Hydrogel-based strategies for periprosthetic joint infection: from osteoimmune mechanisms to clinical translation

Abstract

Periprosthetic joint infection (PJI) is sustained by implant-associated biofilms, ineffective immune activation, oxidative stress, and impaired osseointegration, and therefore requires more than local bacterial killing alone. Hydrogel-based therapies have attracted growing attention, but their biological effects are often attributed indiscriminately to the hydrogel even when they are primarily produced by incorporated antibiotics, antimicrobial peptides, enzymes, nanoparticles, growth factors, or cells. This narrative review develops a material-centered framework that distinguishes three sources of therapeutic activity: matrix-intrinsic functions, payload-derived biological effects, and hydrogel-enabled effects. We summarize the interface-specific pathophysiology of PJI and analyze the hydrogel properties most relevant to peri-implant treatment, including local retention, injectability, conformability to irregular dead space, wet-surface and implant-interface adaptation, tunable degradation, controlled or stimuli-responsive release, and extracellular matrix-like support. Representative antibacterial, antibiofilm, redox-regulating, immunomodulatory, angiogenic, and osteogenic systems are assessed according to their material composition, payload, release mechanism, experimental model, and direct relevance to true PJI. Hydrogels are also compared with polymethylmethacrylate cement, calcium sulfate carriers, nanoparticles or microspheres, electrospun scaffolds, and conventional implant coatings to clarify their scenario-specific advantages and limitations. The available evidence indicates that hydrogels are most valuable when they improve spatial retention, temporal sequencing, interface contact, or compatibility with labile therapeutics; they are not universally superior when mechanical support, established surgical familiarity, or long-term structural stability is required. Translation will depend on clinically representative implant-associated models, standardized reporting, sterilization and storage compatibility, reproducible manufacturing, surgical usability, and proportionate regulatory complexity. This hydrogel-enabled perspective supports indication-driven design and more rigorous evaluation of local biomaterial strategies for PJI.