Diabetic foot ulcers constitute a major health problem and they are recalcitrant to healing due to a constellation of intrinsic and extrinsic factors. The purpose of this article is to review the potential biological mechanisms that deter healing and perpetuate inflammatory responses in chronic diabetes foot ulcers. The link between hyperglycemia induced oxidative stress and its negative impact on cellular functions are explained. Key evidence related to alteration in tissue perfusion, bacterial balance, sustained proteases and cytokines release, leukocyte function, and growth factor production at the local wound level are summarized.
"The formation of advanced glycation end-products (AGEs) under hyperglycemic conditions and interactions with their receptors (RAGE) are also associated with impaired wound healing among diabetic patients . Several dysregulated cellular functions involved in diabetic wounds (defective T-cell immunity, defects in leukocyte chemotaxis, phagocytosis, bactericidal capacity, dysfunctions in fibroblasts and epidermal cells) were attributed to inadequate bacterial clearance and delayed or impaired repair in individuals with diabetes . "
[Show abstract][Hide abstract] ABSTRACT: Diabetic wounds are unlike typical wounds in that they are slower to heal, making treatment with conventional topical medications an uphill process. Among several different alternative therapies, honey is an effective choice because it provides comparatively rapid wound healing. Although honey has been used as an alternative medicine for wound healing since ancient times, the application of honey to diabetic wounds has only recently been revived. Because honey has some unique natural features as a wound healer, it works even more effectively on diabetic wounds than on normal wounds. In addition, honey is known as an "all in one" remedy for diabetic wound healing because it can combat many microorganisms that are involved in the wound process and because it possesses antioxidant activity and controls inflammation. In this review, the potential role of honey's antibacterial activity on diabetic wound-related microorganisms and honey's clinical effectiveness in treating diabetic wounds based on the most recent studies is described. Additionally, ways in which honey can be used as a safer, faster, and effective healing agent for diabetic wounds in comparison with other synthetic medications in terms of microbial resistance and treatment costs are also described to support its traditional claims.
Evidence-based Complementary and Alternative Medicine 10/2014; 2014:1-16. DOI:10.1155/2014/169130 · 1.88 Impact Factor
"Diseases such as diabetes mellitus interfere with wound healing by disrupting the orderly sequence of events at one or more of the stages, thereby compromising the wound-healing process. The deficiency of endogenous growth factors   and/or the excessive production of exudates and expression of high levels of tissue destructive proteinases  are associated to chronic wound formation. Diabetic ulcerations are characterized by impaired neovascularization and blood perfusion. "
[Show abstract][Hide abstract] ABSTRACT: Impaired angiogenesis is a major clinical problem and affects wound healing especially in diabetic patients. Improving angiogenesis is a reasonable strategy to increase diabetes-impaired wound healing. Recently, our lab described a system of transient gene expression due to pegylated poly-l-lysine (PLL-g-PEG) polymer-mediated plasmid DNA delivery in vitro. Here we synthesized peptide-modified PLL-g-PEG polymers with two functionalities, characterized them in vitro and utilized them in vivo via a fibrin-based delivery matrix to induce dermal wound angiogenesis in diabetic rats. The two peptides were 1) a TG-peptide to covalently bind these nanocondensates to the fibrin matrix (TG-peptide) for a sustained release and 2) a polyR peptide to improve cellular uptake of these nanocondensates. In order to induce angiogenesis in vivo we condensed modified and non-modified polymers with plasmid DNA encoding a truncated form of the therapeutic candidate gene hypoxia-inducible transcription factor 1α (HIF-1α). HIF-1α is the primarily oxygen-dependent regulated subunit of the heterodimeric transcription factor HIF-1, which controls angiogenesis among other physiological pathways. The truncated form of HIF-1α lacks the oxygen-dependent degradation domain (ODD) and therefore escapes degradation under normoxic conditions. PLL-g-PEG polymer-mediated HIF-1α-ΔODD plasmid DNA delivery was found to lead to a transiently induced gene expression of angiogenesis-related genes Acta2 and Pecam1 as well as the HIF-1α target gene Vegf in vivo. Furthermore, HIF-1α gene delivery was shown to enhance the number endothelial cells and smooth muscle cells - precursors for mature blood vessels - during wound healing. We show that - depending on the selection of the therapeutic target gene - PLL-g-PEG nanocondensates are a promising alternative to viral DNA delivery approaches, which might pose a risk to health.
"In nonhealing DFUs the normal healing process is stalled. The exact mechanisms involved in this impairment are not fully understood but an increasing number of pathways are suggested with varying levels of evidence and are summarized herein as reviewed in a number of recent excellent articles [13-18]. Hyperglycemia is thought to adversely affect healing by increased levels of advanced glycation end products that inhibit normal extracellular matrix (ECM) deposition and upregulate activity of matrix metalloproteinases (MMPs). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Diabetic foot ulcers (DFUs) represent a significant source of morbidity and an enormous financial burden. Standard care for DFUs involves systemic glucose control, ensuring adequate perfusion, debridement of nonviable tissue, off-loading, control of infection, local wound care and patient education, all administered by a multidisciplinary team. Unfortunately, even with the best standard of care (SOC) available, only 24% or 30% of DFUs will heal at weeks 12 or 20, respectively.The extracellular matrix (ECM) in DFUs is abnormal and its impairment has been proposed as a key target for new therapeutic devices. These devices intend to replace the aberrant ECM by implanting a matrix, either devoid of cells or enhanced with fibroblasts, keratinocytes or both as well as various growth factors. These new bioengineered skin substitutes are proposed to encourage angiogenesis and in-growth of new tissue, and to utilize living cells to generate cytokines needed for wound repair.To date, the efficacy of bioengineered ECM containing live cellular elements for improving healing above that of a SOC control group has not been compared with the efficacy of an ECM devoid of cells relative to the same SOC. Our hypothesis is that there is no difference in the improved healing effected by either of these two product types relative to SOC.
To test this hypothesis we propose a randomized, single-blind, clinical trial with three arms: SOC, SOC plus Dermagraft® (bioengineered ECM containing living fibroblasts) and SOC plus Oasis® (ECM devoid of living cells) in patients with nonhealing DFUs. The primary outcome is the percentage of subjects that achieved complete wound closure by week 12.
If our hypothesis is correct, then immense cost savings could be realized by using the orders-of-magnitude less expensive acellular ECM device without compromising patient health outcomes. The article describes the protocol proposed to test our hypothesis.
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