The Proliferative Phase

The proliferative phase entails neoangiogenesis, autolytic debridement of dead tissue, wound matrix formation, and re-epithelialization of the wound by migrating

Proliferative Phase Wound Healing
Figure 3 The macrophage is a key actor in the initial phases of wound repair. The myriad functions of the macrophage within the wound are shown. (From Ref. 7.)

keratinocytes. The recruitment and proliferation of fibroblasts are the hallmark events in the beginning of the proliferative phase. This begins around day 4 and continues for an additional 10 days. The activation of fibroblasts is influenced by many growth factors including FGF, epidermal growth factor (EGF), and PDGF, all of which are released by platelets and macrophages.

Neoangiogenesis occurs through the migration and proliferation of endothelial cells from intact adjacent venules surrounding the wound. This process is heavily mediated by chemotactic growth factors (principally FGF, TNF-a, and EGF) and degrading proteases released previously by macrophages.

The formation of the wound matrix predominately takes place during the proliferative phase and is mediated primarily by fibroblasts (13). The matrix is mainly comprised of fibrin, glycosaminoglycans, laminins, and fibronectin, and provides a scaffold for new migrating cells.

Keratinocyte proliferation also occurs during the proliferative phase and plays a role in establishing a protective barrier against matrix fluid losses and infection. These cells migrate from the free edges of the wound as well as from skin appendages. Keratinocytic growth factor (KGF), (FGF-7), PDGF, EGF, and TGF-ß influence their activation. As a result of keratinocyte proliferation and migration, most wounds are re-epithelialized within 7-10 days.

Although extensive research has been devoted to exploring the mediators involved in turning on the proliferative phase, little is known about the signals that downregulate this phase and herald the remodeling and maturation phase.

The Remodeling and Maturation Phase |

The main features involved in the remodeling and maturation phase are the removal of the matrix by proteolytic enzymes and the deposition of collagen from fibroblasts. |

This phase begins around the eighth day following injury and can continue for up to

2 years during which time collagen is continually degraded and synthesized in a §

balanced manner.

Plastic Surgery Wound Healing Phases
Figure 4 Chronology of wound matrix composition and wound breaking strength throughout the phases of wound healing. (From Ref. 7.)

The production and deposition of collagen occur either at the end of the proliferative phase or at the beginning of the remodeling phase. Type III collagen production predominates early, peaks at day 2, and is gone by day 7. Type I collagen predominates later and is present throughout the remodeling and maturation phase for at least 4-6 weeks (Fig. 4) (14). The collagen initially involved in the formation of a scar is thin and arranged parallel to the skin. These fibers gradually thicken and will organize along the stress line of the wound. This transformation is accompanied by increased scar strength. These collagen fibers have been shown to differ biochemically from nonscar collagen with greater hydroxylation and glycosylation of lysine (15). Although the scar undergoes remodeling for up to 2 years, it never becomes as organized or exhibits the tensile strength when compared to uninjured skin.

The tensile strength of the wound increases with time. After 1 week, the scar has 3% tensile strength. After 3 weeks, the wound has a tensile strength of 20% of its initial strength. After 3 months, the scar exhibits approximately 80% of tensile strength and no further increase will occur thereafter.

The mature scar is comprised mainly of type I collagen (80-90%) with some interspersed type III collagen. As mentioned, type III collagen predominates during the proliferative phase and is involved in the production of granulation tissue. Its production tapers off later during this phase. The actual role of type III collagen is unknown. Evidence suggests that it does not contribute to the strength of the wound but may play a causal role in the production and deposition of type I collagen because its presence coincides with the appearance of fibronectin.

Another important aspect of wound healing is the process of wound contraction. The degree of contraction varies depending on whether the wound is closed primarily or allowed to heal by secondary intention. Although the exact mechanism o of wound contracture is not clear, two theories have been proposed. The prevailing theory involves the activation of myofibroblasts. After 4 weeks, cells from the prolif- |

erative phase are believed to undergo apoptosis. This process transforms the wound milieu from a cell-rich environment into a scar that is almost completely acellular. The summation of all remaining contracting myofibroblasts then brings the wound edges @

closer together (16). The second theory maintains that the rearrangement of fibroblasts leads to a reorganization of the matrix and subsequent contraction.

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