Antioxidative Collagen Hydrogels as Dermal Fillers to Promote Skin Regeneration for UV-Induced Photoaging Skin

Continuous exposure to ultraviolet (UV) radiation generates reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂), superoxide anion (O₂^.^–), and hydroxyl radical (OH^.), which induce oxidative stress in cellular components. This biological damage activates the mitogen-activated protein kinase (MAPK) pathway, leading to the upregulation of matrix metalloproteinases (MMPs) that degrade collagen fiber. Additionally, ROS enhances the activation of nuclear factor-kappa B (NF-κB), resulting in increased secretion of pro-inflammatory cytokines like interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), which further stimulate MMP synthesis. This imbalance between increased collagen degradation and decreased pro-collagen synthesis exacerbates photoaging.<br/>Dermal fillers are commonly used to improve wrinkles caused by intrinsic and extrinsic aging. Natural polymers like hyaluronic acid (HA) and collagen mainly provide volume enhancement for wrinkled skin, limiting long-term anti-aging effects. Marine-derived collagen is gaining attention due to its low immunogenicity, environmental friendliness, and ease of extraction. Even though collagen injections replenish collagen itself, their practical use is challenging due to their rapid degradation compared to HA filler. Cerium oxide nanoparticles (CeNPs) are well-studied for their antioxidant properties, acting as nanozymes with catalase (CAT) and superoxide dismutase (SOD) mimicking abilities. Their oxygen-deficient structure allows them to have Ce³⁺ and Ce⁴⁺ oxidation states in the lattice, enabling them to convert ROS into harmless water and oxygen.<br/>We propose developing prolonged antioxidative fillers using tilapia-derived collagen hydrogels embedded with CeNPs to treat photoaged skin. CeNPs demonstrated excellent ROS scavenging properties and facilitated the gelation process of tilapia collagen through redox reactions. The resulting CeNP-embedded collagen hydrogels (CeNPs@Col gels) exhibited significant CAT and SOD mimicking properties, along with higher stability in collagenase and H₂O₂ solutions. They also showed suitable mechanical stability and injectability comparable to commercial fillers. Incubating keratinocytes with CeNPs@Col gels efficiently reduced intracellular ROS levels and biomarkers such as MMP and TGF-β. In a UV-induced photoaging mouse model, mice injected with CeNPs@Col gels showed notable anti-aging effects, including decreased epidermal thickness, collagen regeneration, reduced intracellular oxidative products and MMP accumulation, and lower pro-inflammatory cytokine levels. These regenerative effects persisted even seven months post-injection. These findings suggest that CeNP-based antioxidative collagen fillers hold great promise as long-term anti-aging materials.