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 TiO(2) 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 TiO(2) 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.

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In the present work we show the covalent immobilization of two bioactive molecules, epidermal growth factor (EGF) and bone morphogenetic protein-2 (BMP-2), on TiO(2) nanotube surfaces and the resulting influence on the behavior of mesenchymal stem cells. Covalent immobilization of these growth factors onto the oxide surfaces was achieved by N,N-carbonyldiimidazole (CDI) coupling via binding to amine groups of the proteins either directly or via a spacer, namely 11-hydroxy-undecylphosphonic acid (PhoA). The behavior of mesenchymal stem cells can be significantly altered by such an activation procedure. The effect is depending on the diameters of the nanotubes. Most importantly, on 100 nm diameter tubes the cell activity and cell number were drastically increased by grafting such nanotube surfaces with EGF. This demonstrates that the strong diameter dependence on cell activity in the range between 15 and 100 nm observed in prior work can be compensated by coating of the nanotube surfaces with EGF.

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