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 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).
- 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.
- 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
- 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 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 and 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
Image by Lecturio.
Exudative phase (day 1–4): 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 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 Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand a day after falling off a bike onto concrete: day 1
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 2
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 3
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 4
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 5
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 6
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 7
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 8
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 9
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 10
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 11
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Arria Belli – Own Work. License: Public Domain FilesWound on palm of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand after falling off a bike onto concrete: day 12
Image: “Wound on palm of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. 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
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
- 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 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.
- Postinflammatory hyperpigmentation
- 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.
Keloid found on the 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 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
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 Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand
Image: “Treatment of Hypertrophic Scar Hypertrophic scar Hypertrophic scars (HSs) and keloids are raised, red, and rigid (3 Rs) scars that develop during cutaneous wound healing and are characterized by a local abnormal proliferation of fibroblasts with over-production of collagen. Over-expression of growth factors and decreased production of molecules that promote matrix breakdown appear to be involved in the etiology. Hypertrophic and Keloid Scars 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 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.
