The human brain remains one of the least understood organs in the human body, because of its complexity and the difficulty of studying its physiology in the living body. Tufts University researchers today announced development of the first reported complex three-dimensional model made of brain-like cortical tissue that exhibits biochemical and electrophysiological responses and can function in the laboratory for months. The engineered tissue model offers new options for studying brain function, disease and trauma, and treatment. The National Institutes of Health funded research is reported in the August 11 Early Edition of the Proceedings of the National Academy of Sciences.
Advancing the study of brain trauma, disease and therapeutic treatments is something that the paper's senior and corresponding author David Kaplan, Ph.D., has wanted to pursue for a long time. Kaplan is Stern Family professor and chair of biomedical engineering at Tufts School of Engineering. "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," said Kaplan, who directs the NIH-funded P41 Tissue Engineering Resource Center based at Tufts.
Rather than reconstructing a whole-brain network, the Tufts team created a modular design that replicated fundamental features most relevant to the brain's tissue-level physiological functions.
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. Circular modules of cast silk were punched into doughnuts, then assembled into concentric rings to simulate the laminal layers of the neocortex. Each layer was seeded with neurons independently before assembly, without the need for adhesive or glue. The doughnuts were then immersed in the collagen gel matrix.
The silk-collagen gel combination provided an optimum microenvironment for neural network formation and function. "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 the paper's first author, Min D. Tang-Schomer, Ph.D., 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."
Studying Brain Damage
The Tufts researchers were able to use the tissue model to examine multiple post-injury effects, including cellular damage, electrophysiological activity and neurochemical changes. For example, when a weight was dropped on the model tissue to simulate a traumatic brain injury, the tissue released high levels of the chemical glutamate, a neurotransmitter known to be emitted by cells following brain damage; the tissue also showed transient electrical hyperactivity consistent with post-trauma responses observed in vivo.
"This model provides a unique opportunity for mapping out real-time neurophysiological events and function studies in the laboratory, monitoring that is prohibitive with humans or animals," said study co-author Philip Haydon, Ph.D., Annetta and Gustav Grisard professor of neuroscience at the Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine.
Kaplan said that work is underway to further develop the model. It could potentially be applied to study brain structure-function, drug screening, impact of electrodes and implants on brain function, disease formation and treatments, and the effects of nutrition and toxicants. "This is the first step," he said.
Paper authors also included James White, Ph.D., post-doctoral scholar in biomedical engineering at Tufts; Lee W. Tien, Ph.D., licensing associate at Tufts and former graduate research assistant in biomedical engineering; L. Ian Schmitt, Ph.D. in neuroscience from the Sackler School of Graduate Biomedical Sciences at Tufts University School of Medicine; Thomas Valentin, M.S., former Tufts graduate research assistant in biomedical engineering; Daniel Graziano, B.S. in chemical and biological engineering from Tufts and former biomedical research assistant; Amy Hopkins, Ph.D. in biomedical engineering from Tufts; and Fiorenzo G. Omenetto, Ph.D., Frank C. Doble professor of biomedical engineering and professor of physics.
This research was supported by P41 Tissue Engineering Resource Center of the National Institutes of Health under award number: EB002520.
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