Healing chronic wounds

Methods

The material presented in this article has been compiled from the published literature (located by searching Medline, PubMed, Embase, and Zetoc with the search terms “wound healing,” “treatment and venous leg,” “treatment and diabetic foot,” and “treatment and pressure ulcer”) presentations at international meetings, and our own 30 years of clinical experience managing acute and chronic wounds.

The clinical burden of wounds

The management of chronic wounds places an enormous drain on healthcare resources; studies have calculated the cost of wounds to the NHS to be about £1bn a year.¹ In the United Kingdom around 24 000 admissions a year are for patients with diabetic foot ulceration, thereby costing the NHS some £17m.² Foot ulceration is the commonest complication of diabetes that requires hospitalisation, and in the United States management of this problem is estimated to cost $150m a year.³ Venous leg ulceration costs an estimated £400m annually in the United Kingdom,⁴ most of this cost being for dressings and community nurse visits. The cost of treating pressure ulceration, some of which may have been prevented from arising, was estimated to be £300m over 10 years ago.⁵ These sums show only the direct costs and do not reflect the frustration, economic loss, and impaired quality of life experienced by patients with chronic ulcers.

Biology of skin healing

Wound healing involves a complex interaction between epidermal and dermal cells, the extracellular matrix, controlled angiogenesis, and plasma derived proteins—all coordinated by an array of cytokines and growth factors. This dynamic process is classically, but somewhat artificially, divided into three overlapping phases—inflammation, proliferation, and remodelling. Thrombus formation—which requires interaction between endothelial cells, platelets, and coagulation factors—achieves haemostasis after tissue injury. Trapped cells within the clot, predominantly platelets, trigger an inflammatory response by the release of vasodilators and chemoattractants and activation of the complement cascade.⁶

Inflammation—In the early phase of inflammation neutrophils predominate, removing bacteria and other foreign material from the wound by releasing enzymes and by phagocytosis. Later in the inflammatory phase neutrophils reduce in number and are replaced by macrophages. Interest has focused on the role of macrophages in coordinating the transition from inflammation to proliferation through the release of soluble mediators, which include platelet derived growth factor, tumour necrosis factor α, transforming growth factor β, and insulin growth factor 1.⁷

Proliferation—Fibroblasts are the key cells involved in the production of the extracellular matrix. In addition to producing collagen, they produce tenascin, fibronectin, and proteoglycans such as hyaluronic acid. Production of extracellular matrix is seen clinically as formation of granulation tissue. The combination of new tissue and contraction of surrounding tissues is essential for the healing of ulcers.⁸ While new matrix is synthesised, existing matrix in and around the wound margin is degraded by several enzyme systems such as matrix metalloproteinases and plasminogen activators. Research interest has centred on the role of the metalloproteinases, a family of over 14 enzymes with proteolytic activity. The effect of these enzymes is regulated by tissue inhibitors, which are believed to be important in healing by preventing excessive matrix degradation.⁹ While some keratinocytes at the wound edge proliferate, others undergo a marked transformation to enable them to phagocytose debris and migrate across the wound bed. Keratinocyte migration coupled with wound contraction results in re-epithelialisation and wound closure.

Remodelling—Once closure of the wound has been achieved, remodelling of the resulting scar takes places over months or years, with a reduction of both cell content and blood flow in the scar tissue.

This superficial description of wound healing conveys some of the complexity of this biological process and shows the potential for modification in patients' with healing difficulties (fig 1).¹⁰

Why do some wounds fail to heal?

Many factors can impair healing. Local factors include the presence of foreign bodies, tissue maceration, ischaemia, and infection. Systemic factors as diverse as advanced age, malnutrition, diabetes, and renal disease may be important. It is important to quantify the impact of disease states on healing and to target specific treatments to correct the abnormality in individual patients. Although good clinical practice should aim to remove or reduce the impact of these factors, it is not always possible to do so.

In addition to local and systemic factors that impair healing, reduction in tissue growth factors, an imbalance between proteolytic enzymes and their inhibitors, and the presence of senescent cells seem to be particularly important in chronic wounds.

Reduced levels of active growth factors in the wound environment may partly explain why certain wounds fail to heal. Chronic ulcers are known to have reduced levels of platelet derived growth factor, basic fibroblast growth factor, epidermal growth factor, and transforming growth factor β compared with acute wounds.¹¹ It has been suggested that growth factors may become trapped by extracellular matrix molecules¹² or may be degraded by proteases to an excessive degree,¹³ resulting in non-healing.

Imbalance between proteinases and their inhibitors—Excessive proteinase activity in chronic wounds, probably from overexpression of matrix metalloproteins, results in abnormal degradation of the extracellular matrix. Many new treatment strategies are directed at modifying the imbalance—by the topical application of proteinase inhibitors, by inducing the expression of endogenous inhibitors, or by combining proteinase inhibitors with growth factors.¹³

Senescent cells—Dermal fibroblasts have an age related decrease in proliferation potential, called senescence.¹⁴ Fibroblasts in chronic wounds have impaired responsiveness to growth hormone, which may be due to an increased number of senescent cells.¹⁵,¹⁶

New approaches

Future developments

There is a strong theoretical basis to justify the further development and clinical evaluation of proteinase inhibitors as a means of improving healing of chronic ulcers. In the near future gene therapy may allow genes important in healing to be delivered directly into a wound. Interest is presently focused on vascular endothelial growth factor, a key component in the promotion of angiogenesis.³⁰ Another potential treatment lies in the development of skin equivalents from embryonic stem cells. However, the ethical implications of using such technology will first have to be addressed.

Future developments will depend very much on public and professional support for further research. One of the major barriers to effective wound care is the lack of interest and enthusiasm shown by many clinicians for this subject. Provision of an effective service for patients with wound problems requires the skills of many specialties. It is unimportant who is in charge of such patients, but that person must have an interest in the subject and have access to a wide range of interventions, including physical, pharmacological, biological, and surgical options. The real challenge for the future is to select appropriate interventions for each patient. This can be achieved only by developing appropriate clinical services and undertaking more high quality basic and clinical research in this important but neglected subject.