Delivery of a Therapeutic Protein for Bone Regeneration from a Substrate Coated with Graphene Oxide

Abstract

The therapeutic efficacy of drugs often depends on the drug delivery carrier. For efficient delivery of therapeutic proteins, delivery carriers should enable the loading of large doses, sustained release, and retention of the bioactivity of the therapeutic proteins. Here, it is demonstrated that graphene oxide (GO) is an efficient carrier for delivery of therapeutic proteins. Titanium (Ti) substrates are coated with GO through layer-by-layer assembly of positively (GO-NH3+) and negatively (GO-COO-) charged GO sheets. Subsequently, a therapeutic protein (bone morphogenetic protein-2, BMP-2) is loaded on the GO-coated Ti substrate with the outermost coating layer of GO-COO-(Ti/GO-). The GO coating on Ti substrate enables loading of large doses and the sustained release of BMP-2 with preservation of the structure and bioactivity of the drug. The extent of in vitro osteogenic differentiation of human bone marrow-derived mesenchymal stem cells is higher when they are cultured on Ti/GO- carrying BMP-2 than when they are cultured on Ti with BMP-2. Eight weeks after implantation in mouse models of calvarial defects, the Ti/GO-/BMP-2 implants show more robust new bone formation compared with Ti, Ti/GO(-), or Ti/BMP-2 implants. Therefore, GO is an effective carrier for the controlled delivery of therapeutic proteins, such as BMP-2, which promotes osteointegration of orthopedic or dental Ti implants.