Wound healing

Regeneration or scar

• Whether tissue regenerates depends on two things: can the cells divide, and is the connective tissue framework (basement membrane, reticulin) intact?

• If the framework is destroyed (abscess, cirrhosis), even stable cells heal by fibrosis.
• Liver after partial hepatectomy restores its mass over weeks. Cytokines TNF and IL-6 prime hepatocytes to leave G0, then HGF (and EGF/TGF-alpha) act as mitogens. Progenitor (oval) cells take over if hepatocytes cannot divide.
• Peripheral nerves regenerate at about 1 mm per day along Schwann cell tubes after Wallerian degeneration. If axons sprout into scar without a tube, they form a painful traumatic neuroma. CNS axons do not regenerate effectively; brain injury heals by gliosis (astrocytes).

Granulation tissue

• The hallmark of repair, appearing at 3–5 days: new capillaries (angiogenesis driven mainly by VEGF, also FGF-2) and proliferating fibroblasts, with macrophages in loose oedematous matrix. Pink, granular, bleeds easily.
• Myofibroblasts (alpha-smooth muscle actin) pull the edges together, causing wound contraction.
• It matures into a scar: vessels regress, type III collagen is replaced by type I, and matrix metalloproteinases (zinc-dependent collagenases) remodel the matrix.
• The same process organises a thrombus: capillaries grow into it and form new channels (recanalisation), partly restoring flow.

Phases of wound healing

• Tensile strength: about 10% at 1 week (when skin sutures are removed), about 70–80% at 3 months, then plateaus. A scar never regains 100%.
• Epithelium bridges a sutured incision within 24–48 hours.

Primary versus secondary intention

• The main difference is the amount of granulation tissue and wound contraction, both much greater in secondary intention.
• Delayed primary closure: a contaminated wound is left open 3–5 days, then sutured.

Factors that delay healing

• Infection is the commonest local cause. Bacteria prolong inflammation, and neutrophil proteases and toxins destroy new collagen and granulation tissue, so the wound cannot gain strength.
• Other local factors: poor blood supply, foreign body, movement and tension, haematoma, necrotic tissue, previous radiotherapy, venous hypertension.
• Systemic: diabetes, protein malnutrition, vitamin C deficiency (prolyl and lysyl hydroxylation of collagen fails), zinc deficiency (MMP and cell-division enzymes), glucocorticoids (suppress inflammation and collagen synthesis; vitamin A partly reverses this), old age, smoking, anaemia, uraemia, jaundice, chemotherapy.

Abnormal repair

• Keloid treatment: intralesional steroid, pressure, silicone, radiotherapy after excision.
• Wound dehiscence (often days 5–8, heralded by serosanguinous discharge), incisional hernia, contracture over joints after burns, proud flesh (exuberant granulation blocking epithelialisation).
• Marjolin ulcer: squamous cell carcinoma arising in a chronic scar or ulcer (old burn, osteomyelitis sinus); slow-growing with late nodal spread.

Fibrosis in organs

• Cirrhosis: injured hepatocytes and Kupffer cells release TGF-beta and PDGF, activating hepatic stellate (Ito) cells in the space of Disse. These normally store vitamin A; activated, they become myofibroblasts and lay down collagen. Cirrhosis requires diffuse fibrosis plus regenerative nodules.
• Primary myelofibrosis: megakaryocytes release PDGF and TGF-beta that drive marrow fibrosis. Marrow aspiration gives a dry tap; the film shows teardrop cells and leucoerythroblastic changes; the spleen enlarges from extramedullary haemopoiesis.
• Heart after infarction repairs only by scar: neutrophils days 1–3, macrophages days 3–7 (rupture risk), granulation tissue at 1–2 weeks, firm scar by 6–8 weeks. Pulmonary fibrosis follows the same pattern.
• Fracture healing: haematoma, soft callus (fibrocartilage, weeks 1–3), hard callus (woven bone), then remodelling to lamellar bone over months; impaired by movement, infection, poor blood supply (scaphoid, femoral neck), smoking.

Remember Macrophages direct repair; VEGF builds vessels, PDGF brings fibroblasts, TGF-beta lays down collagen.

Exam trap Myofibroblasts cause wound contraction, most marked in secondary intention.

Exam trap A keloid extends beyond the wound margins; a hypertrophic scar stays within them.

How FCPS asks about this

• Cells that store vitamin A and cause liver fibrosis: hepatic stellate (Ito) cells becoming myofibroblasts.
• Components of granulation tissue and the angiogenic factor: new capillaries and fibroblasts; VEGF.
• Main difference between primary and secondary intention: amount of granulation tissue and wound contraction.
• Commonest local cause of delayed healing: infection; systemic causes include vitamin C and zinc deficiency, steroids and diabetes.
• Tensile strength: about 10% at a week, 70–80% at three months, never 100%.
• Teardrop cells and dry tap: primary myelofibrosis.
• Fastest regenerating tissue: labile epithelium such as GI mucosa; neurones and cardiac muscle heal only by scar.