“Open Sandwich” Moisturization Regimen Does Not Affect Bioactivity of Retinols and Retinoids

“To our knowledge, there's never been a scientific study demonstrating the impact on the molecular retinoid bioactivity from various dermatologist-recommended layering techniques. I think it's really important for us to generate scientific data where it can help support a therapeutic recommendation in clinic. Although some of this might be logical and very intuitive for us, we've been simply hypothesizing this whole time what the sandwich technique does and if a patient is in fact losing the benefit of the retinoid treatment by some sort of theoretical dilutional effect from sandwiching,” said Asha Patel Shah, MD, MBA, FAAD, in an interview with Dermatology Times.

Shah, a board-certified dermatologist, adjunct assistant professor of dermatology at Emory University, and head of Medical Affairs North America, Skin Health & Beauty at Kenvue, discussed her team’s recent research on retinol and retinoid bioactivity when layered with moisturizers highlighted in a poster at the 2025 American Academy of Dermatology (AAD) Annual Meeting held March 7-11 in Orlando, Florida.

The poster, “Tretinoin and Retinol Bioactivity are Retained When Layered With Adjunctive Water Gel Moisturizer or A Water Cream Moisturizer in an ‘Open Sandwich’ Regimen,” evaluated the impact of adjunctive moisturization on retinol and tretinoin bioactivity from various layering techniques. Shah and researchers selected lightweight water gel and water cream moisturizers as adjunctive moisturizers in an ex vivo regimen study.

Shah reviewed that although moisturizers are commonly used to reduce retinoid-induced irritation, new ex vivo data from her team’s research demonstrates that open sandwiching—moisturizer applied before or after retinoid—preserves retinoid bioactivity. However, full sandwiching (moisturizer-retinoid-moisturizer) significantly reduces bioactivity, likely due to dilution and penetration barriers.

In their study, Shah and researchers tested retinol 0.1% cream and tretinoin 0.025% cream in combination with lightweight water gel and water cream moisturizers on human skin biopsies from the abdominoplasty of a Caucasian woman. Human skin explants were treated topically for 48 hours with 1) the retinoid formula alone; 2) a 2-step regimen of retinoid plus moisturizer or moisturizer plus retinoid (“open sandwich); or 3) a 3-step regimen of moisturizer plus retinoid plus moisturizer (“full sandwich”).

Four biopsies per treatment were used. RNA extraction was completed at the end of study, and quantitative polymerase chain reaction (qPCR) analyses were performed. Retinoid-induced bioactivity was examined via HBEGF and HAS3 gene expressions.

Results from the study showed that explants treated with the “full sandwich” method had reduced bioactivity (p<0.05), demonstrated by the HBEGF gene expression. Explants treated with the “open sandwich” regimen in either order of application maintained comparable bioactivity to the retinoid treatment alone, as shown by HBEGF gene expression.

In her interview, Shah highlighted the new ex vivo findings evaluating water gel or water cream moisturizers layered with retinoids. The study demonstrated that open sandwiching—either moisturizer applied before or after the retinoid—did not diminish the bioactivity of retinol or tretinoin. According to Shah, this supports the common practice of moisturizing to improve patient tolerability during retinization without compromising the therapeutic effect.

However, full sandwiching—moisturizer, retinoid, moisturizer—reduced retinoid bioactivity by approximately 3-fold, likely due to dilutional and penetration effects. Shah noted that this finding is particularly relevant for managing sensitive skin during initial retinoid use, where reduced potency may be beneficial. Notably, the tested water gel and water cream moisturizers, formulated with natural moisturizing factors and a biomimetic liquid crystal matrix, were shown to enhance skin hydration while preserving retinoid activity. These formulations were also clinically tested and tolerated in patients with acne, rosacea, atopic dermatitis, and cosmetic intolerance syndrome. This data strengthens dermatologists’ ability to guide patients on evidence-based retinoid application techniques, Shah concluded.

Disclosure: The research presented was sponsored by Kenvue Brands, LLC

Reference

Parsa R, Li WH. Patel R, et al. Tretinoin and retinol bioactivity are retained when layered with adjunctive water gel moisturizer or a water cream moisturizer in an “open sandwich” regimen. Poster presented at: 2025 American Academy of Dermatology Annual Meeting; March 7-11, 2025; Orlando, FL.