How does the healing process of a wound occur?

When an injury occurs, whether due to trauma or surgical intervention, a discharge of lymphatic fluid and blood is observed. Immediately following this, a constriction of the severed vascular ends occurs through the action of thromboxane A2 and prostaglandin. Concurrently with this process, the extrinsic and intrinsic coagulation pathways are activated and play a role in the cessation of blood loss. During this phase, a fibrin clot forms at the site of the endothelial injury (blood vessels), and platelets (thrombocytes) aggregate and adhere to the damaged endothelium. This hemostasis is a short-term process, which can occur within minutes after the injury, and is soon followed by vasodilation, allowing the influx of white blood cells and a greater number of platelets. Indeed, the adhered thrombocytes release chemokines, thereby attracting the cellular components of the inflammatory phase.

Approximately 24 hours later, the hemostasis phase is followed by a dilation of the blood capillaries, allowing the influx of various inflammatory cells, such as neutrophils, monocytes, and lymphocytes, to the wound. It is the chemoattractants, growth factors, and cytokines, released by the platelets, that promote this migration of inflammatory cells to reach the damaged tissue. At this stage, the wound exhibits all the characteristic signs of inflammation: redness and heat due to vasodilation, pain due to pressure on sensitive nerve endings, and swelling due to plasma exudation.

Neutrophils are the first inflammatory cells to arrive, peaking after 24 hours. They phagocytize bacteria and eliminate cellular debris, allowing for wound decontamination. Polymorphonuclear leukocytes, on the other hand, release reactive oxygen species (ROS) that potentiate this destruction process.

Macrophages assist in initiating the proliferation phase. These cells also perform various functions, including promoting the inflammatory healing process by releasing cytokines, removing cellular debris, and attracting blast cells to the injury site. All processes occur simultaneously but in a synchronized manner. The duration of the inflammatory phase typically lasts between three and six days.

Once the wound is stabilized, it shifts into reconstruction mode. This proliferation phase does not occur at a specific time, but continues constantly in the background. Immediately after the inflammatory phase begins to organize within a network of collagen and elastin, produced by fibroblasts, a granulation tissue with new capillary formation (neovascularization or angiogenesis) begins to deliver in situ the oxygen, nutrients, and cells necessary for tissue repair. Around days 5 to 7, the platelet-derived growth factor attracts fibroblasts and, along with the transforming growth factor (TGF), enhances the division and multiplication of fibroblasts.

They infiltrate the wound site, proliferate, and differentiate into myofibroblasts to begin producing new collagen, hyaluronic acid, and fibronectin. These components form the core of the wound that will serve as a scaffold. Subsequently, re-epithelialization begins to occur with the migration of cells from the periphery of the wound and adjacent edges.

Initially, only a thin superficial layer of epithelial cells is deposited, but a thicker and more durable layer of cells will fill the wound over time. Subsequently, neovascularization occurs both through angiogenesis, forming new blood vessels from existing ones, and through vasculogenesis, which is the formation of new vessels from endothelial progenitor cells (EPCs). Once collagen fibers are deposited on the fibrin structure, the wound begins to mature. It also begins to contract and is facilitated by the continuous deposit of fibroblasts and myofibroblasts. At this stage, the skin appears red and raised.

At this stage, macrophages still play a crucial role by producing growth factors or cytokines capable of promoting fibroblastic proliferation and collagen synthesis. At this point, the scar is a young fibrosis containing numerous fibroblasts and a loose fibrillar framework on the periphery of the substance loss.

The fleshy bud is composed of fibroblasts, an inflammatory infiltrate (monocytes, lymphocytes, polymorphonuclear cells), fibrin on the surface, and new blood vessels within an edematous fibrillar framework. The contraction of the wound to bring its edges closer together is closely linked to the formation of granulation tissue and the transformation of certain fibroblasts into myofibroblasts capable of contracting and transmitting their contractile activity to the surrounding tissue through interaction between the proteins of the cytoskeleton and the extracellular matrix. This phase, very active from the 7th day, can last up to 3 weeks.

Following tissue repair, the wound contracts and is gradually covered by a new epithelium (epithelialization). The epidermal cells (keratinocytes) multiply and begin to cover the granulation tissue starting from the edges of the wound. In order to properly migrate, these keratinocytes require a healthy, moist, and level granulation tissue. Following the formation of this initial cellular layer, the epithelium is thickened by cell division and soon becomes more resilient. The wound is closed.

Maturation is the healing stage when a scar softens, flattens, and fades. During this final phase, which begins around the third week, the wound reaches maximum strength as it matures. Depending on the severity of the wound, the remodeling can take a year or more to be fully completed.

During this stage, the contraction of the wound has reached its peak. The maximum tensile strength of the incision wound occurs after about 11 to 14 weeks. The resulting scar will never have 100% of the initial strength of the wound and only about 80% of its tensile strength.

The granulation tissue recedes, giving way to fibrous connective tissue. The thickening of collagen fibers increases resistance to tensile forces. The number of capillaries, as well as blood flow, decrease. Excess water and vessels then disappear, and the scar tightens. However, scars are always less resilient and less elastic than normal skin, partly due to a certain deficit in elastin. This phase can last from several months to 2 years.

• HECKMANN M. & al. Regulatory mechanisms of fibroblast activity. Recenti Progressi in Medicina (1989).

• GRINNELL F. Fibroblasts, myofibroblasts, and wound contraction. Journal of Cell Biology (1994).

• MARTIN P. Wound healing—aiming for perfect skin regeneration. Science (1997).

• GIBBS S. & al. 2007. Wound-healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes. Wound Repair and Regeneration (2007).