August 12, 2014
New 3D Tissue Model Could Improve Study Of Brain Trauma And Related Diseases
redOrbit Staff & Wire Reports - Your Universe Online
A team of bioengineers from Tufts University in Massachusetts have developed three-dimensional brain-like cortical tissue that is similar in structure and function to tissues found in the brain of a rat, exhibits biochemical and electrophysiological responses, and can be kept alive in the laboratory for more than eight weeks.
In research published in the August 11 early online edition of the journal Proceedings of the National Academy of Sciences (PNAS) and funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the study authors explain how they were able to create the tissue using a silk protein-based scaffold and ECM composite and primary cortical neurons.
The researchers used the tissue to investigate the chemical and electrical changes that occur within the brain immediately following a traumatic injury, and conducted a separate experiment to observe how the tissue responded to a drug. They report that their creation could serve as a better model for the study of normal brain function, as well as brain injuries and diseases, and could lead to the development of new treatments for these issues.
“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,” senior and corresponding author Dr. David Kaplan, chair of biomedical engineering at Tufts School of Engineering, said in a statement.
“To generate this system that has such great value is very exciting for our team,” he added.
Instead of recreating a whole-brain network from the ground up, Dr. Kaplan and colleagues from the Tufts biomedical engineering, physics and neuroscience departments opted instead to develop a modular design which replicated fundamental features that are most relevant to the physiological functions at the tissue-level of the brain.
“Each module combined two materials with different properties: a stiffer porous scaffold made of cast silk protein on which the cortical neurons, derived from rats, could anchor and a softer collagen gel matrix that allowed axons to penetrate and connect three dimensionally,” the university explained. “Circular modules of cast silk were punched into doughnuts, then assembled into concentric rings to simulate the laminal layers of the neocortex.”
Each of those layers was seeded with neurons independently before they were assembled – a process that did not require glue or adhesive. The doughnuts were then immersed in the collagen gel matrix, and the combination of silk and collagen gel proved to be an optimum microenvironment for the formation and function of neural networks.
“The stiffness of the silk biomaterial could be tuned to accommodate the cortical neurons and the different types of gels, maintaining both stability in culture and brain-like tissue elasticity,” said first author Dr, Min D. Tang-Schomer, a post-doctoral scholar in biomedical engineering at Tufts. “The tissue maintained viability for at least nine weeks – significantly longer than cultures made of collagen or hydrogel alone – and also offered structural support for network connectivity that is crucial for brain activity.”
“This work is an exceptional feat,” added 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.”
Since the 3D brain-like tissue possessed physical properties similar to rodent brain tissue, the research team decided to test whether or not it could be used to study traumatic brain injury. They dropped a weight on the cortical tissue from various heights in order to simulate such an injury, and then recorded changes in the electrical and chemical activity in the neurons. The results were described as similar to those typically found in animal brain injury studies.
However, Kaplan pointed out that the new tissue model has advantages over animal studies, since the latter requires research to be delayed while scientists dissect the brain and prepare it for experiments. The new system, he noted, allows them to “essentially track the tissue response to traumatic brain injury in real time. Most importantly, you can also start to track repair and what happens over longer periods of time.”
He also said that the longevity of the brain-like tissue will be important in studying other brain disorders, since the fact that the tissue can be maintained in the laboratory for at least two months “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.”
Kaplan and his colleagues are also looking for ways in which they can make their tissue model even more brain-like. As they reported in their new study, the cortical tissue can be modified so that the doughnut scaffold is comprised of six concentric rings, each able to be populated with different types of neurons. This set-up would mimic the six layers of the human brain cortex, each of which is home to different types of neurons, the study authors said.
Image 2 (below): This image shows confocal microscope image of neurons (greenish yellow) attached to silk-based scaffold (blue). The neurons formed functional networks throughout the scaffold pores (dark areas). Credit: Tufts University
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