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Tufts sees a touchdown with 3D tissue
MEDFORD/SOMERVILLE, Mass.—The promise of lab-grown tissues and organs is huge, as they can enable the study of live samples of interest that don’t need to be harvested from patients. The leading targets for such research are often the liver and the kidneys, as lab-grown versions could enable studies of the toxicity of drug compounds and how they are cleared from the body, respectively. But another target of interest is the brain, primarily to aid in research into issues such as traumatic brain injury and neurological disease.
However, even as researchers see success with lab-grown livers, similar progress in growing accurate facsimiles of brains has been slow. In recent years, however, labs have begun to see some success. Last September, we reported on work performed at the Institute of Molecular Biotechnology at the Austrian Academy of Sciences (see “Celebrating cerebral organoids”) in which so-called ‘mini brains’ enabled the modeling of microcephaly.
This month, a team of researchers at the Tissue Engineering Resource Center at Tufts University, which is funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health, announced that they had successfully created 3D brain-like tissue with similar functions and features to that of tissue in the brain of a rat. The work was detailed in the paper “Bioengineered functional brain-like cortical tissue,” which appeared in the August 11 early edition of the Proceedings of the National Academy of Sciences.
The current method for studying live neurons consists of growing them in Petri dishes so they can be studied in a controlled environment. As with other types of tissues and cells, however, neurons grown in a dish—specifically a two-dimensional environment—do not replicate the structural organization of grey tissue, which consists of grey and white matter. While grey matter is made up of primarily neuron cell bodies, white matter consists of bundles of axons, the projections neurons extend in order to connect with each other. Both brain diseases and injuries have proven to affect grey and white matter differently, calling for models that can show both tissue types.
And even though 3D gel environments have yielded some success, gel-based tissue models have short lifespans and don’t demonstrate robust, tissue-level function, because the extracellular environment is a complicated matrix in which local signals create different neighborhoods, which in turn engender distinct cell growth and/or development and function.
The Tufts team managed to overcome these obstacles to create functional 3D brain-like tissue demonstrating grey-white matter compartmentalization that can survive in the lab for more than two months.
“This work is an exceptional feat,” said Dr. Rosemarie Hunziker, program director of Tissue Engineering at NIBIB. “It combines a deep understand of brain physiology with a large and growing suite of bioengineering tools to create an environment that is both necessary and sufficient to mimic brain function.”
The team’s success was based on a novel composite structure consisting of a spongy scaffold comprised of silk protein and a softer, collagen-based gel; the neurons could anchor themselves on the scaffold, while the gel encouraged axon growth. (Tufts University researchers have worked with silk protein scaffolds before; they published a study in 2012 [http://www.pnas.org/content/109/20/7699.abstract] detailing their work with this technology in bone repair.) The researchers cut the scaffold into a donut shape, populated it with rat neurons, then filled the middle of the ‘donut’ with the gel, which then permeated the scaffold. In a matter of days, the neurons developed functional networks around the pores of the scaffold and extended longer axon projections through the center gel to connect with neurons on the opposite side of the ‘donut,’ forming a distinct white matter region in the center of the donut that was separate from the surrounding grey matter where the cell bodies concentrated.
Compared to neurons grow only in the collagen gel or in a 2D dish, the neurons in the 3D brain-like tissue showed higher expression of genes involved in neuron growth and function, and maintained stable metabolic activity for up to five weeks, while the other neurons started failing within 24 hours.
“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,” said Dr. David Kaplan, Stern Family Professor of Engineering at Tufts University, director of the Tissue Engineering Resource Center and leader of this research effort.
“There are few good options for studying the physiology of the living brain, yet this is perhaps one of the biggest areas of unmet clinical need when you consider the need for new options to understand and treat a wide range of neurological disorders associated with the brain. To generate this system that has such great value is very exciting for our team,” Kaplan added.
Neurons in the brain-like tissue also showed electrical activity and responsiveness mimicking signals seen in an intact brain. In addition, the brain-like tissue also presented with changes similar to those of a true brain when subjected to traumatic injury.
Moving forward, the team will investigate methods for making the tissue models more brain-like, said Kaplan.
“Good models enable solid hypotheses that can be thoroughly tested,” said Hunziker. “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.”