Studying long-term disorders of the brain can be difficult. The organ is inaccessible in vivo, while human neural tissue cultures can lack the persistence and fidelity to model chronic disease states. For researchers’ studying diseases such as Alzheimer’s or Parkinson’s, it can feel like poking around in the dark.

“If you look at the dearth of understanding of the brain in terms of severe diseases out there, drug affects, aging, you name it, there is no good test system today,” says David Kaplan, Ph.D., chair of the biomedical engineering department at Tufts University. “We need stuff.”

In a paper published recently in ACS Biomaterials Science & Engineering, Dr. Kaplan and his team detail a new tool they believe could fit the bill: A three-dimensional, human-derived neural tissue culture with unprecedented accessibility and longevity, suitable for studying everything from neurodegenerative diseases to long-term drug toxicity.

“We spent a couple of years developing the initial system, which we affectionately call the donut model, because it looks like a mini-donut,” Dr. Kaplan says. It’s a 10-millimeter or so diameter “ring of sponge and the center of the sponge is gel, and it’s a combination of my favorite proteins: collagen in the middle and silk on the ring.”

Initially developed with rodent neurons, the new publication describes the use of human-induced pluripotent stem cells, differentiated into a diverse population of cells, including both neurons and astrocytes, and arranged in a three-dimensional structure mimicking that of the brain, but accessible to researchers.

“The way we set up our system, the donut’s hole is an optically accessible part of the compartment, so you can get direct imaging of what’s happening metabolically, synapse-wise,” explains Dr. Kaplan.

This is in contrast to organoid approaches, he notes, which produce diverse cell populations similar to those of the human brain, but, being roughly spherical cluster of cells, are dense and inaccessible.

Standardization and Scaleup

Another issue with brain organoids is that it’s difficult to standardize and scale up production of these clumps of cells for widespread use, says Milica Radisic, Ph.D., a University of Toronto professor and biomedical engineering researcher who is familiar with but not involved in Kaplan’s team’s work.

“It’s a little bit of an art, you have to watch someone do it. It’s like artisan cell culture like you have artisan coffee, where they make it by hand as you wait,” she says. “We always argued that this field should move toward standardizing this better and taking the cases from bioengineering that have the strength of controlling their structures.”

Dr. Kaplan’s donut, with its supportive scaffolding of silk and collagen, is exactly the sort of bioengineering technique Dr. Radisic had in mind. “He was able to marry the biological fidelity of organoids, and the precision of biomaterials science,” a combination of techniques Dr. Radisic and her colleagues had envisioned and dubbed “synergistic engineering” in a 2017 paper in Cell Stem Cell. “I think David is going exactly where the field should go.”

And that engineering advance could impact multiple neuroscience related fields, according to Gordana Vuajak-Novakovich, Ph.D., a professor of biomedical engineering and medicine at Columbia University who has collaborated with Dr. Kaplan’s team. That’s because researchers won’t need to be an expert in the donut model in order to use it. “You don’t need to be super skilled as a biologist or engineer to use it,” she says. “The elegance and simplicity is one of the system’s advantages.”

Another advantage, Dr. Vuajak-Novakovich says, is that Dr. Kaplan’s team’s cultures are stable over long periods. At the time they wrote the paper, Dr. Kaplan’s 9-month-old cultures, but he noted some of those same cultures are now almost two years old.

“This is very important because it allows you to study physiology, to model diseases and model therapeutic regimes,” Dr. Vuajak-Novakovich continues.

Researchers could build a model of a disease of the brain from a patient’s own cells, with their specific genetics, she notes, something that could be particularly important in treating diseases such as brain cancer. “Glioblastoma is a horrible condition that is really not testable and there is a desperate need to be looking for other options,” points out Dr. Vuajak-Novakovich. “This would be exactly the application of this platform to modeling this disease.”

Dr. Kaplan’s team, it turns out, has a paper on a glioblastoma model using the donut system that is about to be sent out for review. “I think we will show with this model actually allows you to study these tumors in completely new ways we feel will finally let people figure out how to find good treatments,” he says.

The next steps for Dr. Kaplan are pretty clear. Pursue more funding to further develop the system. “This is very expensive work to do, as you can imagine.” Also, get neuroscience researchers using the system in their own work.

“We have probably half a dozen very active collaborations right now in specific area, but we would like to see them continue to blossom,” he says. “We would love to have folks who are excited about his come sit down with us. We would get them up to speed on this and let them go. We are ready today.”

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