Phosphate graphene as an intrinsically osteoinductive scaffold for stem cell-driven bone regeneration

Significance Traumatic bone injuries or deformities are among the most common conditions that require surgical intervention affecting patients in the United States today. Current treatment options suffer shortcomings, clearly demonstrating a clinical need for tissue replacement techniques. An ideal treatment consists of a scaffold that promotes regeneration, matches the chemical and mechanical properties of bone, and degrades with a timeline matching the healing process. However, this ideal scaffold has not been realized. Here, we present a degradable, graphene-based material that mimics the chemical and mechanical composition of bone, promotes differentiation of stem cells, and leads to the formation of new bone in an animal model. Synthetic, resorbable scaffolds for bone regeneration have potential to transform the clinical standard of care. Here, we demonstrate that functional graphenic materials (FGMs) could serve as an osteoinductive scaffold: recruiting native cells to the site of injury and promoting differentiation into bone cells. By invoking a Lewis acid-catalyzed Arbuzov reaction, we are able to functionalize graphene oxide (GO) to produce phosphate graphenes (PGs) with unprecedented control of functional group density, mechanical properties, and counterion identity. In aqueous environments, PGs release inducerons, including Ca2+ and PO43−. Calcium phosphate graphene (CaPG) intrinsically induces osteogenesis in vitro and in the presence of bone marrow stromal cells (BMSCs), can induce ectopic bone formation in vivo. Additionally, an FGM can be made by noncovalently loading GO with the growth factor recombinant human bone morphogenetic protein 2 (rhBMP-2), producing a scaffold that induces ectopic bone formation with or without BMSCs. The FGMs reported here are intrinsically inductive scaffolds with significant potential to revolutionize the regeneration of bone.