Cells have a remarkable ability to modulate the behavior of their neighbors. In the liver, such cell-cell communication is central to both the regulation of normal function and the pathogenesis of disease. Existing multi-cell culture systems rely on random co-cultures, transwells, and micropatterned cell arrays, but typically focus on a single cell pair of cell types and often have limited microenvironment control. Here, we present a compact scalable microfluidic co-culture array that enables a matrix of different co-cultures to be created and studied in parallel. Arrays of microvalves control seeding of distinct cell types in each row and each column, generating a high-density matrix of co-cultures in contact or proximity for distinguishing secreted factor communication from contact-mediated interactions. To demonstrate the approach, we seeded several hepatocyte-like GFP reporter cell lines in rows and nonparenchymal liver cell types such as macrophage and stellate cells in columns. We then used time-lapse fluorescence microscopy to study dynamic transcriptional profiles in the presence of inflammatory stimuli such as LPS and observed several co-culture-specific responses. In summary, the microfluidic co-culture arrays offer a powerful high-throughput experimental system for screening pair-wise interactions between multiple cell types. This tool has the potential to enable dissection of the roles of different cell types in a variety of physiologically relevant settings including hepatic inflammation, atherosclerotic plaque formation, and stem cell differentiation.

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