Fig. 3. The vasodilatory response to the iontophoresis of acetylcholine (hatched bars) and sodium nitroprusside (black bars) at the foot level. The response to acetylcholine (endothelium dependent vasodilation) was equally reduced in the diabetic neuropathic patients with a history of foot ulceration (DN group), the patients with both neuropathy and peripheral vascular disease (DI), and the patients with Charcot neuroarthropathy (DA) when compared with nonneuropathic diabetic patients (D) and healthy controls (C), p < 0.0001. The response to sodium nitroprusside (endothelium independent vasodilation) was more pronounced in the DI group and also, reduced in the DN and DA groups compared with D and C groups, p < 0.0001. These results indicate that both the endothelial cell and vascular smooth muscle cell of the skin microcirculation are impaired in the neuropathic diabetic foot (from ref. 50).

response) (Fig. 4). This response is equal to one-third of the maximal vasodilatory capacity and is responsible for the hyperemia that is observed in areas that are close to injury.

As it would be expected, the nerve-axon-reflex-related vasodilation is almost absent in diabetic naturopathic patients. This response remains absent even after successful bypass surgery to the pedal arteries that establishes satisfactory blood flow in the foot large vessels (58). This is probably the main reason that hyperemia, a major sign of inflammation, is absent in patients with diabetes with infection of the foot. Thus, even the presence of neuropathy alone can lead to impaired blood flow under conditions of stress (59-61).

At the molecular level, the reduction of endothelium-dependent vasodilation seems to be related to the reduced expression of endothelial nitric oxide synthase, by the endothe-lial cells of the micro vasculature that is located in the skin of neuropathic foot (54). Whether this reduction is also related to the development of neuropathy is not clear. However, the expression of endothelial nitric oxide synthase by endothelial cells at the forearm level is not affected by diabetes. Other mechanisms that contribute to the observed functional changes include reduced poly(ADP-ribose) polymerase activity and increased nitrotyrosine formation (57).

Despite the lack of complete understanding of the involved mechanisms, the main understanding from work that was conducted during the last decade is that the microcirculation

Axonal Reflex Histamine

Fig. 4. The nerve axon reflex. Stimulation of the C-nociceptive fibers causes retrograde stimulation of adjacent fibers that release active vasodilators such as histamine, substance P, and cal-citonin gene-related peptide. The final result is hyperemia during injury or inflammation. Because of the presence of peripheral neuropathy, this response (also known in physiology as Lewis triple flare response) is absent in diabetic patients.

Fig. 4. The nerve axon reflex. Stimulation of the C-nociceptive fibers causes retrograde stimulation of adjacent fibers that release active vasodilators such as histamine, substance P, and cal-citonin gene-related peptide. The final result is hyperemia during injury or inflammation. Because of the presence of peripheral neuropathy, this response (also known in physiology as Lewis triple flare response) is absent in diabetic patients.

of diabetic neuropathic foot fails to maximally vasodilate under conditions of stress. Thus, even in the absence of any peripheral disease and in the presence of adequate blood flow in the large vessels, the skin blood flow is impaired when injury occurs and this is one of the major factors that are related to impaired wound healing. Therefore, the neuropathic diabetic foot should be considered functionally ischemic regardless of the presence or absence of vascular disease. In addition, lack of hyperemia should not be interpreted as lack of inflammation or infection.

Impaired Wound Healing

As shown in Fig. 1, impaired wound healing is a major factor that contributes to the development of chronic foot ulceration and amputation. Initially, it was thought that failure to heal a diabetic ulcer was related to continuous walking on the injured foot, mainly because of the pain insensitivity, and the existence of peripheral arterial disease. However, it is currently realized that two other major factors contribute to this impairment, namely the functional changes in the microcirculation and changes in cellular activity, and the expression of the various growth factors and cytokines that are normally involved in tissue repair and 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 physiological processes are altered in the diabetic state and contribute to the poor healing of diabetic foot ulcers. 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 70-80%

tensile strength of the original collagen (62). 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.

The normal 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 (62). In addition to these resident cells, platelets, neutrophils, T-cells, natural killer cells, and macrophages are recruited to the wound site. These cells migrate to the injury site to mediate the inflammation, coagulation, and angiogenesis processes occurring in the wound healing process.

Growth factors influence the wound healing process through inhibitory or stimulatory effect on the local wound environment. Growth factors, such as growth platelet-derived growth factor (PDGF), basic fibroblast growth factor, and vascular endothelial growth factor have all been found in wound fluid. These growth factors are known to be integral in the chemotaxis, migration, stimulation, and proliferation of cells and matrix substances necessary for wound healing. Therefore, the altered secretion or absence of these growth factors in diabetic foot ulcers can potentially impair wound healing. Recent investigation of the role these growth factors play in wound healing appears to support this hypothesis (63).

In diabetes, there are major abnormalities in all the above mechanisms. Thus, collagen synthesis markedly decreased, at both the collagen peptide production level as well as the post-translational modification of collagen degradation (42). In addition, hyper-glycemia can potentially mitigate the cellular activity in the inflammatory process. More specifically, the morphological characteristics of macrophages are transformed in such a manner that it impairs their function (64). Furthermore, inhibition of skin ker-atinocyte proliferation in the presence of increased cellular differentiation leads to an imbalance in keratinocyte production, an essential step in the wound healing process (65). Finally, the expression of various growth factors, such as PDGF and vascular endothelial growth factor is reduced, whereas the expression of matrix metallopro-teinases is increased. The upgraded expression of the matrix metalloproteinases's results in increased proteolytic activity and inactivation of the growth factors that are necessary for proper wound healing.

The final result of the aforementioned changes is that that diabetic ulcers are "stuck" in the inflammatory phase of the wound healing process. Under normal circumstances, during this phase that lasts for only 2-3 days, the wound is cleaned of any bacteria and is covered by an eschar that is devoid of any tensile strength. The inflammatory phase is followed by the proliferative phase that is characterized by angiogenesis, expression of numerous growth factors, cell migration, collagen production, and results in complete wound closure. It is currently believed that aberrant expression of growth factors and cytokines is the main reason that the diabetic foot ulcer fails to progress to the pro-liferative phase and remains in a chronic inflammatory state. Further understanding of this process will help in the development of new treatments in the future (66,67).

Additional Risk Factors

Other risk factors for the development of diabetic foot ulcers include long duration of diabetes, earlier foot ulcer, and earlier amputation. Duration of diabetes for more than 20 years has been found to increase the risk of ulceration sixfold when compared with patients with a history of diabetes of less than 9 years (68). A number of studies have demonstrated that a previous history of ulceration or amputation significantly increases the likelihood of a subsequent ulcer (6,69). Previous surgical intervention including partial amputation may destabilize the foot and the process might accelerate in the intrinsic minus foot. It is also believed that a unilateral amputation might cause additional stress on the contralateral limb.

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