Abstract
The Organ-on-a-Chip field provides better insight into healthy biology, but also disease, and drug development, through more physiologically relevant models. In drug development, Organs-on-Chips aim to improve the evaluation of compound efficacy. In addition, secondary effects and toxicity could be assessed in a more relevant context. Thereby, Organs-on-Chips contribute to multiple phases of the drug discovery and development pipeline.
Here, we report the screening of 1546 compounds on a 3D vascular endothelial sprouting model in the OrganoPlate® 3-lane 64. A plate comprises 64 chips, consisting of three channels each. In this model, the middle channel was filled with collagen-I, supporting a tube of HUVECs in the flanking channel which forms under gravity-driven perfusion. In addition, the ECM serves as scaffold for the angiogenic sprouting, induced through a gradient of angiogenic factors. Using a 1546 compound protein kinase inhibitor library, we screened for an effective inhibitor or enhancer of angiogenic sprouting. Through fluorescent staining and high content imaging, the effect of each compound on multiple sprouting parameters could be captured. In addition, potential off-target effects and toxicity were checked by assessing the morphology of the parent tube simultaneously. In conclusion, our compound screening using the OrganoPlate® 3-lane 64 yielded multiple non-toxic angiogenic modulators. To our knowledge, this effort is also the largest reported Organ-on-a-Chip screen, demonstrating the potential of the OrganoPlate® platform in drug discovery and development.
