fibers produced by the migration of fibroblasts to promote the production of extracellular matrix [5]. Additionally, macrophages are responsible for stimulating the formation of new blood vessels at the wound brim (angiogenesis), providing oxygen, nutrients, and metabolite, and rebuilding the initial clot with new tissue formed by extracellular matrix (granulation tissue). Thus, granulation tissue creates the conditions needed for re-epithelialization [13]. Finally, the remodeling phase is characterized by the resynthesis of the extracellular matrix, which is necessary for creating a balance between apoptosis of existing cells and production of new cells. This phase begins when the collagen is remodeled from type III of the granulation tissue to type I and becomes aligned in parallel bundles, which increase the tensile strength and the wound fully closes [13; 14]. Figure 1: Different phases of normal wound healing. However, chronic wounds are characterized by a significant delay in the repair of the anatomical integrity of the wound [11]. The impaired wound healing is characterized by an interruption of the physiological process in the inflammatory phase, difficult re-epithelialization, disorder levels of growth factors, and/or impaired angiogenesis. All these abnormalities that occur in chronic wounds give rise to different functional disturbances at a cellular level [15].