# Honey Therapy in Diabetic Foot Ulcers: A Promising Strategy for Effective Wound Healing
## 2 Diabetes
### Diabetic Foot Ulcers
#### 2.1.3 Types of Treatment for Wound Healing and their Limitations  
The standard treatment of DFUs comprises wound debridement, offloading, and infection control with antibiotics [3]. This involves removing infected and necrotic tissue with a scalpel, providing a specialized cast model to distribute the body's weight in the foot, and controlling infection through the use of antibiotic treatments, respectively [3]. In this sense, wound management follows the TIME concept (tissue control, infection-inflammation, moisture balance, and edge of wound) [27]. Tissue control corresponds to wound debridement, infection-inflammation comprises the control of the bioburden continuum, moisture balance is related to regulating the wound exudate and restoring the moisture balance, and finally the edge of the wound comprises the promotion of epithelial advancement [27]. The ideal wound dressing material must be non-adherent to the wound, be able to create and maintain a moist environment, reduce the excess of wound exudate, and allow gaseous exchanges [54]. Since a reduction in wound healing time is crucial in lowering the risk of infection and complications in DWs [16], new alternatives such as bioengineered tissue products and natural and synthetic skin grafts have been developed for wound healing [9; 55]. In this sense, biomaterials, such as alginates, collagen, fibronectin, and chitosan, have been exploited to accelerate wound healing, stimulating cell proliferation and angiogenesis [55] in the form of nanofibrous bandages, films, hydrogels, hydrocolloids, tulle, foams, or gauzes [20]. For instance, a chitosan topical gel and film were effective in promoting tissue granulation and DFU closure [56]. The development of a three-dimensional scaffold improves the wound healing result even more, since it acts as a wound dressing, protecting against external infections and also providing an appropriate surface chemistry with nano- and microstructures that facilitate cellular attachment, proliferation, and differentiation [14]. Furthermore, scaffolds are biodegradable, and upon application at the wound site they start to degrade themselves and release drugs in a time-dependent manner into the wound [9]. Despite all of these alternatives, many of these treatments are still expensive, require extensive care, and do not full recover the skin's functionalities [13; 14]. For infection control, the treatment with antibiotics might be performed based on a previous culture of the infected tissue to assess the bacterial colonization profile. The most reported antibiotic therapy options for DFUs in clinical trials are cephalexin and amoxicillin-clavulanate for mild infections and ampicillin-sulbactam, entapenem, impingenem-clastatin, vancomycin, and piperacillin-tazobactam for moderate to severe infections [57]. The systemic administration of antibiotics has been considered an increasing limitation, especially against multidrug-resistant bacteria [16; 58]. Standard antibiotics seem to have a minimal long-term effect on treating chronic wounds, since they are not able to fully penetrate biofilms or attack all species of bacteria embedded in the extracellular polymeric matrix [59]. In the European Union, antibiotic resistance causes 25,000 deaths per year [60], and if not controlled this number might reach 10 million deaths worldwide by 2050 [61]. Among the multidrug-resistant pathogens, _S. aureus_, methicillin-resistant _S. aureus_ (_MRSA_), _P. aeruginosa, E. coli_, extended-spectrum \(\beta\)-lactamase-producing (ESBL) _E. coli_, and vancomycin-resistant _entero cocci_ (_VRE_) have been reported as being challenging in infection treatment [12]. Importantly, 18% of the hospitalized patients with DFUs were positive to multidrug-resistant organisms, mostly _MRSA_[10]. Similarly, another study reported the presence of resistant bacteria in 21.8% of patients, of which 62.7% also presented with _MRSA_[11].