Healing of damaged tissues, healing disorders

Healing is the body’s biological response to tissue injury aimed at restoring structural integrity and function. It involves highly coordinated cellular, vascular, biochemical, and extracellular matrix processes.

The goals of healing are:

• Prevention of blood loss
• Elimination of microorganisms
• Removal of necrotic tissue
• Restoration of tissue continuity
• Recovery of function

Healing depends on:

• Type and extent of injury
• Blood supply
• Presence of infection
• Nutritional status
• Age and systemic health

Types of Cells Involved in Healing

Cell Type	Characteristics	Examples
Labile cells	Continuously dividing	Skin epithelium, bone marrow
Stable cells	Quiescent but capable of division	Hepatocytes, fibroblasts
Permanent cells	Minimal or no proliferative capacity	Neurons, cardiac muscle cells

Regeneration and Repair

Regeneration

Regeneration is replacement of damaged tissue by the same type of functional cells.

Features

• Complete restoration of structure and function
• Requires viable stem cells
• Extracellular matrix scaffold remains intact

Examples

• Liver regeneration
• Regeneration of skin epithelium
• Hematopoietic tissue renewal

Repair

Repair is replacement of injured tissue by connective tissue and scar formation.

Features

• Occurs when injury is severe
• Functional tissue replaced by fibrosis
• May result in permanent loss of function

Examples

• Myocardial infarction healing
• Deep skin wounds

Phases of Healing

Healing occurs in overlapping phases.

1. Hemostasis Phase

Occurs immediately after injury.

Events

• Vasoconstriction
• Platelet aggregation
• Activation of coagulation cascade
• Fibrin clot formation

Functions

• Prevent blood loss
• Provide scaffold for inflammatory cells
• Release growth factors

Important Mediators

• Platelet-derived growth factor (PDGF)
• Transforming growth factor-beta (TGF-β)

2. Inflammatory Phase

Usually lasts for 1–3 days.

Cellular Components

Neutrophils

• First inflammatory cells to arrive
• Remove bacteria and debris through phagocytosis

Macrophages

• Replace neutrophils after 24–48 hours
• Most important cells in healing

Functions of Macrophages

• Phagocytosis
• Cytokine secretion
• Growth factor release
• Stimulation of angiogenesis and fibrosis

Major Cytokines

• IL-1
• TNF-α
• TGF-β
• VEGF

3. Proliferative Phase

Occurs from day 3 onward.

Main processes include:

• Granulation tissue formation
• Angiogenesis
• Fibroblast proliferation
• Collagen synthesis
• Re-epithelialization

Granulation Tissue

Granulation tissue consists of:

• Newly formed capillaries
• Fibroblasts
• Loose extracellular matrix
• Inflammatory cells

Appearance

• Soft
• Pink
• Granular

Angiogenesis

Formation of new blood vessels from preexisting vessels.

Steps

1. Vasodilation
2. Migration of endothelial cells
3. Endothelial proliferation
4. Capillary tube formation
5. Vessel maturation

Important Growth Factors

• VEGF
• Fibroblast growth factor (FGF)

Fibroblast Proliferation

Fibroblasts synthesize extracellular matrix proteins.

Components Produced

• Collagen
• Elastin
• Proteoglycans
• Fibronectin

Initially:

• Type III collagen predominates

Later:

• Replaced by stronger Type I collagen

Re-epithelialization

Migration and proliferation of epithelial cells over the wound surface restore surface continuity.

4. Remodeling Phase

Begins around the third week and may continue for months.

Features

• Collagen remodeling
• Increased tensile strength
• Decreased vascularity
• Scar maturation

Important Enzymes

• Matrix metalloproteinases (MMPs)

Tensile Strength

Healed tissue reaches approximately 70–80% of original strength.

Healing by Primary and Secondary Intention

Healing by Primary Intention

Occurs in clean wounds with closely approximated edges.

Features

• Minimal tissue loss
• Minimal granulation tissue
• Rapid epithelial regeneration
• Small scar formation

Example

• Surgical incision closed with sutures

Healing by Secondary Intention

Occurs in large wounds with extensive tissue loss.

Features

• More inflammation
• Large amount of granulation tissue
• Wound contraction
• Larger scar

Role of Myofibroblasts

Myofibroblasts mediate wound contraction.

Skin Wound Healing

Partial-Thickness Wounds

• Heal mainly by regeneration

Full-Thickness Wounds

• Heal by granulation tissue formation and scarring

Bone Healing

Stages

1. Hematoma formation
2. Soft callus formation
3. Hard callus formation
4. Bone remodeling

Cells Involved

• Osteoblasts
• Osteoclasts
• Chondroblasts

Fracture Healing

Primary Bone Healing

• Direct bone remodeling
• Requires rigid fixation

Secondary Bone Healing

• Most common type
• Involves callus formation

Liver Regeneration

The liver possesses remarkable regenerative ability.

Mechanism

Compensatory hyperplasia of surviving hepatocytes.

Major Stimulators

• Hepatocyte growth factor (HGF)
• IL-6
• TNF-α

Local Factors

Factor	Effect
Infection	Delays healing
Poor blood supply	Causes hypoxia
Foreign bodies	Maintain inflammation
Mechanical stress	Causes wound disruption
Edema	Impairs oxygen diffusion

Systemic Factors

Factor	Effect
Malnutrition	Reduced collagen synthesis
Vitamin C deficiency	Defective collagen formation
Diabetes mellitus	Poor angiogenesis and infection
Glucocorticoids	Suppress inflammation
Smoking	Causes vasoconstriction
Advanced age	Slows repair

Extracellular Matrix in Healing

The extracellular matrix provides:

• Structural support
• Cell adhesion
• Reservoir for growth factors
• Regulation of cell behavior

Components

• Collagen
• Laminin
• Fibronectin
• Proteoglycans

Important Growth Factors

Growth Factor	Main Function
PDGF	Fibroblast migration
VEGF	Angiogenesis
FGF	Fibroblast proliferation
TGF-β	Fibrosis and collagen synthesis
EGF	Epithelial regeneration

Healing Disorders

Abnormal healing may result from inadequate repair or excessive tissue response.

Wound Dehiscence

Definition

Partial or complete reopening of a wound.

Causes

• Infection
• Poor suturing
• Increased mechanical stress
• Malnutrition

Ulcer Formation

Definition

Loss of epithelial surface due to necrosis and inflammation.

Common Causes

• Venous insufficiency
• Diabetes mellitus
• Arterial disease
• Pressure injury

Hypertrophic Scar

Features

• Excess collagen deposition
• Raised scar
• Remains within wound boundaries

Pathogenesis

Excessive fibroblast activity.

Keloid

Features

• Excessive scar tissue extending beyond wound margins
• High recurrence rate after removal

Pathogenesis

• Increased collagen synthesis
• Increased TGF-β activity

Common Sites

• Earlobes
• Sternum
• Shoulders

Excessive Granulation Tissue (Proud Flesh)

Features

• Granulation tissue protrudes above skin level
• Prevents epithelial regeneration

Treatment

• Surgical removal
• Cauterization

Contractures

Definition

Excessive wound contraction causing deformity.

Common After

• Severe burns

Consequences

• Joint deformity
• Restricted movement

Fibrosis

Definition

Excessive deposition of collagen in tissues.

Causes

• Chronic inflammation
• Persistent tissue injury

Examples

• Pulmonary fibrosis
• Liver cirrhosis

Chronic Wounds

Definition

Wounds that fail to heal in the expected period.

Characteristics

• Persistent inflammation
• Impaired angiogenesis
• Biofilm formation
• Cellular senescence

Examples

• Diabetic foot ulcers
• Pressure ulcers
• Venous ulcers

Impaired Healing in Diabetes Mellitus

Mechanisms

• Microvascular disease
• Neuropathy
• Reduced leukocyte function
• Chronic inflammation
• Impaired angiogenesis

Consequences

• Delayed healing
• Increased infection risk
• Chronic ulcer formation

Molecular Basis of Fibrosis

Persistent injury causes:

1. Chronic macrophage activation
2. Release of TGF-β
3. Fibroblast proliferation
4. Excess extracellular matrix deposition

Major Fibrogenic Cytokine

TGF-β

Pressure Ulcers

Caused by prolonged ischemia over bony prominences.

Risk Factors

• Immobility
• Malnutrition
• Neurological disease

Diabetic Foot Ulcers

Result from:

• Peripheral neuropathy
• Ischemia
• Infection

Burn Healing

Partial-Thickness Burns

May heal by regeneration.

Full-Thickness Burns

Heal with fibrosis and may require grafting.