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In response, ALIce-MIRROR proposes a multi-compartmental 3D skin system cultivated under dynamic Air-Liquid Interface (ALI) conditions within a custom-engineered milli-fluidic bioreactor. This bioreactor supports perfusion, immune cell circulation, and real-time tissue maintenance, all under fluidic environments characterized via Particle Image Velocimetry (PIV). Building upon a validated epidermal-dermal construct, the project introduces endothelial and circulating immune components to simulate key mechanisms such as vasculogenesis and immune extravasation. These biological events will be triggered via wounding and high-inflammatory stimuli, with cellular behaviors tracked through advanced imaging and molecular assays. Parallel to the experimental development, an in silico model will be constructed to mirror the in vitro system, simulating the dynamic processes of vascular sprouting, immune cell migration, and mechanical stimuli. This digital twin, calibrated and refined via continuous data exchange, will enhance the predictive power and adaptability of the platform. Technologically, ALIce-MIRROR integrates four critical units: (i) a milli-fluidic bioreactor for dynamic culture; (ii) a 3D human skin construct with endothelial and immune components; (iii) a predictive computational model for vascular and immune dynamics; and (iv) a PIV-based system for flow characterization. The components are at varying Technology Readiness Levels (TRL 1–4), with the goal of integrating them into a fully functional TRL 4 platform. Scientifically, the project advances the understanding of immuno-vascular interactions in human skin, while methodologically, it exemplifies the power of coupling tissue engineering with computational modeling. The outcomes will include novel experimental data, refined in silico models, and open-access dissemination strategies. Economically and societally, the platform represents a robust alternative to animal testing, offering a scalable, reproducible, and ethically aligned solution for drug testing, toxicology, and personalized medicine applications. Finally, ALIce-MIRROR delivers a pioneering framework for real-time in vitro/in silico interaction, creating a mirrored biological-digital system designed to transform preclinical testing and accelerate innovation in health and biotechnology.