Abstract
Introduction
The skin aging process is mainly associated with the appearance of fine wrinkles and flaccid, dry, and dull skin. A hyaluronic acid matrix (HAm) ingredient containing HA, sulfated glycosaminoglycans (GAGs), and collagen is proposed to enhance skin health by improving hydration and structural integrity. The objective of this study was to evaluate the impact of oral supplementation with HAm on skin properties.
Methods
A 12-week, randomized, double-blind, placebo-controlled trial was designed, including 60 healthy women aged 35–65 with signs of natural skin aging (NCT05813054). Participants were assigned to receive either HAm (Dermial®; 60 mg daily) or a placebo and were dermatologically assessed after 6 and 12 weeks. Skin properties were determined by the evaluation of stratum corneum hydration (SCH), brightness/glow, wrinkles, dryness, roughness, smoothness, pH, temperature, elasticity, friction, antioxidant capacity, deformability, melanin index, and erythema index. In addition, global satisfaction and adverse reactions were assessed.
Results
Assessments were performed on data from 50 participants as a per-protocol analysis. Skin wrinkles and smoothness (6 weeks), and roughness (12 weeks) significantly improved in the HAm group compared with the placebo group. Participants receiving HAm had significantly increased skin SCH and brightness, and decreased scaliness and temperature at 6 and 12 weeks versus the baseline value. A statistically significant reduction in the erythema index and a balanced pH were also observed in the HAm group. Global satisfaction was significantly higher in HAm as compared to placebo. No serious adverse events associated with the tested products were registered during the study.
Conclusions
Daily supplementation with HAm effectively improves multiple aspects of skin health and appearance, suggesting its potential as a safe and beneficial antiaging ingredient. These results support the role of HAm in promoting skin brightness/glow and hydration, and reducing the visible effects of aging.
Trial Registration
ClinicalTrials. gov identifier, NCT05813054.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13555-025-01447-6.
Keywords: Skin, Nutricosmetic, Hyaluronic acid, Brightness, Glow, Antiaging, Wrinkles, Collagen, Glycosaminoglycans
Key Summary Points
| Why carry out this study? |
| The aging process involves a decrease in the production of essential molecules such as hyaluronic acid (HA), sulfated glycosaminoglycans (GAGs), collagen, and elastin present in the epidermis and dermis. |
| This study aimed to evaluate the efficacy and safety of a hyaluronic acid matrix (HAm) ingredient composed of HA, chondroitin sulfate (CS), dermatan sulfate (DS), and collagen (Dermial®) in healthy women aged between 35 and 65 years with natural signs of physiological facial aging. |
| What was learned from the study? |
| This study supports that HAm can significantly improve various aspects of skin health, mainly skin roughness, smoothness, brightness/glow, hydration, pH, and wrinkles. |
| The results of this study demonstrated a high level of satisfaction among participants using HAm, exhibiting an excellent safety profile. |
Introduction
Human skin, like other organs, ages naturally, causing changes in its appearance and function. The aging process involves a decrease in the production of essential molecules such as hyaluronic acid (HA), sulfated glycosaminoglycans (GAGs), collagen, and elastin present in the epidermis and dermis [1–3]. HA is highly viscous and retains moisture. It is responsible for facilitating joint movement [4], maintains the normal shape of the vitreous humor, and hydrates the skin [5]. HA is synthesized by hyaluronan synthases in epidermal keratinocytes and dermal fibroblasts [6, 7]. The HA content of the dermis is much higher than that of the epidermis, and its function in the epidermis has not been fully elucidated. Some research has shown that HA is closely involved in keratinocyte proliferation and differentiation and may participate in epidermal structure and turnover [8, 9]. In the dermis, HA is responsible for regulating water balance and maintaining cell structure through its high-water retention and viscosity [10]. Apart from HA, there are other GAGs such as dermatan sulfate (DS) and chondroitin sulfate (CS) that play both structural and signaling roles within the skin. Also, collagen fibers constitute approximately 75% of the skin’s dry weight and are responsible for its tensile strength, while elastin forms a network with these collagen fibers, giving the skin its elasticity [11].
As the aging progresses, the epidermis becomes thinner and loses its natural radiance, while the dermis loses thickness and elasticity [12]. In addition, there is an increased dryness of the skin, decreased tension, and weakened skin barrier, compromising the skin barrier function and its ability to retain moisture, which promotes skin aging and the appearance of wrinkles [13].
Skin aging has been addressed historically by the cosmetic industry. However, the growing body of evidence linking skin aging to diet has raised awareness towards ingredients to care for skin beauty [14]. Thus, oral supplementation with nutraceuticals can improve the quality of aged skin. Once ingested, these ingredients must reach the epidermis and dermis to promote beauty from within through the inhibition of those mechanisms associated with skin aging [15].
In a society like ours, in which physical appearance is becoming more relevant and trends in facial beauty, body care, and nutricosmetics are increasing, the availability of effective and safe HA supplements is necessary [16]. For this reason, the objective of this study is to evaluate the efficacy and safety in healthy women of a new hyaluronic acid matrix ingredient (HAm) composed of HA, CS, DS, and collagen.
Methods
Ethical Approval
A single-center, randomized, double-blind, placebo-controlled clinical trial (NCT05813054) was designed to evaluate the efficacy of HAm supplementation in healthy women aged between 35 and 65 years with natural signs of physiological facial aging. The study was carried out at the Dermatology Department of Hospital Universitario Virgen de las Nieves de Granada in accordance with international standards of Good Clinical Practice and the Declaration of Helsinki and was approved by the Granada Ethics Committee on 30 June 2022 (code 0748-N-22). The study population was healthy women (entirely voluntary) who met all the inclusion criteria and none of the exclusion criteria (Table 1). Participants provided written informed consent before study-related procedures.
Table 1.
Study population: inclusion criteria and exclusion criteria
| Inclusion criteria | Exclusion criteria |
|---|---|
|
Healthy women between 35 and 65 years of age with signs of physiological facial skin aging Women willing not to use any firming medication, skin lightening medication, or any topical or systemic medication known to affect skin aging or dyschromia during the study period Women willing not to become pregnant during the study, using contraceptive methods considered highly effective Signed informed consent |
Women with allergies to the ingredients of the investigational product Women who have used a dietary or nutricosmetic supplement containing HA, or who have undergone botox or HA injections, in the last 6 months prior signing the informed consent Women who have undergone: Superficial or medium-deep chemical peels or dermabrasion within 6 weeks prior to signing the informed consent or inclusion Deep facial chemical peel, non-ablative laser or fractional laser resurfacing within 12 months prior to signing the informed consent or inclusion Facial plastic surgery or ablative laser resurfacing for photoaging within 12 months prior to signing the informed consent or inclusion Suspected uncontrolled disease, such as diabetes mellitus, hypertension, hyperthyroidism or hypothyroidism, renal insufficiency, or hepatic insufficiency Women who have received a platelet-rich plasma injection as a treatment for aesthetic purposes in the 3 months prior to inclusion by signing the informed consent Known presence of pregnancy or breastfeeding Presence of inflammatory skin pathology such as psoriasis, atopic dermatitis, rosacea, acne, or hidradenitis suppurativa Presence of active malignant pathologies or premalignant skin lesions Uncontrolled psychiatric pathology or any other circumstance or pathology that impedes the participant’s understanding of and/or compliance with the study procedures |
Study Participants
Sixty healthy women were enrolled in a 1:1 ratio into one of two groups (i.e., 30 women in each): one supplemented with 60 mg/day HAm composed of HA (> 60%), sulfated GAGs (> 5%), including DS and CS, and collagen (> 5%) (Dermial®; Bioiberica S.A.U., Palafolls, Spain) and the other with placebo for 12 consecutive weeks. Participants were assessed by a dermatologist at weeks 0 (baseline, V1), weeks 6 (V2), and weeks 12 (V3).
Sociodemographic data and anthropometric data were collected. In addition, information on concomitant medication and diseases, allergies, sun exposure pattern, skin phototype, tobacco use, and alcohol consumption of the participants was collected. Finally, the facial aging of the participants measured through the Glogau scale was evaluated along with the use of moisturizing creams, cosmetics, and sunscreens.
Outcome Measures
A randomized, double-blind, placebo-controlled trial was designed to assess stratum corneum hydration (SCH), temperature, pH, and R2 elasticity of the skin using a Corneometer CM 825, Skin-Thermometer ST 500, Skin-pH-Meter PH 905, and Cutometer® Dual MPA 580, respectively. Erythema index and melanin index were both measured using the Mexameter® MX18. Brightness/glow, deformability, and friction were measured using Skin-glossymeter GL-200, Indentometer IDM 800, and Frictiometer FR-700, respectively. All these probes are connected to a Multi Probe Adapter (MPA, Courage + Khazaka electronic GmbH, Bilbao, Spain). The hardness of the skin was measured using the PCE-DDO 10 hardness tester (PCE Instruments, Meschede, Germany). Total antioxidant capacity (TAC) was measured using the eBQC electrochemical method (Bioquochem S.L. (BQCkit), Asturias, Spain).
Skin microtopography was evaluated with SELS (Surface Evaluation of the Living Skin) parameters such as smoothness (SEsm), roughness (SEr), scaliness (SEsc), and wrinkles (SEw) using the Visioscan VC 20plus (Courage + Khazaka electronic GmbH, Bilbao, Spain). Lower SEsm means higher smoothness, lower SEr is related to higher roughness, lower SEsc means less scaliness, and higher SEw is related to more wrinkles.
All variables were measured by a dermatologist in the right periocular area (rPA) or crow’s feet (2 cm below the external corner of the eye). In addition, SCH, elasticity, and all SELS parameters were also measured on the right cheek (rC). The measurements were taken after staying for at least 30 min in a room with controlled ambient air temperature and humidity. All parameters were measured 10 times in each anatomical location using the average for statistical analysis.
At V3, participants were asked about their global satisfaction with the tested product by answering a questionnaire using a 5-point Likert scale (1, very dissatisfied; 2, dissatisfied; 3, neither satisfied nor dissatisfied; 4, satisfied; 5, very satisfied).
Information regarding adverse effects was also collected, including the degree, duration, and possible association with the treatment throughout the study.
Statistical Analysis
Numerical outcomes were described as absolute change (between visits) ± standard error at V1 (baseline), V2 (V2 vs V1), and V3 (V3 vs V1). For the description of categorical variables, the mean of absolute and relative frequencies was used. Numerical data were analyzed using the parametric (Student’s t) or non-parametric (Mann–Whitney U/Wilcoxon) tests for paired data (intragroup analysis) and unpaired data (intergroup analysis). For categorical variables, the chi-square test or Fisher’s exact test was used for comparisons between treatment groups (independent samples) and the parametric (Student’s t) or non-parametric (Mann–Whitney U/Wilcoxon) test was used for comparisons between visits (paired samples). For all statistical tests a statistical significance level of 0.05 was applied. The statistical treatment of the data was carried out with the support of the statistical package SAS (Statistical Package SAS) 9.4 version.
A statistical subanalysis was carried out regarding age, participants were divided into two groups (≤ 55 or > 55 years old).
Results
Participant Characteristics
A total of 60 healthy women were randomized at week 0 and allocated to either the HAm group (HAm-g; n = 30) or placebo group (PBO-g; n = 30). The study enrolled Caucasian women with phototype between II and IV and a mean age of 54 ± 7.8 years and with visible wrinkles. During the study, 98.3% of the study population (n = 59) used moisturizing creams, cosmetics, and sunscreens. Sociodemographic and anthropometric characteristics showed homogeneity in the two study groups (Table 2).
Table 2.
Characteristics of participants of study
| Sociodemographic and anthropometric characteristics | Placebo (n = 30) | HAm (n = 30) |
|---|---|---|
| Age (years) | 56.3 ± 1.1 | 51.6 ± 1.6 |
| Ethnicity (Caucasian %) | 30 (100%) | 30 (100%) |
| Weight (kg) | 62.8 ± 1.7 | 67.5 ± 1.6 |
| Height (cm) | 159.9 ± 1.4 | 164.0 ± 1.0 |
| BMI (kg/m2) | 24.6 ± 0.6 | 25.1 ± 0.9 |
| Concomitant diseases (yes) | 21 (70.0%) | 19 (63.3%) |
| Any concomitant medication in the last 3 months? (yes) | 21 (70.0%) | 23 (76.7%) |
| Known allergies (yes) | 10 (33.3%) | 9 (30.0%) |
| Sun exposure pattern | ||
| Acute | 6 (20.0%) | 8 (26.7%) |
| Intermittent | 16 (53.3%) | 16 (53.3%) |
| Chronic | 8 (26.7%) | 6 (20.0%) |
| Skin phototype | ||
| II | 8 (26.7%) | 13 (43.3%) |
| III | 13 (43.3%) | 11 (36.7%) |
| IV | 9 (30.0%) | 6 (20.0%) |
| Smoking history | ||
| Smoker | 11 (36.7%) | 5 (16.7%) |
| Ex-smoker | 12 (40.0%) | 13 (43.3%) |
| Non-smoker | 7 (23.3%) | 12 (40.0%) |
| Weekly alcohol consumption (SDU) | ||
| 0 | 15 (50.0%) | 10 (33.3%) |
| 1–2 | 12 (40.0%) | 14 (46.7%) |
| 3–5 | 2 (6.7%) | 6 (20.0%) |
| ≥ 6 | 1 (3.3%) | 0 (0.0%) |
| Facial aging type | ||
| I, no wrinkles | 0 (0.0%) | 0 (0.0%) |
| II, expression wrinkles | 6 (20.0%) | 12 (40.0%) |
| III, wrinkles at rest | 20 (66.7%) | 16 (53.3%) |
| IV, wrinkles only | 4 (13.3%) | 2 (6.7%) |
| Uses any moisturizing/cosmetic cream and/or sunscreen? (yes) | 29 (96.7%) | 30 (100.0%) |
Numerical data are expressed as mean (± standard error) and categoric outcomes are expressed as absolute (relative) frequency
HAm hyaluronic acid matrix, BMI body mass index, SDU standard drink unit (1 SDU = 10 g of pure alcohol)
A per-protocol analysis was used to rigorously evaluate the efficacy of the intervention. The analysis included only those participants who strictly adhered to the trial protocol, ensuring compliance with all specified treatment regimens and follow-up visits. After the follow-up, 50 participants complied with the protocol (26 with HAm and 24 with placebo). The flow of participants is described in Fig. 1.
Fig. 1.
Participants flow diagram
The skin parameters at V1 were similar between groups (Table 3). Only temperature was higher in HAm-g than PBO-g (32.1 ± 0.8 °C vs 31.1 ± 1.1 °C, p = 0.0051).
Table 3.
Skin parameters at V1 (baseline; per-protocol analysis)
| Parameters | Area | Placebo (n = 24) | HAm (n = 26) | Pa |
|---|---|---|---|---|
| Hydration (AU) | Periocular area | 62.4 ± 14.4 | 59.6 ± 13.6 | 0.4665 (u) |
| Cheek | 47.6 ± 13.5 | 50.2 ± 15.0 | 0.5231 (t) | |
| Elasticity-R2 (%) | Periocular area | 53.3 ± 14.3 | 59.2 ± 17.3 | 0.2028 (t) |
| Cheek | 63.1 ± 10.9 | 64.0 ± 14.9 | 0.5148 (u) | |
| Hardness (Shore 0) | Periocular area | 11.8 ± 2.8 | 12.7 ± 4.4 | 0.7486 (u) |
| pH | Periocular area | 6.0 ± 0.5 | 5.9 ± 0.4 | 0.3778 (t) |
| Temperature (°C) | Periocular area | 31.3 ± 1.1 | 32.1 ± 0.8 | 0.0051# (t) |
| Total antioxidant capacity (µC) | Periocular area | 7.4 ± 3.0 | 7.4 ± 4.1 | 0.600 (t) |
| Erythema index (AU) | Periocular area | 269.3 ± 54.9 | 281.5 ± 67.3 | 0.4894 (t) |
| Melanin index (AU) | Periocular area | 167.5 ± 37.5 | 175.1 ± 38.8 | 0.4887 (t) |
| Deformability (mm) | Periocular area | 2.5 ± 0.3 | 2.4 ± 0.3 | 0.4636 (u) |
| Friction (AU) | Periocular area | 147.6 ± 49.1 | 134.8 ± 56.3 | 0.3972 (t) |
| Brightness/glow (AU) | Periocular area | 5.9 ± 1.6 | 5.4 ± 1.5 | 0.2364 (t) |
| Wrinkles (SEw) | Periocular area | 111.3 ± 42.0 | 129.0 ± 61.0 | 0.4606 (u) |
| Cheek | 105.7 ± 49.7 | 98.7 ± 33.9 | 0.9923 (u) | |
| Roughness (SEr) | Periocular area | 3.1 ± 1.6 | 3.0 ± 1.1 | 0.7231 (t) |
| Cheek | 3.3 ± 1.4 | 3.1 ± 1.0 | 0.8082 (u) | |
| Scaliness (SEsc) | Periocular area | 1.1 ± 1.1 | 1.3 ± 1.5 | 0.5153 (u) |
| Cheek | 0.7 ± 0.9 | 0.7 ± 0.9 | 0.9303 (u) | |
| Smoothness (SEsm) | Periocular area | 362.5 ± 141.8 | 415.7 ± 161.0 | 0.2175 (u) |
| Cheek | 318.3 ± 105.2 | 312.4 ± 115.2 | 0.7634 (u) |
Data are expressed as mean ± standard error
HAm hyaluronic acid matrix
aP value after using Student t test (t) or Mann–Whitney U test (u) for independent samples to compare the change between placebo and HAm group
#p > 0.05
Skin Barrier Function Parameters and Skin Properties
Skin barrier function parameters and properties after 6 (V2) and 12 (V3) weeks treatment are shown in Table S1.
The SCH in the HAm-g significantly increased at V2 and V3 both in the rPA and rC. On the rPA, the results showed an increase of 5.7 ± 2.6 AU (p = 0.033) at V2 and 5.3 ± 2.6 AU (p = 0.033) at V3 whereas no differences vs baseline were observed in PBO-g (Fig. 2a). On the rC, the SCH significantly increased in the HAm-g at V2 (10.8 ± 3.0 AU, p = 0.002) and at V3 (10.6 ± 3.0 AU, p = 0.002). In the PBO-g, SCH also increased at V2 and V3 (10.2 ± 2.8 AU, p = 0.002; 9.7 ± 2.7 AU, p = 0.004, respectively).
Fig. 2.
Skin barrier function parameters and properties. a Stratum corneum hydration in right periocular area. b Skin pH. c Erythema index. d Skin brightness/glow. Data are expressed as absolute change (mean ± standard error). V2 = changes V2 vs V1. V3 = changes V3 vs V1. *p < 0.05 and **p < 0.01 vs the baseline value
The skin hardness significantly decreased in PBO-g at V2 (1.8 ± 0.7 Shore O, p = 0.011) and at V3 (3.2 ± 0.9 Shore O, p = 0.001) vs baseline. In the HAm-g, the results only showed a significant decrease at V3 (3.5 ± 1.1 Shore O, p = 0.001) vs baseline.
Regarding pH, the results showed statistically significant differences between HAm-g and PBO-g at V3 (p = 0.0298). In terms of change from baseline, the pH in the PBO-g significantly decreased at V2 (0.3 ± 0.1, p = 0.0178) and V3 (0.5 ± 0.1, p < 0.0001) whereas the pH in the HAm-g did not show any statistically significant change at V2 and V3 (Fig. 2b).
The temperature significantly decreased both in the HAm-g and PBO-g at V2 (0.8 ± 0.3 °C, p = 0.0028 and 0.9 ± 0.4 °C, p = 0.038, respectively). This decrease was only maintained in the HAm-g at V3 (0.8 ± 0.2 °C, p = 0.0014).
Erythema index significantly decreased at V2 (23.3 ± 11.0 AU, p = 0.0435) in the HAm-g whereas no differences vs baseline were detected in the PBO-g (Fig. 2c). At V3 no change vs baseline was observed (p = 0.595) in the HAm-g. The measurement of melanin index did not change at V2 and V3 in any of the groups.
The skin brightness/glow showed a statistically significant increase in the HAm-g at V2 (0.8 ± 0.3 AU, p = 0.0167) and V3 (1.3 ± 0.4 AU, p = 0.0011) whereas no differences vs baseline were detected in the PBO-g (Fig. 2d).
Skin deformability no showed significant change at V2 in any of the study groups. However, at V3, the deformability showed a significant decrease in both the HAm-g (0.6 ± 0.1 mm, p < 0.0001) and the PBO-g (0.4 ± 0.1 mm, p = 0.0002) vs baseline.
No significant changes were observed in elasticity (R2), antioxidant capacity, or friction between HAm-g and PBO-g.
Skin microtopography showed a significant improvement in all SELS parameters: skin wrinkles (SEw), roughness (SEr), scaling (SEsc), and smoothness (SEsm) (Table S1). The skin wrinkles showed statistically significant differences between HAm-g and PBO-g at V2 (p = 0.0442) on the rPA. The absolute change in wrinkles decreased 12.4 ± 10.0 SEw at V2 and 3.3 ± 13.5 SEw at V3 in the HAm-g, whereas skin wrinkles increased 16.5 ± 9.8 SEw at V2 and 12.7 ± 9.3 SEw at V3 in the PBO-g (Fig. 3a). On the rC, the wrinkles increased in the treatment group at V2 (p = 0.009), while no change in the skin wrinkles was observed in any group at V3.
Fig. 3.
Changes in skin microtopography. a Crow’s feet wrinkles in periocular area. b Skin scaliness in periocular area. c Skin roughness in cheek. d Skin smoothness in periocular area. Data are expressed as absolute change (mean ± standard error). V2 = changes V2 vs V1. V3 = changes V3 vs V1. *p < 0.05 and **p < 0.01 vs the baseline value. #p < 0.05 vs placebo
Skin scaling in the HAm-g (rPA) significantly decreased at V2 (0.6 ± 0.3 SEsc, p = 0.0101) and at V3 (0.8 ± 0.3 SEsc, p = 0.0086), while in the PBO-g no change vs baseline was observed (Fig. 3b). On rC, no change was observed in any group.
The measurements of roughness performed on the rC showed significant differences between the HAm-g and PBO-g (p = 0.0289) at V3. The absolute change in roughness (rC) improved in the HAm-g at V2 (0.7 ± 0.4 SEr, p = 0.0549) and significantly increased at V3 (0.8 ± 0.3 SEr, p = 0.0129) vs baseline (Fig. 3c). In terms of absolute change from baseline, the roughness on the rPA did not show any change.
The results of smoothness on rPA showed statistically significant differences between HAm-g and PBO-g at V2 (p = 0.0114). In addition, in terms of absolute change from baseline, the skin smoothness in the HAm-g (rPA) significantly improved at V2 (− 71.1 ± 29.3 SEsm, p = 0.0228). At V3, skin smoothness also improved (− 34.0 ± 37.2 SEsm, p = 0.3699) vs baseline, although this change was not significant. However, in the PBO-g an increase was observed in both V2 (34.1 ± 26.9 SEsm, p = 0.2182) and V3 (21.2 ± 39.1 SEsm, p = 0.5927) vs baseline (Fig. 3d). Regarding the skin smoothness on the rC, a significant increase of SEsm was observed at V2 (46.3 ± 20.0 SEsm, p = 0.0293) in the HAm-g vs baseline whereas no change was observed in PBO-g. At V3 no statistically significant change on the rC was observed in any of the study groups.
Satisfaction Survey and Adverse Events
The global satisfaction perceived by the participants was evaluated after 12 weeks of treatment (V3). Considering global satisfaction as a numerical variable, the results showed statistically significant differences between HAm-g and PBO-g (p = 0.0121). From a qualitative point of view, the evaluation of the subject’s global satisfaction showed that 69.2% participants supplemented with HAm were very satisfied (53.8%) or satisfied (15.4%) and none of them reported being dissatisfied or very dissatisfied. In contrast, in the PBO-g, only 41.7% of participants reported being very satisfied (4.2%) or very satisfied (37.5%) and 25.0% of participants reported being dissatisfied (16.7% dissatisfied + 8.3% very dissatisfied).
The results confirmed that HAm is safe and well tolerated for its use as oral supplement because no adverse events associated with the ingredient were registered.
Changes in Skin According to Age
A subanalysis was performed to evaluate the results depending on the age of the participants. The database was divided into two subgroups, one for participants > 55 years old and the other for those ≤ 55 years old.
Participants > 55 Years Old
Assessments were performed on data from 28 participants > 55 years old (n = 11 in HAm-g and n = 17 in PBO-g) with a mean age of 59.4 ± 2.6 years. The results of skin barrier function parameters and skin properties in participants > 55 years old showed significant improvements in the HAm-g compared with the PBO-g in the skin pH (p = 0.0456) and deformability (p = 0.0393) at V3. In addition, the results showed that the pH decreased significantly 0.4 ± 0.1 at V3 in the PBO-g, whereas no difference vs baseline was detected in the HAm-g at V3 (Fig. 4a). The deformability in HAm-g showed a significantly greater decrease (0.8 ± 0.1 mm, p < 0.0001) at V3 as compared with the PBO-g (0.4 ± 0.1 mm, p = 0.0057) (Fig. 4b).
Fig. 4.
Main changes in barrier function parameters, skin properties, and skin microtopography in participants > 55 years old. a Skin pH. b Skin deformability. c Skin brightness/glow. d Skin roughness in the cheek. e Skin smoothness in the periocular area. f Skin scaliness in the periocular area. Data are expressed as absolute change (mean ± standard error). V2 = changes V2 vs V1. V3 = changes V3 vs V1. *p < 0.05 vs the baseline value. # p < 0.05 vs placebo
Regarding SCH, it was higher in HAm-g (14.9 ± 4.3 AU, p = 0.0063) than in PBO-g (8.9 ± 3.4 AU, p = 0.0208) vs baseline at V2 on the rC. In addition, SCH increased in the PBO-g at V3.
Temperature significantly decreased in the HAm-g (1.1 ± 0.3 °C, p = 0.0066) and in the PBO-g (1.1 ± 0.5 °C, p = 0.0438) at V2. This decrease was only maintained in HAm-g at V3 (1.1 ± 0.4 °C, p = 0.0090) vs baseline.
Brightness only improved in the HAm-g at V3, showing a statistically significant increase of 1.7 ± 0.7 AU, p = 0.0308 whereas no differences vs baseline were detected in the PBO-g (Fig. 4c).
Elasticity (R2), hardness, antioxidant capacity, erythema and melanin index, and friction showed no changes in the HAm-g after 12 weeks of treatment (Table S2).
The results in skin architecture showed significant improvements in the HAm-g compared with the PBO-g in the skin roughness and smoothness (Table S2). SEr showed significant differences between treatment groups at V2 (p = 0.0174) and V3 (p = 0.0431) on rC (Fig. 4d). SEr significantly increased on the rC only in the HAm-g at V2 (0.9 ± 0.4 SEr, p = 0.05) vs baseline. At V3 SEr also increased in the HAm-g (1.1 ± 0.5 SEr, p = 0.0601) although it was not significant (p = 0.0601). The SEsm assessment showed that the HAm-g significantly improved skin smoothness compared to the PBO-g at V2 (p = 0.0330) on the rPA. The results in HAm-g (rPA) showed a SEsm numerical reduction (88.3 ± 62.6 SEsm and 79.4 ± 62.8 SEsm) vs baseline, whereas SEsm increased in the PBO-g (51.8 ± 29.8 SEsm and 34.5 ± 53.5 SEsm) at V2 and V3, respectively (Fig. 4e). The parameter SEsm on the rC showed a significant increase in the PBO-g (66.8 ± 30.2 SEsm, p = 0.0384) at V3, whereas no differences vs baseline were detected in the HAm-g.
The skin wrinkles did not show statistically significant changes vs baseline in any groups. However, a numerical reduction of 22.2 ± 16.9 SEw and 12.8 ± 20.1 SEw at V2 and V3, respectively, was observed in the HAm-g (rPA) whereas the wrinkles increased in the PBO-g 16.6 ± 11.2 SEw and 10.0 ± 12.1 SEw at V2 and V3, respectively. SEw did not show any change on the rC in any groups.
Skin scaliness on the rPA showed a statistically significant reduction of 1.4 ± 0.6 SEsc (p = 0.0364) in the HAm-g at V3, whereas no differences vs baseline were detected in the PBO-g (Fig. 4f). On the rC, the HAm-g showed a numerical reduction at V2 (0.3 ± 0.3 SEsc) and at V3 (0.4 ± 0.2 SEsc) vs baseline, whereas the skin scaliness increased in the PBO-g by 0.2 ± 0.1 SEsc and 0.2 ± 0.1 SEsc at V2 and V3, respectively.
Participants ≤ 55 Years Old
The change in skin barrier function parameters, skin properties, and microtopography were evaluated in 22 participants ≤ 55 years old (n = 15 HAm-g and n = 7 PBO-g) with a mean age of 48.0 ± 6.8 years (Table S3).
The SCH in HAm-g (rPA) increased significantly at V2 (4.0 ± 2.9 AU, p = 0.0472) and V3 (7.8 ± 3.6 AU, p = 0.0472) whereas no differences vs baseline were detected in the PBO-g (Fig. 5a). SCH on the rC significantly increased only in the HAm-g at V3 (12.2 ± 3.9 AU, p = 0.0078) (Fig. 5b).
Fig. 5.
Main changes in barrier function parameters, skin properties, and skin microtopography in participants ≤ 55 years old. a Skin hydration in the periocular area. b Skin hydration in the cheek. c Skin brightness/glow in the periocular area. d Skin smoothness in the periocular area. Data are expressed as absolute change (mean ± standard error). V2 = changes V2 vs V1. V3 = changes V3 vs V1. *p < 0.05 and **p < 0.01 vs the baseline value
Hardness and deformability in HAm-g showed a more significant decrease in V3 vs baseline. No statistically significant differences were found between treatments.
Brightness improved in the HAm-g showing a statistically significant increase of 1.0 ± 0.4 AU (p = 0.0494) at V2 and 1.0 ± 0.3 AU (p = 0.0115) at V3, whereas no differences vs baseline were detected in the PBO-g (Fig. 5c). No statistically significant differences were found between treatments.
pH significantly decreased with both treatments at V3 without differences at V2. In the HAm-g, pH significantly decreased 0.3 ± 0.1 (p = 0.0279), and in the PBO-g pH decrease was higher: 0.6 ± 0.2 (p = 0.0051). No significant differences were observed between treatment arms.
Elasticity (R2), temperature, erythema and melanin index, antioxidant capacity, and friction no showed significant differences between groups.
Regarding to skin microtopography (Table S3), the results showed a numerical wrinkle reduction on rPA of 5.3 ± 12.3 SEw at V2 in the HAm-g, whereas wrinkles increased in the PBO-g by 16.3 ± 20.9 Sew. SEsm in the rPA showed a statistically significant reduction at V2 (58.5 ± 23.8 SEsm, p = 0.0286) vs baseline (Fig. 5d) in the HAm-g. No significant differences between groups were detected on wrinkles, roughness, scaliness, and smoothness.
Discussion
The aging process is mainly associated with the appearance of fine wrinkles, flaccid, dry skin, and loss of skin radiance. The results of this study show that an oral supplementation with 60 mg/day of a HAm ingredient containing HA, DS, CS, and collagen (Dermial®) significantly improves various aspects of aging skin such as skin hydration, brightness, pH, temperature, erythema index, wrinkles, smoothness, roughness, and scaliness.
The improvements in skin hydration observed with HAm align with existing literature on the benefits of HA and other GAGs in enhancing skin moisture. HA has the capacity to retain water in the skin, improving hydration and overall skin appearance [17]. In this study, significant increases in skin hydration were noted in the rPA and on the rC after 6 and 12 weeks, supporting the efficacy of HAm in promoting skin moisture.
HAm’s unique ability to increase skin brightness/glow is significant, as skin brightness is a key indicator of healthy and youthful skin. The increase in brightness could be due to improved hydration, reduced erythema, and a smoothing effect on the skin surface, enhancing light reflection [18]. No previous clinical trials have evaluated the impact of oral HA on this skin property but previously it has been observed that mesotherapy with HA can improve skin brightness [19]. This effect is particularly important for user satisfaction and visible skin improvement.
Skin pH is another crucial factor in maintaining skin barrier function and overall health. The results showed that HAm helped maintain stable skin pH levels, while the PBO-g showed greater variability, exhibiting significant decreases. A balanced skin pH is essential for optimal enzyme function and microbial balance [20]. The stabilization of skin pH by HAm underscores its potential role in preserving skin health and preventing disorders associated with pH imbalance.
The observed decrease in skin temperature with HAm may indicate improved hydration and barrier function. Well-hydrated skin tends to have a lower temperature due to better water retention and reduced evaporation [21]. This decrease could also reflect a decrease of inflammation and improved skin homeostasis, contributing to a more balanced skin condition. This is in agreement with the reduction of the erythema index in the HAm-g. The reduction of temperature and erythema index indicates potential anti-inflammatory properties. HA may have soothing effects on the skin, reducing redness and inflammation [22]. This decrease is particularly beneficial for individuals with sensitive or irritated skin, enhancing the skin’s appearance and comfort.
The lack of significant changes in skin elasticity across both treatment groups could be due to the short duration of the study or the specific properties of the treatments. Elasticity improvements might require longer-term treatment or ingredients specifically targeting collagen synthesis and skin resilience [23], which might not be the primary action of HAm. The reduction in skin hardness and deformability in both treatment arms suggests that both HAm and PBO improve skin suppleness. This decrease was more significant in the HAm, which is related to the hydrating and moisturizing effects of the product. This makes the skin more pliable and less prone to mechanical stress. The absence of changes in skin friction indicates that neither HAm nor the PBO significantly alters the surface texture of the skin in a way that affects friction. This might suggest that the treatments do not significantly impact the superficial layers of the skin involved in frictional resistance [24].
The lack of change in antioxidant capacity suggests that HAm does not significantly affect the oxidative state of the skin. This may indicate that its benefits are more related to physical barrier enhancement and hydration rather than biochemical changes involving oxidative stress [25].
Skin microtopography parameters of skin roughness, smoothness, wrinkles, and scaliness in this study showed significant improvements. Specifically, skin aging symptoms such as skin wrinkles, roughness, and smoothness were significantly improved compared to placebo further supporting HAm’s efficacy in enhancing skin appearance and texture. Improvements in smoothness and reductions in roughness were observed, likely due to the synergistic effects of the components in HAm. HA is known to fill the spaces between collagen and elastin fibers, providing structural support and a smoother skin appearance. Additionally, the moisturizing effects of these compounds can soften the skin surface, reducing the appearance of roughness [26, 27].
The reduction in wrinkles in the HAm-g highlights its antiaging benefits. The components of HAm, such as HA and collagen, are known to improve skin structure and hydration, leading to fewer wrinkles and less flaking [24, 28]. DS and CS may also play roles in promoting skin cell turnover and improving the overall skin barrier function, leading to less flaking [29]. Wrinkle reduction could be explained because HA ingestion favors proliferation of fibroblasts which are responsible for producing the extracellular matrix of the dermis, thus allowing the mechanical resistance of the dermis to be improved and maintaining normal skin. Moreover, as fibroblast cells are growing, wrinkle suppression is also increased by the promotion of collagen synthesis [30].
Furthermore, HAm decreased skin scaliness, improving dryness and smoothness, and reducing roughness. The reduction in scaliness can be attributed to the hydrating effects of HA, which enhance the skin’s moisture retention, preventing the excessive shedding of skin cells [31].
The subanalysis by age reveals interesting differences in the effects of HAm-g compared to PBO-g in participants older and younger than 55 years, which could reflect physiological differences in skin associated with aging [32]. In participants over 55 years old of HAm-g, significant improvements in parameters related to skin barrier function, particularly in brightness, hydration, deformability, temperature, smoothness, roughness, and scaliness, were observed. The stability of pH in this group is also noteworthy, suggesting that HAm contributes to maintaining proper skin homeostasis, in contrast to the decline observed in the PBO-g. The more pronounced reduction in deformability and roughness and the improvement in skin brightness in older participants supplemented with HAm further support its potential to address age-related issues, such as reduced elasticity and dry and dull skin. Additionally, improvements in skin smoothness and reduction in scaliness in the rPA highlight HAm’s possible capacity to enhance skin microtopography in sensitive regions.
In participants younger than 55 years, although significant benefits in hydration, brightness, and smoothness were also observed, the differences between groups were less pronounced than in those over 55. This could indicate that younger skin responds differently to treatments, possibly due to its intrinsic ability to maintain more stable homeostasis and its lower susceptibility to alterations in microstructural integrity [33]. A key difference between the two groups is that in participants over 55 years, improvements in skin texture and properties (such as deformability and scaliness) were more pronounced. This may reflect a greater margin for improvement in aging skin, where cumulative deterioration in structural properties offers a higher potential for the effects of a regenerative treatment. Moreover, the sustained reduction in temperature in the HAm in older participants may be related to improved barrier function and a reduction in subclinical inflammation. Collectively, these findings highlight the differential efficacy of HAm based on age, emphasizing its greater impact on mature skin and its ability to address specific issues associated with skin aging.
Finally, the results of this study demonstrated a high level of satisfaction among participants using HAm. This significant difference in satisfaction levels is likely attributable to the observed improvements in skin parameters such as increased brightness, reduced wrinkles, and decreased skin flaking, which are critical indicators of perceived skin health and attractiveness. Enhanced smoothness and hydration further contributed to the positive perception of HAm among participants. In addition to its efficacy, HAm exhibited an excellent safety profile. The study reported no severe adverse events related to the product.
The comprehensive assessment of skin barrier function and skin microtopography in this study provides a holistic view of HAm’s effects on skin health. However, there are limitations to consider. Only women were included, limiting the generalizability of the results to a broader population, including men and individuals of different age groups and ethnic backgrounds. Another limitation is the short duration of the study. While significant improvements were observed over 12 weeks, longer studies are necessary to assess the sustained effects of HAm and to determine the optimal duration of supplementation for long-term benefits. Finally, another limitation to consider is that this clinical study did not restrict the use of topical creams. Thus, 98.3% of the participants, in addition to oral supplementation with HAm or PBO, used moisturizing cosmetic cream and/or sunscreen.
Conclusion
This study provides compelling evidence that daily oral supplementation with HAm (Dermial®) can significantly improve various aspects of skin health, mainly skin roughness, smoothness, brightness/glow, hydration, pH, and wrinkles. The findings suggest that HAm is a safe and effective option for enhancing skin properties, supporting its potential as an antiaging treatment.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the participants of the study.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.
Author Contributions
Patricia Gálvez-Martín and Salvador Arias-Santiago performed the conceptualization; Trinidad Montero-Vilchez and Raquel Sanabria-de la Torre, Carlos Cuenca-Barrales, Alejandro Molina-Leyva performed investigation; Trinidad Montero-Vilchez and Patricia Gálvez-Martín wrote the original draft preparation; Patricia Gálvez-Martín, Daniel Martinez-Puig, Javier Velasco-Alvarez performed funding acquisition. All authors have read and agreed to the published version of the manuscript.
Funding
This study and the journals rapid service fee were funded by Bioiberica.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
The present work was funded by Bioiberica. Patricia Gálvez-Martín, Daniel Martinez-Puig and Javier Velasco-Alvarez are full-time employees of Bioiberica. Trinidad Montero-Vilchez, Raquel Sanabria-de la Torre, Carlos Cuenca-Barrales, Alejandro Molina-Leyva and Salvador Arias-Santiago have nothing to disclose.
Ethical Approval
The study was carried out at the Dermatology Department of Hospital Universitario Virgen de las Nieves de Granada in accordance with international standards of Good Clinical Practice and the Declaration of Helsinki and was approved by the Granada Ethics Committee on 30 June 2022 (code 0748-N-22). The study population was healthy women (entirely voluntary) who met all the inclusion criteria and none of the exclusion criteria. Participants provided written informed consent before study-related procedures.
Footnotes
Prior Presentation: Some of results described in this paper were presented as a poster at the Society for Investigative Dermatology (SID) 2024 Annual Meeting, Dallas, Texas, USA, May 2024.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.