## 2 Hyaluronan Role in Wound Healing  
HA biosynthesis is an energy-consuming process, and, together with its catabolism, is connected to the maintenance of homeostasis. HA production is influenced by signaling pathways such as growth factors and cytokines (i.e., recombinant tumor necrosis factor (TNF-\(\alpha\)), IFN-\(\gamma\), and IL-1) [17]. For normal cells, several signaling cascades activated by receptors on the cellular membrane can induce HA production upon ligand binding. To date, little is known about the role of the extracellular matrix in HA biosynthesis. The microenvironment and stress conditions alter HA metabolism at several levels: Increasing gene expression in response to various stress agents such as hypoxia [18]. Acute hypoxia results in an increase in vascular endothelial growth factor (VEGF) expression that stimulates the proliferation of human dermal fibroblasts. However, the persistence of chronic hypoxia in chronic wounds hinders angiogenesis via multiple mechanisms [19]. The microenvironment regulates HASes to balance the synthesis of HA in the extracellular space and cell surface in response to the organism's state [20]. This regulation is crucial for maintaining tissue homeostasis and responding to physiological and pathological stimuli. Furthermore, cytokines, growth factors, and mechanical stress have been shown to influence the activity of HASes, leading to changes in HA metabolism in many cells [21; 22; 23]. HA serves diverse functions in a variety of cell types, influencing cellular proliferation, motility, differentiation, and survival, and maintaining the ECM structure. HA is essential in the skin, where it helps to maintain proper hydration and viscoelasticity [24]. Particularly, HA is produced by both epidermal and dermal fibroblasts and is accumulated in keratinocyte stem cells, influencing differentiation, migration, and proliferation. Skin aging and other photoinduced pathologies are strongly associated with decreased HA content [25]. In joint tissue, synovial fibroblasts and mast cells produce HA to maintain proper viscoelastic properties of synovial fluid that protect cartilage [26; 27]. Cell lines from patients with osteoarthritis exhibit lower concentrations of HA. Indeed, reduced HA synthesis and increased catabolism are implicated in osteoarthritis [28]. Beyond these, HA is vital for viscoelasticity in the vitreous humor and interaction with epithelial mucin domains [29]. In conditions such as acute injury, chronic inflammation, or systemic infection, ECM undergoes changes due to modification in its structural integrity. During tissue injury or inflammation, high-molecular-weight hyaluron (HMW-HA) is degraded by HYALs, producing smaller, low-molecular-weight hyaluron (LMW-HA) fragments. These fragments play a crucial role in the inflammatory response by interacting with immune cells and activating pro-inflammatory pathways. This degradation has been observed in diseases such as osteoarthritis and systemic lupus erythematosus, where LMW-HA correlates with chronic inflammation and immune activation [30]. The Mw of HA is crucial and determinant in therapeutic application. For instance, HMW-HA is commonly used in viscosupplementation to reduce pain and improve joint function due to its ability to restore synovial fluid viscosity [31]. HA is involved in all the phases of wound healing (Figure 3). _Phase I: hemostasis:_ This phase involves the formation of blood clots to stop bleeding from injured blood vessels. In cases of severe trauma, excessive and uncontrolled bleeding dismisses the body's natural hemostatic capacity, leading to significant blood loss and impaired wound healing. Thus, platelets generate HMW-HA that facilitates the passive diffusion of water into the interstitial space, resulting in edema. This promotes cell migration of inflammatory cells to the wound and provides a temporary scaffold [32].