The current leaders in the commercialization of organoids, their geographical location, and application areas.
Organoids are 3D miniature tissue mimics and have been effectively used for various purposes, including disease modeling, various drug screening, mechanism of pathogenesis, stem cell research, and tumor immunology. Organoids are as varied as the body\'s tissues and organs and have enormous economic potential. They can open new ways to tailored therapy and precision medicine. In clinical investigations, patient-derived organoids have been used to predict patient responses to therapeutic regimens and perhaps improve cancer treatment outcomes. Recent developments in stem cell research and genomic technologies have led to breakthrough innovations in organoid bioengineering, large-scale manufacturing, biobanking, and commercialization. This chapter reviews the notion of organoid biobanking, companies involved and the commercialization aspect, and ethical considerations.
- cell atlas
Organoids are miniature 3D models of
Backed by some significant observations in the proliferative nature of adult tissue stem cells in 2009, the cardinal notion enveloping organoid technology is that stem cells have ingrained potential to self-assemble into 3D constructs with similitude with human organs . As time rolled on, the modus operandi has been implemented to produce several human and murine organoids out of epithelial tissues of various organs such as the liver, intestine, kidney, skin [6, 7, 8, 9]. Another breakthrough entails the evolution of organoids obtained from induced pluripotent stem cells (iPSC), which can circumvent the toil to avail specific tissues like the heart or brain. This prodigious prospect, reinforced with genetic engineering, permits the mutational corrections in patient-derived iPSCs expediting differentiation to generate a specific type of cells [10, 11, 12, 13]. Scrupulous experimental manipulation while maintaining sensitive biological complexity allows organoid technology to bridge the gap between 2D cell culture and 3D models . It has also proved to better simulate human physiology than animal models and has shown the promise to substitute animals in preclinical biology [15, 16].
As ratiocinated from the trends, there will be a steady increase in the demand for organoid technology in the following years [3, 16]. As per reports published in various media, around 20 companies are into business with this technology—their activities include biobanking, manufacturing, commercialization, the implication of robotics for the development of organoids, organoids on a chip, etc. Statistically, priorities are given to heart, brain, intestine, and kidney organoids . Financial models adopted by these companies are—(i) venture capitals, (ii) partnerships (iii) direct collaboration with the originators. Routine use of animals for disease modeling has always been afflicted with stringent moral and ethical queries. Usage of embryonic stem cells has also faced stormy skirmishes regarding the moral status of the embryos. Likewise, the moral and legal status of the organoids has been called in regulatory questions, to mention a few—ownership, consent, IP rights, safety, commercialization, etc. Utilization of ‘matrigel’ (extracellular matrix obtained from animals) has raised some safety concerns regarding compatibility with the human system. The debate revolving around the exchange or donation of human tissue as a commodity is still ongoing. To resolve this, few regulations should be declared and accepted by the global intellect . Quibbles for intellectual property (IP) generation with human tissue should cease to persist, showing proper dignity and preserving the donor's rights. Consent should become a requirement avoiding de-identification of the donor [18, 19, 20, 21]. In the present chapter, we shall highlight the usage of the organoid, organoid cell atlas, followed by shedding light on the commercialization aspect of the technology and future directionality.
2. Applications of organoids
Researchers traditionally used
With the advent of tumor organoid culture, patient-derived tumor organoids (PDTOs) have become popular tools to study molecular tumorigenesis, understand tumor heterogenity, predict drug responses, immunotherapy, and precision cancer therapy. At the moment, several tumor organoid biobanks have been developed catering to a variety of cancer types, including lung , breast , gut , and brain , liver , colorectal , pancreas , prostate , and ovary . The role of tumor immune microenvironments (TIME) is significant in improving cancer immunotherapies, and PDTOs have started playing a crucial role in modeling the tumor-immune landscape. PDTO-based TIME studies can help evaluate immunotherapies such as checkpoint inhibition and adoptive T-cell treatment . Thus, optimizing the tumor organoid culture method is critical for developing organoid-guided customized cancer immunotherapy .
Human organoids are suited for genetic modification and customization and bridge the gap between fundamental research and clinical practice. This technique has aided oncology, biological, pharmacological, regenerative, and personalized medicine studies . Despite the initial advances, the technology is still nascent and is expected to be employed in various applications such as developmental and stem cell biology, toxicology, drug discovery, personalized medicine, disease modeling, immune interaction, and regenerative modeling (Figure 2). Healthy human organoids from different tissues may be utilized to test comparative therapeutic toxicities in combination with disease-related organoids. Cardiac organoids, liver organoids, kidney organoids, and other organoids are now used to dictate intolerable adverse effects, such as hepatotoxicity, cardiotoxicity, nephrotoxicity, and other tissue toxicity . Patient-specific relevant organotypic models will go a long way in reframing basic findings, testing innovative ideas in 3D, and validating crucial data without sacrificing animal life for science. This aspect is dealt with in other publications [42, 43].
3. Application of tumor organoids
The lack of a physiologically relevant model system has delayed the therapeutic development process, and many candidates have failed in clinical trials . Cancer organoids are near-physiological replicas of their parent tumors and bridge the gap between drug screening and clinical trials. Organoids have been utilized to examine personalized cancer patient responses in several research [32, 44, 45]. It may also be utilized to look at the epigenetic and genetic changes that cause drug resistance . Tumor organoids can accurately predict chemotherapeutic response and resistance for certain drugs in some cancers [47, 48]. Finding the right therapeutic combination can be a challenge, and tumor organoids can help solve this dilemma and can make personalized medicine a reality . The advances in genetic engineering technologies like CRISPR-Cas9 are implemented on organoids further to confirm medication sensitivity to specific mutations . Organoids may also be used for pharmacokinetic research, critical in drug development. Results suggest that drug-transporters, their efflux transport functions, drug-metabolism can be efficiently studied using organoids . In addition to cancer biobanks, organoids have a significant role to play in immunotherapy, a kind of cancer treatment in which the patient's immune system is used to eliminate tumor cells . Organoid-based models are explored to study the effect of tumor-immune cell interaction using a coculture system with both components .
4. Organoid cell atlas
Organoids holds promise as a propitious platform in biomedical research and applications for many decades to come. Human organoids currently have a few limitations that require to be circumvented to appreciate their full potential. Some technical and conceptual limitations may be addressed using single-cell sequencing and spatial profiling. Single-cell transcriptome/ epigenome sequencing and spatial profiling can provide a thorough idea about the composition of cells and the state of cells present within the organoids, which may help develop organoids as futuristic models of human biology. In combination with the Human organoids and single-cell technology, a pilot project has been launched within the Human Cell Atlas (HCA) as a “Biological network” (https://www.humancellatlas.org/euh2020/) . HCA is a revolutionary global collaborative initiative aiming at advancing biomedical research opportunities and therapy using single-cell technologies (https://hca-organoid.eu/). This pilot project, under HCA, focuses on the single-cell characterization of organoids and other complex
It is one of the six pilot projects funded by the European Union (EU) Horizon 2020 Framework Programme, which will be helpful in developing the first version of the Organoid Cell Atlas, which may be used as a nucleus for a broader, collaborative, global initiative. The HCA-Organoid association has eight partner Institutions, including EMBL’s European Bioinformatics Institute institutions having experts in organoid technology, single-cell profiling, advanced imaging, and bioinformatics from Austria, Germany, the Netherlands, and Switzerland, and received €5 million by EU funding, as a part of the European contribution to the HCA project. Currently, the project mainly focuses on generating single-cell transcriptome, epigenome maps, and detailed imaging data in a selection of human organoids. The initial objective of the funded project is to derive and characterize two organoids, colon and brain, from 100 whole-genome-sequence individuals each, to have a record of normal population variation and have a reference for disease-centric research .
The colon and brain organoids were one of the first organs to which organoids were demonstrated, so comparatively, more advanced protocols for the two are available with HCA [2, 23]. Apart from this, the colon organoids are derived from adult stem cells while the brain is from the iPSCs, thus spanning the two primary sources of organoid derivation. Both of them have primarily been used for disease-centric studies. If the single-cell characterization of these organoids is done for many individuals, this can help facilitate various biomedical applications. Beyond the initial target, most of the data information in the project is generalized in a way to be applicable to various other types of human organoids. The HCA has also spoken about the possibility that they can collaborate with other institutes for different projects, which can pursue systematic single-cell profiling in other types of human organoids, to explore the possibility of interrelation with the Organoid Cell Atlas .
The main aim of the EU H2020 HCA-Organoid project is to build an Organoid cell atlas portal that may be equipped with the computational infrastructure and a web-based front end that makes the data easily accessible and analyzed. Some of the organoid-specific features that have been focused on while developing an Organoid portal include the interactive exploration of human organoid data, data-driven selection of organoids for functional experiments, and comparison of disease-specific organoids against reference collections of normal organoids.
This portal also focuses on providing the data of the corresponding primary tissues available in the HCA and also will work on showing interactive mappings between single-cell profiles of human organoids. These may be achieved using the algorithms that enable cell-cell alignments between these datasets. This portal is supposed to facilitate the use of organoids in biomedical experiments and encourage the use of organoids as models in various experiments like precision medicine, drug development, disease modeling, etc. Mapping and data integration may detect normal variation between individuals in an interactive manner showcasing organoid as the capable model for the corresponding variation in primary tissues. The analysis and interpretations of disturbances in the human organoids related to the primary tissues will be performed using cell-cell alignments .
A set of strategies have been laid to develop the atlas to be most productive and of high quality. Initially, it was thought to invest in validation and standardization for organoid-related research. Later, a contribution towards the HCA to establish community standards and software infrastructure for data processing and data annotation was strategized. Then the development and validation of computational methods for the comparison of cells between organoids and corresponding primary tissues and their flexible alignments were implemented. Finally, the implementation of interactive visualization tools that helps in establishing user-friendly quality control and exploratory analysis of single-cell organoid datasets contributed to the Organoid Cell Atlas .
5. Commercialization of organoids
With the development and successful commercialization of organoids, the most demanded sector in treating patients and pre-clinical trials in pharmaceutical industries will give a slanting graph in the market in the future . In this present era, many specific and most suitable techniques have been developing over the years for organoid research, leading to competition among industries worldwide. The annual cost of treating brain diseases in Europe is $798 billion, and globally it amounts to $3 trillion. Over 90% of novel drugs that are being developed for brain diseases fail during the developmental process, which further reinforces the scope and opportunities for organoids . The development of the living human brain (LHB) enables culturing of human-derived brain organoids from the cells of any individual; the University of Helsinki provides a new technical idea for preclinical trials of drugs in this area. Helsinki Innovation Services Ltd (HIS) supports the commercialization projects of the University of Helsinki from the funding application stage to completion.
Many startups such as XILIS, CELLESCE, SYSTEM1 BIOSCIENCES, 3DYNAMICS, PATH BIOANALYTICS, KNOWN MEDICINE, CYPRE, DYNOMICS are currently working in the domain of organoid technology. XILIS is developing a patient-derived miniature organoid technology to upgrade precision medicine and pharmaceutical drug discovery; their needed materials lead to 30× speed, 50× throughput, and 300× cost-saving (Hans Clever includes in the founding team of XILIS). CELLESCE is a UK-based startup that invented a bio-processing technology intended to grow and expand organoids in drug discovery and regenerative medicine. $25 million of Series A venture funding is raised in SYSTEM1 BIOSCIENCES incorporation with Charles River Ventures and Pfizer Ventures, upgrading neuro drug discovery through the combined action of human brain models, scaled biology, and machine learning to interpret brain disease from genetics to neural computation. Also, KNOWN MEDICINE raised a total of $2.4 M from Khosla, Cota Capital, and Y-Combinator, offering cutting-edge biology research and the latest AI techniques, giving oncologists an easy spot for treating patient's tumors with the best suitable drug. PATH BIOANALYTICS does bioanalysis of Phenotypic drug discovery and development. CYPRE is developing a tumor model platform intended for transformative 3D cellular research and clinical testing of cancer patients with seed funding from Hemi Ventures and others. DYNOMICS received $500K in pre-seed funding from Boost VC. The details of the organoid-specific startups are presented in Table 1. These different startups contribute a vast platform to save millions of people’s life . Several companies are also operational in the tumor organoid domain, like Charles River and CROWNBio.
|Company name||Country||Application area|
|XILIS INC.||Durham, North Carolina, USA||Micro-organospheres|
|CELLESCE||Wales, UK||Patient-derived organoids (PDO)|
|SYSTEM 1 BIOSCIENCES||San Francisco, CA, USA||Brain organoids|
|3DNAMICS||Baltimore, Maryland, USA||Brain and liver organoids|
|PATH BIOANALYTICS||North Carolina, USA||PDO for precision medicine|
|KNOWN MEDICINE||Salt Lake City, Utah, USA||Patient-specific organoids for cancer drug development|
|CYPRE||San Francisco, CA, USA||3D tumor model|
|DYNOMICS INC.||San Francisco, CA, USA||Human cardiac organoid|
|CHARLES RIVER||Wilmington, MA, USA||Tumor organoid|
|CROWNBio||San Diego, CA, USA||Tumor organoid|
Despite using pre-clinical trials in animal models, concerns are raised about whether the animals will be extinct if used over the years. This will lead to the depletion of species and a significant effect on the ecosystem. Moreover, they may lead to harmful effects on the environment once mutated and released. The Animal Welfare Act of 1970 was implemented in the United States and set standards for animal use and care in research. Three principles of the Act are (1) experiments must be proven necessary for instruction or to save or prolong human life, (2) animals must be appropriately anesthetized, (3) animals must be killed as soon as the experiment is over. Much to our intrigue, different types of organoids such as kidney organoids, lung organoids, liver organoids, intestine organoids, brain organoids, etc., can substitute such animal models in preclinical trials for drug discovery and precision medicine. Even self-organ plantation may occur with the continuous development of organoids.
Globally, the expenses of organ transplantation and post-transplantation maintenance treatment are quite expensive but varies according to variables such as geographical location, medical facility, transplant organ type, and access to insurance coverage . Private hospitals in India now charge around INR 10 lakh to INR 30 lakh for a heart transplant, while in USA, the charges can be very high ~$1,664,800.00 (https://www.statista.com/statistics/808471/organ-transplantation-costs-us/). While the cost of a kidney transplant goes from INR 5 lakh to INR 20 lakh, while in USA it can be around ~$442,500.00. The cost of a liver transplant runs from INR 15 lakh to INR 35 lakh, and ~$878,400.00 in the USA. The eventuality of the unaffordability of such expensive treatment modalities led to the demise of a multitude. Furthermore, organ transplants from other donors are sometimes associated with organ rejection and the onset of auto-immune disease. It is not only the high cost of transplant but also the availability and transport of organs is a major issue in many countries. Though the number of donors have increased but the needs have also reached new heights . One-third of all organ transplants fail due to rejection due to multiple reasons including HLA mismatch and alloantibodies . While modern medicine has halted acute rejection but chronic rejection is a major challenge. The organoid technology may provide a realistic patform to design transplantable tissues in a dish thereby catering to the transplant problem in the near future as current limitation prevent organoids from meeting these expectations.
Another recent scientific area where organoids showed great potential was during the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. SARS-CoV-2 causes respiratory illness and multi-organ dysfunction. Scientists were scrambling to test experimental COVID-19 systemic medicines. Organoids were used to study the adverse effects of SARS-CoV-2 infection on human tissues and for the investigation of prospective therapeutic approaches. With the recent work on mini lungs organoids, a few of the drugs stemmed from the infection of the organoid models, representing a handful of possible treatments for COVID-19 . Scientists must still develop methods to produce more complicated systems, such immune cells and blood arteries, to fully harness the technology . Scientists must also find a way to swiftly and inexpensively produce thousands of identical organoids. Bioprinting is a potential new fast prototyping method that prints cells and accompanying matrices in 3D. Organoid bioprinting uses hydrogel-based bioinks to deposit various cell types that stimulate physiological signaling and can help commercialize the platform faster .
According to a study published by Fior Markets, the global organoids, and spheroids market is predicted to increase from USD 502.92 million in 2019 to USD 2794.79 million in 2027, with a CAGR of 23.91% from 2020 to 2027 [57, 62]. Till now, 19 companies are having an interest in organoid commercialization. Some of them are Thermo Fisher Scientific (Waltham, MA, USA), Merck (Kenilworth, NJ, USA), Corning (Corning, NY, USA), STEMCELL Technologies (Vancouver, Canada), Lonza (Basel, Switzerland), Prellis Biologics (San Francisco, CA, USA), Amsbio (Abingdon, UK), Cellesce (Cardiff, UK), DefiniGEN (Cambridge, UK), OcellO B.V. (Leiden, Netherlands), HUB Organoid Technology (Utrecht, Netherlands), 3Dnamics Inc. (Baltimore, MD, USA), Organoid Therapeutics (Pittsburgh, PA, USA), InSphero (Schlieren, Switzerland), etc. Organome (Baltimore, USA) and HUB (Hubrecht Organoid Technology) are dedicated to organoid biobanking, and other companies aim at manufacturing, organoid marketing, other related technologies. SUN Biosciences (Lausanne, Switzerland) and System1 Biosciences (San Francisco, CA, USA) use robotic automation tools for organoid generation. The semi-automated process enabled researchers to make retinal organoid production and selection faster using the algorithm. The MIMETAS (Leiden, Netherlands)—the organ-on-a-chip company, offers the second-best cell-based model after humans, using human cells growing in three-dimensional structures called Mimetas’OrganoPlates (microfluidics-based culture plates allowing culturing and screening of a range of organ and tissue models), which are affordable and available for nonspecialized end-users. With a consumption market share of about 46% in 2019, North America is the most important consumer of organoids, with Europe in second place. Key manufacturers of the global organoids market are Thermo Fischer Scientific, Merck, and Corning. The top three players took up a market share of about 75% in 2019. Byers of the report can access verified and reliable market forecasts, including those for the overall size of the global organoids’ market in terms of revenue. The Organoids’ market is segmented into 3D Organoid Culture and Biochemical Cues. In the case of Organoids application, the leading players are Biopharmaceutical Companies, Contract Research Organizations, Academics, and Research Institutes. The regional analysis covers North America (USA, Canada, and Mexico), Europe (Germany, France, UK, Russia, and Italy), Asia-Pacific (China, Japan, Korea, India, and Southeast Asia), South America (Brazil, Argentina, Columbia, etc.), Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria, and South Africa) and predicts an upsurge in the usage of organoid technology across the globe in future.
Organoid Biobank is like a commercial bank with a similar modus operandi. In organoid biobank, collected samples from different sources such as stem cells, primary tissues, and biopsies were made into organoids and stored. The organoid samples can be taken from a healthy individual and a patient. These stored organoids are ready to use for different purposes. Organoid biobanks manage the database of organoids and a registry with all the patient details. These stored organoids can be tracked and used for wireless phenotyping with the help of radio-frequency identification (RFID) ultracompact chips inserted within them. The organoid biobanks store and transport organoids using liquid nitrogen.
6. Regulatory guidelines in organoid research
The regulatory rules for organoid research use and commercialization are not very well laid in many countries and needs an update. The scientific, ethical, and regulatory problems related to organoid research are subject to extensive regulatory scrutiny and controlled partly by federal laws and state laws in the US and pertain to International laws in case of foreign collaborations. United States Department of Health and Human Services (HHS) and the Food and Drug Administration (FDA) regulations are implemented in organoid research [63, 64, 65]. Organoid research is subject to the Institutional Review Board (IRB) approvals. Many institutions have Embryonic Stem Cell Research Oversight (ESCRO) or Stem Cell Research Oversight (SCRO) committees that oversee research utilizing human ESCs or iPSCs. These committees are outlined in the National Academies Guidelines for Human Embryonic Stem Cell Research and help evaluate the scientific and ethical aspects. The special committees assess the current state of research, weigh the advantages and hazards, address related ethical problems, including informed consent from the donor, and evaluate suitable supervision methods as per the federal guidelines .
While in Europe, organoids research must be approved by the Research Ethics Committee (REC) as per the guidelines laid down by the European Medicines Agency (EMA). Different European countries also have their individual regulatory agencies. In India, the regulatory board is the Institutional Committee for Stem Cell Research (IC-SCR). At the same time, in China, the measures for Ethical Review of Biomedical Research Involving Human Subjects and Ethical Guidelines for Human Embryonic Stem Cell Research, are used as guidelines . The manufacturing process of organoids for commercial purpose must fulfill the same standards as other pharmaceutical drugs, following good manufacturing practices (GMP) [64, 65]. Additional hurdles exist at the convergence of organoid technology and commercial clinical use, global rules relating to the heterogeneity of approved quality standards, privacy laws and data protection, patent laws and identifying ownership. As a positive step in this direction, the International Society for Stem Cell Research (ISSCR) has set new stem cell research guidelines in 2021 [67, 68, 69]. It is expected that organoid-based biotechnology innovations would need updated global regulatory guidelines and governance in the future.
7. Ethics of organoid commercialization
Organoid technology and biobanking have grown in recent years, paralleling the expansion of stem cell and organoid research. However, ethical, moral, and legal existential questions persist. One crucial aspect is establishing globally recognized consent procedures for research and clinical organoid biobanking protocol. Also, the ethical and moral implications for clinicians while using organ mimics should be called into question. Patenting concerns are bound to arise when organoids are distributed over the world. Collaborations between the public and commercial sectors may lead to data exchange, entitlement sharing, etc. Confidentiality decorum and global patenting rules for organoid rights are therefore evolving. Even the iPSC-based organoids bring new concerns around permission, commercialization, ownership, IP rights, safety, and marketing . The proliferation of big data, genomics, biobanking, and the globalization of the biotechnology sector has complicated the task of setting universal ethical standards. The primary ethical consideration about organoids is who owns them and whether small organ mimics (similar to organs) can be traded? With the advances in organoid technology, where do we draw lines to differentiate between organoids and tissues/organs? Sample de-identification, donor consenting, and licensing rights need to be better defined, especially concerning organoid commercialization. Addressing these bottlenecks may allow quicker commercial application for drug discovery, disease modeling, and research and development.
In the upcoming years, the designed pilot project focuses on substituting animal or human models with the organoid model by encouraging better research and accessibility of organoids. The HCA has been encouraging this shift of models by establishing a reference map of the entire human cells; which will be the first molecular picture of a human that will help the researchers to functionally dissect and systematically analyze human biological systems that would lead to a better exploration of organoids as a model. The initial version of the organoid cell atlas is planned to be established by the upcoming year that will be practically useful and open to advancements. These are thought to help maximize the impact of the project to become helpful in the field of basic biology and biomedical applications. To broader the reach, the single-cell profiles will be made public as soon as possible following HCA's ethical, social, and legal guidelines. Finally, the Organoid Cell Atlas Portal will be made “into a public, sustainable and widely used infrastructure for finding, accessing, analyzing and interpreting single-cell data from human organoids.” The goal of the Organoid Cell Atlas is to make advancements in the biomedical field and develop various regenerative therapies by encouraging and accelerating disease-centric research of rare genetic diseases, precision oncology, or other complex diseases that are yet less understood. So, to achieve all of their objectives, they have made the portal open to create an inclusive research environment that would help in collaborating with a broad range of researchers interested in the field, which would later lead to extremely well-defined growth in the field of organoids.
M.K.P. acknowledges S. Dubinett, B. Gomperts, and V. Hartenstein for providing constant support and mentoring.
Conflict of interest
The authors declare no conflict of interest.
Mahapatra C, Lee R, Paul MK. Emerging role and promise of nanomaterials in organoid research. Drug Discovery Today. 2022; 27(3):890-899
Chhibber T, Bagchi S, Lahooti B, Verma A, Al-Ahmad A, Paul MK, et al. CNS organoids: An innovative tool for neurological disease modeling and drug neurotoxicity screening. Drug Discovery Today. 2020; 25(2):456-465
Takebe T, Wells JM, Helmrath MA, Zorn AM. Organoid center strategies for accelerating clinical translation. Cell Stem Cell. 2018; 22(6):806-809
Liu J, Huang X, Huang L, Huang J, Liang D, Liao L, et al. Organoid: Next-generation modeling of cancer research and drug development. Frontiers in Oncology. 2022; 11
Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-265
Lee J, Bӧscke R, Tang P-C, Hartman BH, Heller S, Koehler KR. Hair follicle development in mouse pluripotent stem cell-derived skin organoids. Cell Reports. 2018; 22(1):242-254
Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013; 494(7436):247-250
Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2015; 526(7574):564-568
Sato T, Stange DE, Ferrante M, Vries RGJ, van Es JH, van den Brink S, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology. 2011; 141(5):1762-1772
Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Tolle K, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2010; 470(7332):105-109
Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013; 501(7467):373-379
Sanjurjo-Soriano C, Erkilic N, Baux D, Mamaeva D, Hamel CP, Meunier I, et al. Genome editing in patient iPSCs corrects the most prevalent USH2A mutations and reveals intriguing mutant mRNA expression profiles. Molecular Therapy - Methods & Clinical Development. 2020; 17:156-173
Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, et al. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells. Nature Communications. 2020; 11(1)
Li M, Izpisua Belmonte JC. Organoids—preclinical models of human disease. New England Journal of Medicine. 2019; 380(6):569-579
Lancaster MA, Knoblich JA. Organogenesis in a dish: Modeling development and disease using organoid technologies. Science. 2014; 345(6194)
Kaushik G, Ponnusamy MP, Batra SK. Concise review: Current status of three-dimensional organoids as preclinical models. Stem Cells. 2018; 36(9):1329-1340
Bredenoord AL, Clevers H, Knoblich JA. Human tissues in a dish: The research and ethical implications of organoid technology. Science. 2017; 355(6322)
Boers SN, Delden JJM, Clevers H, Bredenoord AL. Organoid biobanking: Identifying the ethics. EMBO Reports. 2016; 17(7):938-941
Perrone F, Zilbauer M. Biobanking of human gut organoids for translational research. Experimental & Molecular Medicine. 2021; 53(10):1451-1458
Mollaki V. Ethical challenges in organoid use. BioTech. 2021; 10:3
Mansour AA, Gonçalves JT, Bloyd CW, Li H, Fernandes S, Quang D, et al. An in vivo model of functional and vascularized human brain organoids. Nature Biotechnology. 2018; 36(5):432-441
Mohan SC, Lee T-Y, Giuliano AE, Cui X. Current status of breast organoid models. Frontiers in Bioengineering and Biotechnology. 2021; 9:745943
Sprangers J, Zaalberg IC, Maurice MM. Organoid-based modeling of intestinal development, regeneration, and repair. Cell Death & Differentiation. 2020; 28(1):95-107
Romero-Guevara R, Ioannides A, Xinaris C. Kidney organoids as disease models: Strengths, weaknesses and perspectives. Frontiers in Physiology. 2020; 11
Harrison SP, Baumgarten SF, Verma R, Lunov O, Dejneka A, Sullivan GJ. Liver organoids: Recent developments, limitations and potential. Frontiers in Medicine. 2021; 8
Sanyal R, Paul MK. Organoid Technology and the COVID Pandemic. SARS-CoV-2 Origin and COVID-19 Pandemic Across the Globe. IntechOpen; 24 June 2021. [Published]. DOI: 10.5772/intechopen.98542
Paul Manash K, Bisht B, Darmawan Daphne O, Chiou R, Ha Vi L, Wallace William D, et al. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent notch signaling. Cell Stem Cell. 2014; 15(2):199-214
Wilkinson DC, Alva-Ornelas JA, Sucre JMS, Vijayaraj P, Durra A, Richardson W, et al. Development of a three-dimensional bioengineering technology to generate lung tissue for personalized disease modeling. Stem Cells Translational Medicine. 2017; 6(2):622-633
Cox B, Laporte E, Vennekens A, Kobayashi H, Nys C, Van Zundert I, et al. Organoids from pituitary as a novel research model toward pituitary stem cell exploration. Journal of Endocrinology. 2019; 240(2):287-308
Elbadawy M, Abugomaa A, Yamawaki H, Usui T, Sasaki K. Development of prostate cancer organoid culture models in basic medicine and translational research. Cancers. 2020; 12(4)
Li YF, Gao Y, Liang BW, Cao XQ , Sun ZJ, Yu JH, et al. Patient-derived organoids of non-small cells lung cancer and their application for drug screening. Neoplasma. 2020; 67(02):430-437
Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell. 2018; 172(1-2):373-386.e1
Yan HHN, Siu HC, Law S, Ho SL, Yue SSK, Tsui WY, et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell. 2018; 23(6):882-897.e11
Jacob F, Salinas RD, Zhang DY, Nguyen PTT, Schnoll JG, Wong SZH, et al. A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell. 2020; 180(1):188-204.e22
Broutier L, Mastrogiovanni G, Verstegen MMA, Francies HE, Gavarró LM, Bradshaw CR, et al. Human primary liver cancer–derived organoid cultures for disease modeling and drug screening. Nature Medicine. 2017; 23(12):1424-1435
van de Wetering M, Francies Hayley E, Francis Joshua M, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015; 161(4):933-945
Driehuis E, van Hoeck A, Moore K, Kolders S, Francies HE, Gulersonmez MC, et al. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proceedings of the National Academy of Sciences. 2019; 116(52):26580-26590
Beshiri ML, Tice CM, Tran C, Nguyen HM, Sowalsky AG, Agarwal S, et al. A PDX/organoid biobank of advanced prostate cancers captures genomic and phenotypic heterogeneity for disease modeling and therapeutic screening. Clinical Cancer Research. 2018; 24(17):4332-4345
Kopper O, de Witte CJ, Lõhmussaar K, Valle-Inclan JE, Hami N, Kester L, et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nature Medicine. 2019; 25(5):838-849
Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, et al. Organoid modeling of the tumor immune microenvironment. Cell. 2018; 175(7):1972-1988.e16
Matsui T, Shinozawa T. Human organoids for predictive toxicology research and drug development. Frontiers in Genetics. 2021; 12
Kim J, Koo B-K, Knoblich JA. Human organoids: Model systems for human biology and medicine. Nature Reviews Molecular Cell Biology. 2020; 21(10):571-584
Ashok A, Choudhury D, Fang Y, Hunziker W. Towards manufacturing of human organoids. Biotechnology Advances. 2020; 39
Seidlitz T, Merker SR, Rothe A, Zakrzewski F, von Neubeck C, Grützmann K, et al. Human gastric cancer modelling using organoids. Gut. 2019; 68(2):207-217
Zhou Z, Cong L, Cong X. Patient-derived organoids in precision medicine: Drug screening, organoid-on-a-chip and living organoid biobank. Frontiers in Oncology. 2021; 11
Lee SH, Hu W, Matulay JT, Silva MV, Owczarek TB, Kim K, et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell. 2018; 173(2):515-528.e17
Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernández-Mateos J, Khan K, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018; 359(6378):920-926
Weber C. Organoids test drug response. Nature Cell Biology. 2018; 20(6):634
Verissimo CS, Overmeer RM, Ponsioen B, Drost J, Mertens S, Verlaan-Klink I, et al. Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening. eLife. 2016; 5
Takeda H, Kataoka S, Nakayama M, Ali MAE, Oshima H, Yamamoto D, et al. CRISPR-Cas9–mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes. Proceedings of the National Academy of Sciences. 2019; 116(31):15635-15644
Onozato D, Yamashita M, Nakanishi A, Akagawa T, Kida Y, Ogawa I, et al. Generation of intestinal organoids suitable for pharmacokinetic studies from human induced pluripotent stem cells. Drug Metabolism and Disposition. 2018; 46(11):1572-1580
Qu J, Kalyani FS, Liu L, Cheng T, Chen L. Tumor organoids: Synergistic applications, current challenges, and future prospects in cancer therapy. Cancer Communications. 2021; 41(12):1331-1353
Fiorini E, Veghini L, Corbo V. Modeling cell communication in cancer with organoids: Making the complex simple. Frontiers in Cell and Developmental Biology. 2020; 8
Haniffa M, Taylor D, Linnarsson S, Aronow BJ, Bader GD, Barker RA, et al. A roadmap for the human developmental cell atlas. Nature. 2021; 597(7875):196-205
Bock C, Boutros M, Camp JG, Clarke L, Clevers H, Knoblich JA, et al. The organoid cell atlas. Nature Biotechnology. 2020; 39(1):13-17
Regev A, Teichmann SA, Lander ES, Amit I, Benoist C, Birney E, et al. The human cell atlas. eLife. 2017; 6
Choudhury D, Ashok A, Naing MW. Commercialization of organoids. Trends in Molecular Medicine. 2020; 26(3):245-249
Wang Z, He X, Qiao H, Chen P. Global trends of organoid and organ-on-a-chip in the past decade: A bibliometric and comparative study. Tissue Engineering Part A. 2020; 26(11-12):656-671
Lewis A, Koukoura A, Tsianos G-I, Gargavanis AA, Nielsen AA, Vassiliadis E. Organ donation in the US and Europe: The supply vs demand imbalance. Transplantation Reviews. 2021; 35(2)
Gu Y, Wong YH, Liew CW, Chan CEZ, Murali TM, Yap J, et al. Defining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A*11:01. Nature Communications. 2019; 10(1)
Mahapatra C, Lee R, Paul MK. Emerging role and promise of nanomaterials in organoid research. Drug Discovery Today. 2022; 27(3):890-899
Lee S-J, Lee H-A. Trends in the development of human stem cell-based non-animal drug testing models. The Korean Journal of Physiology & Pharmacology. 2020; 24(6):441-452
The Emerging Field of Human Neural Organoids, Transplants, and Chimeras. 2021
Vives J, Batlle-Morera L. The challenge of developing human 3D organoids into medicines. Stem Cell Research & Therapy. 2020; 11(1)
Lensink MA, Boers SN, Jongsma KR, Carter SE, van der Ent CK, Bredenoord AL. Organoids for personalized treatment of cystic fibrosis: Professional perspectives on the ethics and governance of organoid biobanking. Journal of Cystic Fibrosis. 2021; 20(3):443-451
Peng Y-J, Huang X, Zhou Q. Ethical and policy considerations for human embryo and stem cell research in China. Cell Stem Cell. 2020; 27(4):511-514
Hyun I, Clayton EW, Cong Y, Fujita M, Goldman SA, Hill LR, et al. ISSCR guidelines for the transfer of human pluripotent stem cells and their direct derivatives into animal hosts. Stem Cell Reports. 2021; 16(6):1409-1415.
Turner L. ISSCR’s guidelines for stem cell research and clinical translation: Supporting development of safe and efficacious stem cell-based interventions. Stem Cell Reports. 2021; 16(6):1394-1397
Anthony E, Lovell-Badge R, Morrison SJ. New guidelines for stem cell and embryo research from the ISSCR. Cell Stem Cell. 2021; 28(6):991-992
Rachamalla H, Mukherjee A, K. Paul M. Nanotechnology application and intellectual property right prospects of mammalian cell culture. Cell Culture - Advanced Technology and Applications in Medical and Life Sciences. 2021. DOI: 10.5772/intechopen.99146