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Diabetic foot ulceration (DFU) is one of the most costly and debilitating complications of diabetes and is the leading cause of non-traumatic amputations, affecting 15% of the diabetic population. Impaired wound healing in diabetic patients without large-vessel disease has been attributed to microvascular dysfunction, neuropathy, and abnormal cellular and inflammatory responses. These abnormalities have been examined mainly in animal models although a few studies have been undertaken in diabetic patients. This review provides an overview of the inflammatory and vascular abnormali- ties in DFU and emphasises the role of angiogenic growth factors, endothelial progenitor cells (EPCs), and neuropeptides as mediators of wound healing and potential therapeutic agents for these chronic, non-healing ulcers.

Diabetic foot ulceration stands as one of the most costly and debilitating complications of diabetes and remains the leading cause of nontraumatic lower extremity amputation in the United States. Traditionally, ischemia, neuropathy, trauma, and infection were considered the culprits of the recurring chronic wound and treatment revolved largely around wound debridement and revascularization. However, recent investigations have uncovered an impaired cutaneous wound healing process in diabetes caused by cellular and molecular alterations in the diabetic microenvironment and have subsequently identified an array of potential molecular targets for intervention. Here, we review recent patents describing upcoming molecular technologies at various stages of development for treating foot ulceration in the diabetic patient. Target classes reviewed include immunomodulators, neuropeptides, and growth factors, and targets reviewed include lactoferrin, thymosin beta 4, T cell immune response cDNA 7, substance P, neuropeptide Y, vascular endothelial growth factor, fibroblast growth factor, nerve growth factor, connective tissue growth factor, hepatocyte growth factor, homeobox genes, and treprostinil. In the course of this presentation, the biology of wound healing and the pathobiology of impaired wound healing in diabetes are emphasized to illustrate how these future molecular therapeutics are intended to counteract disease pathology and promote normal wound repair.

Chronic complications of diabetes mellitus represent a major cause of morbidity and mortality among those affected and have an enormous impact on society as a whole. Although these complications manifest as a number of clinically distinct syndromes, the pathology underlying them may be very similar, if not identical. Endothelial dysfunction leading to microcirculatory insufficiency and functional ischemia of tissues are proposed to play a pivotal role in the process of their development and progression. Diabetic complications affecting the nervous system occur not infrequently and may have disastrous consequences. This article reviews diabetic complications affecting central and peripheral nervous systems, focusing on similarities in their underlying microvascular pathology and discussing aspects of potentially successful therapeutic interventions. In addition, the article draws a parallel between microvascular dysfunction observed in persons with overt diabetes and those at risk for it.

Studies over the last decade have revealed impairment of the microcirculation in the diabetic foot. Endothelial dysfunction along with derangements in numerous biochemical pathways has been implicated as causes of microcirculation impairment. Additionally, reduction or absence of the nerve-axon reflex renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury or infection and makes it functionally ischemic even in the presence of satisfactory blood flow under normal conditions. Furthermore, these changes appear to be directly related to the presence of diabetic neuropathy. These alterations in the diabetic microcirculation may explain the poor wound healing commonly observed in diabetes.