Tissue Repair & Wound Healing
A board-focused walkthrough of tissue repair: regeneration vs. scar, the ordered phases of wound healing with their cell types and collagen switches, growth-factor and nutrient biology, and the classic vignettes of impaired (scurvy, dehiscence) and excessive (keloid) healing.
Two ways tissue heals
Tissue repair restores homeostasis after injury by two overlapping routes: regeneration (replacement with identical parenchyma) and repair by connective-tissue scar (fibrosis). Which one dominates depends on the proliferative capacity of the injured cells and whether the extracellular matrix (ECM) scaffold — especially the basement membrane — stays intact. Labile and stable cells regenerate; permanent cells (neurons, cardiac and skeletal muscle) cannot, so their loss is filled by scar. Even in regenerating tissue, if the underlying stroma is destroyed (extensive injury, chronic inflammation), healing defaults to scar. On the boards, wound healing is tested as an ordered sequence — hemostasis → inflammation → proliferation (granulation tissue) → remodeling — with predictable cells, collagen switches, growth factors, and nutrient cofactors at each step, plus classic vignettes of delayed or excessive healing (scurvy, dehiscence, keloid).
- Hemostasis (minutes): platelet plug + fibrin clot; platelets release PDGF and TGF-β.
- Inflammatory (days 1–3): neutrophils peak days 1–2 → macrophages by day ~2–3 — the pivotal repair cell: they clear debris/bacteria and, shifting to an M2 phenotype, orchestrate granulation and fibrosis.
- Proliferative (day ~3 to 2 weeks): granulation tissue = new capillaries (angiogenesis: VEGF, FGF) + fibroblasts depositing type III collagen; myofibroblasts drive wound contraction; re-epithelialization by labile keratinocytes.
- Remodeling/maturation (weeks–months, up to 1 yr): type III collagen is replaced by type I via matrix metalloproteinases (collagenases, Zn²⁺-dependent); scar matures.
- Tensile strength: ~10% at 1 week; rises fast in weeks 1–4; plateaus at ~70–80% of original by ~3 months (never regains 100%).
- Primary intention = clean, sutured, approximated edges → minimal scar. Secondary intention = large/open wound → abundant granulation tissue + strong myofibroblast contraction → larger scar.
Regenerative capacity of cells
| Category | Cell cycle | Examples | Regeneration |
|---|---|---|---|
| Labile | continuously cycling | skin, GI/GU epithelium, bone marrow/hematopoietic, germ cells | Excellent |
| Stable (quiescent) | G0, re-enter cycle on stimulus | hepatocytes, renal proximal tubule, endothelium, fibroblasts, smooth muscle | Good |
| Permanent | terminally differentiated, non-dividing | neurons, cardiac myocytes, skeletal muscle | None → heals by scar |
Collagen cofactors (classic vignette triggers):
- Vitamin C → cofactor for prolyl/lysyl hydroxylase; hydroxyproline lets the triple helix H-bond and stabilize. Deficiency = scurvy (poor healing, reopened old wounds, perifollicular hemorrhage, corkscrew hairs, bleeding gums).
- Copper → cofactor for lysyl oxidase, which covalently cross-links tropocollagen. Deficiency / Menkes disease (ATP7A) → weak collagen.
- Zinc → cofactor for collagenases/MMPs used in remodeling. Deficiency → delayed healing.
Growth factors:
- VEGF, FGF → angiogenesis.
- PDGF (platelets, macrophages) → fibroblast, smooth-muscle, and monocyte/macrophage migration/proliferation.
- TGF-β → fibroblast proliferation + collagen/ECM deposition; anti-inflammatory; key driver of fibrosis.
- EGF → epithelial + fibroblast growth.
Impaired healing: infection (most common cause of delay), diabetes/ischemia, malnutrition, foreign body, and glucocorticoids (inhibit collagen synthesis; vitamin A partially reverses this).
Vignette: A 68-year-old man living alone eats mostly tea and toast. He has swollen, bleeding gums, bruises on his shins, coiled 'corkscrew' body hairs with surrounding hemorrhage, and a years-old surgical scar that has reopened.
Diagnosis: Scurvy (vitamin C deficiency) — impaired prolyl/lysyl hydroxylation → an unstable collagen triple helix and impaired cross-linking → weak scar and fragile vessels.
Next best step: confirm clinically (± low plasma ascorbate) and give vitamin C (ascorbic acid); findings reverse quickly.
Board pearl: 'old wounds falling apart' + perifollicular hemorrhage + gingival bleeding = vitamin C, not vitamin K (vitamin K deficiency causes bleeding via factors II/VII/IX/X but spares collagen and hair).
Vignette: On postoperative day 6 after an exploratory laparotomy, an obese diabetic man coughs, feels a 'pop,' then a sudden gush of pink serosanguineous fluid soaks his abdominal dressing.
Diagnosis: Wound dehiscence — separation of a surgical wound because collagen strength is still low (dehiscence peaks post-op days 5–7); risks evisceration.
Next best step: cover the wound with sterile saline-moistened gauze, keep the patient NPO and flat, and arrange surgical re-closure; if bowel is protruding (evisceration) → emergent operative repair.
Contrast: an abscess/fistula or incisional hernia presents later; a keloid is excess healing, not failure of healing.
Hypertrophic scar vs. keloid
| Feature | Hypertrophic scar | Keloid |
|---|---|---|
| Collagen | ↑ type III (organized, parallel) | ↑ type I and III (disorganized) |
| Borders | confined to original wound | extends beyond the wound edges |
| Course | may regress over time | persists/recurs; does not regress |
| Predisposition | any wound, high-tension sites | darker skin; earlobes, sternum, deltoid; familial |
Collagen types (classic number tricks):
- Type I = bONE — bone, skin, tendon, mature scar (and the type you have most 'one' of, ~90%).
- Type II = carTWOlage — cartilage, vitreous, nucleus pulposus.
- Type III = reTHREEculin — granulation tissue / early wound, blood vessels, uterus (defective in vascular Ehlers-Danlos, COL3A1).
- Type IV = under the FLOOR — basement membrane (defective in Alport, targeted in Goodpasture).
Healing cell order — 'Neutrophils, then Macrophages, then Fibroblasts': Neutrophils (d1–2) → Macrophages (d2–3) → Fibroblasts/granulation tissue (d3–7).
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