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The high cost and risks of anesthesia and sedation have driven the development of smaller endoscopes for unsedated procedures. However, reduced endoscope size limits working-channel dimensions, restricting biopsy forceps to sizes that may yield insufficient or nondiagnostic samples. To address these limitations, we developed an image-guided, depth-controlled, ultrasmall-diameter (1.2-millimeters) cryobiopsy device (\u03bcCryoProbe). We optimized the coolant flow profile into the device to enhance tissue freezing, optimizing device-tissue contact time and freezing depth. We tested the device for gastrointestinal biopsy collection in ex vivo preclinical tissues, in an in vivo porcine model, and in sedated human participants. Dimensions and quality of mucosal cryobiopsies from esophagus, stomach, and duodenum were compared with those of forceps-derived biopsies, and it was found that the \u03bcCryoProbe device consistently produced high-quality biopsies with optimal tissue orientation and no evidence of crush artifacts. We also demonstrated the ability to capture gastrointestinal biopsies from sedated human participants. By capturing large, well-oriented samples using a small-diameter biopsy tool, this technology has the potential to shift procedures from large to small endoscopes, reducing the need for sedation and improving patient diagnosis through the acquisition of tissue samples with better quality.<\/jats:p>","DOI":"10.1126\/scitranslmed.ado9609","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T22:02:49Z","timestamp":1746050569000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["A thin cryobiopsy device compatible with transnasal endoscopy for the gastrointestinal tract"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9334-9599","authenticated-orcid":true,"given":"David O.","family":"Otuya","sequence":"first","affiliation":[{"name":"Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA."},{"name":"Harvard Medical 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