Synergistic Control of Mesenchymal Stem Cell Differentiation by Nanoscale Surface Geometry and Immobilized Growth Factors on TiO2 Nanotubes

The aim of this study is to elucidate whether combined environmental signals provided by nanoscale topography and by growth factors control cell behavior of mesenchymal stem cells (MSCs) in a synergistic or simply additive manner. Chondrogenic and osteogenic differentiation of MSCs is studied on vertically aligned TiO2 nanotubes of size 15 and 100 nm with and without immobilized bone morphogenetic protein‐2 (BMP‐2). Although BMP‐2 coating stimulates both chondrogenic and osteogenic differentiation of MSCs, the response strongly depends on the surface nanoscale geometry of the BMP‐2‐coated nanotubes. Chondrogenic differentiation is strongly supported on 100 nm BMP‐2‐coated nanotubes, but not on 15 nm nanotubes, which induce spreading and de‐differentiation of chondrocytes. A similar response is observed with primary chondrocytes, which maintain their chondrogenic phenotype on BMP‐2‐coated 100 nm nanotubes, but de‐differentiate on 15 nm nanotubes. In contrast, osteogenic differentiation is greatly enhanced on 15 nm but not on 100 nm BMP‐2‐coated nanotubes as shown previously. Furthermore, covalent immobilization of BMP‐2 rescues MSCs from apoptosis occurring on uncoated 100 nm TiO2 nanotube surfaces. Thus, combined signals provided by BMP‐2 immobilized to a defined lateral nanoscale spacing geometry seem to contain environmental cues that are able to modulate a lineage‐specific decision of MSC differentiation and cell survival in a synergistic manner. Combined signals provided by nanoscale topography and growth factors control the behavior of mesenchymal stem cells (MSCs) in a synergistic rather than additive manner. Bone morphogenetic protein‐2 (BMP‐2) stimulates chondrogenic and osteogenic differentiation, but lineage decision depends on nanoscale geometry. Chondrogenic differentiation is only achieved on 100 nm nanotubes, not on 15 nm nanotubes, while the opposite response occurs during osteogenic differentiation.