Organoids by design
Open accessAbstract
Organoids are multicellular structures that can be derived from adult organs or pluripotent stem cells. Early versions of organoids range from simple epithelial structures to complex, disorganized tissues with large cellular diversity. The current challenge is to engineer cellular complexity into organoids in a controlled manner that results in organized assembly and acquisition of tissue function. These efforts have relied on studies of organ assembly during embryonic development and have resulted in the development of organoids with multilayer tissue complexity and higher-order functions. We discuss how the next generation of organoids can be designed by means of an engineering-based narrative design to control patterning, assembly, morphogenesis, growth, and function.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
New strategies to solve nutrient accessibility are being developed, including long-term maintenance of brain slices in vitro.
“However, PSC-derived organoids cannot be fragmented and passaged; and new strategies to solve the nutrient accessibility problem are being developed, including the long-term maintenance of brain slices in vitro234.”
From Organoids (2022) · cites this paper as [234]
“Promoting organoid function and tissue maturity” describes limited nutrient diffusion in organoids and proposes vascularization to improve growth; “Perfusion” describes engineered systems that control nutrient supply. Neither section identifies long-term maintenance of brain slices in vitro as a strategy. The copy also does not substantiate the citing sentence’s assertion that PSC-derived organoids cannot be fragmented and passaged. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Langer, R., & Vacanti, J. P. (1993) · Science · doi:10.1126/science.8493529 · Cited by 9,893 · see citing works
Role of YAP/TAZ in mechanotransduction
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., et al. (2011) · Nature · doi:10.1038/nature10137 · Cited by 5,979 · see citing works
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,517 · see citing works
Vascularized and functional human liver from an iPSC-derived organ bud transplant
Takebe, T., Sekine, K., Enomura, M., Koike, H., Kimura, M., Ogaeri, T., Zhang, R.-R., Ueno, Y., Zheng, Y.-W., Koike, N., et al. (2013) · Nature · doi:10.1038/nature12271 · Cited by 2,170 · see citing works
Self-citationBrain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure
Qian, X., Nguyen, H. N., Song, M. M., Hadiono, C., Ogden, S. C., Hammack, C., Yao, B., Hamersky, G. R., Jacob, F., Zhong, C., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.032 · Cited by 2,127 · see citing works
Self-organizing optic-cup morphogenesis in three-dimensional culture
Eiraku, M., Takata, N., Ishibashi, H., Kawada, M., Sakakura, E., Okuda, S., Sekiguchi, K., Adachi, T., & Sasai, Y. (2011) · Nature · doi:10.1038/nature09941 · Cited by 2,001 · see citing works
Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro
Spence, J. R., Mayhew, C. N., Rankin, S. A., Kuhar, M. F., Vallance, J. E., Tolle, K. A., Hoskins, E. E., Kalinichenko, V. V., Wells, S. I., Zorn, A. M., et al. (2010) · Nature · doi:10.1038/nature09691 · Cited by 1,911 · see citing works
Self-citationKidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis
Takasato, M., Er, P. X., Chiu, H. S., Maier, B., Baillie, G. J., Ferguson, C., Parton, R. G., Wolvetang, E. J., Roost, M. S., Chuva de Sousa Lopes, S. M., et al. (2015) · Nature · doi:10.1038/nature15695 · Cited by 1,627 · see citing works
Eiraku, M., Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Matsumura, M., Wataya, T., Nishiyama, A., Muguruma, K., & Sasai, Y. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.09.002 · Cited by 1,522 · see citing works
Advanced maturation of human cardiac tissue grown from pluripotent stem cells
Ronaldson-Bouchard, K., Ma, S. P., Yeager, K., Chen, T., Song, L., Sirabella, D., Morikawa, K., Teles, D., Yazawa, M., & Vunjak-Novakovic, G. (2018) · Nature · doi:10.1038/s41586-018-0016-3 · Cited by 1,272 · see citing works
An in vivo model of functional and vascularized human brain organoids
Mansour, A. A., Gonçalves, J. T., Bloyd, C. W., Li, H., Fernandes, S., Quang, D., Johnston, S., Parylak, S. L., Jin, X., & Gage, F. H. (2018) · Nature Biotechnology · doi:10.1038/nbt.4127 · Cited by 1,211 · see citing works
Growing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications
Sato, T., & Clevers, H. (2013) · Science · doi:10.1126/science.1234852 · Cited by 1,170 · see citing works
Flow-enhanced vascularization and maturation of kidney organoids in vitro
Homan, K. A., Gupta, N., Kroll, K. T., Kolesky, D. B., Skylar-Scott, M., Miyoshi, T., Mau, D., Valerius, M. T., Ferrante, T., Bonventre, J. V., et al. (2019) · Nature Methods · doi:10.1038/s41592-019-0325-y · Cited by 939 · see citing works
Modelling cancer in microfluidic human organs-on-chips
Sontheimer-Phelps, A., Hassell, B. A., & Ingber, D. E. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-018-0104-6 · Cited by 906 · see citing works
Park, S. E., Georgescu, A., & Huh, D. (2019) · Science · doi:10.1126/science.aaw7894 · Cited by 847 · see citing works
Vertebrate Endoderm Development and Organ Formation
Zorn, A. M., & Wells, J. M. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113344 · Cited by 812 · see citing works
Self-citationHuman blood vessel organoids as a model of diabetic vasculopathy
Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hämmerle, M., Esk, C., Bagley, J. A., et al. (2019) · Nature · doi:10.1038/s41586-018-0858-8 · Cited by 803 · see citing works
Fused cerebral organoids model interactions between brain regions
Bagley, J. A., Reumann, D., Bian, S., Lévi-Strauss, J., & Knoblich, J. A. (2017) · Nature Methods · doi:10.1038/nmeth.4304 · Cited by 790 · see citing works
Three-dimensional organotypic culture: experimental models of mammalian biology and disease
Shamir, E. R., & Ewald, A. J. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3873 · Cited by 719 · see citing works
Xiang, Y., Tanaka, Y., Patterson, B., Kang, Y., Govindaiah, G., Roselaar, N., Çakır, B., Kim, K.-Y., Lombroso, A., Hwang, S., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.07.007 · Cited by 696 · see citing works
Theraulaz, G., & Bonabeau, E. (1999) · Artificial Life · doi:10.1162/106454699568700 · Cited by 665 · see citing works
Collective cell durotaxis emerges from long-range intercellular force transmission
Sunyer, R., Conte, V., Escribano, J. M. G., Elósegui-Artola, A., Labernadie, A., Valon, L., Navajas, D., García‐Aznar, J. M., Muñoz, J. J., Roca‐Cusachs, P., et al. (2016) · Science · doi:10.1126/science.aaf7119 · Cited by 632 · see citing works
Workman, M. J., Mahé, M. M., Trisno, S. L., Poling, H. M., Watson, C. L., Sundaram, N., Chang, C., Schiesser, J. V., Aubert, P., Stanley, E. G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4233 · Cited by 632 · see citing works
Self-citationMicroglia innately develop within cerebral organoids
Ormel, P. R., de Sá, R. V., van Bodegraven, E. J., Karst, H., Harschnitz, O., Sneeboer, M. A. M., Johansen, L. E., van Dijk, R. E., Scheefhals, N., van Berlekom, A. B., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06684-2 · Cited by 624 · see citing works
Organoids: A historical perspective of thinking in three dimensions
Simian, M., & Bissell, M. J. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201610056 · Cited by 620 · see citing works
Sloan, S. A., Darmanis, S., Huber, N., Khan, T. A., Birey, F., Caneda, C., Reimer, R., Quake, S. R., Barres, B. A., & Paşca, S. P. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.035 · Cited by 593 · see citing works
An in vivo model of human small intestine using pluripotent stem cells
Watson, C. L., Mahé, M. M., Múnera, J. O., Howell, J. C., Sundaram, N., Poling, H. M., Schweitzer, J. I., Vallance, J. E., Mayhew, C. N., Sun, Y., et al. (2014) · Nature Medicine · doi:10.1038/nm.3737 · Cited by 561 · see citing works
Self-citationDekkers, J. F., Berkers, G., Kruisselbrink, E., Vonk, A., de Jonge, H. R., Janssens, H. M., Bronsveld, I., van de Graaf, E. A., Nieuwenhuis, E. E. S., Houwen, R. H. J., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad8278 · Cited by 548 · see citing works
The development of a bioengineered organ germ method
Nakao, K., Morita, R., Saji, Y., Ishida, K., Tomita, Y., Ogawa, M., Saitoh, M., Tomooka, Y., & Tsuji, T. (2007) · Nature Methods · doi:10.1038/nmeth1012 · Cited by 547 · see citing works
Blastocyst-like structures generated solely from stem cells
Rivron, N. C., Frias-Aldeguer, J., Vrij, E., Boisset, J.-C., Korving, J., Vivié, J., Truckenmüller, R. K., van Oudenaarden, A., van Blitterswijk, C., & Geijsen, N. (2018) · Nature · doi:10.1038/s41586-018-0051-0 · Cited by 535 · see citing works
Self-formation of functional adenohypophysis in three-dimensional culture
Suga, H., Kadoshima, T., Minaguchi, M., Ohgushi, M., Soen, M., Nakano, T., Takata, N., Wataya, T., Muguruma, K., Miyoshi, H., et al. (2011) · Nature · doi:10.1038/nature10637 · Cited by 497 · see citing works
Cytosystems dynamics in self-organization of tissue architecture
Sasai, Y. (2013) · Nature · doi:10.1038/nature11859 · Cited by 475 · see citing works
Programming self-organizing multicellular structures with synthetic cell-cell signaling
Toda, S., Blauch, L. R., Tang, S. K. Y., Morsut, L., & Lim, W. A. (2018) · Science · doi:10.1126/science.aat0271 · Cited by 470 · see citing works
Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation
Takebe, T., Enomura, M., Yoshizawa, E., Kimura, M., Koike, H., Ueno, Y., Matsuzaki, T., Yamazaki, T., Toyohara, T., Osafune, K., et al. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.03.004 · Cited by 454 · see citing works
Self-citationAssembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro
Harrison, S., Sözen, B., Christodoulou, N., Kyprianou, C., & Zernicka‐Goetz, M. (2017) · Science · doi:10.1126/science.aal1810 · Cited by 393 · see citing works
McCauley, H. A., & Wells, J. M. (2017) · Development · doi:10.1242/dev.140731 · Cited by 322 · see citing works
Self-citationProgrammed assembly of 3-dimensional microtissues with defined cellular connectivity
Gartner, Z. J., & Bertozzi, C. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900717106 · Cited by 317 · see citing works
Apoptotic Force and Tissue Dynamics During Drosophila Embryogenesis
Toyama, Y., Peralta, X. G., Wells, A. R., et al. (2008) · Science · doi:10.1126/science.1157052 · Cited by 309 · see citing works
Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production
Ito, Y., Nakamura, S., Sugimoto, N., Shigemori, T., Kato, Y., Ohno, M., Sakuma, S., Ito, K., Kumon, H., Hirose, H., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.011 · Cited by 297 · see citing works
Programming gene and engineered-cell therapies with synthetic biology
Kitada, T., DiAndreth, B., Teague, B. P., & Weiss, R. (2018) · Science · doi:10.1126/science.aad1067 · Cited by 279 · see citing works
Vascularization and Engraftment of Transplanted Human Cerebral Organoids in Mouse Cortex
Daviaud, N., Friedel, R. H., & Zou, H. (2018) · eNeuro · doi:10.1523/eneuro.0219-18.2018 · Cited by 219 · see citing works
Hill, D. R., Huang, S., Nagy, M. S., Yadagiri, V. K., Fields, C., Thornhill, D., Bons, B., Dedhia, P. H., Chin, A. M., Tsai, Y.-H., et al. (2017) · eLife · doi:10.7554/elife.29132 · Cited by 173 · see citing works
Advances in On-Chip Vascularization
Haase, K., & Kamm, R. D. (2017) · Regenerative Medicine · doi:10.2217/rme-2016-0152 · Cited by 172 · see citing works
Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme
Hughes, A. J., Miyazaki, H., Coyle, M. C., Zhang, J., Laurie, M. T., Chu, D. B., Vavrušová, Z., Schneider, R. A., Klein, O. D., & Gartner, Z. J. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.12.004 · Cited by 169 · see citing works
Diverse mechanisms for endogenous regeneration and repair in mammalian organs
Wells, J. M., & Watt, F. M. (2018) · Nature · doi:10.1038/s41586-018-0073-7 · Cited by 169 · see citing works
Self-citationIntestinal epithelial organoids fuse to form self-organizing tubes in floating collagen gels
Sachs, N., Tsukamoto, Y., Kujala, P., Peters, P. J., & Clevers, H. C. (2017) · Development · doi:10.1242/dev.143933 · Cited by 138 · see citing works
Microglia Increase Inflammatory Responses in iPSC-Derived Human BrainSpheres
Abreu, C. M., Gama, L., Krasemann, S., Chesnut, M., Odwin-DaCosta, S., Högberg, H. T., Härtung, T., & Pamies, D. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02766 · Cited by 131 · see citing works
Mechanically induced development and maturation of human intestinal organoids in vivo
Poling, H. M., Wu, D. X.-Y., Brown, N. E., Baker, M. L., Hausfeld, T. A., Huynh, N., Chaffron, S., Dunn, J., Hogan, S. P., Wells, J. M., et al. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0243-9 · Cited by 107 · see citing works
Self-citationDissecting the stem cell niche with organoid models: an engineering-based approach
Murrow, L. M., Weber, R. J., & Gartner, Z. J. (2017) · Development · doi:10.1242/dev.140905 · Cited by 81 · see citing works
Self-Organization of Animal Tissues: Cadherin-Mediated Processes
Takeichi, M. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.06.002 · Cited by 68 · see citing works
Blueprint for an intestinal villus: Species‐specific assembly required
Walton, K. D., Mishkind, D., Riddle, M. R., Tabin, C. J., & Gumucio, D. L. (2018) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.317 · Cited by 55 · see citing works
Molecular control of macroscopic forces drives formation of the vertebrate hindgut
Nerurkar, N. L., Lee, C., Mahadevan, L., & Tabin, C. J. (2019) · Nature · doi:10.1038/s41586-018-0865-9 · Cited by 52 · see citing works
Investigating biocomplexity through the agent-based paradigm
Kaul, H., & Ventikos, Y. (2013) · Briefings in Bioinformatics · doi:10.1093/bib/bbt077 · Cited by 50 · see citing works
Overview of Lung Development in the Newborn Human
Warburton, D. (2017) · Neonatology · doi:10.1159/000458465 · Cited by 44 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [23]Hill DR, eLife 6, e29132 (2017).29110754
Cited by
Sorted by citations
Zhao, Z., Chen, X., Dowbaj, A. M., Sljukic, A., Bratlie, K., Lin, L., Fong, E. L. S., Balachander, G. M., Chen, Z., Soragni, A., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00174-y · Cited by 1,001 · see citing works
Multi-lineage human iPSC-derived platforms for disease modeling and drug discovery
Sharma, A., Sances, S., Workman, M. J., & Svendsen, C. N. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.02.011 · Cited by 296 · see citing works
Bioengineering Approaches for the Advanced Organoid Research
Yi, S. A., Zhang, Y., Rathnam, C., Pongkulapa, T., & Lee, K. (2021) · Advanced Materials · doi:10.1002/adma.202007949 · Cited by 218 · see citing works
An Automated Organoid Platform with Inter-organoid Homogeneity and Inter-patient Heterogeneity
Jiang, S., Zhao, H., Zhang, W., Wang, J., Liu, Y., Cao, Y., Zheng, H., Hu, Z., Wang, S., Zhu, Y., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100161 · Cited by 188 · see citing works
Skylar-Scott, M. A., Huang, J. Y., Lu, A., Ng, A. H. M., Duenki, T., Liu, S., Nam, L. L., Damaraju, S., Church, G. M., & Lewis, J. A. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00856-8 · Cited by 160 · see citing works
Articular cartilage repair biomaterials: strategies and applications
Wang, M., Wu, Y., Li, G., Lin, Q., Zhang, W., Liu, H., & Su, J. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.100948 · Cited by 145 · see citing works
Papamichail, L., Koch, L. S., Veerman, D., Broersen, K., & van der Meer, A. D. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2025.1515340 · Cited by 120 · see citing works
En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH
Kimura, M., Iguchi, T., Iwasawa, K., Dunn, A., Thompson, W. L., Yoneyama, Y., Chaturvedi, P., Zorn, A. M., Wintzinger, M., Quattrocelli, M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.031 · Cited by 115 · see citing works
Self-citationUnderstanding Immune‐Driven Brain Aging by Human Brain Organoid Microphysiological Analysis Platform
Ao, Z., Song, S., Tian, C., Cai, H., Li, X., Miao, Y., Wu, Z., Krzesniak, J., Ning, B., Gu, M., et al. (2022) · Advanced Science · doi:10.1002/advs.202200475 · Cited by 77 · see citing works
The challenge of developing human 3D organoids into medicines
Vives, J., & Batlle-Morera, L. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-1586-1 · Cited by 65 · see citing works
Engineering Liver Microtissues for Disease Modeling and Regenerative Medicine
Huang, D. (., Gibeley, S. B., Xu, C., Xiao, Y., Celik, O., Ginsberg, H. N., & Leong, K. W. (2020) · Advanced Functional Materials · doi:10.1002/adfm.201909553 · Cited by 65 · see citing works
Ultrasound-assisted tissue engineering
Melde, K., Athanassiadis, A. G., Missirlis, D., Shi, M., Seneca, S., & Fischer, P. (2024) · Nature Reviews Bioengineering · doi:10.1038/s44222-024-00166-5 · Cited by 59 · see citing works
<i>In vitro</i> functional models for human liver diseases and drug screening: beyond animal testing
Paradiso, A., Volpi, M., Rinoldi, C., Celikkin, N., Contessi Negrini, N., Bilgen, M., Dallera, G., Pierini, F., Costantini, M., Święszkowski, W., et al. (2023) · Biomaterials Science · doi:10.1039/d1bm01872h · Cited by 40 · see citing works
Engineering Biomimetic Microenvironment for Organoid
Chen, S., Wang, L., Yang, L., Rana, A. S., & He, C. (2023) · Macromolecular Bioscience · doi:10.1002/mabi.202300223 · Cited by 10 · see citing works
- Authors
- Takebe, T., & Wells, J. M.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Takebe, Takanori
- Wells, James M.
- Venue
- Science
- Published
- 2019-06-07
- Volume
- 364
- Issue
- 6444
- Pages
- 956-959
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8212787
- OpenAlex
- W2948307638
- Cited by
- 417
- References
- 54
- Citations by year
- 2026: 60 · 2025: 61 · 2024: 60 · 2023: 46 · 2022: 60 · 2021: 60 · 2020: 54 · 2019: 16
- FWCI
- 16.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01DK092456, U19 AI116491, P01 HD093363, UG3 DK119982)
- New York Stem Cell Foundation
- Takeda Science Foundation
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- organoids, organoid engineering, pluripotent stem cells, tissue patterning, morphogenesis, embryonic development, organ function, cellular complexity
- MeSH terms
- Cell Differentiation, Humans, Organoids, Body Patterning, Tissue Engineering, Narration, Embryonic Development
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
