Abstract / Summary
ABSTRACT Background The paradigm of cosmetic dermatology has shifted heavily toward combination therapies involving energy‐based devices (EBDs) and injectable biostimulators. However, conventional efficacy assessments remain largely limited to subjective clinical grading or single‐parameter, uni‐dimensional approaches. Given the complex cross‐talk within the epidermal‐dermal microenvironment, a multi‐dimensional objective framework is required to achieve evidence‐based precision medicine. Aims This study introduces a multi‐parametric biophysical stratification model to evaluate baseline patient suitability, reveal hidden antagonistic interferences (negative synergy), and establish an optimized treatment sequence for combined treatments. Methods A retrospective cohort of 93 patients who underwent skin rejuvenation treatments was analyzed. Baseline (T0) biophysical profiles were measured via SKENA (V&Co., Seoul, Korea) with eight quantitative parameters: hydration, trans‐epidermal water loss (TEWL), dermal thickness via 10‐MHz ultrasound, erythema index, and elasticity parameters (R0, R2, R6/R5, R7). To eliminate multi‐collinearity and physiological cross‐talk, a Mahalanobis distance metric tensor utilizing the inverse covariance matrix was established. Modality‐specific suitability scores () and non‐linear combination synergy margins (Ω) were algebraically derived. A 12‐week longitudinal kinetic simulation was performed to compare concurrent and sequential treatment pathways. Results Baseline stratification identified distinct phenotypic cohorts. EBD solo analysis separated patients into HIFU‐dominant ( N = 51) and RF‐dominant ( N = 42) cohorts, partitioned significantly by erythema ( p = 0.0004) and viscoelastic creep (R6/R5, p = 0.0183). Scaffold analysis partitioned PN‐dominant ( N = 48) and PLLA‐dominant ( N = 45) cohorts via barrier integrity and dermal thinning ( p = 0.0039). Incorporating an unclamped synergy model revealed robust supralinear synergy (Ω > 0) in barrier‐compromised phenotypes, where PN‐priming effectively harnessed EBD‐induced neocollagenesis. The model successfully rescued 14 patients from a “therapeutic desert” ( < 45%) to a high‐suitability zone (> 75%). While the model identified potential antagonistic interferences (Ω ≤ 0) in approximately 50%–60% of cases involving PLLA when applied indiscriminately, these were localized to specific barrier‐disrupted phenotypes. Longitudinal kinetics demonstrated that a 4‐week sequential PN‐priming pathway completely bypassed the acute barrier crisis seen in concurrent pathways and achieved a significantly superior 12‐week net elasticity endpoint. Conclusions Multi‐parametric biophysical stratification successfully translates complex interactions into actionable clinical guidelines. Recognizing negative synergy zones highlights the absolute clinical necessity of spatiotemporal sequential tracking rather than indiscriminate concurrent combinations, paving the way for data‐driven precision aesthetics.