To achieve grey-white matter compartmentalization, the researchers cut the spongy scaffold into a donut shape and populated it with rat neurons. They then filled the middle of the donut with the collagen-based gel, which subsequently permeated the scaffold. In just a few days, the neurons formed functional networks around the pores of the scaffold, and sent longer axon projections through the center gel to connect with neurons on the opposite side of the donut. The result was a distinct white matter region (containing mostly cellular projections, the axons) formed in the center of the donut that was separate from the surrounding grey matter (where the cell bodies were concentrated).
Over a period of several weeks, the researchers conducted experiments to determine the health and function of the neurons growing in their 3D brain-like tissue and to compare them with neurons grown in a collagen gel-only environment or in a 2D dish.
The researchers found that the neurons in the 3D brain-like tissues had higher expression of genes involved in neuron growth and function. In addition, the neurons grown in the 3D brain-like tissue maintained stable metabolic activity for up to five weeks, while the health of neurons grown in the gel-only environment began to deteriorate within 24 hours. In regard to function, neurons in the 3D brain-like tissue exhibited electrical activity and responsiveness that mimic signals seen in the intact brain, including a typical electrophysiological response pattern to a neurotoxin.
Because the 3D brain-like tissue displays physical properties similar to rodent brain tissue, the researchers sought to determine whether they could use it to study traumatic brain injury. To simulate a traumatic brain injury, a weight was dropped onto the brain-like tissue from varying heights. The researchers then recorded changes in the neurons’ electrical and chemical activity, which proved similar to what is ordinarily observed in animal studies of traumatic brain injury.
Kaplan says the ability to study traumatic injury in a tissue model offers advantages over animal studies, in which measurements are delayed while the brain is being dissected and prepared for experiments.
"With the system we have, you can essentially track the tissue response to traumatic brain injury in real time," said Kaplan. "Most importantly, you can also start to track repair and what happens over longer periods of time."
Kaplan emphasized the importance of the brain-like tissue’s longevity for studying other brain disorders. "The fact that we can maintain this tissue for months in the lab means we can start to look at neurological diseases in ways that you can't otherwise because you need long timeframes to study some of the key brain diseases," he said.
Hunziker added, "Good models enable solid hypotheses that can be thoroughly tested. The hope is that use of this model could lead to an acceleration of therapies for brain dysfunction as well as offer a better way to study normal brain physiology."
Kaplan and his team are looking into how they can make their tissue model more brain-like. In this recent report, the researchers demonstrated that they can modify their donut scaffold so that it consists of six concentric rings, each able to be populated with different types of neurons. Such an arrangement would mimic the six layers of the human brain cortex, in which different types of neurons exist.
As part of the funding agreement for the Tissue Engineering Resource Center, NIBIB requires that new technologies generated at the center be shared with the greater biomedical research community.
"We look forward to building collaborations with other labs that want to build on this tissue model," said Kaplan.
This work was supported by NIH’s National Institute of Biomedical Imaging and Bioengineering under award #EB002520
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