Wound Fluid Diagnostics in Diabetic Foot Ulcers

Abstract

Wound fluid seems -at least theoretically- easily accessible and might open a new window to the local wound microenvironment that cannot be evaluated by the analysis of serum or plasma markers. Recently, this strategy has been supported by a first time wound fluid proteome analysis comparing acute and chronic wounds (Eming et al. 2010). Interestingly, there seem to be essential differences with respect to wound fluid protein composition when comparing acute and chronic wounds. The wound fluid proteome of healing tissue is characterised by proteins involved in tissue growth and protection from inflammatory activity, whereas non-healing wounds are characterised by a chronic inflammatory environment primarily consisting of leukocyte proteases and inflammatory mediators (Eming et al. 2010). This is particularly striking since the non-healing state in diabetic foot ulcers has previously been linked to persistent inflammatory activity (Acosta et al. 2008). Thus, the wound fluid of chronic wounds seems to be characterised by an altered wound micro-milieu and may, therefore, provide deeper insights into the causes of delayed wound healing. Tissue repair can be clearly characterised as an ubiquitous process and a wound is more precisely described as a transitional tissue rather than a static tissue. Physiological wound healing can be recognised as continuous change, which might be seen as a dynamic and interactive process resulting in remodelling and tissue restitution. This nature of transitional tissues comes down to the difficulty of obtaining appropriate sample materials. Nevertheless, the classical phases of healing are useful as a broad roadmap of the course of healing, since more precise models and clear landmarks are not available. The historical view on wound healing categorises the healing process in separate phases: starting with acute injury > I. coagulation > II. an early inflammatory phase > III. a late inflammatory phase > IV. a proliferative phase, and > V. remodelling, which ends with tissue restitution (Velnar, Bailey, and Smrkolj 2009). Changes in wound fluid markers, cytokines or cell populations are more suitable for describing the local wound microenvironment than are alterations of systemic markers. The nature of systemic serum-based markers is likely the sum of different effects all over the body. Of course distinct and rather exceptional markers obtained from blood -such as PSA (prostate specific antigen) (Balk, Ko, and Bubley 2003) or troponin- have been proven to be tissue specific (Apple 1999) and can therefore reveal insights into local processes. However, most of the markers found in the bloodstream instead result from systemic alterations rather than from local changes. Wound healing takes place simultaneously at a variety of locations in the body. Therefore, the impact of serum markers on the assessment of the wound microenvironment is questionable so long as there is no systemic affection by septicaemia. In addition, many systemic inflammatory markers are altered in response to a variety of immune mediators which in turn are triggered by inflammatory events somewhere in the body. In this context, the secretion of CRP by the liver upon stimulation by circulatory cytokines such as IL-6 (Pepys and Hirschfield 2003) can be exemplified. In line with this concept, several studies evaluating CRP as a valuable marker of infection in diabetic foot ulcers were judged to be unable to underline its sole effectiveness (Dinh, Snyder, and Veves 2010). Since most systemic markers do not exhibit clear tissue specificity, it might be of special interest to gain insights into the local wound microenvironment by assessing biochemical markers in wound fluid, which in turn might give us a clue about the local processes reflecting the current status of wound healing. In the diabetic foot in particular -which is characterised by delayed healing- local biomarkers facilitating the evaluation of the wound may be of great clinical value. Being able to determine the probability of healing and the risk of infection by assessing markers in wound fluid might have a great impact on clinical practice.