Bioactive integration and stimuli-responsive therapeutic regulation in additively manufactured metallic orthopedic implants

Additive manufacturing (AM) has accelerated the evolution of metallic orthopedic implants from passive structural substitutes toward multifunctional therapeutic platforms. Benefiting from the geometric freedom and compositional flexibility of AM, bioactive substances can be integrated into metallic implants through multiple strategies to regulate the peri-implant microenvironment and improve tissue regeneration. This review summarizes recent advances in bioactive integration and responsive therapeutic release in additively manufactured metallic orthopedic implants. First, major biofunctionalization strategies are discussed, including surface modification, bulk alloying, and structurally integrated reservoirs. These approaches enable the incorporation of antibacterial, osteogenic, angiogenic, and immunomodulatory functions through localized delivery of antibiotics, bioactive ions, peptides, growth factors, and small-molecule therapeutics. Subsequently, recent progress in stimuli-responsive release systems is reviewed, including endogenous stimuli triggered by pH, enzymes, and reactive oxygen species, as well as exogenous regulation through light, magnetic fields, and electrical stimulation, which enable on-demand and microenvironment-adaptive therapy. The relationships among implant architecture, bioactive integration, and dynamic therapeutic regulation are further discussed to highlight the unique advantages of AM in constructing multifunctional implants. Finally, current challenges associated with multifunctional AM metallic implants are discussed, particularly in terms of achieving synergistic biofunctionality, maintaining structural and mechanical integrity under process constraints, ensuring predictable therapeutic release, and establishing reliable process structure property relationships.This review provides insights into the development of intelligent metallic implants capable of simultaneously achieving mechanical support and active therapeutic regulation.