Innovations in 3D Tissue Models of Human Brain Physiology and Diseases

3-dimensional (3D) laboratory tissue cultures have emerged as an alternative to traditional 2-dimensional (2D) culture systems that do not recapitulate native cell behavior. The discrepancy between <i>in vivo</i> and <i>in vitro</i> tissue-cell-molecular responses impedes understanding of human physiology in general and creates roadblocks for the discovery of therapeutic solutions. Two parallel approaches have emerged for the design of 3D culture systems. The first is biomedical engineering methodology, including bioengineered materials, bioprinting, microfluidics and bioreactors, used alone or in combination, to mimic the microenvironments of native tissues. The second approach is organoid technology, in which stem cells are exposed to chemical and/or biological cues to activate differentiation programs that are reminiscent of human (prenatal) development. This review article describes recent technological advances in engineering 3D cultures that more closely resemble the human brain. The contributions of <i>in vitro</i> 3D tissue culture systems to new insights in neurophysiology, neurological diseases and regenerative medicine are highlighted. Perspectives on designing improved tissue models of the human brain are offered, focusing on an integrative approach merging biomedical engineering tools with organoid biology.