Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia

Abstract

Diabetic wounds result in significant morbidity, prolonged hospitalization, and enormous health-care expenses. Pigs have been shown to have wound healing resembling that in humans. The aim of this study was to develop a large-animal model for diabetic wound healing. Diabetes was induced by streptozotocin injection in Yorkshire pigs. Full-thickness wounds were created and dressed with a sealed chamber. Nondiabetic pigs with or without high glucose wound fluid concentration served as controls. Glucose concentration in serum and wound fluid was measured and collected. Wound contraction was monitored, and biopsies were obtained for measurement of reepithelialization. Wound fluid was analyzed for insulin-like growth factor-1 (IGF-1), platelet-derived growth factor, and transforming growth factor. Glucose concentration in wound fluid initially followed serum levels and then decreased to undetectable on day 9. Reepithelialization was significantly delayed in diabetic pigs. In nondiabetic pigs, wounds treated in a local hyperglycemic environment, and thus excluding the effects of systemic hyperglycemia, showed no difference in wound closure compared with controls. This suggests that delayed wound healing in diabetes is not induced by local highglucose concentration itself. Analysis of growth factor expression showed a marked reduction in IGF-1 in the diabetic wounds. Diabetic pigs have impaired healing that is accompanied by a reduction of IGF-1 in the healing wound and is not due to the local hyperglycemia condition itself.Approximately 5 million patients in the United States suffer from chronic wounds. 1 With the increased longevity, obesity, and diabetes, the problem of chronic wounds has increased, resulting in significant morbidity, lost time from work, and enormous health-care expenses. According to the American Diabetes Association, 25% of people with diabetes will suffer from a wound problem during their lifetime, and approximately 82,000 limb amputations for nontraumatic wounds were performed in people with diabetes in 2002. 2 The Agency for Health Care Policy and Research reports that wound care for pressure ulcers uses $200 billion a year for hospitalization, durable medical goods, nursing home care, physicians, and transportation. 3 Surgical treatment of diabetic wounds remains difficult and often insufficient, leading to high morbidity among those patients. 4 We need better ways to treat diabetic wounds and relevant preclinical models are needed to develop new therapeutic strategies.Numerous diabetic wound healing models have been described. 5,6 Small mammals, such as rats, rabbits, guinea pigs, and mice, are frequently used in wound healing studies because of cost and ease of handling. However, the anatomy and physiology of small mammals differ from those of humans in many ways. 7 Pig physiology and wound healing has been found to be significantly more similar to humans. 8,9 In wound healing models investigating basic fibroblast growth factor (bFGF), wounds in genetically diabetic db/db mice treate...

Insulin‐like growth factor‐1 gene therapy and cell transplantation in diabetic wounds

“…In a previous study, we could show that wounds in a nondiabetic pig showed 96% re-epithelialization by day 12 after wounding using the same animal model [7]. Thus, we were able to significantly enhance diabetes impaired wound healing close to the normal (nondiabetic) level of reepithelialization in the present study.…”

“…On the other hand, IGF-1 showed proliferative effects on keratinocytes and fibroblasts in vitro [6]. In our diabetic wound-healing model, we confirmed these data: Expression of human IGF (hIGF)-1 in diabetic wounds was markedly reduced compared to nondiabetic wounds [7]. These findings led us to the hypothesis that enhanced IGF-1 expression in diabetic wounds can alter wound healing.…”

Effects of hyperglycemia and ageing on the healing of colonic anastomoses in rats

“…There is a compromise of the chemotaxis, phagocytosis and bactericide capacity 9,27 , reduced expression of shock proteins 39 , lower antioxidant production and increased production of oxygen free radicals 40,41 during the initial phase of the process, which adversely affects healing. Furthermore, there is depletion of growth factors [5][6][7][8]11,12 , increased levels of glucocorticoids 42 , loss of cellular proliferation and increased regulation of apoptosis 10,11,[43][44][45] , characteristics of the later phase of healing in diabetics, which results in poor granulation tissue formation 11 . Franzén and Roberg 46 , studying healing in diabetic rats, showed that fibroblasts have a lower number of cytoplasmatic protrusions with lower surface density of the plasmatic membrane, which indicates the reduced motility of these cells, a condition linked to reduced healing.…”

“…Franzén and Roberg 46 , studying healing in diabetic rats, showed that fibroblasts have a lower number of cytoplasmatic protrusions with lower surface density of the plasmatic membrane, which indicates the reduced motility of these cells, a condition linked to reduced healing. Velander et al 12 , working with pigs that had diabetes induced by streptozotocin, observed a significant fall of the levels of TGF-ß and IGF-1 on the seventh day, the latter being an important stimulator of the proliferation of keratinocytes and fibroblasts.…”

“…Several factors are known to contribute to deficient healing in individuals with diabetes. These include: a reduction in the production of growth factors, angiogenic response, macrophage function, collagen accumulation, epidermal barrier function, quantity of granulation tissue, proliferation and migration of keratinocytes and fibroblasts, bean healing and the balance between the accumulation of extra (MMPs) [3][4][5][6][7][8][9][10][11][12] .…”