Yansong Peng, E. C. LEE
The lymphatic system-integral to fluid balance, immune surveillance, and lipid absorption-is frequently overlooked despite its vital roles. Traditional research modalities, including static two-dimensional cultures and animal models, have illuminated key molecular and cellular features but fall short in recapitulating human lymphatic function, due to limited physiological relevance, throughput, and mechanobiological complexity. Recent advances in microfluidic organ-on-a-chip systems offer biomimetic platforms that integrate three-dimensional architecture, fluid flow, and biomechanical stimuli alongside human lymphatic endothelial and supporting cells. These lymphatics-on-a-chip constructs faithfully reproduce dynamic behaviors such as fluid drainage, junction remodeling, and cell trafficking under physiological and pathological responses. This review highlights the foundational lymphatic biology and engineering principles behind these devices, their capacity for disease modeling and drug testing, and their potential to drive future innovation through induced pluripotent stem cell integration, organ-specific customization, and computational modeling. Merging bioengineering, cell biology, and machine learning, lymphatic microphysiological systems stand poised to significantly expand our understanding and treatment of lymphatic-related disorders.