# Advances in Three Dimensional Bioprinting for Wound Healing: A Comprehensive Review
## 3 Overview of Wound Pathophysiology and Wound Healing Process  
Wounds can be classified as acute or chronic according to the recovery period. Acute wounds can usually be recovered within an acceptable period; however, certain factors may delay the healing process. Chronic wounds can be healed very slowly or not be healed due to several factors such as varied diseases, environmental conditions, nutrition, and increased bacterial loads leading to a weakening of the immune system. The physical signs of chronic wounds include exudation, persistent infection, and necrosis, all of which contribute to the complexity of managing and caring for these wounds [36; 37; 38; 34]. The process of healing consists of four main phases: hemostasis, inflammation, proliferation, and remodeling (Figure 1B) [8; 39; 34]. The first step of the healing process starts with the contraction of the vessels, which slows the blood flow to the wound area. In the hemostasis phase, platelet receptors in the blood interact with ECM proteins and attach to the walls of blood vessels. Once attached, the platelet becomes activated, causing a conformational change and the release of bioactive molecules that enhance coagulation. With coagulation, a clot formation containing fibrin, fibronectin, vitronectin, and thrombospondin prevents bleeding and protects the blood environment from external pathogens [40]. Once the wound is hemostasized, the inflammatory process begins. During the process, immune system agents try to prevent infection by targeting pathogens in the region. Vascular permeability increases with vasodilation, allowing neutrophils and monocytes to accumulate in the wound area. About three days after wound formation, the proliferative phase initiates the accumulation of keratinocytes, fibroblasts, macrophages, and endothelial cells to regulate wound closure, matrix deposition, and angiogenesis. The activation of keratinocytes is triggered by changes in mechanical tension, electrical gradients, hydrogen peroxide, pathogens, growth factors, and cytokines. The endothelial cells enter a rapid growth phase and angiogenesis occurs within the granulation tissue [41]. The last and longest phase of wound healing is the formation of the ECM, which may take several years to remodel. This stage ends with the formation of granulation tissue through either fibroblast death by apoptosis, or their differentiation into myofib. Parameters affecting wound healing are divided into systemic and local factors. Systemic factors are related to the person's age, diseases and their lifestyle. Local factors include temperature, pH, water content, microbial content, oxygen (O\({}_{2}\)), carbon dioxide (CO\({}_{2}\)), infection, foreign body and venous insufficiency. However, depending on the type of wound, local factors may differ. Particularly, O\({}_{2}\) is a crucial element providing the energy needed by the cells. By supporting the immune system, O\({}_{2}\) protects the wound from infection and induces angiogenesis. In addition, O\({}_{2}\) increases keratinocyte differentiation, migration, re-epithelialization, fibroblast proliferation, and collagen synthesis. A disruption in the structural integrity of the skin results in direct exposure to external factors. Since microorganisms cause infection due to the contamination of the wound, it is essential to isolate the wound from the external environment [7; 42; 43]. The success of the wound healing process depends on growth factors, cytokines and chemokines, as they are involved in the integration of signals in cellular processes in the wound. However, the wound healing process may be delayed by the diseases a patient might have, which can reduce the amount of vascularity in the wound area. In such cases, it is necessary to use wound dressings containing active substances [44; 45; 46]. Even though all wounds follow similar healing stages, their components, microenvironments, and recovery time may vary depending on the type of the wound.