Organs-on-Chips Technology: A Platform for Advancing Efficacy and Safety Testing in Drug Discovery and Development
Geraldine A. Hamilton
Organs-on-Chips are micro-engineered systems that recapitulate the tissue microenvironment. Each Organ-Chip, which is composed of a clear flexible polymer, is about the size of a AA battery and contains tiny hollow channels lined with living cells. The Chips are cultured under continuous flow within engineered 3D microenvironments that go beyond conventional 3D in vitro models by recapitulating in vivo intercellular interactions, spatiotemporal gradients, vascular perfusion, and mechanical forces — all key drivers of cell architecture, differentiated function, and gene expression.
In this presentation, we discuss data from studies conducted with academic, clinical, and industry collaborators that demonstrates the utility of the system as a more predictive, human-relevant alternative for efficacy and safety testing of new chemical entitites. The data also demonstrates the ability to model aspects of normal and disease physiology of the lung, liver, and intestine. In one case, we investigated the potential of the Liver-Chip for drug safety testing. The Liver-Chip showed improved viability and hepatic function compared to conventional hepatocyte culture systems over long-term culture. In addition, the Liver-Chip maintained stable physiologic levels of key hepatic functions, such as albumin secretion, urea secretion, and expression of CYP450s drug metabolizing enzymes. The Liver-Chip also provided mechanistic insight into drug action. Moreover, we were able to recapitulate toxicity findings from the clinic that were not previously observed in other in vitro systems or predicted by animal models. This presentation will also address the ability to study species differences in toxicity by comparing data from rat, dog, and human Liver-Chip systems.
Implementation of Organ-on-Chips technology within the pharmaceutical industry aims to improve the probability of success of drugs by generating pre-clinical models that are more human-relevant and enable mechanistic understanding of human diseases and drug action.
A Micro-engineered Airway Lung-Chip that Recapitulates Unique Features of Human Viral-Induced Exacerbation of Asthma
C. Lucchesi1, D. Cheng1, J. Nawroth1, J. Ngyuen1, T. Shroff1, H-H. Lee2, S. Alves2, G. Hamilton1, M. Salmon2± and R. Villenave1*.
[presented by Remi Villenave]
1Emulate, Inc., Boston, MA; 2Merck Research Laboratories, Boston, MA; ±New address: Emulate, Inc., Boston, MA
New therapies for severe asthma, particularly treatments that reduce exacerbations, remain a significant unmet medical need. Exacerbations are characterized by an inappropriate response of asthmatic airways to invading pathogens not seen in healthy lungs. Development of advanced preclinical models are needed to further elucidate the complex mechanisms underlying asthma exacerbation and investigate new therapeutic strategies.
Here we present a novel human Airway Lung-Chip containing a fully-differentiated human mucociliary airway epithelium separated from a pulmonary microvascular endothelium by a semi-permeable membrane that allows for immune cell infiltration. Infection with human rhinovirus, the most common cause of asthma exacerbation in adults and children, was restricted to ciliated cells and resulted in ciliated cell apical sloughing and goblet cell hyperplasia, replicating hallmarks of cytopathology observed in vivo. Rhinovirus-induced inflammatory response was characterized by apical and basal secretion of Eotaxin, IFN-λ1, CXCL10, IL-6 and IL-8. Generation of a Th2 microenvironment through interleukin-13 (IL-13) stimulation induced features of asthmatic airways and induced vascular wall activation through increased expression of E- and P-Selectin, but did not alter rhinovirus growth. High resolution kinetic analysis of IL-6 and interferon responses revealed significant inhibition by IL-13 treatment, suggesting an IL-13-mediated alteration of the resolution of the immune response. Airway Lung-Chips perfused with freshly isolated human neutrophils recapitulated neutrophil extravasation observed in viral-induced asthma exacerbation in vivo, and treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil velocity and diapedesis.
This micro-engineered Airway Lung-Chip recapitulates key features of viral-induced human asthma exacerbation and provides unique opportunities to explore the complex mechanisms underlying asthma exacerbation in a human-relevant model. The system can be used by researchers as a model to elucidate how viral infections contribute to exacerbations, gain insight into mechanism of action of drugs, and could potentially help identify new therapeutic targets.
The anti-CD40L Therapeutic Monoclonal Antibody hu5c8 Induces Formation of Fibrin-Rich Blood Clots and Secretion of Thrombin-anti-Thrombin Complex in a Microengineered Human Vascular-Chip.
Riccardo Barrile1, Andries D. van der Meer2, Hyoungshin Park1, Jacob Fraser1, Damir Simic3, Fang Teng3, David Conegliano1, Justin Nguyen1, Chaitra Belgur1, Mimi Zhou3, Yang Wang3, Katia Karalis1, Donald E. Ingber 3, Geraldine A. Hamilton1, Monicah A. Otieno3
[presented by Riccardo Barrile]
1Emulate Inc., USA; 2University of Twente, The Netherlands; 3Janssen Pharmaceutical, USA; 4Wyss Institute for Biologically Inspired Engineering at Harvard University, USA
Blocking of CD40L-mediated signaling represents a validated therapeutic strategy for treatment of auto-immune disorders and for preventing organ transplant rejection. Despite its potential broad applications, clinical development of Hu5c8, a monoclonal antibody intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic and cardiovascular events in patients. These life-threatening side effects are usually not revealed during preclinical testing due to a lack of specific predictive models. In the present study, we describe the development of a microengineered Vascular-Chip that is able to detect the pro-thrombotic effects of Hu5c8 and provide a patient-specific platform for safety testing. The vessel formed on the chip includes a channel lined by human endothelial cells and perfused with human whole blood. Our data showed that complex prothrombotic events and clinically relevant events could be recapitulated on-Chip including endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and expression of clinically relevant biomarkers. Treatment-related increase in thrombin anti-thrombin (TAT) complexes in the effluent from the Chips demonstrated the capability of our model to couple imaging endpoints with the detection of associated biomarkers. The data generated with this model are consistent with clinical findings, and highlight the significant contribution of this Organ-on-Chip technology to recapitulate and even predict the risk for thrombotic events of novel drug candidates. This model offers unique capabilities for preclinical assessment of thrombosis risk in a patient-specific manner, including efficacy testing of anti-thrombotic agents, elucidation of mechanism of action, and, potentially, biomarker identification, all providing a much-needed platform for drug discovery and development.