![]() Three-dimensional (3D) cell culture in general and the ability to generate organ-like aggregates (‘organoids’) in particular have found a rapid following over the past few years ( Sato et al., 2009 Eiraku et al., 2011 Nakano et al., 2012 Lancaster et al., 2013 Quadrato et al., 2017 Paşca et al., 2015 Iefremova et al., 2017 Takasato et al., 2015 Dye et al., 2015 Takebe et al., 2013 McCracken et al., 2014 Pașca, 2018) due to their potential to mimic cellular niches more closely than 2D cell cultures. IntroductionĪ number of uniquely human diseases, including Parkinson’s disease, would greatly benefit from a comprehensive human cellular in vitro model that recapitulates key characteristics of midbrain tissues in a high-throughput-compatible format. This approach has the potential to reduce research waste by increasing the chances that a drug that works in the lab will also ultimately work in a patient and reduce animal experiments, as drugs that do not work in human tissues will not proceed to animal testing. This research, which shows that organoids can be grown and tested in a fully automated, reproducible and scalable way, creates a platform to quickly, cheaply and easily test thousands of drugs for Parkinson's and other difficult-to-treat diseases in a human setting. also generated forebrain organoids using an automated approach for both generation and analysis. Perhaps more importantly, other types of organoids can be created using the same technique to model diseases that affect other areas of the brain, or other organs altogether. They can be used to test new drugs for Parkinson's, and to better understand the biology of the brain. These mini-brains, which are the size of the head of a pin, mimic the part of the brain where Parkinson's disease first manifests. The robots perform a series of precisely controlled tasks – including dispensing the initial cells into wells, feeding organoids as they grow and testing them at different stages of development. have been able to overcome these issues by using robotic technology to create thousands of identical, mid-brain organoids from human cells in the lab. It is also tough to grow a large number of organoids that all behave in the same way, making it hard to know whether a particular drug works or whether it is just being tested on a 'good' organoid. For another, the cells that do grow often fail to connect and communicate with each other in biologically realistic ways. For one thing, it is hard to recreate the multitude of cell types that make up an organ. Growing three-dimensional miniature organs or 'organoids' that behave in a similar way to real organs is the next step towards creating better platforms for drug screening, but there are several difficulties inherent to this process. These cell layers are often used to test new drugs, but they cannot recapitulate the complexity of a real organ made from multiple cell types within a living, breathing human body. Cells are still grown in much the same way in modern laboratories: a single layer of cells is placed in a warm incubator with nutrient-rich broth. In 1907, the American zoologist Ross Granville Harrison developed the first technique to artificially grow animal cells outside the body in a liquid medium. ![]() This allows assessing drug effects at the single-cell level within a complex 3D cell environment in a fully automated HTS workflow. By automating the entire workflow from generation to analysis, we enhance the intra- and inter-batch reproducibility as demonstrated via RNA sequencing and quantitative whole mount high-content imaging. ![]() They present significant features of the human midbrain and display spontaneous aggregate-wide synchronized neural activity. The resulting organoids possess a highly homogeneous morphology, size, global gene expression, cellular composition, and structure. Here, we present a scalable, HTS-compatible workflow for the automated generation, maintenance, and optical analysis of human midbrain organoids in standard 96-well-plates. However, current protocols yield either complex but highly heterogeneous aggregates (‘organoids’) or 3D structures with less physiological relevance (‘spheroids’). Three-dimensional (3D) culture systems have fueled hopes to bring about the next generation of more physiologically relevant high-throughput screens (HTS).
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