Microphysiological Systems of Lymphatics and Immune Organs.

Microphysiological systems (MPS) that incorporate engineered blood vasculatures have enabled new opportunities to study human physiology and disease, offering platforms for drug development, tissue modeling, and regenerative medicine. However, most human tissues also contain an equally complex yet underrepresented secondary vascular network, the lymphatic system. Lymphatics play indispensable roles in interstitial fluid drainage, immune cell trafficking, and antigen presentation, and are central to the pathophysiology of diseases such as lymphedema, chronic inflammation, and cancer metastasis. Despite their critical biological functions, lymphatic vessels and associated immune structures, such as lymph nodes, remain absent from current in vitro models. Integrating lymphatics into biomaterials-based MPS is essential for capturing the dynamic interplay between fluid transport, immune surveillance, and tissue homeostasis. This review surveys recent progress in engineering lymphatic microenvironments and immune organoids within biomaterials-based MPS, emphasizing innovative strategies to recreate the biochemical and biophysical complexity of native lymphatic tissues. Advances are highlighted in tunable extracellular matrix platforms, humanized cell sourcing, and precision fabrication techniques, including perfusable, modular, and scalable models. The integration of lymphatic components with multi-organ systems, combined with the application of computational modeling and machine learning, offers unprecedented opportunities to build personalized and physiologically relevant immune models. Incorporating lymphatics into next-generation MPS promises to illuminate fundamental disease mechanisms and accelerate the development of more predictive therapeutic testing platforms with improved clinical translation.