Recent advances in microarray 3D bioprinting for high-throughput spheroid and tissue culture and analysis

Three-dimensional (3D) cell culture in vitro has proven to be more physiologically relevant than two-dimensional (2D) culture of cell monolayers, thus more predictive in assessing efficacy and toxicity of compounds. There have been several 3D cell culture techniques developed, which include spheroid and multicellular tissue cultures. Cell spheroids have been generated from single or multiple cell types cultured in ultralow attachment (ULA) well plates and hanging droplet plates. In general, cell spheroids are formed in a relatively short period of culture, in the absence of extracellular matrices (ECMs), via gravity-driven self-aggregation, thus having limited ability to self-organization in layered structure. On the other hand, multicellular tissue cultures including miniature tissues derived from pluripotent stem cells and adult stem cells (a.k.a. 'organoids') and 3D bioprinted tissue constructs require biomimetic hydrogels or ECMs and show highly ordered structure due to spontaneous self-organization of cells during differentiation and maturation processes. In this short review article, we summarize traditional methods of spheroid and multicellular tissue cultures as well as their technical challenges, and introduce how droplet-based, miniature 3D bioprinting ('microarray 3D bioprinting') can be used to improve assay throughput and reproducibility for high-throughput, predictive screening of compounds. Several platforms including a micropillar chip and a 384-pillar plate developed to facilitate miniature spheroid and tissue cultures via microarray 3D bioprinting are introduced. We excluded microphysiological systems (MPSs) in this article although they are important tissue models to simulate multiorgan interactions.