## 4 Current Challenges for the Wound Healing Applications of HA  
Current challenges in wound healing management include infection control, moisture management, adhesion to the tissue, pain, and discomfort during removal of the patches. Wound dressings should present porosity and adequate Young's modulus. Building dressings with strong interfacial force, mechanical strength, and biodegradation that mimic the surrounding tissues is very challenging. Moreover, hydrogels should be characterized by adequate porosity, lap-shear strength, and controlled biodegradation. Some groups started reporting the use of lap-shear testing for characterizing adhesion to the tissue. But the methodologies do not exactly follow the norms. The characterization of commercially available products greatly varies. Hydrogels have the advantage of being reservoirs of active pharmaceutical ingredients (antimicrobials, antiseptics, painkillers). But they are usually characterized by poor mechanical properties. Therefore, building hydrogel-based wound dressings with strong interfacial force, mechanical strength, and biodegradation that mimic the surrounding tissues is consequently extremely difficult. The incorporation of synthetic polymers for wound management could present several drawbacks, such as occlusion of exudates, as they are not adsorbents. These polymers present different structures than the ECM with risks of infection, foreign body response, or immunogenic reactions. Hydrocolloid dressings are occlusive (Duoderm, Granuflex, Comf eel) [134]. They are usually composed of polysaccharides or natural materials (agar, alginate, carrageenan, gelatin, or pectin) to avoid irritation after skin contact. They are formulated with carboxymethylcellulose to increase their adsorption capacity and poly(urethane) for strength, but they are not designed to prevent infections or to use for bleeding wounds. It is worth mentioning that novel developments should be compared to commercial hydrogel wound dressings, which occur in limited cases in the literature. For example, Medifoam(r), a commercially available polyurethane foam-film dressing, has one of the smallest pores (25-75 \(\upmu\)m and 100-350 \(\upmu\)m in the cross-section) and cell sizes with excellent uniformity on the wound contact layer, with elongation at break corresponding to 400% and tensile stress of 0.033 kgf/mm\({}^{2}\)[135]. Mechanical characterization of commercial wound dressings is scarcely reported in the literature. For example, [PERSON] et al. determined the Young's modulus of commercially available fibrous dressings such as Kaltostat(r), Aquacel(r) Ag, Aquacel(r) Extra, and Exufiber(r). The tested values vary between 0.24 and 0.95 MPa, with a total elongation from 68 to 134% [136]. [PERSON] et al. reported elongation at break from 85.0 to 202.2%, the tensile strength was only 71.5 kPa [137]. Thus, it should be a compromise between bioactivity and functionality. Some other authors tested lap-shear strength to assess the hydrogel's adhesive properties. In this case, a lap-shear test and a T-peel should be performed according to norms ASTM F2255-05 (Standard Test Method for Strength Properties of Tissue Adhesives in Lap-Shear by Tension Loading) and ASTM F2256-05 (Standard Test Method for Strength Properties of Tissue Adhesives in T-Peel by Tension Loading). It is worth mentioning that the main challenges of HA-based products for wound healing are their short shelf life and low stability due to their enzymatic degradation in vivo [43]. This is the main reason to use chemical modification by the reactions described in Section 3. However, inconsistent biological properties of the prepared materials may occur due to a lack of testing and correct description of physicochemical properties during research. A known challenge is colonization of the wound bed with bacterial pathogens. This fact is responsible for delayed wound healing. Furthermore, persistent inflammation, odor, erythema of periwound skin, and increasing exudate promote progression to a chronic, non-healing wound type [138].