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Modeling the lung-liver connection
SEATTLE—Researchers at Philip Morris International (PMI) have developed a novel multi-organ-on-a-chip in-vitro model that includes combined, stable-state lung and liver tissues. This lung-liver model may facilitate important discoveries relating to lung-liver interactions in toxicological assessments of airborne compounds, potentially impacting the costly development process of therapeutics in multiple fields of study and reducing the need for animal testing.
Although single organ-on-a-chip (OoC) models are increasingly becoming relatively common, a primary challenge for developing useful multi-organ models has been maintaining tissues from multiple organs in a stable state long enough to allow for toxicological assessments.
“We have reached an important milestone, demonstrating that our lung-liver-on-a-chip holds both lung and liver tissues in a stable state for at least four weeks,” says Dr. David Bovard, a postdoctoral fellow in Systems Toxicology at Philip Morris International.
Another challenge facing the PMI team was to demonstrate that the liver tissue used in their model was capable of processing substances foreign to the human body in a manner consistent with a live organ.
“To assess this, we measured the activity of key enzymes that are known to be essential to the metabolization of a class of compounds called aromatic hydrocarbons,” says Bovard. “We also measured the formation of metabolites following exposure of the liver tissues to nicotine and nicotine-derived nitrosamine ketone (NNK), one of the key carcinogenic components of tobacco smoke. The major nicotine and NNK metabolites normally found in smokers were detected, confirming the metabolic capacity of the liver tissues.”
The successful development of a multi-organ-on-a-chip model that assesses both lung and liver toxicity promises several advantages over existing single OoC models. Notably, the model may help to streamline toxicological assessments by simultaneously modeling toxicity of compounds processed in either organ, and by measuring important—sometimes complex—organ-to-organ interactions.
“Airborne compounds are generally absorbed through the lung, so in assessing their toxicity it is of course important to look at how they affect lung tissues,” says Bovard. “However, understanding the true toxicity of some of these compounds also requires an assessment of how they affect the liver, since the liver is one of the most highly perfused organs in the human body and plays a key role in the metabolization of foreign substances.
“Adding relevant liver tissues to in-vitro models of the lung is therefore essential for the thorough toxicological assessment of airborne compounds.”
The applications for such toxicity modeling could be far-reaching, theoretically including toxicity assessments of virtually any airborne compound. These models could prove useful in a wide variety of applications ranging from environmental studies and consumer product safety assessments to pharmaceutical development.
By using human tissues, OoCs (including multi-organ-on-a-chip models) both reduce the need for animal testing and help to avoid the challenge of translating results observed in one species to another.
“[Multi-organ models] may unlock new approaches to drug development by providing an improved understanding of dose responses, enabling the detection of drug resistance and highlighting potential side effects,” says Bovard. In conjunction with computational modeling to translate in-vitro data into in-vivo predictions, he says, these models will also help to decrease the rate of failure of new drugs at the clinical trial stages. Clinical failures of new therapeutics can financially devastate drug development companies, and are estimated to cost between $800 million and $1.4 billion annually for anticancer drugs alone, according to Definiens' chief medical officer Dr. Ralf Huss in an October 2016 article in Clinical Leader.
The research team at PMI plans to begin by using their lung-liver-on-a-chip model to better understand the interactions between the two organs using a series of well-defined drugs.
“We are planning to more closely examine the mechanism of toxicity elicited by compounds that are applied to the lungs first (to mimic inhalation exposures) versus those that arise following liver or systemic application,” Bovard explains. “With such studies we hope to gain insights into how we can use this MOC [multi-organ chip] to, for example, predict liver toxicity associated with inhaled medications.”
In addition, the research team at PMI presented details of a new 3D vasculature-on-a-chip model at the 10th World Congress on Alternatives and Animal Use in the Life Sciences in Seattle in August of 2017. The model, developed in collaboration with the privately owned biotech company MIMETAS, is intended to create a lifelike model of the human blood vessel.
“We have successfully used this model to measure the attachment of immune cells to the blood vessel wall, a feature of early onset atherogenesis,” says Bovard. “As with the lung-liver-on-a-chip, the aim of the 3D vasculature-on-a-chip is to improve the prediction of the effects of toxicants and therapeutic drugs in humans, while reducing the use of laboratory animals.”