Wound Bed Preparation: The Science Behind the Removal of Barriers to Healing

Stuart Enoch, MBBS, MRCSEd, MRCS (Eng), Keith Harding, MB ChB, MRCGP, FRCS


Wounds. 2003;15(7) 

In This Article

Cellular Dysfunction and Biochemical Imbalance

The process of normal wound healing involves the complex interaction between several cell types, ECM molecules, and soluble mediators, such as growth factors, cytokines, and MMPs. However, in chronic wounds, the ordered cellular and molecular processes that are present in acute wounds are disrupted and incorrectly regulated. These differences, termed cellular dysfunction and biochemical imbalance, respectively, are likely to be of great importance in explaining why the healing process in chronic wounds is impaired.

Fibroblasts play a pivotal and multifaceted role in wound healing ranging from the synthesis of ECM to mediating its remodeling by cytokine and metalloproteinase activity.[142] Fibronectin, synthesized by fibroblasts, promotes keratinocyte migration, and this glycoprotein was shown to be completely degraded in chronic wounds.[27,138] Grinnell and Zhu[27] also demonstrated a correlation between the degradation of fibronectin and the increased levels of the serine protease, neutrophil elastase. Moreover, naturally occurring protease inhibitors, such as a2-macroglobulin and a1-proteinase inhibitor, were shown to be degraded and nonfunctional in chronic wound fluid.[27,64] In summary, degradation of proteins involved in ECM synthesis and increased protease levels, due in part to degradation of their inhibitors, also contribute to delayed wound healing.

Degradation of adhesion proteins in the wound bed may also be an important factor in the inability of chronic wounds to close. When cell adhesion assays were performed on varying chronic venous ulcers, the cell adhesion-promoting activity was significantly reduced, and this correlated with degraded vitronectin and fibronectin.[143] These data may explain why chronic wounds become "stuck" in the inflammatory phase and why impaired keratinocyte migration is seen in the proliferative phase of repair.

Cells within the chronic wound bed may exhibit altered phenotypes, which could contribute to the failure of a wound to heal. Levels of MMPs and their endogenous inhibitors TIMPs are expressed differently in chronic and acute wounds. In stromal cells, MMP-13 is abundantly expressed in chronic wounds but to a much lesser extent in acute wounds. MMP-13 is involved in the degradation of type I and type III collagen in the wound bed, and deregulated expression of this MMP may play a role in the pathogenesis of chronic ulcers.[144] Furthermore, TIMP-3 expression levels were absent from the epidermis of chronic venous ulcers, even though it was abundantly expressed in acute wounds.[145]

Another element pertinent to chronic wounds is the proliferation rate of cells together with their altered morphology.[26,146] In an actively healing wound, fibroblasts are highly proliferative, and if they lose this proliferative capacity, for example by becoming senescent, this would have major implications for wound repair. Fibroblasts taken from the edges of chronic venous leg ulcers are less proliferative than fibroblasts taken from normal healthy skin.[146] In addition, fibroblasts from the wound edges were larger and responded poorly to growth factors.[30,146] This suggests that cellular senescence is related to a delay in healing.[147] Since fibroblasts from chronic wounds display signs of senescence,[30,148] this may explain why these cells show a reduced response to PDGF-b and TGF-b in vitro.[29,149] If fibroblasts within chronic wounds have been altered and become senescent, the addition of exogenously applied growth factors may not be sufficient to stimulate proliferation and wound repair.