Wound Healing

Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. The overall process protects underlying structures from further damage. Wound healing stages include hemostasis Hemostasis Hemostasis refers to the innate, stepwise body processes that occur following vessel injury, resulting in clot formation and cessation of bleeding. Hemostasis occurs in 2 phases, namely, primary and secondary. Primary hemostasis involves forming a plug that stops the bleeding temporarily. Secondary hemostasis involves the activation of the coagulation cascade. Hemostasis, inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, granulation, and remodeling. Certain conditions such as diabetes, peripheral vascular disease, and malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries can limit the body’s ability to heal itself, thus resulting in complications.

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Stages of Wound Repair

There are 3 main stages of wound healing:

  1. 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 Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
    • Inflammation: clears cellular debris through phagocytosis. There is a migration of inflammatory cells that facilitate tissue regeneration (via growth factors).
  2. Proliferative stage (day 2–16)
    • Granulation: lays the framework for new connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue and vasculature
      • Fibroblast growth factor and vascular endothelial growth factor promote cellular proliferation and angiogenesis, respectively.
  3. 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
Wound healing timeline

Timeline of wound healing

Image: “Timeline of Wound Healing” by Wikimedia Commons. License: Public Domain Files
Timeline and steps of wound healing
Day 1
  • Fibrin clot (hematoma)
  • Neutrophils infiltrate
Day 2
  • Squamous cells seal off the wound
  • Macrophages migrate into the 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; used by cancer cells to metastasize)
Week 2
  • Tensile strength ~10%
Month 1
  • Remodeling of the wound (collagenase/lysyl oxidase)
  • Tensile strength approximately 80% in 3 months (never reaches 100% tensile strength after injury)

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

  1. Primary intention: when the tissue surface edges have been approximated
    • Small defect with little risk of complications and/or infection
  2. Secondary intention: when there are significant tissue losses and the wound surface cannot be brought together (e.g., lacerations, burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns, and ulcers)
    • Granulation tissue (consisting of connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue cells and ingrowing young blood vessels) is needed to close the defect → scar formation occurs with a higher risk of infection 
  3. Tertiary or delayed primary intention: when there is a need to delay the closure of a wound (due to contamination risk, poor circulation, etc.)
Wound healing

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 Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. 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 Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin grafts after burns Burns A burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin.
  • Incisional hernias: increased risk in obese patients and patients with chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)
  • 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 Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview 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 Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids: inhibits the inflammatory phase of wound healing
  • Genetic factors: connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue disorders ( Ehlers-Danlos syndrome Ehlers-Danlos syndrome Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders that are characterized by hyperextensible skin, hypermobile joints, and fragility of the skin and connective tissue. Ehlers-Danlos Syndrome: various mutations in collagen and collagen-binding proteins, most common is type III collagen; Marfan syndrome Marfan syndrome Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. Marfan Syndrome: fibrillin-1 gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
  • Color of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin: Darker-skinned individuals tend to be more prone to keloids.
    • Post-injury pigmentation disorders can occur, leading to either hyper- or hypopigmentation.

Clinical Relevance

  • Ehlers-Danlos syndrome Ehlers-Danlos syndrome Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders that are characterized by hyperextensible skin, hypermobile joints, and fragility of the skin and connective tissue. Ehlers-Danlos Syndrome is a deficiency of type III or V collagen. Patients with this condition will often present with hyperextensible skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin.
  • Osteogenesis imperfecta Osteogenesis imperfecta Osteogenesis imperfecta (OI), or "brittle bone disease," is a rare genetic connective tissue disorder characterized by severe bone fragility. Although OI is considered a single disease, OI includes over 16 genotypes and clinical phenotypes with differing symptom severity. Osteogenesis Imperfecta is a deficiency of type I collagen. Patients with this condition often present with multiple fractures and blue sclera.

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