Four overlapping phases | Haemostasis, inflammation, proliferation, remodelling | Granulation tissue then scar | Many factors can impair it
- Four overlapping phases: haemostasis (immediate clot and platelet plug), inflammation (neutrophils then macrophages clear debris), proliferation (granulation tissue, angiogenesis, re-epithelialisation, collagen), and remodelling (collagen reorganisation and maturation over months)
- The macrophage is the key orchestrating cell: it clears debris, then switches phenotype to release growth factors that drive angiogenesis and fibroblast activity - the bridge from inflammation to repair
- Granulation tissue is the hallmark of the proliferative phase - new capillaries plus fibroblasts laying down a provisional collagen matrix, giving the red, granular wound bed
- Collagen switch: early wound collagen is type III, which is later replaced and cross-linked into stronger type I during remodelling - a scar regains only about 80 percent of original tensile strength at best
- Repair, not regeneration: skin and most soft tissues heal by forming a fibrous scar, they do not regrow the original organised tissue - and many factors (infection, poor blood supply, diabetes, smoking, steroids, malnutrition) can stall the process
- “Order of the inflammatory cells: neutrophils arrive first (peak around 24-48 hours), then macrophages take over (peak around days 2-3) and are essential for progression to repair
- “A wound is at its weakest in the first week, when the old clot has gone but mature cross-linked collagen has not yet formed - this is when dehiscence is most likely
- “Wound contraction is driven by myofibroblasts (fibroblasts that have acquired smooth-muscle actin), not by new tissue growth
- “Chronic wounds are stuck in a prolonged inflammatory phase - they fail to progress to proliferation and remodelling
Clinical Imaging
What healing actually looks like - gross and histology
Know them in order and overlapping: haemostasis (clot, platelet plug), inflammation (neutrophils then macrophages), proliferation (granulation tissue, angiogenesis, re-epithelialisation, collagen synthesis) and remodelling (collagen reorganised and cross-linked over months). They are a continuum, not separate boxes.
Platelets start it (clot plus first growth factors). Neutrophils clear bacteria early. Macrophages are the master regulators - they clear debris and then drive repair. Fibroblasts lay down collagen, and myofibroblasts contract the wound.
Early scar is type III collagen, later remodelled to stronger type I. A scar never regains full strength - around 80 percent of normal at best. The wound is weakest at the end of the first week, the high-risk time for dehiscence.
Healing fails or slows with poor blood supply or hypoxia, infection, diabetes, smoking, corticosteroids, malnutrition, foreign material and excess tension. Chronic wounds are stuck in inflammation and never reach proliferation.
Memory aids
HIPRThe Phases in Order
Hook:HIPR - Haemostasis, Inflammation, Proliferation, Remodelling, in the order they happen.
DIDNT HEALFactors That Impair Healing
Hook:A wound that DIDNT HEAL - run through the systemic and local reasons one by one.
123Healing by Intention
Hook:1-2-3: edges together, fill from the bottom, or close later when clean.
Overview
Wound healing is the body's organised response to tissue injury. After any cut, surgical incision, ulcer or open injury, a predictable sequence of events restores the protective barrier and structural integrity of the tissue. For most adult soft tissues and skin this is repair - the wound is filled with a fibrous scar - rather than true regeneration of the original organised tissue.
The process is usually described as four overlapping phases: haemostasis, inflammation, proliferation and remodelling. They are not separate, tidy steps; they blend into one another, and different parts of the same wound can be in different phases at the same time.
For the exam, three threads recur throughout this topic and are worth holding onto: the phases and their key cells (a classic basic-science viva), how a surgical wound closed by primary intention differs from an open wound healing by secondary intention, and why healing fails - the long list of local and systemic factors that examiners love, because they are exactly what you manipulate at the bedside.
Principles: The Four Phases of Healing
| Phase | Timing | What happens | Key cells / mediators |
|---|---|---|---|
| Haemostasis | Immediate (minutes) | Vasoconstriction, platelet plug, fibrin clot forms a provisional matrix | Platelets, clotting cascade, fibrin |
| Inflammation | Day 0 to about day 3 | Clear bacteria and debris; recruit and activate repair cells | Neutrophils first, then macrophages; histamine, cytokines |
| Proliferation | About day 3 to day 21 | Granulation tissue, new vessels, re-epithelialisation, collagen synthesis | Macrophages, fibroblasts, endothelial cells, keratinocytes |
| Remodelling (maturation) | Weeks to many months | Collagen reorganised and cross-linked, type III replaced by type I, scar matures | Fibroblasts, myofibroblasts, matrix metalloproteinases |
1. Haemostasis - stopping the bleeding
Within seconds of injury, damaged vessels constrict and exposed collagen activates platelets. The platelets aggregate and the clotting cascade lays down fibrin, forming a clot that both stops bleeding and acts as a provisional matrix (a scaffold) for cells to migrate along. Activated platelets also release the first wave of growth factors - notably platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) - that recruit inflammatory cells and start the repair signal.
2. Inflammation - cleaning the wound
Over the first few days, blood vessels become leaky and inflammatory cells flood in. Neutrophils arrive first (peaking at roughly 24 to 48 hours) to kill bacteria and clear debris. Macrophages then take over (peaking around days 2 to 3) and are the central orchestrating cell: they finish the clearance, then switch to a reparative phenotype and release the growth factors that drive angiogenesis and fibroblast activity. A wound that cannot move on from this phase becomes a chronic wound.
3. Proliferation - rebuilding the tissue
This is where the wound is filled in, and it has several parallel processes:
- Granulation tissue forms - the red, granular wound bed made of new capillaries plus fibroblasts in a loose collagen matrix.
- Angiogenesis - endothelial cells sprout new capillaries (driven by vascular endothelial growth factor, VEGF) to supply the metabolically active wound.
- Fibroplasia - fibroblasts migrate in and lay down type III collagen and ground substance.
- Re-epithelialisation - keratinocytes migrate from the wound edges and skin appendages across the granulation tissue to restore the surface barrier.
- Wound contraction - some fibroblasts become myofibroblasts (expressing smooth-muscle actin) and pull the wound edges together, shrinking the defect.
4. Remodelling - making the scar
The longest phase, lasting months to over a year. The disorganised type III collagen of the early scar is gradually replaced and cross-linked into stronger, better-aligned type I collagen, while excess capillaries and cells regress (the scar pales and flattens). The balance between collagen synthesis and its breakdown by matrix metalloproteinases determines the final result. Even a well-healed scar regains only about 80 percent of the original tissue's tensile strength.
Growth Factors and Collagen
A small group of growth factors are worth knowing by name, because examiners ask which cell makes them and what they do:
| Factor | Main source | Main role |
|---|---|---|
| PDGF (platelet-derived growth factor) | Platelets, macrophages | Recruits and activates fibroblasts and macrophages; early repair signal |
| TGF-beta (transforming growth factor-beta) | Platelets, macrophages | Drives fibroblast collagen synthesis - central to scar formation and fibrosis |
| VEGF (vascular endothelial growth factor) | Macrophages, endothelial cells | Drives angiogenesis - the new capillaries of granulation tissue |
| FGF (fibroblast growth factor) | Macrophages, fibroblasts | Stimulates fibroblasts, angiogenesis and re-epithelialisation |
| EGF (epidermal growth factor) | Platelets, keratinocytes | Drives keratinocyte proliferation and re-epithelialisation |
The collagen story is high-yield: the wound starts with type III collagen (laid down quickly but mechanically weak) and, during remodelling, this is steadily replaced by type I collagen, which is stronger and better organised. The shift in the type I to type III ratio back toward normal is a marker of a maturing, strengthening scar. Vitamin C is essential here because it is a cofactor for the hydroxylation of proline and lysine during collagen synthesis - which is why scurvy causes wound breakdown.
Primary, Secondary and Delayed Closure
| Feature | Primary intention | Secondary intention |
|---|---|---|
| Typical wound | Clean incision with edges apposed (sutured) | Open wound with tissue loss left to heal from the base |
| Granulation tissue | Minimal | Abundant - fills the defect |
| Wound contraction | Little | Marked (myofibroblasts) |
| Speed and scar | Fast, fine scar | Slow, larger scar, higher infection risk |
Tertiary intention (delayed primary closure) sits in between: the wound is deliberately left open for a few days - to let contamination, swelling or doubtful tissue viability declare themselves - and then closed surgically once it is clean and safe. This is common in contaminated trauma wounds and in compartment syndrome fasciotomies.
A closed surgical incision heals by primary intention with very little granulation tissue, so the visible "wound bed" of granulation tissue you see in an open wound or ulcer is the picture of secondary-intention healing. Recognising granulation tissue is a common clinical-photo question.
Factors That Impair Healing
Examiners group these into local and systemic factors - a clean framework that scores well.
Poor blood supply / hypoxia, infection (the commonest local cause of failure), excess tension on the closure, foreign material or necrotic tissue, dead space and haematoma, and repeated trauma or pressure (for example pressure ulcers).
Diabetes, smoking (vasoconstriction and hypoxia), corticosteroids and immunosuppression, malnutrition (protein, vitamin C, zinc), older age, obesity, renal or liver failure, chemotherapy and radiotherapy, and peripheral vascular disease.
Why Local and Systemic Factors Matter (Phases and Modifiers)
- Successful healing requires the four phases (haemostasis, inflammation, proliferation, remodelling) to occur in the correct sequence and time frame
- Many factors interfere with one or more phases and so cause impaired healing
- Reviewed modifiers include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcohol, smoking and nutrition
- Most impaired wounds are stalled by a disrupted or prolonged inflammatory phase
Smoking is one of the most important and most modifiable risk factors for wound problems in orthopaedic and arthroplasty surgery. Nicotine causes vasoconstriction and tissue hypoxia and impairs collagen synthesis, raising the risk of wound breakdown, infection and (in fractures and fusions) non-union. Where possible, stop smoking before elective surgery.
Abnormal Scars and Chronic Wounds
When healing goes wrong it tends to fail in one of two directions - too much scar, or no progress at all:
| Feature | Hypertrophic scar | Keloid |
|---|---|---|
| Extent | Stays within the original wound boundary | Grows beyond the original wound boundary |
| Onset and course | Soon after injury, often regresses with time | Can appear later, persists and recurs |
| Typical patient / site | Across joints and high-tension areas | More common in darker skin; sternum, shoulders, earlobes |
| Recurrence after excision | Lower | High - excision alone often makes it worse |
A chronic wound is one that has failed to heal in the expected time, typically because it is stuck in a prolonged inflammatory phase and never progresses to proliferation and remodelling. Common examples are diabetic foot ulcers, venous and pressure ulcers, and infected surgical wounds. Management aims to restart the process: debride non-viable tissue, control infection and pressure, improve blood supply, and optimise systemic factors.
Clinical Relevance
Wound healing underpins almost everything in orthopaedic practice. Every surgical incision relies on it, and a wound complication after a joint replacement or fracture fixation can be the gateway to deep infection and disaster. In trauma, the decision to close a wound primarily, leave it open, or use delayed closure is a daily judgement that flows directly from these principles. In basic-science vivas, the phases, key cells and growth factors, and the local-versus-systemic list of impairing factors are classic, examinable material. And at the bedside, the things that most improve healing - good blood supply, no infection, controlled diabetes, no smoking, adequate nutrition, and a tension-free closure - are exactly the modifiable factors this topic teaches.
Evidence and Mechanisms
Cellular and Molecular Mechanisms of Skin Wound Healing
- Healing requires tightly coordinated cell migration, proliferation, matrix deposition and remodelling alongside inflammation and angiogenesis
- Small wounds heal in days, while large traumatic or surgical wounds take weeks and usually leave a fibrotic scar
- Both innate and adaptive immune cells shape the behaviour of keratinocytes, fibroblasts and endothelial cells
- Understanding these mechanisms is the basis for therapies to reduce scarring and heal chronic wounds
Negative Pressure Wound Therapy for Diabetic Foot Ulcers (Systematic Review)
- Systematic review and meta-analysis of randomised controlled trials of negative pressure wound therapy (NPWT) in diabetic foot ulcers
- Fourteen trials reviewed; NPWT showed superior total wound healing where this outcome was reported
- Most trials comparing wound area reduction favoured NPWT over standard care
- Authors note methodological limitations and heterogeneity but a consistent potential benefit
Exam Viva Scenarios
Practise clinical reasoning and management decisions out loud
“The examiner shows you a healing open wound with a red granular base and asks you to take them through how a wound heals.”
Framework: I would describe four overlapping phases - haemostasis, inflammation, proliferation and remodelling.
Haemostasis: Immediate vasoconstriction, a platelet plug and a fibrin clot that also acts as a provisional matrix; platelets release the first growth factors such as PDGF and TGF-beta.
Inflammation: Over the first few days neutrophils arrive first to clear bacteria, then macrophages take over - macrophages are the key cell that clears debris and then switches to drive repair.
Proliferation: This is the granulation tissue I can see - new capillaries from angiogenesis plus fibroblasts laying down type III collagen, with keratinocytes re-epithelialising from the edges and myofibroblasts contracting the wound.
Remodelling: Over months the type III collagen is replaced and cross-linked into stronger type I collagen and the scar matures, regaining at best about 80 percent of normal strength.
“A 62-year-old man with type 2 diabetes who smokes has a surgical wound on the leg that is still open and discharging six weeks after a fracture fixation. How do you think about and manage this?”
Framing: This is a chronic, non-healing wound - it has failed to progress through the normal phases, almost certainly stalled in a prolonged inflammatory phase. I would look for the reasons across local and systemic factors.
Local factors: Infection (including deep infection around the metalwork), poor blood supply, necrotic or non-viable tissue, dead space or collection, excess tension, and exposed implant or bone.
Systemic factors: His diabetes and smoking are the headline modifiable problems; I would also check nutrition, peripheral vascular disease and any immunosuppression.
Management: Assess and image the wound and deep tissues, send cultures and treat infection, debride non-viable tissue, and address dead space. Optimise the patient - tighten glycaemic control, stop smoking, improve nutrition, and assess vascular supply. Adjuncts such as negative pressure wound therapy can help a clean wound granulate; if there is deep infection around the implant, that has to be dealt with as a surgical problem on its own merits.
The Four Phases
- Haemostasis: clot, platelet plug, provisional fibrin matrix (immediate)
- Inflammation: neutrophils first, then macrophages (days 0 to 3)
- Proliferation: granulation tissue, angiogenesis, re-epithelialisation, collagen (days 3 to 21)
- Remodelling: type III to type I collagen, scar matures (weeks to months)
Key Cells and Factors
- Macrophage: master regulator - clears debris then drives repair
- Myofibroblast: contracts the wound
- PDGF and TGF-beta: fibroblast recruitment and collagen
- VEGF: angiogenesis; vitamin C: collagen cofactor
Closure and Strength
- Primary intention: edges together, minimal granulation, fine scar
- Secondary intention: open, granulation and contraction, big scar
- Tertiary: delayed primary closure when clean
- Scar regains about 80 percent of strength; weakest at end of week 1
What Impairs Healing
- Local: infection, hypoxia, tension, foreign material, dead space
- Systemic: diabetes, smoking, steroids, malnutrition, age, vascular disease
- Chronic wound: stuck in prolonged inflammation
- Modifiable wins: control diabetes, stop smoking, treat infection, nutrition
Guidelines, Registries and Global Practice
- Surgical site infection prevention guidance worldwide (for example WHO global guidelines and NICE in the UK) targets exactly the modifiable wound-healing factors - perioperative glycaemic control, smoking cessation, normothermia, tissue oxygenation and tension-free closure - because these protect the healing wound from breakdown and infection.
- Diabetic foot ulcer care is standardised across major bodies (such as the International Working Group on the Diabetic Foot and national diabetes societies), centred on debridement, offloading pressure, infection control, vascular assessment, and good glycaemic control - the practical application of restarting a stalled wound.
- Negative pressure wound therapy (NPWT) is widely endorsed as an adjunct for open, exuding and difficult wounds, promoting granulation and contraction; the strongest randomised evidence is in diabetic foot and complex surgical wounds.
- Across all settings the principle is the same: healing is a biological process you support rather than force - keep the wound clean, perfused and tension-free, and correct the systemic factors that hold it back.