Abstract

Organs-on-Chips Technology Enables Better Understanding of Human Pathogenesis and Development of Therapeutics

Janna Nawroth, Principal Investigator, R&D Lead, Emulate, Inc.

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 an 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 and industry collaborators that demonstrates the utility of the system as a more predictive, human-relevant alternative for preclinical disease modeling and drug discovery.  In one case, we investigated the potential for our Small Airway-Chip to demonstrate asthma exacerbation in response to viral infection. First, we induced key pathophysiological hallmarks of the asthmatic epithelium by exposing the epithelial side to clinically relevant doses of IL-13. Then, we administered a rhinoviral infection and recapulated complex clinical features of viral-induced asthma exacerbation in real time. For example, we observed increased ciliated cell sloughing, altered ciliary beating frequency, goblet cells hyperplasia, increased expression of adhesion molecules in microvascular endothelial cells and inflammatory mediator release that have been observed in asthmatics and individuals infected with rhinovirus. A novel, high resolution temporal analysis of secreted inflammatory markers revealed alteration of IL-6, IFN-?1 and CXCL10 secretory phases after rhinovirus infection in the IL-13 enriched environment. Furthermore, using real time high resolution imaging and quantitative analysis of circulating inflammatory cells, we also demonstrated the efficacy of a CXCR2 antagonist to reduce adhesion, motility and transmigration of perfused human neutrophils. These studies demonstrate how our Organs-on-Chips technology provides a platform to obtain powerful preclinical data for understanding the mechanisms that underlie disease pathologensis and enable development of new therapeutics.