## 3 Nanosized-Lipid-Based Drug Delivery Systems in Wound Healing
### Lipid Nanoparticles in Wound Healing
#### 3.2.2 Nanostructured Lipid Carriers in Wound Healing
For instance, in vivo and in vitro research assessed the efficiency of eucalyptus essential oil loaded in NCLs as potential therapy for skin wounds. NCLs were prepared with cocoa butter (solid lipid) and olive oil (liquid lipid). As a surfactant, lecithin was used to increase stability and prevent aggregation. This formulation increased the bioavailability and efficiency of eucalyptus oil regarding antimicrobial effects and proliferation enhancement. A high level of oleic acid present in olive oil could be the reason for these better effects [52]. Another recent study evaluated the efficiency of peppermint essential oil loaded in NLCs. Peppermint oil loaded in NLCs presented an optimal EE% and particle size and was better than free peppermint oil in terms of neovascularization, the wound contraction ratio and re-epithelialization. The in vivo study results emphasized significant antibacterial activity against _S. epidermidis, S. aureus, L. monocytogenes, E. coli_ and _P. aeruginosa_ species [87]. _Mentha pulgeium_, another essential oil with antiseptic and anti-oxidant effects, was also encapsulated in NCLs, and in vivo research showed an important effect against the same bacterial species. Moreover, an in vivo study on BALB/c mice showed that this new formulation reduced the inflammatory phase and accelerated wound healing [164]. Another concern is the oxidative stress associated with chronic inflammation. Oxidative stress is caused by an imbalance between the production of pro-oxidants on the one hand and the capacity of a biological system for the rapid detoxification of free radicals on the other. Oxidative stress is involved in various conditions affecting the skin [165; 166; 167; 168] and also is frequently encountered in association with diabetes-induced chronic wounds [169]. A wound-healing natural compound with bifunctional properties that can respond to oxygen species and increases antioxidant enzyme production is curcumin (diferuloyl-methane), an active substance of turmeric. While various studies in the last decade have shown numerous properties of curcumin, such as anti-inflammatory, antineoplastic or antimicrobial effects, its clinical applications are limited due to its low bioavailability caused by reduced water solubility and stability [170]. Hence, encapsulation of curcumin in nanoparticles was investigated in order to increase its delivery capacity. A recent article evaluated the encapsulation of curcumin and epidermal growth factor (EGF) in NCLs, showing excellent results in stimulating wound healing in a diabetic murine model. EGF plays a paramount role in cell proliferation and the migration of fibroblasts and keratinocytes, and its administration into wounds leads to rapid re-epithelialization and reduces the risk of infection. In vivo research showed better cell migration when NCLs were loaded with both EGF and curcumin. The in vivo studies on diabetic rats revealed a shorter half-healing time associated with this formulation [57]. Melatonin, a molecule known for its anti-oxidant and anti-inflammatory effects, was investigated in several studies for its possible role in wound dressings [171; 172]. Recently, a group of researchers developed a hybrid system of melatonin integrated into NLC-loaded, chitosan-based microspheres, a wound-dressing innovation for moderate exiting wounds. Melatonin NCLs presented a small size particle, a positive zeta potential, a great EE% and a sustained drug release. Furthermore, in vivo research manifested antimicrobial effects against planktonic bacteria and _Staphylococcus aureus_[171]. Additional studies have explored the potential of various drugs incorporated in NCLs to decrease inflammation. For instance, in interesting research, thymol, a compound with anti-inflammatory properties, was encapsulated in NCLs to enhance its bioavailability. The study on the murine skin inflammation model revealed that NCL-thymol had stronger anti-inflammatory effects than free thymol [173].