## 3 Nanosized-Lipid-Based Drug Delivery Systems in Wound Healing
### Vesicular Systems
#### 3.1.1 Conventional Liposomes in Wound Healing
mixed liposome-formulated micro-RNA-132 mimics with pluronic F-127 gel. This mixture was topically applied onto human ex vivo skin wounds immediately after injury, resulting in an increased level of micro-RNA-132 in the wounds a few days after the beginning of treatment. The healing process was reinforced, which greatly accelerated wound closure, repressed inflammation and increased keratinocyte proliferation [99]. Encapsulation of adenosine triphosphate (ATP) in unilamellar lipid vesicles was used for intracellular energy delivery and was tested on ear skin wounds in rabbits. The essential finding of this study was the extremely rapid granulation tissue growth in ischemic and non-ischemic rabbit ear skin treated with intracellular ATP liposomes compared with a saline-treated group [100]. The impairment of wound healing is mainly caused by inadequate blood perfusion, leading to hypoxia within the wound area. Buffomedial hydrochloride is a vasoactive drug that has been encapsulated in liposomes, causing significant wound epithelialization and a reduced period until complete wound closure [101]. Topical formulation, applied daily until complete neovascularization, has been shown to be beneficial in wound care, thus overcoming the side effects of systemic administration [101]. In another study, an improved wound closure rate and reduced inflammation were obtained by delivering syndecan-4 into liposomes along with platelet-derived growth factor BB, all embedded in alginate dressing [102]. Recent studies have highlighted that epidermal growth factor (EGF) or related peptides play essential roles in healing wounds resulting from burn lesions. However, these peptides have shown low stability in conventional formulations. An in vivo experiment evaluated the stability and effects of EGF loaded in liposomes as follows. Researchers inflicted second-degree burn wounds on female Sprague Dawley rats and split them into six groups. The rats treated with a liposome formulation containing 10 \(\upmu\)g/mL EGF, applied daily for two weeks, recorded the best healing effect [50]. Furthermore, the same research group performed a study where multilamellar EGF-loaded liposomes carried in chitosan gel were developed and assessed for burn wounds. Chitosan is a polysaccharide with excellent biological properties, such as hemostatic activity, biocompatibility, antimicrobial activity and the capacity to accelerate wound healing when administered as a wound dressing. At the end of the treatment, the EGF-loaded liposome group's epithelization rate was the highest when considering the histochemical results among all the other groups [103]. Regarding natural agents, we found studies that evaluated their incorporation in vesicles as a wound treatment. Essential oils (EO) loaded in vesicular systems represent a practical approach to enhancing their biopharmaceutical properties. Despite the wide use of these plant extracts on account of their antiseptic properties, issues such as high volatility and low stability led to limited use in clinical practice [65]. In an in vivo study, _Rosmarinus officinalis_ and _Salvia triloba_ essential oils were loaded into liposomes. Due to the strength of the anionic charge repulsion into their surfaces and a zeta potential of \(-30\) mV, these systems were highly stable. There was no significant variability in the stability of each formulation. The antimicrobial effect of these vesicles was tested using different bacterial strains. As a result, EO effectively counteracted bacterial growth, with a substantial inhibitory effect on _Klebsiella pneumoniae_. Additionally, the antioxidant properties of the EO were preserved [81]. Another study loaded liposomes with citral and compnia EO, promoting their dermal delivery and enhancing their antimicrobial activity against all the assayed microorganisms [104]. Liposome encapsulation also exceeded the reduced membrane permeability of a highly potent compound used in treating wounds called madecassoside (MA).