Abstract
Refractory anastomotic restenosis following surgery for congenital esophageal atresia (CEA) or congenital esophageal stenosis (CES) remains a serious complication in pediatric surgery. Repeated endoscopic balloon dilatation (EBD) under general anesthesia often impairs growth, feeding function, and overall quality of life (QOL). We have developed a regenerative therapy using autologous oral mucosal epithelial cell sheets. This study aimed to evaluate the long-term safety and efficacy of epithelial cell sheet transplantation for refractory esophageal restenosis in pediatric patients. Between 2018 and 2024, epithelial cell sheet transplantation was performed immediately after EBD in six patients (aged 8–41 years) with refractory anastomotic restenosis following surgery for CEA and/or CES. The cell sheets were fabricated by culturing oral mucosal tissue harvested from each patient in temperature-responsive culture dishes with autologous serum, then non-enzymatically detached and endoscopically transplanted onto the stricture site. Postoperatively, patients were monitored for 48 weeks to assess EBD frequency, endoscopic patency, dietary status, and adverse events. In later cases, evaluation for eosinophilic esophagitis (EoE) was also performed. No serious adverse events were observed in any of the patients, confirming the safety of the procedure. One patient showed only temporary improvement and required surgical reconstruction. In four patients, long-term patency was achieved without the need for additional EBD, with the longest recurrence-free period lasting up to five years. Swallowing function, dietary intake, and overall QOL markedly improved in all of these cases. Notably, two patients had concomitant EoE, suggesting that inflammation control may influence therapeutic outcomes. Transplantation of autologous oral mucosal epithelial cell sheets appeared to promote safe and sustained epithelial regeneration and functional recovery in pediatric patients with refractory esophageal strictures. Combining intervention before irreversible fibrotic remodeling is established with control of inflammation and optimization of the local environment to support engraftment may further enhance therapeutic efficacy.
Trial registration: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393. jRCT, jRCTb030190278, registered 31 March 2020, https://jrct.mhlw.go.jp/en-latest-detail/jRCTb030190278.
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Abbreviations
- CEA:
-
Congenital esophageal atresia
- CES:
-
Congenital esophageal stenosis
- EBD:
-
Endoscopic balloon dilatation
- RIC:
-
Radial incision and cutting
- EoE:
-
Eosinophilic esophagitis
- CPF:
-
Cell processing facility
- PPI:
-
Proton pump inhibitor
- ESD:
-
Endoscopic submucosal dissection
Acknowledgements
We would like to express our sincere thanks to K. Ishikawa for providing expert technical assistance, to C. Ketcham for English editing and proofreading, to E. Suzuki for English writing, and to K. Akaumi and K. Saito for secretarial work.
Funding
This research was supported by AMED under Grant Numbers JP18bk0104006, JP22bk0104140, and JP25bk0104195.
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Competing interests
AU is a co-researcher with CellSeed Inc. MM is the CEO of MakeWay LLC. The other authors have no conflicts of interest regarding the work described herein. AU is the editorial board member of the journal and was not involved in the peer review process of the article.
Ethics approval and consent to participate
The entire study including the clinical intervention component and experiments with human cells and tissues, was approved by the Institutional Review Board and Certified Special Committee for Regenerative Medicine at the National Center for Child Health and Development (project title: Clinical trial of autologous oral mucosal epidermal cell sheet transplantation in patients with anastomotic restenosis after repair of congenital esophageal atresia, approval number: 1202, date of approval: December 17th, 2018). Human cells in this study were utilized in full compliance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects (Ministry of Health, Labor, and Welfare (MHLW), Japan; Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan). Consent to participate in this study was obtained from the parents of patients or from patients him/herself and their parents.
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Consent for publication was obtained from the parents of patients or from patients him/herself and their parents.
Declaration of generative AI and AI-assisted technologies in the writing process
During the preparation of this work, YY and YF used DeepL, Grammarly, and ChatGPT for English writing. After using DeepL, Grammarly, and ChatGPT, YF reviewed and edited the content as needed and takes full responsibility for the content of the publication.
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Fuchimoto, Y., Yamamoto, Y., Fujino, A. et al. Sustained efficacy and long-term outcomes of autologous oral mucosal epithelial cell sheet transplantation for pediatric esophageal anastomotic restenosis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-51724-3
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DOI: https://doi.org/10.1038/s41598-026-51724-3
