## 4 Current Challenges for the Wound Healing Applications of HA
By forming physical crosslinking between HA and a second polymer, it is possible to increase the mechanical properties. Silk fibroin (SF), a protein in epithelial cells within the glands of arthropods, presents considerable advantages such as compatibility [154]. A key benefit of SF-based scaffolds is their ability to closely resemble ECM thanks to their fibrous structure and biochemical properties. Furthermore, SF has been approved by the Food and Drug Administration. Despite its versatility, hydrogels based on native HA often have limitations in terms of mechanical properties and stability; thus, the combination of HA/SF/alginate for skin repair was reported by [PERSON] et al. After 7 days, the presence of collagen fibers was observed, and on the 14 th day, a considerable amount of collagen and new tissue formation was observed. After 21 days the HA/SF/SA group only had a reduction of 97% of wound size with regularly distributed collagen [155]. A second strategy for increasing mechanical properties is the preparation of nanocomposites. For example, the use of active bioglass (BG) nanoparticles and their derivatives, such as copper-doped bioglass (CuBG) NPs, has been extensively used in bone repair because of their osteogenic and angiogenic activities [156]. As a strategy, [PERSON] and collaborators synthesized thiolated HA and combined it with bioactive glass and SF to build a composite hydrogel. The degree of substitution (DS) of thiolated HA (T-HA) was around 7.8%. The hydrogels showed enhanced strength and stiffness compared to the gels built from HA-SH and SF with well-defined elasticity and injectability. The BG/HA-SH/SF gels stimulated the migration of both fibroblasts and human umbilical vein endothelial cells. Furthermore, CD31, a typical biomarker for endothelial cells, was followed; thus, the gels stimulated angiogenesis and facilitated revascularization of neonatal skin tissues [157]. [PERSON] et al. developed a composite consisting of HA-tyramine, thiolated glycol chitosan (TG-Chitosan), and CuBG for fast wound healing. HA (7.0 \(\times\) 10\({}^{4}\)) was activated by EDC/NHS and grafted with tyramine (DS = 6.0%). Glycol chitosan (8.0 \(\times\) 10\({}^{4}\) g/mol, 0.8 percent of substitution) was chemically modified by 3,3'-dithiodipropionic acid. The mechanical strength reached 1.91 kPa. L929 cells were cultured in contact with composites to explore their migration using scratch assay. The migration of silica and copper ions stimulated the migration of human umbilical vein endothelial cells. The regeneration of hair follicles, sebaceous glands, and skin appendages was observed after 15 days [158]. Normal healing processes are impaired in conditions characterized by hypoxia, a common occurrence in the wound bed. This condition is treated by oxygen delivery or generating materials for wound dressings [159]. The use of metal peroxides that produce oxygen in the presence of humidity is also a known strategy. In wound healing, calcium peroxide (CPO) is the most used metal peroxide due to its desirable oxygen-generation potential and good thermal stability. Recently, the use of nanozymes such as HA/MnO\({}_{2}\) was constructed via in situ mineralization and used Mn-hydrazide coordination crosslinking. This kind of material can be used for O\({}_{2}\) generation by phototherapy applied to wound healing. [160]. [PERSON] et al. reported lyophilized perfluorodecalin encapsulated in albumin nanoparticles immersed in an HA (unknown Mw) gel able to administer supplemental oxygen and improve wound healing. The hydrogel enhanced cell migration and angiogenesis in vitro [161]. Combining HA with conductive materials such as polypyrrole (PPy) is also helpful for macrophage activation and regeneration. [PERSON] et al. combined polyethylene glycol (PEG), PVA, and HA with PPy nanoparticles prepared in alcohol solution via radical polymerization. The hydrogels were prepared by four freeze-thaw cycles using a composition of 0.74:0.11:0.11 up to 0.04% of PPy.