## 5 Clinical Products Containing Hyaluronan Used for Wound Healing
[PERSON] and [PERSON] revised clinical evidence that supported the effectiveness of esterified HA for patients with difficult, non-progressive wounds, including venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). The authors found evidence that the wound area decreased, with a 50% increase in granulation tissue after 55 days [171]. Creams and ointments offer several advantages over other preparations due to the possibility of incorporation of water- and oil-soluble ingredients. Creams containing HA and sulfur sulfadiazine are indicated for use in burns, chronic wounds, surgical wounds, and skin abrasions/irritations. [PERSON] and collaborators recently reported the results of the efficacy and tolerability of Connettivina Bio(r) Plus (group A) gauze and cream containing HA and compared them to Fitostimoline(r) Plus (group B) gauze and cream for the treatment of acute superficial skin lesions containing a wheat-derived polysaccharide, polyhexanide and glycols using a single-center, parallel, randomized trial. The total healing observed for group A was 56.6%, while for group B it was 93.3% (\(p\) = 0.001), with 100% of healing for both patient groups [172]. [PERSON] and collaborators reported the use of LMW-HA (1-4 \(\times\) 10\({}^{5}\) g/mol) and V. alginolyticus collagenase to treat 4 patients with deep traumatic skin lesions, or ulcers. The local application of collagenases has been reported to increase the effect of macrophage collagenases that break proteins of dead tissue; thus, it provides wound debridement. The lesion is covered by Hyalomatrix that maintains the moisture on the wound site [173]. New therapies include the use of bio-functionalized scaffolds. For example, [PERSON] et al. reported the use of HA-based scaffolds enriched with platelet-rich plasma (PRP) tested on a total of 364 patients affected by chronic ulcers (diabetic and vascular); 182 patients were treated by bio-functionalized scaffold PRP + HA, and the results were compared with a control group of 182 patients treated with traditional dressings containing only HA (group 1). PRP was obtained from the patient's own blood, and the gel was applied to the wound bed after disinfection. The treatment was complemented with elastic pressure and antibiotics. After 30 days, the patients who underwent a combined treatment had 96.8% \(\pm\) 1.5% of reepithelial compared to 78.4% \(\pm\) 4.4% in group 1 (\(p<\) 0.01). The in vitro study includes the analyses of biopsies. The post-treatment images showed regenerated skin with reactive epidermal proliferation, newly formed dermal tissue, collagen deposition, and newly formed vessels [174]. New formulations include the use of emulsions. For example, [PERSON] and collaborators prepared a nanohydrogel composed of HA (2.8 \(\times\) 10\({}^{5}\) g/mol), quercetin, and oleic acid for foot skin wound healing in diabetic patients. This study involved 83 patients (mean age 68.5 \(\pm\) 9.6 years) with a history of diabetic foot ulcers (DFUs) unresponsive to SoC treatments. The use of HA alone developed an infection, while a synergism of HA/curcumin/oleic significantly (\(p<\) 0.01) reduced the wound healing time. Furthermore, the nanogel applied topically was demonstrated to be effective and safe for skin repair [175]. Hyalo-silver(r) is a topical spray powder combining HA and metallic silver. Recently, a single-site, prospective, open-label study involving patients with a vascular ulcer or pressure ulcers (PUs) category I-II with a bacterial infection was conducted. Patients with a wound size of \(\leq\)15 cm\({}^{2}\) were enrolled. A reduction in the wound area was observed after one day of application in 56% of patients, with up to 99% healing after 28 days [138]. Even though the most widely studied antimicrobial agent is silver [176; 177]. Several concerns have been raised due to its possible toxicity. This is the reason why new formulations included the incorporation of antiseptics.