3D Peri-Implant Epi-Mucosa-on-a-Chip Reveals Alterations in Epithelial Barrier Function Mediated by Host-Bacteria-Biomaterial Interactions

Peri-implantitis is characterized by disruption of the epithelial barrier at the implant-mucosa interface, driven by complex interactions between mechanical, microbial, and material factors. Histological and immunohistochemical analysis of human peri-implant and periodontal tissues revealed significant epithelial abnormalities specific to peri-implantitis, which indicated compromised barrier integrity. Specifically, peri-implant tissues had increased intercellular edema, inflammatory infiltration, and marked loss of junctional proteins E-cadherin and ZO-1. To further investigate these findings in a controlled environment, we developed a novel <i>3D Peri-implant Epi-mucosa-on-a-chip</i> model incorporating clinically relevant titanium surfaces, hydrostatic pressure, and bacterial challenge to mimic peri-implant crevicular fluid dynamics and disease pathogenesis. Using this microfluidic platform, we demonstrated that untreated titanium surfaces significantly increased epithelial leakiness and disrupted the localization of junctional proteins, such as E-cadherin. In contrast, acid-etched titanium with defined microroughness restored barrier function and preserved junctional integrity. High hydrostatic pressure, mimicking inflammatory mechanical stress, independently impaired epithelial cohesion, whereas the combination of <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) and implant-derived titanium microparticles (i-TiPs) synergistically exacerbated barrier breakdown. i-TiPs also altered matrix architecture and stiffness, further compromising epithelial integrity and potentiating bacterial damage. These results underscore the critical role of implant surface properties and the mechanical microenvironment in modulating host barrier responses and highlight the utility of our 3D model in elucidating the mechanobiology of peri-implantitis. This platform may pave the way for the development of new therapeutic strategies against peri-implantitis, aimed at preserving epithelial sealing and preventing disease progression.