## 2 Wound Healing Process: The Role of the Wound-Dressing  
Wound healing is a complicated, multi-step, and multifactorial process, which involves different cells, signals, and biochemical substances. The wound-healing phases include hemostasis, inflammatory, proliferative, and maturation, in which different molecules, cells, and signals/stimuli are involved (Figure 1). Hemostasis begins at the onset of injury, aiming to stop the bleeding. It is reported that uncontrolled bleeding from a wound, hemorrhage, is the leading cause of complications and death. While passive wound-dressings cannot initiate or accelerate blood clotting, unprecedented attempts have been conducted to design interactive hemostatic wound-dressings capable of controlling bleeding. Moreover, there are different specialized hemostatic wound-dressings on the market, such as HemCon Bandage PRO and Stasilon(r), Entegrion, Inc. of Durham, NC, USA, which exhibit promising performance [17].  
The second step of wound-healing is the defensive/inflammatory phase, which prepares the wound bed for new tissue growth by destroying bacteria and removing debris. Generally, anti-microbial substances have been tried to incorporate into the interactive wound-dressing to facilitate the defensive/inflammatory wound-healing phase. Since providing a moist environment facilitates the body's enzymatic debridement, several studies have tried to develop a wound-dressing structure for this purpose [19; 20; 21]. Although inflammation is a vital step in the wound-healing process, chronic inflammation is an undesirable condition that makes chronic wounds and subsequently induces some complications, such as mature scar formation. Wound dressings containing anti-inflammatory agents have been developed to modulate the inflammatory responses and prevent chronic wound progression [22].  
The transition from the defensive/inflammatory phase to the proliferative phase is critical during the wound-healing process. In this phase, the provisional fibrin matrix, formed in the previous stage, replaces a new matrix of fibronectin, proteoglycans, and collagen fibers. Moreover, angiogenesis, granulation tissue formation, and epithelialization are vital processes in this step [1]. Fibroblasts and keratinocytes have critical roles in this phase, and several substances have been investigated to modulate their migration and activities. Several studies applied wound-dressings as the drug-delivery vehicle. These studies included  
Figure 1: The wound-healing stages and various involved elements. (**A**) the hemostasis, (**B**) the inflammation, (**C**) the proliferation, and (**D**) the remodeling stages. PDGF: platelet-derived growth factor, TNF: tumor necrosis factor, TGF: transforming growth factor, KGF: keratinocyte growth factor, FGFs: fibroblast growth factors, IGF: insulin-like growth factor, IL-1: interleukin-1, IFN: interferon, TIMP: tissue inhibitor of metalloproteinase, VEGF: vascular endothelial growth factor, MMP: matrix metalloproteinase, HGF: hepatocyte growth factor. Reproduced with permission from Reference [18].  
efforts to deliver various growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF-1), and platelet-derived growth factor (PDGF) to modulate the functions of these cells. Moreover, different phytochemicals and naturally derived substances have been combined with wound-dressings to improve their efficacy [22; 23; 24].  
The remodeling stage, also called the maturation stage, is the final stage of wound-healing, in which collagen type III remodels to type I, and the wound fully closes. During this process, the disorganized collagens align along tension lines, absorb water, and crosslink together. These events make the skin area of the wound stronger and reduce scar thickness. Although wound-dressings are more applicable in the first phases of the wound-healing process, it is possible to modulate the latest wound-healing stage using proper wound-dressings and reduce scar formation [3; 5].