Toward in vitro models of brain structure and function

The development of effective tissue-engineered models of the brain remains an elusive challenge because of its inherent complexity. Such models would be extremely important to understanding brain development, and for exploring therapeutic options for disorders of the CNS, including the treatment of traumatic brain injury (TBI) and related damage to the brain. One million, seven hundred thousand TBIs occur in the United States annually (1). These in vitro models would also be invaluable test beds for drug-discovery investigations and in toxicology evaluations. In PNAS, Tang-Schomer et al. (2) describe a promising model of a cortical tissue mimic and demonstrate its applications to a better understanding of response to TBI. Several classes of in vitro models of the brain have been described (3), including acute preparations (or explants of CNS tissues), organotypic cultures or thin slices of CNS maintained for greater than 7 d, cerebral organoids (which can be formed from the self-organization of human pluripotent stem cells in 3D cultures) (3), and tissue-engineered constructs (2, 4, 5). Here we focus on the cell-based techniques for organoids and tissue-engineered constructs. In organoids, the formation of cortex-like structures that are reminiscent of the human developing cerebral cortex have been observed (6). These structures promise to be useful models for brain development and neurodevelopmental disorders. Using human patient-specific induced pluripotent stem cells (iPSC), Lancaster et al. (6) were able to model microcephaly through observations of premature neuronal differentiation. The authors used a spinning bioreactor to grow organoids up to 4 mm in diameter that could be maintained for up to 10 mo. Although this technology is truly impressive, there are key limitations to these models. Currently, adult neuronal behavior is difficult to mimic with iPSC technology and when—and if—this is possible remains an open question. Furthermore, the self-organization in the organoids …