# Honey Therapy in Diabetic Foot Ulcers: A Promising Strategy for Effective Wound Healing
## 6 Honey in Diabetic Foot Treatment  
Several studies carried out with animal models have shown the efficacy of honey in DW treatment [17]. In animal models of diabetes, honey is able to accelerate the wound healing, promoting epithelialization, improving the tissue granulation, and increasing the wound contraction [136; 138; 139]. Streptozotocin-induced mice with diabetes treated with honey from the nectar of _Thymus serpillum_ and _Astragalus microcephalus_ showed reduced wound areas with greater wound contraction and epithelization than animals treated with isotonic saline solution [111]. The treatment with propolis honey hydrogel dressings derived from Seoul Propolis Co., Ltd. (Daejon, Korea), in _db/db_ female mice was effective against _S. aureus_ and _E. coli_ and improved the amounts of wound area reduction and contraction [41]. The topical application of manuka (_Leptsospermum_) and jamun (_Syzygium cumini_) honeys in animals with diabetes not only accelerated the wound closure and reepithelialization but also improved the collagen deposition and modulated the essential angiogenic markers, namely hypoxia-inducible factor and vascular endothelial growth factor [136]. In diabetic mice, heme oxygenase-1 (HO-1), which is a cytoprotective, pro-angiogenesis, and anti-inflammatory enzyme, is usually found to decrease, impairing the regulation of angiogenesis [140]. The application of a chestnut (_Castanae sativa_) honey hydrogel in db/db mice was able to rapidly upregulate HO-1 proteins at the wound site, which might mediate the coordination of keratinocytes and enhance the expression of Ki-67 proliferation markers [138]. The topical application of mad honey, a _Rhododend_ honey containing grayanotoxins, also decreased the gene expression of inflammatory markers such as TNF-\(\alpha\) and metalloproteinases 9 (MMP-9) and increased the IL-10 expression [139]. According to the authors, the honey's characteristics, such as its optimum phenolic and flavonoid contents, were responsible for the mad honey's antioxidant properties. The information from experimental studies involving models of diabetic animals treated with honey is summarized in Table 1.  
In humans, honey has been shown to be effective in DFU treatment, decreasing the bacterial load and inflammation, regenerating the granulation tissue, and reducing the wound size, as well as the rate of amputation [141; 142; 143; 144]. A clinical study over 16 weeks carried out in 63 patients with DFU treated with manuka-honey-impregnated dressings showed accelerated rates of wound healing and disinfection, as well as a nullified need for antibiotics or hospitalization, in comparison with conventional saline-soaked dressings [110]. Another clinical trial compared the DFU treatments from debridement to wound closure in 33 patients and found a higher wound healing rate in those treated with a thin layer of Australian honey dressings covered with gauze (mean: 14.4 days; range: 7-26) than with poviodone-soaked gauze (mean: 15.4 days; range: 9-36) [145]. A reduced wound size and higher wound healing rate were observed in patients submitted to bei (_Ziziphus jujuba_) honey dressings (\(n=136\); median 18 days) than in patients treated with saline dressings (\(n=97\); median 29 days) [146]. Currently, five clinical cases have exhibited the effectiveness of medical grade honey in reducing the wound area, exudate volume, and severity of infection, as well as wound-related pain, in diabetic patients [147]. Allergy and irritation symptoms were also decreased in DFU patients treated with Jordanian natural honey [142]. Despite these benefits, in cases of severe vascular compromise, exposed bone, or established osteomyelitis, honey was not as effective [19]. The characteristics of the studies carried out with human DFUs treated with honey are detailed in Table 2.  
\begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Authors** & **Animal Models** & **Reagents** & **Honey Characteristics** & **Results** \\ \hline \begin{tabular}{} \end{tabular}  \\