## 3 Nanosized-Lipid-Based Drug Delivery Systems in Wound Healing
### Lipid Nanoparticles in Wound Healing
#### 3.2.1 Solid Lipid Nanoparticles in Wound Healing
This new formulation showed higher skin permeability and extended the drug release for more than 24 h. THC-SLN gel can be a safer alternative to the currently available products, increasing patient compliance with treatment due to its non-staining, non-irritating, non-greasy and easily spreadable properties [83]. Concerning drugs with antimicrobial activity, we found many studies that used SLN encapsulation to enhance this effect. Cefadroxil-loaded SLN-based topical gels were evaluated for in vivo wound healing activity in male rats. This formulation could eradicate bacterial growth and effectively treat an infectious wound in a short span of time [147]. Other research evaluated the potential therapeutic effects of combining LL37 and Serpin A1 into a single nanoparticle formulation using SLNs as a delivery system. LL37 is a human peptide with broad antimicrobial activity. It also plays an efficient role in angiogenesis and epithelial cell migration. Regarding Serpin A1, also known as \(\alpha\)1-antitrypsin, it is a major physiological elastase inhibitor and immunomodulator. The in vivo experiments on BJ fibroblasts and keratinocytes showed an accelerated wound healing effect, stimulating wound closure. Moreover, this formulation increased antibacterial activity, especially against _S. aureus_ and _E. coli_, and presented anti-inflammatory effects [85]. As mentioned before, one of the preferred antimicrobial agents in burn wound therapy is silver sulfadiazine (SSD). However, in several cases, the wound-healing process was delayed due to its toxicity on fibroblasts and keratinocytes [148]. Hence, a chitosan gel rich in SLN-SSD along with deoxyribonuclease-I was tested and showed an essential cytoprotective activity with fibroblasts. Moreover, this new formulation improved the therapeutic effect of SSD on biofilm resistance associated with wound infection and significantly increased the wound closure [145]. Another study evaluated curcumin and ampicillin SLNs incorporated in semi-solid formulations (ointments and gels) as potential forms of therapy in burn wounds. Both SLN-based formulations presented a mean particle size of 112-121 nm, low zeta potential and increased wound healing rate in vivo without any sign of toxicity. Moreover, they exhibited a synergistic antibacterial effect [149]. A recent study evaluated another antiseptic drug used in wound healing therapy, povidone-iodine, incorporated in SLNs. The povidone-iodine encapsulation in SLNs created a formulation with good stability, a mean particle size of 285.4 nm and an optimal EE% [150]. Topically applied opioids have shown an enhancing keratinocyte migration effect, which can hasten wound healing, but their poor concentration at the target site failed to maintain pain control. Therefore, researchers attempted to improve wound healing through a new human-based, 3D wound-healing model using morphine-loaded SLNs with a mean size of about 180 nm. This unique formulation, compared with the conventional one, improved wound closure, with lower cytotoxicity and irritation risk, associated with a prolonged morphine release [151]. Valsartan, an antagonist of the angiotensin 1-receptor, was used in an experimental study to increase the diabetic wound-healing process. Based on previous studies, which reported its efficacy in chronic diabetic wounds [152, 153], Valsartan was encapsulated in SLNs and integrated into a gel composition in order to improve its dermal permeability. Evaluation of valsartan SLNs showed a small particle size, sustained drug release and high EE%. In vivo investigation revealed complete healing of the diabetic ulcers in rats in 12 days [154]. Even though SLNs have broad applicability in wound-healing therapy, these nanoparticles have encountered several disadvantages, such as a propensity to gelation, a low incorporation rate due to their crystalline structure or lipid particle growth [42], thus encouraging further research for the discovery of new, more efficient carriers.