3D-Printed Collagen/Silk Fibroin/Matrigel Scaffold Combined with iPSC-Derived Cells for Tissue Regeneration of Salivary Glands

Abstract Salivary gland defects from tumors or trauma are often accompanied by irreversible secretory dysfunction and remain a clinical challenge. Alternative cell sources and suitable scaffolds for salivary gland regeneration remain lacking. A functionalized scaffold system is fabricated by three-dimensional printing combined with freeze-drying to prepare a collagen-silk fibroin-Matrigel scaffold. The scaffold exhibits high porosity and strong water absorption capacity. Its internal surface is coated with a basement membrane extract-rich layer that enhances hydrophilicity and creates a physiologically relevant cell niche. In vitro, a synergistic co-culture system incorporating urine-derived induced pluripotent stem cells (iPSCs), parotid mesenchymal stem cells, and parotid epithelial cells directs the differentiation of iPSCs into KRT18+/VIM+/AQP5+ iPSC-derived cells. These cells readily adhere to the scaffold, proliferate, and form acinar-like aggregates within its porous architecture. In a rat model of parotid gland trauma, implantation of the scaffold progressively promotes tissue regeneration and attenuates trauma-induced atrophy. Histological analysis reveals that the scaffold recruits host cells to organize within its pores, forming amylase-secreting acinar-like structures. This study provides a reliable seed cell source and a suitable scaffold for structural and functional parotid restoration, offering a potential strategy for salivary gland tissue engineering.