Stages of Wound Repair
There are 3 main stages of wound healing:
- Exudative stage (day 1–4)
- Hemostasis: limits blood loss from the wound via vasoconstriction. There is a release of inflammatory mediators (growth factors, chemokines, and cytokines) via the activation of platelets.
- Inflammation: clears cellular debris through phagocytosis. There is a migration of inflammatory cells that facilitate tissue regeneration (via growth factors).
- Proliferative stage (day 2–16)
- Granulation: lays the framework for new connective tissue and vasculature
- Fibroblast growth factor and vascular endothelial growth factor promote cellular proliferation and angiogenesis, respectively.
- Granulation: lays the framework for new connective tissue and vasculature
- Remodeling stage (day 5–25): modifies the wound contents to increase its tensile strength
- May last years after an injury
- Apoptosis of excess cells
- Degradation and alignment of collagen fibers
Timeline of wound healing
Image: “Timeline of Wound Healing” by Wikimedia Commons. License: Public Domain Files| Day 1 |
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Exudative phase (immediately after injury): hemostasis and inflammation
Image by Lecturio.
Exudative phase (day 1–4): inflammation and resorption
Image by Lecturio.
Proliferative phase (day 2–16): granulation
Image by Lecturio.
Reparative phase (day 5–25): epithelization
Image by Lecturio.
Wound on palm of the hand a day after falling off a bike onto concrete: day 1
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 2
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 3
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 4
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 5
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 6
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 7
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 8
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 9
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 10
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 11
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand after falling off a bike onto concrete: day 12
Image: “Wound on palm of hand” by Arria Belli – Own Work. License: Public Domain Files
Types of Wound Healing
Regeneration vs. reparation
- Regeneration (epithelialization) is the process of returning the site of injury to its original state.
- This is seen in re-epithelialization after having minor lacerations.
- Reparation (or tissue repair, a form of wound healing) is the process of generating a scar or less functional tissue with a different form and/or composition of the original tissue.
- Does not restore complete functionality
Three types of reparation
- Primary intention: when the tissue surface edges have been approximated
- Small defect with little risk of complications and/or infection
- Secondary intention: when there are significant tissue losses and the wound surface cannot be brought together (e.g., lacerations, burns, and ulcers)
- Granulation tissue (consisting of connective tissue cells and ingrowing young blood vessels) is needed to close the defect → scar formation occurs with a higher risk of infection
- Tertiary or delayed primary intention: when there is a need to delay the closure of a wound (due to contamination risk, poor circulation, etc.)
Processes of primary, secondary, and tertiary wound healing
Image by Lecturio.Complications and Impaired Wound Healing
Wound healing complications
- Hypertrophic scars
- Confined to wound borders
- Common in young individuals and particularly prevalent in dark-skinned individuals
- Common after burns
- Occur when there is excess immature collagen production during the reparative phase of wound healing
- Often do not require treatment and resolve spontaneously
- Increased proportion of type III collagen compared with type I
- Keloids
- Extends beyond wound borders
- More common in dark-skinned individuals
- Seen in patients who participate in contact sports (e.g., boxing, football) and in those with piercings
- Occur when excessive collagen production occurs during the reparative phase of wound healing
- Especially prevalent on the ear lobe and sternum
- Remain years after injury and may need intervention (excision, steroid injections, radiotherapy, etc.)
- Hyper/hypopigmentation
- Postinflammatory hyperpigmentation
- Also called acquired melanosis
- Temporary pigmentation following injury or inflammation of the skin
- More common in dark-skinned individuals
- More severe injuries result in postinflammatory hypopigmentation that is usually permanent.
- Pathogenesis: Inflammation and injury stimulate melanocytes to increase melanin synthesis and transfer pigment to keratinocytes.
- Clinical features:
- Located at site of original disease after healed
- May become darker if exposed to sunlight
- Hyperpigmentation
- Can be seen with skin grafts after burns
- Pigmentation disorders are common among dark-skinned burn patients, in particular Africans and Asians.
- Characterized by hyperpigmentation in darker-skinned individuals and hypopigmentation in lighter-skinned individuals
- This is often due to genetic as well as environmental factors.
- Hypopigmentation
- Common with deep wounds when melanocytes are the only remaining cell in the wound
- Melanocytes act as stem cells to heal the wound (being converted into epithelial cells) and therefore cannot act in their role of providing pigmentation to the skin.
- Postinflammatory hyperpigmentation
- Incisional hernias: increased risk in obese patients and patients with chronic obstructive pulmonary disease
- Wound dehiscence: increased risk in patients taking corticosteroids or other medications that inhibit phases of wound healing
- Contractures: in burn wounds and wounds across joints
Patient-related factors negatively affecting wound healing
- Infection: Bacteria degrade the building blocks of wound healing,
- Diabetes: Decreased blood flow and excess of serum glucose prevents the migration of inflammatory cells into the wound.
- Diabetic foot syndrome is often a primary manifestation of problems with wound healing in diabetics: ulceration of the foot (distally from the ankle and including the ankle) is associated with neuropathy and different degrees of ischemia and infection.
- Malnutrition: Insufficient protein leads to a relative immunodeficient state.
- Vitamin C (cofactor for hydroxylases) deficiency → impedes collagen cross-linking
- Zinc (cofactor for collagenase) and copper (cofactor for lysyl oxidase) deficiencies: impede remodeling and maturation of collagen
- Use of corticosteroids/glucocorticoids: inhibits the inflammatory phase of wound healing
- Genetic factors: connective tissue disorders (Ehlers-Danlos syndrome: various mutations in collagen and collagen-binding proteins, most common is type III collagen; Marfan syndrome: fibrillin-1 gene mutation)
- Color of skin: Darker-skinned individuals tend to be more prone to keloids.
- Post-injury pigmentation disorders can occur, leading to either hyper- or hypopigmentation.
Keloid found on the left foot of a patient
Image: “Preoperative appearance of a patient” by Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Seoul; Deokjeok Health Care Center, Incheon. License: CC BY 2.0
Diabetic foot syndrome
Image: by Intermedichbo from Wikimedia Commons. License: CC BY-SA 4.0
Example of a patient with Ehlers-Danlos syndrome
Image: by Division of Ophthalmology and Visual Sciences, Queen Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK. License: CC BY 2.0
Two examples of hypertrophic scars on the dorsum of the hand
Image: “Treatment of Hypertrophic Scar in Human with Autologous Transplantation of Cultured Keratinocytes and Fibroblasts along with Fibrin Glue” by Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. License: CC BY 2.5, edited by Lecturio.
Clinical Relevance
- Ehlers-Danlos syndrome is a deficiency of type III or V collagen. Patients with this condition will often present with hyperextensible skin.
- Osteogenesis imperfecta is a deficiency of type I collagen. Patients with this condition often present with multiple fractures and blue sclera.