Emerging Treatments in Diabetic Wound Care
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Treatment of diabetic foot ulceration is much more complex than simply putting a dressing over a wound. Diabetic foot ulceration is a significant cause of morbidity and is the most common reason for hospital admission in diabetic patients. Annually, two to three percent of diabetic patients1,2 will develop foot ulcers, and up to 15 percent of diabetic patients will develop chronic ulcers during their lifetimes.3 In those who require lower-limb amputation, 70 to 90 percent will be preceded by a foot ulceration.
Physiology of Wound Healing
The three general phases involved in wound healing are the acute inflammatory phase, the proliferative phase, and the maturation phase. The initiation and transition of these phases have no clear-cut boundaries but are descriptors on a continuum of events. The initial phase, inflammation, involves transient vasoconstriction of local arterioles and capillaries followed by an influx of inflammatory cells and plasma proteins to mediate the repair process. The next phase is proliferation, where fibroblastic activity and angiogenesis by the endothelial cells begin. The maturation phase may last for up to two years and involves collagen synthesis and breakdown.
Developments in Physiological Aspects of Wound Healing
Chronic diabetic foot ulcers have been shown to result from a number of causes, one of which involves faulty wound healing. The normal wound healing process entails a complex interplay between connective tissue formation, cellular activity, and growth factor activation. All three of these physiologic processes are altered in the diabetic state and contribute to the poor healing of diabetic foot ulcers. More specifically, the chronic diabetic foot ulcer is stalled in the inflammation phase of the normal wound healing process.4 During this delay, there is a cessation of epidermal growth and migration over the wound surface.5,6 Analyses of fluid from chronic wounds have demonstrated elevated levels of matrix metalloproteinases (MMPs) directly resulting in increased proteolytic activity and inactivation of the growth factors that are necessary for proper wound healing. A number of recent studies have investigated these alterations in an attempt to better understand the wound healing abnormalities in diabetes and to target therapy specifically aimed at correcting these deficiencies, as described below.
Collagen. Collagen, the most abundant protein in connective tissue, is an integral component of dermis, bones, tendons, and ligaments. Collagen synthesis and degradation in wound repair are complex processes that continue at the wound site long after the injury. The resulting scar tissue following wound repair never fully regains the tensile strength of the original intact skin. Instead, scar collagen retains only 70- to 80-percent tensile strength of the original collagen.7 The balance between collagen synthesis and degradation in wound repair is tenuous, and disease states, such as diabetes, can shift the balance to one side, disrupting the wound healing process.
In diabetes, collagen synthesis is markedly decreased, resulting in chronic connective tissue complications. The defect in collagen metabolism in diabetes is present at both the collagen peptide production level as well as the posttranslational modification of collagen degradation. The resultant collagen production deficits can be observed in several systems, including thickening of the vascular basement membrane, limited joint mobility, and poor wound healing.
Cellular activity. The inflammatory stage of wound repair involves an orchestrated interaction of resident cells, such as epithelial cells, fibroblasts, dendritic cells, and endothelial cells, with biochemical activity. In addition to these resident cells, platelets, neutrophils, T-cells, natural killer cells, and macrophages are recruited to the wound site.
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