Angiogenic apoptotic vesicle-laden silk fibroin /sodium alginate hydrogel for pulp regeneration

Angiogenesis remains a key challenge in pulp regeneration due to the ischemic and hypoxic root canal environment. Apoptotic vesicles (ApoVs) offer unique advantages as a breakthrough strategy due to their stability in hypoxic environments, resistance to immune clearance, and high yield. However, a critical gap persists in biomaterials capable of spatiotemporal ApoVs delivery for pulp regeneration. To address this, an ApoVs-laden silk fibroin/sodium alginate (SF/SA/ApoVs) hydrogel with tunable release kinetics was fabricated. This hydrogel exhibited superior shapeability, injectability, and self-healing properties. SF/SA/ApoVs hydrogel improved angiogenesis by enhancing paracrine functions of dental pulp stem cells (DPSCs), and promoting capillary lumen formation of human umbilical vein endothelial cells via the focal adhesion signaling pathway. It also effectively created an odontogenic and neurogenic inductive micro-environment for pulp-dentin complex formation. Furthermore, in-vivo studies showed that semi-orthotopic transplantation of SF/SA/ApoVs hydrogel accelerated micro-vessels formation, and orthotopic transplantation further confirmed its capacity in generating full-length vascularized pulp tissue with aligned odontoblast-like cells and neuronal extension. Our study pioneers an ApoVs-functionalized hydrogel system with advanced angiogenic potential for promoting pulp regeneration.