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Paul Banaszkiewicz Paul Banaszkiewicz Section Editor
Nickil Nickil Agni Segment Author


  • The process of healing is a continuous process with minor differences between injured tissue types.
  • We typically divide healing into three stages beginning at the time of injury: inflammatory phase; proliferative phase and maturation phase. The duration of each phase depends on tissue type, systemic and local factors.
  • It is also important to appreciate the difference between repair and regeneration.
    • Repair: the original tissue is not restored to its pre-injury state, the defect is filled with a variable extent of scar tissue, e.g. skin, muscle, viscera.
    • Regeneration: healing restores the original structure and function of the tissue without scar tissue formation, e.g. bone, peritoneum.

Table 1. Pro-inflammatory factors involved in wound healing

Examples of pro-inflammatory factors involved in wound healing:

Vasoactive amines

 Inflammatory phase (days 0–5)

  • This begins at the time of injury and starts with a haematoma formation through activation of the clotting cascade. Chemokines and cytokines are produced at this stage to signal cells to phagocytose bacteria and damaged tissue (polymorphonuclear cells (PMNs) and macrophages). The proliferative stage is initiated through signalling molecules from these cells.
  • Clotting
    • Exposure of blood to collagen activates platelet aggregation and pro-inflammatory cytokines and mediators which result in cell proliferation, migration and vasodilatation at the local tissue (oedema).
  • Circulating immune cells
    • PMNs arrive shortly after injury and peak between 24 and 48 hours after injury. Function is to phagocytose; however, they are not essential in the wound healing process and numbers decline after 72 hours.
    • Macrophages are the essential immune cell in wound healing peaking at 72 hours and are responsible for phagocytosis and neo-vascularisation. Macrophage cell signalling initiates the proliferative phase.

Proliferative phase (days 3–14)

  • This is characterised by formation of granulation tissue.
  • Angiogenesis
    • Capillary endothelial cells are stimulated by growth factors from macrophages and platelets to grow in to the repair zone resulting in neovascularisation.
    • Mediators responsible include fibroblast growth factors, transforming growth factors and epidermal growth factors.
  • Granulation tissue formation
    • Begins in the inflammatory phase and consists of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts and extracellular matrix.
    • Fibroblasts are stimulated to migrate and proliferate in the area to secrete matrix components and collagen by growth factors and fibronectin.
  • Collagen deposition
    • Collagens are a family of triple chain glycoproteins and are ultimately responsible for the tensile strength of the scar.
    • Collagen is detected from day 3 post-injury and levels rapidly increase for approximately 3 weeks.
    • Fibroblasts gain smooth muscle filaments and attach to adjacent cells to become myofibroblasts and are responsible for wound contraction.

Maturation phase (day 7–2 years)

  • This is the final phase of wound healing. Type III collagen is remodeled to type I and cellular activity and blood vessel numbers reduce in the wounded area.
  • Disorganised collagen fibres are rearranged and cross-linked resulting in increased tensile strength.
  • Strength of the scar is 20% at 3 weeks and reaches maximum by 3 months at 80% of normal skin.
 Table 2. Factors affecting wound healing



Inadequate vascularisation (reduced blood supply creating a low oxygen environment)



Drugs, e.g. steroids, immunosuppressants, cytotoxic drugs

Foreign material, e.g. sutures, foreign body

Diabetes mellitus

Mechanical, e.g. excessive movement, wound tension

Patient social factors, e.g. age, smoking, ethyl alcohol (ETOH) excess


Connective tissue disorders, e.g. Ehlers Danlos increases risk of keloid formation


 Abnormal scar formation

  • Hypertrophic
    • Broad and raised due to an imbalance of collagen homeostasis in scar maturation.
    • It does not extend beyond the scar and usually settles spontaneously in 18 months.
  • Keloid
    • This is again the result of excessive collagen type 3 production in scar maturation, which is replaced by collagen type 1.
    • Atypical fibroblasts are responsible for this.
    • The abnormality is deposition of collagen beyond the edges of the wound.
    • Unlike hypertrophic scars keloids do not self-resolve.


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  • 5. Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms.J Int Med Res 2009; 37(5): 1528–1542.