# Honey Therapy in Diabetic Foot Ulcers: A Promising Strategy for Effective Wound Healing
## 2 Diabetes
### Diabetic Foot Ulcers
#### Infection and Wound Healing  
In general, wounds can be characterized as acute, which have a normal healing process, and chronic, where the healing process is impaired [33]. A normal wound healing process is composed of four overlapping steps, namely hemostasis, inflammation, proliferation, and remodeling [34]. These phases are orchestrated by different cell types that progressively operate within the wound milieu, namely monocytes, macrophages, neutrophils, keratinocytes, and fibroblasts [35; 36]. The first phase is characterized by the release of growth factors by the platelet plug that is formed during primary hemostasis, such as transforming growth factor beta (TGF-\(\beta\)) and epidermal growth factors [5]. During the subsequent inflammatory phase, neutrophils recruited to the wound site initiate phagocytosis to remove foreign materials, bacteria, and damaged tissue [34]. Monocytes are stimulated to migrate to the tissue and release inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-\(\alpha\)) and interleukin 6 (IL-6) [37]. After neutrophil infiltration ceases, macrophages continue the phagocytosis process to clean the wound site in preparation for the next phase [33; 34]. Following the proliferative phase, the processes of angiogenesis, collagen deposition, granulation tissue formation, re-epithelialization, and wound contraction occur [18]. The re-epithelialization process results from the keratinocytes' migration and proliferation to the skin surface. Afterwards, during the remodeling phase, the previously deposited collagen is remodeled and the unnecessary cells present in the wound undergo apoptosis [33]. The chronic wound state is characterized by a persistent injury state during wound healing due to the lack of or the severe slowdown of at least one of the healing phases [35]. Chronic wounds are usually infected and exhibit a persistent aberrant inflammatory profile, with hyperproliferative keratinocytes, elevated matrix metalloproteinases, and poor fibroblast infiltration and angiogenesis [36; 38]. Chronic wounds represent one of the major public health issues worldwide, impairing patients' quality of life and mobility [39]. Almost 90% of chronic wounds contain microorganisms such as bacteria and fungi, creating a multispecies biofilm that protects them from antimicrobial therapies and the immune system [6; 8]. Diabetic foot infections caused by _Pseudomonas aeruginosa, Escherichia coli, Citrobacter_ spp., _Acinetobacter_ spp., and _Staphylococcus aureus_ usually develop non-healing chronic wounds [16]. The polymicrobial biofilm infection can impair wound healing with more than a single bacterial infection, becoming even more resistant to antimicrobial therapies [40]. The wound healing process in patients with diabetes is impaired due to the multifactorial disruption of cellular coordination and the molecular process underlying wound repair [5]. Moreover, diabetes causes microvascular complications, favoring the local wound ischemia and delaying the healing process [6]. The increased blood viscosity, dysfunctional activity of polymorphonuclear neutrophils, and declined delivery of nutrients and oxygen to the wound site promoted by diabetes are also important factors that justify the wound healing delay [33]. Moreover, DWs usually exhibit a persistent inflammatory phase, impairing tissue granulation and the connective tissue's tensile strength [6]. Diabetes impairs the functions of neutrophils and macrophages, including cell adherence, chemotaxis, phagocytosis, and cytokine production and secretion [41]. The hyperglycemia and oxidative stress that diabetes patients are exposed to lead to epigenetic changes, thereby altering the macrophages' polarization [42]. In fact, lower numbers of macrophages are found in DWs, contributing to impaired tissue repair [43]. Macrophage migration inhibitory factor (MIF) was also found to decrease in DM [44], which could affect the recruitment of endothelial progenitor cells [45].