Titanate biomaterials with enhanced antiinflammatory properties Ramiro Contreras, Herman Sahlin, John A. Frangos La Jolla Bioengineering Institute, 505 Coast Boulevard South, La Jolla, California 92037 Received 30 April 2006; revised 15 May 2006; accepted 16 June 2006 Published online 29 September 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.30961 Abstract: While titanium implants are generally recognized as having excellent biocompatibility, the mechanistic basis for this has yet to be established. We previously demonstrated that TiO 2 , found on surfaces of titanium, has antioxidant properties that degrade the reactive oxygen species (ROS) which mediate the inflammatory response. We hypothesized that the antioxidant mechanism was similar to that known to mediate photocatalysis by titanium oxides. Specifically, we investigated whether the electronic or valence state of the surface titanium atoms mediates the catalytic degradation of ROS. Surface Ti(IV) atoms in TiO 2 and SrTiO 3 single crystal substrates were converted into Ti(III) while maintaining the bulk crystalline structure by vacuum annealing or Niobium doping. The degradation of both chemically-induced and neutrophil-derived ROS were significantly increased by changing the valence state of surface titanium. These results suggest that titanium-mediated degradation of ROS is through a catalytic mechanism. Furthermore, we describe a series of novel biomaterials that have antioxidant properties superior to those of titanium. Ó 2006 Wiley Periodicals, Inc. J Biomed Mater Res 80A: 480–485, 2007 Key words: antioxidant; perovskite; free radical; titanium dioxide; cation doping INTRODUCTION Titanium is a widely used implant material, but the mechanisms of its superior biocompatibility are largely unknown. When titanium is exposed to air or water, an oxide layer consisting predominantly of titanium dioxide (TiO 2 ) is spontaneously formed. 1,2 It has been proposed that the oxide layer plays a fundamental role in the tissue response. 3 Earlier work has shown that TiO 2 has the ability to break down reactive oxygen species (ROS) which are known mediators of the inflammatory response. 4–6 Further defining the mechanism by which titanium mediates the degradation of ROS will enable the de- velopment of biomaterials with even greater biocom- patibility. Titanium dioxide is a member of a group of semi- conductors which are used industrially as photocata- lysts to generate ROS to purify water and degrade industrial waste. 7–9 This group includes perovskites SrTiO 3 and BaTiO 3 in which the titanium cations have octahedral oxygen coordination, and all share similar surface structures and electronic states. 10–12 Central to the photocatalytic mechanism is the ability of titanium ions in these crystalline structures to readily and reversibly change valence states from þ4 to þ3. 13–15 When a high energy photon strikes these surfaces an oxygen vacancy defect is created with a charge of 2e  . 15 To preserve charge neutrality, two Ti ions adjacent to the defect trap the electrons and are reduced from Ti 4þ to Ti 3 . The photocatalytic properties can be enhanced by the addition of defects, such as by generating oxygen vacancies by vacuum annealing at 8508C, or by aliovalent substi- tution where cations with a larger valence than Ti are doped into the crystalline lattice. 12,16 For every aliovalent dopant substitution, one adjacent Ti ion changes its valence state from þ4 to þ3. 12 The Ti 3þ ions at these surface defects then become the active sites for catalytic reduction reactions to take place, which in turn oxidize the Ti to a valence state of þ4. The purpose of the present study was to test the hypothesis that the mechanism of the antioxidant reactivity of titanium-based materials is similar to that which mediates their photocatalytic properties. Our approach was to determine whether the elec- tronic or valence state of surface titanium atoms mediates a catalytic degradation of ROS, and if mod- Correspondence to: J. A. Frangos; e-mail: frangos@ljbi.org Contract grant sponsor: National Institutes of Health; contract grant numbers: R01EB00823, R01AR47032 ' 2006 Wiley Periodicals, Inc.