Next generation human brain models: engineered flat brain organoids featuring gyrification

Abstract

Brain organoids are considered to be a highly promising in vitro model for the study of the human brain and, despite their various shortcomings, have already been used widely in neurobiological studies. Especially for drug screening applications, a highly reproducible protocol with simple tissue culture steps and consistent output, is required. Here we present an engineering approach that addresses several existing shortcomings of brain organoids. By culturing brain organoids with a polycaprolactone scaffold, we were able to modify their shape into a flat morphology. Engineered flat brain organoids (efBOs) possess advantageous diffusion conditions and thus their tissue is better supplied with oxygen and nutrients, preventing the formation of a necrotic tissue core. Moreover, the efBO protocol is highly simplified and allows to customize the organoid size directly from the start. By seeding cells onto 12 by 12 mm scaffolds, the brain organoid size can be significantly increased. In addition, 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. We consider our efBO protocol as a next step towards the generation of a stable and reliable human brain model for drug screening applications and spatial patterning experiments.

Developments and Opportunities for 3D Bioprinted Organoids

“…DAPI was used as counterstain. (Adapted with permission from Trevino AE, et al , Science, 367: eaay1645, Copyright 2020, The American Association for the Advancement of Science[ 72 ]) and (Adapted with permission from Theresa S P Rothenbücher et al , Biofabrication, 2021,13 011001, IOP Publishing Ltd[ 76 ]).…”

Bioelectric Potential in Next-Generation Organoids: Electrical Stimulation to Enhance 3D Structures of the Central Nervous System

“…Additionally, both brain region and whole-brain organoids lack broader structure, particularly the characteristic cortical folding, or gyrification, present in the human brain in vivo . Recently, a biomaterial scaffold was used to induce a flattened morphology in brain organoids ( Rothenbücher et al, 2021 ). The resulting organoids were size and shape controlled due to a larger surface area for oxygenation, and primitive cortical folding.…”

Alzheimer’s Disease: Current Perspectives and Advances in Physiological Modeling

“…Fortunately, researchers have already begun to tackle the vascularization issue. In their recent work, Rothenbucher and co-workers developed flat brain organoids (fBOs) by growing the organoids with cells seeded in polycaprolactone scaffolds and altering their shape systematically into flat structures [ 118 ]. These flat brain organoids demonstrated excellent diffusion conditions, allowing for better oxygen and nutrient supply and hindering the formation of necrotic tissue.…”