{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:54:42Z","timestamp":1790506482661,"version":"4.1.0"},"reference-count":74,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clayton Biotechnologies Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Organoids allow to model healthy and diseased human tissues. and have applications in developmental biology, drug discovery, and cell therapy. Traditionally cultured in immersion\/suspension, organoids face issues like lack of standardization, fusion, hypoxia-induced necrosis, continuous agitation, and high media volume requirements. To address these issues, we developed an air\u2013liquid interface (ALi) technology for culturing organoids, termed AirLiwell. It uses non-adhesive microwells for generating and maintaining individualized organoids on an air\u2013liquid interface. This method ensures high standardization, prevents organoid fusion, eliminates the need for agitation, simplifies media changes, reduces media volume, and is compatible with Good Manufacturing Practices. We compared the ALi method to standard immersion culture for midbrain organoids, detailing the process from human pluripotent stem cell (hPSC) culture to organoid maturation and analysis. Air\u2013liquid interface organoids (3D-ALi) showed optimized size and shape standardization. RNA sequencing and immunostaining confirmed neural\/dopaminergic specification. Single-cell RNA sequencing revealed that immersion organoids (3D-i) contained 16% fibroblast-like, 23% myeloid-like, and 61% neural cells (49% neurons), whereas 3D-ALi organoids comprised 99% neural cells (86% neurons). Functionally, 3D-ALi organoids showed a striking electrophysiological synchronization, unlike the heterogeneous activity of 3D-i organoids. This standardized organoid platform improves reproducibility and scalability, demonstrated here with midbrain organoids. The use of midbrain organoids is particularly relevant for neuroscience and neurodegenerative diseases, such as Parkinson\u2019s disease, due to their high incidence, opening new perspectives in disease modeling and cell therapy. In addition to hPSC-derived organoids, the method\u2019s versatility extends to cancer organoids and 3D cultures from primary human cells.<\/jats:p>","DOI":"10.3390\/cells14151211","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T15:09:53Z","timestamp":1754492993000},"page":"1211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Generation of Individualized, Standardized, and Electrically Synchronized Human Midbrain Organoids"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9738-7226","authenticated-orcid":false,"given":"Sanae","family":"El Harane","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"},{"name":"Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahareh","family":"Nazari","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"El Harane","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"},{"name":"Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"},{"name":"Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bochra","family":"Zidi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"},{"name":"Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9772-8406","authenticated-orcid":false,"given":"St\u00e9phane","family":"Durual","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials, Faculty of Dental Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abderrahim","family":"Karmime","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology and Therapeutic Drug Monitoring, Geneva University Hospitals, 1205 Geneva, 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Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5364-967X","authenticated-orcid":false,"given":"Olivier","family":"Preynat-Seauve","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"},{"name":"Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9033-6768","authenticated-orcid":false,"given":"Karl-Heinz","family":"Krause","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland"},{"name":"Department of Diagnostics and Department of Medicine, Geneva University Hospitals, 1206 Geneva, 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