Phases of Wound Healing: Haemostasis, Inflammation, Proliferation and Remodelling

Learning outcomes

• Describe the timing, dominant cells, mediators and matrix changes in each phase.
• Explain how haemostasis creates a provisional scaffold for inflammation and repair.
• Describe the neutrophil-to-macrophage transition and why resolution is essential.
• Explain re-epithelialisation, angiogenesis, fibroblast migration, collagen deposition and contraction.
• Describe collagen remodelling and the time course of tensile strength.
• Recognise normal healing versus infection, dehiscence, excessive scar and chronic non-healing.
• Apply the timeline to wound review and emergency decision-making.

1. Master timeline

Phase	Approximate timing	Dominant cells/signals	Main events
Haemostasis	Seconds to hours.	Platelets, coagulation factors, fibrin.	Vasoconstriction, platelet plug, fibrin clot and provisional matrix.
Inflammation	Hours to days.	Neutrophils first; macrophages later.	Debris/microbial clearance, cytokines, transition to repair.
Proliferation	Day 2 to several weeks.	Keratinocytes, fibroblasts, endothelial cells, myofibroblasts.	Re-epithelialisation, granulation, angiogenesis, collagen III and contraction.
Remodelling/maturation	Weeks to months or longer.	Fibroblasts, MMPs/TIMPs and collagen I.	Matrix turnover, fibre alignment, scar contraction and increasing strength.

Phases overlap: macrophages remain active during proliferation, and remodelling begins before the wound is fully closed.

2. Phase 1 — Haemostasis

2.1 Immediate vascular response

Injury exposes collagen and tissue factor. Brief vasoconstriction limits blood loss; endothelial contraction and local reflexes reduce flow. Excessive vasospasm or arterial injury can instead worsen tissue ischaemia.

2.2 Platelet adhesion and activation

1. Von Willebrand factor binds exposed collagen and platelet glycoprotein Ib.
2. Platelets change shape and release ADP, thromboxane A₂, serotonin and calcium.
3. Activated glycoprotein IIb/IIIa binds fibrinogen and cross-links platelets.
4. Platelet-derived growth factor (PDGF), TGF-β, VEGF and EGF signal to fibroblasts, endothelial cells and keratinocytes.

2.3 Coagulation and provisional matrix

Tissue factor activates thrombin, which converts fibrinogen to fibrin. The fibrin-fibronectin clot traps red cells and provides a temporary scaffold. It also concentrates growth factors and creates a surface across which leukocytes and fibroblasts can migrate.

2.4 Clinical relevance

• Anticoagulants, platelet disorders and severe liver disease can prolong bleeding.
• Haematoma separates tissue planes, increases infection risk and may require drainage.
• Ischaemia, hypothermia and acidosis impair coagulation in major trauma.

3. Phase 2 — Inflammation

3.1 Early neutrophilic phase

Neutrophils arrive within hours in response to IL-8/CXCL8, C5a, LTB4 and bacterial peptides. They phagocytose microbes and necrotic debris and release ROS, proteases and antimicrobial granules. Excessive neutrophil activity damages viable matrix and delays closure.

3.2 Macrophage transition

Monocytes enter after the first day and differentiate into macrophages. Early inflammatory macrophages release TNF, IL-1, IL-6 and chemokines. As the trigger is cleared, macrophages perform efferocytosis, release IL-10 and TGF-β, and stimulate fibroblasts, endothelial cells and keratinocytes.

3.3 Resolution checkpoint

Healing cannot progress if the wound remains infected, necrotic or contaminated. Neutrophils must undergo apoptosis, oedema must drain and macrophages must switch from inflammatory clearance to repair. Retained sutures, foreign bodies, biofilm and poor perfusion prolong this phase.

3.4 Clinical appearance

Mild warmth, redness, swelling and tenderness are expected early. Increasing pain, expanding erythema, purulent discharge, foul odour, fever, crepitus, skin anaesthesia or systemic toxicity suggests infection or necrotising injury rather than normal inflammation.

4. Phase 3 — Proliferation

4.1 Re-epithelialisation

Keratinocytes at the wound margin loosen desmosomes, migrate across the provisional matrix and proliferate behind the leading edge. EGF, TGF-α, keratinocyte growth factor and adequate moisture support migration. The epidermal barrier is initially fragile and easily disrupted by friction or desiccation.

4.2 Angiogenesis

Hypoxia stabilises HIF-1α and increases VEGF. Endothelial cells degrade their basement membrane, migrate through the matrix, proliferate and form capillary loops. New vessels deliver oxygen and nutrients but make granulation tissue red and prone to bleeding.

4.3 Fibroblast recruitment

PDGF, FGF and TGF-β recruit fibroblasts into the wound. Fibroblasts produce fibronectin, proteoglycans, collagen III and later collagen I. They remodel the provisional fibrin matrix and connect the wound edges.

4.4 Granulation tissue

Granulation tissue contains capillaries, fibroblasts, macrophages, loose extracellular matrix and type III collagen. Healthy granulation is moist, pink-red and finely granular. Pale, necrotic or malodorous tissue suggests poor perfusion or infection.

4.5 Myofibroblasts and contraction

Myofibroblasts express contractile actin and attach to collagen. Their contraction reduces wound area, especially in secondary healing. Excessive contraction across joints, eyelids, mouth or the neck creates functional contractures.

5. Phase 4 — Remodelling and maturation

5.1 Collagen transition

Early collagen III is relatively weak and loosely organised. Fibroblasts and matrix metalloproteinases replace it with stronger collagen I. Cross-linking and alignment along lines of tension improve tensile strength.

5.2 MMPs and TIMPs

Matrix metalloproteinases degrade damaged collagen and basement membrane. Tissue inhibitors of metalloproteinases limit their activity. An imbalance causes chronic ulceration, excessive matrix breakdown or pathological fibrosis.

5.3 Tensile strength

Approximate stage	Strength and appearance
First days	Strength depends mainly on sutures, fibrin and wound support; collagen is weak.
1–3 weeks	Rapid collagen deposition and cross-linking; epithelial surface closes but deep tissue remains vulnerable.
1–3 months	Collagen I alignment and remodelling increase strength; scar becomes less vascular.
Long term	Strength plateaus below original tissue, commonly around 70–80%.

6. How phases interact

Interaction	Why it matters
Platelet clot → inflammation	Fibrin and platelet growth factors recruit leukocytes and repair cells.
Macrophage resolution → proliferation	Pro-repair macrophages release VEGF, TGF-β and PDGF.
Hypoxia → angiogenesis	Moderate hypoxia induces VEGF; severe persistent hypoxia prevents repair.
Inflammation → remodelling	Proteases clear damaged matrix, but excess protease causes ulceration.
Mechanical tension → collagen alignment	Appropriate tension strengthens scar; excessive tension causes dehiscence or hypertrophy.

7. Normal versus abnormal timeline

Expected finding	Concerning deviation	Possible cause
Mild early redness, warmth and tenderness.	Rapidly expanding redness, severe pain or systemic toxicity.	Cellulitis, abscess or necrotising infection.
Small amount of clear or blood-tinged fluid.	Purulent, foul or increasing discharge.	Infection, dehiscence or foreign body.
Pink granulation tissue appears.	Pale, dusky or black tissue.	Ischaemia, necrosis or pressure.
Edges progressively contract and epithelialise.	Wound remains open or enlarges.	Diabetes, vascular disease, pressure, infection or malnutrition.
Scar gradually flattens and pales.	Raised scar extends beyond margins or restricts movement.	Keloid, hypertrophic scar or contracture.

8. Factors that disrupt particular phases

Phase affected	Examples of disruption
Haemostasis	Anticoagulation, thrombocytopenia, coagulopathy, hypothermia, acidosis.
Inflammation	Infection, retained foreign body, steroids, neutropenia or immunodeficiency.
Proliferation	Ischaemia, smoking, anaemia, protein/vitamin C/zinc deficiency, diabetes.
Remodelling	Excess tension, hypertrophic scarring, keloid, persistent inflammation or genetic collagen disorders.

9. Emergency and clinical application

1. Control bleeding and shock: pressure, haemostatic measures, warming and correction of coagulopathy.
2. Assess tissue viability: colour, temperature, pulses, capillary refill, sensation and movement.
3. Remove contamination and devitalised tissue: irrigation, debridement and foreign-body removal when indicated.
4. Choose closure timing: primary closure for suitable clean wounds; delayed closure when infection/contamination risk is high.
5. Protect the proliferative phase: maintain moisture, perfusion, nutrition, glucose control and mechanical stability.
6. Recognise dangerous inflammation: rapidly spreading erythema, pain out of proportion, bullae, crepitus, fever or hypotension.
7. Plan follow-up: dressing changes, offloading, rehabilitation, tetanus prevention and review for dehiscence or infection.

10. Applied cases

Case 1: Sutured laceration

After haemostasis and irrigation, close a clean wound without tension. Mild warmth and tenderness are expected during inflammation. Increasing pain or purulent drainage after several days indicates a failure of resolution and requires reassessment.

Case 2: Burn wound

Thermal injury damages the barrier and creates oedema. Early inflammation may progress to fluid loss, airway swelling and infection. Assess airway, perfusion, burn depth and circumferential pressure, then protect the wound and coordinate specialist care.

Case 3: Diabetic foot ulcer

Neuropathy causes repetitive trauma, ischaemia limits angiogenesis and hyperglycaemia impairs leukocyte function. The wound becomes trapped in chronic inflammation. Offloading, vascular evaluation, infection control, nutrition and glucose management are essential.

11. Quick self-test

1. What are the four phases of wound healing?
   Answer: Haemostasis, inflammation, proliferation and remodelling/maturation.
2. Which cells dominate early inflammation?
   Answer: Neutrophils.
3. Which cell transitions the wound toward repair?
   Answer: The macrophage.
4. What growth factor is central to angiogenesis?
   Answer: VEGF.
5. Which collagen is deposited early, and which becomes stronger later?
   Answer: Type III early; type I during maturation.
6. Why does severe infection delay proliferation?
   Answer: Persistent neutrophils, proteases, microbial toxins and tissue necrosis prevent the resolution-to-repair transition.
7. What findings suggest abnormal rather than normal healing?
   Answer: Rapidly spreading redness, severe pain, pus, foul odour, dusky tissue, dehiscence, persistent ulcer or systemic toxicity.

12. Take-home summary

Selected references

• NCBI Bookshelf: Wound Healing
• NCBI Bookshelf: Wound Closure Techniques
• NCBI Bookshelf: Inflammation and Repair

Educational note: This resource supports learning and clinical reasoning. Current local protocols, senior supervision and national guidelines take precedence in patient care.