## 4 Current Challenges for the Wound Healing Applications of HA
Even though HA is bacteriostatic, it is not bactericidal; therefore, HA-based dressings can be incorporated with inorganic nanoparticles [139; 140], antibiotics [88], antimicrobial peptides [80], antiseptics [141; 142], and materials capable of generating reactive oxygen species, which can be obtained via chemical modification [143] for imparting antimicrobial properties. A key characteristic of modern dressings is their ability to retain or create a moist environment around the wound [9]. Moisture-retentive wound dressings represent a new window toward wound therapy. Recently, considerable efforts have been made toward the design of shape-personalized wound dressings using electrospinning [144]. However, a pure HA solution cannot be processed in a nanofiber matrix by electrospinning. Polymers such as polyethylene oxide (PEO) are used during the processing with a consequent problem due to loss of biocompatibility. A second challenge is the use of organic solvents such as 1,1,1,3,3,3-hexafluoro-2-propanol (HFP), which makes scaling-up difficult due to high price and toxicity. A third challenge is the fast dissolution of the polymeric mats, which is solved by using chemical crosslinking [145]. The use of 3D printing for the design of dressings with customizable shapes, drug dosage, and drug release rate is also a novel technology to be considered [146; 147; 148]. This technology allows forms able to fill the ulcer cavity. Hence, it could potentially lead to the fabrication of a new generation of wound dressings. In this case, the scale-up of 3D printing could decrease the price of personalized dressings. The last challenge is the cost of wound dressings. As the patient needs continuous changes of dressings, a high cost is common. Indeed, evidence comparing the cost-effectiveness of HA and SoC dressings is still missing [149]. Educating patients on proper dressing changes and care to ensure optimal healing is a possible solution [150]. The current generation of wound dressings clinically used lacks hemostatic properties, as no components of theirs have been designed with the goal of reducing the clotting time, which would, in turn, reduce the propensity for infection or allergic reaction and speed up the healing. The combination of HA with active molecules (peptides, proteins) could impart the required bioactivity such as adhesion, hemostasis, and more. During the last five years, the most studied formulations found in the literature are hydrogels or injectable hydrogels. Table 2 describes highly potential developments in the field of HA. \begin{table}
\begin{tabular}{p{42.7 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**Biological Testing** **In Vitro** & **Physicochemical Characterization** & **Form** & **Composition** & **Major Outcomes** & **Ref.** \\ \hline \multirow{4}{*}{
\begin{tabular}{} \end{tabular} } & In vivo & & & & Modulation of macrophages. \\  & In vivo & & & & Induction of angiogenesis. \\  & In vivo & & & & Induction of angiogenesis. \\  & In vivo & & & & Induction of wound contraction on day \\  & In vivo & & & & 14 th. \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Selected examples of novel developments containing HA describing in vitro, in vivo, and physicochemical properties.