Amphiphilic TiO 2 Nanotube Arrays: An Actively Controllable Drug Delivery System Yan-Yan Song, Felix Schmidt-Stein, Sebastian Bauer, and Patrik Schmuki* Department of Materials Science, WW4-LKO, UniVersity of Erlangen-Nuremberg, Martensstrasse 7 D-91058, Erlangen, Germany Received January 8, 2009; E-mail: Patrik.Schmuki@ww.uni-erlangen.de In 1999, the formation of self-organized arrays of TiO 2 nanotubes by electrochemical anodization of Ti was reported by Zwilling and co-workers. 1 Since then, TiO 2 nanotube arrays have generated much interest because of the combination of geometric features with the unique functional properties of TiO 2 (for a recent review, see ref 2). A key feature of TiO 2 is its excellent photocatalytic properties, 3 which are significantly enhanced for nanotubular structures. 4 This not only allows the controlled decomposition of organic materials 5,6 but also allows the highly controlled scission of surface attached organic monolayers. 7,8 Moreover, TiO 2 nanotubes show excellent biocompatibility, 9,10 and therefore the open volume in the tubes may be exploited as a drug release platform. However, when the drug is simply filled into a porous network or tubes (for example to be used on a titanium implant or bone-filling material 11-13 ), a main problem is the uncontrolled release of drugs or therapeutics. Therefore, providing a controlled release kinetics is a key objective of many novel drug delivery approaches, 14,15 and as a result, over the past few years, new structures, 9 surface modification, 13,16 and release principles have been widely explored. Hydrophobic surface modifications are typically used to avoid undesired nonspecific adsorption of critical proteins (e.g., bovine serum albumin) 17 to the drug delivery device. In this context, also amphiphilic structures attract considerable attention, as they for example allow combining a hydrophilic drug with a hydrophobic surface. In the present work, we demonstrate the fabrication and use of an amphiphilic TiO 2 nanotubular structure that provides a highly controllable drug release system based on a hydrophobic cap on a hydrophilic TiO 2 nanotube. This hydrophobic cap prevents uncon- trolled leaching of the hydrophilic drug into an aqueous environ- ment. By exploiting the photocatalytic nature of TiO 2 for UV induced chain scission of attached organic monolayers, the cap can be removed and a highly controlled release of drugs can be achieved. Figure 1 schematically describes the procedure for the fabrication of amphiphilic TiO 2 nanotubes (Figure 1A) and drug loading approaches explored in this work (Figure 1B). To produce am- phiphilic tubes, the procedure consists of a first anodization step forming tubes, followed by a hydrophobic surface modification. Then, a second neat (hydrophilic) tube layer is grown underneath the first one by a second anodization process. The first tube layer was grown in a glycerol/water/NH 4 F 18 electrolyte to a thickness of ∼750 nm with individual nanotube diameters of ∼90 nm (Figure 2). Then a hydrophobic monolayer of octadecylphosphonic acid (OPDA) was attached to the tube walls. The sample is then anodized again in an ethylene glycol/NH 4 F electrolyte (experimental details are given in the Supporting Information SI X1). In contrast to water- based electrolytes, ethylene glycol electrolytes enter into the hydrophobic tubes and therefore allow for a second anodization. The voltages for anodization were chosen to match the nanotube diameter in the first and second layers. 19-21 In our case, the second layer consists of 2 μm long tubes (Figure 2B) with a diameter of ∼90 nm (inset of Figure 2A). To evaluate the growth of the second layer after the first layer has been formed, we performed detailed scanning electron microscopy (SEM) characterization of the interface between the layers, with examples shown in Figure 2C and D. From these investigations it is clear that the second anodization penetrates the bottom of the tubes grown during the first anodization, 19-21 and tube growth (Figure 2C and D) is re- established. This implies that field-induced breakdown of the monolayer occurs only at the tube bottom. After growth has been re-established, the length of the underneath tubes can simply be controlled by the anodization time. Figure 1. (A) Scheme of the procedure for fabricating amphiphilic TiO 2 nanotube layers, and (B) four methods for drug loading using horseradish peroxide (HRP) as a hydrophilic model drug: (I) immersion without any TiO 2 surface modification (for reference), (II) immersion after OPDA modification in the upper nanotube layer (hydrophobic cap), (III) covalently attached HRP over the entire nanotube layers, (IV) OPDA cap in the upper nanotube layer and covalently attached HRP in the lower nanotube layer. Surface analytical support for the processes is provided in SI X3. Published on Web 03/06/2009 10.1021/ja810130h CCC: $40.75  2009 American Chemical Society 4230 9 J. AM. CHEM. SOC. 2009, 131, 4230–4232