The brain is the most complex organ in the human body with billions of neurons and trillions of connections. I have always been intrigued by the brain’s mechanisms and by the pathologies that affect the “mind”. As I have learned of how little we understand about the mechanisms behind some of the treatments prescribed for those who suffer from mental illnesses and the unsystematic way in which some treatments have been developed, I have come to consider it my scientific duty to contribute to the world-wide effort to create a proper test platform for treatments for neurological disorders.
Three-dimensional (3D) neuronal models, such as brain organoids and assembloids (also known as “mini brains”), have provided pioneering platforms for understanding various aspects of brain development1–5 and brain pathologies6–14. However, despite this progress, building a manipulatable in-vitro model to study the altered or disrupted 3D functional interconnectivity in multiregional network pathologies such as a focal epileptic seizure remains a major challenge.
At the same time, microfluidic organ-on-chip platforms have been developed, aiming to study neuronal interactions. However, these approaches lack either the 3D connectivity or clinically relevant cellular diversity and complex functionality of organoid approaches.15,16
To fill this gap, in this study we introduce a novel method to develop 3D neuronal tissues which, while preserving the potential of organoids, opens a range of possibilities for engineering approaches to mechanistically analyze clinically relevant 3D functional network connectivity.
In this method, by promoting matrix-supported active cell reaggregation, we engineered multiregional cerebral tissues (Figure 1) with intact 3D neuronal networks and functional interconnectivity characteristic of brain networks. Furthermore, using a multi-chambered tissue-culture chip, we show that our separated but interconnected cerebral tissues can mimic neuropathological signatures of a seizure, such as the propagation of epileptiform discharges (Figure 2).
To our knowledge, this is the first method to produce “mini brains” that is not based on the SFEBq (or even SFEB) method, which uses (a quick) mechanically-enforced aggregation of the (dissociated) cells.
The combination of this culturing method and culturing platform holds the potential to mimic any pathology whereby the activity of one area of the brain is (pharmacologically) altered, which can in turn contribute to drug development.
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