Overview
- When tissue is injured, the body responds with a tightly orchestrated sequence of cellular and molecular events aimed at restoring structural integrity.
- This process spans a spectrum from regeneration, the ideal outcome in which lost cells are replaced by identical functional cells, through to scar formation and, at its pathological extreme, fibrosis.
- The balance between these outcomes determines not just cosmesis but organ function, and understanding this balance is essential for managing wounds, predicting complications, and interpreting pathology encountered daily in the ED.
- Emergency physicians encounter the consequences of disordered healing constantly: the infected wound that won't close, the post-MI patient whose ventricle is stiffening with fibrous replacement, the cirrhotic patient presenting in acute liver failure, the burns patient whose escharotomy site will ultimately scar and contract.
- Knowing the underlying biology allows rational decisions about wound management, the timing of surgical referral, and the expected natural history of organ injury.
- Healing proceeds through overlapping phases, haemostasis, inflammation, proliferation, and remodelling, each dependent on the last.
- Failure or excess at any phase produces predictable pathology.
- The distinction between healing by primary intention (clean, approximated wound edges) and secondary intention (open wound healing from the base) is fundamental to wound management in the ED.
Phases of Wound Healing
Phase 1: Haemostasis (Minutes to Hours)
- Immediately after tissue injury, vasoconstriction limits blood loss while the coagulation cascade is activated.
- Platelet adhesion to exposed collagen, mediated by von Willebrand factor and glycoprotein Ib, initiates primary plug formation.
- Subsequent platelet activation releases α-granule contents including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and fibrinogen.
- The coagulation cascade generates thrombin, which cleaves fibrinogen to fibrin, forming a provisional matrix that serves both as a haemostatic plug and as a scaffold for subsequent cellular infiltration.
Key principle: The fibrin clot is not merely a mechanical seal, it is an active signalling scaffold releasing chemokines that recruit the inflammatory phase.
Phase 2: Inflammation (Hours to Days 1-4)
- Neutrophils are the first responders, arriving within hours under the influence of complement fragments (C3a, C5a), IL-8, and leukotriene B₄.
- Their primary roles are phagocytosis of bacteria and cellular debris and the release of proteases to debride damaged matrix.
- They are short-lived and undergo apoptosis within 24-48 hours.
Macrophages (derived from circulating monocytes) arrive by day 2-3 and are indispensable for healing, a fact demonstrated by experiments showing impaired repair when macrophages are depleted. They serve multiple functions:
- Continued phagocytosis and debridement
- Release of growth factors: PDGF, TGF-β, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)
- Orchestration of the transition to the proliferative phase
- Polarisation into M1 (pro-inflammatory, antimicrobial) and M2 (pro-repair, anti-inflammatory) phenotypes, the shift from M1 to M2 dominance marks the transition to resolution
- Clinically: Prolonged or excessive neutrophil activity, as seen in infected wounds or poorly controlled diabetes, perpetuates inflammation and impairs progression to healing.
- This is the cellular basis for the clinical observation that infection disrupts wound healing.
Phase 3: Proliferation (Days 3-21)
The proliferative phase is characterised by three overlapping processes: angiogenesis, fibroplasia, and epithelialisation.
- Angiogenesis is driven principally by VEGF released from macrophages and hypoxic tissue.
- New capillary sprouts invade the fibrin scaffold, forming the vascular component of granulation tissue, the pink, granular, friable tissue that fills open wounds.
- Granulation tissue also contains a matrix of type III collagen, fibronectin, and hyaluronic acid.
- Fibroplasia refers to fibroblast proliferation and migration into the wound, stimulated by PDGF and FGF.
- Fibroblasts synthesise type III collagen (the provisional collagen of early healing) and lay down the extracellular matrix.
- A subset of fibroblasts differentiates into myofibroblasts under the influence of TGF-β₁ and mechanical tension.
- Myofibroblasts express α-smooth muscle actin (α-SMA) and are responsible for wound contraction, a process that can reduce open wound surface area by up to 40-80% in secondary intention healing.
- This is highly beneficial in the abdominal wall but catastrophic across a joint, where contracture causes functional disability.
- Epithelialisation begins within hours at the wound edge as keratinocytes migrate across the moist wound surface under the influence of epidermal growth factor (EGF) and hepatocyte growth factor (HGF).
- They dissolve the superficial fibrin clot with plasminogen activators and metalloproteinases, advancing at approximately 1-2 mm/day.
- Contact inhibition halts migration once the epithelial layer is re-established.
Phase 4: Remodelling (Weeks to Years)
- Once the wound is closed, the matrix undergoes progressive remodelling.
- The key transition is replacement of type III collagen by type I collagen, synthesised by fibroblasts and cross-linked by lysyl oxidase.
- This process is coordinated by matrix metalloproteinases (MMPs), collagenases, gelatinases, and stromelysins, balanced against their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).
- Tensile strength increases progressively but never fully recovers: healed wounds reach approximately 50% of original tensile strength at 3 months and a maximum of ~80% by 1-2 years.
- Myofibroblasts undergo apoptosis, the vascular density decreases, and granulation tissue is replaced by an avascular, relatively acellular scar.
Primary Versus Secondary Intention Healing
| Feature | Primary Intention | Secondary Intention |
|---|---|---|
| Wound edges | Approximated (sutured/stapled/glued) | Open, separated |
| Granulation tissue | Minimal | Prominent |
| Wound contraction | Minimal | Major (myofibroblasts) |
| Epithelialisation distance | Short (mm) | Long (cm in large wounds) |
| Scar size | Small, linear | Larger, broader |
| Time to closure | Days to ~2 weeks | Weeks to months |
| Infection risk | Lower | Higher |
| Typical example | Sutured laceration | Abscess cavity, pressure sore |
- Tertiary intention (delayed primary closure) is the intentional delay of wound closure, typically 3-5 days, to allow bacterial load reduction and debridement before suturing.
- It is appropriate for contaminated wounds, bite wounds in high-risk locations, and wounds presenting late (>6-8 hours for most body regions).
Factors Affecting Wound Healing
Understanding modifying factors allows prediction of complications and rationalises clinical interventions.
Local Factors
| Factor | Effect |
|---|---|
| Infection | Prolongs inflammation, impairs collagen synthesis, increases MMP activity |
| Foreign body | Sustained inflammatory response; biofilm formation |
| Haematoma | Physical barrier, bacterial culture medium |
| Tissue hypoxia/ischaemia | Impairs fibroblast function, collagen hydroxylation (O₂-dependent), angiogenesis |
| Radiation damage | Obliterative endarteritis → chronic ischaemia → poor healing |
| Wound tension | Excessive tension impairs microvascular flow; some tension stimulates fibroblast activity |
Systemic Factors
| Factor | Mechanism of Impairment |
|---|---|
| Diabetes mellitus | Microvascular disease, neuropathy, neutrophil dysfunction, advanced glycation end-products impairing collagen cross-linking |
| Malnutrition | Deficiency of protein (collagen substrate), vitamin C (prolyl/lysyl hydroxylation), zinc (MMP cofactor), vitamin A |
| Corticosteroids | Suppress inflammation (phase 2), reduce fibroblast proliferation and collagen synthesis, increase MMP activity |
| Age | Reduced inflammatory response, reduced fibroblast proliferation, slower epithelialisation |
| Anaemia/hypoxaemia | Reduced O₂ delivery to healing tissue |
| Uraemia | Platelet dysfunction, impaired neutrophil chemotaxis |
| Immunosuppression | Impaired phagocytosis, increased infection risk |
- Clinically: Vitamin C deficiency (scurvy) produces a particularly instructive example, collagen cannot be properly hydroxylated without ascorbic acid as a cofactor for prolyl hydroxylase, leading to defective cross-linking, wound dehiscence, and reopening of previously healed scars.
- Zinc deficiency impairs MMP activity, DNA synthesis, and cell proliferation.
Abnormal Scar Formation
Hypertrophic Scar
- A hypertrophic scar remains within the boundaries of the original wound but is raised, firm, erythematous, and pruritic.
- It is the result of excess collagen deposition relative to degradation during remodelling, with persistent myofibroblast activity and elevated TGF-β₁ levels.
- Most hypertrophic scars soften and flatten over 1-2 years, though this process can be accelerated by pressure garments or intralesional corticosteroid injection.
Keloid
- A keloid extends beyond the original wound margins into surrounding normal skin and does not regress spontaneously, this distinguishes it from a hypertrophic scar.
- Keloids are more common in individuals with darker skin pigmentation, in the 10-30-year age group, and on the earlobes, sternum, and shoulders.
- Histologically, they show disorganised, thick, hyalinised collagen bundles with continued fibroblast activity.
- Management is difficult: excision alone leads to recurrence in up to 80% of cases; adjuncts include intralesional triamcinolone (typically 10-40 mg/mL), pressure therapy, and silicone gel sheeting.
Wound Dehiscence and Chronic Wounds
- When the balance tips toward excess degradation or inadequate synthesis, healing fails. Dehiscence, disruption of a surgical wound, is more common with infection, haematoma, obesity, corticosteroid use, and excessive tension. Chronic wounds (classically defined as failing to heal within 3 months) are typically arrested in the inflammatory phase and include venous leg ulcers, diabetic foot ulcers, and pressure injuries.
- They are characterised by persistently elevated MMP levels, high bacterial burden, impaired growth factor activity, and senescent fibroblasts.
Fibrosis
- Fibrosis represents pathological, excessive connective tissue deposition that disrupts organ architecture and impairs function.
- It is the end-stage of chronic, unresolved inflammation in parenchymal organs.
- Whereas scarring in the skin preserves barrier function even at the cost of cosmesis, fibrosis in the lung, liver, or myocardium irreversibly compromises the physiological functions of those organs.
Pathogenesis of Fibrosis
The central mediator is TGF-β₁, released by chronically activated macrophages, platelets, and injured epithelial cells. TGF-β₁:
- Stimulates fibroblast-to-myofibroblast differentiation
- Upregulates collagen I and III synthesis
- Suppresses MMP activity and upregulates TIMPs
- Promotes epithelial-to-mesenchymal transition (EMT), in which epithelial cells lose their polarity and adhesion molecules and acquire fibroblastic properties, a major source of myofibroblasts in renal and pulmonary fibrosis
The activated stellate cell in the liver is the hepatic equivalent of the myofibroblast: normally quiescent and storing vitamin A, it is activated by TGF-β₁, PDGF, and reactive oxygen species from injured hepatocytes and Kupffer cells, transforming into a collagen-secreting, contractile cell.
Organ-Specific Fibrosis
| Organ | Condition | Cause | Clinical Consequence |
|---|---|---|---|
| Liver | Cirrhosis | Alcohol, viral hepatitis, NASH, cholestasis | Portal hypertension, hepatic synthetic failure |
| Lung | Idiopathic pulmonary fibrosis (IPF) | Unknown (repetitive alveolar micro-injury) | Restrictive pattern, progressive respiratory failure |
| Kidney | Chronic kidney disease | Hypertension, diabetes, glomerulonephritis | Loss of nephron mass, CKD progression |
| Heart | Post-infarction fibrosis; dilated cardiomyopathy | Ischaemic necrosis; chronic pressure/volume overload | Diastolic dysfunction, arrhythmia substrate, reduced EF |
| Peritoneum | Encapsulating peritoneal sclerosis | Chronic PD, abdominal surgery | Bowel obstruction |
| Retroperitoneum | Retroperitoneal fibrosis | Idiopathic (IgG4-related), drugs (methysergide), malignancy | Ureteric obstruction |
- Key principle: Fibrosis is largely irreversible once established because the cross-linked collagen matrix resists degradation.
- Early recognition and treatment of the underlying driver, viral hepatitis, uncontrolled hypertension, autoimmune disease, is the most effective strategy for preventing fibrosis rather than reversing it.
Contrast with Physiological Scarring
| Feature | Scar (skin) | Fibrosis (parenchymal organ) |
|---|---|---|
| Trigger | Acute discrete injury | Chronic repetitive injury or inflammation |
| Architecture | Replaces epidermis/dermis without parenchymal loss | Replaces functional parenchyma |
| Functional consequence | Mechanical (contracture, cosmesis) | Physiological (organ failure) |
| Reversibility | Limited but partial remodelling possible | Largely irreversible |
| Key cell | Myofibroblast (from local fibroblasts) | Myofibroblast (from stellate cells, EMT, fibrocytes) |
Growth Factors in Repair: A Summary
| Growth Factor | Source | Principal Role in Healing |
|---|---|---|
| PDGF | Platelets, macrophages | Fibroblast and smooth muscle cell chemotaxis and proliferation |
| TGF-β₁ | Platelets, macrophages, most cells | Fibroplasia, matrix synthesis, immunomodulation; master profibrotic mediator |
| VEGF | Macrophages, keratinocytes, hypoxic cells | Angiogenesis |
| FGF (bFGF) | Macrophages, endothelium | Fibroblast proliferation, angiogenesis, keratinocyte migration |
| EGF | Platelets, salivary/lacrimal glands | Keratinocyte proliferation and migration, epithelialisation |
| IGF-1 | Liver, fibroblasts | Collagen synthesis, cell proliferation |
ED-Relevant Clinical Integration
The phases and principles above translate directly into common ED decisions:
- Wound irrigation and debridement reduce bacterial load and remove necrotic tissue, allowing progression from a stalled inflammatory phase to proliferation.
- Timing of closure: contaminated wounds, bites (particularly human and cat bites), and wounds presenting >6-8 hours in high-risk anatomical areas (hands, feet) generally warrant delayed primary closure or secondary intention healing.
- Tetanus prophylaxis decisions depend partly on wound characteristics (contaminated, devitalised tissue) that impair local defence, these same characteristics impair healing.
- Corticosteroid-treated patients heal poorly; wounds in these patients warrant careful follow-up and a lower threshold for hospital admission.
- Diabetic wounds: even apparently minor, may represent the beginning of a chronic wound trajectory requiring multidisciplinary management from the outset rather than simple ED discharge.
- Recognising fibrosis as end-stage organ damage guides the interpretation of investigations (elevated creatinine, cirrhotic liver architecture on ultrasound, reduced DLCO on spirometry) and informs prognosis in resuscitation and critical care decisions.