Patient-as-bioreactor in-body tissue architecture generates autologous multicellular constructs for durable diabetic wound repair

Patient-as-bioreactor in-body tissue architecture generates autologous multicellular constructs for durable diabetic wound repair | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Patient-as-bioreactor in-body tissue architecture generates autologous multicellular constructs for durable diabetic wound repair Ryuji Higashita, Yasuhide Nakayama, Ryosuke Iwai, Marina Funayama-Iwai, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8946692/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Chronic diabetic foot ulcers remain refractory to contemporary care, partly because durable repair requires reconstruction of an integrated, multicellular regenerative niche—an outcome rarely achieved without complex ex vivo manufacturing. We advance a patient-as-bioreactor paradigm in which in-body tissue architecture (iBTA) repurposes the body for in vivo manufacturing of autologous multicellular regenerative constructs (“biococktails”) using a temporary subcutaneous device. In a first-in-human exploratory study, 37 devices were successfully implanted, and the primary endpoint—generation of ≥ 1 construct meeting predefined quality criteria—was achieved in all 10 patients. A single application initiated sustained wound repair, reaching a mean 84.15% wound-area reduction at 12 weeks. Reproducible, self-assembled niches enriched for stem cell–associated programs, reparative macrophage signatures, nascent vasculature, extracellular matrix components, and broad regenerative signaling were observed. No amputations or treatment-related serious adverse events occurred. These findings establish iBTA as a scalable, patient-specific in vivo manufacturing platform for multicellular regenerative therapies. Biological sciences/Biotechnology/Biomaterials/Tissues Biological sciences/Stem cells/Regeneration Full Text Additional Declarations Yes there is potential Competing Interest. R.H. and Y.N. are stockholders of Biotube Co., Ltd. Y.N. is an executive board member of Biotube Co., Ltd. All other authors declare no competing interests. Tables are available in the Supplementary Files section. Supplementary Files Table3.pdf Table 3 Table2.pdf Table 2 Table1.pdf Table 1 Table4.pdf Table 4 SupplementarytableS2.pdf Supplementary Table S2 supplementarymaterials.pdf Supplementary methods SupplementarytableS1.docx Supplementary Table S1 Table3.docx Table 3 Table4.docx Table 4 SupplementaryTableS2.docx Supplementary Table S2 supplementarymaterials.docx Supplementary methods Table1.docx Table 1 Table2.docx Table 2 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8946692","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":608331938,"identity":"dfa8152c-0e24-4c2c-bc64-5546bb95948c","order_by":0,"name":"Ryuji Higashita","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABMElEQVRIie3Rv0rDQBzA8V84uCzXuEZa2lc4ucGl9FkSAplEAoXSoYRAIS6iazefwTe44yBdQlwDdaj0BQyKFITinaFgaVJXwftC/l3yyeUPgMn0JyPA1drDen8KQ1SP4npDTxJ9UQ6hIuh3ovOgJhIOSFOXSUeI91l87Qzma+DTJ5uu7sUmmgzh7IbDODomPe54spfJMcaYAs9XiD5LxBZFCG7uAVscExcIlS7mfoqBoipVpAxwt5OqJywBGGkju1gR+xXErtDE/tRkcIKIKkWKEAoi4d+zIE1oG0FqFutOKnIVcZ4F6LwMWJcUIbnI/aTxXexbVm0/Yv9hvnxc89kocEr/5Y1Mhv3+Umas4Yvpn4D2s3O1BPsTatBKWYPQWdsfB6OD+21aiMlkMv2rvgCnuGMtnQvCiwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1337-192X","institution":"Juntendo University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Ryuji","middleName":"","lastName":"Higashita","suffix":""},{"id":608331939,"identity":"82231798-62d0-41d4-8d17-b18a3222dcd8","order_by":1,"name":"Yasuhide Nakayama","email":"","orcid":"","institution":"Biotube Co. 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