Singer 1999 - NEJM - Cutaneous wound healing

Summary

This review article published in the New England Journal of Medicine in 1999 discusses the complex biological processes involved in cutaneous wound healing. The authors outline the different phases of wound healing - inflammation, new tissue formation, and tissue remodeling.

In the inflammation phase, platelets and inflammatory cells like neutrophils and macrophages migrate to the wound site. These cells release cytokines and growth factors that regulate the wound healing process.

In the new tissue formation phase, new blood vessels form to supply the healing tissue (angiogenesis). Fibroblasts migrate into the wound and produce extracellular matrix proteins like collagen to form new connective tissue (granulation tissue). Epithelial cells also migrate over the wound surface to restore the epithelium (re-epithelialization).

In the tissue remodeling phase, collagen fibers reorganize, myofibroblasts contract the wound, and apoptosis causes a reduction in cells in the maturing scar tissue.

Abnormal wound healing can occur due to underlying medical conditions like diabetes or keloid disorders. The use of cultured skin grafts and growth factors to promote healing are discussed.

This comprehensive review summarizes the important cellular and molecular events in cutaneous wound repair. It would be highly relevant for plastic surgeons focused on understanding biology of wound healing and developing new therapies to optimize healing.

Phases of Wound Healing

Inflammation Phase

• Platelets clot stops bleeding. Platelets release growth factors like PDGF that attract macrophages.

• Neutrophils phagocytose debris and bacteria. Later replaced by macrophages.

• Macrophages release growth factors like PDGF, TGF-β, VEGF that initiate tissue formation. Adherence to matrix activates macrophages.

• Cytokines like TNF-α, IL-1 have pleiotropic effects.

• Macrophages essential for transition from inflammation to repair.

Tissue Formation Phase

Epithelialization

• Epidermal cells migrate over wound bed within hours by dissolving cell junctions and secreting proteases like MMPs.

• Proliferation behind migrating front restores barrier function.

• EGF, TGF-α, KGF likely stimulate migration and proliferation.

• Basement membrane proteins like laminin and collagen IV reappear.

Angiogenesis

• New vessels grow into granulation tissue around day 5 supply oxygen and nutrients.

• FGF, VEGF, TGF-β, PDGF and matrix molecules stimulate angiogenesis.

• Vessels guided by matrix proteins like fibronectin. Endothelial cells secrete proteases like MMPs to facilitate migration.

• Vessels regress later by apoptosis.

Granulation Tissue Formation

• Fibroblasts enter wound by day 4, produce new extracellular matrix like collagen.

• PDGF, TGF-β1 stimulate fibroblast invasion, proliferation, collagen production.

• Fibronectin matrix provides scaffold for fibroblast migration.

• Fibroblasts become less active as collagen accumulates.

Remodeling Phase

• Myofibroblasts contract wound by attaching to collagen matrix. TGF-β1 stimulates contraction.

• Collagen fibers remodel and align over months, increasing tensile strength.

• Cells are removed by apoptosis. Scar remains weaker than normal skin.

Abnormal Wound Healing

• Many factors impair healing in diabetes - ischemia, high glucose, infection, inflammatory changes.

• Excess collagen in keloids due to increased TGF-β1 and fibroblast abnormalities.

Treatment Approaches

• Skin grafts of patient's own cells or cadaver sources can heal wounds. Limitations exist.

• Growth factors like PDGF, FGF speed healing but clinical benefit is limited.

• Fetal wounds heal rapidly with less scarring, insights for new treatments.