The multi-organ chip directly measures the biological impact of nanoparticles

What happens when we breathe in nanoparticles emitted by a laser printer, for example? Could these nanoparticles damage the respiratory tract or perhaps even other organs? To answer these questions, Fraunhofer researchers are developing the “NanoCube” exposure device. The Nanocube’s integrated multi-organ chip implemented in the laboratory of the Technical University of Berlin (TU Berlin) and by its spin-off organization “TissUse” detects the interaction between nanoparticles and lung cells, the absorption of nanoparticles in the bloodstream and possible effects on the liver.

Having a laser printer right next to your workstation is certainly very practical. That said, there is a risk that these machines, much like 3D printers, will emit aerosols during operation that contain, among other things, nanoparticles – particles between one and a hundred nanometers in size. By comparison, a hair is about 60,000 to 80,000 nanometers thick. Nanoparticles are also produced by the passage of road vehicles, for example by the abrasion of tires. However, little is known about how these particles affect the human body when inhaled into the lungs. Until now, the only way to study this would have been through animal testing. In addition, large quantities of samples of the aerosol concerned would have to be collected at great expense.

Directly measurable biological impact

Researchers from the Fraunhofer Institute for Toxicology and Experimental Medicine ITEM and the Fraunhofer Institute for Algorithms and Scientific Computing SCAI are collaborating with TU Berlin and its spin-off organization TissUse GmbH on the “NanoINHAL” project to study the impact of nanoparticles on the human body. The project is funded by the German Federal Ministry of Education and Research (BMBF).

We are able to analyze the biological impact of aerosols directly and easily using in vitro methods – and without animal testing.”

Dr. Tanja Hansen, Group Manager at Fraunhofer ITEM

The combination of two existing technologies made this possible: the Humimic Chip3 multi-organ chip from TU Berlin and its spin-off organization TissUse, and the PRIT® ExpoCube®, developed by Fraunhofer ITEM. The Humimic Chip3 is a standard lab slide sized chip measuring 76 x 26mm. Tissue cultures miniaturized 100,000 times can be placed there, with nutrient solutions delivered to the tissue cultures by micropumps. In this way, for example, tissue samples from lung and liver and their interaction with nanoparticles can be artificially recreated.

Four of these multi-organ chips fit into the PRIT® ExpoCube®. It is an exposure device used to study airborne substances such as aerosols in vitro. Using a sophisticated system of micropumps, heating electronics, aerosol lines and sensors, the ExpoCube® is able to expose the cell samples on the multi-organ chip to various aerosols or even nanoparticles at the air-liquid interface – such as in the human lung – in a controllable and reproducible way.

The nanoparticles circulate in a microconduit, from which several branches descend to conduct air and the nanoparticles to the four multi-organ chips. “If lung cells are to be exposed to the air-liquid interface, many parameters come into play, such as temperature, flow rate of culture medium through the chip, and aerosol flow rate. This makes the experiments of this very complicated type.” Hansen explains.

The system is currently being optimized. At the end of the project, the combination of the NanoCube and the multi-organ chip will facilitate detailed studies of aerosols in vitro. Only then will it be possible to study the direct impact of potentially harmful nanoparticles on the respiratory tract and, at the same time, the possible effects on other organs, such as the liver.

Simulations help optimize development

But how to direct aerosols, in particular nanoparticles, towards the lung cells in such a way that a determined quantity is deposited on the surface of the cells? This is where the expertise of Fraunhofer SCAI comes in: the researchers investigated this and similar aspects in a simulation. They had to overcome special challenges in the process: for example, the physical and numerical models required for detailed simulation of nanoparticles are significantly more complex than for larger-diameter particles. This, in turn, leads to a significant increase in computation time.

But the time and effort are worth it, because the compute-intensive simulation helps optimize the real test system. Let’s take an example: As mentioned above, the aerosol must flow through a line with several branches extending downwards to direct the nanoparticles onto the multi-organ chips, with conditions at the sampling points that are as identical as possible. The inertial forces of the nanoparticles are weak, however, so the particles would be less likely to move out of the diverted flow path and onto the cell surface. Gravity alone is not enough in this case. Researchers solve the problem by exploiting the phenomenon of thermophoresis. “It concerns a force in a fluid with a temperature gradient that causes particles to migrate to the colder side,” explains Dr. Carsten Brodbeck, project leader at Fraunhofer SCAI. “By allowing the aerosol to flow through the line in a heated state, as the cells grow naturally at body temperature, the nanoparticles move toward the cells, which the simulation clearly shows.”

The researchers also used simulations to study how to achieve the highest possible temperature gradient without damaging the cells and how the corresponding device should be constructed. They also looked at how different flow velocities and feeder geometries would affect absorption. The temperature distribution in the exposure device was optimized by selecting different materials, adjusting the geometry and changing the design of cooling and heating.

“Using simulations, we can quickly and easily change boundary conditions and understand the effects of these changes. We can also see things that would remain hidden in the experiments,” says Brodbeck.

Basic technology issues have been resolved. Now, the initial prototype of the NanoCube exposure device, including a multi-organ chip, should be ready in the fall, after which the first experiments with the system will be carried out. For now, the Fraunhofer researchers are using reference particles instead of printer aerosols, for example zinc oxide nanoparticles or so-called “carbon black”, i.e. say the black pigment of printing inks. In future practical applications, the measuring system should be installed where the nanoparticles are produced, for example next to a laser printer.

Innovative test system for toxic effects

The NanoINHAL project will see the creation of an innovative test system that can be used to study the toxic effects of airborne nanoparticles on cells in the airways and lungs, as well as on downstream organs such as the liver. . Thanks to the combination of two organ systems in a microphysiological system, it will also be possible to study the absorption and distribution of nanoparticles in the body. In the future, the test system will provide data on the long-term effects of inhaled nanoparticles as well as their biokinetics. This will play a major role in assessing the potential health hazard posed by these particles.

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