Repair of Cutaneous Wound Healing Pathology Notes

Repair

Repair is defined as a process in which lost/damaged tissue is replaced by firous tissue or scar. Repair is often used for parenchymal and connective tissues and healing for surface epithelia. However, these terms are used interchangeably.

Introduction Of Repair

Define the term healing, regeneration, and repair

Injury to cells and tissues results in loss of cells and tissues. It sets in inflammation (restricts tissue damage) and initiates the replacement of lost tissue by living tissue.

Healing Of Repair

Healing Of Repair Definition: Healing is a process of replacement of dead tissue by living tissue.

It can be broadly divided into:

1. Regeneration and
2. Repair

Read And Learn More: Pathology for Dental Students Notes

1. Regeneration:

Regeneration Definition: Regeneration is a process in which lost tissue is replaced by tissue of a similar type.

• It results in the complete restoration of lost or damaged tissue.
• By the proliferation of residual uninjured cells and replacement from stem cells.

2. Repair:

Repair Definition: Repair is defined as a process in which lost/damaged tissue is replaced by firous tissue or scar.

• Repair is often used for parenchymal and connective tissues and healing for surface epithelia.
• However, these terms are used interchangeably.

Factors Deciding the Pattern of Healing:

The proportion of regeneration and repair process in healing depends on:

Proliferative Capacity of the Tissue:

According to the proliferative capacity of the cells, the tissues of the body can be divided into three groups:

1. Labile (continuously dividing) tissues: The cells of labile tissues proliferate throughout life, replacing the lost cells from stem cells.
   • Examples:
     • Hematopoietic cells of the bone marrow
     • Surface epithelia of the skin, oral cavity, vagina, and cervix
     • Columnar epithelium of the GI tract and uterus.
2. Stable (quiescent) tissues: Cells of stable tissue normally do not proliferate, But can proliferate in response to injury or loss of tissue.
   • Examples:
     • Parenchymal cells of the liver, kidneys, and pancreas
     • Mesenchymal cells: Fibroblasts, vascular endothelial cells, smooth muscle cells, chondrocytes, and osteocytes.
3. Permanent (non-dividing) tissues: Cells of these tissues cannot proliferate after birth. In
   these tissues, repair is by scar formation.
   • Example:
     • Neurons: Damaged neurons are replaced by the proliferation of the glial cells
     • Skeletal muscle cells
     • Cardiac muscle cells.

The extent of Tissue Injury:

1. Mild and short duration: The damaged tissue is healed by regeneration without significant scarring.
2. Severe and chronic: Healing occurs by fibrous tissue forming a scar.
   • Severe tissue injury damages both parenchymal cells and the extracellular matrix
   • (ECM) framework
   • Chronic inflammation.

Cell Cycle And Cell Proliferation

• Inflammation is the primary response of living tissue to injury.
• With inflammation, there will be damage or loss of tissue, which has to be replaced by living tissue.
• This replacement is done by a transient increase in cellularity due to the proliferation of cells by either regeneration and/or by repair.
• The proliferation of cells is characterized by DNA replication and mitosis.
• The sequence of events that control DNA replication and mitosis is known as the cell cycle.

Definition of cell cycle: Cell proliferation is a regulated process, which involves activators and inhibitors, as well as checkpoints.

Phases of Cell Cycle:

• G₁(Synthetic)
• S (DNA synthesis)
• G₂ (Premitotic)
• M (mitotic) phase

Checkpoints:

They check whether there is any damage to DNA and chromosomes in the replicating cells. These checkpoints make sure that only normal cells complete replication.

There are two checkpoints:

1. G₁/S checkpoint monitors the integrity of DNA before replication.
2. G₂/M checkpoint checks DNA after replication and monitors whether the cell can safely enter mitosis.

Healing By Repair Scar Formation And Fibrosis

• Healing may be either by regeneration or repair or a combination of both. With mild and transient injury, there is regeneration.
• If the tissue injury or damage persists, inflammation becomes chronic, resulting in excessive deposition of connective tissue is known as fibrosis (repair).

Steps in Healing by Repair (Scar Formation):

Inflammation:

Whenever there is tissue injury, an inflammatory reaction begins, which tries to limit the damage and remove the injured tissue. At the same time, it also promotes the deposition of ECM components at the site of injury and stimulates angiogenesis.

Definition of Angiogenesis :

Angiogenesis is the process of the formation of new blood vessels from existing vessels. It supplies nutrients and oxygen needed to support the repair process.

• These vessels are leaky because of incomplete inter endothelial junctions and
• VEGE (the growth factor responsible for angiogenesis).

Steps in angiogenesis :

1. Vasodilatation: Vasodilatation in response to nitric oxide and increased permeability of the preexisting vessel due to VEGF.
2. Separation of pericytes: From the outer surface of blood vessels and breakdown of the basement membrane. This allows the formation of a vessel sprout.
3. Migration and proliferation of endothelial cells toward the site of injury.
4. Maturation of endothelial cells into capillary sprouts/tubes.
5. Formation of a mature vessel: It involves the recruitment of pericytes and smooth muscle cells to form the per endothelial layer.
6. Suppression of endothelial proliferation and migration, and deposition of the basement membrane.

Formation of Granulation Tissue:

The first 24 to 72 hours of the repair process begins with the proliferation of fibroblasts and vascular endothelial cells. It forms a specialized type of tissue known as granulation tissue, which is a hallmark/characteristic of tissue repair. The term granulation tissue is derived from its pink, soft, granular appearance on the surface of healing wounds.

1. Microscopy: Its characteristic features are:
   • Presence of new small blood vessels (angiogenesis): Th new blood vessels are leaky, which allow the passage of plasma proteins and fluid into the extravascular space, which is responsible for edema often seen in granulation tissue.
   • Proliferation of fibroblasts.
2. The amount of granulation tissue formed depends on the:
   • Size of the tissue deficit created by the wound
   • Intensity of inflammation.

Scar Formation:

• The leukocytes, edema, and angiogenesis disappear, accomplished by the increased accumulation of collagen. The granulation tissue scaffolding is converted into a pale, avascular scar.
• Components of scar: It is composed of spindle­shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components.
• By the end of the first month: The scar consists of acellular connective tissue without inflammatory infiltrate.

Connective Tissue Remodeling:

• Remodeling of the connective tissue framework is an important feature. It is the long­lasting phase of tissue repair.
• Remodeling indicates that the equilibrium/balance between ECM synthesis (collagen deposition) and degradation has been restored.

Cutaneous Wound Healing

Describe the healing of a surgical wound /healing by the first intention

Healing by Primary Union or by First Intention:

Definition of healing:  Healing of a clean, uninfected surgical incision in the skin joined with surgical sutures are known as healing by primary union or by first intention.

• Surgical incision causes the death of a minimum number of epithelial and connective tissue cells. The disruption of epithelial basement membrane continuity is also minimal.
• Reepithelialization occurs by regeneration and there is a relatively thin scar. This is the simplest type of cutaneous wound healing.

Stages in the Healing by First Intention.

1. First 24 hours:
   • Formation of a blood clot: It is formed in the space between sutured margins.  Blood clot contains not only trapped red cells but also fibrin, fibronectin, and complement components.  Clot stops bleeding and acts as a scaffold for migrating and proliferating cells. Dehydration at the external surface of the clot leads to the formation of a scab over the wound.
   • Neutrophil infiltration: Within 24 hours of the wound, neutrophils appear at the margins of the incision. Neutrophils use the scaffold produced by the fibrin clot for its migration. They release proteolytic enzymes which clean out debris.
   • Epithelial changes: At the cut edges of the wound, the basal cells of the epidermis begin to show mitotic activity. Epithelial cells from both edges of the wound proliferate and migration across the wound along the dermis.
2. Two days:
   • Neutrophils are replaced by macrophages.
   • The epithelial cells fuse in the midline below the surface scab and epithelial continuity is re­established in the form of a thin continuous surface layer.
3. Three to seven days:
   • Granulation tissue begins to invade the incision space. It progressively grows into the incision space/wound and fills the wound area in 5 to 7 days. Collagen is progressively laid down.
   • The surface epidermis achieves its normal thickness and differentiation. It matures with
     surface keratinization.
   • The acute inflammatory response begins to subside.
4. Ten to fourteen days:
   • Leukocytic infiltration, edema, and angiogenesis disappear during the second week.
   • Increased accumulation of collagen and regression of vascular channels. The granulation tissue scaffolding is converted into a pale, avascular scar. The wound normally gains about 10% strength of normal skin. Further, fibroblast proliferation occurs with collagen deposition.
5. Weeks to months:
   • The scar appears as acellular connective tissue covered by an intact epidermis and without inflammatory infiltrate.
   • Collagen deposition along the line of stress and wound gradually achieves a maximal 80% of the tensile strength of normal skin.’

Healing by Secondary Union or by Second Intention Or Describe the mode of healing of a wound by the second intention

Definition of Healing of Secondary Union:

When injury produces large defects on the skin surface with extensive loss of cells and tissue, the healing process is more complicated. Healing in such cutaneous wounds is referred to as healing by a secondary union or by the second intention.

Features of Healing by Secondary Intention Or Mention the differences between healing by first intention and second intention.

Larger wounds show more exudate and necrotic tissue. The clot or scab formed at the surface of the wound is large. Full epithelialization of the wound surface is slow because of the larger gap.

• Severe inflammatory reaction: Because of larger defects and greater necrotic tissue.
• The larger defect requires more amount of (abundant) granulation tissue.
• Extensive deposition of collagen with substantial scar formation.
• Wound contraction: Wound contraction generally occurs in large surface wounds and is an important feature in healing by secondary union.
• Myofibroblasts: Myofibroblasts of granulation tissue have ultrastructural features of smooth muscle cells. They contract in the wound tissue and are responsible for wound contraction.

Wound Strength:

Major portion of the connective tissue in repair is fibrillar collagens (mostly type I collagen) and is responsible for the development of strength in healing wounds.

Time for a skin wound to achieve its maximal strength:

• At the end of the first week: When sutures are removed from an incisional surgical wound, wound strength is about 10% that of normal unwounded skin.
• Four weeks: Wound strength quickly increases over the next 4 weeks, and then slows down.
• Three months: Wound strength reaches 70% to 80% of the tensile strength of unwounded skin.

Factors That Influence Wound Healing

List the Factors that influence wound healing Or List factors that delay healing 

Local Factors:

1. Infection: It is the single most important cause of delay in healing. The infection causes persistent tissue injury and inflammation.
2. Mechanical factors: Movement of the wounded area may compress the blood vessels and separate the edges of the wound and can result in delayed healing.
3. Foreign bodies: Unnecessary sutures or foreign bodies (fragments of steel, glass), or even
   bone can delay healing.
4. Size and type of wound: Small surgical incisional or other injuries heal quickly with less scar formation than large excisional wounds or wounds caused by blunt trauma.
5. Location of injury: Wound over the skin covering bone with little intervening tissue prevents wound contraction (for example, Skin over the anterior tibia). The edges of skin lesions (for example, Burns) in such locations cannot be opposed.
6. Blood supply:
   • Wounds in areas with good blood supply, such as the face, heal faster than those with poor blood supply, such as the foot.
   • Varicose veins of the legs decrease venous drainage and can cause nonhealing ulceration.
   • Bed sores (decubitus ulcers) result due to prolonged, localized pressure, which diminishes both arterial and venous blood flow.
7. Ionizing radiation decreases the repair process.
8. Complications may delay wound healing.

Systemic Factors:

1. Nutritional deficiencies: Delays wound healing and these include:
   • Protein deficiency (for example, Malnutrition)
   • Vitamin C deficiency: Inhibits collagen synthesis and retard healing
   • Trace elements: Copper and zinc deficiency.
2. Age: Wound healing is rapid in young compared to aged individuals.
3. Metabolic status: Diabetes mellitus is associated with delayed healing due to microangiopathy.
4. Circulatory status: Inadequate blood supply (due to arteriosclerosis) or venous abnormalities (for example, Varicose veins) that retard venous drainage, and delay healing.
5. Hormones: Glucocorticoids have anti-inflammatory effects and also inhibit collagen synthesis, thereby impairing wound healing.
6. Hematological abnormalities: Quantitative or qualitative defects in neutrophils and bleeding disorders may slow the healing process

Complications Of Wound Healing

Mention the complications of wound healing

1. Inadequate Granulation Tissue Formation:

Inadequate formation of granulation tissue or a deficient scar formation can cause wound dehiscence and ulceration.

• Dehiscence: Dehiscence (the wound splitting) or rupture of a wound is the most common life­threatening
  complication after abdominal surgery. It is due to increased abdominal pressure/ mechanical stress on the abdominal wound from vomiting, coughing, or ileus.
• Ulceration:
  • Wounds can ulcerate due to inadequate angiogenesis during healing. For example, wounds in the leg of patients with atherosclerotic peripheral vascular disease or varicose veins usually ulcerate.
  • Non-healing wounds also develop in regions devoid of sensation. These neuropathic or trophic ulcers may be seen in diabetic peripheral neuropathy, nerve damage from leprosy.
• Incisional hernia: Incisional hernia resulting from weak scars of the abdominal wall due to a defect caused by prior surgery. They are due to insufficient deposition of the extracellular matrix or inadequate cross­linking in the collagen matrix.

2. Excessive Scar Formation:

Excessive formation of the components of the repair process can result in:

• Hypertrophic scar: Th accumulation of excessive amounts of extracellular matrix, mostly collagen may give rise to a raised scar at the site of wound known as a hypertrophic scar. They usually develop after thermal or traumatic injury, which involves the deep layers of the dermis.
• Keloid: If the scar tissue grows/progresses beyond the boundaries of the original wound and does not regress, it is called a keloid. The keloid is an exuberant scar that recurs with a still larger keloid after surgical excision.
• Exuberant granulation:
  • Pyogenic granuloma or granuloma pyogenic:
    • This consists of the localized formation of excessive amounts of granulation tissue.
    • Such exuberant granulation tissue projects above the level of the surrounding skin and prevents re­epithelialization. The mass formed is often named as proud flesh.
  • Desmoids or aggressive fibromatosis:
    • Incisional scars or traumatic injuries may be followed by excessive proliferation of fibroblasts and other connective tissue elements.
    • They are known as desmoids, or aggressive fibromatosis, which may recur after excision.

3. Excessive Contraction:

• A decrease in the size of a wound due to myofibroblasts is known as contraction.
• An exaggeration of this contraction is termed contracture and results in deformities of the wound and the surrounding tissues.

Consequences of contractures:

• Compromise movements: for example, contractures that follow severe burns can compromise the movement of the involved region and joint movements.
• Obstruction: for example, in GI tract contracture (stricture) can cause intestinal obstruction.

Others of Excessive Contraction:

• Infection: Infection of wounds by microbes.
• Epidermal: Ccysts can develop due to the persistence of epithelial cells at the site of wound healing.
• Pigmentation: May develop due to either colored particles left in the wound or hemosiderin pigment.
• Neoplasia: For example, squamous cell carcinoma may develop in Marjolin’s ulcer, which is the scar that follows burns in the skin.

Fibrosis of Excessive Contraction:

• Normal wound healing is associated with the deposition of collagen.
• The excessive deposition of collagen and other ECM components in a tissue is termed as fibrosis. It is usually observed in chronic inflammation.
• TGF-β is an important fibrogenic agent.
• Examples of disorders with fibrosis: Cirrhosis of the liver, pneumoconioses, chronic pancreatitis, and glomerulonephritis.

Healing Of A Fracture

Describe the healing of fractures in long bones.

Phases of Fracture Healing :

Bone can repair by reactivating processes that normally take place during embryogenesis. There are three major phases of fracture healing.

Inflammatory Phase:

• Fracture and hemorrhage:
  • Soon after fracture, blood vessels (in the periosteum, cortex and medullary cavity) rupture leads to extensive hemorrhage (hematoma), at the fracture site and surrounding tissue.
  • Necrosis of bone also occurs at the fracture site.

• Inflammatory cells:
  • Fibrin meshwork in the clotted blood helps
    • To seal the fracture site
    • Inflx of inflammatory cells (neutrophils and macrophages) to the area
    • Ingrowth of fibroblasts and new capillary vessels (neovascularization) to the site, producing granulation tissue between the fracture fragments.
  • Activation of osteoprogenitor cells: The inflammatory cells and platelets release
    • Periosteum
    • Medullary cavity
    • Surrounding soft tissues.
• Formation of granulation tissue: It consists of proliferating capillaries and fibroblasts and
  are formed at the site of fractures

Soft tissue callus or precalculus formation:

• Osteoprogenitor cells → Activate both osteoblastic and osteoclastic activities at the fracture site.
• Osteoblasts: Derived from activated osteoprogenitor cells migrate into the granulation tissue and differentiate into osteoid synthesizing units. They deposit large quantities of osteoid collagen in a haphazard pattern producing woven bone (unmineralized bone is called osteoid).
• Granulation tissue containing (mineralized or unmineralized) bone or cartilage is termed a callus.
• At this stage, the callus is predominantly uncalcified and is called soft-tissue callus or precalculus, which provides a type of temporary connection between the ends of the fractured bones. However, precalculus does not have any structural rigidity for any weight bearing. The callus depending on its size and appearance can be divided into external and internal callus.
• External callus: It is formed from the osteoprogenitor cells of the periosteum and surrounding soft tissue and is found on the surface of the bone. It bridges the fracture site outside the bone and continues to grow inwards toward the fracture site. In this region, the osteoprogenitor cells may also differentiate into chondroblasts, which
  form fibrocartilage and hyaline cartilage around the fracture site.
• Internal callus: It is derived from osteoprogenitor cells of the medullary cavity and grows outward toward the fracture site. This bridges the fracture in the region of the medullary cavity but in contrast to the external callus does not contain cartilage.
• The repair tissue attains maximal thickness at the end of the second or third week and consists of hyaline cartilage and woven bone.

Reparative Phase:

• Lamellar bone formation: As the healing advances, the hyaline cartilage and woven bone of the original fracture callus are replaced by lamellar bone. This is stronger and consists of parallel collagen fibers.
• Endochondral ossification: The replacement process is known as endochondral ossification with respect to the hyaline cartilage and bony substitution with respect to the woven bone.
• Bony callus: At this stage, the callus is mineralized (calcified) and is known as a bony (osseous) callus. As the mineralization proceeds, the stiffness and strength of the callus increase. By the second or third week, controlled weight bearing can be tolerated.

Remodeling Phase:

• Several weeks after a callus has sealed the bone ends, the remodeling phase begins.
• Resorption of excess portions of bony callus: During healing, an excess of bony callus is formed around the fracture site.
• As the callus is subjected to weight­bearing forces, the portions of the bony callus that are not physically stressed by this weight are slowly resorbed by osteoclasts. This, the osteoclasts act to remodel bone and decrease the size of the callus.
• The remodeling phase substitutes the trabecular bone with compact bone.
• The remodeling phase continues till the original bone shape (contour), outline, and strength of the fractured bone is re­established.
• The whole process of healing of a bone fracture usually takes about 6 to 8 weeks.

Major Causes Of Delayed Fracture Healing

Major causes of delayed fracture healing:

Complications of Healing:

Mention the complications of healing of fractured bone.

• Delayed union and nonunion of fracture.
• Pseudoarthrosis: In the case of nonunion, too much movement along the fracture gap can cause cystic degeneration in the callus, creating a false joint or pseudoarthrosis.
• Large callus with deformity