Bilayer Silk Fibroin/Sodium Alginate Scaffold Delivered hUC-MSCs to Enhance Skin Scarless Healing and Hair Follicle Regeneration with the IRE1/XBP1 Pathway Inhibition.

Efficient local delivery of mesenchymal stem cells (MSCs) is a decisive factor for their application in regeneration processes. Here, we prepared a biomimetic bilayer silk fibroin/sodium alginate (SF/SA) scaffold to deliver human umbilical mesenchymal stem cells (hUC-MSCs) for wound healing. An SA membrane was prepared by the casting method on the upper layer of the scaffold to simulate the dense epidermal structure. On the lower layer, porous materials simulating the loose structure of the dermis were formed by the freeze-drying method. , the scaffold was proven to have a high-density pore structure, good swelling property, and suitable degradation rate. The hUC-MSCs could survive on the scaffold for up to 14 days and maintain cell stemness for at least 7 days. , SF/SA scaffolds loaded with hUC-MSCs (M-SF/SA) were applied to full-thickness defect wounds and compared with the local injection of hUC-MSCs. The M-SF/SA group showed excellent therapeutic efficacy, characterized by induction of macrophage polarization, regulation of TGF-β expression and collagen components, and enhancement of vascular regeneration, thereby preventing scar formation and promoting hair follicle regeneration. Furthermore, the expression of endoplasmic reticulum stress markers IRE1, XBP1, and CHOP was inhibited significantly in M-SF/SA treatment. In conclusion, the bilayer SF/SA scaffold is an ideal delivery platform for hUC-MSCs, and the M-SF/SA system could locally promote scarless skin healing and hair follicle regeneration by alleviating the IRE1/XBP1 signal pathway.