Abstract
Human brain is undoubtedly the most complex organ in the body. Thus, it is difficult to develop adequate and at the same time human relevant test systems and models to cover the aspects of brain homeostasis and even more challenging to address brain development. Animal tests for Developmental Neurotoxicity (DNT) have been devised, but because of complex underlying mechanisms of neural development, and interspecies differences, there are many limitations of animal-based approaches. The high costs, high number of animals used per test and technical difficulties of these tests are prohibitive for routine DNT chemical screening. Therefore, many potential DNT chemicals remain unidentified. New approach methodologies (NAMs) are needed to change this. Experts in the field have recommended the use of a battery of human in vitro tests to be used for the initial prioritization of high-risk environmental chemicals for DNT testing. Microphysiological systems (MPS) of the brain mimic the in vivo counterpart in terms of cellular composition, recapitulation of regional architecture and functionality. These systems amendable to use in a DNT test battery with promising features such as (i) complexity, (ii) closer recapitulation of in vivo response and (iii) possibility to multiplex many assays in one test system, which can increase throughput and predictivity for human health. The resent progress in 3D brain MPS research, advantages, limitations and future perspectives are discussed in this review.
Highlights
Overview of Brain Microphysiological SystemsMicrophysiological systems (MPS) have emerged over the last years and are representing new, more physiologically relevant cell cultures recapitulating organ architecture and functionality (Marx et al, 2020)
The MPS can have different levels of complexity going from simpler spheroids to organoids, microfluidics and organs-on-chip (Figure 1)
What if animal MPS perfectly correlates with human MPS response but not with the animal in vivo response or both MPS and in vivo animal models do not correlate with human MPS? This might be the challenge to address as more data is being generated. Another challenge with iPSC-derived 3D brain models is how the in vitro differentiation process is comparable with human primary cells
Summary
Microphysiological systems (MPS) have emerged over the last years and are representing new, more physiologically relevant cell cultures recapitulating organ architecture and functionality (Marx et al, 2020). Experts in the field have recommended the use of a battery of in vitro tests covering the cellular key events of neural development to be used for the initial prioritization of high-risk environmental chemicals for DNT testing (Bal-Price et al, 2018a; Bal-Price et al, 2018b) These tests, are mostly based on traditional monolayer cell cultures, have been developed in different laboratories and measure different endpoints of DNT. The important interactions between different cell types and key events during development are often missing For this reason, fewer more complex unified MPS covering most key neurodevelopmental events would streamline this process of DNT testing.
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