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wound on palm of hand

Image: “Wound on palm of hand a day after falling off a bike onto concrete.” by Arria Belli – Own work. License: Public Domain


Definition of Wound Healing

Wound healing is a complex process involving the regeneration of damaged and lost cells and tissues.

Pathophysiology and Stages of Wound Repair

Hemostasis

Hemostasis is the immediate stage following an injury.

It starts with vasoconstriction of a blood vessel and a platelet plug, which activates more platelets. Vasoconstriction limits blood loss. The intrinsic and extrinsic clotting cascade is activated by platelets and damaged tissues to form a fibrin mesh consisting of platelets, white blood cells, and red blood cells.

Activated platelets release growth factors, chemokines, and cytokines, including platelet-derived growth factor and transforming growth factor-beta, to help with cellular proliferation and granulation. Released cytokines attract inflammatory cells and initiate the next stage of healing.

Inflammation

The next stage, inflammation, clears dead cells, bacteria, and cellular debris with phagocytes and inflammatory cells. Growth factors are released from these cells to facilitate migration and proliferation of cells to allow tissue regeneration.

Fibrin and thrombin increase vascular permeability and help in the migration of inflammatory cells to the site of injury; thus, intravascular cells responsible for healing are released in the extravascular space.

Neutrophils migrate from the circulation and into the intercellular space within hours, guided by the complement system and cytokines. These help to cleanse the wound of pathogens and debris. Monocytes leave the circulation to become macrophages, which are responsible for more cleaning of dead cells and debris within the first few days after injury. These are the most important cells in healing. Macrophages phagocytize debris and pathogens. They release many factors responsible for the proliferation of fibroblasts and muscle cells and attract endothelial cells to the site of injury for the formation of vessels.

Cytokines, tumor necrosis factor, interlukin-1, and platelet-derived growth factor are all secreted by macrophages to facilitate growth of fibroblasts, myofibroblasts, smooth muscle cells, epithelial cells, and endothelial cells. This stage lasts for a few days after injury, with neutrophils acting in three days and macrophages in the first week.

Granulation

Granulation tissues consist mainly of new blood vessels, connective tissue, and collagen. Collagen in the wound is mainly type III, which converts to type I collagen.

Fibroblast growth factor and vascular endothelial growth factor promote angiogenesis and cellular proliferation.

Angiogenesis is the formation of new vasculature, with migration and proliferation of endothelial cells to form new capillaries along the basement membrane surrounded by myofibroblasts. Fibroblasts divide and promote contraction of the wound edges to facilitate epithelialization from the periphery to the center. This stage can last for a few weeks.

Day 1
  • Fibrin clot (hematoma)
  • Neutrophils infiltrate
Day 2
  • Squamous cells seal off wound
  • Macrophages migrate into wound
Day 3
  • Granulation tissue begins to form
  • Initial deposition of type III collagen
  • Macrophages replace neutrophils
Days 4-6
  • Peak granulation tissue formation
  • Fibronectin (key glycoprotein)
Week 2
  • Tensile strength about 10%
Month 1
  • Remodeling of wound (collagenase/lysyl oxidase)
  • Tensile strength about 80% in 3 months

Remodeling

Remodeling makes constant changes in the wound starting after about three weeks, and the process may continue as long as several years. Remodeling includes apoptosis of excess cells and degradation and the alignment of collagen fibers with skin tension lines. This phase can last for years after injury.

Factors Affecting Wound Healing

Several factors can delay wound healing and lead to formation of chronic ulcers or scars. Such factors may be systemic factors or local factors within the wound.

Systemic factors include diabetes mellitus, vascular and connective tissue diseases, age, nutritional deficiency, smoking, and alcohol consumption.

Local factors that impair wound healing include the presence of a foreign body within the wound, infection, edema, and moisture.

Types of Wound Healing

There are 3 different types of wound healing: primary closure, secondary closure, and delayed primary closure. However, the healing mechanisms of all 3 are similar to each other.

Primary closure (or healing by primary intention) occurs with simple wounds such as paper cuts and small surgical incisions when a small defect exists with little risk of complications or infections. All stages of healing follow smoothly without interruption.

Secondary closure (or secondary intention) occurs when a large wound has a gap or tissue defect that prevents the edges from closing by means of primary intention (e.g., lacerations, burns, ulcers). Granulation tissue with new blood vessels and collagen are needed to close the defect or skin loss, leading to scar formation. With this type of healing, granulation and proliferation take longer, there is risk of infection, and the wound needs more time to close.

Delayed primary closure (or tertiary intention) occurs mainly in wounds that are left open to ensure no contamination by organisms, after which the wound is surgically closed. The open wound is watched for a few days and then closed surgically to heal through primary and secondary intention. Examples of such wounds are dog bites, wounds that contain foreign bodies, and wounds healing by tissue grafting.

Complications of Wound Healing

Wound healing can result in hypertrophic scars or keloids, which are raised above the skin due to the proliferation of fibroblasts. A keloid is different in that it extends beyond the borders of the wound site, with irregular, dense collagen fibers, and it is usually painful. Keloids are not common in people of white origin; dark-skinned people are at higher risk of developing keloids. Hypertrophic scars stay within wound borders and regress spontaneously. They occur immediately after injury, whereas keloids may remain years after injury.

Hypotrophic scars (also called or atrophic scars) are depressions in wound sites due to insufficient collagen, such as in the case of acne and some viral infections.

Rapid healing of a wound will affect scar size. The more rapid the healing process is, the smaller the scar will be.

Long-term complications include hypo- or hyperpigmentation, calcification, and incisional hernia. Other complications include excess contracture (as with burns), joint contractures, and wound dehiscence due to defective granulation.

Impaired healing may occur in the following cases and secondary to:

Impaired-Healing

Image: Impaired healing. Vitamin C deficiency. By Lecturio

  • Infection (e.g., Staphylococcus aureus)
  • Diabetes: risk of infection, reduced blood flow
  • Poor nutrition: risk of infection, insufficient protein
  • Vitamin C deficiency:  Collagen cross-linking (areas of hydroxylation)
  • Metal deficiency: zinc (collagenase) and copper (lysyl oxidase)
  • Glucocorticoids: collagen synthesis, scars from bacterial meningitis/wounds
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