Poly‐ L ‐Lactic Acid Microspheres Promote Skin Rejuvenation via Enhanced Fibroblast Function

ABSTRACT Skin aging is marked by fibroblast decline and extracellular matrix (ECM) degradation, prompting the widespread use of poly‐ L ‐lactic acid (PLLA) dermal injectables for activating fibroblasts, stimulating neocollagenesis, and rejuvenating the skin. However, current PLLA formulations show variable efficacy and may trigger undesirable inflammatory responses. In this study, we compared two different PLLA formulations ‐one containing novel microspherical PLLA (PLLA‐LASYNPRO) and the other containing a microflake‐like PLLA ‐to assess their differing effects on human dermal fibroblasts and skin tissue. The results show that PLLA microspheres promote fibroblast migration, ECM synthesis, and wound contraction, while PLLA microflakes inhibit proliferation and elicit inflammatory gene expression. Transcriptomic profiling reveals that PLLA microspheres upregulate genes involved in fat cell differentiation and energy metabolism, with minimal immune activation. In contrast, PLLA microflakes trigger immune pathways and suppress regenerative signals. Importantly, each formulation induces unique long non‐coding RNA (lncRNA) signatures, implicating lncRNAs in fibroblast‐mediated skin remodeling. These findings highlight the novel design of PLLA microspheres as a critical determinant of their therapeutic outcome, offering a molecular basis for developing safer and more effective skin rejuvenation strategies.