Multiscale evaluation of collagen-stimulating materials: linking physicochemical properties to dermal regeneration outcomes.

Biostimulatory dermal fillers are widely used for skin rejuvenation, but how particle physicochemical properties regulate fibroblast-macrophage interactions and collagen remodeling remains unclear. We compared calcium hydroxylapatite (CaHA), polycaprolactone (PCL), spherical poly-L-lactic acid (PLLA-Sp), and irregular PLLA fragments (PLLA-Ir) through comprehensive characterization (SEM, FTIR, zeta potential, AFM, roughness, tapped density, rheology in HA matrices) along with in vitro (human dermal fibroblasts, RAW264.7 macrophages, mono- and co-culture for viability, cytoskeleton, YAP mechanotransduction, macrophage polarization, cytokines, collagen) and in vivo (rat intradermal injection) analyses. CaHA exhibited the highest surface roughness, stiffness, and tapped density with a porous nanosurface and low aggregation, whereas PCL and PLLA-Sp were smoother and more aggregated. CaHA triggered stronger fibroblast cytoskeletal organization, YAP nuclear translocation, and type I collagen-related responses. All materials promoted M2-like macrophage polarization; however, PLLA-Sp induced the greatest total collagen deposition with predominant type III collagen and persistent mixed inflammation, while CaHA led to denser, more organized collagen bundles with a higher type I/III ratio and CD206/CD68 ratio. These findings indicate that particle micro/nanotopography and local cellular microenvironment bias collagen subtype remodeling, providing a physicochemical rationale for selecting biostimulators.