Wound Repair Notes

Mechanism of Wound Repair

Regeneration vs. Repair

  • Regeneration:

    • Involves stem cell activation and proliferation of surviving cells.

    • Replaces damaged tissue with identical structure and function (limited in adults).

    • No scar formation; full recovery of structure and function.

  • Healing/Repair:

    • Triggered by blood vessel injury, clotting, and deposition of fibrous connective tissue.

    • Quickly restores tissue structure.

    • Sensory cells, glands, and hair follicles are usually lost.

    • Leads to scar formation; original tissue is only partially restored.

Regeneration vs. Repair - Normal

  • Mild, superficial injury leads to regeneration.

  • Severe injury leads to scar formation.

What is a Wound?

  • A wound is any disruption or damage to the normal structure and function of body tissues.

  • Types of Wounds (by healing timeframe):

    • Acute Wounds: Heal in a predictable, timely manner (5–30 days).

    • Chronic Wounds: Healing is delayed or incomplete.

  • Extent of Injury:

    • Can involve just the skin (epidermal break).

    • Or go deeper, affecting muscles, tendons, vessels, nerves, organs, and even bone.

Wound Classification

Feature

Acute wounds

Chronic wounds

Healing time

5–30 days

Prolonged or incomplete

Healing Process

Predictable, orderly progression

Disrupted progression; fails to follow normal phases

Outcome

Restoration of function and structure

Incomplete repair; functional restoration compromised

Common Causes

Trauma, surgery

Pressure, arterial/venous insufficiency, burns, vasculitis

Contributing Factors

Infection, hypoxia, necrosis

Infection, hypoxia, necrosis, prolonged inflammation

Wound Classification - Normal vs. Impaired

  • Normal healing process in acute wounds:

    • Scab formation.

    • Immune cell Infiltration.

    • Re-epithelialisation.

    • Angiogenesis.

    • Fibroblast migration.

    • Collagen deposition.

  • Impaired healing process in chronic wounds:

    • Colonization, infection.

    • Hyperproliferative epidermis.

    • Persistent inflammation, exudate.

    • Fibroblast senescence.

    • Impaired angiogenesis.

    • Fibrin cuffs (barrier to oxygen).

    • Elevated MMPs.

Key Molecular Players in Wounds

  • Acute Wounds:

    • Platelet-Derived Growth Factor (PDGF) – attracts immune and repair cells.

    • Transforming Growth Factor-β (TGF-β) – stimulates fibroblasts.

    • VEGF – promotes angiogenesis.

    • Fibrin, fibronectin – form provisional matrix.

    • Interleukins (e.g., IL-6) – coordinate inflammation.

  • Chronic Wounds:

    • Excess pro-inflammatory cytokines (e.g., TNF- α, IL-1).

    • High matrix metalloproteinases (MMPs) – degrade ECM.

    • Low tissue inhibitors of MMPs (TIMPs) – can't regulate matrix breakdown.

    • Reduced growth factor activity – impairs angiogenesis, fibroblast function.

    • Persistent infection & ROS – perpetuate inflammation.

Stages of Wound Healing

  1. Haemostasis: Stop bleeding.

  2. Inflammation: Prevent infection.

  3. Proliferation: Fill + cover wound.

  4. Remodelling: New epithelium + final scar formation.

Stages of Wound Healing Timeline

  • Hemostasis (minutes)

  • Inflammation (Days 0-5)

  • Proliferation & Re-epithelialization (Days 5-20)

  • Remodeling (Extends beyond Day 20)

Phase 1: Haemostasis

  • Prevents excessive blood loss by clotting and vasoconstriction.

    • Exposed collagen binds to and activate platelets, and vasoconstriction occurs

    • Platelets release clotting factors which initiate platelet aggregation

    • Clotting factors activate thrombin and coagulation cascade begins

    • Thrombin activates fibrins strands and adhere to form insoluble fibrin plug

Phase 2: Inflammation

  • Protects the wound from infection and prepares the site for tissue regeneration and repair.

  • Key Cellular Events:

    1. Vasodilation and Increased Vascular Permeability

      • Blood vessels dilate in response to mediators like histamine and prostaglandins.

      • Plasma proteins and immune cells exit the vessels and enter the wound site.

    2. Leukocyte Recruitment

      • Neutrophils are the first cells to arrive (within minutes to hours).

      • Phagocytose pathogens and debris.

      • Release reactive oxygen species (ROS) and enzymes.

      • Monocytes arrive later and differentiate into macrophages.

      • Continue debris clearance.

      • Secrete cytokines and growth factors (e.g., VEGF, TGF-β).

    3. Initiation of Healing

      • Macrophages switch roles from inflammation to repair.

      • They begin to stimulate angiogenesis and fibroblast activity for the next phase.

  • Why This Phase Matters:

    • Without proper inflammation, the wound cannot transition to the proliferation phase.

    • In chronic wounds, this phase becomes prolonged, often due to persistent infection or excessive cytokines, leading to delayed healing.

Phase 2: Inflammation - Extravasation

  • Leukocyte rolling, adhesion, and migration through the endothelium.

  • Cytokines (TNF, IL-1) cause endothelial cells to express selectin, which binds to leukocyte with low affinity.

  • Endothelial cells express ICAM-1, which binds to leukocyte with high affinity once integrin is activated by chemokines.

  • For diapedesis, leukocytes interact with endothelial cells via PECAM-1 (CD31).

Phase 2: Inflammation - Phagocytosis

  • Chemotaxis and adherence of phagocyte to microbe.

  • Ingestion of microbe by phagocyte, forming a phagosome.

  • Fusion of phagosome with a lysosome to form a phagolysosome.

  • Digestion of ingested microbes by enzymes and ROS in the phagolysosome.

  • Discharge of waste materials.

Phase 2: Inflammation - Early, Mid and Late Phase

  • Early-phase: platelet, erythrocytes, neutrophil

  • Mid-phase: monocytes, Atoptotic neutrophil, M1 macrophages

  • Late-phase: M2 macrophages

Phase 2: Inflammation - Acute vs. Chronic Infiltration

  • Acute: Neutrophils infiltrate

  • Chronic: Plasma cells, lymphocytes, macrophages, eosinophils

Phase 2: Inflammation - Acute vs. Chronic Features

Feature

Acute inflammation

Chronic inflammation

Onset

Minutes to hours

Follows unresolved acute inflammation

Duration

Hours to few days

Weeks to years

Cells Involved

Neutrophils

Macrophages, lymphocytes, plasma cells

Tissue Injury

Self-limited

Progressive damage

Outcomes

Resolution, abscess, or chronic

Fibrosis, tissue destruction, granuloma

Phase 2: Inflammation - Acute Morphological Patterns

  1. Serous inflammation

  2. Fibrinous inflammation

  3. Suppurative inflammation

  4. Ulcerative inflammation

  • Depend on severity of reaction, cause, tissue and site involved

  • Manifestations of spectrum of increased vascular permeability caused by inflammation

Serous Inflammation

  • Clear, watery fluid (few or no immune cells) collects between tissue layers.

  • Seen in blisters, effusions.

  • Caused by mild injury or irritation.

  • Function: dilutes toxins.

Fibrinous Inflammation

  • Fibrin-rich exudate due to severe vascular leakage.

  • Often affects serosal surfaces (e.g. pericardium).

  • Example: fibrinous pericarditis (“hairy heart” appearance).

Suppurative Inflammation

  • Accumulation of pus: dead neutrophils, bacteria, necrotic debris.

  • Common in abscesses, boils.

  • Caused by pyogenic (pus-forming) bacteria.

  • Example: abscess - collection of pus typically with a central, largely necrotic region and surrounding wall of granulated tissue.

Ulcerative Inflammation

  • Epithelial lining sloughed or excavated and replaced by inflammatory debris and necrotic material.

  • Surface tissue loss → ulcer formation.

  • Inflammation involves the base and margins of ulcer.

  • Common in peptic ulcers, pressure sores.

Granulomatous Inflammation

  • A form of chronic inflammation.

  • Characterized by:

    • Aggregates of epithelioid macrophages

    • Multinucleated giant cells

    • Surrounding lymphocytes and fibrosis

  • Seen in TB, sarcoidosis, Crohn’s disease.

Phase 3: Proliferation

  • Fills the wound gap and restore tissue integrity by generating new tissue and covering the wound surface.

  1. Granulation tissue formation

  2. Neovascularisation (new blood vessel formation)

  3. Epithelialisation – cover wound

  4. Wound contraction – close wound

Phase 3: Proliferation - Details

  • Granulation tissue formation

    • Fibroblasts proliferate and migrate to the wound site.

    • Begin producing extracellular matrix proteins (e.g. fibronectin, glycosaminoglycans, and collagen).

    • Forms the temporary framework for tissue repair.

  • Neovascularisation

    • Involves:

      • Angiogenesis – new vessels from existing ones

      • Vasculogenesis – from endothelial progenitor cells

      • Lymphangiogenesis – new lymph vessels

    • Ensures oxygen and nutrient supply for healing tissue

  • Epithelialisation

    • Basal epithelial stem cells migrate across wound bed.

    • First form a single cell layer, then undergo proliferation and differentiation.

    • Migration stops when edges meet (contact inhibition).

    • New basement membrane established

  • Contraction of wound margin

    • Fibroblasts transforms to myofibroblasts

    • These cells pull wound edges together by attaching to the ECM and contracting

    • Important for closing large wounds and reducing wound size

Phase 4: Remodelling

  • Strengthen, reshape, and finalize the repaired tissue after initial closure.

  1. Re-organisation of collagen fibers

  2. Refinement of blood vessels network

  3. Inflammatory response resolved

Phase 4: Remodelling Details

  • Collagen Remodelling

    • Initial collagen is Type III (thin, weak).

    • Replaced by Type I collagen (stronger, ticker).

    • Controlled by matrix metalloproteinases (MMPs) and their inhibitors.

    • Collagen becomes organized and cross-linked, improving tensile strength

  • Vascular Maturation

    • Excess blood vessels formed during proliferation are pruned

    • Remaining vessels mature into a functional, efficient network.

  • Resolution of Inflammation

    • Neutrophils undergo apoptosis, cleared by macrophages.

    • Macrophages deactivate via anti-inflammatory cytokines and contact inhibition

    • Inflammatory cells exit via vasculature or lymphatics

Phase 4: Remodelling End Result

  • Formation of a mature scar.

  • Tensile strength reaches up to 80% of original tissue.

  • Tissue is stable but may lack original function (e.g. glands, follicles not restored).

Different Types of Healing

  • Primary Intention:

    • Wound edges are clean cut with minimal tissue trauma.

    • Wound edges apposed with sutures.

    • Leaves minimal scar.

    • Rapid healing.

    • E.g. surgical incision

  • Secondary Intention:

    • Gaping wound is open.

    • Granulation tissue fills the gap.

    • Requires contraction, epithelialisation

    • Leaves a large scar

    • Longer healing time

    • E.g. pressure ulcer

  • Tertiary Intention:

    • Utilized when there is a high chance of wound infection

    • Wound left open for a few days – delayed primary closure

    • Late suturing done to allow healing by first intention

    • Longer healing time

    • Greater access for pathogens, more inflammation, more granulation

    • Leaves a large scar

    • E.g. abdominal wound ‘left open’ to allow drainage but later closed

Healing by Second Intention - Ulcer

  • A – pressure ulcer of skin, commonly found in diabetic patients

  • B – skin ulcer with a large gap between edges of lesion

  • C – A thin layer of epidermal re-epithelialization (slow process), and extensive granulation tissue formation in the dermis

  • D – Continuing re- epithelialization of the epidermis and wound contraction.

Healing by Second Intention - Keloid

  • Abnormal wound healing with excessive collagen deposition

  • Results in a raised, thickened scar that may extend beyond original wound margins

  • Associated with:

    • Atypical fibroblast activity

    • Replacement of skin structures (e.g. hair, glands)

    • Seen in chronic inflammation (e.g. RA, cirrhosis)

Factors Affecting Healing

  • Systemic Factors (Patient-related)

    • Age

    • Smoking and alcohol

    • Anaemia

    • Steroid use

    • Jaundice

    • Cancer / Chemotherapy

    • Uremia

    • Chronic Inflammation

    • Diabetes

    • Malnutrition / Nutrient deficiency

    • HIV or immunosuppression

  • Local Wound Factors

    • Moisture

    • Mechanical stress or trauma

    • Oedema (swelling)

    • Radiation exposure

    • Ischemia (poor blood supply)

    • Necrotic tissue

    • Foreign bodies (e.g. sutures)

    • Low oxygen tension

    • Dry environment (lack of moisture)

    • Hematoma

    • Infection