Microphysiological systems for in vitro ADME and systemic repeated dose toxicity testing
The proliferation of microfluidic systems in the scientific literature makes it difficult to keep up with this emerging technology. However, only a portion of these are microphysiological or “human-on-a-chip” systems being developed for toxicity testing applications.
An interesting one that caught our eye is the article, “Chip-based human liver–intestine and liver–skin co-cultures – A first step toward systemic repeated dose substance testing in vitro.”
The research in this paper describes the development of a multi-organ chip (MOC) platform supporting two different human organ equivalents (liver spheroids with skin punch biopsies or intestinal cultures) to model systemic repeated dose testing.
The research presented in this paper was summarized as follows by the authors:
“The MOC supports submersed cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at 1/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance – troglitazone – to the chip-based co-cultures.”
A video illustrating many of the steps in the development and use of the technology in this paper can be viewed in the Journal of Visualized Experiments.
In another publication, “A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents,” scientists in the same laboratory report the development of a four-organ microphysiological system as a platform for in vitro ADME and repeated dose testing. The four human organ equivalents (3D small intestine, skin biopsy, 3D liver equivalent, and kidney proximal tubule compartment) maintained barrier function, molecular transport against gradients, and metabolic activity over the 28 days in culture. The proposed capability to test for ADME is explained as follows: “This arrangement of our four-organ-chip enables physiological absorption, first path metabolism in the liver tissue, secondary metabolism and finally excretion through the kidney model. Permanent access to the different compartments and the organ equivalents themselves enable to evaluate pharmacokinetic and pharmacodynamics parameters, such as effective concentration, maximum tolerable dose, time course and intensity of therapeutic and adverse effects.”
We look forward to seeing more impressive developments from these German researchers and from the other laboratories pioneering the human-on-a-chip technologies.
Maschmeyer, et al. (2015). Chip-based human liver–intestine and liver–skin co-cultures – A first step toward systemic repeated dose substance testing in vitro. Eur. J. Pharm. Biopharm. In press, doi: 10.1016/j.ejpb.2015.03.002.
Materne, E. M., Maschmeyer, I., Lorenz, A. K., Horland, R., Schimek, K. M. S., Busek, M., et al. (2015). The Multi-organ Chip – A Microfluidic Platform for Long-term Multi-tissue Coculture. J. Vis. Exp. 98, e52526, doi:10.3791/52526. Available at: http://www.jove.com/video/52526/the-multi-organ-chip-microfluidic-platform-for-long-term-multi-tissue
Maschmeyer, I., Lorenz, A.K., Schimek, K., et al. (2015). A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip 15, 2688-2699, doi: 10.1039/c5lc00392j.
Posted: June 26, 2015