## 5 Clinical Products Containing Hyaluronan Used for Wound Healing  
Clinical studies provided useful information on the safety, tolerability, and efficacy of medical devices. Particularly, products containing HA were evaluated in human probands with various types of wounds, including hard-to-heal wounds (wounds that have not been healed for more than three months), post-traumatic ulcers, diabetic ulcers, and burns. Clinical trials include wound healing outcomes, adverse events, and patient satisfaction. However, patient satisfaction is a subjective parameter that depends on many external factors. The efficacy could vary due to the comorbidities of the patient. Clinical evidence demonstrated that dressings and topical agents containing HA are safe, effective, and well tolerated, with some studies reporting very positive outcomes in terms of wound closure and high healing rates compared with other dressings [2]. Traditional wound dressings in the market include gauzes, films, foams, sprays, hydrogels, hydrocolloids, or multi-layered dressings [163]. Gauze pads containing HA have been developed and marketed for 20 years for treating non-infected, exuding, or super-infected wounds, including leg ulcers [164]. [PERSON] and collaborators reported the results of a 60-day double-blind, randomized, controlled superiority trial designed to investigate the efficacy and safety of HA-impregnated gauze pads in the local treatment of venous leg ulcers, compared with a neutral vehicle. Totally 89 patients were included. At day 45, the percentage of ulcer surface reduction was significantly greater in the HA group (\(73\pm 4.6\%\)) versus the neutral vehicle group (\(46\pm 9.6\%\), \(p=0.011\)) [165]. The combination of HA and equine-type I collagen (Hyalo4 Regen) has been applied for diabetic foot ulcers. The ulcer affects subcutaneous skin and bone tissues. The clinical evaluation included the surface of the wounds on day 7 up to complete healing and size contraction of the wound [166]. [PERSON] et al. recently reported the clinical efficacy and applicability of a gel comprising HA/Iodine for treating hard-to-heal wounds of different etiologies. Patients (n = 56) with venous leg ulcers (VLU), diabetic foot ulcers (DFU), pressure ulcers (PU), or ulcers originating from post-surgical wounds (pSW) were involved in this study. The highest healing rate was in DFU (71.4%), followed by pSW (62.5%), VLU (55.6%), and PU (44.4%) [167]. [PERSON] published a review, \"Effectiveness of Hyaluronic Acid and Its Derivatives on Chronic Wounds\" [168]. However, the review included a description of clinical trials involving HYAFF derivatives. Similarly, [PERSON] et al. reported the efficacy and safety of HYAFF-11(r)-based autologous dermal and epidermal grafts for treating diabetic foot ulcers. Complete ulcer healing was observed in 65.3% of the patients treated with the grafts compared with 49.6% of the control group using a non-adherent paraffin gauze after 11 weeks. The material is readily hydratable and transforms into a clear, viscous gel in contact with body fluids [87]. HYAFF-based dressings are part of the treatment for severe, non-progressive wounds, including venous leg and diabetic foot ulcers. Benzolylated esters of HA have been studied since 2003 and identified as Hylase Wound Gel(r). This product is one of the most frequently found in the European market for wounds, burns, and non-healing venous leg ulcers [169]. [PERSON] et al. recently revised HA wound dressings available on the market, including Hyalofil(r), Hyalosafe(r), or Hyalo Regen [1]. Hyalofil(r) is a wound care treatment for chronic wounds, composed of 75% esterified HA and presented as a non-woven fleece. The clinical evidence that supports the use of this product was described in 1998. Hyalosafe is a transparent film made of HYAFF-11(r), or an esterified benzyl ester of HA (\(\geq\)90% of carboxylic groups are modified), which is one of the most studied HA derivatives for wound healing [170].