3D Stem Cell Spheroids with 2D Hetero‐Nanostructures for In Vivo Osteogenic and Immunologic Modulated Bone Repair

Abstract

Three‐dimensional (3D) stem cell spheroids have immense potential for various tissue engineering applications. However, current spheroid fabrication techniques encounter cell viability issues due to limited oxygen access for cells trapped within the core, as well as non‐specific differentiation issues due to the complicated environment following transplantation. In this study, we developed functional 3D spheroids using mesenchymal stem cells (MSCs) with two‐dimensional (2D) hetero‐nanostructures (HNS) composed of single‐stranded DNA (ssDNA) binding carbon nanotubes (sdCNT) and gelatin‐bind black phosphorus nanosheets (gBPNS). An osteogenic molecule, dexamethasone (DEX), was further loaded to fabricate an sdCNTgBP‐DEX hetero‐nanostructure. This approach aimed to establish a multi‐functional cell‐inductive 3D spheroid with improved oxygen transportation through hollow nanotubes, stimulated stem cell growth by phosphate ions supplied from BP oxidation, in‐situ immunoregulation, and osteogenesis induction by DEX molecules after implantation. Initial transplantation of the 3D spheroids in rat calvarial bone defect showed in vivo macrophage shifts to an M2 phenotype, leading to a pro‐healing microenvironment for regeneration. Prolonged implantation demonstrated outstanding in vivo neovascularization, osteointegration, and new bone regeneration. Therefore, these engineered 3D spheroids hold great promise for bone repair as they allow for stem cell delivery and provide immunoregulative and osteogenic signals within an all‐in‐one construct.

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