Diabetic Wound Healing: New Targets and Approaches

Pouriska Kivanany

Introduction. Diabetes is characterized by elevated blood glucose levels, decreased blood circulation, and reduced immune response.1, 2 Diabetic foot ulcers are the primary complication with diabetes and are responsible for 84% of diabetic lower leg amputations.3 In normal wound healing, there is an interplay between cells, extracellular matrix, and biochemical/biophysical factors that culminate in facilitating tissue repair and wound closure.4, 5 After injury, fibroblasts secrete keratinocyte growth factor-1 (KGF-1), which can stimulate keratinocytes to secrete TGF-b1 (transforming growth factor-beta-1) in order to allow production of myofibroblasts for wound contraction.6-8 Vascular endothelial growth factor (VEGF) plays a role in promoting angiogenesis to facilitate wound repair.9, 10 Poly(D,L-lactide-co-glycolide) acid (PLGA) is a polymer that is biocompatible, biodegradable, and can enhance VEGF stability.11, 12, 14 Wound closure is delayed in diabetes due to decreased levels of growth factors (i.e, KGF-1), suppression of angiogenesis, and impaired cell migration into the wound area.4 Methods. For the KGF-1 studies, Sprague Dawley rats were injected with streptozotocin to induce diabetes.13, 14 Square-shaped 1 cm2 wounds were created, and either PBS or KGF-1 (50 ng/ml) was added to the wound site.14 Wound closure rates were assessed for 12 days.14 For the PLGA/VEGF studies, VEGF was embedded into PLGA nanoparticles using a modified W/O/W emulsion/solvent evaporation technique.15, 16 RjHan:NMRI and db/db leptin receptor deficient mice were used, and dorsal skin injuries were created using a 6 mm diameter biopsy punch.16 Wound closure was assessed for up to 28 days in vivo.16 Results. Treatment with KGF-1 in diabetic rats allows for a faster rate of wound contraction and healing compared to control treatment.14 Levels of TGF-b1 were elevated with treatment of KGF-1 in diabetic rats.14 Wounds from diabetic and non-diabetic mice have improved wound closure with treatment of VEGF embedded into PLGA nanoparticles compared to VEGF without PLGA embedding and non- VEGF treated groups.14 The degradation rate of PLGA is tunable based on the ratio of lactic acid and glycolic acid (i.e., more lactic acid reduces degradation rate).11 PLGA can be electrospun into a mesh to facilitate application to wound sites.11 Conclusions. Diabetic wound healing is an ongoing medical issue in the clinic that can affect quality of life and can even lead to amputations.17 The various targets of healing provide direction in developing potential therapies, including embedding KGF-1 and VEGF into a customized PLGA electrospun mesh to improve wound healing outcomes.

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