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Rethinking organoid technology through bioengineering


In recent years considerable progress has been made in the development of faithful procedures for the differentiation of human pluripotent stem cells (hPSCs). An important step in this direction has also been the derivation of organoids. This technology generally relies on traditional three-dimensional culture techniques that exploit cell-autonomous self-organization responses of hPSCs with minimal control over the external inputs supplied to the system. The convergence of stem cell biology and bioengineering offers the possibility to provide these stimuli in a controlled fashion, resulting in the development of naturally inspired approaches to overcome major limitations of this nascent technology. Based on the current developments, we emphasize the achievements and ongoing challenges of bringing together hPSC organoid differentiation, bioengineering and ethics. This Review underlines the need for providing engineering solutions to gain control of self-organization and functionality of hPSC-derived organoids. We expect that this knowledge will guide the community to generate higher-grade hPSC-derived organoids for further applications in developmental biology, drug screening, disease modelling and personalized medicine.

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Fig. 1: Advances in engineering hPSC-derived organoids.
Fig. 2: Engineering approaches to guide hPSC-derived organoids self-organization.
Fig. 3: Integrating emergent technologies for understanding tissue morphogenesis.
Fig. 4: Strategies for engineering hPSC-derived organoids vascularization.
Fig. 5: Approaches for engineering tissue–tissue interactions.


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We thank SOLIDCAM ESTUDIO for support with figure illustrations. This work has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (StG-2014-640525_REGMAMKID to N.M., CoG-2013-616480_TensionControl to X.T., CoG-2016-725722_OVOGROWTH to S.M.C.S.L. and StG-757710 to M.A.L.). This research has been supported by the EFSD/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes, and EIT Health under grant ID 20366 (R2U‐Tox‐Assay) to E.G. and N.M. R.D.K. received support from the US National Science Foundation (CBET-0939511). M.A.L. received funding from the Medical Research Council (MC_UP_1201/9). R.W. received support from the NIH (R01EB024591 and R01EB025256) and the NSF (0939511 and 1446474) research grants. X.T. is also supported by the European Commission (project H2020-FETPROACT-01-2016-731957). I.H. is funded by the Greenwall Foundation’s ‘Making a Difference’ grant. This work also received funding from the Spanish Ministry of Economy and Competitiveness (MINECO)/FEDER (SAF2015-72617-EXP to N.M. and SAF2017-89782-R to N.M. and PGC2018-099645-B-I00 to X.T.), Generalitat de Catalunya and CERCA programme (2017 SGR 1306 to N.M. and SGR-2017-01602 to X.T.), Asociación Española contra el Cáncer (AECC) (LABAE16006 to N.M.). N.M. is also supported by Instituto de Salud Carlos III (Tercel, Cardiocel and ACE2ORG). The Institute for Bioengineering of Catalonia is the recipient of a ‘Centro de Excelencia Severo Ochoa’ award from the MINECO (funded by the Agencia Estatal de Investigación: SEV2014-0425 and CEX2018-000789-S) and MIT-SPAIN "la Caixa” Foundation SEED FUND project “Bioenginering Against Cancer” funded by MISTI Global Seed Funds and “la Caixa” Foundation.

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N.M. conceived the outline of the Review, and wrote and revised the manuscript. E.G. wrote and revised the manuscript. R.D.K. contributed in the section on engineering vascularization and revised the manuscript. S.M.C.S.L. contributed on the section of single-cell transcriptomics and commented on the manuscript. M.A.L. contributed to the section of understanding self-organization and symmetry breaking. R.W. commented on the manuscript. X.T. contributed to the section of probing mechanics in hPSC-organoids. I.H. wrote the section of engineering ethics and commented on the manuscript. N.M. and E.G. created the figures.

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Correspondence to Nuria Montserrat.

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R.D.K. is co-founder and has a substantial financial interest in AIM Biotech, and receives research support from Amgen, Biogen and Gore.

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Garreta, E., Kamm, R.D., Chuva de Sousa Lopes, S.M. et al. Rethinking organoid technology through bioengineering. Nat. Mater. 20, 145–155 (2021).

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