Mini Caps for Mini Brains

A research team led by scientists from Johns Hopkins University have developed a tiny EEG electrode cap to measure activity in a brain model the size of a pen dot. Its designers expect the device to lead to better understanding of neural disorders and how potentially dangerous chemicals affect the brain.

The researchers published their study, “Shell microelectrode arrays (MEAs) for brain organoids,” in Science Advances and say their work expands what can be accomplish with organoids, including mini brains—the lab-grown balls of human cells that mimic some of a brain’s structure and functionality.

“This provides an important tool to understand the development and workings of the human brain,” notes David Gracias, PhD, a Johns Hopkins chemical and biomolecular engineer and one of the creators. “Creating micro-instrumentation for mini-organs is a challenge, but this invention is fundamental to new research.”

A brain organoid, shown in green, encapsulated in an electrode device, depicted in blue. [Qi Huang, Gayatri Pahapale, Gracias Lab, Johns Hopkins University]

“Brain organoids are important models for mimicking some three-dimensional (3D) cytoarchitectural and functional aspects of the brain. Multielectrode arrays (MEAs) that enable recording and stimulation of activity from electrogenic cells offer notable potential for interrogating brain organoids. However, conventional MEAs, initially designed for monolayer cultures, offer limited recording contact area restricted to the bottom of the 3D organoids,” write the investigators.

“Inspired by the shape of electroencephalography caps, we developed miniaturized wafer-integrated MEA caps for organoids. The optically transparent shells are composed of self-folding polymer leaflets with conductive polymer–coated metal electrodes. Tunable folding of the minicaps’ polymer leaflets guided by mechanics simulations enables versatile recording from organoids of different sizes, and we validate the feasibility of electrophysiology recording from 400- to 600-μm-sized organoids for up to 4 weeks and in response to glutamate stimulation.

“Our studies suggest that 3D shell MEAs offer great potential for high signal-to-noise ratio and 3D spatiotemporal brain organoid recording.”

Stem cells modified to create small-scale kidneys, lungs, livers, and brains

Since organoids were first created more than a decade ago, researchers have modified stem cells to create small-scale kidneys, lungs, livers, and brains. The complex, miniature models are used to study how the organs develop. Researchers study unaltered organoids next to ones that are genetically modified, injected with viruses, and exposed to chemicals. Organoids, particularly mini brains, are increasingly important in medical research because they can be used in experiments that would otherwise require human or animal testing.

But because the conventional apparatus to test organoids is flat, researchers have been able to examine only limited cells on their surface. Knowing what’s happening to a larger number of cells in the organoid would help reveal how organs function and diseases progress, according to Gracias.

“We want to get information from as many cells as possible in the brain, so we know the state of the cells, how they communicate, and their spatiotemporal electrical patterns,” he continued.

Humans “are not ‘Flat Stanley,” said co-author Lena Smirnova, PhD, a research associate in the department of environmental health and engineering. “Flat measurements have inherent limitations.”

The microcaps wrap around the entirety of an organoid’s spherical shape, enabling 3D recording from the entire surface so that, among other things, researchers can listen to the spontaneous electrical communication of neurons during drug tests. The data is expected to be superior to the current readings from conventional electrodes on a flat plate.

“If you record from a flat plane, you only get recordings from the bottom of a 3D organoid sphere. However, the organoid is not just a homogeneous sphere,” said first author Qi Huang, a PhD candidate in the department of chemical & biomolecular engineering. “There are neuron cells that communicate with each other. That’s why we need a spatial-temporal mapping of it.”

With more detailed information from organoids, researchers can study whether chemicals used in consumer products cause problems in brain development, pointed out co-author Thomas Hartung, MD, PhD, director of the Center for Alternatives to Animal Testing at the Johns Hopkins Bloomberg School of Public Health.

“Some chemicals like pesticides are especially suspicious, as many kill insects by damaging their nervous system,” Hartung explained. “Flame retardants are another class of chemicals where we have concerns.”

Researchers hope that readings from the caps could reduce the number of animals needed to test chemical effects. Traditional testing of just one chemical requires about 1,000 rats and costs about $1 million. The results from organoids are also more germane, said Hartung, because human brains are different from rat and mice brains.

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