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

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.