Engineered models of the lymphatic vascular system: Past, present, and future

The lymphatic vascular system is crucial for optimizing body fluid level, regulating immune function, and transporting lipid. Relative to the experimental models to investigate blood vasculature, there are significantly fewer tools to explore lymphatics. Although in vivo studies have contributed to major discoveries in the field, finding and characterizing lymphatic specific markers has opened the door to isolating lymphatic vessels and cells for building ex vivo and in vitro platforms. These preparations have enabled the study and analysis of lymphatic vasculature in various physiological and pathophysiological conditions leading to a better understanding of cellular expressions and signaling. In this review, a broad range of ex vivo and in vitro engineered models are highlighted and categorized based on the major lymphatic function they model including contractile function, inflammation, drainage and immune regulation, lymphangiogenesis, and tumor-lymphatic interactions. Then, the novel 3D engineered tissues are introduced consisting of acellularized scaffolds and hydrogels to form vessels and cellular structures close to in vivo morphology. This paper also compares traditional in vitro methods with recent technologies and elaborates on the inherent advantages and limitations of each preparation by critically discussing simplest to most complex tissue-cellular structures. It concludes with an outlook of the lymphatic vasculature models and the possible future direction of contemporary tools, such as organ-on-chips.