## 1 Introduction  
Chronic skin wounds affect more than 40 million patients globally and represent a severe growing burden for the healthcare systems, with annual costs expected to exceed USD 15 billion in this decade [1]. Particularly, HA considerably improved the healing of leg ulcers compared to other vehicles without the polysaccharide or placebo [2]. Still, it is uncertain if there is any difference in effectivity between HA and other dressings on diabetic types of wounds. The vast majority of randomized controlled trials showed that HA and its derivatives significantly improved the healing of wounds versus traditional therapies or placebo [3]. Bandages and gauzes, serving as materials to absorb exudates and offer physical shielding, are the most used procedures for wound management [4]. Advanced wound dressings containing HA actively promoted wound healing in non-infected wounds compared to standard-of-care (SoC) treatments [5]. Even though several reviews described the use of polymers (synthetic and polysaccharides) for wound healing, HA is ubiquitously present in the human body and metabolism; thus, it presents more advantages. Therefore, this review presents the latest developments in HA-based formulations, including relevant clinical trials. Sodium hyaluronate (hyaluuronan, abbreviated as HA) is a linear polysaccharide consisting of D-glucuron acid (GlcNAc) and \(N\)-acetyl-D-glucosamine (GlcNAc) disaccharides, linked via alternating \(\beta\)-(1,4) and \(\beta\)-(1,3) glycosidic bonds (Figure 1). HA is a polysaccharide found in mammalian connective tissues and extracellular matrix (ECM) in high concentrations. HA plays an essential role in cell-cell interactions (adhesion), has unique hydrophilic properties, and forms elastic fibers in the ECM. HA biochemistry plays a vital role in both basic research into biological phenotypes. HA is involved in many recent developments concerning the regeneration of injured organs. Finally, HA is involved in the process of inflammation and cancer [6; 7], immunity [8], and infection [9]. Hyaluronan is synthesized at the inner face of the cell plasma membrane by hyaluron syntheses (HASes). Three isoforms of HAS (HAS 1, 2, and 3) have been identified. HAS1 and HAS3 synthesize HA of medium molecular weight MMW-HA (\(\sim\)2.0 \(\times\) 10\({}^{5}\) to 2.0 \(\times\) 10\({}^{6}\) g/mol). Very large MW-HA (>2 \(\times\) 10\({}^{6}\) g/mol) is synthesized by HAS2. HASes catalyze the biosynthesis of HA by using UDP-glucuron acid (UDP-GlcNAcUA) and UDP-\(N\)-acetylglucosamine (UDP-GlcNAc) as substrates. The synthesis of HA in mammalian cells is regulated at the level of gene transcription and pathophysiologic conditions. Most gene transcription factors regulate the expression of the three HAS isoenzymes in a coordinated manner, leading to an overall decrease in HA production. The synthesis of HA in cells is primarily regulated by UDP-\(N\)-acetylglucosamine, \(N\)-acetylglucosamineaminylphosphotransferase, and UDP-glucuron acid, which is rapidly transported into the cell lysosomal compartment [10]. To date, HASes have been found in bacteria, pathogenic yeast, protozoa, nematodes, plants, and vertebrates [11; 12]. Synthesized via the Embden-Meyerhof-Parnas pathway, the precursor glucose-6-phosphate is converted to glucose-1-phosphate by phosphoglucomutase (pgm) before UDP-glucose pyrophosphylase (hasC) transfers a phosphate group from UTP to glucose-1-phosphate, forming UDP-glucose (UDP-GlcNAc). UDP-GlcNAc is oxidized to UDP-glucuron acid (UDP-GlcNAc) by UDP-glucose dehydrogenase (hasB). The associated genes--hasB, hasC, hasD, and hasE--encode several enzymes such as UDP-glucose dehydrogenase (hasB),  
Figure 1: Hyaluuronan chain is composed of D-glucuron acid and \(N\)-D-acetylglucosamine linked together with \(\beta\) (1–3) and \(\beta\) (1–4) glycosidic bonds, respectively. UDP-glucose pyrophosphoryylase (hasC), the bifunctional enzyme (\(N\)-acetyltransferase and pyrophosphoryylase, hasD), and phosphoglucoisomerase (hasE), respectively.