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

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

Disclosures

Wounds. 2003;15(7) 

In This Article

The Chronic Wound

A chronic wound can be defined as a wound in which the normal process of healing has been disrupted at one or more points in the phases of hemostasis, inflammation, proliferation, and remodeling.[15] Chronic wounds have several distinctive features ( Table 1 ) and in contrast to acute wounds, they fail to heal in a timely and orderly manner. Chronic wounds are often regarded as being "stuck" in the inflammatory or proliferative phases of wound healing. Since growth factors, cytokines, and proteases all play important roles in each phase of the wound healing process, alterations in one or more components of these factors may account for the impaired healing observed in chronic wounds. Analyses of the molecular and cellular environments of acute and chronic wounds have revealed several important differences.

The cytokine environment of chronic wounds is substantially altered, and the levels of IL-1a, a pro-inflammatory cytokine, have been shown to be elevated in chronic wounds.[16] Trengove, et al.,[17] found that the levels of other pro-inflammatory cytokines (IL-1b and TNF-a), along with IL-1a, were significantly elevated (p = 0.01 for IL-1a, p = 0.005 for IL-1b, and p = 0.013 for TNF-a) in nonhealing wound fluids from leg ulcers compared to those from healing wounds. Moreover, the levels of these cytokines decreased substantially as the chronic wound healed, indicating a significant correlation between nonhealing wounds and increased levels of pro-inflammatory cytokines. They also found that there was a statistically significant (p = 0.002) decrease in the mitogenic activity in nonhealing wounds compared to healing wounds. Similarly, when chronic wound fluid is added to cultures of fibroblasts, keratinocytes, or vascular endothelial cells, it fails to stimulate DNA synthesis in these cells, which is in direct contrast to the DNA-synthesizing ability of acute wound fluid.[18,19]

Oxygen-derived free radicals have been implicated in the causation of venous ulceration and their persistence. Scavenging such radicals using antioxidants expedites healing of venous ulcers.[20] Nitric oxide (NO) is known to combine with hydroxyl free radicals forming peroxynitrate, a potent free radical, which causes tissue destruction. NO overexpression in chronic venous ulcers may be involved directly or indirectly (through production of peroxynitrate) in the pathogenesis and delayed healing of chronic venous ulcers through its effects on vasculature, inflammation, and collagen deposition.[21] In a study of 44 patients with chronic venous disease, Howlander and Coleridge Smith[22] observed that the total plasma NO levels were elevated in patients with severe skin damage. Similarly, Jude, et al.,[23] found that diabetic patients with recurrent neuropathic and neuroischemic foot ulcers had significantly higher plasma NO levels compared to patients with nonrecurrent foot ulcers (46.9 +/- 6.3 microm/L versus 30.2 +/-2.4 microm/L respectively, p < 0.01).

Another important biochemical difference in chronic wounds is the level of protease activity, which is considerably higher than in acute wounds. In the phases of normal wound healing, the production and activity of proteases are tightly regulated, but this regulation appears to be disrupted in chronic wounds. For instance, the levels of various MMPs and serine proteases are markedly increased in fluids from chronic wounds. Levels of MMP-1, -2, and -9 have been shown to be elevated in fluid derived from pressure ulcers and venous leg ulcers compared with acute mastectomy wounds.[24,25] Furthermore, during granulation tissue formation in chronic pressure ulcers, data indicate a decrease in levels of MMPs and an increase in the levels of their inhibitors, TIMPs.[26] Other proteases, such as neutrophil elastase, were also observed to be significantly higher in chronic wounds.[27] Increased levels of serine proteases have been linked to the degradation of fibronectin, which is an essential protein involved in the remodeling of ECM and is necessary for granulation tissue formation during the remodeling phase. Moreover, in addition to being implicated in degrading essential ECM factors, in-vitro studies show that proteases in chronic wounds also degrade growth factors.[24,28]

A further aspect of chronic wounds that is distinct from acute wounds is the inability of cells to respond correctly to molecular regulators. Research has demonstrated that fibroblasts in skin ulcers that have failed to heal may not be as capable of responding to growth factors, such as PDGF and TGF.[29] Moreover, cells from venous ulcers that had been present for longer than three years grew more slowly, and some cells became senescent.[30,31]

The physiological implications of all these studies are that the altered molecular and cellular environment of chronic wounds contributes to the failure of these wounds to heal. This aberration of the healing process can compromise the overall anatomical and functional integrity of the wound. Moreover, most chronic wounds are complicated by an underlying physiological abnormality, such as diabetes, vascular insufficiency, or ischemia, which may contribute further to the failure of wound healing. The key to encouraging chronic wounds to heal more quickly is the rapid correction of the underlying physiological problems together with adequate preparation of the wound bed. The healing process of a chronic wound will be significantly hindered if the underlying pathology is not considered along with local barriers to healing.[32,33,34]

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