A multicellular vessel-on-a-chip model reveals context-dependent roles for platelets in inflammation and inflammatory...

The immune system identifies and destroys invading pathogens. However, chronic inflammation and excessive tissue damage can occur if inflammation is not resolved or if the immune system misidentifies a threat. Therefore, the immune system must be tightly controlled. However, the complex cell-cell and cell-microenvironment interactions that regulate immune-cell recruitment are challenging to recapitulate in 2-dimensional in vitro models, and poorly representative of human physiology in in vivo animal models. Organ-on-a-chip technology has the potential to overcome these limitations and provide powerful preclinical models. In this study, we developed a vessel-on-a-chip model to investigate the role of platelets in inflammation and inflammatory hemostasis. Endothelial vessels cultured in the OrganoPlate exhibited physiological barrier function to macromolecules and red blood cells (RBCs), which was enhanced by platelets. Cytokine stimulation increased vessel permeability and induced neutrophil transmigration. Leakage of RBCs occurred at sites of inflammation and/or neutrophil transmigration, depending on the extracellular matrix composition. Addition of platelets prevented RBC leakage at these sites, while simultaneously increasing permeability and neutrophil transmigration, demonstrating the multifaceted role of platelets in inflammatory hemostasis. In angiogenic neovessels, platelets played a protective role, preventing leakage of both small molecules and RBCs. Together, our model successfully recapitulated the modulation of endothelial barrier function and inflammation by platelets and demonstrated the feasibility of investigating complex cellular interactions in in vitro models.