Trends in the global organoid technology and industry: from organogenesis in a dish to the commercialization of organoids

Animal models have been standard methods for non-clinical research in drug development for decades. However, many drugs that have shown satisfactory results in non-clinical studies have failed in the clinical stage, presumably because animal data are not fully convertible to human data. Human organoid technology has recently been considered as an alternative to existing non-clinical testing methods, and it could potentially serve a role as a bridge from non-clinical to clinical trials, compensating for the current limitations arising from non-clinical animal models. For this reason, organoid technology is being utilized in various fields of research including academic studies, disease modeling, drug screening, biobanks, and regenerative medicine. In addition, as organoid technology progressively develops, it has been combined with bioengineering to develop applications from manufacturing to drug evaluation platforms, which is leading to a demand for commercialization of organoids for researchers. In accordance with this global trend, the organoid industry continues to grow throughout the world, and organoid research and the market for organoids have been boosted by the demand for efficient and rapid drug development in response to the coronavirus disease 2019 pandemic. In this review, we discuss recent global trends in organoid research, based on tissue types and applications, as well as the organoid market and its prospects.

Engineered models for studying blood-brain-barrier-associated brain physiology and pathology

The blood-brain barrier (BBB) is a transport barrier that suppresses the translocation of potentially harmful substances to the brain tissue. Although the BBB is known to be associated with many kinds of neuropathology, such as neuroinflammation and neurodegenerative diseases, the conventionally used animal and Transwell models cannot provide sufficient information due to genetic and functional heterogeneity in comparison with humans and limited monitoring capabilities. Recently, human cell-based three-dimensional BBB models have been developed, and these models provide in vivo-like BBB structures and functions. In this review, we provide an overview of the recent advances in BBB models with a particular focus on the simulation of BBB-associated brain physiology and neuropathology. To this end, important factors for recapitulating the in vivo characteristics of the BBB are described. Furthermore, approaches to recapitulate the BBB physiology using engineering methods are summarized. The applications of BBB models in the study of neuropathology, such as inflammation and neurodegenerative diseases, are also presented.

Disease modeling and drug screening using human airway organoids: a systematic review

Increasing levels of fine environmental dust particles due to industrialization and emerging respiratory illnesses, such as coronavirus disease 2019, pose serious threats to human life. The use of organoids for disease modeling and drug screening has been proposed as a new treatment approach for respiratory diseases. As discussed in this review, various pathogen models, genetic disease models, and patient-derived lung cancer organoid models have been reported for disease modeling and drug testing using human airway organoids. Despite these promising recent advances, several issues must be addressed before the disease modeling potential of human airway organoids can be fully realized. If systematic methods to produce mature airway organoids can be developed, and reproducible organoid models can be implemented using standardized protocols, airway organoids will likely become valuable respiratory disease models and drug screening tools.

Optimizing a three-dimensional spheroid clearing method for the imaging-based evaluation of cardiotoxicity

Toxicity evaluation based on two-dimensional cell culture shows differences from clinical results and has the disadvantage of not accurately reflecting cell-to-cell cross-signaling. Since almost all cells in the human body are arranged in a three-dimensional structure and constitute a tissue, the in vitro reproduction of three-dimensional tissues composed of human cells can be used as effective models for drug development and toxicity evaluation. The clearing technique improves image resolution and can be used to generate three-dimensional bio-images throughout the organized structure, improving the efficiency of toxicity evaluation for disease models using spheroids. Herein, we report the first optical spheroid clearing protocol for an image-based toxicity prediction model. In our results, spheroid clearing significantly increased fluorescence intensity and enabled image-based toxicity prediction. We propose that this spheroid clearing method can be utilized for image-based cardiotoxicity evaluation. Furthermore, we also present the possibility that our protocol can be utilized for patient-tailored toxicity prediction.

Therapeutic applications of three-dimensional organoid models in lung cancer

Lung cancer, which remains a major cause of mortality worldwide, is a histologically diverse condition and demonstrates substantial phenotypic and genomic diversity among individual patients, manifesting as both intertumoral and intratumoral heterogeneity. This heterogeneity has made it difficult to develop lung cancer models. Two-dimensional (2D) cancer cell lines have been used to study genetic and molecular alterations in lung cancer. However, cancer cell lines have several disadvantages, including random genetic drift caused by long-term culture, a lack of annotated clinical data, and most importantly, the fact that only a subset of tumors shows 2D growth on plastic. Three-dimensional models of cancer have the potential to improve cancer research and drug development because they are more representative of cancer biology and its diverse pathophysiology. Herein, we present an integrated review of current information on preclinical lung cancer models and their limitations, including cancer cell line models, patient-derived xenografts, and lung cancer organoids, and discuss their possible therapeutic applications for drug discovery and screening to guide precision medicine in lung cancer research. Altogether, the success rate of generating lung cancer organoids must be improved, and a lung cancer organoid culture system is necessary to achieve the goal of designing an individualized therapeutic strategy for each lung cancer patient.

Human brain organoids in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurological disorder that typically involves neuronal damage leading to the deterioration of cognitive and essential body functions in aging brains. Major signatures of AD pathology include the deposition of amyloid plaques and neurofibrillary tangles, disruption of the blood-brain barrier, and induction of hyper-activated proinflammation in the brain, leading to synaptic impairment and neuronal loss. However, conventional pharmacotherapeutic modalities merely alleviate symptoms, but do not cure AD, partly because drug screening has used model systems with limited accuracy in terms of reflecting AD pathology in human brains. In this regard, several AD organoids have received substantial attention as alternatives to AD animal models. In this review, we summarize the key characteristics required for the generation of a pathologically relevant AD brain organoid. We also overview major experimental organoid models of AD brains, such as spheroids, three-dimensional (3D) bioprinted constructs, and 3D brain-on-chips, and discuss their strengths and weaknesses for AD research. This review will provide valuable information that will inspire future efforts to engineer authentic AD organoids for the study of AD pathology and for the discovery of novel AD therapeutic strategies.