Endothelial-immune cells-on-chip for multiplex evaluation of drug responses through patient plasma screening

Most organ-on-chip models focus on parenchymal cell function, overlooking the critical role of endothelial-immune interactions in metabolic disease pathophysiology. Drugs for metabolic conditions, such as SGLT2 inhibitors, provide not only metabolic improvements but also vascular-protective effects, underscoring the need for human platforms that capture immunovascular dynamics. Here, we developed a human endothelial-immune cells-on-chip system integrating patient-derived blood outgrowth endothelial cells, T cells, and hepatocytes to model the liver sinusoidal microenvironment. Using plasma from type 2 diabetes patients treated with dapagliflozin, the platform revealed reduced endothelial inflammatory activation, attenuated T cell migration, and decreased hepatocyte lipid accumulation, indicating systemic modulation of vascular and hepatic phenotypes. Despite the presence of endothelial SGLT2 protein expression, glucose uptake in vitro was unaltered by dapagliflozin, suggesting these beneficial effects might occur indirectly via plasma factors. Our multiplexed, human-relevant cellular platform enables simultaneous assessment of endothelial, immune, and hepatic responses, offering a versatile tool for personalized plasma-based drug screening and preclinical evaluation of vascular-protective therapies in metabolic diseases.