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interface often deteriorate concurrently, and disease progression may depend on interactions among these failures rather than on any single defect. Multi-tissue organoid models can mimic disease-relevant pathology in vitro, but the field lacks a simple framework for comprehensive interrogation. Here, we propose mesoscale maladaptation as an operational concept for multi-tissue disease modelling, defined as a synergistic decline in interdependent functions that can occur between two or more tissue elements. To detect maladaptation, we introduce a stepwise workflow that identifies the failing tissue elements, defines directionality of potential interdependence between these elements and compares combined perturbations with single perturbations to evaluate synergistic decline. We apply this framework to intestinal neuromuscular, hepatic sinusoidal, blood\u2013brain barrier and tumour\u2013neural interfaces, but it can be extrapolated to other organs and systems. This framework will illuminate future directions for in vitro complex disease modelling by enriching biological insights to disentangle progressive pathology, shifting the focus from localised biological failures to concurrent multi-tissue failures that produce synergistic pathology.<\/jats:p>","DOI":"10.1242\/dmm.052951","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:39:52Z","timestamp":1782722392000},"source":"Crossref","is-referenced-by-count":1,"title":["Mesoscale maladaptation in disease organoids"],"prefix":"10.1242","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6636-9837","authenticated-orcid":false,"given":"Masashi","family":"Okamoto","sequence":"first","affiliation":[{"name":"Graduate School of Medicine, and Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), the University of Osaka 1 Department of Genome Biology , , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Graduate School of Medicine, the University of Osaka 2 Department of Respiratory Medicine and Clinical Immunology , , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6989-3041","authenticated-orcid":false,"given":"Takanori","family":"Takebe","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, and Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), the University of Osaka 1 Department of Genome Biology , , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Human Biology Research Unit, Institute of Integrated Research, Institute of Science Tokyo (Science Tokyo) 3 , 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510 ,","place":["Japan"]},{"name":"Cincinnati Children's Hospital Medical Center 4 Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology , , 3333 Burnet Avenue, Cincinnati, OH 45229-3039 ,","place":["USA"]},{"name":"The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center 5 , 3333 Burnet Avenue, Cincinnati, OH 45229-3039 ,","place":["USA"]},{"name":"University of Cincinnati College of Medicine 6 Department of Pediatrics , , 3333 Burnet Avenue, Cincinnati, OH 45229-3039 ,","place":["USA"]},{"name":"Communication Design Center, Advanced Medical Research Center, Yokohama City University 7 , Yokohama, Kanagawa 236-0004 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"2026062904394887100_DMM052951C1","doi-asserted-by":"publisher","first-page":"115361","DOI":"10.1016\/j.isci.2026.115361","article-title":"Glioblastoma invasion into different organoid hosts reveals cell-intrinsic and proliferative migratory programs","volume":"29","author":"Akhunbay-Fudge","year":"2026","journal-title":"iScience"},{"key":"2026062904394887100_DMM052951C2","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.bioactmat.2023.09.005","article-title":"AI-enabled organoids: construction, analysis, and application","volume":"31","author":"Bai","year":"2024","journal-title":"Bioact. 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