## 8 Functional Aspects of Honey-Loaded Scaffolds for Wound Healing
Similarly, dual crosslinked alginate hydrogels presented a disarranged crystalline structure for high honey concentrations, while honey incorporation up to 4% ensured a morphology favourable for cellular adhesion, a significantly better bactericidal activity compared to the other honey dilutions, and ultimately skin re-epithelialisation with characteristics indicative of healthy uninjured skin and minimal scar thickness [170]. The successful loading of Manuka  
Figure 4: Microphotographs by SEM showing surface morphology of crosslinked silk fibroin (SF) and honey silk fibroin scaffolds (a1) SF, (a2) HSF1 with 1% honey concentration, (a3) HSF2 with 2% honey concentration, (a4) HSF4 with 4% honey concentration, and (a5) HSF6 with 6% honey concentration. Reproduced from Materialia, 12 (2020), 100703; [PERSON] et al. ; Honey-loaded silk fibroin 3D porous scaffold facilitates homeostatic full-thickness wound healing (reproduced with permission from [171], Elsevier, 2020). Figure 3: Pictomicrographs of DNG/Ch/MH (dextran/nanosov/glycerol/chitosan with Manuka honey) dressings at different drug concentrations (10–40%). Reproduced from International Journal of Biological Macromolecules 120 (2018) 1581-1590; [PERSON] et al., Scar-free healing mediated by the release of aloe vera and Manuka honey from dextran bionanocomposite wound dressings (reproduced with permission from [166], Elsevier, 2018). honey into dextran-based dressings was achieved for concentrations up to 20% with a uniform distribution of honey. However, when the honey concentration was above 20%, the dressings were found to be fragile, sticky, and stiff. In addition to these structural disadvantages, a functional drawback was also observed, as the antibacterial activity of the highly concentrated samples was also compromised, in particular against the Gram-negative _E.coli_, as demonstrated by a halved inhibition zone diameter at concentrations beyond 20% [166]. The outcome achieved with a treatment can be affected not only by the intrinsic properties of that given honey variety but also by the protocol design. A factor to take into consideration could be the number of honey applications during the observation time as well as the frequency of the dressing replacements. For example, two daily applications of thyme honey on a rat wound model induced faster healing with a significantly higher fibroblast count and collagen deposition, and early formation of granulation tissue with angiogenesis compared to the control and the single daily application [130]. Lastly, particular attention should be given to the possible interactions between the compound of interest and the hydrogel components, other active agents, and excipients, and how these can affect the pharmacokinetic aspects of the active principle, for example by modulation of its release. For instance, it is worth mentioning that the incorporation of polyphenols within a scaffold or delivery system might restrict their antioxidant potential, as shown by a diminished responsiveness to radical scavenging tests such as ABTS and DPPH of different quercetin-hydrogel formulations compared to the free flavanol [173]. In addition, no statistical difference in antibacterial potency was observed between Manuka honey samples with different UMF when these were loaded into scaffolds for medical engineering, despite a significantly different bacterial inhibition being obtained with direct application of the same honeys [92].