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.