Wound Bed Preparation: Future Approaches

W ith acceptance of the concept wound bed preparation comes the understanding that many different methods and procedures that were being used for the treatment of chronic wounds now can be incorporated in a unified approach. Reviewing the options for wound bed preparation allows clinicians to consider what lies beyond this concept and what must be considered in years to come in terms of therapeutic modalities based on solid scientific concepts. The Concept The history of wound bed preparation can be traced to the late 1990s, when certain advanced therapeutic products were receiving regulatory approval in the US and making their way into clinicians' hands. Advanced therapies such as topically applied platelet-derived growth factor (PDGF) and bioengineered skin were clearly a step beyond what previously had been been available to treat difficult-to-heal wounds. Product approval by the Food and Drug Administration was seen as the beginning of a new era in the field of wound care. However, despite substantial educational efforts by the companies who marketed these products, two kinds of problems quickly appeared. First, the wound care (eg, treatment of infection, the debridement process, and the compression or offloading regimen) that had been practiced in the clinical trials of these therapeutic agents was more thorough than what was normally available outside the experimental situation. Hence, the results from using these therapies in general practice were not as good as expected. Second, which is very much related to the first, clinicians began to realize that growth factors, bioengineered skin, or other advanced products would not help patients if wound care was not first maximized. Because the wound bed, including appearance, is the most obvious marker of whether proper wound care is being delivered, the term wound bed preparation was born. The concept was formalized in a 2000 editorial on the subject.1 The overall goal of wound bed preparation is to take all required steps to optimize the wound bed and ensure unimpeded wound repair; debridement is only one part. Eliminating increased bacterial burden, removing edema, providing appropriate compression and offloading, and paying close attention to other local and systemic factors also are important for wound repair. Therefore, wound bed preparation is an overall program of wound care, especially designed for chronic wounds. An additional value of the creating the term wound bed preparation is that it has led to independence of chronic wounds from models of acute injury. Before the concept of wound bed preparation, clinicians always considered how to apply knowledge of acute wounds to chronic wounds. However, the chronic wound is now known to be a separate clinico-pathophysiologic entity, deserving of its unique studies and approaches, and hopefully leading to better products and approaches to treatment. Wound bed preparation is, in some ways, still under construction (see Figure 1). As understanding progresses, clinicians are becoming more cognizant of the complexities inherent in the fact that some chronic wounds exhibit severely impaired healing or simply do not heal. While infection is a major concern, correction of cellular and biochemical abnormalities that eventually become part of wound bed preparation also need to be addressed. Cellular and Biochemical Abnormalities in Chronic Wounds One of the barriers to healing and proper wound bed preparation consists of the cellular abnormalities within the wound (see Figure 1). In chronic wounds, the actual "wound" is larger than what clinicians recognize - eg, venous ulcers are generally surrounded by a fibrotic process called lipodermatosclerosis, which is associated with greater difficulty in healing.2 A callus is almost always present around diabetic ulcers and probably plays a role in the pathogenesis by causing additional pressure.3,4 Tissue beneath and around ulcers is also affected by the fundamental abnormality leading to the ulceration, whether venous hypertension or pressure. However, as the wound became chronic and failed to heal, other abnormalities may have occurred independently of the underlying physiological problem. Inflammation may have set in due, in part, to chronic bacterial colonization. Also, as the resident cells (ie, fibroblasts, keratinocytes, and endothelial cells) go through several cycles of replication, they may have reached their proliferation limit and become senescent. Aging of the organisms may lead to decreased wound repair.5-7 In the experimental situation, fibroblasts cultured from older animals exhibited decreased proliferative potential in vitro.8 However, the consideration here is whether, in vivo, the resident cells of the wound are senescent and if that plays a role in impaired healing. Indirect evidence suggests decreased proliferative potential of fibroblasts from diabetic9-11 and venous12-15 ulcer fibroblasts compared to normal control fibroblasts. The reasons remain unclear. As mentioned earlier, repeated attempts at wound repair may have led to proliferative arrest and senescence of involved cells. However, the emerging literature presents evidence that telomere shortening or abnormalities may be involved.16-20 Perhaps the closest link yet to evidence that senescence may lead to impaired healing is a study where the diminished replicative potential of venous ulcer fibroblasts proved to be directly correlated to increased difficulty in healing.21 Cellular Unresponsiveness to Growth Factors in Chronic Wounds Growth factors are potent biological agents with a variety of effects in vitro and in vivo. They not only affect growth (and not always) but also play an important role in cell migration, differentiation, and apoptosis.22 Considerable progress was made when topically applied PDGF was first shown to be effective in accelerating the healing of diabetic neuropathic foot ulcers.4,23,24 Over the years, promising results have been obtained using a variety of topically applied growth factors for the treatment of different types of chronic wounds. Since the first report of the use of a recombinant growth factor in humans,25 many published clinical trials have shown encouraging results in this area.26,27 However, the results have not been of the magnitude expected for biological agents that are so powerful in vitro. A number of explanations have been proposed for this discrepancy between in vitro and in vivo effects. The dosage and formulations of the growth factors may not have been correct or ideal.28 Chronic wounds have a maldistribution or excessive amounts of tissue metalloproteinases (MMPs) which may break down growth factors.29 It also has been hypothesized that growth factors in wounds are "trapped" by the extravasated plasma components (eg, alpha-2-macroglobulin) and fibrin.30,31 Ultimately, however, the future of topically applied growth factors in the treatment of wounds is in question.32 Another possible explanation for the less-than-expected effectiveness of growth factors can be found in emerging evidence suggesting that resident cells in chronic wounds are unresponsive to the action of certain cytokines and growth factors. For example, fibroblasts cultured from venous ulcers are unresponsive to the action of transforming growth factor-beta 1 (TGF-beta 1)33 and PDGF.12 Also, venous ulcer fibroblasts respond to certain cytokines but not others.15 Similarly, fibroblasts from diabetic foot ulcers have shown an unusual response to single growth factors.34 Some researchers35 have suggested that combinations of growth factors were required to stimulate diabetic ulcer fibroblasts.34 For reasons that are not yet clear, some chronic wound fibroblasts exhibit selective unresponsiveness to the action of certain specific growth factors, at least when the growth factors are used singly and not in combination. Whether senescence is related to the unresponsiveness of ulcer fibroblasts to growth factors is unknown. Also unclear is whether other resident cells within wounds are affected to the same extent. Fibroblasts are relatively easy to culture and that may be the reason why the available data on this subject are mostly restricted to this cell type at this time. In the context of wound bed preparation, how senescence of cells, their possible unresponsiveness to growth factors, and impaired healing are related becomes an important question. The answer lies in the fact that chronic wounds may end up with a population of resident cells with diminished proliferative potential and unable to respond to certain signals (cellular burden).1 Controversy exists regarding whether senescent cells are more resistant to apoptosis.36-38 However, certain manipulations (ie, adding ceramide or tumor necrosis factor-alpha [TNF-alpha]) can induce senescent fibroblasts to undergo apoptosis.39 The latter observation suggests possibilities exist, other than frank removal of cells (eg, debridement, eliminating the cells within wounds that have become phenotypically abnormal). Also, some of the therapeutic agents presently available or under investigation (ie, bioengineered skin or stem cell therapy) may work by introducing cells into the chronic wound that, at least for a period of time, may alter the behavior of the resident cells. The constructs do not remain in the wound for more than a few weeks, at least for bioengineered skin,40 but that might be long enough to jump-start the healing process. As for the unresponsiveness to growth factors in resident cells in chronic wounds, it is possible that the number of receptors for growth factors may be diminished. Venous ulcer fibroblasts may have decreased expression of TGF-beta 1 receptors.33 Interestingly, receptors for TGF-beta 1 are decreased in the hypoxic environment typical of chronic wounds.41,42 Conclusion Clinicians now have better ways to address important questions regarding the role of bacteria in impaired healing and have improved approaches to the "de-colonization" of wounds. Although attention must be paid to individual components of wound bed preparation, clinicians must not lose sight of the big picture. Figure 1 is a reminder that wound bed preparation remains under "construction"; one of the arrows points to a black box, suggesting that other parameters and obstacles may not, as yet, be recognized. Wound bed preparation is more than debridement, more than control of infection, and more than compression therapy and edema removal. In the future, wound bed preparation will include rational ways to address what seem to be cellular and biochemical problems within the wound.

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