First-in-human autologous oral mucosal epithelial sheet transplantation to prevent anastomotic re-stenosis in congenital esophageal atresia

Akihiro Fujino,Takanori Iwata,Yasushi Fuchimoto,Ryo Takagi,Yoshiyuki Baba,Akihiro Umezawa,Masanori Maeda,Nobutaka Isogawa,Katsuhiro Arai,Nobuo Kanai,Makoto Abe

doi:10.1186/s13287-022-02710-9

Abstract

BackgroundCongenital esophageal atresia postoperative anastomotic stricture occurs in 30–50% of cases. Patients with severe dysphagia are treated with endoscopic balloon dilatation (EBD) and/or local injection of steroids, but many patients continue to experience frequent stricture. In this study, we investigated the transplantation of autologous oral mucosa-derived cell sheets (epithelial cell sheets) as a prophylactic treatment for congenital esophageal atresia postoperative anastomotic stricture.MethodsEpithelial cell sheets were fabricated from a patient’s oral epithelial tissue, and their safety was confirmed by quality control tests. The epithelial cell sheets were transported under controlled conditions from the fabrication facility to the transplantation facility and successfully transplanted onto the lacerations caused by EBD using a newly developed transplantation device for pediatric patients. The safety of the transplantation was confirmed by follow-up examinations over 48 weeks.ResultsThe dates that EBD was performed were recorded for one year before and after epithelial cell sheet transplantation, and the intervals (in days) were evaluated. For about 6 months after transplantation, the intervals between EBDs were longer than in the year before transplantation. The patients were also aware of a reduction in dysphagia after transplantation.ConclusionsThese results suggest that cell sheet transplantation may be effective in preventing anastomotic stricture after surgery for congenital esophageal atresia, but the effect was temporary and limited in this case. Although we chose a very severe case for the first human clinical study, it may be possible to obtain a more definitive effect if the transplantation is performed before the disease becomes so severe. Future studies are needed to identify cases in which cell sheet transplantation is most effective and to determine the appropriate timeframes for transplantation.Trial registration: UMIN, UMIN000034566, registered 19 October 2018, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000039393.

Highlights

Congenital esophageal atresia postoperative anastomotic stricture occurs in 30–50% of cases
The disaggregated oral mucosal cells were suspended in a keratinocyte culture medium (KCM) composed of a basal medium consisting of three parts of Dulbecco’s modified Eagle’s medium (DMEM) and one part of nutrient mixture F-12 Ham (Sigma-Aldrich) supplemented with 40 μg/mL gentamicin (Gentacin, Takata Pharmaceutical, Saitama, Japan), 0.25 μg/mL amphotericin B (Fungizone, Bristol-Myers Squibb, NY, USA), 5% autologous serum, 5 μg/mL insulin (Humulin; Eli Lilly, IN, USA), 10 ng/mL human recombinant epidermal growth factor (Higeta-Syoyu, Chiba, Japan), 1 ng/mL cholera toxin (List Biological Laboratories, CA, USA), 2 nmol/L triiodothyronine (Fujifilm Wako Pure Chemicals), and 0.4 μg/mL hydrocortisone (Saxizon, Teva Takeda Pharma, Aichi, Japan)
Fabrication of epithelial cell sheets Autologous epithelial cell sheets were prepared from oral epithelial tissue of a patient with congenital esophageal atresia (Fig. 1)

Summary

Introduction

Congenital esophageal atresia postoperative anastomotic stricture occurs in 30–50% of cases. Patients with severe dysphagia are treated with endoscopic balloon dilatation (EBD) and/or local injection of steroids, but many patients continue to experience frequent stricture. Anastomotic stricture after surgery for congenital esophageal atresia is reported to occur in 30–50% of cases [1,2,3]. Because balloon dilation under fluoroscopy can cause a great deal of physical and mental distress to the patient, EBD often requires general anesthesia in pediatric patients. For these reasons, patients often become reluctant to consume food and are unable to enjoy it. Absorbable stenting is associated with restenosis after stent resorption, and there are no ideal treatments for anastomotic stenosis [4]

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