EUROPEAN  TISSUE  REPAIR  SOCIETY

A Rethink of the Complexity of Chronic Wounds
– Implications for Treatment
W. Y. J. Chen, A. A. Rogers, M. Walker, M. Waring, P. G. Bowler and S. M. Bishop
Wound Healing Research Institute, ConvaTec Global Development Centre, Deeside, U.K.

Introduction

Winter’s publications in Nature, 40 years ago,1–3 have been credited for starting the modern wound healing shift towards moist healing. Winter documented the cell biology of faster epithelialisation on swine and human wounds under moist versus dry conditions. His work has been replicated and documented by many researchers on deep and shallow wounds, reporting greater benefits of occlusive versus traditional permeable dressings4.

Much work has been done to characterise wound healing in moist conditions, particularly the constituents of wound exudate. In general, acute wound exudate is rich in growth factors.5–7 These are beneficial to acute wound healing in that they promote growth and migration of fibroblasts, endothelial cells and keratinocytes. The benefits of moist wound healing may, at least in part, be explained by the retention of growth factors within the wound environment. However, occlusive dressings when applied to highly exuding wounds can lead to excessive fluid retention. This can result in poor healing and maceration of surrounding skin.8

Pathological Nature of Chronic Wounds
The meaning of ‘moist healing environment’ is clearly more complex than just the management of moisture level in the wound such that the wound does not dry out. In chronic wounds, excessive wound exudate can invariably cause maceration.8 Yet most cell cultures are performed with cells in contact with copious amounts of fluid in the form of cell culture medium. The work using wound chambers to maintain the wound surface in contact with free fluid clearly showed that healing was not compromised and indeed may be enhanced by this system.9,10

Figure 1: Example of hyperproliferative activities in chronic wounds. Immunohistochemical staining of a representative biopsy sample from the periphery of a pressure ulcer with anti-collagen IV antibodies. Thickened epidermal and dermal layers, a very convoluted epidermal-dermal junction (E-D) and glomerular appearance of the blood vessels (BV) are all indicative of chronic inflammation of the skin and associated hyperproliferative activities.

Instead, it appears that the content of the wound exudate is of primary importance in determining whether the wound would heal or not. The above cited work involved synthetic tissue culture media rich in nutrient. These are very different from exudate from chronic wounds which has been shown to be corrosive in nature by work in many laboratories.11–16 It is now clear that most of the common chronic wounds, such as venous ulcers, diabetic foot ulcers and pressure ulcers, are chronically inflamed,17–22 and that the chronic inflammation contributes to the corrosive nature of chronic wound exudate.

While inflammation is responsible for elaboration of cytokines and growth factors that subsequently trigger the healing process, leukocytes are also potent sources of tissue degrading enzymes and enzymes that contribute to generation of reactive oxygen metabolites. Therefore, on one hand, prolonged inflammation can lead to hyperpro-liferation. This can be seen in the epidermis and dermis at the wound periphery (Fig. 1), and the fibrosis of the blood vessels, previously thought of as ‘fibrin cuffs’ (Fig. 2). On the other hand, tissue degrading enzymes produced within the chronic wound, primarily the leukocytes, are accumulated in the wound tissue (Fig. 3) and are also carried in the exudate. Consequently, chronic wound tissue and exudate generally contains large amounts of tissue degrading enzymes, including metalloproteinases, elastases and others.11–16,23–25 Acting in concert, they are capable of degrading every known constituent of soft connective tissue. Chronic wound exudate can therefore be regarded as a wounding agent in its own right by virtue of its tissue destruction capability (Table 1).

The simultaneous presence of fibroproliferative and tissue destruction activities indicate the possibility that chronic wounds are far from static from the point of view of biological activities (Fig. 4). The wounds only appear static because the fibroproliferative efforts are undone by the tissue destruction activities. While past efforts of progressing chronic wounds to healing have been focussed mostly on stimulation of fibroproliferative activities, currently available study data suggest an alternative approach – that of inhibiting the tissue degradation activities.

New Implications on Treatment Approaches

It is possible to inhibit tissue degradation activities by application of pharmacological inhibitors to these tissue degradation agents. However, the search for pharmacological agents is a very expensive undertaking beyond the capability of many apart from the major pharmaceutical companies. To date there has not been success in developing clinically efficacious agents for wound applications.

An alternative to the direct inhibition approach is to investigate whether dressing materials can absorb and sequester these harmful constituents in chronic wound exudate. While sequestration does not inhibit their action, by removing them from the immediate wound environment, their harmful effects may be contained.
The understanding that chronic wound exudate is a ‘corrosive’ biological fluid adds another dimension to fluid handling attributes we consider in the design of wound dressings. While the fluid absorption capacity is undoubtedly an important attribute, equally important considerations must be placed on the additional attributes of fluid retention and lateral transmission of fluid.26 A dressing must be able to absorb and retain the fluid under compression, in order that the absorbed fluid (and its contents) cannot be expelled out of the dressing mass following a change in applied pressure. Lateral transmission of fluid within the dressing must also be minimised, in order to minimise the transmission of wound exudate and its corrosive contents to the surrounding skin. It is not ideal to rely on a dressing system which is purely absorbent but not retentive, or a dressing which does not retain fluid from leakage onto the surrounding skin.

In infected wounds, or wounds with heavy microbial contamination, the exudate may also contain tissue degrading enzymes as well as other products, such as bacterial toxins, from these foreign organisms. These may also contribute to cell and tissue damage directly and indirectly by eliciting and/or maintaining a host inflammatory response.27 By the same principle of dressing materials that can absorb and retain wound exudate and its proteolytic contents, likewise there is a possibility that harmful substances from microbial organisms may also be sequestered in such materials and therefore reducing their harmful effects on the direct wound environment. It is also possible to take the sequestration of harmful substances further by direct sequestration of microorganisms in the dressing materials, as demonstrated previously in some dressing materials.28

Another consequence of leukocyte accumulation in chronic wound tissue is the generation of reactive oxygen metabolites.29 Myeloperoxidase is abundant in leukocytes (Fig. 5) and they are responsible for generation of hypo-halides which are very potent degraders of connective tissue. Also very damaging to tissue are the hydroxyl radicals produced via the Fenton and Haber-Weiss reactions. Although the primary functions of these reactive oxygen metabolites are for combatting infection as part of the body’s natural defence, if over-produced, they are capable of breaking down connective tissue and other tissue components in a non-specific manner30 (Table 2).

They can also contribute to activation of proteinases, many of which are initially secreted by body cells as inactive proenzymes and require activation in order to become functionally pro-teolytic. There is a possibility that dressing materials may contribute to reducing the damage caused by reactive oxygen metabolites. It is known that hyaluronan, a normal constituent of skin connective tissue is a scavenger of oxygen free radicals and recently it has been demonstrated that a benzyl derivative of hyaluronan which is used as wound care products is also a scavenger of certain oxygen free radicals.31–32

Figure 4: Picture of a venous ulcer illustrating the various pathological features
of the ulcer and the peripheral tissue.

Conclusions

It has been over forty years since the beginning of the modern wound healing shift towards moist healing. In the intervening years we have in particular come to a much better understanding of the pathological mechanisms that contribute to the major chronic wounds aetiologies. The understanding that exudate from chronic wounds are generally corrosive in nature indicate that a moist wound healing environment is not as simple as just retaining moisture in the wound so that it does not dry out. By careful consideration of how dressing materials interact with both the water and other contents of wound exudate, we are beginning to be able to effect a moist healing environment that not just keeps the wound from drying out. The content of the wound exudate, in particular the harmful substances generated in chronic wounds, may also be efficiently removed and kept away from the immediate wound environment, therefore reducing the tissue destruction burden of the chronic wound.

Figure 5: Staining of biopsies from a venous ulcer (A), pressure ulcer (B), and a 3-week old acute wound (C) for endogenous peroxidase activities, showing high level expression of reactive oxygen metabolite generating enzymes in the chronic wound but not in the acute wound.

Reference

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Address correspondence:

W. Y. John Chen PhD
Principal Scientist
Wound Healing Research Institute
ConvaTec Global Development Centre
First Avenue
Deeside Industrial Park
Flintshire UK
CH5 2NU

Tel: +44 (0)1244 584300
Fax: +44 (0)1244 584311

E-mail: john.chen@bms.com

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