Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform

Abstract

Many drugs have progressed through preclinical and clinical trials and have been available – for years in some cases – before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.

From Shape to Function: The Next Step in Bioprinting

“…Moreover, these technologies can be successfully used to create miniaturized tissue models to study pathological processes and the effect of drugs on multitissue platforms on‐a‐chip. Eventually, integrating multiple cell types and tissues in one single process can pave the way toward the “holy grail” of bioprinting full organs for transplantation, but also to create advanced models for biomedical research to improve our understanding of intertissue interactions in disease and regeneration …”

In Vitro Tissue‐Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease

“…Recent advances in organ-on-a-chip technologies can allow multiple engineered tissue types to be multiplexed by: 1) direct coupling via microfluidic flow or 2) functional coupling via sequential culturing and transferring media from one tissue type to another. Direct coupling better replicates the in vivo milieu but considerations such as organ-specific flow rates, rapid accumulation of metabolic waste, and the requirement of a common media for all organs pose significant technical challenges [267,268] Direct coupling has been achieved with three to four organs, [269,270] including one system that incorporated skeletal muscle, cardiac muscle, liver, and neuronal tissues and demonstrated expected responses to known toxic drugs. [271] The benefit of these microphysiological platforms for identifying unexpected drug toxicity was shown in a system integrating the heart, lung, and liver, whereby adding bleomycin to cardiomyocytes alone showed no toxic effect, but coupling with the lung resulted in severe cardiomyocyte toxicity.…”

“…[271] The benefit of these microphysiological platforms for identifying unexpected drug toxicity was shown in a system integrating the heart, lung, and liver, whereby adding bleomycin to cardiomyocytes alone showed no toxic effect, but coupling with the lung resulted in severe cardiomyocyte toxicity. [270] Additionally, functional coupling of hepatocytes and skeletal muscle demonstrated that liver tissues could prevent the potent myotoxic effects of terfenadine, an anti-histamine known to have cardiac arrhythmogenic effects. [272] Improved predictive capacity in future studies will require addition of other tissue-engineered organs, including the gut and intestine to model first-pass metabolism that regulates the concentration and chemical form of any drug that enters the bloodstream.…”

Toxicological evaluation of airborne particulate matter. Are cell culture technologies ready to replace animal testing?

“…Research and development in the area of lung‐on‐chip technology has recently been applied to drug screening (Benam et al, ; Skardal et al, ) and to the study of lung physiology (Benam et al, ; Henry et al, ; Humayun, Chow, & Young, ; J. D. Stucki et al, ) and pathophysiology (Huh et al, ; Jain et al, ), and we wonder whether this technology was also used in investigations related to environmental toxicology. However, although the technology is promising and does not have ethical and regulatory limitations, its use to study the response of human cells to ambient toxicants has not yet been presented in the literature (Cho & Yoon, ).…”