Jung Park, Anca Mazare, Holm Schneider, Klaus. von der Mark, Michael J.M. Fischer, Patrik Schmuki
Division of Molecular Pediatrics, Department of Pediatrics, University of Erlangen-Nuremberg, Erlangen, Germany
Cellular behaviour and cell fate of stem cells on biocompatible implants are determined by biological, electrochemical, and stress signals from the biomaterial and host tissue. Modifications of the biophysical, chemical, and electrochemical properties of the biomaterial surface and its nanoscale geometry have been shown to be of crucial significance for cell-implant surface interactions, and thus for biocompatibility and tissue integration. Titanium has been widely accepted as the most favourable material for osteogenic differentiation in vitro and bone regeneration in vivo. We have previously developed a technique to generate self-assembled layers of vertically oriented TiO2 nanotubes with defined diameters. We have shown that osteogenic differentiation of MSC is stimulated by nanotubular titanium oxide layers fabricated in distinct nanoscale geometry. In spite of the long history and beneficial effects of electric fields (EF) on bone regeneration, the electric stimuli-sensing mechanism leading to osteogenic induction in bone is poorly understood. To identify the mechanism of EF-guided osteogenic induction, we investigated the stem cell fate of mesenchymal stem cell (MSC) under EF stimulation on geometrically well-defined nanotubular TiO2 surfaces. In our study, we found that constant electric fields triggered connexion 43 (Cx43)-mediated extracellular calcium influx and gap junctional propagation of intracellular calcium increase, leading to simultaneous osteogenic differentiation via downstream calcium signaling pathway including calcineurin/CAMKII phosphorylation and NFAT dephosphorylation. The information gained from these studies will contribute to our understanding of the synergistic role of electric fields and nano-size surface structures on osteogenesis and will open new tools for the generation of highly biocompatible implant surfaces in orthopaedic and dental tissue repair.