Beyond Biocompatibility: Immune Dysregulation, Oxidative Stress, and Tissue Intolerance Associated with Ti-6Al-4V...

Titanium and its alloys are widely used in dental implantology due to their favorable mechanical properties and well-documented long-term clinical performance. Among them, Ti-6Al-4V is particularly common in load-bearing applications. Nevertheless, a growing body of experimental and clinical evidence suggests that Ti-6Al-4V implants cannot be regarded as biologically inert in all patients. Adverse tissue responses, such as impaired healing, chronic peri-implant inflammation, and unexplained implant failure, have been reported even in the absence of classical risk factors, including infection, mechanical overload, or confirmed metal allergy. This critical review challenges the prevailing assumption that these complications are driven primarily by mechanical or immunoallergic mechanisms. Instead, oxidative stress is proposed as a central and unifying factor underlying adverse tissue reactions to Ti-6Al-4V dental implants. Corrosion, tribocorrosion, and mechanical wear lead to the release of titanium-, aluminum-, and vanadium-containing particles and ions, which promote excessive generation of reactive oxygen species at the implant-tissue interface. The resulting redox imbalance disrupts bone remodeling, impairs osteogenic differentiation, and maintains a pro-inflammatory microenvironment. Importantly, pathology arises not merely from increased reactive oxygen species production, but from the failure of local antioxidant defense systems to counteract this burden. Insufficient enzymatic and transcriptional antioxidant responses result in persistent redox imbalance, sustained innate immune activation, and progressive tissue intolerance. Oxidative stress is therefore conceptualized not as a secondary byproduct of inflammation, but as a primary driver of immune dysregulation through chronic macrophage activation and inflammasome signaling. This redox-driven feedback loop amplifies tissue damage and compromises long-term osseointegration independently of classical adaptive immune sensitization. Recognizing oxidative stress as a key determinant of implant-tissue interactions offers a more coherent framework for understanding implant-related complications and underscores the need for redox-aware biomaterial strategies and individualized patient risk assessment.