## 6 Latest Advances of Honey Applications in Wound Care
Due to the severity of the potential consequences, urgent progress in the management of diabetic ulcerations is required, with early intervention and preventative plans of action as cardinal elements in the therapeutical strategy. Clinical use of honey as an alternative option in the treatment of DFUs is described in the medical literature, with the main limitations being the small number of patients involved in the studies and the difficulty of quantifying the dose employed in case of direct honey application, as the quantity is usually determined simply by the need to cover the wound and surrounding skin area [122; 123; 124; 125; 126; 127]. [PERSON] et al. illustrated the case study of a large leg ulceration on a female diabetic patient with metatarsal exposure and concurrent systemic infection, requiring surgical debridement of necrotic and devitalised tissue. After two months of daily propolisis-enriched Trigona honey applications, full re-epithelialisation could be observed on the wound site, which on clinical observation was observed to display reduced signs of inflammation [128]. Six patients diagnosed as at risk of limb amputation due to infected DFUs non-respondent to conventional therapies were successfully treated with Manuka honey-containing commercial formulations. The infections, due to bacteria resistant to antibiotics, were managed in 2.6 weeks (average time), and the honey treatments also reduced malodour after just a few days of application. The use of these cost-effective medical grade honey products, enriched with vitamin C and E, induced autolytic debridement and replacement with granulation tissue within 3.5 weeks, thus reducing the healing time [129]. In all the examined cases, honey application induced positive clinical outcome with improved tissue regeneration and successful wound contraction, with no allergic reactions nor maceration of the perivound area. Further studies, possibly randomised clinical trials with significantly more patients recruited, is now needed to corroborate these promising results and support an evidence-based use of honey in the treatment of DFUs. Honey destined for consumption as a food product contains inactive endospores and other innocuous contaminants, and so it needs to be filtered to remove the impurities [130] or decontaminated by gamma-ray exposure prior to the application on wounds in order to meet the standards for medical use [131]. Likewise, gamma irradiation is employed to sterilise hydrogels designed to treat skin injuries [132; 133]. Furthermore, gamma irradiation is an essential step in the gelation of some polymer materials, as it initiates the process of crosslinking [134; 135; 136]. However, despite neutralising the total bacterial count on samples, this process of sterilisation does not compromise honey's efficacy against bacteria and biofilms, as demonstrated on fir honeydew honey at 10, 20, and 30 kGy [137]. Nonetheless, this treatment induced a significant dose-related reduction in small peptides such as defensin-1 at radiation doses over 10 kGy, which was probably by conformational alteration and aggregation, whereas higher molecular weight proteins such as GOx were not affected. Despite this report of a reduction in defensin-1, considering that the honey antimicrobial activity is ascribed to a multifactorial mechanism and that the other factors do not seem to be affected by the sterilisation, honey can be considered a safe and effective alternative option for the management of infected wounds. Honey incorporation within scaffolds with different designs has been explored as a strategy to potentiate its medical effects on skin injuries, providing a favourable environment to facilitate complete healing across all the skin strata. Typical design considerations include an easy-to-handle structure that is suitable for commercialisation and while also safe for home medication.