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. 2022 Nov 23;16(6):061301.
doi: 10.1063/5.0121476. eCollection 2022 Dec.

Brain organoid-on-a-chip: A next-generation human brain avatar for recapitulating human brain physiology and pathology

Jiyoung Song  1 , Seokyoung Bang  2 , Nakwon Choi, Hong Nam Kim
Affiliations

Brain organoid-on-a-chip: A next-generation human brain avatar for recapitulating human brain physiology and pathology

Jiyoung Song et al. Biomicrofluidics. .

Abstract

Neurodegenerative diseases and neurodevelopmental disorders have become increasingly prevalent; however, the development of new pharmaceuticals to treat these diseases has lagged. Animal models have been extensively utilized to identify underlying mechanisms and to validate drug efficacies, but they possess inherent limitations including genetic heterogeneity with humans. To overcome these limitations, human cell-based in vitro brain models including brain-on-a-chip and brain organoids have been developed. Each technique has distinct advantages and disadvantages in terms of the mimicry of structure and microenvironment, but each technique could not fully mimic the structure and functional aspects of the brain tissue. Recently, a brain organoid-on-a-chip (BOoC) platform has emerged, which merges brain-on-a-chip and brain organoids. BOoC can potentially reflect the detailed structure of the brain tissue, vascular structure, and circulation of fluid. Hence, we summarize recent advances in BOoC as a human brain avatar and discuss future perspectives. BOoC platform can pave the way for mechanistic studies and the development of pharmaceuticals to treat brain diseases in future.

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Figures

FIG. 1.
FIG. 1.
Comparison of human brain avatars and representative examples. (a) The feature of brain-on-a-chip. (a)-(i) A neural circuit-on-a-chip able to three-dimensional neuron patterning and neurite alignment was developed through the alignment of microfibrils in the hydrogel. Reproduced with permission from Kim et al., Nat. Commun. 8, 1 (2017). Copyright 2017 Springer Nature. (a)-(ii) The perfusable blood–brain barrier-on-a-chip recapitulated the low permeability of brain microvasculature to brain tissue. Reproduced with permission from Bang et al., Sci. Rep. 7, 1 (2017). Copyright 2017 Springer Nature. (b) The feature of brain organoid. (b)-(i) Brain assembloid created by attaching two brain organoids formed neural circuits through the extension of neurites. Reproduced with permission from Fligor et al., Stem Cell Rep. 16, 9 (2021). Copyright 2021 Cell press. (b)-(ii) In brain organoids co-cultured with endothelial cells, lumen structures were formed that are not perfusable. (c) The feature of brain organoid-on-ah-chip. (c)-(i) Brain organoids cultured in microchannels exhibited wrinkles, which are a structural characteristic of the brain. Reproduced from Karzbrun et al., Nat. Phys. 14, 5 (2018) Copyright 2018 Pub Med Central. (c)-(ii) Perfusable vascularized brain organoids were created by culturing brain organoids on a perfusable microvasculature-on-a-chip. Reproduced with permission from Shi et al., PLoS Biol. 18, 5 (2020) Copyright 2020 Public Library of Science.
FIG. 2.
FIG. 2.
High-throughput screening of human brain avatar and machine learning techniques for new drug discovery. (a) Large size of data are required to apply machine learning techniques for biological data analysis. The injection-molded microfluidic chip allows the high-throughput screening of brain-organoids-on-a-chip. (b)-(i) From supervised learning to unsupervised learning, a variety of machine learning algorithms can be applied. (b)-(ii) Representative data that can be achieved from the application of machine learning techniques are displayed for the time-efficient and cost-effective preclinical validation of drug efficacy. The figures were created using BioRender (https://biorender.com/).
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