Building brains with bioengineering

A few years ago, Jürgen Knoblich and his team at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) developed a method for cultivating three-dimensional brain-like structures, known as cerebral organoids, in a dish. Now, scientists from IMBA and the University of Cambridge have teamed up to present a new method that combines the organoid method with bioengineering.

The IMBA’s initial lab-grown organ models were found to mimic early human brain development in a surprisingly precise way, allowing for targeted analysis of human neuropsychiatric disorders that was otherwise not possible. Using this cutting-edge methodology, research teams around the world have already revealed new secrets of human brain formation and its defects that can lead to microcephaly, epilepsy or autism.

Seeking to build on this work, scientists led by Madeline Lancaster used polymer fibres made of a material called PLGA to generate a floating scaffold that was then covered with human cells. Using this combination of engineering and stem cell culture, the scientists were able to form more elongated organoids that more closely resemble the shape of an actual human embryo. By doing so, the organoids became more consistent and reproducible.

“This study is one of the first attempts to combine organoids with bioengineering,” said Lancaster, group leader at Cambridge’s MRC Laboratory of Molecular Biology. “Our new method takes advantage of and combines the unique strengths of each approach — namely the intrinsic self-organisation of organoids and the reproducibility afforded by bioengineering. We make use of small microfilaments to guide the shape of the organoids without driving tissue identity.”

This guided self-organisation allows engineered cerebral organoids, or enCORs, to more reproducibly form cerebral cortical tissue but maintain the tissue complexity and overall size that comes about when the tissues are still allowed to develop according to intrinsic developmental programs. As a result, enCORs also develop later tissue architecture that more faithfully models the organisation seen in an actual developing brain.

“An important hallmark of the bioengineered organoids is their increased surface to volume ratio,” said Knoblich, last author on the new paper published in Nature Biotechnology. “Neurons have ‘more space’ and can properly migrate and position themselves in a layer that in an actual developing brain would later become the grey matter. Because of their improved tissue architecture, enCORs can allow for the study of a broader array of neurological diseases where neuronal positioning is thought to be affected, including lissencephaly (smooth brain), epilepsy, and even autism and schizophrenia.”

Image caption: Bioengineered organoids, or enCORs, are supported by a floating network of PLGA fibre microfilaments. ©IMBA