Wound healing is a complicated and integrated process. Although there is some tolerance in terms of redundancy and interrelated control mechanisms, pushing beyond such limits may contribute to delayed wound healing, and in extreme cases lead to chronic wounds/ulcers and thus potentially to lower extremity amputation. Diabetes is associated with such disruption in wound healing. Research in humans and in animal models has identified a large number of changes associated with diabetes at the molecular level in delayed wound healing and to a lesser extent in chronic diabetic ulcers. Better overall understanding of these changes and how they are interrelated would allow for specifically targeted treatment, thus ensuring improved quality of life for patients and providing savings to the high costs that are associated with all aspects of chronic diabetic ulcers. This review examines the work done at the molecular level on chronic diabetic ulcers, as well as considering changes seen in diabetes in general, both in humans and animal models, that may in turn contribute to ulcer formation.

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Mice are increasingly used to investigate mechanobiology in fracture healing. The need exists for standardized models allowing for adjustment of the mechanical conditions in the fracture gap. We introduced such a model using rigid and flexible external fixators with considerably different stiffness (axial stiffnesses of 18.1 and 0.82 N/mm, respectively). Both fixators were used to stabilize a 0.5 mm osteotomy gap in the femur of C57BL/6 mice (each n = 8). Three-point bending tests, CT, and histomorphometry demonstrated a different healing pattern after 21 days. Both fixations induced callus formation with a mixture of intramembranous and enchondral ossification. Under flexible conditions, the bending stiffness of the callus was significantly reduced, and a larger but qualitatively inferior callus with a significantly lower fraction of bone but a higher fraction of cartilage and soft tissue was formed. Monitoring of the animal movement and the ground reaction forces demonstrated physiological loading with no significant differences between the groups, suggesting that the differences in healing were not based on a different loading behavior. In summary, flexible external fracture fixation of the mouse femur led to delayed fracture healing in comparison to a more rigid situation.

The lack of TGF-beta1 up-regulation in both diabetic foot ulcers and venous ulcers may explain the impaired healing in these chronic wounds, and could represent a general pattern for chronicity.

SUMMARYThis paper reviews the changes which occur in the human lens in diabetes. They include refractive changes and cat aract and age-related increases in thickness, curvatures, light scattering, autofluorescence and yellowing. The inci dence of cataract is greatly increased over the age of 50 years, slightly more so in women, compared with non diabetics. Experimental models of sugar cataract provide some evidence for the mechanism of the uncommon, but morphologically distinct, juvenile form of human dia betic cataract, where an osmotic mechanism due to sugar alcohol accumulation has been thoroughly studied in dia betic or galactose-fed rats. The discrepancy between the ready accumulation of sugar alcohol in the lens in model systems and the very slow kinetics of aldose reductase (AR) has not been satisfactorily explained and suggests that the mechanism of polyol formation is not yet fully understood in mammalian systems. The activity of AR in the human lens lies mainly in the epithelium and there appears to be a marginal expectation that sufficient sorbi tol accumulates in cortical lens fibres to explain the lens swelling and cataract on an osmotic basis. This is even more so in the cataracts of adult diabetics, which re semble those of age-related non-diabetic cataracts in appearance. The very low levels of sorbitol in adult dia betic lenses make an osmotic mechanism for the increased risk of cataract even less likely. Other mech anisms, including glycation and oxidative stress, are dis cussed. The occurrence of cataract is a predictor for increased mortality in the diabetic.The diabetic lens is larger than normal, disposed to refrac tive change and at increased risk of cataract, sometimes of a specific type. This paper discusses the factors involved. ANATOMY AND PHYSIOLOGYThe lens is enclosed in a collagenous capsule containing other matrix proteins and proteoglycans. A monolayer of epithelial cells is interposed between the anterior capsule and the main cellular mass of lens fibres. The lens fibres are laid down in a series of onion-skin layers, which arch over the equator to meet their opposite numbers at the lens sutures. The innermost fibres comprising the nucleus of the lens are free of organelles and show limited metabolic activity. The outer fibres comprise the cortex. The most superficial fibres of the cortex are nucleated and, like the epithelium, show the normal complement of organelles. Glucose, which enters the lens by facilitated transport, I is its main energy supply, although energy may also derive from amino acids? The metabolism of the cortex is chiefly anaerobic, with 70% of the energy supply of the lens deriving from anaerobic glycolysis. If a lens is incubated in nutrient medium in anaerobic conditions with an adequate supply of glucose it remains transparent for a number of hours.3.4 The metabolism of the epithelium is aerobic. New lens fibres arise by cell division in the germi native zone in the pre-equatorial region of the lens. The epithelium and superficial cortical cells are major ...

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Dynamization of fracture fixation is used clinically to improve the bone healing process. However, the effect of early dynamization remains controversial. This study evaluated the effect of early dynamization, by reduced stiffness of fixation on callus stiffness and size after 5 weeks of healing in a rat diaphyseal femoral osteotomy. An external unilateral fixator allowed either a rigid (R-group; n ¼ 8) or a flexible (F-group; n ¼ 8) fixation. The dynamized group (D-group: n ¼ 8) had a rigid fixation for 1 week, and then a flexible fixation for the remaining 4 weeks. The pre-and postoperative activity of the rats was measured. After 5 weeks, the rats were sacrificed, and healing was evaluated by biomechanical and densitometric methods. The R-group had a higher activity more closely approaching preoperative levels, compared to the D-group throughout all time points measured. This difference was significant after 14 days and 21 days. The flexural rigidity of the R-group was 82% (tested in the anterior-posterior direction; p ¼ 0.01) and 93% (tested in the medial-lateral direction; p ¼ 0.002) greater than the flexural rigidity of the D-group. The rigid fixation led to a stiffer callus with a smaller callus volume, but better mineralized tissue in the whole callus and at the level of the osteotomy gap than the flexible or the dynamized fixation. Early dynamization did not improve healing compared to rigid or flexible fixation in a rat femoral osteotomy model. ß

The continuously increasing worldwide prevalence of diabetes will be accompanied by a greater incidence of diabetic foot ulcer, a complication in which many of the morphological processes involved in normal wound healing are disrupted. The highly complex and integrated process of wound healing is regulated by a large array of molecular factors. These often have overlapping functions, ensuring a certain degree of tolerance through redundancy. In diabetes, changes to the expression of a large number of molecular factors have been observed, overwhelming this inbuilt redundancy. This results in delayed healing or incomplete healing as in ulceration. Understanding the relationship between altered levels of molecular factors and the inhibited healing process in such ulcers will permit the development of targeted treatments aimed to greatly improve the quality of life of patients, at the same time helping to reduce the huge costs associated with treating this diabetic condition and its long-term consequences. This short review examines how changes in the expression of molecular factors are related to altered morphology in diabetic foot ulceration and very briefly considers treatment strategies at molecular level.