Barrier Function and Biophysical Effects of 0.104% and 0.247% Retinol Creams in Mature Facial Skin: A Prospective Study

Retinol, a bioactive small molecule of the vitamin A family, contributes epidermal and dermal tissue repair through retinoic acid receptor γ (RARγ)/retinoid X receptor (RXR) receptor-mediated transcriptional regulation of keratinocyte differentiation, extracellular matrix (ECM) remodeling, and barrier restoration. However, the relationship between applied concentration, tissue-level regenerative outcomes, and tolerability remains incompletely characterized. This prospective, randomized, single-blind study compared biophysical effects and tolerance of two retinol concentrations in EU-compliant facial creams, high-performance liquid chromatography (HPLC)-verified as 0.104% and 0.247% (w/w). Thirty-eight women aged 40–61 years (Fitzpatrick phototypes II–III) participated across three independent sub-studies: 28 were randomized to either concentration for 12 weeks; 5 underwent split-face ultrasound imaging (0.247% versus retinol-free control) for 8 weeks; and 5 participated in a tape stripping sub-study quantifying stratum corneum interleukin-1 alpha (IL-1α) and interleukin-1 receptor antagonist (IL-1ra) by ELISA before and after 6 weeks of 0.247% retinol treatment. Main cohort assessments included transepidermal water loss (TEWL), hydration, melanin, erythema, pH, sebum, biomechanical parameters, and wrinkle grading. Both concentrations significantly improved barrier parameters—hydration, TEWL, brightness, pH, and sebum—with no inter-group differences. In the ultrasound sub-group, 0.247% retinol increased epidermal thickness (+12.4 μm), epidermal density (+3.84%), and dermal density (+1.81%) versus control, consistent with ECM reorganization and epidermal stratification. Biomechanical parameters showed no significant changes, consistent with retinol’s remodeling timeline. Consumer assessment indicated comparable efficacy; 0.247% demonstrated superior smoothing but higher erythema incidence. In the tape stripping sub-study, IL-1α decreased in all participants (median: 25.1 → 13.2 picograms per tape [pg/Tape]; 5/5 concordant), while IL-1ra increased in 4/5 participants (median: 352.8 → 1403.1 picograms per three sequential tapes [pg/3sT]), indicating a directionally consistent shift in the IL-1α/IL-1ra balance; these results are exploratory and require replication in larger cohorts. These findings collectively support clinically meaningful barrier restoration and structural remodeling within current EU safety limits (Commission Regulation EU 2024/996), with 0.104% offering a favorable efficacy-to-tolerability profile for initial therapy.