3D-Printed Silk Fibroin Scaffolds Loaded with Adipose-Derived Stem Cells Prevent Post Endoscopic Submucosal Dissection Esophageal Stricture in a Porcine Model

Abstract Endoscopic submucosal dissection (ESD) is the preferred treatment for early esophageal cancer. However, extensive mucosal dissection frequently results in esophageal stricture. This study aimed to evaluate the efficacy of 3D-printed silk fibroin scaffolds (SFS) loaded with adipose-derived stem cells (ADSCs) in preventing post-ESD esophageal stricture, and to explore the underlying mechanisms. A near-circumferential ESD model was established in pigs, three groups were set: Control, SFS, and ADSCs-SFS. The dynamic change of postoperative esophageal healing and stricture formation were monitored endoscopically. On postoperative day 28, esophageal specimens were collected to measure mucosal contraction rate, followed by histological evaluation of inflammation and fibrosis, as well as mRNA transcriptome sequencing to analyze gene expression and the change of the enriched signaling pathways. On day 28, the ADSCs-SFS group showed significantly less weight loss and a markedly reduced mucosal contraction rate. Histological examination revealed more complete mucosal regeneration and significantly reduced collagen deposition in the ADSCs-SFS group. Molecular analyses indicated significant downregulation of inflammatory and fibrotic markers in the ADSCs-SFS group. Transcriptome analysis suggested that ADSCs-loaded SFS effectively alleviates esophageal stricture following ESD in pigs, likely through suppression of the PI3K/AKT signaling pathway and reduction of inflammation and fibrosis.