Residency · Residency · Plastic Surgery

Phases of Wound Healing

Overview

Wound healing is a dynamic, overlapping process consisting of four phases: hemostasis, inflammation, proliferation, and remodeling. Understanding the molecular mediators, cellular events, and temporal sequence of each phase is fundamental to plastic surgery practice, guiding decisions on wound management, timing of surgery, and optimization of healing. ---

Phase I: Hemostasis (Seconds to Minutes)

Vascular Response

Immediate vasoconstriction mediated by endothelin and thromboxane A2. Lasts 5-10 minutes before vasodilation takes over. Damaged endothelium exposes subendothelial collagen.

Platelet Plug Formation

Platelet adhesion via glycoprotein Ib binding to von Willebrand factor on exposed collagen. Platelet activation and aggregation via glycoprotein IIb/IIIa receptors. Platelet degranulation releases alpha granules and dense bodies.

Coagulation Cascade

Intrinsic and extrinsic pathways converge on the common pathway. Thrombin converts fibrinogen to fibrin, forming a stable clot. Fibrin mesh serves as a provisional matrix for cellular migration.

Growth Factors Released from Platelets

PDGF (platelet-derived growth factor) -- chemoattractant for neutrophils, macrophages, and fibroblasts. TGF-beta -- stimulates extracellular matrix production. VEGF -- initiates angiogenesis. EGF (epidermal growth factor) -- stimulates epithelial cell proliferation. ---

Phase II: Inflammation (Hours to Days)

Early Inflammation (0-48 Hours)

Neutrophils are the first cells to arrive (within 6 hours). Recruited by chemotactic signals: complement fragments (C5a), IL-8, bacterial products. Function: phagocytosis of bacteria and debris, release of reactive oxygen species and proteases. Neutrophils are expendable -- wound healing proceeds normally without them (unless infection is present).

Late Inflammation (48-96 Hours)

Monocytes/Macrophages become the predominant cell by day 2-3. Macrophages are THE most critical cell in wound healing -- wounds do not heal without them. Functions: Phagocytosis and debridement.

Antigen presentation. Release of growth factors (PDGF, TGF-beta, FGF, VEGF, IL-1, TNF-alpha). Transition from M1 (pro-inflammatory) to M2 (pro-healing) phenotype. Lymphocytes arrive by day 5-7; regulate the immune response and modulate fibroblast activity.

Cardinal Signs of Inflammation

Rubor (redness) -- vasodilation. Calor (heat) -- increased blood flow. Tumor (swelling) -- increased vascular permeability. Dolor (pain) -- bradykinin, prostaglandin stimulation of nerve endings. Functio laesa (loss of function).

<image>Sequential timeline illustration showing the four phases of wound healing (hemostasis, inflammation, proliferation, remodeling) with key cell types depicted at each phase: platelets forming a fibrin clot in hemostasis, neutrophils and macrophages in inflammation, fibroblasts and endothelial cells forming granulation tissue in proliferation, and organized collagen bundles in remodeling. A time axis spans from injury to 1 year with overlapping phase curves.</image>

Phase III: Proliferation (Day 4 to Day 21)

Fibroplasia

Fibroblasts migrate into the wound along the fibrin scaffold. Stimulated by PDGF, TGF-beta, and FGF. Produce collagen (predominantly Type III initially), fibronectin, glycosaminoglycans, and proteoglycans. Myofibroblasts differentiate from fibroblasts -- contain alpha-smooth muscle actin and drive wound contraction.

Angiogenesis

New blood vessel formation driven by VEGF, FGF-2, and hypoxia (low wound oxygen tension). Endothelial cell proliferation, migration, and tube formation. Creates granulation tissue -- the hallmark of the proliferative phase. Granulation tissue is highly vascular, resistant to infection, and provides a bed for epithelialization.

Epithelialization

Epithelial cells migrate from wound edges and skin appendages (hair follicles, sweat glands). Contact inhibition stops migration when epithelial sheets meet. Rate: approximately 1 mm/day from each wound edge. In partial-thickness wounds, epithelialization occurs from residual dermal appendages. In full-thickness wounds, epithelialization can only occur from wound edges.

Wound Contraction

Mediated by myofibroblasts. Can reduce wound area by 40-80% in open wounds. Most effective in loose, mobile tissue (trunk > extremities > face). Excessive contraction leads to contracture -- pathologic loss of function.

Extracellular Matrix Deposition

Initial matrix: fibronectin and Type III collagen. Gradual replacement with Type I collagen during remodeling. Proteoglycans and glycosaminoglycans regulate collagen fibril organization. ---

Phase IV: Remodeling (Day 21 to 1-2 Years)

Collagen Maturation

Type III collagen progressively replaced by Type I collagen. Normal skin ratio: 80% Type I, 20% Type III. Scar ratio initially: 30% Type I, 70% Type III -- gradually normalizes. Collagen cross-linking increases tensile strength.

Tensile Strength Recovery

1 week: 3% of normal skin strength. 3 weeks: 20% of normal skin strength. 6 weeks: 60% of normal skin strength. 3 months: 80% of normal skin strength. Maximum: 80% of normal skin strength (never returns to 100%).

Matrix Metalloproteinases (MMPs)

Collagenases (MMP-1, MMP-8, MMP-13), gelatinases (MMP-2, MMP-9), and stromelysins. Regulated by tissue inhibitors of metalloproteinases (TIMPs). Balance between MMPs and TIMPs determines net collagen content. Imbalance contributes to chronic wounds (excess MMP) or hypertrophic scars (excess TIMP).

<image>Comparative microscopic illustration showing collagen organization at three time points: early proliferative phase with disorganized fine Type III collagen fibrils in a random pattern, mature scar at 6 months with parallel bundles of Type I collagen in a more organized pattern, and normal uninjured dermis with basket-weave collagen arrangement. Each panel labeled with collagen type ratios and relative tensile strength percentages.</image>

Wound Healing by Type

Primary Intention (First Intention)

Surgical wounds closed with sutures, staples, or adhesives. Minimal granulation tissue formation. Fastest healing, least scar.

Secondary Intention

Wound left open to heal by contraction and epithelialization. Significant granulation tissue formation. Used when closure would trap infection or when tissue loss is extensive.

Tertiary Intention (Delayed Primary Closure)

Wound initially left open (for debridement or infection control). Closed surgically after 3-5 days when wound bed is clean. Combines benefits of debridement with reduced healing time. ---

Fetal Wound Healing

Key Differences

Scarless healing occurs in early gestation (first two trimesters). Higher ratio of Type III to Type I collagen. Reduced inflammatory response -- fewer neutrophils and macrophages. Higher levels of hyaluronic acid in the ECM.

TGF-beta3 predominates over TGF-beta1 and TGF-beta2. Implication: anti-TGF-beta1 and anti-TGF-beta2 strategies may reduce scarring in adults. ---

Molecular Mediators Summary

Factors Affecting Wound Healing

Systemic Factors

Nutrition: protein-calorie malnutrition, vitamin C deficiency (collagen cross-linking), vitamin A (reverses steroid effects), zinc deficiency. Diabetes: impaired neutrophil function, microangiopathy, neuropathy. Smoking: vasoconstriction (nicotine), carbon monoxide impairs oxygen delivery, cyanide inhibits oxidative metabolism. Steroids: suppress inflammation and collagen synthesis; vitamin A partially reverses effect.

Chemotherapy and radiation: impair cell proliferation. Age: decreased fibroblast proliferation, reduced collagen synthesis. Anemia: tissue oxygenation is maintained until Hb < 5 g/dL (wound healing is oxygen tension dependent, not Hb dependent).

Local Factors

Infection: bacterial count > 10^5 organisms per gram of tissue impairs healing. Hypoxia: impairs oxidative killing by neutrophils and collagen synthesis. Foreign bodies: provoke chronic inflammation. Radiation: progressive endarteritis obliterans reduces tissue vascularity. Mechanical factors: tension, pressure, desiccation. Denervation: reduces neuropeptide-mediated healing.

<image>Infographic-style medical illustration comparing normal wound healing on the left versus impaired wound healing on the right, showing a clean surgical wound progressing through organized inflammatory phase, robust granulation tissue, and mature scar on the normal side, versus a chronic wound with prolonged inflammation, biofilm, elevated MMP activity, and stalled healing on the impaired side. Key molecular differences (growth factor levels, MMP/TIMP ratios) annotated at each stage.</image>

Clinical Pearls

The macrophage is the single most important cell in wound healing -- it orchestrates the transition from inflammation to proliferation and releases critical growth factors. Wounds never regain more than 80% of the tensile strength of unwounded skin -- this is why scars remain vulnerable to re-injury. Neutrophils are dispensable for wound healing in uninfected wounds; their prolonged presence indicates infection or chronic inflammation. Vitamin C deficiency (scurvy) impairs collagen cross-linking by inhibiting prolyl and lysyl hydroxylase -- patients with poor nutrition should be supplemented.

Vitamin A (25,000 IU daily) can partially reverse the wound healing impairment caused by corticosteroids. Smoking cessation for a minimum of 4 weeks preoperatively is recommended to allow normalization of tissue oxygenation and inflammatory cell function. Wound oxygen tension (not hemoglobin level) is the key determinant of healing -- supplemental oxygen and adequate perfusion are more important than blood transfusion. The transition from Type III to Type I collagen during remodeling is the basis for the recommendation to wait 12-18 months before scar revision. ---.

References

• Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314-321.
• Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738-746.
• Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6.
• Levenson SM, Geever EF, Crowley LV, et al. The healing of rat skin wounds. Ann Surg. 1965;161(2):293-308.
• Lorenz HP, Longaker MT. Wounds: biology, pathology, and management. In: Norton JA, ed. Surgery: Basic Science and Clinical Evidence. 2nd ed. Springer; 2008.
• Whitby DJ, Ferguson MW. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol. 1991;147(1):207-215.

Read this lecture as Markdown