Madison, WI – 3D cell culture models replicate in vivo tissue biology more accurately than conventional 2D monoculture, however their use in high throughput screening applications has been limited because of the difficulties in using matrix components like collagen in multiwell plates. In addition, 3D models often rely on primary cells, which are usually not available in sufficient quantity for a large screen. This largely prevents the use of 3D cell models in most drug discovery and clinical applications where automated HTS assays are the norm. In a study entitled “3D microchannel co-culture: method and biological validation” published in Integrative Biology, Maret Bauer, working in the laboratory of Andreas Friedl in the Department of Pathology and Laboratory Medicine at the University of Wisconsin-Madison, showed that a 3D breast cancer model that uses stromal and epithelial cells embedded in extracellular matrix was fully functional in BellBrook Lab’s new iuvo Microconduit Array plates. The Microconduit Array plates have 192 submicroliter channels in an SBS/ANSI format and are fully compatible with typical liquid dispensing and automated microscopy equipment. The successful reacapitulation of the breast carcinoma model with immunocytochemical endpoints in the highly miniaturized, automated microconduit array format establishes the feasibility of using 3D cell models in previously inaccessible drug discovery and clinical applications.

Friedl’s laboratory developed the 3D co-culture model to study the relatively underappreciated contribution of stromal cells to tumorigenesis. In the model, human mammary fibroblasts stimulate the growth of breast carcinoma cells in a collagen matrix. The effects are dependent upon soluble factors, such as chemokines secreted from the fibroblasts, as well as proteases that degrade the matrix, and inhibitors of these effectors abrogate the growth stimulation. In the recent study, Bauer and her colleagues compared results observed with the 3D model in the microconduit array plates with those in conventional 24 well tissue culture plates using morphological and immunocytochemical endpoints. They observed essentially identical fibroblast-dependent increases in the size of epithelial cell clusters, the number of cells, and the density of a common cell proliferation marker, as well as abrogation of these effects by inhibitors that target matrix metalloproteases and chemokine receptors. Establishing the model in the microconduit array required approximately 100-fold fewer cells and proportionately lower reagent usage than in the conventional multiwell plates.

The demonstration that 3D cell culture model can be successfully employed in a highly miniaturized format that is compatible with automated liquid handling and detection platforms raises the possibility of performing compound screens for drug discovery in the presence of key drivers of tumorigenesis that are usually lacking in conventional assays, including cell-ECM interactions and paracrine signaling. The authors of the study speculate that the use of such assays could lead to the discovery of anti-cancer compounds that might be missed using conventional culture methods. The high degree of miniaturization achieved in the microconduit arrays also raises the possibility of using patient cell samples to determine individual differences in tumor signaling pathways or response to drugs.

BellBrook Labs is a privately held company that develops assays and devices to accelerate drug discovery. The iuvo™ Microconduit Array technology is a line of unique microscale devices for miniaturization and automation of advanced cell models that are more representative of human physiology. The plates incorporate passive pumping technology developed by David Beebe at the Department of Biomedical Engineering, UW-Madison, who is also a co-author on the 3D cell culture study, and licensed to BellBrook by the Wisconsin Alumni Research Foundation. For more information please visit www.bellbrooklabs.com