A new flat brain model that self-initates gyrification is a large step towards more stable and complex human brain models.
WHO estimates that by 2030 more than 12% of all deaths globally will be caused by neulogical disorders. Research into the human brain is therefore a priority, but as the human brain is the most complex organ of the body and also inaccessible, there is a lack of scientific knowledge about the brain development and diseases.
To overcome these problems, researchers have developed miniaturized and simplified versions of the human brain called brain organs and grown them in the laboratory. They do not reproduce the exact anatomy of a human brain, but are an important step towards mimicking the human brain and can replace the use of animal models in research and in drug screening for toxicity and the understanding of disease development.
Important step towards better brain models
The spherical shape of existing brain organoids make it difficult to diffuse nutrients and oxygen into the core. This limits both the viable size and lifespan of the organoids as the cells in the core die. In order to address several of these shortcomings of existing brain organoids an international team of researchers from DTU and The Autonomous University of Madrid have engineered a flat brain organoid using a 3D printed scaffold, which can diffuse oxygen and nutrients throughout the brain organoid..
“By culturing brain organoids with a polycaprolactone scaffold, we were able to modify their shape into a flat morphology. Engineered Flat Brain Organoids possess advantageous diffusion conditions and thus their tissue is better supplied with oxygen and nutrients, preventing the formation of a necrotic tissue core. The shift from a spherical to a flat shape leads to a significant increase in size and surface-to-volume ratio of the brain organoids,” says one of the lead authors, Hakan Gürbüz from DTU Bioengineering.
Engineered Flat Brain Organoids also offer increased potential to create biologically relevant systems due to the complexity of the models that they enable. Ensuring the long-term viability of these models is a major aim of this branch of research, which has been difficult until now; flat organoids address the problem of longevity by avoiding the formation of necrotic tissue.
3D printing of scaffolds was key to overcoming the shape limitations of the previous spherical models. According to contributing author Jenny Emnéus from DTU Bioengineering, 3D printing enables: “reproducible fabrication of specific 3D scaffolds with high architectural complexity, precision and design versatility. By introducing a 3D-printed scaffold into the culture protocol, the size of the brain organoids and the tissue density and thickness can be tuned.”
Self-folding resembling the human brain
The new model showed consistent formation of neuroepithelial folding resembling gyrification, which is the process that forms the characteristic folds in the cerebral cortex. Contributing author Alberto Martínez Serrano says: “We were able to observe folding reminiscent of gyrification around day 20, which was self-generated by the tissue. To our knowledge, this is the first study that reports intrinsically caused gyrification of neuronal tissue in vitro.”
The appearance of gyrification reflects a further increase of the surface area and resembles the process of human brain development. Alberto Martínez Serrano, who has contributed to the study, adds “We consider the flat brain organoid as a next step towards the generation of a stable and reliable human brain model for drug screening applications and spatial patterning experiments.”
The study is part of a large EU project, MSCA-ITN project Training4CRM into neurodegenerative disorders, such as Parkinsons´disease.
Read the study Next generation human brain models: engineered flat brain organoids featuring gyrification in the journal Biofabrication