A Human‐Based Skin‐Lymphoreticular Model‐on‐Chip to Emulate Inflammatory Skin Conditions

ABSTRACT Despite fast‐paced advances in bioengineering human‐based models, emulating fine‐tuned and interdependent immunoregulations of the human body remains challenging. While many bioengineered models contain immune cells, secondary lymphoid tissues are typically missing. Here, we report a self‐assembled, minimally functional lymphoreticular unit composed of fibroblastic reticular, lymphatic endothelial and CD4 + T cells that emulate structural and functional interactions with the skin under inflammatory conditions. Following the optimization of the culture conditions, a layer‐by‐layer approach combining the relevant cell types yielded a self‐organized and compartmentalized lymphoreticular model mirroring human lymphoid tissue. Following verification of T cell motility, we established a skin‐lymphoreticular co‐culture within a microfluidic organ‐on‐chip to mimic interactions between skin and its draining lymph nodes. Co‐cultivation with atopic‐like skin models and the topical application of the skin sensitizer 2,4‐dinitrochlorobenzene stimulated strong migration and T cell infiltration from the lymphoreticular models while maintaining tissue integrity. The addition of anti‐inflammatory drugs abrogated the T cell mediated effects verifying the functionality of the model system. Taken together, the presented human‐based skin‐lymphoreticular model resembles a minimally functional unit that allows to study interactions between the skin and adjacent lymphoid tissues in a human‐based setup.