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However, most approaches have focused on cell or organ structures. This manuscript presents a reproducible deep learning methodology for pixel-level analysis of amorphic patterns in haematoxylin and eosin-stained whole-slide histological images. This study analysed the pixel patterns in the extracellular matrix (ECM) part of connective tissue to identify differences in airway wall ECM compartments and their heterogeneity, which are microscopically similar and difficult to discern with the human eye. Through a targeted preprocessing pipeline, the deep learning model is guided to emphasise learning from pixel-level patterns in non-cellular tissue components while reducing the influence of cellular structures and artefacts. Combined with transfer learning, the model accurately distinguishes the characteristics of the airway submucosa and adventitia, achieving a test area under the curve of 0.84. Using visualisation techniques and statistical analysis, we demonstrate that random pixel imputation successfully reduces the effects of cellular structures on model learning. The framework is applied in a proof-of-principle study of lung tissue from patients with chronic obstructive pulmonary disease, illustrating how this quantitative approach can study population heterogeneity and inform novel research directions. Ultimately, this study provides an innovative and adaptable framework that unlocks the analytical potential of often-overlooked amorphic components in AI-empowered histopathology.<\/jats:p>","DOI":"10.1038\/s41598-026-56138-9","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T09:35:16Z","timestamp":1782120916000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A deep learning framework for histopathological analysis of pixel-level extracellular matrix variation in standard H&amp;E-stained images"],"prefix":"10.1038","volume":"16","author":[{"given":"Merlijn","family":"van Breugel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esm\u00e9e","family":"de Jong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk J.","family":"Buikema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya","family":"Petoukhov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn C.","family":"Nawijn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janette K.","family":"Burgess","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Timens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"56138_CR1","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1146\/annurev-bioeng-071516-044442","volume":"19","author":"D Shen","year":"2017","unstructured":"Shen, D., Wu, G. & Suk, H. 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Open Source Softw."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56138-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56138-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56138-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:51:31Z","timestamp":1789084291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-56138-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":63,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["56138"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-56138-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]},"assertion":[{"value":"20 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study used archived lung tissue samples obtained from leftover surgical material at the University Medical Center Groningen (UMCG). According to the General Data Protection Regulation (GDPR) Art. 9 and U-AVG Art. 24, the use of such archival materials for research can be exempt from individual patient informed consent requirements. Under Dutch law, this is also consistent with the Medical Treatment Agreement Act (WGBO) Art. 458. The use of these archival materials was approved by the UMCG Central Ethics Review Board (CTc UMCG), Research Register number 202200107. This material was also not subject to the Medical Research Involving Human Subjects Act (WMO) in the Netherlands, as the research uses material from routine clinical care without additional patient intervention, and all patient data were fully de-identified prior to analysis. All methods were performed in accordance with the relevant guidelines and regulations, and the study was conducted in accordance with the Declaration of Helsinki. The study protocol was consistent with the Research Code of the University Medical Center Groningen (\n                      \n                      ) and national ethical and professional guidelines (\u201cCode of Conduct for Health Research\u201d:\n                      \n                      ).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"28453"}}