- Phases and Timelines:
- Hemostasis (minutes – hours):
- Platelets → fibrin clot:
- Releases PDGF, TGF-β, vWF, fibrinogen, Factor V, thrombospondin
- Platelets → fibrin clot:
- Inflammatory phase:
- Last roughly from day 0 to day 3/4:
- Can last up to ~7 days in larger / contaminated wounds
- PMNs dominate first 48 hours:
- Macrophages peak ~ 48 hours to 72 hours
- Key signals:
- TNF-α, IL-1, IL-6, TGF-β, PDGF
- Last roughly from day 0 to day 3/4:
- Proliferative / Regenerative Phase:
- From rougly day 3 to day 21
- Fibroblasts:
- Lay down type III collagen
- Endothelial cells:
- Neovascularization
- Keratinocytes:
- Re-epithelialization:
- Approximalty 1 mm / day, (range 0.5 mm to 1.5 mm)
- Re-epithelialization:
- Growth factors:
- PDGF, FGF (including KGF / FGF-7), EGF, VEGF, TGF-β
- Remodeling / Maturation phase:
- From 3 weeks to 12 to 18 months
- Collagen Type III → type I collagen:
- Collagen fibers re-align, cross-link; decreased cellularity and vascularity
- Hemostasis (minutes – hours):
- Who Arrives When?
- Immediate:
- Platelets
- Hours to Day 2:
- PMNs
- Day 2 to 4:
- Macrophages:
- Switch from M1 → M2 phenotype to drive repair
- Macrophages:
- Day 3+:
- Peak ~ 1 to 2 weeks):
- Fibroblasts and endothelial cells
- Peak ~ 1 to 2 weeks):
- ~ Day 5+:
- Lymphocytes:
- Modulate later phases
- Lymphocytes:
- Immediate:
- Matrix and Collagen:
- Provisional matrix:
- Fibrin + fibronectin + hyaluronic acid:
- Scaffold for cells
- Fibrin + fibronectin + hyaluronic acid:
- Fibronectin (from fibroblasts, platelets):
- Chemotactic for macrophages
- Anchors fibroblasts
- Collagen synthesis requires:
- α-ketoglutarate, O₂, Fe²⁺, vitamin C for prolyl/lysyl hydroxylases:
- Hydroxylation → triple-helix stability
- Cross-linking:
- Lysyl oxidase (Cu²⁺-dependent) forms intermolecular cross-links:
- Equals tensile strength
- Lysyl oxidase (Cu²⁺-dependent) forms intermolecular cross-links:
- Triple helix motif:
- Glycine is every 3rd amino acid (Gly-X-Y; X/Y often Pro/Hyp).
- α-ketoglutarate, O₂, Fe²⁺, vitamin C for prolyl/lysyl hydroxylases:
- Collagen types (surgical high-yield):
- Type I:
- Skin, tendon, bone:
- Predominant in healed wounds
- Skin, tendon, bone:
- Type II:
- Cartilage
- Type III:
- Granulation tissue, vessels, early wound
- Type IV:
- Basement membranes
- Type V:
- Widespread
- Enriched in cornea / placenta
- Type I:
- Drugs:
- d-Penicillamine (and β-aminopropionitrile:
- Impair cross-linking
- d-Penicillamine (and β-aminopropionitrile:
- Tensile Strength (what really matters for primary closure):
- ~ 10% by end of week 1
- ~ 20%to 30% by 3 weeks:
- Collagen content near max by ~ 3 to 4 weeks
- ~ 50% to 60% by 6 to 8 weeks
- 80% by ~ 3 months:
- Plateau (never returns to 100%) through 6 to 12 months
- Provisional matrix:
- Epithelialization and Contraction:
- Epithelialization sources:
- Hair follicles (#1), wound edges, sweat glands
- Rate ≈ 1 mm / day
- Requires healthy granulation bed
- Myofibroblasts (α-SMA+, gap junctions):
- Drive wound contraction:
- Greatest where skin is lax:
- Perineum, scrotum
- Least on scalp / tight skin
- Greatest where skin is lax:
- Drive wound contraction:
- Epithelialization sources:
- Open wounds (secondary intention):
- Epithelial integrity is key; until closed
- Leak protein-rich exudate and are prone to colonization
- Practical Timelines:
- Suture removal (general guide; adjust for tension / vascularity):
- Face: 5 to 7 days
- Scalp: 7 to 10 days
- Trunk / Upper limb: 10 to 14 days
- Lower limb / Joints/Back: 12 to 14 days
- Bowel strength:
- Submucosa is the strength layer:
- Anastomosis weakest at day 3 to 5:
- Collagenolysis > synthesis
- Anastomosis weakest at day 3 to 5:
- Submucosa is the strength layer:
- Peripheral nerve regeneration: ~ 1 mm/day (range: 0.5 mm to 3 mm/day)
- Suture removal (general guide; adjust for tension / vascularity):
- Essentials to Optimize Healing:
- Moist wound environment:
- Avoid desiccation
- Oxygen delivery:
- Correct anemia, optimize perfusion, pain control, stop nicotine (vasoconstriction), consider revascularization if PAD
- Transcutaneous oxygen measurement (TCOM) targets:
- Greater than 40 mm Hg predicts healing
- 25 to 40 mm Hg borderline
- < 25 mm Hg poor
- Edema control:
- Elevation, compression (if ABI adequate)
- Debridement:
- Remove necrotic tissue / biofilm:
- Consider enzymatic or surgical debridement
- Remove necrotic tissue / biofilm:
- Infection control:
- ≥ 10⁵ CFU/g tissue (not per cm²) impairs healing:
- Debride +/- topical / systemic therapy as indicated
- ≥ 10⁵ CFU/g tissue (not per cm²) impairs healing:
- Nutrition:
- 1.2 to 1.5 g/kg/day protein
- Adequate calories, vitamin C, zinc (short-term if deficient), copper, arginine / glutamine if malnourished
- Moist wound environment:
- Impediments and Meds (nuance):
- Diabetes:
- Impaired neutrophil chemotaxis / killing
- Microvascular disease and neuropathy → pressure injury
- Tight peri-op glycemic control helps.
Steroids:- Blunt inflammation and collagen synthesis → ↓ tensile strengt
- Vitamin A 25,000 IU/day for 1 to 2 weeks can reverse steroid effects (avoid in pregnancy / liver disease)
- Cytotoxics / antimetabolites (5-FU, MTX) and calcineurin inhibitors (cyclosporine, tacrolimus):
- Impair early proliferative phase
- Biggest impact within ~2 weeks of injury
- Radiation:
- Endarteritis obliterans, fibroatrophy
- Consider HBOT for selected compromised grafts / flaps
- Smoking / nicotine:
- Vasoconstriction, ↑ COHb, ↓ oxygen delivery – cessation is critical
- Diabetes:
- Specific Clinical Entities:
- Keloids:
- Extend beyond original borders
- Familial predisposition (higher in patients of African / Asian ancestry)
- Treatment:
- Intralesional triamcinolone ± 5-FU, silicone, pressure therapy
- Consider post-excision RT in select cases
- Hypertrophic scars:
- Confined within original wound
- Common in high-tension areas (shoulders, presternal, joints)
- Treatment as above:
- Often regress with time
- Pyoderma gangrenosum:
- Neutrophilic dermatosis
- Avoid aggressive debridement (pathergy)
- Treatment: steroids / immunosuppressants
- Epidermolysis bullosa:
- Structural protein defects:
- Examples – keratin, laminin, collagen VII
- Supportive care; wound-care expertise
- Structural protein defects:
- Diabetic foot ulcers:
- Most commonly plantar metatarsal heads and heel
- Charcot midfoot deformity shifts pressure to plantar midfoot:
- Treatment:
- Off-loading (total contact cast), debridement, infection control, revascularization if needed
- Treatment:
- Leg ulcers:
- ~ 70% to 80% venous, 10% to 15% arterial, rest mixed
- Use ABI before compression:
- Unna boot or multilayer compression for venous disease
- Scar revision:
- Delay roughly 12 to 18 months for maturation
- Infants vs fetal healing:
- Fetal wounds (early gestation) may heal scar-lessly
- Infants still scar (often less conspicuously)
- Keloids:
- Primary vs Secondary Intention:
- Primary intention:
- Tensile strength hinges on collagen deposition and cross-linking
- Secondary intention:
- Epithelial integrity over a healthy granulation bed is paramount
- Delayed primary (tertiary) closure:
- Leave open initially for contaminated wounds:
- Close once clean – reduces infection risk:
- Ensure no residual infection to avoid abscess
- Close once clean – reduces infection risk:
- Leave open initially for contaminated wounds:
- Primary intention:
- Platelet Granules and Aggregation:
- Alpha granules:
- PDGF, TGF-β, vWF, fibrinogen, Factor V, thrombospondin, P-selectin, β-thromboglobulin
- Dense granules:
- ADP / ATP, serotonin, Ca²⁺, (± epinephrine)
- Key aggregation / activation mediators:
- It’s β-thromboglobulin in platelets:
- Binds thrombin
- PF4 (CXCL4):
- Is a chemokine that neutralizes heparin and modulates coagulation
- Alpha granules:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 