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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