Last updated: Apr 2005
Keywords: Wound healing; chronic wounds; non-healing wounds; biological products; growth factors; skin substitutes; gene therapy; stem cell therapy.
A renaissance in the biology of wound care has resulted in the development of a range of advanced therapeutic products: growth factors, skin substitutes, gene therapy and stem cell therapy.
To make the best use of these advanced products and speed their introduction to standard practice, a more co-ordinated international approach to clinical trials is required and researchers need to broaden their remit to include more complex wound types.
Further research is necessary to increase understanding of the clinical factors that impair healing and develop a rational strategy for the effective use of advanced therapeutic products.
The science of wound healing is advancing rapidly, particularly as a result of new therapeutic approaches such as growth factors, skin substitutes, and gene and stem cell therapy. This article reviews the latest developments in wound healing products and their progress through clinical trials, and suggests ways to maximise their clinical effectiveness and hasten their integration into wider clinical practice.
Clinicians' understanding of and ability to achieve wound healing has increased significantly over the past few years, particularly as a result of advances in molecular biology such as the use of growth factors, the ability to grow cells in vitro and the development of bioengineered tissue . Knowledge of scarring has also increased fundamentally , and the science behind wound healing and the identification of the critical components of the healing process have benefited from technical advances such as transgenic and knock-out animal models . This paper describes the clinical experiences to date of the advanced products being developed as a result of this dynamic process.
Over the past two decades several recombinant growth factors have been tested for their ability to accelerate the healing of chronic wounds. Among others, some promising results have been obtained using epidermal growth factor  and keratinocyte growth factor-2  for venous ulcers, and fibroblast growth factor  and platelet-derived growth factor (PDGF) for pressure ulcers ,.
However, the only topically applied growth factor widely approved for use is PDGF, which randomised controlled clinical trials have shown accelerates the healing of neuropathic diabetic foot ulcers by about 15 percent . Why, then, has a wider range of growth factors not been approved for clinical use and why have the results of clinical trials not lived up to the expectations created by preclinical data?
A number of explanations have been put forward, all of which may apply. It has been suggested that the dosage and mode of delivery for topically applied growth factors may have been incorrect and that growth factors need to be used in combination to achieve a better response . It is also possible that closer attention should have been paid to appropriately preparing the chronic wound before treatment with the growth factor being tested . Notably, there is evidence that the aggressive approach to surgical debridement taken in the initial PDGF trial for diabetic neuropathic ulcers seems to have worked synergistically with the application of the growth factor .
A number of bioengineered skin products or skin equivalents have become available for the treatment of acute and chronic wounds as well as burns. Since the initial use of keratinocyte sheets , several more complex constructs have been developed and tested in human wounds. Skin equivalents may contain living cells, such as fibroblasts or keratinocytes, or both , , while others are made of acellular materials or extracts of living cells . The clinical effect of these constructs is 15-20 percent better than conventional 'control' therapy, but there is debate over what constitutes an appropriate control.
In US trials, saline-soaked gauze and off-loading have been accepted by the Food and Drug Administration as the control. However, methods for off-loading differ between countries and the wound dressings to be used are also subject to controversy. As a result, in spite of notable successes with the use of bioengineered skin to treat diabetic neuropathic foot ulcers, acceptance of this type of therapy by clinicians is not likely to become as widespread as desired.
Bioengineered skin may work by delivering living cells which are known as a 'smart material' because they are capable of adapting to their environment. There is evidence that some of these living constructs are able to release growth factors and cytokines ,, but this cannot yet be interpreted as their mechanism of action. It should be noted that some of these allogeneic constructs do not survive for more than a few weeks when placed in a chronic wound .
The technology to introduce certain genes into wounds by a variety of physical means or biological vectors, including viruses, has existed for some time. These range from ex vivo approaches, where cells are manipulated before being re-introduced into the wound, to more direct in vivo techniques that may rely on a simple injection or the use of a gene gun . Gene therapy as a whole is a very active area of research, with 320 clinical protocols submitted to regulatory bodies around the world since 1999 .
An inability to achieve stable and prolonged expression of a gene product, which has been a problem in the gene therapy treatment of systemic conditions, could be an advantage in the context of non-healing wounds, where only transient expression may be required .
Most work with gene therapy in relation to wounds has been done in experimental animal models , but there are promising indications that certain approaches may work in humans. For example, the introduction of naked plasmid DNA encoding the gene for vascular endothelial growth factor (VEGF) has been reported to enhance healing and angiogenesis in selected patients with ulcers resulting from arterial insufficiency .
The introduction of the gene rather than its product, for example a growth factor, is seen as a less expensive and potentially more efficient delivery method so there is no doubt that research into gene therapy for chronic wounds will increase over the next few years.
Extending the hypothesis that cell therapy may be required to recondition chronic wounds and accelerate their healing leads to the conclusion that stem cells may offer even greater advantages. Pluripotential stem cells (PSCs), the precursors to all more specialised stem cells, are capable of differentiating into a variety of cell types, including fibroblasts, endothelial cells and keratinocytes, all of which are critical cellular components for healing. Although most PSCs are derived from human embryonic research, which is the subject of some controversy, pluripotential mesenchymal stem cells, which are the source of new connective tissue, may be present in bone marrow .
A recent report on an uncontrolled clinical trial suggests that direct application of autologous bone marrow and its cultured cells may accelerate the healing of non-healing chronic wounds . This needs to be confirmed in a larger controlled trial, but when considering the pathophysiological abnormalities present in chronic wounds there is the potential that stem cells may reconstitute dermal, vascular and other components required for optimal healing.
Considerable progress has been made on advanced products in the field of wound healing and a number of new therapeutic approaches are now available. It is hoped that continued advances will come about which, when combined with basic medical and surgical approaches, will accelerate the healing of chronic wounds to an extent that is still not possible with current therapeutic agents.
It is important to note that the treatment of chronic wounds has evolved rapidly over the past few years and it could be argued that the increased number of randomised clinical trials for chronic wounds has improved standard wound care. If this is so, in the future new products will be required to perform much better than the controls to show efficacy.
In addition, to make the best use of advanced products clinical trials will have to include more complex wound types. For example, existing advanced therapeutic products tested on diabetic foot ulcers, such as growth factors and skin equivalents, have focused entirely on neuropathic ulcers of the metatarsal heads. Arterial insufficiency and more complex heel ulcers have been exclusion criteria in these trials. Purely neuropathic ulcers are relatively straightforward and many clinicians believe they can be effectively treated with sound surgical debridement and off-loading. While it might be argued that accelerating the healing of these relatively simple ulcers may prevent complications arising from infection, more needs to be done to show cost-effectiveness to our society as a whole.
A rational strategy for the effective use of advanced products in chronic wound healing is likely to require greater understanding of the clinical factors involved as well as the pathophysiological components that underlie impaired healing.
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