The haemostasis phase occurs immediately after injury and results in the formation of a provisional wound matrix
[1]. To prevent exsanguination, vasoconstriction occurs and platelets undergo activation, adhesion and aggregation at the site of injury. The key glycoproteins released from the platelet alpha granules include fibrinogen, fibronectin, thrombospondin and von Willebrand factor
[2]. As platelet aggregation proceeds, clotting factors are released, resulting in the deposition of a fibrin clot at the site of injury. Near to the damaged area, platelet alpha granules release pro-inflammatory cytokines such as Transforming Growth Factor-α (TGF-α), TGF-β, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), Platelet-derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF)
[3]. PDGF is a chemotactic factor which promotes neutrophils migration to the wound site for eliminating contaminating bacteria. With the help of TGF-β, monocytes are transformed to macrophages, which play a key role in increasing the inflammatory response and tissue debridement. Macrophages start the formation of granulation tissue and secretion of various proinflammatory cytokines as IL-1 and IL-6 and growth factors as FGF, EGF, TGF-β and PDGF. Due to the release of VEGF and FGF by platelets, endothelial cells proliferate, resulting in angiogenesis initiation. This event is of vital importance for the synthesis, deposition and organization of a novel ECM. FGF, TGF-β and PDGF then allow fibroblast infiltration. Moreover, TGF-β and PDGF begin phenotypic modifications, transforming fibroblasts into myofibroblasts
[4]. Neutrophils, monocytes and macrophages are the fundamental cells of the inflammatory phase
[5].
Neutrophils are crucial for eliminating the microbes and cellular debris in the wound site; they release inflammatory factors such as IL-1, IL-6 and TNF-α, and also produce molecules such as proteases and Reactive Oxygen Species (ROS), which may contribute to tissue damage
[6].
Macrophages are responsible for the clearance of apoptotic cells, including the removal of dying neutrophils, which terminates the inflammatory response. As inflammation occurs, macrophages undergo a phenotypic transition to a reparative state that activates keratinocytes, fibroblasts and endothelial cells to induce angiogenesis that restores tissue integrity
[7]. Angiogenesis, growth of new blood vessels, supply essential nutrients and oxygen to the damaged tissues and play a crucial part in wound healing
[8][9]. Macrophages positively regulate the transition to the proliferation phase of healing
[10][11].
The third event in wound healing is the proliferation phase. The proliferation stage is characterized by epithelial proliferation and migration over the provisional matrix within the wound, which is referred to as re-epithelialization
[12]. The main events during this phase are the substitution of the provisional fibrin matrix with a novel matrix of collagen fibres, proteoglycans and fibronectin to renew the structure of the tissue and help regain its function
[13][14].
Once the wound is closed, the immature scar can proceed to the final remodelling phase. The remodelling phase can last up to a year, depending on the severity of the wound
[15]. The wound also undergoes physical contraction through the complete wound healing event, which is considered to be orchestrated by contractile fibroblasts (myofibroblasts) that emerge in the wound
[16][17].
In pathological wound healing, however, myofibroblasts activity persists and drives tissue alterations, which is particularly evident in hypertrophic scars developing after burn injury and in the fibrotic phase of scleroderma
[18]. Myofibroblasts-generated contractions are also typical for fibrosis, affecting vital organs such as the liver
[19], heart
[20], lung
[21][22] and kidney
[23].