Diabetes mellitus (DM) is a chronic metabolic disease characterized by a high sugar concentration in blood. It can be caused by low production of insulin, resistance to insulin or both. The so called Diabetes type 2 is much more often than the type 1, roughly corresponding to 90% of all diabetic persons, usually present at adult ages.
The World Health Organization (WHO) has reported a prevalence of 170 – 194 millions of diabetic people world-wide in 2005, value that will be higher than 300 millions by the year 2025. Therefore, it has been argued that this disease could cause more death that AID, and it is currently the fourth cause of dead in the world. Almost 100% of people affected by DM develop complications that compromise morpho-functional integrity of tissues and organs. Clinical complications in diabetic patients impose devastating consequences during the base disease. In the mean while, these complications are a risk factor for the patient life. A high and sustained glucose concentration in blood is a condition for non-enzymatic protein glycosylation, as such as tissues from the wall of blood vessels, nerves and skin collagen material. These elements, among others, are factors that contribute to blockade the natural repair pathway in diabetic people. Vascular complications, such as diabetic macro-angiopathy cause a deficit of tissue reperfusion, among which is the skin. Diabetic neuropathy is another complication that affects the sensitive, motor and autonomic innervations with a particular clinic effect on peripheral soft tissues. Often, ulcerative lesions in diabetic persons take place as a consequence of neuropathy, when pain sensitivity is lost alone with other primary skin defense mechanisms.
The diabetic foot syndrome is a sever complication, mutilating, in most cases, with physiopathology and clinic convergence of peripheral neuropathy, microvasculopathy, and microangiopathy, often associated to bone and skin mechanic alterations, and a higher susceptibility to infections. It is a multifactor etiology, with a major relevance for vascular lesions in some cases, and neurologic lesions in other, being the most common a mix lesion, where are present several predisposing, precipitating and worsening factors, such as acute ischemia, ulcers and local infections. The most fatal outcome of the diabetic foot syndrome is amputation. Ulcerative lesions of the diabetic foot, like other chronic wounds, are characterized by a dismetabolism where extracellular matrix degradation may be predominant over the synthesis.
Therefore, catabolic process may be predominant over anabolic process. As a distinguish feature, however, the risk of sepsis is much higher than in other wounds. An insufficient phagocytosis capacity of neutrophils and macrophages has been described in diabetic patients, as such as the incapacity to start a productive inflammatory response. The presence of a pro-oxidant environment as a result of final products release from peroxidation and nitrosilation reactions has been demonstrated in several studies. In addition, an unfavorable unbalance of pro-inflammatory cytokine modulation takes place in such a way that vascular precursors, fibroblasts and other tissue granulation cell become the process in a pro-inflammatory bioreactor far away from its pro-anabolic function. This pro-inflammatory polarization is related to metaloprotein expression that degrades the scarce extracellular matrix and reduces mechanical resistance of the wound. Several of these characteristics have been demonstrated in non diabetic animal models where a chronic non enzymatic glycosylation has been induced. Diabetic foot lesions heal slowly and asynchronically or do not heal. In that way, a closed cycle of open wound – infection and vice versa is set up which increases the risk of gangrene and amputation.
As a consequence of a persistent glycosylation and other unidentified factors, fibroblasts and vascular precursors show a poor meiotic and mitogenic response, coexisting with a trend to an imperfect angiogenesis and to a substantial deterioration of the contraction mechanism. The fail of this mechanism seem to be related to the instruction and signaling mechanisms in the fibroblasts to reach a pro-contractile phenotype. Ischemia, hyperglycemia, hypoglycemia and other systemic complications are also associated to the erratic limited environment of the wound. The insufficient healing in the diabetic persons is a world-wide unmet medical problem. It has been estimated that 10 – 15% of diabetic patients develop a diabetic foot ulcer (DFU) at a given moment of the life, and between 10 and 15% of them finish in amputation.
Near to 50% of amputated patients suffer a second amputation of the counter lateral limb in a period of 2 – 5 years, significantly affecting the patient quality of life with high costs for health systems. This situation can become more serious, since after a major amputation less than 50% of patients survive in the following 5 years.