This research marks a significant milestone in a collaboration between Emulate and Janssen that began in June 2015 and has resulted so far in a total of three publications related to modeling thrombosis in Organ-Chips. The results in this paper demonstrate functionality of using Organ-Chips for testing for thrombosis and show the translational potential of the system to better predict human response.
In the study, the Blood Vessel-Chip recapitulated the occurrence of thrombosis with the anti-CD154 monoclonal antibody and recreated the key parameters of thrombosis, such as endothelial cell activation, platelet adhesion, platelet aggregation, fibrin clot formation and thrombin anti-thrombin (TAT) complexes.
In addition to reproducing clinically-observed thrombosis with the anti-CD154 antibody, this approach also offers several meaningful contributions to the future development of antibody drugs, such as immuno-therapeutics and oncology drugs, which have the potential to cause thrombosis as a side effect, including:
• New insights into the mechanisms of thrombosis induced by the anti-CD154 monoclonal antibody were gained by examining the interaction of the antibody with specific blood components within the Blood Vessel-Chip;
• Blood Vessel-Chip enabled analysis of potential new biomarkers of thrombosis risk thanks to a new chip design that makes this kind of analysis possible;
• Blood Vessel-Chip was used to evaluate a modified anti-CD154 antibody, designed with distinct binding properties (with an Fc domain that does not bind FcγRIIa receptor) to avoid the thrombosis risk of the original antibody. No pro-thrombotic effects were observed with the modified antibody in the Blood Vessel-Chip, suggesting a therapeutic design with a low potential risk for thrombosis.
The Blood Vessel-Chip provides a platform for preclinical assessment of thrombosis risk, efficacy testing of anti-thrombotic agents, mechanism of action elucidation, and potential biomarker identification. And it can do these in a patient-specific manner, as it utilizes human whole blood.
Advance in Human-Relevant R&D: Blood Vessel-Chip for Predicting Thrombosis in Drug Discovery and Development
In the published study, the Blood Vessel-Chip recreated the conditions and various physiologic parameters involved in clot formation in the human body and provided a mechanistic understanding of the factors implicated in thrombosis. Using Organ-Chips, researchers demonstrated:
• Creating a microenvironment to emulate the physiological function of endothelium-platelet interactions, flow of blood, and related mechanical forces involved in platelet aggregation and clot formation;
• Analytical methods integrated into the new chip design allowed for measurement of clinically relevant biomarkers and showed the potential of the technology for new biomarker identification
• Molecular and cellular level resolution to evaluate platelet activation and aggregation and interaction of endothelial dysfunction and blood-derived factors in causing thrombosis or bleeding;
• Analyzing platelet-endothelial interactions under pathophysiological conditions relevant for thrombosis research.
About the “Human Emulation System” Powered by Organs-On-Chips Technology
Based on the Organs-on-Chips technology, Emulate has created a new living Human Emulation System™ that provides a real-time window into the inner workings of human biology and disease – offering researchers a new technology designed to predict human response with greater precision and detail than today’s cell culture or animal-based experimental testing. Each of Emulate’s proprietary Organ-Chips – such as the lung, liver, brain, intestine or kidney – contains tiny hollow channels lined with tens of thousands of living human cells and tissues, and is approximately the size of an AA battery. An Organ-Chip is a living, micro-engineered environment that recreates the natural physiology and mechanical forces that cells experience within the human body.
About Emulate, Inc.
Emulate Inc. is a privately held company that creates living products for understanding how diseases, medicines, chemicals, and foods affect human health. Our Human Emulation System™ sets a new standard for recreating true-to-life human biology and is being used to advance product innovation, design, and safety across a range of applications including drug development, agriculture, cosmetics, food, and chemical-based consumer products. Emulate continues to develop a wide range of Organ-Chips and disease models through collaborations with industry partners and internal R&D programs. Emulate is also working with clinical partners to produce Organ-Chips personalized with an individual patient’s stem cells, for applications in precision medicine and personalized health. Our founding team pioneered the Organs-on-Chips technology at the Wyss Institute for Biologically Inspired Engineering at Harvard University. Emulate holds the worldwide exclusive license from Harvard University to a robust and broad intellectual property portfolio for the Organs-on-Chips technology and related systems.
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Image 1 caption:
Image of Thrombosis-Chip showing all the characteristic features of a blood clot in vivo. System validated for use in determining risk of drugs to cause blood clots in patients
Image credit: Emulate, Inc.
Image 2 caption:
Blood clot in our Organ-Chip
Image credit: Emulate, Inc.