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Phases of Wound Healing Stages of Wound Healing

Phases in Normal Wound Healing

Phases of wound healing are Most tissues in the body heal by going through the three R’s: Reaction, Regrowth, and Remodeling.

Reaction Phase

The first set of events in wound healing is the reaction, reactive, or inflammatory phase. In this phase, blood clots seal the wound and a normal inflammatory reaction begins to remove bits of dirt and debris.

The reaction phase begins immediately after an injury, as blood vessels constrict temporarily and blood clotting begins. Soon, the local capillaries become excessively permeable, fluid flows out, and the tissues swell, producing edema. The blood coagulation process releases chemical activators from inside entrapped blood platelets; these activators increase the capillary permeability and attract wandering tissue cells (macrophages) and white blood cells.

The first white blood cells on the scene—polymorphonuclear cells, also called neutrophils—chew up debris and release chemicals that attract more white blood cells. The various biologically active molecules being released into the wound also hypersensitize the endings of local pain nerves, making them react to smaller amounts of chemical and mechanical irritation, making the wound site tender. Together, the processes in the reaction phase produce local inflammation.

Large wounds, such as ulcerative pressure sores or burns, do not seal during this phase. Instead, the accumulating fluid, cells, and clotting materials form a pale yellowish viscous exudate, an eschar. As they age, the coagulant proteins of the exudate link together and dry, making the wound bed crusty.

During the reaction phase, neutrophils remove bacteria and debris. If the wound does not become colonized with bacteria, neutrophils stop entering the wound by about day 2 following the injury. Neutrophils live for less than 24 hours, so in a healthy wound most neutrophils are gone by about day 3. In infected wounds, however, neutrophils continue to pour in and, as they die, they accumulate to form pus.Under healthy conditions, most of the new cells entering the wound after day 2 are mononuclear cells (monocytes), which are the second wave of white blood cells to migrate into a wound. Monocytes transform into macrophages. Macrophages are scavengers that continue to debride the wound biologically by removing dead and dying bits of tissue, dirt, and bacteria. Macrophages also release growth factors, chemicals that stimulate the growth of fibroblasts, endothelial cells, and epithelial cells, all of which are players in the next phase of wound healing.

Regrowth Phase

The second set of events in wound healing is the regrowth, reparative, or proliferative phase. In this phase, new cells grow into the wound and begin to lay down the collagen and other extracellular fibers that will give strength to the scar. At the same time, new blood vessels are growing into the wound. Together, the newly forming cells, blood vessels, and loose extracellular matrix are called granulation tissue. Granulation tissue fills the base of an open wound (e.g., a pressure ulcer) during the regrowth phase of wound healing.

The phases of wound healing overlap. Even as white blood cells are cleansing the wound area in the reaction phase, epithelial cells are moving over the granulation tissue from the cut edges of the wound to begin the regrowth phase. These epithelial cells come from germinative cells in the adjacent skin, and the new epithelial cells will eventually give rise to the epidermis covering the scar.

If the granulation tissue is moist, the epithelial cells can move quickly. In contrast, if the granulation tissue is covered with a dry, scabby exudate, the epithelial cells migrate slowly. For this reason, wounds that are kept moist heal more quickly than those that dry out.

When the wound area is not too large, epithelial cells repopulate the entire surface and generate a new epidermal covering; this process is called re-epithelialization. A healthy wound that has been closed (e.g., with sutures) has only a small area to be covered with epidermis, and it will re-epithelialize in less than two days.

When a wound has been re-covered with epithelium, it is impermeable to water. Over the next few days, the new epithelium continues to deepen and differentiate, and eventually, it becomes a typical epidermal layer. In the process, the new epithelium grows along the top of the granulation tissue but it grows under the crust from the wound exudate and under any remaining blood clots. This dried matter forms the scab, and as the underlying epithelium turns into an epidermis, it loosens the scab, which eventually crumbles off the top of the scar.

Underneath the growing epithelial layer, the granulation tissue is thickening and solidifying. Within 48 hours after the injury, fibroblasts are filling the granulation tissue and laying down collagen and elastin fibers. Collagen is the principal structural protein of the body, and healthy tissue repair requires that new collagen be synthesized, deposited, and cross-linked (i.e., strengthened). Besides making collagen, fibroblasts also secrete sticky amorphous extracellular matrix molecules, the glycoproteins.In a healthy wound, fibroblasts begin to fill the wound during days 2 to 4 after an injury. Fibroblasts grow especially well in the low oxygen/high lactate environment of a healing wound, when it is still covered by an exudate or a scab.

Remodeling Phase

The final set of events in wound healing is the remodeling, or maturational, phase. In this phase, the number of fibroblasts in the new scar decreases and the temporary dense capillary network thins. The scar tissue contracts, edema disappears, and the wounded region continues to strengthen and to adjust to the tensions applied during day-to-day life. This remodeling continues for 6 to 12 months.

As the wound heals, a special class of cells, the myofibroblasts, begins to pull the edges of the wound toward one another. Myofibroblasts are modified fibroblasts. Like fibroblasts, myofibroblasts secrete extracellular molecules. Unlike fibroblasts, however, myofibroblasts can contract like smooth muscle cells. Over a period of 3 to 4 days, the myofibroblasts in the scar contract and slowly shrink the wound (Tomasek et al., 2002).

Wound contraction usually begins after about a week of healing. The contraction is not only a surface phenomenon: the whole thickness of the wound edge is gradually pulled toward the center of the wound. Significant contraction occurs mainly in large wounds, such as ulcers, that are not yet entirely covered by a regrown epithelium.

The new scar is weak for the first five days. Its strength increases markedly over the next month, as new collagen is laid down and then cross-linked. Nonetheless, most scars will never be as strong as the original tissues they replace. Scar strengthening and remodeling taper off after about a year.