An improved osseointegration of metal implants by pitavastatin loaded multilayer films with osteogenic and angiogenic properties

Abstract

An increasing number of works have highlighted the importance of metal implants surface modification in enhancing bone defect healing through the synergistic osteogenesis-angiogenesis regulation. Studies have shown that pitavastatin has the effect of promoting osteogenesis and angiogenesis. However, how to prepare pitavastatin functionalized implants and how pitavastatin regulates the synergies of osteogenesis and angiogenesis around implants as well as the related mechanisms remain unclear. In the present study, multilayer films with osteogenic and angiogenic properties were constructed on pure titanium substrates via the layer-by-layer assembly of pitavastatin-loaded β-cyclodextrin grafted chitosan and gelatin. In vitro experiments demonstrated that locally applied pitavastatin could dramatically enhance osteogenic potential of mesenchymal stem cells (MSCs) and angiogenic potential of endothelial cells (ECs). Moreover, pitavastatin loaded multilayer films could regulate the paracrine signaling mediated crosstalk between MSCs and ECs, and indirectly increase the angiogenic potential of MSCs and osteogenic potential of ECs via multiple paracrine signaling. The results of subcutaneous and femur implantation confirmed that locally released pitavastatin had potentially triggered a chain of biological events: mobilizing endogenous stem cells and ECs to the implant-bone interface, in turn facilitating coupled osteogenesis and angiogenesis, and eventually enhancing peri-implant osseointegration. This study enlarges the application scope of pitavastatin and provides an optional choice for developing a multifunctional bioactive coating on the surfaces of mental implants.

Keywords: Angiogenesis; Crosstalk; Osseointegration; Osteogenesis; Pitavastatin.