Growth Factors in Wound Healing

Cutaneous wound healing is an orchestra of cell division, cell migration, and the production and degradation of extracellular matrix. For each stage of the process, large number of growth factors act as triggers, modulators, and terminators. Our basic understanding of wound healing comes from pathological descriptions of cellular migration and the appearance and disappearance of various types of extracellular matrices. More recently, the increasing availability of knockout animals and specific protein antagonists has allowed the elucidation of critical elements in the healing of cutaneous wounds.

PDGF was the first factor described to have an effect on wound healing. It induces neutrophil chemotaxis, fibroblast proliferation, and extracellular matrix production. Released in large quantities by platelets within the wound, it has been shown to be absent during the dysfunctional healing of diabetic wounds. Preclinical studies using PDGF on wounds have been mixed, but on average encouraging [2]. PDGF-treated wounds have shown a consistent increase in granulation tissue formation. Its effects on epithelialization and wound contraction have, however, been variable and some-

Table I Table of Platelet-Derived Factors and Their Presumed Role in Wound Healing.

Growth factor

Effects

PDGF

Neutrophil chemotaxis, fibroblast proliferation,

extracellular matrix production

EGF

Keratinocyte proliferation and migration

TGF-b

Fibroblast chemotaxis, angiogenesis, extracellular

matrix production

Basic FGF

Angiogenesis

Acidic FGF

Angiogenesis

PF-4

Antiangiogenic

times nonreproducible. In a guinea pig partial thickness skin wound model, the application of PDGF showed no effects on either epithelialization or contraction. However, there was a greater amount of granulation tissue compared to vehicle alone. Similar results were obtained using a pig full-thickness skin wound model. Only in rabbit ear and diabetic mice wound models did PDGF increase the amount of granulation tissue as well as the extent of epithelialization. PDGF was found to have a dramatic effect in enhancing wound closure as well as the amount of fibroblasts and capillaries in the wound. The combination of these studies led to the testing of PDGF in a series of clinical trials, which ultimately resulted in its approval by the U.S. Food and Drug Administration (FDA) for the treatment of chronic neuropathic ulcers in diabetic patients. In addition to PDGF, platelets also produce many other growth factors (Table I). Many of them have also been tested in the context of wound healing.

Despite the seemingly central role that platelets and their reservoir of growth factors play in wound healing, the addition of a neutralizing anti-platelet antibody to mice has surprisingly led to no change in the wound healing rates, but significantly increased the number of macrophages and T cells present in the wound [3]. This is just a reminder that our understanding of wound healing is still rudimentary and much work still needs to be done.

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