Abstract
Objective
Skin ageing, hyperpigmentation, and texture are common dermatological concerns. Retinoids, including retinol, are widely used for their efficacy in treating these conditions. However, their side effects, such as irritation, often limit their use. Bakuchiol, a plant‐derived retinoid alternative, has gained attention for its gentler profile, but its efficacy remains a subject of comparison with traditional retinoids. The aim of the present study was to evaluate the efficacy of a novel microalgae‐derived bioretinoid (MBR) in comparison to retinol and bakuchiol in promoting skin regeneration, reducing ageing signs, and addressing hyperpigmentation.
Methods
The effects of MBR were evaluated in vitro for cell proliferation, melanin production, and extracellular matrix modulation. Clinically, MBR was applied to assess improvements in skin texture, firmness, elasticity, and pigmentation compared with reference treatments.
Results
In vitro, MBR significantly outperformed both retinol and bakuchiol in cell proliferation, melanin reduction, and ECM modulation. In vivo, MBR improved skin texture, firmness, and pigmentation, showing results comparable to retinol. MBR also synergistically enhanced retinol's effects, improving hydration and reducing irritation.
Conclusion
MBR is a promising alternative to traditional retinoids, offering enhanced efficacy in skin regeneration and pigmentation control with a more favourable safety profile, especially when combined with retinol.
A novel microalgae‐derived bioretinoid (MBR) enhances skin regeneration, improves pigmentation, and reduces signs of ageing more effectively than bakuchiol and comparably to retinol—without the irritation. MBR also synergizes with retinol, boosting hydration and safety. A powerful, gentle alternative for advanced skincare.
RÉSUMÉ
Objectif
Le vieillissement cutané, l'hyperpigmentation et la texturation de la peau sont des problèmes dermatologiques courants. Les rétinoïdes, dont le rétinol, sont largement utilisés pour leur efficacité dans le traitement de ces affections. Cependant, leurs effets secondaires, tels que l'irritation, limitent souvent leur utilization. Le bakuchiol, une alternative d'origine végétale au rétinol, a attiré l'attention pour son profil plus doux, mais son efficacité reste sujette à comparaison avec les rétinoïdes traditionnels. Cette étude avait pour objectif d'évaluer l'efficacité d'un nouveau bio‐rétinoïde dérivé de microalgues (BRM) par rapport au rétinol et au bakuchiol dans la promotion de la régénération cutanée, la réduction des signes de vieillissement et le traitement de l'hyperpigmentation.
Méthodes
Les effets du BRM ont été évalués in vitro pour la prolifération cellulaire, la production de mélanine et la modulation de la matrice extracellulaire. Sur le plan clinique, le BRM a été utilisé pour évaluer les améliorations de la texture, de la fermeté, de l'élasticité et de la pigmentation de la peau par rapport aux traitements de référence.
Résultats
In vitro, le BRM a largement surpassé le rétinol et le bakuchiol en termes de prolifération cellulaire, de réduction de la mélanine et de modulation de la MEC. In vivo, le BRM a amélioré la texture, la fermeté et la pigmentation de la peau, avec des résultats comparables à ceux du rétinol. Le BRM a également renforcé de manière synergique les effets du rétinol, améliorant l'hydratation et réduisant l'irritation.
Conclusion
Le BRM est une alternative prometteuse aux rétinoïdes traditionnels, offrant une efficacité accrue dans la régénération cutanée et le contrôle de la pigmentation, avec un profil d'innocuité plus favourable, en particulier lorsqu'il est associé au rétinol.
INTRODUCTION
Skin ageing, hyperpigmentation, and acne are common dermatological concerns that affect both the aesthetic appearance and overall health of the skin. Retinoids, particularly retinol, have long been recognized as one of the most effective treatments for these conditions due to their ability to regulate gene expression related to cell differentiation, proliferation, and extracellular matrix (ECM) modulation. Retinoids have been shown to enhance skin regeneration by stimulating collagen production, reducing wrinkles, and improving skin texture [1, 2]. Furthermore, their ability to modulate pigmentation has made them a key treatment for hyperpigmentation disorders, such as age spots and melasma [3]. However, despite their efficacy, retinol and other synthetic retinoids are often associated with side effects, including skin irritation, dryness, and photosensitivity, particularly in individuals with sensitive skin. These adverse effects limit their widespread use and call for the development of more tolerable alternatives [1, 2].
Retinoid‐like compounds have garnered significant attention in dermatology due to their ability to replicate many of the therapeutic effects of traditional retinoids while often minimizing associated side effects [4]. These compounds can activate retinoic acid receptors (RARs), which play a critical role in regulating skin cell proliferation, differentiation, and the synthesis of ECM proteins such as collagen. As a result, retinoid‐like agents help improve skin texture, reduce the appearance of fine lines and wrinkles, and enhance overall skin tone and elasticity [5]. Importantly, many retinoid‐like compounds, especially those derived from plants or microbial sources, demonstrate improved skin tolerability [6]. This balance of efficacy and safety positions retinoid‐like compounds as valuable tools in both therapeutic and cosmetic dermatology.
In recent years, bakuchiol has gained attention as a promising plant‐derived retinoid‐like compound, known for its anti‐ageing, anti‐inflammatory, and acne‐reducing properties. Bakuchiol has been found to exhibit similar biological activities to retinol, including the stimulation of collagen production and the promotion of cell turnover [7, 8]. Furthermore, several studies have also highlighted bakuchiol's efficacy in reducing skin inflammation, treating acne, and reducing signs of ageing, such as fine lines and wrinkles, without the irritation typically associated with retinoids [9, 10]. These findings suggest that bakuchiol may offer a promising alternative to traditional retinoids, particularly for individuals with sensitive or reactive skin. Despite reducing skin side effects, bakuchiol is generally considered less effective than retinoids and retinol, a limitation that highlights the need for the development of more potent alternatives [9].
The present study aims to evaluate the efficacy of a microalgae‐derived bioretinoid (MBR) both in vitro and in clinical studies to promote skin regeneration, reduce signs of ageing, and address hyperpigmentation concerns, in comparison with traditional treatments, including retinol and bakuchiol. This study also investigates the potential of MBR to synergistically enhance the effects of retinol while minimizing its common side effects, such as irritation and dryness, thus providing a promising alternative in the treatment of ageing and pigmentation‐related skin conditions.
MATERIALS AND METHODS
Microalgae‐derived bioretinoid obtention
Microalgae‐derived bioretinoid (MBR) was obtained from Chlorella vulgaris extract and was supplied by ALGAKTIV S.L (Barcelona, Spain).
Cell cultures
For the cell proliferation assay, human skin fibroblasts (SF‐TY; JCRB Cell Bank, Osaka, Japan) were cultivated in minimum essential medium Eagle (MEME; Merck Group, Darmstadt, Germany) at 37°C and 5% CO2. Cells were seeded in a 96‐well plate at 3.5 × 104 cells per well and maintained for 24 h at standard culture conditions (37°C, 95% RH, 5% CO2). Cells were then exposed to the treatments (1% MBR, 1% Retinol or 1% Bakuchiol) or vehicle for 6 days.
For the melanin quantification study, human epidermal melanocytes (Cell Applications Inc., San Diego, CA, USA) were cultivated in growth media at 37°C and 5% CO2 in a humidified incubator. Cells were then exposed to the treatments (1% MBR, 1% Retinol or 1% Bakuchiol) or vehicle for 24 h.
For the MMP and HA study, human skin fibroblasts (SF‐TY; JCRB Cell Bank) were cultivated in minimum essential medium Eagle (MEME; Merck) with 10% fetal bovine serum and 1% antibiotics at 37°C and 5% CO2. Cells were seeded in a 96‐well plate at 1 × 104 cells per well and maintained for 24 h at standard culture conditions (37°C, 95% RH, 5% CO2). Treatments (1% MBR, 1% Retinol or 1% Bakuchiol) or vehicle were added for 24 h.
For the retinoid acid receptor (RAR) agonist assay, RAR‐alpha, beta, or gamma‐UAS‐bla HEK 293T cells were thawed and resuspended in assay media (DMEM phenol red free, 2% CD‐treated FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U mL−1–100 μg mL−1 penicillin–streptomycin) to a concentration of 312 500 cells mL−1.
For transepidermal penetration study and collagen evaluation, a reconstructed full‐thickness human skin model (RFTHS, EpiDerm FT; MatTek Life Sciences, Ashland, MA, USA) was used. Briefly, 6‐well plates were filled with 1000 μL maintenance culture medium (MatTek Life Sciences). Tissues were then cleaned with sterile absorbent paper and transferred to well plates for incubation at 37°C, 5% CO2, 95% RH until test item application.
Cell proliferation assay
MTT assay was performed every 24 h of the incubation period to evaluate cell viability and proliferation index comparing treatments with untreated control. Specifically, MTT‐medium was prepared at a concentration of 1 mg mL−1 in culture medium. After exposure of cells to the test items, they were washed with 200 μL of PBS. After removal of the washing solution, 200 μL of MTT‐medium was added to each culture well and then incubated for 3 h at 37°C and 5% CO2. At the end of the incubation period, the MTT‐medium was removed and 200 μL of isopropanol was added. The plate was shaken on a rotatory plate for 30 min, and the absorbance was measured at 570 nm on a microplate reader. The results were expressed as % cell viability compared with untreated control.
Melanin content determination
A fluorometric commercial kit (Abnova, Taipei, Taiwan) was used for the melanin determination following the manufacturer's instructions. Briefly, the standards and test samples were prepared in assay buffer according to the kit recommendations, and 50 μL of each were added per duplicate in a 96‐well microplate. Signal enhancer was added to all the wells (50 μL per well) and the reaction mixture was incubated at RT for 30– 60 min. The fluorescence signal was measured in a fluorescence plate reader at λ Ex/λ Em of 470/550 nm with an established cutoff at 515 nm.
Hyaluronic acid and matrix metalloproteinases quantification
Cell culture supernatant was collected for the quantification of HA and MMP‐1 using commercial kits (Abbkine Scientific Co., Ltd., GA, USA) that were performed as specified by the manufacturer. For the MMP‐1 determination, samples and standards were added to the microplate. Then a biotinylated detection antibody specific for MMP‐1 and Avidin‐Horseradish Peroxidase (HRP) conjugate was added to each well and incubated for 30 min at 37°C. After washing steps, the substrate solution was added to each well. Finally, the stop solution was added, and the optical density (OD) was measured at a wavelength of 450 nm.
For the HA‐quantification, samples, standards, and biotinylated detection antibody were added to the microtiter plate precoated with HA. Excess conjugate and unbound samples or standards were washed, and HRP‐streptavidin was added to each well and incubated for 30 min at 37°C. Then, TMB substrate solution was added to each well. Finally, acid solution was added, and the OD was measured spectrophotometrically at a wavelength of 450 nm.
Collagen immunohistochemistry analysis
Treatments (1% MBR, 0.15% Retinol, 1% Bakuchiol) or vehicle (60 μL) were applied on the surface of the cultured tissue for 24 h. Tissues were then rinsed several times with 25 mL PBS and dried on a sterile absorbent paper. After that tissues were fixed in 4% formaldehyde in PBS, dehydrated and paraffin embedded. After cutting tissue sections of 5 μm thick on a microtome and placing them on microscope slides, thee immunohistochemistry protocol was followed. Briefly, slides were deparaffinized and dipped in citrate buffer for 30 min at 98°C. After a short wash in TBS, a blocking step was performed by adding 1% hydrogen peroxide. After further washing steps, the slides were incubated for 30 min in 10% normal horse serum in TBS and ON at 4°C with collagen I and III antibodies (ThermoFisher Scientific, MA, USA). Slides were incubated with a biotinylated anti‐rabbit IgG secondary antibody, followed by incubation with peroxidase‐conjugated streptavidin. After that the signal was developed using 3,3′‐diaminobenzidine (DAB) for 2 min. Finally, slides were rinsed with distilled water, counterstained with Mayer's haematoxylin, dehydrated and mounted with a coverslip. Images were acquired and quantitatively analysed using ImageJ software. The results were expressed as percentages of positive coloured area.
Retinoid acid receptor agonist assay
The RAR assay was conducted according to SelectScreen™ Cell‐Based Nuclear Receptor Profiling (Thermofisher Scientific). Specifically, 4 μL of a 10× serial dilution of All‐Trans‐Retinoic Acid (ATRA, control agonist) or testing compound was added to appropriate wells of the 384‐well assay plate. Then, 32 μL of cell suspension (10 000 cells) was added to each well. To bring the final assay volume to 40 μL, 4 μL of assay media was added to all wells. After an incubation period of 16–24 h at 37°C and 5% CO2 in a humidified incubator, 8 μL of 1 μM substrate loading solution was added to each well. The plate was incubated for 2 h at room temperature (RT) and immediately read on a fluorescence plate reader at λ Ex/λ Em of 409/530 nm.
Transepidermal penetration study
Sixty microliters treatment (MBR, MBR contained in normal liposomes or MBR in algae oligosaccharides‐coated liposomes) was applied on the surface of the cultured tissue for 24 h. Tissues were then rinsed several times with 25 mL PBS and dried on a sterile absorbent paper. After that, tissues were immediately included in optimal cutting temperature (OCT) compound, cut in sections of 20 μm with a microtome—cryostat and placed on a slide. Slides with tissue sections were mounted with DAPI and a coverslip and observed under a fluorescence (confocal) microscope for the localization of stained nuclei and phycocyanin‐labelled active present in tested products. Images were acquired and quantitative analysis of the active was performed using ImageJ software. Five different tissue sections were analysed. The results were expressed as percentages of positive coloured area.
Clinical efficacy studies
These studies were a randomized, double‐blind, placebo‐controlled cosmetic efficacy investigation designed to assess the performance and tolerability of a topical formulation to assess remodelling properties and colour correction of the MBR on skin. The formulation was designed with retinol stability in mind, to support ingredient integrity throughout the study. Additionally, internal stability studies confirmed that MBR remained stable over all the studies period, reinforcing the robustness of the active under typical use conditions. The study was conducted in healthy adult volunteers aged 18 years and older under dermatological supervision. Participation was entirely voluntary, and all subjects provided written informed consent after being fully informed of the study objectives, procedures, and any foreseeable risks. Subject selection followed defined inclusion and exclusion criteria, with oversight by a qualified dermatologist. All procedures were carried out in compliance with the ethical principles outlined in the Declaration of Helsinki (adopted by the 18th WMA General Assembly, Helsinki, 1964, and subsequent revisions). Prior to the study, all product and ingredient safety data were reviewed. Tolerability was systematically monitored via dermatologist assessments and subject self‐reporting, focusing on common retinoid‐related symptoms such as burning, itching, and dryness, and any unexpected adverse effects were evaluated by a medical investigator and managed accordingly. A sample size of 30 subjects was selected in line with industry standards for cosmetic clinical studies, which typically involve 20–35 participants to balance statistical sensitivity with practical and ethical considerations. Although no formal power calculation was conducted, this sample size was supported by prior internal data and published literature, indicating that n = 30 is sufficient to detect moderate‐to‐strong effect sizes (Cohen's d > 0.5) in parameters such as wrinkle depth, firmness, and radiance, particularly when using high‐resolution instruments such as PRIMOS® 3D and Cutometer®.
To study the remodelling properties and colour correction of MBR, 30 healthy female volunteers aged between 40 and 60 years old and showing visible signs of photoageing (e.g., fine lines/wrinkles in the crow's feet and dark spots) were enrolled in a randomized controlled clinical instrumental study. Volunteers were asked to apply twice a day a simple hydrogel cream containing 2% MBR on one side of the face and the same base with 0.3% Retinol on the contralateral side for 56 days. Photoageing (wrinkles, skin elasticity, firmness, and smoothness) and hyperpigmentation parameters were measured at baseline (D0) and after 7 (D7), 14 (D14), 28 (D28), and 56 (D56) days of product use. Skin elasticity (R2 parameter) and firmness (R0 parameter) were measured using the Cutometer®MPA 580 (Courage + Khazak electronic GmbH, Köln, Germany). Wrinkles depth and pores size were assessed by Primos 3D (GFMesstechnik GmbH, Berlin, Germany). The intensity of dark spots colour was measured by means of a spectrophotometer/colorimeter CM‐700D (Konica Minolta, Milan, Italy) by calculating the Individual Typology Angle (ITA° value). Images were also acquired with VISIA®‐CR (Canfield Imaging Systems, NJ, USA) for the evaluation of dark spots and skin smoothness.
To study the efficacy of the compound against acne, 30 healthy female volunteers aged between 18 and 40 years old with oily, acne‐prone skin (maximum 25 comedones and slight erythema on face) were included in a randomized controlled clinical instrumental study. Subjects were asked to apply twice a day a simple hydrogel cream containing 1% MBR on one side of the face and the same base with 1% Bakuchiol on the contralateral side for 28 days. Skin clearing (moisturization, sebum, and pore size) and soothing (erythema) parameters were measured at baseline (D0) and after 1 (D1), 2 (D2), 7 (D7), 14 (D14) and 28 (D28) days of use. Erythema index (a.u. value) was measured by Mexameter® MX 18 (Courage + Khazak electronic GmbH). Skin moisturization (c.u. value) was evaluated by means of Corneometer® CM 825 (Courage + Khazak electronic GmbH). The sebum content was measured by Sebumeter® 815 (Courage + Khazak electronic GmbH). Pore size was assessed by Primos 3D (GFMesstechnik GmbH). Digital pictures were also acquired for the evaluation of skin redness (VISIA®‐CR; Canfield Imaging Systems, NJ, USA) and imperfections.
For the evaluation of the synergistic efficacy of the compound when combined with retinol, 30 healthy female volunteers aged over 40 years and showing visible signs of skin ageing (dark spots and slight to moderate wrinkles) were enrolled in a randomized controlled clinical instrumental study. The included subjects applied once a day a simple hydrogel cream containing a blend of 1% MBR and 0.1% Retinol on one side of the face and the same base with 0.5% Retinol on the contralateral side for 28 days. Photoageing (moisturization, elasticity, firmness, wrinkles and pore size), hyperpigmentation, and soothing (erythema) parameters were measured at baseline (D0) and after 1 (D1), 2 (D2), 7 (D7), 14 (D14), and 28 (D28) days of use. All parameters were assessed according to previously described methods.
Statistical methods and analysis
Data were statistically analysed using Student's t‐test, Fisher's exact test, and ANOVA test for comparison between treatment groups. Data are presented as means ± SD. Results were considered statistically significant for p < 0.05.
RESULTS
In vitro efficacy
Cell proliferation enhancement
Cell viability of human skin fibroblasts was evaluated after 24 and 48 h of treatment with three different products (1% MBR, 1% retinol, and 1% bakuchiol). As shown in Table 1, treatment with 1% MBR resulted in the highest cell viability at both time points compared with the control group (24 h: 137.9%; 48 h: 121.8%; p < 0.05). The other two treatments also promoted cell proliferation relative to the control. However, the effect was markedly lower, particularly in the case of 1% bakuchiol. Overall, the results indicate that all tested products enhanced fibroblast proliferation, with 1% MBR showing the most pronounced effect.
TABLE 1.
Cell viability after 24 and 48 h treatment of human skin fibroblasts with 1% MBR, 1% retinol, and 1% bakuchiol.
| 24 h | 48 h | |||
|---|---|---|---|---|
| % Cell viability | SD | % Cell viability | SD | |
| Ctl | 100.00 | 4.90 | 100.00 | 8.36 |
| 1% MBR | 137.89* | 9.73 | 121.80* | 2.83 |
| 1% Retinol | 115.31* | 0.46 | 111.20* | 6.48 |
| 1% Bakuchiol | 103.35* | 7.06 | 104.94* | 0.75 |
p < 0.05 vs. Ctl group at the same experimental time.
Melanin reduction
Melanin concentration was quantified after 24 h of treatment of human epidermal melanocytes with three different products (1% MBR, 1% retinol, and 1% bakuchiol). As given in Table 2, all tested products significantly reduced intracellular melanin levels compared to the control, with 1% MBR demonstrating the greatest effect (67.02%, p < 0.05). These findings suggest that 1% MBR exhibits the highest potential for reducing melanin concentration in human melanocytes.
TABLE 2.
Melanin concentration after 24 h treatment of human epidermal melanocytes with 1% MBR, 1% retinol, and 1% bakuchiol.
| Concentration (ng mL−1) | Concentration (%) | SD | |
|---|---|---|---|
| Ctl | 1.91 | 100.00 | 0.06 |
| 1% MBR | 1.28* | 67.02* | 0.12 |
| 1% Retinol | 1.74* | 91.10* | 0.09 |
| 1% Bakuchiol | 1.50* | 78.53* | 0.12 |
p < 0.05 vs. Ctl group.
Extracellular matrix components modulation
The influence of three different products (1% MBR, 1% retinol, and 1% bakuchiol) on hyaluronic acid (HA), matrix metalloproteinase‐1 (MMP‐1) and type I and III collagen synthesis was evaluated after 24 h treatment of human skin fibroblasts or RFTHS. In Figure 1a, we can observe that all products tested significantly increased the synthesis of HA in skin fibroblasts compared with the control, being 1% MBR, the one inducing the highest production (22.95 ng mL−1 vs. 20.95 ng mL−1; p < 0.05).
FIGURE 1.
Extracellular matrix components concentration in in vitro cultures after 24 h of treatment with 1% MBR, 1% retinol, and 1% bakuchiol. (a) Hyaluronic acid (HA) synthesis on human skin fibroblasts. All products tested significantly increase the synthesis of HA compared to control. 1% MBR induces the highest production of HA compared to control. (b) Matrix metalloproteinase‐1 (MMP‐1) concentration on human skin fibroblasts. All products reduce the concentration of MMP‐1 compared to the control group but 1% MBR is most effective. (c) Collagen I expression on reconstructed human epidermis–dermis skin models. Treatment with 1% MBR induces the highest level of collagen I compared to the control group. (d) Collagen III expression on reconstructed human epidermis–dermis skin models. Treatment with 1% MBR induces the highest level of collagen I compared to the control group. *p < 0.05 compared to the control group.
Regarding MMP‐1, all products were able to reduce the concentration of MMP‐1 in skin fibroblasts compared to the control group (Figure 1b). This effect was most evident when cells were treated with 1% MBR (2052.9 pg mL−1 vs. 2611.8 pg mL−1; p < 0.05).
As shown in Figure 1c,d, collagen I and collagen III expression was evaluated in the RFTHS model. An increased expression of both collagen types was observed following treatment with all tested products, with type I collagen being more abundant. Notably, treatment with 1% MBR resulted in the highest levels of collagen compared to the control group (Collagen I: 40.93% vs. 18.06%, p < 0.05; Collagen III: 8.86% vs. 3.22%, p < 0.05). Based on the experimental data, all products significantly increased the levels of HA, Collagen I, and Collagen III, while reducing MMP‐1 content in the culture. Among them, 1% MBR induced the most pronounced effects.
Retinoid acid receptor regulation
The effect of MBR on the different isoforms of the RAR was evaluated using nuclear functional assays in keratinocyte cultures. Exposure to increasing concentrations of MBR led to a dose‐dependent increase in RARβ activation, reaching up to 50% activation at the highest concentration tested (Figure 2). Overall, these findings indicate that MBR exerts a significant dose‐dependent activation of RARβ.
FIGURE 2.
Cell‐based nuclear receptor profiling in vitro assay for retinoic acid receptors after exposure to increasing concentrations of MBR. The product only induces the activation of the RARβ isoform in a dose‐dependent manner.
Transepidermal penetration study
Three different delivery systems for MBR were evaluated using a RFTHS model to assess the product's penetration capacity across the different skin layers. In Figure 3a,d, we can observe that in the absence of a delivery system, 96.2% of MBR was retained in the epidermis, with only 3.8% reaching the dermis. When MBR was delivered via conventional liposomes, 27.8% penetrated the dermis (Figure 3b,d). In contrast, MBR encapsulated in algae oligosaccharide‐coated liposomes achieved the highest dermal penetration, with 65.7% reaching the dermis (Figure 3c,d). These results demonstrate that algae oligosaccharide‐coated liposomes are the most effective delivery system for enhancing the deeper skin penetration of MBR.
FIGURE 3.
Transepidermal penetration study in reconstructed full‐thickness human skin model using immunofluorescence techniques after 24 h of treatment with MBR delivered through three different systems. (a) MBR penetration without a delivery system. (b) MBR penetration using conventional liposomes. (c) MBR penetration using algae oligosaccharide‐coated liposomes. Red fluorescence indicates phycocyanin present in MBR; blue fluorescence (DAPI) marks cell nuclei. (d) Quantitative analysis of MBR localization in skin layers depending on the delivery system. Without a delivery system, 96.2% of MBR is retained in the epidermis and only 3.8% reaches the dermis. Conventional liposomes deliver 27.8% of MBR to the dermis, while algae oligosaccharide‐coated liposomes achieve 65.7% dermal penetration.
Clinical efficacy
Remodelling properties and colour correction
The remodelling capacity and colour correction effects of MBR on facial skin were evaluated in vivo through a clinical study. As given in Table 3, after 56 days of treatment, a statistically significant decrease in the R0 parameter and an increase in the R2 parameter were observed with 2% MBR (R0: −9.7%, p < 0.001; R2: 8.4%, p < 0.001) compared to baseline. However, the time‐dependent variations observed with 2% MBR were comparable to those obtained with 0.3% retinol. Overall, these findings indicate that 2% MBR improves skin firmness and elasticity over time, showing a similar efficacy to that of 0.3% retinol. Regarding wrinkles and pore size, treatment with 2% MBR for 56 days resulted in a statistically significant decrease of wrinkle depth (−18.7%, p < 0.001) and in pore size diameter (−8.9%, p < 0.001) compared to baseline (Table 3). However, no significant differences were observed between products over time. These results confirm that both 2% MBR and 0.3% retinol improve skin smoothness and texture over time. As presented in Table 3, an increase in the ITA° parameter was observed at the end of the treatment with 2% MBR (29.9%, p < 0.001) and 0.3% retinol (25.1%, p < 0.001) compared to D0, indicating skin whitening over time (Figure 4). It should be noted that ITA° was not determined at D7 or D14 because hyperpigmentation requires at least 28 days to become measurable. Changes in skin tone and melanin‐related parameters typically need a full epidermal renewal cycle to show visible results. Overall, no significant differences were observed between the two treatments. These data indicate that after 56 days of use, both products induce a lighter skin colour.
TABLE 3.
Variation of photoageing and hyperpigmentation parameters after 56 days of treatment with 2% MBR or 0.3% retinol compared with baseline.
| D7 | SD | D14 | SD | D28 | SD | D56 | SD | ||
|---|---|---|---|---|---|---|---|---|---|
| Firmness (R0) | 2% MBR | −2.9*** | 3.6 | −5.9*** | 4.5 | −8.1*** | 5.4 | −9.7*** | 5.8 |
| 0.3% Retinol | −2.9** | 4.3 | −5.9*** | 4.6 | −7.6*** | 4.8 | −8.5*** | 5.4 | |
| Elasticity (R2) | 2% MBR | 3.3*** | 2.7 | 5.8*** | 3.3 | 8.0*** | 3.5 | 8.4*** | 3.6 |
| 0.3% Retinol | 2.4*** | 2.6 | 4.8*** | 3.0 | 7.2*** | 3.3 | 8.2*** | 3.7 | |
| Wrinkle depth (μm) | 2% MBR | −6.7** | 11.7 | −11.5** | 13.5 | −17.4*** | 16.2 | −18.7*** | 17.7 |
| 0.3% Retinol | −9.7** | 12.7 | −12.2*** | 14.5 | −15.8*** | 16.2 | −16.2*** | 14.9 | |
| Pores size (μm) | 2% MBR | −5.8*** | 6.5 | −7.3*** | 6.3 | −7.9*** | 6.3 | −8.9*** | 6.8 |
| 0.3% Retinol | −5.9*** | 7.0 | −6.7*** | 5.1 | −9.8*** | 6.6 | −11.1*** | 7.4 | |
| Dark spots (ITA) | 2% MBR | NA | — | NA | — | 20.9*** | 16.9 | 29.9*** | 17.1 |
| 0.3% Retinol | NA | — | NA | — | 19.0*** | 17.2 | 25.1*** | 16.7 |
Note: The values in the table represent the percentage of variation relative to the baseline (D0).
Abbreviation: NA, not analysed.
p < 0.01 vs. D0.
p < 0.001 vs. D0.
FIGURE 4.
Digital images showing the effect of 2% MBR on dark spots over time in the facial skin of a volunteer enrolled in the clinical study. After 28 and 56 days of treatment with 2% MBR, the dark spots appear visibly lighter in colour compared to baseline.
Acne and redness correction
The effect of MBR on skin clarity and smoothness was evaluated in vivo through a clinical study. In Table 4, we can observe that after 28 days of treatment with 1% MBR, a statistically significant decrease in the erythema index (−9.3%, p < 0.001) was observed compared with baseline, indicating a reduction in skin redness (Figure 5a). No significant differences were observed between 1% MBR and 1% bakuchiol at any evaluated time point. At D7, erythema was evaluated clinically but not instrumentally, as this early checkpoint focused on safety and tolerance. Instrumental assessments were performed at D14 and D28 to quantify longer term changes more precisely. Volunteers treated with 1% MBR exhibited very mild to mild erythema after 7 days, whereas those treated with 1% bakuchiol showed very mild to moderate erythema, indicating already a better skin tolerability with 1% MBR after 1 week. Overall, these results indicate that 1% MBR reduces skin redness with an efficacy comparable to that of 1% bakuchiol. Regarding moisturization and pore size, Table 4 depicts that treatment with 1% MBR for 28 days resulted in a statistically significant increase in skin moisturization (20.7%, p < 0.001) and a reduction in pore size diameter (−9.2%, p < 0.001) compared with baseline (Figure 5b). However, no significant differences were observed between the two treatments over time. These findings indicate that, by the end of the study, both products enhance skin hydration and contribute to the improvement of acne‐related skin texture. Finally, a decrease in sebum content was observed after 28 days of treatment with 1% MBR (−32.9%, p < 0.001) and 1% bakuchiol (−27.4%, p < 0.001) compared to D0 (Table 4). Notably, the effect of 1% MBR was significantly greater than that of bakuchiol at D14 (p < 0.01) and at the end of the study (D28, p < 0.05). These data indicate that 1% MBR is more effective in reducing sebaceous secretion compared to the reference treatment.
TABLE 4.
Variation of skin clarity and smoothness parameters after 28 days of treatment with 1% MBR or 1% bakuchiol compared to baseline.
| D7 | SD | D14 | SD | D28 | SD | ||
|---|---|---|---|---|---|---|---|
| Erythema (a.u.) | 1% MBR | NA | — | −7.1*** | 6.7 | −9.3*** | 8.5 |
| 1% Bakuchiol | NA | — | −5.5*** | 7.1 | −7.7*** | 7.5 | |
| Moisturization (c.u.) | 1% MBR | 11.5*** | 8.6 | 15.8*** | 10.2 | 20.7*** | 11.6 |
| 1% Bakuchiol | 10.8*** | 6.8 | 15.2*** | 6.6 | 18.2*** | 8.1 | |
| Sebum content (μg cm−2) | 1% MBR | −23.5*** | 10.9 | −29.1***^^ | 8.1 | −32.9***^ | 9.3 |
| 1% Bakuchiol | −20.1*** | 8.3 | −22.1***^^ | 8.3 | −27.4***^ | 6.7 | |
| Pores size (μm) | 1% MBR | −2.5*** | 3.7 | −7.9*** | 2.8 | −9.2*** | 8.4 |
| 1% Bakuchiol | −2.3** | 3.2 | −7.0*** | 3.3 | −7.6*** | 3.8 |
Note: The values in the table represent the percentage of variation relative to the baseline (D0).
Abbreviation: NA, not analysed.
**p < 0.01 vs. D0; ***p < 0.001 vs. D0; ^p < 0.05; ^^p < 0.01; ^^^p < 0.001 between treatment groups at a specific experimental time point.
FIGURE 5.
Digital images showing the effect of 1% MBR on facial redness and acne over time in volunteers enrolled in the clinical study. (a) Facial redness after 14 days of treatment in volunteer no. 1. Treatment with 1% MBR for 14 days reduces skin redness compared to baseline. (b) Acne correction after 14 days of treatment in volunteer no. 13. Treatment with 1% MBR for 14 days improves acne‐related skin texture compared to baseline.
Synergistic efficacy when combined with retinol
The boosting effect of MBR on retinol was assessed in vivo through a clinical study. In Table 5, we can observe that after 28 days of use, both treatments not only induced a statistically significant decrease in the erythema index and wrinkle depth (p < 0.001), as well as an increase in skin moisturization (p < 0.001) compared to the baseline. In this case, at D7, erythema was also only evaluated clinically but not instrumentally. Notably, the combined treatment with 1% MBR and 0.1% retinol produced significantly greater effects than 0.5% retinol alone at day 28 (p < 0.05) (Table 5 and Figure 6a). As shown in Figure 6a, no visible increase in erythema was observed during the first days of application with 1% MBR + 0.1% retinol, suggesting that the typical ‘retinization’ response, characterized by transient erythema and irritation, is effectively mitigated by the presence of MBR. These findings suggest that the combination of 1% MBR with 0.1% retinol enhances the efficacy of 0.5% retinol in improving skin redness, signs of ageing, and hydration. Regarding firmness and elasticity, Table 5 presents a statistically significant decrease in the R0 parameter and an increase in the R2 parameter with the combined treatment (R0: −9.1%, p < 0.001; R2: 7.1%, p < 0.001) compared to baseline at day 28. While the time‐dependent variations in firmness observed with the combined treatment were comparable to those obtained with 0.5% retinol, the improvement in elasticity was significantly greater with the combination of 1% MBR and 0.1% retinol compared to the reference treatment (7.1% vs. 5.1%, p < 0.01) (Table 5). Overall, these results indicate that the combined treatment enhances both skin firmness and elasticity over time, and specifically potentiates the improvement in elasticity compared to 0.5% retinol alone. In Table 5, we can observe that treatment with 1% MBR and 0.1% retinol resulted in a statistically significant reduction (p < 0.001) in pore diameter at all evaluated time points compared to day 0. However, no statistically significant differences were observed between the two treatments at any time point. Finally, Figure 6b shows an increase in the ITA° parameter at day 28 with both 1% MBR combined with 0.1% retinol (22.2%, p < 0.001) and 0.5% retinol (20.3%, p < 0.001) compared to baseline, indicating progressive hypopigmentation over time (Figure 6c). In fact, no statistically significant differences were observed between the two treatments. These findings indicate that after 28 days of use, both products contribute to a reduction in dark spot pigmentation. Of the 30 subjects enrolled for the synergistic efficacy study with retinol, three discontinued due to product‐related skin reactions, and three others experienced mild to moderate irritation but completed the study with adjusted application frequency. All reactions resolved without medical intervention, and no serious or persistent adverse events were observed.
TABLE 5.
Variation of skin redness, photoageing, and soothing parameters after 28 days of treatment with 1% MBR combined with 0.1% retinol and 0.5% retinol compared to baseline.
| D7 | SD | D14 | SD | D28 | SD | ||
|---|---|---|---|---|---|---|---|
| Erythema (a.u.) | 1% MBR + 0.1% Retinol | NA | — | −8.7*** | 6.6 | −11.9***^ | 7.2 |
| 0.5% Retinol | NA | — | −6.4*** | 3.1 | −8.6***^ | 3.7 | |
| Moisturization (c.u.) | 1% MBR + 0.1% Retinol | 11.5***^^ | 5.5 | 17.5***^^^ | 7.5 | 23.5***^^^ | 8.4 |
| 0.5% Retinol | 7.2*** | 3.6 | 11.5***^ | 6.2 | 15.3***^ | 6.5 | |
| Wrinkle depth (μm) | 1% MBR + 0.1% Retinol | −5.2*** | 4.2 | −10.6*** | 7.8 | −17.2***^ | 5.6 |
| 0.5% Retinol | −7.4*** | 4.8 | −11.1*** | 4.7 | −14.1***^ | 4.8 | |
| Firmness (R0) | 1% MBR + 0.1% Retinol | −1.4 | 4.6 | 4.0*** | 6.7 | −9.1*** | 8.3 |
| 0.5% Retinol | −1.9 | 5.6 | −3.3*** | 7.6 | −7.3*** | 7.1 | |
| Elasticity (R2) | 1% MBR + 0.1% Retinol | 2.1*** | 2.7 | 4.8** | 3.5 | 7.1***^^ | 3.6 |
| 0.5% Retinol | 2.1*** | 1.1 | 4.2** | 2.0 | 5.1***^^ | 2.5 | |
| Pores size (μm) | 1% MBR + 0.1%Retinol | −5.5*** | 2.3 | −7.8*** | 2.1 | −9.0*** | 2.5 |
| 0.5% Retinol | −6.3*** | 3.1 | −8.0*** | 3.3 | −3.4*** | 3.6 |
Note: The values in the table represent the percentage of variation relative to the baseline (D0).
Abbreviation: NA, not analysed.
*p < 0.05 vs. D0; **p < 0.01 vs. D0; ***p < 0.001 vs. D0; ^p < 0.05; ^^p < 0.01; ^^^p < 0.001 between treatment groups at a specific experimental time point.
FIGURE 6.
Effect of the combined treatment of 1% MBR + 0.1% retinol and 0.5% retinol on skin redness and hyperpigmentation over time. (a) Skin redness after 2 days of treatment with 1% MBR combined with 0.1% retinol and 0.5% retinol in volunteer no. 19. The combination of 1% MBR with 0.1% retinol reduces skin irritation after 2 days of use compared to 0.5% retinol. (b) Variation in dark spots colour after 28 days of treatment with 1% MBR combined with 0.1% retinol and 0.5% retinol compared to baseline. ITA° parameter increases with both treatments, indicating progressive hypopigmentation over time compared to day 0. ***p < 0.001 compared to the baseline. (c) Dark spots progression after 14 days of treatment with 1% MBR + 0.1% retinol in volunteer no. 15. Treatment with 1% MBR and 0.1% retinol for 14 days results in reduced dark spot pigmentation compared to baseline.
DISCUSSION
The present study highlights the potent efficacy of a novel MBR in enhancing skin health, as demonstrated through both in vitro and clinical evaluations and in comparison with traditional skin treatments. Several well‐known ‘retinol‐like’ or ‘retinol‐alternatives’ have gained attention in recent years, such as bakuchiol, widely marketed for its comparable anti‐ageing benefits with improved tolerability, and other commercial active ingredients NovoRetin® (Mibelle Biochemistry), RetinAlt® (CLR Berlin), Revinage® (Chemyunion), Vit‐A‐Like™ (BASF), Retilactyl D® (Silab), which claim to either increase endogenous retinoic acid levels or modulate skin‐related genes in a retinol‐like manner. While these ingredients are often positioned as ‘retinol‐like’, they do not act through direct activation of retinoid receptors (RAR/RXR) and instead rely on indirect pathways or general antioxidant and anti‐inflammatory activity. Crucially, most of these alternatives lack robust clinical benchmarking against standard concentrations of retinol, making it difficult to objectively assess their comparative efficacy.
As shown in the in vitro efficacy section, data showed that 1% MBR significantly promoted cell proliferation, reduced melanin production, and modulated key ECM components, outperforming both 1% retinol and 1% bakuchiol. Clinically, 2% MBR resulted in significant improvements in skin texture, firmness, elasticity, and pigmentation, with effects comparable to 0.3% retinol. Additionally, MBR synergistically enhanced retinol's efficacy in reducing wrinkles and pigmentation, while improving skin hydration and reducing side effects. These findings suggest that MBR is a promising novel compound with potential applications in both anti‐ageing and skin lightening treatments.
Previous studies reported that retinoid‐like compounds are effective stimulants of fibroblast activity [11, 12]. Our in vitro studies are consistent with these findings, demonstrating that 1% MBR has remarkable biological activity, particularly in enhancing fibroblast proliferation. Notably, the cell proliferation effects of MBR were more pronounced than those of the reference treatments (1% retinol and 1% bakuchiol), further suggesting that MBR might be a more potent mitogenic agent for skin regeneration and repair.
Furthermore, MBR showed the most significant reduction in melanin concentration among reference treatments. This melanin‐lowering effect is crucial for addressing hyperpigmentation concerns and suggests that MBR could be an effective treatment for conditions like age spots or melasma. Previous studies have reported the role of retinoids in modulating melanogenesis via RARs [13, 14], and our results reinforce this by demonstrating MBR's ability to significantly lower melanin levels. In this regard, our study also demonstrated the ability of MBR to modulate RARs. Notably, our results revealed that MBR induced dose‐dependent activation of RARβ. This finding suggests that MBR might operate similarly to traditional retinoids in regulating gene expression involved in skin cell differentiation and proliferation [15, 16]. However, the unique profile of MBR's effects on RAR isoforms may contribute to its distinct biological activity compared to synthetic retinoids, with the potential for a more favourable safety profile or enhanced efficacy in specific skin conditions [17]. Although the exact mechanism is not yet fully defined, the selective activation of RARβ by MBR may be related to its structure. Given that MBR is derived from microalgae known to produce natural retinoid precursors, it is plausible that this contributes to its receptor selectivity. In pharmacology, even subtle modifications to ligand structure can significantly alter isoform binding affinity and downstream signalling, suggesting that MBR's bio‐retinoid architecture may favour specific interaction with RARβ.
In terms of ECM modulation, MBR was found to enhance the synthesis of HA, reduce MMP‐1, and increase the expression of collagen types I and III. These changes are crucial for improving skin elasticity and firmness, as both collagen and HA are essential to maintain the skin's structural integrity [14, 18, 19]. The superior ECM modulation by MBR compared to retinol and bakuchiol highlights its potential as an anti‐ageing treatment, similar to the effects reported of other retinoid‐based treatments [20, 21].
The clinical efficacy of MBR was assessed through a series of in vivo studies evaluating its impact on skin remodelling, colour correction, acne‐related conditions, and ageing signs.
The clinical studies showed that treatment with 2% MBR significantly improved skin firmness, elasticity, and texture, with effects comparable to 0.3% retinol. These results are promising, as retinol is widely considered one of the most effective agents for skin remodelling and rejuvenation [22, 23]. The fact that MBR achieved similar improvements suggests it could serve as a viable alternative or complement to retinol in anti‐ageing formulations for clinical settings. Moreover, MBR exhibited a remarkable effect on skin whitening, comparable to 0.3% retinol, highlighting the potential of MBR in addressing skin hyperpigmentation. These findings are consistent with MBR's potent effects on melanin reduction in vitro, further solidifying its potential as a skin lightening agent [24, 25].
Furthermore, MBR demonstrated significant benefits in the management of acne and redness. The 1% MBR treatment significantly reduced skin erythema, showing its potential in calming skin irritation and redness, a benefit comparable to 1% bakuchiol, a known alternative to retinol with anti‐inflammatory properties [26, 27]. This finding supports the hypothesis that MBR may have anti‐inflammatory properties, which could be beneficial in treating conditions such as acne or rosacea. Moreover, MBR was shown to significantly enhance skin moisturization and reduce pore size, both of which are critical for improving skin texture and overall appearance [28].
Importantly, the synergistic effects of MBR when combined with retinol were evident in the clinical trials, where the combination of 1% MBR with 0.1% retinol provided superior results compared with 0.5% retinol alone. This combination enhanced the improvement in skin redness, elasticity, wrinkle depth, and hydration. The selected retinol concentrations were based on both regulatory considerations and market relevance. The 0.3% retinol concentration reflects the current maximum permitted level for facial leave‐on products in the European Union, as defined by the SCCS opinion SCCS/1632/21 (2023), and now serves as a regulatory benchmark. On the other hand, the 0.5% retinol concentration, while exceeding this limit, remains widely used in international markets and is perceived as a high‐efficacy standard. This dual selection allowed us to evaluate the performance of our combination active relative to both regulatory and market‐driven references.
In conclusion, MBR offers a novel, biomimetic alternative to retinol with comparable or superior efficacy when combined at low concentrations (1% MBR + 0.1% retinol), while maintaining excellent tolerability. Unlike traditional ‘retinol‐like’ ingredients, MBR supports retinoid pathway activation, making it effective both alone and as a synergistic booster. These findings suggest that MBR may enhance retinol's benefits while reducing side effects such as irritation, commonly seen with higher retinol doses [29, 30].
CONCLUSION
Our findings support the promising role of MBR as a novel ingredient in dermatological treatments, offering significant benefits in skin regeneration, anti‐ageing, and pigmentation control. Furthermore, MBR's ability to enhance the effects of retinol in a synergistic manner suggests that it could be an invaluable addition to dermatological treatments, offering both efficacy and a potentially improved safety profile. Future clinical studies with larger cohorts are warranted to confirm these findings and explore the full therapeutic potential of MBR in dermatology.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflicts of interest regarding the publication of this article.
ACKNOWLEDGEMENTS
ALGAKTIV, S.L. is kindly acknowledged for providing the Chlorella vulgaris‐derived bio‐retinoid (MBR). The authors also thank ALGAKTIV, S.L. and GAT Therapeutics, S.L. for their financial support and collaboration.
Sánchez‐Díez S, Lapeyre A, García‐Delgado N, Ayats J. Bioretinoids from microalgae: Boosting retinol performance and tolerability. Int J Cosmet Sci. 2026;48:146–160. 10.1111/ics.70027
Contributor Information
Noemí García‐Delgado, Email: ngarciadelgado@algaktiv.com.
Jordi Ayats, Email: jayats@algaktiv.com.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.