A Hyaluronic Acid‐Based Gel Ameliorates Wound Bed Appearance of Acute and Chronic Wounds: Prospective, Multicentric Clinical Investigation

ABSTRACT

The aim of this study was to assess the performance and safety of daily treatment with a 0.2% hyaluronic acid‐based hydrogel (Hyalo4 Skin Gel) in patients with chronic and acute wounds. The primary endpoint was the amelioration rate after 14 days of treatment, defined as the percentage of patients showing improvement in at least one of the following wound characteristics: wound tissue type, exudate amount, or type. Secondary endpoints included assessments of the treatment's effects on wound bed type, exudate amount and type, and patients' quality of life (EQ‐5D QoL), as well as its safety and ease of application. Data were collected up to 56 days of treatment. A total of 170 patients were enrolled. Wound bed amelioration was observed in 46.0% of the patients after 14 days. The amelioration rate increased from 0.291 after 7 days to 0.561 after 56 days. The treatment promoted wound healing, increased granulation tissue formation, and normalized exudate levels. Additionally, QoL significantly improved, and the product was deemed easy to apply and safe, with no serious treatment‐related adverse events reported. Being effective in enhancing the re‐epithelialization of both acute and chronic wounds, Hyalo4 Skin Gel emerges as a promising strategy, improving clinical outcomes across a wide range of patients.

1.

Summary.

• Chronic and hard‐to‐heal wounds remain a major clinical challenge, often associated with poor vascularization, persistent inflammation, or metabolic disorders. There is a need for safe, versatile and effective solutions that promote re‐epithelialisation and tissue repair.

• Treatment with Hyalo4 Skin Gel significantly improved wound bed appearance, achieving an overall amelioration rate of 56.1% after 56 days. The best outcomes were seen in first‐ and second‐degree burns (87.5%), surgical wounds (70.7%), and pressure ulcers (76.9%), with metabolic and vascular ulcers also showing meaningful improvement.

• Thanks to its hydrated and biocompatible structure, hyaluronic acid supports cell migration, angiogenesis, and granulation tissue formation while maintaining an optimal moist environment and reducing the risk of infection and biofilm formation.

• Quality‐of‐life scores (EQ‐5D and EQ‐VAS) improved significantly, reflecting reduced pain, anxiety, and depression. Both patients and clinicians rated the product as easy to apply (⟩85% “excellent”), and safety was high, with only three mild treatment‐related adverse events.

• Hyalo4 Skin Gel proved to be an effective, safe, and practical option for managing both acute and chronic wounds, including in home‐care settings. Although the study lacked a control group, the findings support further clinical and biomolecular research to clarify the regenerative mechanisms of hyaluronic acid–based therapies.

2. Introduction

Wound healing is a physiological process that restores the skin's barrier integrity after an injury. This multi‐step mechanism involves various cell types participating in the hemostatic, inflammatory, proliferative, and remodelling phases. Briefly, the vascular phase—aimed at achieving haemostasis and forming a temporary blood clot—is followed by the inflammatory phase, where neutrophils are initially recruited to the wound site to begin cleaning up, followed by M1 macrophages. Later in inflammation, M1 macrophages are replaced by M2 macrophages, which begin signalling for the proliferative phase to begin. Inflammation then leads to the activation of fibroblasts, which, along with angiogenesis triggered by endothelial cells, ultimately results in the deposition of extracellular matrix [1].

The duration of the wound healing is highly variable and may be negatively impacted by certain pathological conditions. Chronic inflammation, infections, or repeated ischemia/reperfusion injuries can slow down healing, potentially resulting in what are known as chronic wounds (CWs) [1, 2]. As such, CWs commonly occur in patients with diabetes, venous or arterial insufficiency, obesity, aging, or continuous skin pressure [3]. Thus, the most frequent types of CWs are pressure ulcers, diabetic ulcers, and venous ulcers, affecting millions of people worldwide [4, 5].

Although there is no clear consensus on the definition of “chronicity”, a systematic review highlighted the significant impact of CWs on both quality of life and medical care costs [6]. This underscores the importance of treating acute wounds promptly to prevent them from becoming chronic, especially in patients affected by the aforementioned conditions. Specifically, wound management relies on the preparation and restoration of the wound bed according to the TIME concept; this consists of the removal of pathogens and devitalized or necrotic tissue (T), the control of inflammation or infection (I), the maintenance of proper moisture levels (M), and the management of non‐advancing wound edges (E) [7, 8].

Dressings are indispensable to modern moist wound care; however, no single product suits every wound, and selection must be guided by healing stage and exudate volume [9].

An ideal wound dressing should ensure a moist environment, facilitate epidermal migration, allow gas and nutrient exchanges, and protect against infections. To meet all these criteria, various polymer‐based dressings have been developed, with hyaluronic acid (HA) being one of the most commonly used [10, 11]. HA is a constituent of the skin extracellular matrix composed of disaccharide units of β‐D‐glucuronic acid and N‐acetyl‐D‐glucosamine linked by β‐1,3 and β‐1,4 glycosidic bonds. Thanks to its high hydrophilicity, it has a key role in maintaining hydration, osmotic pressure [12, 13] and moisture in the wound bed, preventing dehydration or maceration. Altogether, the microenvironment produced by HA is able to facilitate cellular anchoring, proliferation, and differentiation, sustaining the proliferative and remodeling phases of wound healing [14]. Moreover, its application on the skin is considered safe because of its biocompatibility and biodegradability [15, 16]. A broad portfolio of HA‐based dressings—sponges, films, hydrogels, foams, and scaffolds—is commercially available [10]. These biomaterials are tailored to different wound types and healing stages [17], but their heterogeneous composition and indications hamper direct comparison. The primary contact layer, placed directly on the wound before the secondary dressing, critically modulates the microenvironment and can markedly influence healing [18].

A meta‐analysis by Shaharudin et al. which evaluated nine RCTs on CWs, reported favourable outcomes, including pain reduction in mixed arterial and venous ulcers treated with different HA formulations [19]. While overall evidence remains limited, these data support further studies such as the present investigation. Belonging to this category of dressings, Hyalo4 Skin Gel (Fidia farmaceutici S.p.A., Abano Terme, Italy), is a topical gel preparation containing 0.2% of HA and is indicated for acute (post‐operative incisions and first‐ and second‐degree burns) and chronic wounds (pressure ulcers and vascular and metabolic ulcers) treatment [20]. A 2010 case series by Slonková et al. involving 27 patients and 38 lesions of mixed acute and chronic aetiology, reported accelerated healing, rapid pain relief, and improved scar quality with HA‐based treatment [21, 22]. Likewise, a 2007 prospective controlled study by Ivanov [23] on 47 obstetric surgical wounds reported significantly reduced oedema and exudate and zero dehiscence in HA‐treated patients compared with standard care [23].

The highly hydrated 3D polymeric structure helps maintain a moist environment, essential for wound healing [9], and the combination of the hydrogel and HA offers protective benefits, shielding the wound bed from microbial infiltration and reducing the risk of biofilm formation [12, 13, 24, 25]. Other HA‐based products, similar to Hyalo4 Skin Gel, have been available on the market for years, and several clinical studies have demonstrated their effectiveness in promoting the re‐epithelialization of wounds from various etiologies [9, 19, 21, 23, 26, 27]. For instance, Koutna et al. described 19 CWs of mixed origin treated with various HA preparations—Hyalo4 Start, Hyalo4 Plus, Hyalo4 Foam, and Hyalo4 Regen—and documented significant area reduction without adverse events [28].

Thanks to its versatility and ease of use, this HA‐based gel is considered suitable for treating a wide range of wounds typically encountered in real‐world scenarios [24].

In this context, this multicenter study aimed to gather data on the performance and safety of Hyalo4 Skin Gel in the management of acute and chronic wounds of various etiologies.

3. Patients and Methods

3.1. Study Design

In this multicenter study, patients with wounds of various etiologies were prospectively enrolled to evaluate the performance and safety of Hyalo4 Skin Gel application. The study was conducted across six Slovakian centers between March 2022 and August 2023. It was designed, conducted, and reported in accordance with the guidelines for Good Clinical Practice (GCP), the ethical principles laid down in the Declaration of Helsinki, and ISO 14155 standards.

3.2. Product Description and Application

Hyalo4 Skin Gel (Fidia Farmaceutici S.p.A., Abano Terme, Italy) is a topical medical device containing 0.2% hyaluronic acid sodium salt. The hyaluronic acid used in the formulation has an average molecular weight (M _w) ranging from approximately 90 000 to 230 000 Da, corresponding to an intrinsic viscosity of 3–6 dL/g (0.3–0.6 m³/kg).

The first application of the product, as well as those performed during the scheduled visits, was carried out by the investigator or specialist nurse, according to wound care guidelines [7]. Before each application, the wound was cleaned of debris with saline solution. Cleaning the wound with quaternary ammonium salt solutions was not allowed because their use can alter the product. Patients or their caregivers received appropriate training for self‐medication and were instructed to apply the product daily, covering the whole wound area.

Patients whose wounds healed before the end of the study could discontinue treatment based on the clinician's advice. Any deviations from the application schedule were recorded.

3.3. Study Population

The study included patients meeting the following inclusion criteria: (i) provided written informed consent, (ii) aged 18 years or older, (iii) being treated on an outpatient or home basis, (iv) presence of actively healing chronic ulcers, (v) presence of first‐ and second‐degree burns, surgical wounds, vascular ulcers, metabolic ulcers, or pressure ulcers, and (vi) a wound area ≥ 3 and ≤ 100 cm², or surgical wounds with a minimum length of 3 cm. Patients were excluded from the study if they did not meet the inclusion criteria, had infected lesions, were at high risk of infection, had stalled wounds without any clinical sign of healing progression, suffered from immune system disorders, experienced protein‐energy malnutrition, engaged in alcohol (50 mL of spirit, 500 mL of wine per day), smoking (10 cigarettes per day) or drug abuse, had conditions associated with hypoxia and/or poor tissue perfusion, or were undergoing corticosteroid, cytotoxic, or immunosuppressive therapy.

3.4. Concomitant Medications

Patients informed the medical staff about any new medication or treatment started after enrollment in the study. Additionally, any other medication needs were discussed with the medical team. The following therapies were not permitted, and their use resulted in patients' discontinuation from the study: (i) antibiotics; (ii) chemotherapeutic agents or radiation therapy; (iii) silver‐based or other hyaluronic acid‐based products; (iv) bioactive dressings delivering anti‐microbial substances or other bioactive components.

3.5. Study Visits and Investigation Procedures

Patients followed the visit schedule as outlined: visit 1 at day 0 (V1), visit 2 at day 7 ± 1 (V2), visit 3 at day 14 ± 2 (V3), visit 4 at day 21 ± 2 (V4), visit 5 at day 28 ± 2 (V5), visit 6 at day 42 ± 3 (V6), and visit 7 at day 56 ± 4 (V7).

At each study visit, photographs of the wound, as well as records of the use of secondary dressings, cleansing solution, and concomitant medications, were documented alongside the clinical evaluation of the wound. Demographic data and medical history were collected at V1, during which patients also completed the baseline QoL questionnaire. Except for V1, patients received product applications during each study visit (from V2 to V7). At V7, patients completed the follow‐up QoL questionnaire, and the ease of treatment application was rated. All adverse events (AEs) were recorded and assessed by the clinician during each visit involving treatment application and continued to be monitored for 30 days after V7.

3.6. Objectives and Endpoints

The primary objective of the study was to evaluate the performance of Hyalo4 Skin Gel in improving wound bed appearance after 14 days of treatment. Accordingly, the primary endpoint was the assessment of the amelioration rate after 14 days, defined as the percentage of patients showing improvement in at least one of the following parameters: wound tissue type, exudate amount, or exudate type. These features were evaluated considering the subtypes reported in Table 1 [29, 30].

TABLE 1.

Description of the parameters used to evaluate the amelioration rate of the wound.

Wound bed type	Necrotic (eschar): Black, brown, or tan tissue firmly adherent to the wound bed or ulcer edges
	Slough tissue: Yellow, white or mucinous tissue adherent to the ulcer bed in strings or thick clumps
	Granulation tissue: Pink or beefy red tissue with a shiny, moist, granular appearance
	New skin: A superficial wound that is re‐epithelializing
	Closed wound: Wound completely covered with epithelium
Exudate amount	Dry: no exudate
	Moist
	Slightly exuding
	Heavily exuding
	Wet
Exudate type	Bloody
	Clear
	Serous

Secondary objectives were (i) to describe the use of Hyalo4 Skin Gel in clinical practice, focusing on clinical wound characteristics, the type of secondary dressing applied, and the wound aetiology, (ii) to evaluate the product's performance in improving wound bed appearance at each visit, (iii) to assess the quality of life (QoL) following treatment, (iv) to evaluate the ease of application, and (v) the safety and local tolerability of the product during all scheduled visits and until 30 days after study termination. Accordingly, secondary endpoints were: (i) a descriptive analysis to define wound characteristics and etiologies from V1 to V7; (ii) the amelioration rate, as defined for the primary endpoint, categorised by wound aetiology and type of secondary dressing from V2 to V7; (iii) the patients' QoL score evaluated through the validated EuroQoL‐5D (EQ‐5D) questionnaire at V1 and V7; (iv) the ease of treatment application rated by the clinician and patients as excellent, good, acceptable, bad, or unacceptable at V7; and (v) a descriptive analysis to assess the frequency of all adverse events occurring until 30 days after V7.

3.7. Statistical Analysis

3.7.1. Sample Size Calculation

The sample size was calculated based on a two‐sided confidence level of 97.5%, an expected response rate of 45% for wound bed amelioration after 14 days of treatment, and a precision level of 15%. Considering a 10% dropout rate during the observation phase, the final required sample size was determined to be 170 patients.

3.7.2. Populations

For statistical analysis, four populations were defined as follows: (i) enrolled population, including all patients with written informed consent; (ii) evaluable population, including all enrolled patients with at least one application of the product and at least one evaluation of wound bed appearance after baseline; (iii) per protocol population, including all enrolled patients with the evaluation of wound bed appearance at day 14 and without major protocol violation; (iv) safety population, including all enrolled patients with at least one application of the product. Except for the primary endpoint, which was evaluated in the per protocol population, all other endpoints were evaluated in the evaluable population.

3.7.3. Data Analysis

Categorical variables were described as frequencies and percentages, whereas continuous variables were described using the mean, standard deviation (SD), range, median, first, and third quartiles. The amelioration rate was reported using the Agresti‐Coull confidence interval for binomial proportion (90%).

Normality was assessed using the Shapiro–Wilk test. Amelioration rate by wound aetiology was analysed using Fisher's test. The mean improvement of QoL between V1 and V7 was analysed with the Wilcoxon signed‐rank test. Statistical significance was set for p < 0.05. Analyses were performed using the qualified SAS Analytics Pro software version 9.4 (SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA).

4. Results

4.1. Baseline Characteristics

One hundred and seventy patients meeting the inclusion criteria constituted the enrolled population. Of this, 165 met the criteria for inclusion in the evaluable population and 150 in the per protocol population. Overall, the discontinuation rate throughout the study period was 8.8% (n = 15).

The evaluable population included slightly more males (57.6%) than females (42.4%), with a mean age of 61.0 ± 15.8 years, and a mean BMI of 29.44 ± 5.98 kg/m². A full summary of demographic characteristics is reported in Table 2.

TABLE 2.

Demographic and baseline characteristics. Q1 = first quartile; Q3 = third quartile.

Gender, n (%)	Female	70 (42.4)
	Male	95 (57.6)
Ethnicity, n (%)	Caucasian	164 (99.4)
	Other or unknown or not reported	1 (0.6)
Age (years)	Mean (SD)	61.0 (15.8)
	Q1/Median/Q3	50.0/63.0/72.0
	Min/Max	20/94
Weight (kg)	Mean (SD)	88.4 (21.7)
	Q1/Median/Q3	74.0/86.0/98.0
	Min/Max	48/190
Height (cm)	Mean (SD)	172.8 (9.6)
	Q1/Median/Q3	167.0/172.0/179.0
	Min/Max	150/200
BMI (kg/m2)	Mean (SD)	29.44 (6.0)
	Q1/Median/Q3	24.9/28.7/32.8
	Min/Max	17.5/53.2
Systolic blood pressure (mmHg)	Mean (SD)	135.9 (15.1)
	Q1/Median/Q3	128.0/135.0/145.0
	Min/Max	90/195
Diastolic blood pressure (mmHg)	Mean (SD)	82.4 (8.2)
	Q1/Median/Q3	77.0/80.0/89.0
	Min/Max	60/103
Heart rate (bpm)	Mean (SD)	74.9 (11.2)
	Q1/Median/Q3	70.0/72.0/80.0
	Min/Max	43/113

Abbreviation: SD, standard deviation.

Concerning the type of wounds, 30.3% were metabolic ulcers (n = 50), 29.7% were surgical wounds (n = 49), 25.5% were vascular (both venous and arterial) ulcers (n = 42), 9.7% were pressure ulcers (n = 16), and 4.8% were first‐ and second‐degree burns (n = 8). Overall, granulation tissue was present in the majority of the wounds examined (n = 89, 53.9%), while slough tissue or the presence of new skin were reported in 50 wounds (15.2% for each type). Four wounds (2.4%) were slightly covered by necrotic tissue. As for exudate amount, 31.5% of the wounds were heavily exuding, and 15.2% were dry. Concerning the type of exudate, it was serous in most of the wounds (64.2%) and completely absent in 18.8%. Table 3 summarises baseline characteristics of wound bed type, exudate amount, and exudate type by wound aetiology.

TABLE 3.

Number (%) of patients by wound aetiology and characteristics at baseline (V1).

	Metabolic ulcer	Surgical wound	Vascular ulcer	Pressure ulcer	First‐ and second‐degree burns
Total	50 (30.3)	49 (29.7)	42 (25.5)	16 (9.7)	8 (4.8)
Wound bed type
Closed wounds	0	20 (40.8)	0	0	2 (25.0)
New skin	3 (6.0)	14 (28.6)	3 (7.1)	3 (18.8)	2 (25.0)
Granulation tissue	40 (80.0)	10 (20.4)	29 (69.0)	7 (43.8)	3 (37.5)
Slough	5 (10.0)	4 (8.2)	10 (23.8)	5 (31.3)	1 (12.5)
Necrotic	2 (4.0)	1 (2.0)	0	1 (6.3)	0
Exudate amount
Dry	1 (2.0)	16 (32.7)	4 (9.5)	2 (12.5)	2 (25.0)
Moist	6 (12.0)	17 (34.7)	7 (16.7)	5 (31.3)	3 (37.5)
Slightly exuding	13 (26.0)	6 (12.2)	4 (9.5)	5 (31.3)	0
Heavily exuding	28 (56.0)	2 (4.1)	20 (47.6)	2 (12.5)	0
Wet	2 (4.0)	8 (16.3)	7 (16.7)	2 (12.5)	3 (37.5)
Exudate type
Bloody	2 (4.0)	8 (16.3)	3 (7.1)	1 (6.25)	3 (37.5)
Clear	6 (12.0)	2 (4.1)	3 (7.1)	0	0
Serous	41 (82.0)	19 (38.8)	32 (76.2)	13 (81.25)	1 (12.5)
None	1 (2.0)	20 (40.8)	4 (9.5)	2 (12.5)	4 (50.0)

4.2. Wound Bed Status and Type and Amount of Exudate

The percentage of wounds characterised by granulation tissue remained relatively stable until V7 (n = 66, 44.6%), while the number of patients with necrotic or slough tissue decreased. This shift led to more wounds either showing signs of healing or displaying new skin characteristics. Indeed, the percentage of patients with closed wounds gradually increased from 13.3% at V1 to 33.8% at V7 (Figure 1a).

FIGURE 1.

Distribution of wound bed type (a), amount of exudate (b), and type of exudate (c) at each visit.

The percentage of patients with dry wounds increased from 15.2% at V1 to 41.2% at V7, and those of patients with moist, slightly exuding, and wet wounds decreased from 23.0%, 17.0%, and 13.3% to 16.9%, 7.4%, and 3.4%, respectively (Figure 1b).

At V1, 18.8% (n = 31) of the patients presented no exudate and, when present, it was most frequently serous (n = 106, 64.2%). At the end of the study, 90.5% of the patients presented no or serous exudate, and the percentage of wounds with bloody exudate decreased from 10.3% at V1 to 3.0% at V7 (Figure 1c).

4.3. Amelioration of Wound Bed Appearance

Amelioration of wound bed appearance after 14 days of treatment was observed in 46.0% of patients (n = 69), thus resulting in a 0.46 amelioration rate (90% CI, 0.394; 0.527). Overall, the amelioration rate increased from 0.291 at V2 to 0.475 at V4 and, after settling between V5 and V6 (0.484 and 0.483, respectively), it further increased to 0.561 at V7 (Figure 2).

FIGURE 2.

Amelioration rate of wound bed appearance at V2, V4, V5, V6, and V7. Error bars represent 90% CI.

The categorization of patients by wound aetiology revealed that, at each visit, the amelioration rates varied significantly across different wound types (V2 p = 0.023; V3 p = 0.025; V4 p = 0.0010; V5 p = 0.0026; V6 p = 0.0006; V7 p = 0.0042). At V7, the highest amelioration rate was obtained in patients with first‐ and second‐degree burns (0.875), followed by those with pressure ulcers and surgical wounds (0.769 and 0.707, respectively). Conversely, the lowest rates were observed in patients with vascular and metabolic ulcers (0.450 and 0.413, respectively). Overall, amelioration rates increased up to V3 and either persisted or further improved until V7 (Figure 3 and Table 4). Representative pictures of metabolic and surgical wounds at V1 and V7 are reported in Figure 4.

FIGURE 3.

Amelioration rate of wound bed categorized by wound aetiology.

TABLE 4.

Amelioration rate categorized by wound aetiology at each evaluated timepoint.

	Visit	Metabolic ulcer	Surgical wound	Vascular ulcer	Pressure ulcer	1st and 2nd degree burns	p *
Amelioration rate	V2	0.160	0.429	0.238	0.313	0.500	0.0223
	V3	0.240	0.542	0.390	0.625	0.750	0.0025
	V4	0.265	0.659	0.439	0.563	0.750	0.0010
	V5	0.313	0.636	0.390	0.688	0.750	0.0026
	V6	0.319	0.595	0.375	0.786	0.875	0.0006
	V7	0.413	0.707	0.450	0.769	0.875	0.0042

^*Fisher's exact test for association between amelioration rate and wound aetiology at specified visit.

FIGURE 4.

Pictures of representative wounds at V1 and V7. (a) metabolic ulcers; (b) surgical wounds; (c) vascular ulcers.

4.4. Secondary Dressings

Concerning secondary dressings, cotton dressings were more frequently used in metabolic and vascular ulcers (47.6% and 24.4%, respectively), followed by surgical wounds, pressure ulcers, and first‐ and second‐degree burns (20.7%, 6.1%, and 1.2%, respectively). Basic and low adherence wound contact dressings were mostly used by patients with surgical wounds and vascular ulcers (46.0% and 22.0%, respectively), and less frequently by those with metabolic and pressure ulcers and in first‐ and second‐degree burns (8.0%, 10.0%, and 14.0%, respectively) (Table 5). When patients were categorized by secondary dressing type, the results showed that the highest amelioration rates were associated with those primarily using basic and low adherence wound contact dressings (Figure 5).

TABLE 5.

Number (%) of patients grouped by aetiology and by the two most frequently used secondary dressings at V1.

	Metabolic ulcer	Surgical wound	Vascular ulcer	Pressure ulcer	First‐ and second‐degree burns
Cotton dressing	39 (47.6)	17 (20.7)	20 (24.4)	5 (6.1)	1 (1.2)
Basic and low adherence wound contact dressing	4 (8.0)	23 (46.0)	11 (22.0)	5 (10.0)	7 (14.0)

FIGURE 5.

Amelioration rate of wound bed categorized by type of secondary dressing.

The subgroups of wounds achieving the highest amelioration rates—such as pressure ulcers, surgical wounds, and first‐ and second‐degree burns—more frequently used basic and low adherence wound contact dressings. Patients with metabolic and vascular ulcers, who showed lower amelioration rates, more commonly used cotton dressings.

4.5. Quality of Life

As detailed in Table 6, analysis of the QoL questionnaires showed that the mean EQ‐5D index increased from 0.705 ± 0.3246 at V1 to 0.806 ± 0.2645 at V7, with a significant mean fold change of 0.088 ± 0.1641 (p < 0.0001). Similarly, the EQ‐VAS score evaluating the overall health significantly increased from 71.9 ± 18.26 at V1 to 81.9 ± 16.47 at V7, with a 9.5 ± 13.22 mean fold change (p < 0.0001). Analysis of the individual domains revealed a decrease in the number of patients experiencing moderate, severe, or extreme pain/discomfort from 35 (21.2%), 15 (9.1%), and 3 (1.8%) at V1 to 17 (10.7%), 9 (5.7%), and 0 at V7, respectively. Additionally, the incidence of patients with moderate and severe anxiety/depression dropped from 12 (7.3%) and 4 (2.4%) at V1 to 8 (5.0%) and 1 (0.8%) at V7, respectively.

TABLE 6.

Quality of life assessment from baseline (V1) to day 56 of treatment (V7).

	V1	V7	p *
EQ‐5D index
Mean (SD)	0.705 (0.3246)	0.806 (0.2645)
Q1/Median/Q3	0.580/0.838/0.903	0.762/0.899/1.000
Min/Max	−0.43/1.00	−0.22/1.00
Change from baseline in EQ‐5D index
Mean (SD)		0.088 (0.1641)
Q1/Median/Q3		0.000/0.047/0.114	< 0.0001
Min/Max		−0.27/0.98
Overall health (VAS)
Mean (SD)	71.9 (18.26)	81.9 (16.47)
Q1/Median/Q3	60.0/75.0/87.0	70.0/85.0/98.0
Min/Max	20/100	35/100
Change from baseline in Overall health (VAS)
Mean (SD)		9.5 (13.22)
Q1/Median/Q3		0.0/10.0/15.0	< 0.0001
Min/Max		−35/72

Note: p < 0.05 (in bold).

^*One‐sample Wilcoxon signed‐rank test for comparing changes from baseline.

4.6. Ease of Treatment Application

The ease of treatment application was rated as excellent by 87.4% of patients and 85.5% of clinicians, and as good by 11.3% of patients and 8.8% of clinicians. Among the 8 acceptable evaluations given by clinicians, 6 were related to patients using basic and low‐adherence wound contact dressing.

4.7. Safety and Local Tolerability

A total of 21 AEs were reported by 20 patients. Overall, only 3 mild AEs (i.e., burning sensation, pain at the application site, and application site warmth) were considered possibly related to the device. Of these, 2 resolved, 1 persisted, and none led to treatment discontinuation. Serious AEs were reported by 9 patients and were deemed unrelated to the use of the device. One of these serious AEs, involving a moderate rash, was attributed to the patient's underlying condition, erysipelas. This required hospitalization and discontinuation of treatment.

5. Discussion

Managing both acute and chronic wounds is a significant clinical challenge that demands careful attention. In line with the TIME concept, HA‐based dressings appear to be an effective strategy for supporting the re‐epithelialization of wounds [19, 31]. Accordingly, this multicentric study evaluated the performance and safety of a hydrogel‐based product (Hyalo4 Skin Gel) when used in clinical practice to treat patients with acute and chronic wounds of various etiologies.

Overall, results showed that the percentage of patients with improved wound bed appearance increased throughout the study, reaching over half (56.1%) by the end of the study (56 days of treatment). As acute and chronic wounds heal differently, patients were also stratified according to wound aetiology, showing benefits for all subgroups, though at varying extents and timeframes. The highest amelioration percentage at the last visit was observed in first‐ and second‐degree burns (87.5%), followed by surgical wounds and pressure ulcers (76.9% and 70.7%, respectively). Chronic wounds such as metabolic ulcers and vascular ulcers showed improvement in 41.3% and 45.0% of the patients, respectively. Given the chronic nature of such ulcers, their healing is hindered by underlying pathological conditions [32, 33] – such as diabetes—which are characterised by compromised microcirculation and a persistent inflammatory state. These factors substantially impair wound repair [34]. These results demonstrate that the application of HA‐based hydrogel is an effective strategy to accelerate healing, even in hard‐to‐heal wounds.

Chronic hyperglycaemia contributes to microvascular dysfunction and insufficient angiogenesis, leading to local ischemia, while simultaneously promoting a sustained pro‐inflammatory wound environment [34, 35]. Together, these factors create a hostile microenvironment that delays tissue regeneration and likely underlies the lower response rate observed in metabolic ulcers.

Despite longer treatment periods being necessary to achieve results comparable to those seen with other wound etiologies, these results highlight the role of HA hydrogel in supporting the epithelization and healing of acute and chronic wounds.

Regardless of wound type, the complete healing rates reported in this study are consistent with data from the literature. Specifically, previous research has shown that HA‐based gauzed pads and creams achieved complete healing in 39.8% and 31.3% of wounds, respectively, in patients with mixed aetiology ulcers after 20 weeks of treatment [36, 37]. Despite the limitations of comparing different protocols, HA hydrogel formulations appear to provide comparable benefits to creams and gauze pads, achieving similar results (33.8%) within a shorter treatment period (8 weeks). Further supporting this positive result, the number of patients presenting clean wounds with granulation tissue progressively increased until 28 days of treatment. These observations align with previous research showing that HA‐based dressings effectively support the growth of granulation tissue [38, 39].

Alongside assessing the wound bed status, evaluating the amount and type of exudate can provide valuable insights into the wound healing process. For instance, a high amount of exudate may be present during the inflammatory phase, as it helps eliminate bacteria, clear debris, and prepare the wound bed for healing. As healing progresses, the exudate should decrease and become serous [40]. Accordingly, the percentage of patients with dry wounds increased from baseline (15.2%) to the end of the study (41.2%), at which point exudate was absent or serous in 90.5% of the patients. The percentage of heavily exuding wounds was stable over time (from 31.5% V1 to 31.1% V7), with this trend being likely due to the high prevalence of venous ulcers, which are always characterised by a high amount of exudate [41]. Compared to similar literature on HA‐based creams, the hydrogel under investigation demonstrated comparable effectiveness in reducing exudate levels [22, 42]. In particular, the retrospective study by De Francesco et al. reported an average wound surface reduction of 80% after 6 weeks in 85 patients treated with 0.2% HA cream or gauze pads. Histological analyses revealed a transition from an inflammatory to a reparative profile, characterised by increased fibroblast activity, collagen deposition, and the presence of elastic fibres. From a clinical perspective, the observations included reduced inflammation, minimal exudate and fibrin, and enhanced tissue remodelling. These findings provide further support for the efficacy of HA‐based treatments in wound healing and are consistent with our findings.

Preclinical data also strengthen the therapeutic potential of HA‐based treatments. In a recent rat dermal wound model, Lee et al. compared HA‐based hydrogel dressings with hydrocolloid dressings [43]. HA treatment led to earlier collagen deposition, increased inflammatory cell infiltration, and enhanced angiogenesis by day 7. After 21 days, both treatments achieved wound closure, but the HA group displayed a significantly thicker new epithelial layer than the hydrocolloid group, reflecting more advanced epithelial regeneration. These findings underscore the superior regenerative capacity of HA‐based hydrogels in promoting extracellular matrix remodelling, neovascularization, and epithelial regeneration compared to hydrocolloids [43].

Since wounds can severely affect patients' daily lives, especially CWs resulting from other conditions, treatment evaluations should also consider their ability to improve patients' QoL [44]. In this study, the EQ‐5D index increased significantly over the course of the treatment weeks. The analysis of the individual domains of the questionnaire showed that the already low proportion of patients experiencing moderate anxiety or depression dropped from 7.3% at baseline to 5.0% at the end of the study. More notably, the percentage of patients reporting moderate and severe pain fell from 21.2% and 9.1% at baseline to 10.7% and 5.7% at the end of the study, respectively. This potential beneficial effect of HA is further supported by previous studies reporting a significant reduction in pain intensity after 60 days of treatment with a 0.2% hyaluronic acid‐based cream [45].

The use of topical products for wound healing is often coupled with a secondary dressing, which can significantly impact the healing process. In this study, patients use the most suitable secondary dressing, according to the clinicians' indications. Specifically, cotton dressings were more frequently used by patients with metabolic and vascular ulcers, whereas basic and low‐adherence dressings were used by those with surgical wounds. This observation may reflect the nature of the wounds, as the preference for cotton dressings among patients with chronic ulcers is likely due to the high absorbent properties of this type of dressing [16]. On the other hand, patients with surgical wounds are likely to prefer low‐adherence dressings to minimize pain [46]. Our findings suggest that, even though different types of basic dressings were used, an amelioration of hard‐to‐heal wounds (i.e., vascular and chronic wounds) was observed, suggesting that the use of the device supports the wound healing process regardless of the dressing used. Moreover, while a trend of greater improvement with one dressing over another was noted, this is likely more related to the type of wound than to the dressing itself. This aspect deserves a deeper investigation, as data from clinical surveys suggest that the choice of wound dressing is mainly based on the patient's primary disease and on the type and stage of wound [47].

Besides being effective, HA hydrogel also proved to be easy to apply and safe. In fact, most clinicians (85.5%) and patients (87.4%) rated the ease of application as excellent or good and, out of 21 recorded AEs, only three mild events were considered possibly related to the product. Given the high costs associated with chronic wound care, the ease and safety of applying such HA hydrogel offers a practical solution for home‐based management of these patients. This approach not only improves patient comfort and autonomy but also has the potential to significantly reduce healthcare expenses by minimising the need for frequent in‐person visits and hospitalizations.

The findings presented here should be considered in the context of the study's limitations. The sample size varied across wound subtypes, which may have introduced some variability in subgroup comparisons and limited the generalizability of specific observations. The primary outcome (amelioration rate) is not formally validated across wound care trials, but it was selected because it reflects routine clinical practice. Although it integrates clinically meaningful parameters (e.g., tissue type, exudate characteristics), it does not offer the same level of standardisation as tools such as the Wound Bed Score (WBS). While not formally validated, these scales were adopted to maintain the clinical relevance of the study outcomes and their consistency with routine practice. Imaging procedures were not standardised across study centers in terms of equipment or acquisition protocols, and no blinded wound assessor was employed. The absence of a control group limits the strength of conclusions regarding treatment efficacy, as improvements observed over time may also reflect the natural course of wound healing. Furthermore, the self‐application of the product may have introduced some variability in adherence, frequency, or technique. However, it reflects the realities of routine outpatient wound care and enhances the applicability of the findings to real‐world settings. Unblinded assessment might have introduced bias, as observers' knowledge of the treatment could influence wound scoring. This could lead to bias in detection and confirmation, especially for subjective outcomes like granulation or epithelialization. Future investigations incorporating validated scoring systems, standardised imaging, and comparator arms will be important to further substantiate and expand upon these findings. The study protocol did not include analyses such as correlations with pro‐angiogenic or ECM remodelling markers, which limits the ability to clarify the biological mechanisms underlying the observed effects. Nevertheless, the results provide a strong rationale for future studies incorporating biomarker assessments to better elucidate the pathways involved in HA‐induced tissue regeneration. Despite the long‐term follow‐up, it may still not have fully captured all the longer‐term healing dynamics of chronic wounds, where extended observation could provide additional insights. Overall, the findings of this study suggest that treatment with Hyalo4 Skin Gel is an effective strategy to promote re‐epithelialization in both acute and chronic wounds and to significantly enhance patients' QoL. Notably, the improvements in wound re‐epithelialization were observed as early as 14 days of treatment and were maintained up to 2 months of treatment. The relevance of these findings is particularly significant, as the product was used in a clinical practice context, demonstrating both its safety and ease of use in home‐based management of the condition and across a wide range of wound types. This underscores the potential of Hyalo4 Skin Gel as a valuable tool in wound care, supporting improved patient outcomes.

Ethics Statement

The study protocol was approved on November 18, 2021, by a multicenter independent ethics committee (Etická komisia Košického samosprávneho kraja, Námestie Maratónu mieru 1, 042 66 Košice) and six additional local independent ethics committees.

Consent

All patients provided written informed consent to participate in the study.

Conflicts of Interest

Elisa Tramentozzi, Michele Moruzzi, and Nicola Giordan are employees of the study sponsor, Fidia Farmaceutici S.p.A. (Abano Terme, Italy). The other authors declare no conflicts of interest.

Jautová J., Váňa J., Medvecký V., et al., “A Hyaluronic Acid‐Based Gel Ameliorates Wound Bed Appearance of Acute and Chronic Wounds: Prospective, Multicentric Clinical Investigation,” International Wound Journal 22, no. 11 (2025): e70773, 10.1111/iwj.70773.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.