## 3 Nanosized-Lipid-Based Drug Delivery Systems in Wound Healing
### Vesicular Systems
#### 3.1.2 Ultra-Deformable Liposomes or Transfersomes in Wound Healing  
Currently, conventional liposomes are less utilized as transdermal delivery systems due to the development of new vesicular systems named ultra-deformable liposomes, elastic vesicles or transfersomes [108]. The chemical structure of transfersomes consists of a phospholipid bilayer, an edge activator and water [40] (see Figure 2b). Surfactants such as sodium deoxycholate, sorbitan monostearate, sorbitan monooleate (Span 80), sorbitan monolaurate or polysorbate 80 (Tween 80) are commonly used edge activators [109]. Moreover, Span 80 is more effective than Tween 80, and sodium deoxycholate provides maximum deformability to the vesicle membrane pores [110]. The evaporation of water when the lipid suspension is dispersed on the skin surface determines the penetration capacity. The elasticity of vesicles helps them deform and penetrate, as intact vesicles, skin pores that are much smaller than their diameters. Edge activators play an important role in this remarkable deformability of transfersomes, having the potential to solubilize and fluidize the skin lipids, leading to a higher permeation capability [111]. Two standard techniques were reported in order to manufacture transfersomes, which are the thin-film hydration and modified handshaking methods. Transfersomes are chemically unstable during storage as a consequence of their propensity to oxidative degradation. Hence, lyophilization is a method used to increase the storage stability of the transfersomes with satisfactory results [112]. In most cases, they present a high EE% of 90%, particularly for lipophilic drugs [111], a high drug loading capacity [113] and a size range between 100 and 400 nm [114]. These novel carriers combine the benefits of traditional liposomes and exhibit more advantages in topical treatment, enabling the controlled release of the active substance and augmenting the stability of unsteady drugs [115]. Several studies have explored the encapsulation of peptides, such as growth factors, to ensure optimal delivery. For instance, recombinant human epidermal growth factor (rhEGF) is an endogenous polypeptide that regulates cell proliferation and differentiation [116]. This peptide can be an excellent formulation for skin conditions such as chronic wounds, diabetic ulcers or burns. Nevertheless, its instability is prone to affect the properties of the product, also diminishing its biochemical actions [117]. A great approach to enhancing their penetration was the encapsulation of rhEGF in transfersomes. The skin penetration of rhEGF was increased using transfersomal rather than non-transfersomal emulgel formulation. In this study, the best formulation of transfersomes was achieved with a vesicle-to-active-ingredient ratio of 200:1. These newly formed vesicles were spherical and unilamellar, with a size range of less than 200 nm and a zeta potential less than \(-30\) mV, demonstrating great stability, excellent deformability and high entrapment efficiency. The emulgel formulation used in this study can be more advantageous, enhancing the drug stability and release compared with gel base-incorporated active substances [116]. In another experiment on growth factors, a topical delivery system for the low-molecular-weight-protamine (LMWP)-fused growth factors (GFs) combined with hyaluronic acid (HA) was developed. In this study, cationic elastic liposomes, along with the GF-HA complexes, were explored as better suited carriers in diabetic wound therapy. This formulation allowed for extended exposure of the GF-HA vesicles in the wound bed, reducing the required dose for GFs. Transfersomes containing the LMWP-fused GFs along with HA improved the wound healing capacity in a diabetic mouse model, inducing a decrease in wound size of approximately 65% [64]. Recent research on diabetic rats evaluated the healing capacity of deferoxamine-loaded transfersomes in pressure ulcers.