Phases of Wound Healing

Phases of wound healing are distinct continuous sequences in wound healing. Wound healing is a continuous process that begins immediately after the injury to repair the defect by restoring cellular structure and tissue layers.

There are three distinct phases of wound healing. Each phase is a complex and well-coordinated at cellular level.

Distinct phases are

• Hemostasis
• Inflammatory Phase
• Proliferative or Granulation Phase
• Remodeling Phase

Hemostasis

Some authors consider this a separate entity and do not include in phases of wound healing. Anyway hemostasis is series of events that aims to minimize the bleeding.

Before actual inflammatory phase begins, there occurs an event called clotting cascade, which helps to minimize bleeding and generate factors for actual inflammatory phase.

Clotting cascade is initiated when blood comes in contact with collagen. This triggers  blood platelets to secreting inflammatory factors. Platelets stick to each other to form an aggregate.

Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles to  prevents further blood loss and offer structural support for the wound. Platelets adhere to it and secrete a number of factors into the blood which includes extracellular  matrix proteins, cytokines and growth factors.

Other proinflammatory factors like serotonin, bradykinin, prostaglandins, prostacyclins, thromboxane, and histamine are also released by the platelets. These increase  increase cell proliferation, causes other cells to migrate to the area and dilate the vessels.

Inflammatory Phase

Ruptured cell membranes, immediately on getting injured release inflammatory factors like thromboxanes and prostaglandins causing blood vessels to constrict and prevent blood loss.

This vasoconstriction lasts five to ten minutes and is followed by vasodilation which peaks about 20 minutes after injury [widening of blood vessels].

Vasodilation is the result of factors like histamine, which also causes porosity of the vessels and leakage of  proteins from the bloodstream into the extravascular space, and the entry of inflammatory cells like leukocytes into the wound site.

Within an hour of wounding, polymorphonuclear neutrophils arrive at the wound site phagocytise debris and bacteria. They also kill bacteria by releasing free radicals.

T cells, other type of leukocytes enter the area and  secrete cytokines. These cytokines cause further T cell division, increase inflammation, enhance vasodilation and vessel permeability.

T cells also increase the activity of macrophages.Macrophages  replace polymorphonuclear cells in the wound by two days after injury. Macrophages are mature monocytes which are attracted to wound sites by growth factors released by platelets.

Macrophages phagocytise bacteria and damaged tissue and they also debride damaged tissue by releasing proteases.

Macrophages also secrete  growth factors and cytokines, which attract cells involved in the proliferation stage of healing to the area.

With passage of time  fewer inflammatory factors are secreted and numbers of neutrophils and macrophages are decreased at the wound site indicating end of the inflammatory phase.

Proliferative or Granulation Phase

For ease of sequencing and understanding, the proliferative phase has been divided into different subphases, which occur in continuation and overlapping manner.

The subphases are

• Fibroplasia
• Matrix deposition
• Angiogenesis
• Re-epithelialization

In days 5-7, fibroblasts have migrate into the wound, lay down new collagen of the subtypes I and III.

The fibroblasts produce glycoaminoglycans and fibronectin including including heparan sulfate, hyaluronic acid, chondroitin sulfate, and keratan sulfate. These lead to matrix deposition.

Angiogenesis is formation of new blood vessels which is regulated by basic fibroblast growth factor and vascular endothelial growth factor.

Migration and division of peripheral cells occurs in hours 48-72, resulting in a thin epithelial cell layer, which bridges the wound. This process is called reepithelialization.

This proliferative phase lasts about  4 weeks.

Remodeling

Remodeling commences around third week and leads to changes in wound structure and strength by replacing the type of collagen present in the wound  to match the that in normal tissue.

Specialized fibroblasts termed myofibroblasts also lead to wound contraction, which results in movement of the edges of a wound towards the center to close it.