Molecular Aspects of Wound Healing and the Rise of Venous Leg Ulceration: Omics Approaches to Enhance Knowledge and Aid Diagnostic Discovery

Abstract

Chronic wounds, in particular venous leg ulcers (VLU), represent a substantial burden for economies, healthcare systems and societies worldwide. This burden is exacerbated by the recalcitrant nature of these wounds, despite best practice, evidence-based care, which substantially reduces the quality of life of patients. Furthermore, co-morbidities such as diabetes and cardiovascular disease within ageing populations further contribute to the increasing prevalence in developed countries. This review provides an overview of the literature concerning the cellular and molecular mechanisms of wound healing and aspects where this process fails, resulting in a chronic wound. VLU may arise from chronic venous disease, which presents with many clinical manifestations and can lead to a highly complex disease state. Efforts to comprehend this state using various omics based approaches have delivered some insight into the underlying biology of chronic wounds and revealed markers of differentiation at the genomic, transcriptomic, proteomic and metabolomic levels. Furthermore, this review outlines the array of analytical tools and approaches that have been utilised for capturing multivariate data at each of these molecular levels. Future developments in spatiotemporal analysis of wounds along with the integration of multiple omics datasets may provide much needed information on the key molecules that drive wound chronicity. Such biomarkers have the potential to be developed into clinically relevant diagnostic tools to aid in personalised wound management.

Figure 1.

Four phases of wound healing including: (i) Haemostasis; (ii) Inflammation; (iii) Proliferation; and (iv) Remodelling. Many events occur during the various stages of the wound healing process and at any stage a wound can stall or become perturbed. Adapted from: , , , .

Figure 2.

The progression of chronic venous disease (CVeD) into venous ulceration. CVeD progresses from mild symptoms (seen in CEAP classes 1–3) to severe pathology (seen in CEAP classes 4–6). There is a clear relationship between sustained venous hypertension and the development of microangiopathy and chronic venous insufficiency, from which more severe disease states such as lipodermatosclerosis and venous ulceration can arise. The fundamental aspect in the progression of venous pathology is the perpetuation of inflammatory processes. The current standard of treatment for patients who experience severe symptoms of CVeD is compression therapy, designed to apply continual pressure on the microvasculature of the lower limb and reduce peripheral hypertension and its implications in inflammation. Although many patients experience relief from such treatment, a large proportion continue to endure severe symptoms of CVeD despite compliance with best practice care.,