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

Abstract

Background 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. 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. Methods Epithelial 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. Results The 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. Conclusions These 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.

Evaluation of safety and efficacy of autologous oral mucosa-derived epithelial cell sheet transplantation for prevention of anastomotic restenosis in congenital esophageal atresia and congenital esophageal stenosis: three case studies

“…In accordance with our previous study, quality control tests were carried out by CellSeed Inc. before transplantation of cultured autologous oral mucosal epithelial cell sheets [4]. Culture media collected during cultivation of the epithelial cells were subjected to sterility tests by (1) cultivation for aerobic and anaerobic bacteria and fungi, (2) endotoxin detection by a limulus amoebocyte lysate assay, and (3) mycoplasma testing by real-time qPCR.…”

“…Culture media collected during cultivation of the epithelial cells were subjected to sterility tests by (1) cultivation for aerobic and anaerobic bacteria and fungi, (2) endotoxin detection by a limulus amoebocyte lysate assay, and (3) mycoplasma testing by real-time qPCR. Quantification for cellular density, viability, and percentage of epithelial cell in the epithelial cell sheets were also implemented using similar protocols to a previous study [4].…”

“…EBD was performed on each subject as in the first transplantation on subject 1 [4]. An esophageal balloon dilation catheter (CRE Fixed Wire, Boston Scientific Corporation, Natick, Massachusetts, USA) were inserted under endoscopic (XQ240, Olympus, Tokyo, Japan) observation.…”

“…Cell sheets were transplanted into each subject under the same conditions as for the first transplantation in subject 1 [4]. Using a pediatric cell sheet transplantation device developed for this study, epithelial cell sheets were applied to the area of mucosal defect created by EBD avoiding overlap each other.…”

“…Based on these previous studies, we first confirmed the safety and efficacy of cell sheet transplantation in a preclinical study using a porcine model in order to apply cell sheet transplantation to refractory anastomotic stenosis after surgery for congenital esophageal atresia [8]. Then, we conducted the world’s first clinical trial in humans [4]. Autologous oral mucosa-derived cell sheets were produced from the subject’s oral epithelial tissue, and the sheets were transplanted into a lacerated wound after EBD surgery using a newly developed pediatric transplantation device.…”