## 3 Nanosized-Lipid-Based Drug Delivery Systems in Wound Healing
### Lipid Nanoparticles in Wound Healing
#### 3.2.1 Solid Lipid Nanoparticles in Wound Healing  
SLNs were described as alternative drug delivery systems to emulsions and liposomes. They consist of 0.1-30% \(w/w\) solid lipid dispersed in an aqueous medium and can be stabilized with 0.5-5% \(w/w\) surfactant (see Figure 2d). Several of the solid lipids used are free fatty acids (stearic acid and palmitic acid), waxes (cetyl palmitate), triglycerides (tri-stearin), monoglycerides, diglycerides, fatty alcohols and glycerol esters [45]. The mean particle sizes of SLNs range from 40 to 1000 nm [138]. They are composed of substances recognized as safe; most lipids are biodegradable, also presenting low local adverse reactions and low cytotoxic effects on the human cells [45]. SLNs showed the ability to shield active substances against physicochemical degradation, also maintaininga controlled release over an extended period. Aside from that, they are more affordable, biodegradable and easy to sterilize [45; 139]. The reported data showed that SLNs have a typical EE% between 50% and 100% [140], a mean particle size between 50 and 500 nm [141] and a drug loading capacity up to 33%. During storage, due to its solid lipid structure, the rigid core formed conducts the drug expulsion through the matrix [142]. Hence, the lyophilization process is a suitable method to increase the physical and chemical stability of SLNs [143]. Moreover, they can be easily scaled up to industrial-scale through homogenization at 500 bar pressure [144]. Other available methods to produce SLNs are ultrasonication, double emulsion, high shear homogenization, spray drying methods, solvent injection, melt dispersion or using microemulsions [145; 41]. Based on these properties, several studies have investigated the advantages of SLNs for cutaneous application, evaluating their release profile and potential use for wound-healing treatments. Additionally, many studies have used the encapsulation of molecules in SLNs to increase collagen settlement and reduce inflammation. For instance, all-trans retinoic acid (ATRA) is a derivative of vitamin A that has been suggested as a possible efficient wound-healing medication [55]. However, several issues, such as its insolubility in water, instability and the high risk of adverse reactions, have limited the topical use of ATRA. ATRA was encapsulated in SLNs and incorporated in a chitosan film to overcome these problems, presenting a high encapsulation efficiency and controlled drug release. In in vivo studies on diabetic mice, SLNs exhibited accelerated wound healing rates, improved collagen deposition and reduced scar and leukocyte infiltration. Moreover, no local adverse reactions were observed [55]. An in vivo study on HaCaT cells highlighted that tristearin encapsulation and hyaluronic acid in SLNs significantly improved wound healing [146]. Regarding chamomile oil, one of the most frequently used herbs with a great effect in stimulating wound healing, it has a limited application as a topical treatment due to its inadequate tissue permeability and rapid degradation after exposure to environmental factors. Encapsulation of chamomile oil in SLN (CM-SLN) revealed an enhancement in wound contraction and accelerated healing activity, restoring skin integrity. Moreover, rats treated with CM-SLNs presented higher levels of transforming growth factor-\(\beta\)1 (TGF-B1) compared with the control group, with this factor playing a pivotal role in fibroblast contraction and collagen settlement [84]. In another complex study with in vivo, ex vivo and in vitro research, tetrahydro-cumin (THC), a substance with great antioxidant and anti-inflammatory features, was incorporated in SLNs in order to elevate its topical bioavailability. The results indicated a faster and better wound healing rate in the mice treated with THC-SLN gel.