Deciphering molecular responses to radiofrequency microneedling in a 3D human skin model: new insights and modulation by aftercare treatment

Background: Radiofrequency microneedling (RFMN) is an emerging therapeutic approach that enhances skin rejuvenation by delivering targeted thermal injury to the dermal and subdermal layers while sparing the epidermis. However, the molecular mechanisms underlying its biological effects especially in comparison to medical microneedling remain poorly understood. In this study, we aimed to investigate, for the first time, the molecular and histological responses to RFMN using a standardized three-dimensional (3D) human skin model. As a secondary objective, we assessed the modulatory effects of RFMN aftercare treatment with a dexpanthenol-containing ointment. Methods: We investigated the molecular and histological responses to RFMN utilizing a previously established standardized human 3D skin model composed of primary dermal fibroblasts and epidermal keratinocytes. Histological assessments and transcriptomic analyses employing next-generation sequencing were conducted 48 and 120 h after RFMN treatment. In addition, the effects of a topical dexpanthenol-containing ointment administered immediately following RFMN on wound healing and gene regulation were evaluated. Results: Histological analysis of RFMN-treated 3D skin models showed dermal coagulation zones that disappeared after post-treatment with a dexpanthenol-containing ointment. Transcriptomic profiling 48 h after RFMN showed an early pro-inflammatory response with upregulated chemokines and cytokines (e.g., CCL7, CXCL2, IL24) and downregulated matrix metalloproteinases and barrier genes, indicating controlled inflammation and skin renewal initiation. Aftercare with the dexpanthenol-containing ointment elicited distinct gene expression changes at 120 h post-RFMN, including increased expression of cytokines (IL37), matrix metalloproteinases (MMP3, MMP8), and epidermal regeneration markers (LCE1B, VEGFA), consistent with accelerated wound healing, re-epithelialization, and inflammation modulation. Conclusion: In conclusion, this study elucidates the molecular and histological effects of RFMN and highlights the benefits of dexpanthenol-containing topical post-treatment, which may further shorten the already brief downtime. These findings support the optimization of clinical protocols for safer and more effective skin rejuvenation.