From ECM Aging to Mechanobiological Restoration: Injectable Fillers and Dermal Fibroblast Mechanotransduction-A...

Skin aging reflects the accumulation of molecular damage and a progressive disruption of dermal mechanical homeostasis. Fragmentation and disorganization of the dermal extracellular matrix (ECM) impair force transmission to resident fibroblasts. Reduced cell spreading and mechanical force generation are associated with increased matrix metalloproteinase expression and reduced collagen synthesis, partly through c-Jun/AP-1 activation and attenuation of TGF-β/TβRII signaling. Reduced YAP/TAZ mechanosignaling has also been linked to cGAS-STING-dependent senescence in experimental models. However, its causal role in aging human dermis remains unresolved. This narrative review considers dermal mechanobiology as an integrative framework alongside ultraviolet exposure, oxidative stress, glycation, and cellular senescence. It examines how injectable fillers may influence the dermal mechanical microenvironment. A filler's material properties may constitute a mechanical exposure, although bulk rheological measurements do not define force transmission at the cellular scale. Human in vivo studies of cross-linked hyaluronic acid provide the most direct evidence that enhanced structural support is associated with fibroblast spreading, activation of TGF-β-related signaling, and increased type I collagen deposition. Evidence for calcium hydroxylapatite and other biostimulatory fillers is complementary but more heterogeneous. A composite of PEGDE-cross-linked hyaluronic acid and calcium hydroxylapatite microspheres is considered as an explicitly preliminary example. This review defines the current evidence, its key limitations, and the mechanistically informed studies needed to determine whether, and which, fillers can meaningfully modify dermal mechanobiology.