Wound Healing & Repair

Wound healing is the body's orchestrated response to tissue injury, restoring structural and functional integrity through regeneration or repair (fibrosis). For NEET PG, this topic links tightly with acute/chronic inflammation, growth factors, collagen biology and the cell-cycle classification of tissues — expect multi-item stems combining these threads.

Regeneration vs Repair — the core dichotomy

The outcome of injury depends on the proliferative capacity of the tissue and whether the extracellular matrix (ECM) scaffold (basement membrane) is intact.

• Regeneration = restoration of original tissue by proliferation of surviving (residual) cells and replacement from tissue stem cells. Requires intact connective tissue framework.
• Repair (fibrosis/scarring) = laying down of connective tissue (collagen). Occurs when the damaged tissue is incapable of regeneration or when the supporting framework is destroyed.

Tissues are classified by their regenerative ability based on cell-cycle activity:

Tissue type	Cell-cycle behaviour	Examples	Healing tendency
Labile	Continuously dividing (always in cycle)	Surface epithelia (skin, GI, urinary tract), bone marrow / haematopoietic cells	Excellent regeneration
Stable	Quiescent (G0), divide on stimulation	Hepatocytes, renal tubular cells, fibroblasts, endothelium, smooth muscle	Limited regeneration
Permanent	Non-dividing (left cell cycle permanently)	Neurons, cardiac myocytes, skeletal muscle	Repair by scar only

High-yield: Liver is the classic example of a stable tissue with remarkable regenerative capacity (after partial hepatectomy, via priming by IL-6/TNF and growth factors HGF, TGF-α). The framework (reticulin) must be intact — if destroyed (as in cirrhosis), you get nodular regeneration with scarring, not orderly restoration.

Phases of wound healing

Healing proceeds through four overlapping phases. Remember the sequence Haemostasis → Inflammation → Proliferation → Remodelling.

1. Haemostasis (immediate, minutes)

Vasoconstriction → platelet plug → coagulation cascade → fibrin clot forms a provisional matrix. Platelets degranulate, releasing PDGF, TGF-β, FGF — the first wave of growth factors that recruit inflammatory cells.

2. Inflammation (0–3 days)

• Neutrophils arrive first (peak ~24–48 h) — debride and kill bacteria.
• Macrophages arrive by day 2–3 and are the key orchestrating cell of healing. They clear debris, then switch phenotype to drive repair.

High-yield: The macrophage is the single most important cell in wound healing. M1 (classically activated) macrophages are pro-inflammatory/microbicidal; M2 (alternatively activated) macrophages secrete TGF-β and VEGF to drive angiogenesis, fibroblast proliferation and ECM deposition. The M1→M2 transition is essential for resolution.

3. Proliferation (day 3 to ~week 2–3)

The hallmark is granulation tissue — pink, soft, granular tissue comprising:

• Angiogenesis (new capillaries; VEGF-driven)
• Fibroblast proliferation + migration (PDGF, FGF, TGF-β)
• Loose ECM with type III collagen

Concurrent events:

• Re-epithelialisation: keratinocytes migrate from wound edges (stimulated by EGF, TGF-α).
• Myofibroblasts (modulated fibroblasts expressing α-smooth-muscle actin) mediate wound contraction.

4. Maturation / Remodelling (week 3 to months–years)

• Type III collagen is replaced by type I collagen (increasing tensile strength).
• Remodelling balanced by matrix metalloproteinases (MMPs, zinc-dependent) vs their inhibitors TIMPs.
• Vascularity regresses → scar becomes pale and avascular.

High-yield: Collagen remodelling shifts the type III : type I ratio toward type I. MMPs (collagenases) require zinc as a cofactor — relevant to why zinc deficiency impairs healing.

Tensile strength milestones:

Time after suturing	Approx. tensile strength of original
End of 1st week	~10%
~3 months	~70–80% (plateau)
Maximum (ever)	~70–80% — never returns to 100%

High-yield: Suture removal timing reflects early weak strength: a wound at 1 week has only ~10% of original strength. Maximum recovered tensile strength plateaus at ~70–80% of unwounded skin.

Healing by primary vs secondary intention

A heavily tested comparison.

Feature	Primary (first) intention	Secondary (second) intention
Wound type	Clean, sutured, apposed edges (e.g., surgical incision)	Large, open wound with tissue loss (e.g., ulcer, infarct, abscess)
Tissue gap	Minimal	Large
Granulation tissue	Scant	Abundant
Inflammation	Mild	Intense
Wound contraction	Negligible	Marked (myofibroblasts)
Scar	Small, neat	Large
Healing time	Fast	Slow
Infection risk	Low	Higher

High-yield: Wound contraction is a feature of secondary intention healing and is mediated by myofibroblasts. Contraction can reduce wound size by up to ~70–80%. (Do not confuse with contracture — a pathological deformity from excessive contraction, classic over joints and after burns.)

A useful flow for primary healing:

Day 1: clot + neutrophils → Day 2–3: macrophages, epithelial bridging → Day 3–5: granulation tissue + type III collagen + angiogenesis peak → Week 2: collagen accumulation, vascular regression → Month 1+: type I collagen scar, remodelling.

Growth factors & their roles

Growth factor	Major source	Principal action
PDGF	Platelets, macrophages	Chemotaxis & proliferation of fibroblasts, smooth muscle, monocytes
VEGF	Mesenchymal cells	Angiogenesis (the master angiogenic factor); also vascular permeability
FGF (bFGF)	Macrophages, fibroblasts	Angiogenesis, wound repair, fibroblast proliferation
TGF-β	Platelets, macrophages, lymphocytes	Fibrogenic — stimulates collagen/ECM, inhibits MMPs, anti-inflammatory; key in scarring & fibrosis
EGF / TGF-α	Macrophages, salivary glands, keratinocytes	Epithelial & fibroblast proliferation (re-epithelialisation)
HGF	Fibroblasts, endothelium	Hepatocyte & epithelial proliferation; liver regeneration

High-yield: TGF-β is the most pro-fibrotic cytokine — it drives collagen deposition, suppresses MMPs, and is implicated in chronic fibrotic diseases (pulmonary, hepatic, renal fibrosis) and in keloid formation. VEGF is the key angiogenic factor.

Mnemonic for angiogenic factors: "VF" — VEGF and FGF are the two great vessel-builders.

Keloid vs hypertrophic scar

A perennial favourite in pathology and surgery vivas.

Feature	Hypertrophic scar	Keloid
Extent	Confined within original wound margins	Extends beyond the wound margins
Regression	May regress spontaneously	Does not regress; recurs after excision
Collagen	Type III, organised, parallel	Type I & III, thick hyalinised "keloidal" collagen bundles
Predisposition	Any	Darker skin (Africans, Asians); genetic predisposition
Common sites	Across joints/flexures	Earlobes, sternum/presternal, shoulder, upper back, deltoid
Treatment	Often conservative; pressure	Intralesional steroids, silicone, excision + adjuvant, radiation

High-yield: A scar that grows beyond the boundaries of the original wound and recurs after excision = keloid. Histology shows thick, hyalinised, eosinophilic ("keloidal") collagen. Excision alone is contraindicated as monotherapy (high recurrence) — combine with intralesional triamcinolone ± radiation/silicone.

Aberrations & complications of healing

1. Deficient scar formation
   • Wound dehiscence — rupture of a wound (classically abdominal, often around 5–8 days post-op); raised by increased intra-abdominal pressure (vomiting, coughing, ileus, obesity).
   • Ulceration — from inadequate vascularisation (e.g., peripheral vascular disease, diabetic foot).
2. Excessive scar formation
   • Keloid / hypertrophic scar (above).
   • Exuberant granulation ("proud flesh") — protrudes above skin level, blocks re-epithelialisation; cauterise/resect.
   • Desmoid / aggressive fibromatosis.
3. Contractures — exaggerated contraction causing deformity & restricted movement; classic on palms, soles, anterior thorax, and across joints after burns.
4. Implantation (epidermal) cysts, painful neuromas, and incisional hernias.
5. Dystrophic calcification / malignant transformation — chronic non-healing wounds/scars/sinuses can develop squamous cell carcinoma (Marjolin ulcer).

High-yield: Marjolin ulcer = squamous cell carcinoma arising in a chronic wound, burn scar, or chronic sinus. Wound dehiscence classically presents around post-operative day 5–8 with serosanguinous discharge ("pink fluid" sign).

Factors that impair wound healing

Systemic factors

• Nutrition: Vitamin C deficiency → defective collagen cross-linking (impaired hydroxylation of proline/lysine) → scurvy; protein deficiency; zinc deficiency (MMP cofactor).
• Diabetes mellitus — microangiopathy, neuropathy, impaired neutrophil function, infection.
• Glucocorticoids — anti-inflammatory and inhibit collagen synthesis & TGF-β → weak scar (sometimes therapeutically exploited to reduce scarring).
• Age, hypoxia/poor perfusion, smoking.

Local factors

• Infection — the single most important cause of delayed healing.
• Foreign body, poor blood supply / ischaemia, mechanical movement, venous stasis, denervation, irradiation.

High-yield: Infection is the most important and most common cause of impaired wound healing. Vitamin C is essential for collagen synthesis (hydroxylation step requiring it as a cofactor) — its deficiency gives poor wound healing and reopening of old wounds in scurvy.

Mnemonic for healing impairment — "DIDN'T HEAL": Diabetes, Infection, Drugs (steroids), Nutritional deficiency, Tissue hypoxia/Tension, Haematoma, Edges not apposed, Age, Low oxygen/perfusion.

Collagen biology essentials

• Collagen synthesis requires hydroxylation of proline and lysine residues, needing vitamin C, oxygen, iron (Fe²⁺), and α-ketoglutarate as cofactors.
• Lysyl oxidase (a copper-dependent enzyme) performs cross-linking that gives tensile strength → copper deficiency and Menkes disease impair this.
• Type I collagen: skin, bone, tendon (mature scar). Type III: early granulation tissue, blood vessels, reticulin (and predominates in keloids alongside type I).

High-yield: Vitamin C → proline/lysine hydroxylation; Copper (lysyl oxidase) → cross-linking. Defects: scurvy (Vit C), Menkes (Cu), Ehlers–Danlos (various collagen/processing defects), osteogenesis imperfecta (type I collagen).

Diagnosis & assessment angle

Wound healing is largely a clinical/histopathological concept rather than a single "investigation of choice," but exam-relevant assessment includes:

• Histology of granulation tissue: proliferating capillaries + fibroblasts + mixed inflammatory infiltrate.
• Special stains: Masson trichrome for collagen; reticulin stain for type III collagen framework.
• Clinical monitoring of chronic wounds (diabetic foot, pressure ulcers) for area, depth, granulation quality, slough, and signs of infection.

Management / "drug of choice" pearls

• Optimise the patient: glycaemic control, nutrition (protein, vitamin C, zinc), oxygenation, smoking cessation.
• Debridement of necrotic tissue; control infection (culture-directed antibiotics).
• Keloid: intralesional triamcinolone is first-line; add silicone gel sheeting, pressure, or excision with adjuvant therapy.
• Excess granulation tissue ("proud flesh"): silver nitrate cautery or curettage.
• Chronic non-healing wounds: moist wound dressings, negative-pressure wound therapy (NPWT/vacuum-assisted closure), and treat the underlying cause (venous/arterial/diabetic).

Key differentials & confusions to avoid

• Granulation tissue vs granuloma — granulation tissue = repair (capillaries + fibroblasts); granuloma = organised collection of epithelioid macrophages (chronic inflammation). Don't conflate.
• Contraction vs contracture — contraction is a normal part of secondary healing; contracture is the pathological end-result causing deformity.
• Keloid vs hypertrophic scar — boundary of original wound is the discriminator.
• Regeneration vs repair — depends on tissue type and intact framework.
• Resolution vs organisation — resolution restores normal architecture (e.g., lobar pneumonia clears completely); organisation replaces exudate/infarct with granulation tissue → scar (e.g., organising pneumonia, healed MI).

Recently asked / exam angle

• Identify the first growth factor released at injury (PDGF/TGF-β from platelets) and the master angiogenic factor (VEGF).
• Macrophage as the key cell and the M1→M2 phenotype switch — increasingly tested with immunology integration.
• Tensile strength values — 1 week ≈ 10%; maximum ≈ 70–80%.
• Keloid features (beyond wound margin, recurs, keloidal collagen, presternal/earlobe sites) — image-based and clinical stems.
• Vitamin C role in collagen (hydroxylation) and copper/lysyl oxidase in cross-linking — biochemistry-pathology crossover.
• Most important factor delaying healing = infection.
• Type III → Type I collagen switch during remodelling and MMP/TIMP (zinc-dependent) balance.
• Marjolin ulcer and wound dehiscence (day 5–8) as complication MCQs.
• Multi-item stems pairing phases of inflammation with phases of healing (neutrophil day 1, macrophage day 2–3, granulation tissue day 3–5).

Rapid revision

1. Sequence: Haemostasis → Inflammation → Proliferation → Remodelling.
2. Labile (epithelia, marrow) regenerate best; permanent cells (neurons, cardiac, skeletal muscle) heal only by scar.
3. Liver = stable tissue, outstanding regeneration if framework intact.
4. Macrophage = central orchestrating cell; M2 drives repair (TGF-β, VEGF).
5. PDGF & TGF-β first from platelets; VEGF = key angiogenesis; TGF-β = most fibrogenic.
6. Granulation tissue = new capillaries + fibroblasts + loose ECM (type III collagen).
7. Myofibroblasts cause wound contraction — feature of secondary intention healing.
8. Remodelling: type III → type I collagen; MMPs are zinc-dependent, opposed by TIMPs.
9. Tensile strength: ~10% at 1 week, plateaus ~70–80% (never 100%).
10. Keloid extends beyond wound margins, recurs after excision, keloidal collagen; first-line Rx intralesional steroid.
11. Vitamin C → proline/lysine hydroxylation; copper (lysyl oxidase) → cross-linking.
12. Infection = commonest cause of impaired healing; steroids inhibit collagen/TGF-β; Marjolin ulcer = SCC in chronic scar/wound.