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18 New and Alternative Treatments for Diabetic Foot Ulcers: Hormones and Growth Factors Matthew J. Hardman and Gillian S. Ashcroft
In diabetic patients, the major underlying causal changes that lead to foot ulcers are neuropathy and ischaemia.
Impaired pain sensation often leads to patients inadvertently injuring their foot, whilst changes in local circulation increase the risk of infection and reduce tissue oxygenation.
These and other local changes are responsible for converting an acute wound into a chronic non-healing ulcer.
Current best practice involves wound assessment/classification, offloading of pressure, debridement and control of infection.
However, despite these measures, a significant proportion of wounds fail to heal, ultimately leading to amputation, highlighting the need for new and improved therapies.
This chapter will outline the role of hormones and growth factors during normal and perturbed wound healing.
The current use of hormones and growth factors will be summarised and future prospects for treatments of non-healing diabetic wounds discussed.
INTRODUCTION Under normal circumstances an acute wound heals via a carefully orchestrated series of overlap- ping events, involving multiple cell types.
These complex and diverse local cellular changes are controlled by an equally complex extracellular milieu of locally synthesised cytokines, growth factors and newly deposited extracellular matrix (ECM).
Specific cell types exhibit changes in morphology, function and gene expression, in response to a range of extracellular factors (Table 18.1).
A healing wound represents a delicate balance between matrix deposition and inflammation-associated matrix remodelling, with subtle signals leading to the resolu- tion of inflammation and formation of a mature scar.
Non-healing wounds, such as diabetic ulcers, generally arise from an imbalance between these key processes.
In diabetic patients, changes in the microvasculature circulation predispose to poor oxygenation (ischaemia), whilst high blood glucose levels retard inflammatory cell function leading to increased incidence of
The Foot in Diabetes, 4th Edition. Edited by Andrew J.M. Boulton, Peter R. Cavanagh and Gerry Rayman. C 2006 John Wiley & Sons, Ltd. ISBN: 0-470-01504-7
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INTRODUCTION 215
Table 18.1 Growth factors and cytokines in the wound environment
Growth factor Main cellular source Effects on healing
PDGF family Platelets, macrophages Promotes neutrophil/fibroblast chemotaxis.
Induces myofibroblast differentiation FGF family Fibroblasts, endothelial cells Stimulates angiogenesis.
Broad mitogenic spectrum FGF-7 (KGF) Fibroblasts Promotes keratinocyte chemotaxis EGF Platelets, keratinocytes Mitogenic for keratinocytes and fibroblasts TGF-α Macrophages, keratinocytes Mitogenic for inflammatory cells and fibroblasts TGF-β isoforms Multiple Stimulate fibroblast differentiation and matrix deposition.
Inhibit proliferation VEGF family Keratinocytes, macrophages Stimulates angiogenesis IGF-I Keratinocytes, macrophages Potent mitogenic factor involved in survival of many cell types Activin Keratinocytes, fibroblasts Increases granulation tissue deposition, promotes re-epithelialisation GM-CSF Monocytes, fibroblasts Stimulates neutrophil function and endothelial migration.
Keratinocyte mitogen HGF/SF Fibroblasts, keratinocytes Stimulates keratinocyte migration/MMP production and angiogenesis NGF Keratinocytes, fibroblasts Stimulates nerve growth, keratinocyte proliferation and myofibroblast differentiation MCP-1 Monocytes, keratinocytes Major monocyte/macrophage chemoattractant IL-6 Neutrophils, macrophages Regulates immune cell activation, fibroblast chemotaxis, keratinocyte activation IL-10 Keratinocytes, neutrophils Terminates inflammation, regulates keratinocyte and endothelial cell growth MIF Keratinocytes, macrophages Promotes inflammation and matrix degradation SLPI Macrophages, keratinocytes Inhibits proteases and activates leucocytes to accelerate healing
PDGF, platelet-derived growth factor; FGF-7, fibroblast growth factor 7; KGF, keratinocyte growth factor; EGF, epidermal growth factor; TGF-α, transforming growth factor α; TGF β, transforming growth factor β; VEGF, vascular endothelial growth factor; IGF-I, insulin-like growth factor I; GM-CSF, granulocyte-monocyte colony-stimulating factor; HGF/SF, hepatocyte growth factor/scatter factor; NGF, nerve growth factor; MCP-1, monocyte chemotactic protein 1; IL-6, interleukin 6; IL-10, interleukin 10; MIF, macrophage migration inhibitory factor; SLPI, secretory leucocyte protease inhibitor.
infection.
These changes result in impaired tissue repair, susceptibility to ulcers and a poor long-term prognosis, with wounds that are non-responsive to current treatment often leading to amputation.
Diabetic ulcers are characterised by prolonged and excessive inflammation, in con- junction with impaired inflammatory cell chemotaxis/function, and reduced ECM deposition.
Interestingly, these general changes are common to many types of impaired cutaneous repair, e.g. venous ulcer, and hormonally associated delayed healing.
In diabetic patients changes in the microvasculature circulation predispose to poor oxygenation (ischemia) and high blood glucose levels retard inflammatory cell function leading to increased incidence of infection.
These changes are responsible for converting an acute wound into a chronic non-healing ul- cer.
Current best practice involves wound assessment/classification, offloading of pressure,
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216 TREATMENTS FOR DIABETIC FOOT ULCERS
debridement and control of infection. However, a significant proportion of wounds fail to heal, ultimately leading to amputation, highlighting the need for new and improved therapies. This chapter will outline the role of hormones and growth factors during normal and perturbed wound healing. The current use of hormones and growth factors will be summarized and future prospects for treatments of non-healing wounds discussed.
ROLE OF HORMONES The authors have previously demonstrated a clear inverse correlation between age and effi- ciency of acute wound healing.
Elderly subjects heal more slowly, with an excessive local inflammatory response.
In females, this shift in healing ability precisely correlates with the dramatic reduction in sex steroids, which occurs as a result of the menopause.
Systemic hor- mone replacement therapy (HRT) significantly accelerates acute wound healing in the elderly, as does topical oestrogen treatment1−2 (Figure 18.1).
Using genetically null animals, we have recently identified macrophage migration inhibitory factor (MIF) as a downstream mediator of oestrogen’s effects on wound healing.3 In vitro oestrogen directly regulates MIF by an oestrogen-receptor-mediated mechanism.
MIF levels are high in chronic non-healing ulcers,
Figure 18.1 Diagrammatic representation of the effects of estrogen on cutaneous wound healing. Estrogen promotes healing (compare left with right). Reduced estrogen leads to substantially increased granulation tissue area, increased inflammation resulting in enhanced proteolysis, reduced fibroblast- derived matrix deposition and retarded reepithelialization. GAGs, Glycosaminoglycans.
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ROLE OF GROWTH FACTORS 217
Table 18.2 Effects of hormones on wound healing
Process Oestrogens Androgens
Inflammation ↓ ↑ Cytokine expression ↓ ↑ Re-epithelialisation ↑ ↔ Angiogenesis ??? ??? Matrix deposition ↑ ↓ Wound contraction ↑ ??? Overall rate of healing ↑ ↓