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Illinois team develops first-of-a-kind in vitro 3D neural tissue model

Mike Koon
12/11/2019

Researchers at the University of Illinois at Urbana-Champaign have successfully used stem cells to engineer living biohybrid nerve tissue to develop 3D models of neural networks with the hopes of gaining a better understanding of how the brain and these networks work.

Gelson Pagan-Diaz, second from right, is pictured with his interdisciplinary team, from left, Dean Rashid Bashir, Karla Ramos-Cruz, Onur Aydin, Prof. Gabriel Popescu, and Mikhail Kandel, far right. Not pictured are Prof. Taher Saif and Richard Sam.
Gelson Pagan-Diaz, second from right, is pictured with his interdisciplinary team, from left, Dean Rashid Bashir, Karla Ramos-Cruz, Onur Aydin, Prof. Gabriel Popescu, and Mikhail Kandel, far right. Not pictured are Prof. Taher Saif and Richard Sam.

Gelson Pagan-Diaz, Bioengineering Ph.D. student and first author of the study, likens the produced tissue to a computer processing unit, which provided the basic foundation to today’s supercomputer.

“Being able to form 3-dimensional tissue consisting of neurons can give us the ability to develop tissue models for drug screening or processing units for biological computers,” Pagan-Diaz said.

The brain is challenging to study in an actual person, but being able to understand how these networks develop using a 3D model outside the body promises to give researchers a new tool to better understand how it works. These models will be able to help understand, for example, how abnormalities form what gives rise to diseases such as Alzheimer’s.

Different neural tissue geometries formed with the new biofabrication method and imaged using confocal microscopy
Different neural tissue geometries formed with the new biofabrication method and imaged using confocal microscopy
The team was able to give 3D geometry to the living tissue made of neurons with optogenetics, so they could be activated with blue light. These tissues could be used to study complex behaviors that happen in the brain and how the tissues react to new drugs being developed. The work also could lead to less reliance on animals to test new drugs in the future. 

“If we can control how these neurons communicate with each other, if we can train them using optogenetics, if we can program them, then we can potentially use them to perform engineering functions,” said Rashid Bashir, Dean of the Grainger College of Engineering, Grainger Distinguished Chair in Engineering and professor in Bioengineering. “In the future, our hope is that by being able to design these neural tissues, we can begin to realize biological processing units and biological computers similar to the brain.”

The project was funded through the National Science Foundation's Science and Technology Center EBICS (Emergent Behaviors of Integrated Cellular Systems) project and was published in December 2019 in the Proceedings of the National Academy of Sciences. The study was inspired by work done five years ago in developing functioning muscles, in which researchers in Bashir’s lab developed biobots that can move when stimulated with electricity or light.

One of the advantages of this biofabrication method is that the tissues can be incorporated into platforms that otherwise would have been too difficult. Here, a ring-shaped neural tissue mimic was installed onto a cylindrical glass rod, and the image shows how dense neural extensions are able to form on this substrate due to the geometrical advantage of the tissue.
One of the advantages of this biofabrication method is that the tissues can be incorporated into platforms that otherwise would have been too difficult. Here, a ring-shaped neural tissue mimic was installed onto a cylindrical glass rod, and the image shows how dense neural extensions are able to form on this substrate due to the geometrical advantage of the tissue.
This new work was performed by an interdisciplinary team consisting of: Pagan-Diaz; Bashir; Karla Ramos-Cruz, Bioengineering Ph.D. student; Richard Sam, student in Molecular and Cellular Biology; Mikhail Kandel, graduate student in Electrical and Computer Engineering; Gabriel Popescu, professor in Electrical and Computer Engineering and member of the graduate program faculty in BIoengineering; Onur Aydin, graduate student in Mechanical Science and Engineering; and M. Taher Saif, associate head for Graduate Programs and Research, and Edward William and Jane Marr Gutgsell Professor in Mechanical Science and Engineering, and member of the graduate program faculty in BIoengineering.

In this study, the team developed neural tissue mimics that can form different shapes. The team used hydrogels and fibrin to make millimeter-to-centimeter-scale structures that don’t have rigid scaffolds and can be molded into a number of desired shapes.

“It’s a bundle of hundreds to thousands of microns of cells that contains a lot of populations with a genetic makeup similar to in vivo tissues,” Pagan-Diaz explained. “As we continue to develop these bio-fabrication methods, we should be able to capture a lot of the phenomena that happens in vivo. Once we can prove that, we will be able to mimic the morphology that we see in the brain. Once we show that the tissue engineered outside the body is similar to the tissue in the body, then we can fabricate them over and over again.”

Besides drug testing, the team is especially interested in being able to recapitulate the way these networks might develop learning and memory. 

“Being able to fabricate these tissue mimics outside the body allows us to characterize and study their electrical activity in great detail,” Pagan-Diaz said. “The broad set of design rules due to the 3D structure and shapes gives you a lot more experimental freedom and opens up new avenues of research in neuroscience, medicine, and engineering applications.”

The paper, "Engineering geometrical 3-dimensional untethered in vitro neural tissue mimic," is online at www.pnas.org/content/116/51/25932.

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