# Honey Therapy in Diabetic Foot Ulcers: A Promising Strategy for Effective Wound Healing
###### Abstract  
Diabetic foot ulcers (DFUs) are considered a major problem for public health, leading to high rates of lower-limb amputations. Moreover, due to the high prevalence rate of predisposing factors, the incidence rate of DFU is still rising. Although DFUs are complex in nature, foot ulceration usually precedes diabetic foot amputations. These impaired chronic wounds usually promote a microbial biofilm, commonly characterized by the presence of multidrug-resistant microorganisms, hampering the efficacy of conventional antibiotic treatments. Honey has been shown to be an effective antibacterial component, including against multidrug-resistant bacteria. Honey's physical-chemical characteristics, such as the presence of hydrogen peroxide, its low pH levels, and its high sugar and phenolic contents, promote anti-inflammatory and antioxidative activities, improving wound healing. This review aims to explore honey's effects in wound healing, especially for DFUs, and to show how the different physical-chemical features among different honey types might influence the treatment's effectiveness. For this, the mechanisms by which honey can promote wound healing and the potential use of honey dressings in diabetic wounds were investigated in animal models and humans. After revising the diabetic wound impairment mechanisms, we found that most of the clinical studies that treated DFUs with honey in animal models or humans reported accelerated wound healing, greater wound contraction, and lower amputation or hospitalization rates; however, few studies characterized the features of honey used for wound treatment, hindering the possibility of extensively comparing the different types of honey and identifying characteristics that most successfully promote wound healing. According to this review, honey is a cost-effective and safe option for DFU management.  
honey; diabetic foot ulcer; diabetic wounds; wound dressing +
Footnote †: journal:are considered the major cause of lower-limb amputations [4]. The hyperglycemic and inflammatory state promoted by diabetes can impair wound healing through multifactorial mechanisms [5; 6], leading to the development of chronic wounds and ulcers, and in the latter case to limb amputation [7]. Furthermore, diabetic wounds (DWs) are usually colonized by a microbial biofilm with multidrug-resistant microorganisms, reducing the efficacy of antibiotic treatments [8]. Despite many advances in bioengineering to promote the best DFU management approaches [9], concerns regarding the bacterial resistance usually found in DWs [10; 11; 12] and the high costs associated with DFU treatments are still major hindrances to promoting the best wound dressing options for patients [13; 14].  
In order to promote a cost-effective treatment and avoid drug side effects, natural sources have been extensively studied for DFU management [13; 15; 16]. Among them, a growing body of evidence shows that honey has antioxidant, anti-inflammatory, and antibacterial activities, including against multidrug-resistant bacteria [17]. Furthermore, honey's characteristics promote a physical barrier against external microbes, as well as a suitable acidic and moisturized environment that favors wound healing, including in DWs, through different mechanisms [18]. All of these benefits make honey a potential DFU treatment [19]. In this context, this review aims to review the mechanisms of impaired wound healing in diabetes and honey's antimicrobial and anti-inflammatory activities and to explore DFU models treated with different types of honey dressings.