11.1.1　Production and healing of skin wounds

Skin is the largest organ of the human body，which is in direct contact with the surrounding environment and acts as a protective barrier at the interface between the human body and the surrounding environment.The skin has many important functions，including preventing the loss of body fluids and regulating body surface temperature.Due to certain factors，such as an injury and a surgery，the anatomical structure and physiological functions of normal skin can be destroyed and skin trauma occurs.Skin wounds can be classified into acute or chronic wounds depending on the healing process.Acute wounds originate from superficial abrasions to deep injuries，and they can usually heal within 3 weeks.Acute wounds that fail to heal within 2 months usually develop into chronic wounds，such as certain types of ulcers or diabetic wounds.Wound healing requires multiple processes to occur in a specific order.As shown in Figure 11-1，these processes are generally divided into four major stages，namely hemostasis，inflammation，migration，and remodeling/maturation.

The wound healing process begins with hemostasis，i.e.，blood clots form and the wounds close.At this stage，blood vessels constrict to stop bleeding，and platelets are activated.Platelets play several important roles in wound healing，including regulating hemostasis during the aggregation phase and secondary hemostasis during the coagulation phase.Platelets can also produce biologically vasoactive mediators and chemokines，such as proteases，cytokines，and growth factors.Cytokines send chemotactic signals to inflammatory cells and cell populations.Fibrin is formed during secondary hemostasis.The fibronectin clot acts as a temporary matrix，allowing epithelial cells and fibroblasts to migrate to the wound.A blood clot forms and thrombin is activated.Activation of the fibrinolytic system leads to fibrin degradation.In this process，peptides are released to stimulate chemotaxis and increase capillary permeability.Cytokines can also trigger an inflammatory response and play a role in removing debris，damaged or necrotic tissues，and microorganisms，which is followed by granulation tissue formation，re-epithelization，and connective tissue matrix formation.The granulation tissue is composed of dense macrophages，fibroblasts，capillary networks，fibronectin，hyaluronic acid，and endothelial cells.During the formation of granulation tissue，macrophages，fibroblasts，and endothelial cells are interdependent.(https://www.daowen.com)

Hypoxia is an important factor that triggers the formation of new blood vessels at early stage of wound healing.Before the basement membrane is formed，the wound will continue to seep fluid.At the same time，fibroblasts gather from the edge of the wound，and circulating fibroblasts and mesenchymal stem cells migrate to the immature connective tissue matrix.Re-epithelialization begins at the edge of the wound，where epithelial cells lose hemidesmosome connections and migrate across the wound through a temporary fibrin—fibronectin matrix until they encounter the same cells.Directional migration and proliferation require an effective，balanced，and enzyme-supported“cut and paste”program.After this process，the epithelial cells on the edge of the wound are in direct contact，which is called primary healing.In addition，secondary healing occurs after the migrating cells connect for a certain period.Due to the delayed epithelial closure and the higher formation rate of granulation tissue，the healing process of open wounds is slower.The final stage of the wound healing process is called the contraction stage and begins with the formation of large amounts of collagen in the granular tissue.In the contraction phase，the distance between the edge of the wound is reduced until the wound is tightly closed.This process occurs due to the differentiation of fibroblasts and the differentiation of progenitor cells into myofibroblasts.Myofibroblasts rich in actin skeletal matrix cause the matrix to contract.After the wound shrinks，it enters the remodeling process，in which the production of the matrix is stopped，and fibroblasts and myofibroblasts undergo apoptosis and degeneration.The final result of wound healing may be completely scarless，or it may leave obvious scars due to fibrosis.