Residency · Residency · Dermatology

Wound Healing Physiology

Overview

Wound healing is a highly orchestrated process involving four overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Dysregulation at any stage leads either to impaired healing (chronic wounds) or excessive scarring (keloids, hypertrophic scars). Understanding these mechanisms is essential for procedural dermatology, wound management, and the treatment of fibrotic skin conditions.

Phase 1: Hemostasis (Seconds to Hours)

Vascular Response

The moment tissue is injured, blood vessels in the area undergo immediate vasoconstriction, mediated by endothelin and thromboxane A2. This lasts 5 to 10 minutes and serves to limit blood loss while the clotting cascade gets underway.

Platelet Plug Formation

Exposed subendothelial collagen activates platelets through the glycoprotein VI receptor, and von Willebrand factor (vWF) bridges platelets to collagen fibers. Activated platelets change shape, degranulate, and aggregate. Their alpha granules release a cocktail of growth factors that will orchestrate much of what follows: PDGF (platelet-derived growth factor), which is a chemoattractant for fibroblasts and macrophages; TGF-beta, which stimulates extracellular matrix production; VEGF, which initiates angiogenesis; and fibronectin and fibrinogen. Dense granules release ADP and serotonin, which recruit and activate additional platelets.

Fibrin Clot

The coagulation cascade generates thrombin, which converts fibrinogen to fibrin. The resulting fibrin mesh is stabilized by factor XIIIa cross-linking and serves as a provisional matrix for cell migration. Growth factors trapped within the clot are gradually released as it is degraded, providing a sustained signaling gradient.

Phase 2: Inflammation (Hours to Days)

Neutrophil Recruitment (Day 1-2)

Neutrophils are the first immune cells to arrive, peaking at 24 to 48 hours. They are recruited by IL-8 (CXCL8), complement fragments (C5a), and bacterial products, and their job is to phagocytose bacteria and debris and release reactive oxygen species and proteases. Once their work is done, neutrophils undergo apoptosis and are cleared by macrophages. Prolonged neutrophil presence is a red flag — it indicates wound infection or the transition to a chronic wound state.

Macrophage Recruitment (Day 2-5)

Monocytes infiltrate the wound and differentiate into macrophages, which are arguably the single most critical cell type for wound healing — macrophage depletion experiments show severely impaired healing. Macrophages exist in two polarization states: M1 (pro-inflammatory) macrophages produce TNF-alpha, IL-1, IL-6, and reactive oxygen species and phagocytose debris; M2 (pro-repair) macrophages produce IL-10, TGF-beta, and VEGF and promote angiogenesis and matrix deposition. As the wound progresses, macrophages transition from the M1 to the M2 phenotype. Failure to make this transition is a hallmark of chronic non-healing wounds, such as diabetic ulcers.

Mast Cells

Mast cells degranulate early in the process, releasing histamine (causing vasodilation and increased permeability), TNF-alpha, IL-4, and proteases. They also contribute to angiogenesis through VEGF and FGF release.

Phase 3: Proliferation (Days 4-21)

Granulation Tissue Formation

Granulation tissue is the highly vascularized, pink-red tissue that fills the wound bed during the proliferative phase. It is composed of new capillaries, fibroblasts, macrophages, and provisional extracellular matrix. Clinically, healthy granulation tissue appears beefy red, has a granular surface, and bleeds easily.

Angiogenesis

New blood vessels form from pre-existing vessels through a process driven primarily by VEGF (the most important mediator), FGF-2, and angiopoietins. Hypoxia is a major stimulus, acting through HIF-1alpha (hypoxia-inducible factor). Endothelial cells proliferate, migrate, and form tubular structures, and vessel maturation requires the recruitment of pericytes in a PDGF-dependent process.

Fibroplasia and ECM Deposition

Fibroblasts migrate into the wound guided by PDGF, TGF-beta, and fibronectin. They initially produce type III collagen, which will later be replaced by type I collagen during the remodeling phase. The early provisional matrix consists of fibronectin and hyaluronic acid, and proteoglycans such as decorin and biglycan regulate collagen fibrillogenesis.

Myofibroblast Differentiation

Under the influence of TGF-beta1 (the most potent inducer), mechanical tension, and ED-A fibronectin, fibroblasts differentiate into myofibroblasts. These cells express alpha-smooth muscle actin (alpha-SMA) in their stress fibers, enabling them to generate the contractile force needed for wound contraction. Normally, myofibroblasts undergo apoptosis after wound closure. When they persist, however, the result is pathologic scarring — keloids and hypertrophic scars.

Re-epithelialization

Keratinocytes at wound margins and from hair follicle stem cells proliferate and migrate across the wound bed in a "leapfrog" pattern, with cells at the leading edge extending lamellipodia and crawling over the wound surface. This requires dissolution of hemidesmosomes, expression of migration-associated integrins (alpha-5-beta-1), and activation of MMPs. Migration stops through contact inhibition when epithelial sheets from opposite sides meet. A moist wound environment accelerates re-epithelialization — this is the scientific rationale for occlusive dressings.

Phase 4: Remodeling (Weeks to Years)

Collagen Remodeling

During remodeling, type III collagen is gradually replaced by type I collagen. Normal skin contains approximately 80 percent type I and 20 percent type III collagen. Early scars have an increased type III collagen ratio, which approaches (but never fully reaches) the normal ratio as the scar matures. Collagen cross-linking increases tensile strength over months, but even a fully mature scar achieves only about 80 percent of the tensile strength of unwounded skin — it never reaches 100 percent.

Matrix Metalloproteinases (MMPs)

MMPs are a family of zinc-dependent endopeptidases that degrade extracellular matrix components and play essential roles in wound remodeling. | MMP | Name | Key Substrates |

Key members include MMP-1 (collagenase-1, which cleaves types I and III collagen), MMP-2 and MMP-9 (gelatinases, which degrade type IV collagen in basement membranes), and MMP-3 (stromelysin, which has a broad ECM substrate range). MMP activity is regulated by tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP balance is critical: excess MMP activity leads to chronic non-healing wounds (where newly deposited matrix is destroyed faster than it can accumulate), while insufficient MMP activity leads to excessive scarring.

Scar Maturation

An immature scar is red, raised, and often pruritic, reflecting ongoing vascularity and active remodeling. Over 12 to 18 months, a mature scar typically becomes flat, pale, and soft. Final scar appearance depends on wound tension, anatomic site, genetics, and skin type.

Abnormal Scarring

Hypertrophic Scars

Hypertrophic scars remain within the boundaries of the original wound. They develop within weeks of injury and often improve spontaneously over 1 to 2 years. They are more common at sites of high mechanical tension, such as the shoulders, sternum, and flexor surfaces. Histologically, they show organized collagen bundles parallel to the skin surface with nodular myofibroblast aggregates.

Keloids

Keloids, in contrast, extend beyond the boundaries of the original wound. They can develop months to years after injury and do not regress spontaneously. There is a strong genetic predisposition, with higher prevalence in African, Asian, and Hispanic populations. Histologically, keloids show thick, disorganized ("keloidal") collagen bundles, increased mucin, and notably no myofibroblast nodules — distinguishing them from hypertrophic scars. The pathogenesis involves persistent TGF-beta signaling, failure of myofibroblast apoptosis, altered mechanotransduction (increased tissue stiffness), and possibly mast cells and IL-13.

Treatment of Abnormal Scars

First-line treatment is intralesional triamcinolone acetonide (10 to 40 mg/mL), which inhibits collagen synthesis. Silicone sheeting and gel are widely used, though their mechanism is unclear — it may relate to hydration and occlusion. Pressure therapy is another option. Intralesional 5-fluorouracil (50 mg/mL) is antiproliferative and often combined with triamcinolone for synergistic benefit. Additional options include cryotherapy, pulsed dye laser (targeting scar vascularity), and surgical excision — though excision alone carries a 50 to 80 percent recurrence rate for keloids without adjuvant therapy. Adjuvant radiation delivered within 24 to 48 hours of excision reduces keloid recurrence to 10 to 20 percent. Emerging therapies include bleomycin injection, verapamil, and botulinum toxin (which reduces wound tension).

Factors Impairing Wound Healing

Systemic Factors

Several systemic conditions impair wound healing. Diabetes mellitus compromises neutrophil function and causes neuropathy, microangiopathy, and a persistent M1 macrophage phenotype that prevents progression to the repair phase. Peripheral vascular disease limits oxygen and nutrient delivery. Malnutrition — particularly deficiencies in protein, vitamin C, zinc, and iron — impairs the cellular machinery of healing. Immunosuppression from corticosteroids or chemotherapy slows all phases. Smoking causes vasoconstriction, reduces oxygen delivery, and impairs neutrophil function. Advanced age slows cellular responses and reduces growth factor production.

Local Factors

Local impediments include infection (particularly biofilm formation by S. aureus and Pseudomonas, which prevents wound progression), foreign bodies, ischemia and hypoxia, excessive moisture (maceration) or desiccation, repeated trauma, and radiation damage.

<image>Sequential four-panel illustration of wound healing phases: (1) Hemostasis showing platelet plug formation and fibrin clot with trapped growth factors; (2) Inflammation showing neutrophil infiltration followed by macrophages phagocytosing debris; (3) Proliferation showing granulation tissue with new blood vessels, fibroblasts depositing collagen, myofibroblasts contracting the wound, and keratinocytes migrating across the wound bed; (4) Remodeling showing collagen reorganization and scar maturation. Include a timeline bar below showing the overlapping nature of each phase.</image>

<image>Comparative histopathology illustration of normal mature scar versus hypertrophic scar versus keloid. Normal scar shows organized collagen parallel to the surface. Hypertrophic scar shows nodular myofibroblast aggregates with collagen bundles parallel to the surface but staying within wound boundaries. Keloid shows thick, disorganized "keloidal" collagen bundles extending beyond the original wound margins, increased mucin deposition, and absence of myofibroblast nodules. Label distinguishing features in each panel.</image>

<image>Diagram showing myofibroblast differentiation and its role in wound contraction and scarring. Show the transition from fibroblast to proto-myofibroblast to differentiated myofibroblast under the influence of TGF-beta1, mechanical tension, and ED-A fibronectin. Depict alpha-SMA expression in stress fibers generating contractile force. Show the normal outcome (apoptosis after wound closure) versus pathologic outcome (persistent activation leading to excessive collagen deposition and keloid formation).</image>

Clinical Pearls

Macrophages are the single most important cell in wound healing; their transition from M1 (pro-inflammatory) to M2 (pro-repair) phenotype is essential for wound progression. Wounds achieve a maximum of approximately 80 percent of the tensile strength of unwounded skin, even after years of remodeling. Moist wound healing with occlusive dressings accelerates re-epithelialization by up to 50 percent compared to air-exposed wounds. Keloids extend beyond wound margins and do not regress, while hypertrophic scars stay within wound margins and often improve over 1 to 2 years. The sternum, deltoid, and ear lobes are high-risk sites for keloid formation, whereas pre-auricular and eyelid wounds rarely form keloids. Intralesional triamcinolone is first-line for keloids; combining it with 5-FU improves efficacy while reducing steroid side effects such as atrophy and telangiectasia. In chronic wounds (diabetic, venous), elevated MMP activity destroys newly deposited matrix faster than it can be produced — this is the rationale for MMP-modulating dressings. Vitamin C deficiency (scurvy) impairs hydroxylation of proline and lysine residues in collagen, leading to defective collagen synthesis and poor wound healing.

References

• Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314-321.
• Berman B, et al. Keloids and hypertrophic scars: pathophysiology, classification, and treatment. Dermatol Surg. 2017;43(Suppl 1):S3-S18.
• Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6.
• Rodrigues M, et al. Wound healing: a cellular perspective. Physiol Rev. 2019;99(1):665-706.
• Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738-746.

Read this lecture as Markdown