Tissue-Engineered Models of the Human Brain: State-of-the-Art Analysis and Challenges.

Neurological disorders affect billions of people across the world, making the discovery of effective treatments an important challenge. The evaluation of drug efficacy is further complicated because of the lack of in vitro models able to reproduce the complexity of the human brain structure and functions. Some limitations of 2D preclinical models of the human brain have been overcome by the use of 3D cultures such as cell spheroids, organoids and organs-on-chip. However, one of the most promising approaches for mimicking not only cell structure, but also brain architecture, is currently represented by tissue-engineered brain models. Both conventional (particularly electrospinning and salt leaching) and unconventional (particularly bioprinting) techniques have been exploited, making use of natural polymers or combinations between natural and synthetic polymers. Moreover, the use of induced pluripotent stem cells (iPSCs) has allowed the co-culture of different human brain cells (neurons, astrocytes, oligodendrocytes, microglia), helping towards approaching the central nervous system complexity. In this review article, we explain the importance of in vitro brain modeling, and present the main in vitro brain models developed to date, with a special focus on the most recent advancements in tissue-engineered brain models making use of iPSCs. Finally, we critically discuss achievements, main challenges and future perspectives.