T. Kokubo et al./ Biomaterials 24(2003)2161-2175 rabbit femur, a cylindrical rod of NaoH- and heat- assessment in artificial hip joints in which the treatments treated titanium metal formed apatite on its surface are applied to the proximal site of the titanium alloy within 3 weeks, and was completely covered with bone stem and cup surface, where a macroporous titanium owing to the apatite layer within 12 weeks, as shown in surface layer is formed by using a plasma spraying Fig. 11. Therefore, the bone-bonding strength of technique, as shown in Fig 13. So far, there have been NaOH-and heat-treated titanium metal is significantly 70 implants, and these have been so successful that higher in terms of both detachment and pull-out approval for sales is expected soon from the Ministry of racture loads than that of untreated metal, as shown Health, Labor, and Welfare of Japan. Furthermore, the in Fig. 12. When macroporous titanium objected NaOH and heat treatments can be applied to any type of to NaOH and heat treatments and implanted into a ready-made titanium metal or titanium alloys for canine femur, it greatly encouraged bony ingrowth into implant devices, such as knee joints, spinal cages, and its porous structure and integration of bone, owing to dental roots, to make them bioactive apatite formation on its surface The NaOH and heat treatments to induce bioactivity Bioactive titanium and titanium alloys prepared by can be also applied to tantalum metal, which has Naoh and heat treatments are now under clini excellent fracture toughness and malleability. For example, when tantalum metal is treated with 0.5M Naoh at 60 C for 24 h and subsequently heat-treated FNGa⊥Ast Bone at 300C, amorphous sodium tantalate with a graded structure is formed on its surface [72-74]. This tantalum metal can form apatite on its surface on exposure to SBF, as the sodium tantalate on the metal exchanges its Na+ ion with the h o+ ion in the fluid to form Ta-Oh groups, which can induce apatite nucleation [75]. This metal also forms apatite in vivo, and bonds tightly to bone through the apatite layer [76], as shown in Fig. 14 The THOH groups in the anatase structure are the most effective for apatite nucleation among Ti-OH groups, as described above. Anatase and rutile layers can be formed on the surface of titanium metal when the metal is subjected to anodic oxidation, e.g., by using a I M H SO4 solution at 25 C under direct electric field of oum 155V for I min [77]. The anodized titanium metal also forms bone-like apatite on its surface in SBF within 3 d as shown in Fig. 15. This metal also forms an apatite on Fig10. SEM-EDX profile of the interface between the NaOH- and its surface in vivo to bond to living bone [78]. This type heat-treated titanium metal and a rabbit tibia (8 weeks after of bioactive metal is also useful as an orthopedic or Bo Bone New bone Metal 1mm Fig l1. Confocal laser scanning micrograph(A)of a cross-section of the NaoH- and heat-treated titanium metals implanted in the intramedullar anal of a rabbit femur (3 weeks after implantation), and an SEM photograph(B) of the cross-section of the same material(12 weeks afterrabbit femur, a cylindrical rod of NaOH- and heat￾treated titanium metal formed apatite on its surface within 3 weeks, and was completely covered with bone owing to the apatite layer within 12 weeks, as shown in Fig. 11. Therefore, the bone-bonding strength of NaOH- and heat-treated titanium metal is significantly higher in terms of both detachment and pull-out fracture loads than that of untreated metal, as shown in Fig. 12. When macroporous titanium was subjected to NaOH and heat treatments and implanted into a canine femur, it greatly encouraged bony ingrowth into its porous structure and integration of bone, owing to apatite formation on its surface. Bioactive titanium and titanium alloys prepared by NaOH and heat treatments are now under clinical assessment in artificial hip joints in which the treatments are applied to the proximal site of the titanium alloy stem and cup surface, where a macroporous titanium surface layer is formed by using a plasma spraying technique, as shown in Fig. 13. So far, there have been 70 implants, and these have been so successful that approval for sales is expected soon from the Ministry of Health, Labor, and Welfare of Japan. Furthermore, the NaOH and heat treatments can be applied to any type of ready-made titanium metal or titanium alloys for implant devices, such as knee joints, spinal cages, and dental roots, to make them bioactive. The NaOH and heat treatments to induce bioactivity can be also applied to tantalum metal, which has excellent fracture toughness and malleability. For example, when tantalum metal is treated with 0.5 m NaOH at 60C for 24 h and subsequently heat-treated at 300C, amorphous sodium tantalate with a graded structure is formed on its surface [72–74]. This tantalum metal can form apatite on its surface on exposure to SBF, as the sodium tantalate on the metal exchanges its Na+ ion with the H3O+ ion in the fluid to form Ta–OH groups, which can induce apatite nucleation [75]. This metal also forms apatite in vivo, and bonds tightly to bone through the apatite layer [76], as shown in Fig. 14. The Ti–OH groups in the anatase structure are the most effective for apatite nucleation among Ti–OH groups, as described above. Anatase and rutile layers can be formed on the surface of titanium metal when the metal is subjected to anodic oxidation, e.g., by using a 1 m H2SO4 solution at 25C under direct electric field of 155 V for 1 min [77]. The anodized titanium metal also forms bone-like apatite on its surface in SBF within 3 d, as shown in Fig. 15. This metal also forms an apatite on its surface in vivo to bond to living bone [78]. This type of bioactive metal is also useful as an orthopedic or dental implant. Fig. 10. SEM-EDX profile of the interface between the NaOH- and heat-treated titanium metal and a rabbit tibia (8 weeks after implantation). Fig. 11. Confocal laser scanning micrograph (A) of a cross-section of the NaOH- and heat-treated titanium metals implanted in the intramedullar canal of a rabbit femur (3 weeks after implantation), and an SEM photograph (B) of the cross-section of the same material (12 weeks after implantation). 2168 T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175