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

Exudate Levels in Chronic Wounds

Several studies indicate that chronic wounds become "stuck" in the inflammatory phase of the wound healing process.[85,132,133] Due to their inflammatory state, chronic wounds often produce copious amounts of exudate, and this may be increased further in wounds that are heavily colonized or infected by bacteria. The amount of fluid produced by a chronic wound can be a barrier to healing.[18,33,36,134] Furthermore, it is not just the amount of exudate produced by a chronic wound that is important but also an understanding of the altered molecular and biochemical changes in the fluid. Hence, studies comparing acute and chronic wound fluid have focused on analyzing the molecular and biochemical environment in order to understand more about chronic ulcers.

There has been some interest in investigating the effects of chronic wound fluid on the proliferation of the various cell types involved in wound healing. Bucalo and colleagues[18] collected wound exudate from the venous ulcers of six patients in order to investigate the effects of chronic wound fluid on the proliferation of human dermal fibroblasts, microvascular endothelial cells, and keratinocytes in culture. The results of this study showed chronic wound fluid inhibited or failed to stimulate the proliferation of dermal fibroblasts, endothelial cells, and keratinocytes. The study also found that the chronic wound fluid was cytotoxic and that this may have contributed to the effect on cell proliferation. In contrast, fluid from acute wounds has been found to stimulate fibroblast proliferation, and this is likely to be mediated in part by platelet-derived growth factor-like peptides.[135]

Other studies have focused on analyzing how pro-inflammatory cytokines and growth factors can contribute to delayed wound healing. Clinical research comparing exudate from acute mastectomy wounds and exudate from chronic wounds demonstrated that the chronic wound fluid had an imbalance of the pro-inflammatory cytokines IL-1b, TNF-a, and IL-6.[133] The high levels of pro-inflammatory cytokines found in this exudate are responsible for promoting a chronic inflammatory response. Growth factors from acute and chronic wound fluid also show considerable variability. For example, chronic wound fluid was shown to contain lower levels of EGF and higher levels of TGF-a, TGF-b, and IGF-1 compared with fluids from acute wounds.[133]

Similar studies have confirmed that other growth factors, such as TGF-b1 and PDGF, are degraded by proteases present in chronic wound exudate.[24,28] Moreover, the degradation of these growth factors was shown to occur when serine proteases were not inhibited, suggesting that growth factor degradation as a result of protease action is more likely to be due to serine proteases, such as neutrophil elastase, rather than MMPs. Significantly, the reduced activity of proteases present in chronic wound ulcers was directly correlated with improved healing. In contrast to the above, another inhibitor study examining protease activity in chronic wounds indicated that MMPs rather than serine proteases are crucial in delaying wound repair.[136] Likewise, Weckroth, et al.,[137] found MMPs (gelatinase and collagenase) in chronic leg ulcer exudates and not serine proteases (elastase and cathepsin G). The reported differences observed in the above studies could be due to the heterogeneity of the patients involved in the studies or variations in the components of the chronic wound fluid from wounds at different stages of the healing process.

Chronic wounds of different etiologies may display varied levels of protease activity depending on the underlying pathophysiology. Disordered proteolytic activity is almost certainly associated with the failure of chronic wounds to heal.[137,138,139] Whatever the precise mechanisms, collectively published data demonstrate that exudate from chronic wounds contains an imbalance of growth factors and pro-inflammatory cytokines, excessively high levels of proteases, and a decreased level of TIMPs. All these factors will contribute to a delay in wound healing.

Likewise, degradation of angiogenic mediators (cytokines) might be an underlying cause in chronic wounds. Drinkwater, et al.,[140] compared wound fluids collected from 16 venous ulcers and acute wound fluids collected from subcutaneous drains in seven patients using VEGF as control. They found that venous ulcer exudates significantly inhibited angiogenesis compared with acute wound (p < 0.002) and VEGF (p = 0.01). Furthermore, among the 16 venous ulcers, five ulcers were slow to heal (> 1 year) and they inhibited angiogenesis more significantly (p = 0.03) than the five rapidly healing (< 3 months) ulcers from the same group.

Analysis of wound exudate presents many technical difficulties, and different studies are unlikely to follow standardized methodologies. This makes it difficult to interpret the data and draw definitive conclusions at this stage.[141] Despite this reservation, it is clear that exudate from chronic wounds is biochemically different to that of acute wounds. However it seems likely that disruption of the subtle balance between the cellular and biochemical components of the microenvironment within a chronic wound may contribute to delayed wound healing.

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