Availableonlineatwww.sciencedirect.com D Biomaterials ELSEVIER Biomaterials 24(2003)2161-2175 www.elsevier.com/locate/biomaterials Novel bioactive materials with different mechanical properties Tadashi Kokubo*, Hyun-Min Kim, Masakazu Kawashita Department of Material Chemistry, Faculty of Engineering, Graduate School of Engineering, Kyoto Unicersity, Yoshida, Sakyo-k Kyoto 606-8501, Japan Received 29 October 2002: accepted 19 January 2003 Abstract Some ceramics, such as Bioglass, sintered hydroxyapatite, and glass-ceramic A-W, spontaneously bond to living bone. They are called bioactive materials and are already clinically used as important bone substitutes. However, compared with human cortical bone, they have lower fracture toughness and higher elastic moduli. Therefore, it is desirable to develop bioactive materials with improved mechanical properties. All the bioactive materials mentioned above form a bone -like apatite layer on their surfaces in the living body, and bond to bone through this apatite layer. The formation of bone-like apatite on artificial material is induced by functional groups, such as Si-OH, Ti-OH, Zr-OH, Nb-OH, Ta-OH, -COOH, and PO4H2. These groups have specific structures revealing negatively charge, and induce apatite formation via formations of an amorphous calcium compound, e. g, calcium silicate. calcium titanate, and amorphous calcium phosphate. These fundamental findings provide methods for preparing new bioactive materials with different mechanical properties. Tough bioactive materials can be prepared by the chemical treatment of metals and ceramics that have high fracture toughness, e.g., by the Naoh and heat treatments of titanium metal, titanium alloys, and tantalum metal, and by H3 PO4 treatment of tetragonal zirconia Soft bioactive materials can be synthesized by the sol-gel process, in which the bioactive silica or titania is polymerized with a flexible polymer, such as polydimethylsiloxane or polytetramethyloxide, at the molecular level to form an inorganic-organic nano-hybrid. The biomimetic process has been used to deposit nano-sized bone-like apatite on fine polymer fibers, which were textured into a three-dimensional knit framework. This strategy is expected to ultimately lead to bioactive composites that have a bone-like structure and, hence, bone-like mechanical properties. C 2003 Elsevier Science Ltd. All rights reserved Keywords: Bioactivity: Bone; Apatite: Simulated body fluid(SBF); Biomimetic process; Titanium: Hybrid; Apatite-polymer composite 1. Introduct do not damage healthy tissue, do not pose any viral or bacterial risk to patients, and can be supplied at any Bone disease is a serious health condition that directly time in any amount. However, artificial materials mpacts on the quality of life of sufferers, particularly implanted into bone defects are generally encapsulated among the aged. In most cases, the treatment of bone by a fibrous tissue, and become isolated from the defects requires a bone graft, and sometimes in extensive surrounding bone. Consequently, they do not adhere to amount. In the EU and the USA, bone grafts have used bone, and this has been a critical problem in their use in mainly autogenous and allogenic bones. However, bone repair. Since the early 1970s, this issue has been collecting autogenous bones damages healthy body, ly, overcome by using bioactive ceramics that sponta and the amount that can be collected is severely limited. neot The recipients of allogenic bones sometimes succumb to body y bond to and integrate with bone in the living viral and bacterial infections from the donors and, in Various types of bioactive ceramics have been addition, the amount of allogenic bone that can be given developed over the last three decades. Among these, is limited. As a result, there is an impetus for thethe main bioactive ceramics used clinically are: the development of artificial bone substitute materials that Bioglass in the Na20-Cao-SiOr-P2O5 system [1] sintered hydroxyapatite(HA)(CaIo(PO4)6(OH)2 [2, 3 482 Orresponding author. Tel:+81-75-753-5527: fax: +81-75-753. sintered B-tricalcium phosphate(TCP)(Ca3 (PO4)2 []. HA/TCP bi-phase ceramic [5, and glassceramic A-W E-mail address: kokubo@sung. kuic kyoto-u ac jp(T. Kokubo containing crystalline oxyfluoroapatite(Calo(PO4)(O, 0142-9612/03/Ssee front matter o 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0142-9612(03)0004-9
Biomaterials 24 (2003) 2161–2175 Novel bioactive materials with different mechanical properties Tadashi Kokubo*, Hyun-Min Kim, Masakazu Kawashita Department of Material Chemistry, Faculty of Engineering, Graduate School of Engineering, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Received 29 October 2002; accepted 19 January 2003 Abstract Some ceramics, such as Bioglasss, sintered hydroxyapatite, and glass-ceramic A-W, spontaneously bond to living bone. They are called bioactive materials and are already clinically used as important bone substitutes. However, compared with human cortical bone, they have lower fracture toughness and higher elastic moduli. Therefore, it is desirable to develop bioactive materials with improved mechanical properties. All the bioactive materials mentioned above form a bone-like apatite layer on their surfaces in the living body, and bond to bone through this apatite layer. The formation of bone-like apatite on artificial material is induced by functional groups, such as Si–OH, Ti–OH, Zr–OH, Nb–OH, Ta–OH, –COOH, and PO4H2. These groups have specific structures revealing negatively charge, and induce apatite formation via formations of an amorphous calcium compound, e.g., calcium silicate, calcium titanate, and amorphous calcium phosphate. These fundamental findings provide methods for preparing new bioactive materials with different mechanical properties. Tough bioactive materials can be prepared by the chemical treatment of metals and ceramics that have high fracture toughness, e.g., by the NaOH and heat treatments of titanium metal, titanium alloys, and tantalum metal, and by H3PO4 treatment of tetragonal zirconia. Soft bioactive materials can be synthesized by the sol–gel process, in which the bioactive silica or titania is polymerized with a flexible polymer, such as polydimethylsiloxane or polytetramethyloxide, at the molecular level to form an inorganic–organic nano-hybrid. The biomimetic process has been used to deposit nano-sized bone-like apatite on fine polymer fibers, which were textured into a three-dimensional knit framework. This strategy is expected to ultimately lead to bioactive composites that have a bone-like structure and, hence, bone-like mechanical properties. r 2003 Elsevier Science Ltd. All rights reserved. Keywords: Bioactivity; Bone; Apatite; Simulated body fluid (SBF); Biomimetic process; Titanium; Hybrid; Apatite-polymer composite 1. Introduction Bone disease is a serious health condition that directly impacts on the quality of life of sufferers, particularly among the aged. In most cases, the treatment of bone defects requires a bone graft, and sometimes in extensive amount. In the EU and the USA, bone grafts have used mainly autogenous and allogenic bones. However, collecting autogenous bones damages healthy body, and the amount that can be collected is severely limited. The recipients of allogenic bones sometimes succumb to viral and bacterial infections from the donors and, in addition, the amount of allogenic bone that can be given is limited. As a result, there is an impetus for the development of artificial bone substitute materials that do not damage healthy tissue, do not pose any viral or bacterial risk to patients, and can be supplied at any time, in any amount. However, artificial materials implanted into bone defects are generally encapsulated by a fibrous tissue, and become isolated from the surrounding bone. Consequently, they do not adhere to bone, and this has been a critical problem in their use in bone repair. Since the early 1970s, this issue has been overcome by using bioactive ceramics that spontaneously bond to and integrate with bone in the living body. Various types of bioactive ceramics have been developed over the last three decades. Among these, the main bioactive ceramics used clinically are: the Bioglasss in the Na2O–CaO–SiO2–P2O5 system [1], sintered hydroxyapatite (HA) (Ca10(PO4)6(OH)2 [2,3], sintered b-tricalcium phosphate (TCP) (Ca3(PO4)2 [4], HA/TCP bi-phase ceramic [5], and glassceramic A-W containing crystalline oxyfluoroapatite (Ca10(PO4)6(O, *Corresponding author. Tel.: +81-75-753-5527; fax: +81-75-753- 4824. E-mail address: kokubo@sung7.kuic.kyoto-u.ac.jp (T. Kokubo). 0142-9612/03/$ - see front matter r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0142-9612(03)00044-9
162 T. Kokubo et al. Biomaterials 24(2003)2161-2175 F2) and B-wollastonite(Cao. SiO2) in an MgO-Cao- materials with different mechanical properties. There SiO2 glassy matrix [6]. The above have been developed fore, this paper reviews the mechanism of integration of in the forms of bulks and particulates with dense and bioactive ceramics with living bone, which has been porous structures. For example, Bioglass and Bio- revealed from recent in vitro and in vivo studies, and glass-type glasses in the form of particulates have gained presents some examples of novel bioactive materials over a million successes in periodontal bone repair (for with different mechanical properties. example [7D). HA, in bulk and granular forms with dense and porous structures, is popularly used as bone spacers nd fillers, and a number of clinical successes have been 2. Fundamentals for designing new bioactive materials documented (for example [8]. Glass-ceramic A-W. owing to its superior mechanical strength and excellent 2. 1. Mechanism of integration of bioactive ceramics with bone-bonding ability, has been applied, not only as bone living bone spacers and fillers in the bulk and granular forms with dense and porous structures, but also as artificial Bioactive ceramics have a common characteristic at ertebrae, intervertebral discs, and iliac crests in dense the interface with bone after integration. In fact, bulk form(for example [9]. These products are shown ctive ceramics, including Bioglass, HA, and in Fig. I grass-ceramic A-W, reveal a layer of apatite at the As the clinical applications of bioactive ceramics interface, mediating integration with bone [10, 11],as progress, their limited mechanical properties are becom- shown in Fig. 2. Histological examinations in vivo show ng apparent. As indicated in Table 1, even glass-ceramic that this apatite layer is formed on the ceramic surface A-w, which has higher mechanical strength than the early in the implantation period and, thereafter, the other bioactive ceramics and human cortical bone, bone matrix integrates into the apatite [12-15]. Detailed cannot be used to repair bone defects in high-load characterization indicates that this apatite layer consists bones, such as femoral and tibial bones, as its fracture of nano-crystals of carbonate-ion-containing apatite toughness is lower and elastic modulus higher than that has a defective structure and low crystallinity those of cortical bone. Therefore, the development of [13, 14, 16]. These features are, in fact, very similar to bioactive materials that have improved and ultimately those of the mineral phase in bone and, hence, bone- bone-like mechanical properties is desirable producing cells, i.e., osteoblasts, can preferentially The mechanism of integration of bioactive ceramics proliferate on the apatite, and differentiate to form an with living bone has been investigated considerably in extracellular matrix composed of biological apatite and detail. The fundamental understanding of this mechan- collagen [11, 16, 17]. As a result, the surrounding bone ism provides the guidelines for designing novel bioactive comes into direct contact with the surface apatite layer Fig. l. Glass-ceramic A-W in clinical use: intervertebral discs(A), artificial vertebrae(B), spinal spacer(C), iliac crests(D), porous spacer(E), and bone filler (F Table I Mechanical properties of bioactive ceramics and human cortical and cancellous bones Strength(MPa) (GPa) Fracture toughness, KIC(MP Compressive oglass(45S5) 500-1000 15-200 80-110 Glass-ceramic A-W Human bone 0.05-0.5 50-150
F2)) and b-wollastonite (CaO SiO2) in an MgO–CaO– SiO2 glassy matrix [6]. The above have been developed in the forms of bulks and particulates with dense and porous structures. For example, Bioglasss and Bioglass-type glasses in the form of particulates have gained over a million successes in periodontal bone repair (for example [7]). HA, in bulk and granular forms with dense and porous structures, is popularly used as bone spacers and fillers, and a number of clinical successes have been documented (for example [8]). Glass-ceramic A-W, owing to its superior mechanical strength and excellent bone-bonding ability, has been applied, not only as bone spacers and fillers in the bulk and granular forms with dense and porous structures, but also as artificial vertebrae, intervertebral discs, and iliac crests in dense bulk form (for example [9]). These products are shown in Fig. 1. As the clinical applications of bioactive ceramics progress, their limited mechanical properties are becoming apparent. As indicated in Table 1, even glass-ceramic A-W, which has higher mechanical strength than the other bioactive ceramics and human cortical bone, cannot be used to repair bone defects in high-load bones, such as femoral and tibial bones, as its fracture toughness is lower and elastic modulus higher than those of cortical bone. Therefore, the development of bioactive materials that have improved and ultimately bone-like mechanical properties is desirable. The mechanism of integration of bioactive ceramics with living bone has been investigated considerably in detail. The fundamental understanding of this mechanism provides the guidelines for designing novel bioactive materials with different mechanical properties. Therefore, this paper reviews the mechanism of integration of bioactive ceramics with living bone, which has been revealed from recent in vitro and in vivo studies, and presents some examples of novel bioactive materials with different mechanical properties. 2. Fundamentals for designing new bioactive materials 2.1. Mechanism of integration of bioactive ceramics with living bone Bioactive ceramics have a common characteristic at the interface with bone after integration. In fact, bioactive ceramics, including Bioglasss, HA, and grass-ceramic A-W, reveal a layer of apatite at the interface, mediating integration with bone [10,11], as shown in Fig. 2. Histological examinations in vivo show that this apatite layer is formed on the ceramic surface early in the implantation period and, thereafter, the bone matrix integrates into the apatite [12–15]. Detailed characterization indicates that this apatite layer consists of nano-crystals of carbonate-ion-containing apatite that has a defective structure and low crystallinity [13,14,16]. These features are, in fact, very similar to those of the mineral phase in bone and, hence, boneproducing cells, i.e., osteoblasts, can preferentially proliferate on the apatite, and differentiate to form an extracellular matrix composed of biological apatite and collagen [11,16,17]. As a result, the surrounding bone comes into direct contact with the surface apatite layer. Fig. 1. Glass-ceramic A-W in clinical use: intervertebral discs (A), artificial vertebrae (B), spinal spacer (C), iliac crests (D), porous spacer (E), and bone filler (F). Table 1 Mechanical properties of bioactive ceramics and human cortical and cancellous bones Strength (MPa) Young’s modulus (GPa) Fracture toughness, KIC (MPa m1/2) Compressive Bending Bioglasss (45S5) — 42 35 — HA 500–1000 115–200 80–110 1.0 Glass-ceramic A-W 1080 220 118 2.0 Human bone Cancellous 2–12 — 0.05–0.5 — Cortical 100–230 50–150 7–30 2–12 2162 T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175
T. Kokubo et al./ Biomaterials 24(2003)2161 2163 components for it to have apatite-forming ability and for it to be able to integrate with bone in the body. However, assessments of apatite formation on material with different compositions in SBF imply that CaO and P2O5 are not the essential components for apatite formation. Fig 3 shows the compositional dependence of apatite formation in SBF of glasses in the systems Cao-P2O5-SiO2 [25]. Na20-CaO-SiO2 [26], and K20-SiO -T10, [27]. Interestingly, in the Cao-P2O5- SiO2 system, the composition of the glass forming an apatite layer in an SBF was based on the Cao-sio system and not on the Cao-P2Os system. The P2Os-free Fig. 2. TEM photograph of the interface between glass-ceramic A-w Cao-SiO2 glasses were actually shown to bond to living and a rat tibia(8 weeks after implantation) bone in animals by forming apatite on their surfaces [28]. Evaluation of the Na, O-CaO-Sio, system indi Table 2 cates that, not only the P2Os-free Cao-Sio2 glasses, but lon concentrations of human blood plasma, SBF and m-SBF also the CaO- and P2Os-free Na,O-SiO2 glasses can form apatite in SBF. furthermore even the k0-TiO based glasses have been shown to form apatite. On Na K Mg Ca-CI HCO3 HPOA SO4 glasses such as those in the binary systems, CaO-Sio ood plasma 142.0 5.0 1.5 5103.027.01.00.5 Na2O-SiO2, and K2O-TiO2, apatite formation is SBF 14205.01.52.5148.84.21.0 speculated to proceed by the following mechanism m-SBE 14205.01.52.5103.010.01.00.5 The glass releases Ca, Na*, or K ions from its Buffered at pH 7.40 with tris-hydroxymethylaminomethane and surfaces via an exchange with the h3o ion in the sBF IM HCI to form Si-OH or Ti-OH groups on their surfaces b Buffered at pH 7.40 with 2-(4-(2-hydroxyethyl)-l-piperazinylethane Water molecules in the sbF then or simultaneously sulfonic acid and IM NaOH react with the Si-O-Si or Ti-O-ti bond to form additional Si-OH or Ti-OH groups. The Si-OH and When this process occurs, a chemical bond is formed Ti-oH groups formed induce apatite nucleation, and between the bone mineral and the surface apatite to decrease the interfacial energy between them. It can be nucleation by increasing the ionic activity product (IAP) concluded from these findings that an essential require of apatite in the fluid [26, 27, 29]. Once the apatite nuclei are formed, they can grow spontaneously by consuming ment for an artificial material to bond to living bone is the calcium and phosphate ions in the surrounding fluid the formation of a layer of biologically active bone-like apatite on its surface in the body. because the body fluid is highly supersaturated with The in vivo formation of an apatite layer on the respect to the apatite [18,191 surface of a bioactive ceramic can be reproduced in a protein-free and acellular simulated body fluid(SBF 2. 3. Functional groups for apatite nucleation which is prepared to have an ion concentration nearly equal to that of human blood plasma [13-15, 18-24 The catalytic effect of the Si-OH groups and Ti-OH (Na+142.0,K+5.0,Ca2+2.5,Mg2+1,C1-147.8, groups for the apatite nucleation has been proven by the HCO3 4.2, HPO4 1.0, and SO4 0.5 mM, and a ph of observation that silica and titania gels produced by the 7.25 or 7.40), as given in Table 2. Therefore, the sol-gel method form apatite on their surfaces in SBF bioactivity of an artificial material can be evaluated by and these functional groups are abundant on their examining the formation of apatite on its surface in surfaces [30, 31]. Zirconia [32], niobium oxide [33], and SBF. In this case, what types of materials form an tantalum oxide [34] gels have also been shown to form apatite layer on their surfaces in the living body? apatite on their surfaces in SBF, as shown in Fig 4. This indicates that Zr-OH, Nb-OH, and Ta-OH groups are ffective for apatite nucleation. Other assessments using 2. 2. Mechanism of apatite formation on bioactive self-assembled monolayers (SAM)in SBf have indi ceramIcs cated that COOH and PO,H2 groups are also effective for apatite nucleation [35] Representative bioactive ceramics, e. g, Bioglass, However, it has been suggested that the efficacy of HA, and grass-ceramic A-W, contain Ha or its apatite nucleation of the above functional groups is such as CaO and P2Os. Therefore, it had determined, not by their composition alone, but ved that a material should have these in a complicated fashion that is dependent on their
When this process occurs, a chemical bond is formed between the bone mineral and the surface apatite to decrease the interfacial energy between them. It can be concluded from these findings that an essential requirement for an artificial material to bond to living bone is the formation of a layer of biologically active bone-like apatite on its surface in the body. The in vivo formation of an apatite layer on the surface of a bioactive ceramic can be reproduced in a protein-free and acellular simulated body fluid (SBF), which is prepared to have an ion concentration nearly equal to that of human blood plasma [13–15, 18–24] (Na+ 142.0, K+ 5.0, Ca2+ 2.5, Mg2+ 1.5, Cl 147.8, HCO3 4.2, HPO4 2 1.0, and SO4 2 0.5 mm, and a pH of 7.25 or 7.40), as given in Table 2. Therefore, the bioactivity of an artificial material can be evaluated by examining the formation of apatite on its surface in SBF. In this case, what types of materials form an apatite layer on their surfaces in the living body? 2.2. Mechanism of apatite formation on bioactive ceramics Representative bioactive ceramics, e.g., Bioglasss, HA, and grass-ceramic A-W, contain HA or its components, such as CaO and P2O5. Therefore, it had been believed that a material should have these components for it to have apatite-forming ability and for it to be able to integrate with bone in the body. However, assessments of apatite formation on materials with different compositions in SBF imply that CaO and P2O5 are not the essential components for apatite formation. Fig. 3 shows the compositional dependence of apatite formation in SBF of glasses in the systems: CaO–P2O5–SiO2 [25], Na2O–CaO–SiO2 [26], and K2O–SiO2–TiO2 [27]. Interestingly, in the CaO–P2O5– SiO2 system, the composition of the glass forming an apatite layer in an SBF was based on the CaO–SiO2 system and not on the CaO–P2O5 system. The P2O5-free CaO–SiO2 glasses were actually shown to bond to living bone in animals by forming apatite on their surfaces [28]. Evaluation of the Na2O–CaO–SiO2 system indicates that, not only the P2O5-free CaO–SiO2 glasses, but also the CaO- and P2O5-free Na2O–SiO2 glasses can form apatite in SBF. Furthermore, even the K2O–TiO2- based glasses have been shown to form apatite. On glasses such as those in the binary systems, CaO–SiO2, Na2O–SiO2, and K2O–TiO2, apatite formation is speculated to proceed by the following mechanism. The glass releases Ca2+, Na+, or K+ ions from its surfaces via an exchange with the H3O+ ion in the SBF to form Si–OH or Ti–OH groups on their surfaces. Water molecules in the SBF then or simultaneously react with the Si–O–Si or Ti–O–Ti bond to form additional Si–OH or Ti–OH groups. The Si–OH and Ti–OH groups formed induce apatite nucleation, and the released Ca2+, Na+, or K+ ions accelerate apatite nucleation by increasing the ionic activity product (IAP) of apatite in the fluid [26,27,29]. Once the apatite nuclei are formed, they can grow spontaneously by consuming the calcium and phosphate ions in the surrounding fluid because the body fluid is highly supersaturated with respect to the apatite [18,19]. 2.3. Functional groups for apatite nucleation The catalytic effect of the Si–OH groups and Ti–OH groups for the apatite nucleation has been proven by the observation that silica and titania gels produced by the sol–gel method form apatite on their surfaces in SBF, and these functional groups are abundant on their surfaces [30,31]. Zirconia [32], niobium oxide [33], and tantalum oxide [34] gels have also been shown to form apatite on their surfaces in SBF, as shown in Fig. 4. This indicates that Zr–OH, Nb–OH, and Ta–OH groups are effective for apatite nucleation. Other assessments using self-assembled monolayers (SAM) in SBF have indicated that COOH and PO4H2 groups are also effective for apatite nucleation [35]. However, it has been suggested that the efficacy of apatite nucleation of the above functional groups is determined, not by their composition alone, but in a complicated fashion that is dependent on their Table 2 Ion concentrations of human blood plasma, SBF and m-SBF Concentration/mm Na+ K+ Mg2+ Ca2+ Cl HCO3 HPO4 2 SO4 2 Blood plasma 142.0 5.0 1.5 2.5 103.0 27.0 1.0 0.5 SBFa 142.0 5.0 1.5 2.5 148.8 4.2 1.0 0.5 m-SBFb 142.0 5.0 1.5 2.5 103.0 10.0 1.0 0.5 aBuffered at pH 7.40 with tris-hydroxymethylaminomethane and 1m HCl. bBuffered at pH 7.40 with 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethane sulfonic acid and 1m NaOH. Fig. 2. TEM photograph of the interface between glass-ceramic A-W and a rat tibia (8 weeks after implantation). T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175 2163
T. Kokubo et al. Biomaterials 24(2003)2161-2175 aoNa2O如04680cao mol% mo% Fig 3. Compositional dependence of apatite formation on glasses in the systems: CaO-P2O5-SiO2. Na20-CaO-SiOz, and K20-SiOr-TiOz after f for 28d Fig 4. SEM photographs of the surfaces of silica(A), titania(B), zirconia(C), niobium oxide(D), and tantalum oxide(e) gels after soaking in an SBF for 14d concentration and structural arrangements. For exam- however, the amorphous gel forms no apatite, even ple, a silica gel that has been derived by hydrolysis and though it has much more abundant Ti-OH groups than polycondensation of tetraethoxysilane(TEOS) in water the anatase and rutile gels [39), as shown Fig. 5. Sodium- in the presence of polyethylene glycol(PEG-silica) loses or calcium-containing titania gels can release sodium or its apatite-forming ability on heat treatment at tem- calcium ions on immersion in SBf to increase the IAP peratures above 900 C, owing to a decrease in the and thereby provide much more favorable conditions number of Si-OH groups [36]. Silica gels, which are for apatite nucleation than for a pure titania gel derived in water in the absence of polyethylene glycol or However, even these gels do not form apatite if they the different arrangea b ay s theel, have an equivalent do not assume the anatase structure [40, 41]. Similarly in the presence of polyacrylic ad number of Si-OH groups PEG-Silica. but these pure zirconia gel and zirconia gels containing sodium or how no apatite- form ity, presumably because of calcium form apatite in SBF only when they assume a ent of the Si-OH groups [37]. tetragonal and/or a monoclinical structure [42]. Con However, silicate ions dissolved from silica gel can cerning this structural dependence, it has been suggested induce apatite formation, independent of the source that the Ti-Oh or Zr-oh groups in anatase or silica gels [38] the tetragonal /monoclinic structures may provide effec- A titania gel prepared from tetraisopropyl titanate tive epitaxial nucleation sites for apatite crystals (TiPT)assumes an amorphous, anatase, or rutile For example, the arrangement of oxygen ions in the structure, when it is heat-treated at 500"C, 600.C and anatase structure along the (100) plane fits well to that 800C, respectively. Among these, the anatase gel forms of the hydroxide ions in Ha along the(000 1)plane apatite most effectively, followed by the rutile gel; [39, 42
concentration and structural arrangements. For example, a silica gel that has been derived by hydrolysis and polycondensation of tetraethoxysilane (TEOS) in water in the presence of polyethylene glycol (PEG–silica) loses its apatite-forming ability on heat treatment at temperatures above 900C, owing to a decrease in the number of Si–OH groups [36]. Silica gels, which are derived in water in the absence of polyethylene glycol or in the presence of polyacrylic acid, have an equivalent number of Si–OH groups as the PEG–silica, but these show no apatite-forming ability, presumably because of the different arrangement of the Si–OH groups [37]. However, silicate ions dissolved from silica gel can induce apatite formation, independent of the source silica gels [38]. A titania gel prepared from tetraisopropyl titanate (TiPT) assumes an amorphous, anatase, or rutile structure, when it is heat-treated at 500C, 600C and 800C, respectively. Among these, the anatase gel forms apatite most effectively, followed by the rutile gel; however, the amorphous gel forms no apatite, even though it has much more abundant Ti–OH groups than the anatase and rutile gels [39], as shown Fig. 5. Sodiumor calcium-containing titania gels can release sodium or calcium ions on immersion in SBF to increase the IAP, and thereby provide much more favorable conditions for apatite nucleation than for a pure titania gel. However, even these gels do not form apatite if they do not assume the anatase structure [40,41]. Similarly, pure zirconia gel and zirconia gels containing sodium or calcium form apatite in SBF only when they assume a tetragonal and/or a monoclinical structure [42]. Concerning this structural dependence, it has been suggested that the Ti–OH or Zr–OH groups in anatase or the tetragonal/monoclinic structures may provide effective epitaxial nucleation sites for apatite crystals. For example, the arrangement of oxygen ions in the anatase structure along the (1 0 0) plane fits well to that of the hydroxide ions in HA along the (0 0 0 1) plane [39,42]. Fig. 3. Compositional dependence of apatite formation on glasses in the systems: CaO–P2O5–SiO2, Na2O–CaO–SiO2, and K2O–SiO2–TiO2 after soaking in an SBF for 28 d. Fig. 4. SEM photographs of the surfaces of silica (A), titania (B), zirconia (C), niobium oxide (D), and tantalum oxide (E) gels after soaking in an SBF for 14 d. 2164 T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175
T. Kokubo et al. I Biomaterials 24(2003)2161-2175 Fig. 5. SEM photographs of the surfaces of titania gels with amorphous(A), anatase(B) and rutile( C)structures after soaking in an SBF for 7d. Apatite ca/P=1.65 100nm Energy /keV Energy /keV Fig. 6. TEM-EDX profiles of the nano-sized apatite formed on amorphous sodium titanate(A)and Ha sintered at 800C(B). after soaking in an SBF for 72 and 48 h, respectively. (center of the electron diffraction). 2.4. Mechanism of apatite nucleation by functiona the fluid to form amorphous calcium titanate. This calcium titanate later combines with phosphate ions in the fluid to form amorphous calcium phosphate with a and glass-ceramic A-W are multi-compo- low Ca/P ratio. The calcium phosphate transforms into nent systems that are based upon the Na2O-SiO2 or apatite, which exhibits a Ca/P ratio of 1.65, and contains Cao-SiO2 binary system. As a model of these materials, a small concentration of Mg and Na, similar to bone apatite formation on a simple binary sodium silicate mineral, as shown in Fig 6A (20Na20-80SiO2 in mol%) glass was investigated in To reveal the reasons why this complex process is detail using X-ray photoelectron spectroscopy (XPS) required for apatite formation, the zeta potential of the Ind transmission electron microscopy accompanied by surface of sodium titanate was measured by laser energy-dispersive X-ray analysis (TEM-EDX). This electrophoresis at various SBF soaking times [47]. It glass releases Na ions into SBF via an exchange with was found that the surface of the sodium titanate was the H3O ions in the fluid to form Si-OH groups on its highly negatively charged immediately after it was surface [43, 44]. The Si-OH groups formed immediately soaked in the SBF, as shown in Fig. 7. The surface combine with Ca- ions in the fluid to form an potential increased with increasing soaking time up to a amorphous calcium silicate on the glass surface. After maximum positive value. Thereafter, it decreased with a long soaking period, this calcium silicate combines increasing soaking time, reached a negative value with phosphate ions in the fluid to form an amorphous and finally converged to a constant negative value. On calcium phosphate with a low Ca/P atomic ratio, and basis of this finding, the complex process of apatite his phase later transforms into bone-like apatite crystal, formation described above is well interpreted in terms of increasing its Ca/P ratio and incorporating minor ions the electrostatic interaction of the functional groups such as Na, Mg+, and CI with the ions in the fluid. The Ti-Oh groups formed on In a different model, the mechanism of apatite the surface of sodium titanate after soaking in SBF are formation on an amorphous sodium titanate for negatively charged and, hence, combine selectively with on titanium metal was also examined by XPS and TEM- the positively charged Ca- ions in the fluid to form EDX 145, 46]. In the sBf, the sodium titanate releases calcium titanate, as shown in Fig. 7. As the calcium ions Na ions via exchange with the H3o ions in the fluid accumulate on the surface, the surface gradually gains to form Ti-OH groups on its surface. The Ti-OH an overall positive charge. As a result, the positively groups formed immediately combine with Ca- ions in charged surface combines with negatively charged
2.4. Mechanism of apatite nucleation by functional groups Bioglasss and glass-ceramic A-W are multi-component systems that are based upon the Na2O–SiO2 or CaO–SiO2 binary system. As a model of these materials, apatite formation on a simple binary sodium silicate (20Na2O 80SiO2 in mol%) glass was investigated in detail using X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy accompanied by energy-dispersive X-ray analysis (TEM-EDX). This glass releases Na+ ions into SBF via an exchange with the H3O+ ions in the fluid to form Si–OH groups on its surface [43,44]. The Si–OH groups formed immediately combine with Ca2+ ions in the fluid to form an amorphous calcium silicate on the glass surface. After a long soaking period, this calcium silicate combines with phosphate ions in the fluid to form an amorphous calcium phosphate with a low Ca/P atomic ratio, and this phase later transforms into bone-like apatite crystal, increasing its Ca/P ratio and incorporating minor ions such as Na+, Mg2+, and Cl. In a different model, the mechanism of apatite formation on an amorphous sodium titanate formed on titanium metal was also examined by XPS and TEMEDX [45,46]. In the SBF, the sodium titanate releases Na+ ions via exchange with the H3O+ ions in the fluid to form Ti–OH groups on its surface. The Ti–OH groups formed immediately combine with Ca2+ ions in the fluid to form amorphous calcium titanate. This calcium titanate later combines with phosphate ions in the fluid to form amorphous calcium phosphate with a low Ca/P ratio. The calcium phosphate transforms into apatite, which exhibits a Ca/P ratio of 1.65, and contains a small concentration of Mg and Na, similar to bone mineral, as shown in Fig. 6A. To reveal the reasons why this complex process is required for apatite formation, the zeta potential of the surface of sodium titanate was measured by laser electrophoresis at various SBF soaking times [47]. It was found that the surface of the sodium titanate was highly negatively charged immediately after it was soaked in the SBF, as shown in Fig. 7. The surface potential increased with increasing soaking time up to a maximum positive value. Thereafter, it decreased with increasing soaking time, reached a negative value again, and finally converged to a constant negative value. On basis of this finding, the complex process of apatite formation described above is well interpreted in terms of the electrostatic interaction of the functional groups with the ions in the fluid. The Ti–OH groups formed on the surface of sodium titanate after soaking in SBF are negatively charged and, hence, combine selectively with the positively charged Ca2+ ions in the fluid to form calcium titanate, as shown in Fig. 7. As the calcium ions accumulate on the surface, the surface gradually gains an overall positive charge. As a result, the positively charged surface combines with negatively charged Fig. 5. SEM photographs of the surfaces of titania gels with amorphous (A), anatase (B), and rutile (C) structures after soaking in an SBF for 7 d. Fig. 6. TEM-EDX profiles of the nano-sized apatite formed on amorphous sodium titanate (A) and HA sintered at 800C (B), after soaking in an SBF for 72 and 48 h, respectively. (* center of the electron diffraction). T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175 2165
T. Kokubo et al./ Biomaterials 24(2003)2161-2175 Ti-OH groups ee eleele Formation of TI-OH groups Formation of amorphous Formation of amorphou Before soaking in SBF Formation of Apatite 个不个不 Time/h Fig. 7. Schematic showing the relationship between the changes in surface structure and the potential of amorphous sodium titanate in the apatite formatio on its surface in phosphate ions to form amorphous calcium phosphate. ately after soaking in the SBF, owing to its surface OH This calcium phosphate spontaneously transforms into and PO4 ions, and selectively combines with the the apatite, because the apatite is the stable phase in positively charged Ca- ions in the fluid to form Ca- body environment [48. A similar electrostatic mechan- rich calcium phosphate As the calcium ions accumulate, ism for apatite formation might hold for the other the surface imparts a positive charge and thus combine apatite nucleation, because all these functional groups to form amorphous calcium phosphate with a lonGo functional groups described above that are effective for with the negatively charged phosphate ions in the flui have isoelectric zero points at pH values much lower ratio. This phase is metastable, and eventually trans than 7 and, thus, should be negatively charged in the forms into stable bone-like apatite living body [49 It is has been reported that the bioactivity of HA As already described, even sintered HA forms a bone- decreases with increasing sintering temperature [51] like apatite layer on its surface in the living body, and This can be interpreted in terms of the degree of negative bonds to bone through this apatite layer. HA has none charge on its surface and the rate of bone-like apatite of such functional groups for the apatite nucleation as formation. In the case of HA sintered at 1200C,it described above. Despite this, how does HA form bone- implies a low negative charge after soaking in an SBF, like apatite on its surface in the living body? When HA owing to a smaller number of OH ions on its surface sintered at 800 C is soaked in an SBF, observations of compared with HA sintered at 800C. Thus, this HA its surface using TEM-EDX show that the Ca/P ratio has a low reaction rate in the process described above increases from 1.67 to 1.87 within 3 h [50], as shown in Therefore, the rate of formation of bone-like apatite Fig 8. The Ha then decreases its Ca/P ratio to 1. 41 layer on the Ha decreases with increasing sintering within the next 6h, forming an amorphous calcium temperature phosphate, and then gradually increases its Ca/P ratio to 1.65, forming nano-sized bone-like apatite, as shown in Fig 6B. During this process, the zeta potential of the 3. Preparation and properties of novel bioactive materials urface of the ha varies with soaking time as shown in Fig 8. Initially, it has a negative zeta potential that 3.1. Tough bioactive materials increases to a maximum positive value within 3 h, and then this decreases rapidly to a negative value within 6 h The fundamental findings on bone-like apatite for which gradually converges to a constant negative value. mation on bioactive ceramics provide a basis for the This means that the ha is negatively charged immedi- design of various types of bioactive materials. For
phosphate ions to form amorphous calcium phosphate. This calcium phosphate spontaneously transforms into the apatite, because the apatite is the stable phase in body environment [48]. A similar electrostatic mechanism for apatite formation might hold for the other functional groups described above that are effective for apatite nucleation, because all these functional groups have isoelectric zero points at pH values much lower than 7 and, thus, should be negatively charged in the living body [49]. As already described, even sintered HA forms a bonelike apatite layer on its surface in the living body, and bonds to bone through this apatite layer. HA has none of such functional groups for the apatite nucleation as described above. Despite this, how does HA form bonelike apatite on its surface in the living body? When HA sintered at 800C is soaked in an SBF, observations of its surface using TEM-EDX show that the Ca/P ratio increases from 1.67 to 1.87 within 3 h [50], as shown in Fig. 8. The HA then decreases its Ca/P ratio to 1.41 within the next 6 h, forming an amorphous calcium phosphate, and then gradually increases its Ca/P ratio to 1.65, forming nano-sized bone-like apatite, as shown in Fig. 6B. During this process, the zeta potential of the surface of the HA varies with soaking time, as shown in Fig. 8. Initially, it has a negative zeta potential that increases to a maximum positive value within 3 h, and then this decreases rapidly to a negative value within 6 h, which gradually converges to a constant negative value. This means that the HA is negatively charged immediately after soaking in the SBF, owing to its surface OH and PO4 3 ions, and selectively combines with the positively charged Ca2+ ions in the fluid to form Carich calcium phosphate. As the calcium ions accumulate, the surface imparts a positive charge, and thus combine with the negatively charged phosphate ions in the fluid to form amorphous calcium phosphate with a low Ca/P ratio. This phase is metastable, and eventually transforms into stable bone-like apatite. It is has been reported that the bioactivity of HA decreases with increasing sintering temperature [51]. This can be interpreted in terms of the degree of negative charge on its surface and the rate of bone-like apatite formation. In the case of HA sintered at 1200C, it implies a low negative charge after soaking in an SBF, owing to a smaller number of OH ions on its surface compared with HA sintered at 800C. Thus, this HA has a low reaction rate in the process described above. Therefore, the rate of formation of bone-like apatite layer on the HA decreases with increasing sintering temperature. 3. Preparation and properties of novel bioactive materials 3.1. Tough bioactive materials The fundamental findings on bone-like apatite formation on bioactive ceramics provide a basis for the design of various types of bioactive materials. For Fig. 7. Schematic showing the relationship between the changes in surface structure and the potential of amorphous sodium titanate in the apatite formation process on its surface in an SBF. 2166 T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175
T. Kokubo et al. Biomaterials 24(2003)2161-2175 Ca-rich calcium phosphate Bonelike nano-apatite 1500 Fig 9. AES depth profiles of the surface of titanium before(A)and after(B) the NaOH and heat treatments, and after subsequent soaking Time/h Fig8.The Ca/P atomic ratio and zeta potential of the surface of HA titanate formed is integrated with the metal substrate as a function of soaking time in an SBF through a graded structure, where it gradually changes into metallic titanium on moving inwards toward the example, bioactivity can be induced on surfaces of non- substrate within a depth of 1. 5 um [59], as shown in bioactive materials either by the formation of the Fig 9. The sodium titanate layer on the titanium metal functional groups that are able to induce apatite forms bone-like apatite on its surface in Sbf by the formation, or by forming thin ceramic phases that have mechanism described above. The formed apatite reveals the potential to form the functional groups on exposure a graded structure that mirrors that of the sodium o a body environment. titanate, as shown in Fig 9; this, in turn, imparts a tight itanium metal and its alloys are very tough, and adhesion to the metal substrate, i. e,>30 MPa [60]. have been widely used as orthopedic and dental The NaOh and heat treatments can even be applied implants. They are, however, non-bioactive, and there- to titanium metal with a complex macroporous structure fore, are usually coated with ha by using a high- to uniformly form the sodium titanate. This sodium temperature process, such as the plasma spraying titanate can induce apatite formation in a way guided by method, which partially decomposes and melts the ha the surface and cross-sectional macrotextures of the [52,53]. It has been suggested that such HA coatings are metal [61]. When titanium alloys, such as Ti-6Al-4V, liable to delaminate from the substrate, and to dissolve Ti-6A1-2Nb-Ta, and Ti-l5Mo-5Zr-3Al, are subjected in a short period after implantation. In view of the to NaOH and heat treatments, they form sodium composition of the above functional groups effective for titanate, which is free of the alloying components and apatite nucleation, titanium metal and its alloys have the hence, show apatite-forming ability in SBF [55, 62, 63 potential to exhibit intrinsic bioactivity by a surface The NaoH- and heat-treated titanium metal and its modification alloys have been investigated in a number of animal For example, when titanium metal is soaked in a 5M models, presenting promising results that could lead to aqueous NaOH solution at 60%C for 24 h and subse- eventual clinical application [64-71]. For example, when quently subjected to a heat treatment at 600C for l h, it a rectangular plate of pure titanium metal subjected to forms a layer of essentially amorphous sodium titanate the Naoh and heat treatment was implanted into a on its surface [54-57]. These NaOH and heat treatments rabbit tibia, it formed an apatite layer on its surface and do not induce a change in strength under tensile loading bonded to bone through this apatite layer at an early nor in fatigue strength under cyclic loading of the stage in the implantation period, as shown Fig 10. On titanium metal in saline solution [58. The sodium being implanted into the intramedullar canal of the
example, bioactivity can be induced on surfaces of nonbioactive materials either by the formation of the functional groups that are able to induce apatite formation, or by forming thin ceramic phases that have the potential to form the functional groups on exposure to a body environment. Titanium metal and its alloys are very tough, and have been widely used as orthopedic and dental implants. They are, however, non-bioactive, and therefore, are usually coated with HA by using a hightemperature process, such as the plasma spraying method, which partially decomposes and melts the HA [52,53]. It has been suggested that such HA coatings are liable to delaminate from the substrate, and to dissolve in a short period after implantation. In view of the composition of the above functional groups effective for apatite nucleation, titanium metal and its alloys have the potential to exhibit intrinsic bioactivity by a surface modification. For example, when titanium metal is soaked in a 5 m aqueous NaOH solution at 60C for 24 h and subsequently subjected to a heat treatment at 600C for 1 h, it forms a layer of essentially amorphous sodium titanate on its surface [54–57]. These NaOH and heat treatments do not induce a change in strength under tensile loading nor in fatigue strength under cyclic loading of the titanium metal in saline solution [58]. The sodium titanate formed is integrated with the metal substrate through a graded structure, where it gradually changes into metallic titanium on moving inwards toward the substrate within a depth of 1.5 mm [59], as shown in Fig. 9. The sodium titanate layer on the titanium metal forms bone-like apatite on its surface in SBF by the mechanism described above. The formed apatite reveals a graded structure that mirrors that of the sodium titanate, as shown in Fig. 9; this, in turn, imparts a tight adhesion to the metal substrate, i.e., >30 MPa [60]. The NaOH and heat treatments can even be applied to titanium metal with a complex macroporous structure to uniformly form the sodium titanate. This sodium titanate can induce apatite formation in a way guided by the surface and cross-sectional macrotextures of the metal [61]. When titanium alloys, such as Ti–6Al–4V, Ti–6Al–2Nb–Ta, and Ti–15Mo–5Zr–3Al, are subjected to NaOH and heat treatments, they form sodium titanate, which is free of the alloying components and, hence, show apatite-forming ability in SBF [55,62,63]. The NaOH- and heat-treated titanium metal and its alloys have been investigated in a number of animal models, presenting promising results that could lead to eventual clinical application [64–71]. For example, when a rectangular plate of pure titanium metal subjected to the NaOH and heat treatment was implanted into a rabbit tibia, it formed an apatite layer on its surface and bonded to bone through this apatite layer at an early stage in the implantation period, as shown Fig. 10. On being implanted into the intramedullar canal of the Fig. 8. The Ca/P atomic ratio and zeta potential of the surface of HA as a function of soaking time in an SBF. Fig. 9. AES depth profiles of the surface of titanium before (A) and after (B) the NaOH and heat treatments, and after subsequent soaking T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175 2167
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 after
rabbit femur, a cylindrical rod of NaOH- and heattreated 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
T. Kokubo et al. Biomaterials 24(2003)2161-2175 旧mdmm NaOH- and heat-treated 亘 12 Time /week Time/ week Fig 12. Detaching fracture loads of the untreated and the NaoH- and heat-treated titanium metals implanted in a rabbit tibia(A), and the pull-out fracture loads of those implanted in a rabbit femur(B) for various periods BC A Screw: Ti-6A1-2Nb-Ta alloy B. Socket: Ti-6Al-2Nb-Ta alloy C Socket surface: macroporous Ti (NaOH and heat treatments) D. Cup: Ultra-high molecular weight polyethylene E Head: Y-TZP F Proximal NaoH and heat treatments) G Stem: Ti-6Al-2Nb-Ta alloy Fig. 13. Bioactive titanium metal in a clinical hip joint system(photograph courtesy of Kobe Steel Ltd, Japan) The Zr-OH groups in the tetragonal structure are also effective for apatite nucleation, as described above. A Metal Apatite Bone nano-composite of ceria-stabilized tetragonal zirconia (Ce-TZP)and alumina has been suggested to have excellent wear and fracture resistance as well as a low- temperature degradation in its strength [79]. When this Ta type of nano-composite was subjected to treatment in an aqueous solution of concentrated H, PO4, H2 SO4, HCI or Naoh at 95C for 4d, it formed many Zr-OH groups on its surface and, as a result, formed apatite in SBF [80]. By using this type of bioactive TZP, it is expected that bifunctional implants can be designed that have wear resistance and bone-bonding ability. These will be useful in the repair of joint systems 3. 2. Soft bioactive materials Fig 14. SEM-EDX profile of the interface between the NaoH-and heat-treated tantalum metal and a rabbit tibial bone(8 weeks after All the bioactive ceramics and metals described above ave higher elastic moduli than that of human cortical
The Zr–OH groups in the tetragonal structure are also effective for apatite nucleation, as described above. A nano-composite of ceria-stabilized tetragonal zirconia (Ce-TZP) and alumina has been suggested to have excellent wear and fracture resistance as well as a lowtemperature degradation in its strength [79]. When this type of nano-composite was subjected to treatment in an aqueous solution of concentrated H3PO4, H2SO4, HCl, or NaOH at 95C for 4 d, it formed many Zr–OH groups on its surface and, as a result, formed apatite in SBF [80]. By using this type of bioactive TZP, it is expected that bifunctional implants can be designed that have wear resistance and bone-bonding ability. These will be useful in the repair of joint systems. 3.2. Soft bioactive materials All the bioactive ceramics and metals described above have higher elastic moduli than that of human cortical Fig. 12. Detaching fracture loads of the untreated and the NaOH- and heat-treated titanium metals implanted in a rabbit tibia (A), and the pull-out fracture loads of those implanted in a rabbit femur (B) for various periods. Fig. 13. Bioactive titanium metal in a clinical hip joint system (photograph courtesy of Kobe Steel Ltd., Japan). Fig. 14. SEM-EDX profile of the interface between the NaOH- and heat-treated tantalum metal and a rabbit tibial bone (8 weeks after implantation). T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175 2169
70 T. Apatite Fig 15. SEM photographs of the surface of titanium metal after anodic oxidation in I M H,SO4 under 155V for I min(A), and after subsequent oaking in an SBF for 3d ( B). 200一 Organic segment for flexibility Inorganic segment for bioactivity 0 Fig. 16. Schematic drawing of the structure of a bioactive inorganic- organic hybrid. Fig 17. TEM photograph of the PTMO-TiO2 hybrid (center of the electron dif bone and, hence, are liable to induce bone resorption owing to the stress shielding that surrounds them. It is expected that bioactive materials with low elastic moduli er,these hybrids have decreased mechanical strength in SBF when they tain Cao. and h as well as deformability can be obtained if bioactive forming ability when they do not contain Cao [88] inorganic components, such as silica and titania, can be combined with a flexible organic component at the In contrast to these hybrids, CaO-free PDMS-TiO2 or molecular level. as shown in Fig. 16. It has been shown PTMO-TiO2 binary hybrids prepared by the sol-gel that this type of inorganic-organic hybrid can be method show apatite-forming ability as well as stability prepared by using the sol-gel process in SBF when they are immersed in water at 80%C for 7d, The organic component in such a bioactive hybrid or 95C for 2d, respectively. This is because nano-sized is derived from precursor of polydimethylsiloxane anatase particles are precipitated homogeneously in the (HO-[Si(CH3)2-OI-H, PDMS) or poly(tetramethylene hybrids by the hot water treatment, as shown in Fig. 17 (C2H5O)3Si(CH2)3NHCOO-(CH2)4O) [89, 90]. These hybrids show bending strength and CONH(CH,)3Si(OCHs)3) terminated with 3-isocyana Youngs modulus that are almost equal to human cancellous bone as well as high deformability, as shown topropyltriethoxysilyl(Si-PTMO). The inorganic com- in Fig. 18. It is expected that their mechanical strengths TiPT(Ti(OC2H5)) precursor with or without incorpor ating calcium salts, such as CaCl, and Ca(NO3)2. The one if they were reinforced with some fibrous material hydrolysis and polycondensation of these precursors yields pore- and crack-free monolithic hybrids in the 3.3. Bioactive composites with bone-like mechanical PDMS or PTMO)CaO-SiOr-TiO2 system [81-87. properties These hybrids can exhibit elastic moduli that are almost equal to human cancellous bone, and have large As is well known, bone is a composite in which nano- deformability as well as apatite-forming ability. How- sized crystals of apatite are deposited on collagen fibers
bone and, hence, are liable to induce bone resorption owing to the stress shielding that surrounds them. It is expected that bioactive materials with low elastic moduli as well as deformability can be obtained if bioactive inorganic components, such as silica and titania, can be combined with a flexible organic component at the molecular level, as shown in Fig. 16. It has been shown that this type of inorganic–organic hybrid can be prepared by using the sol–gel process. The organic component in such a bioactive hybrid is derived from precursor of polydimethylsiloxane (HO–[Si(CH3)2–O]n–H, PDMS) or poly(tetramethylene oxide ((C2H5O)3Si(CH2)3NHCOO–((CH2)4O)n– CONH(CH2)3Si(OC2H5)3) terminated with 3-isocyanatopropyltriethoxysilyl (Si-PTMO). The inorganic component is derived from a TEOS (Si(OC2H5)4), and/or a TiPT (Ti(OC2H5)4) precursor with or without incorporating calcium salts, such as CaCl2 and Ca(NO3)2. T he hydrolysis and polycondensation of these precursors yields pore- and crack-free monolithic hybrids in the (PDMS or PTMO)–CaO–SiO2–TiO2 system [81–87]. These hybrids can exhibit elastic moduli that are almost equal to human cancellous bone, and have large deformability as well as apatite-forming ability. However, these hybrids have decreased mechanical strength in SBF when they contain CaO, and have no apatiteforming ability when they do not contain CaO [88]. In contrast to these hybrids, CaO-free PDMS–TiO2 or PTMO–TiO2 binary hybrids prepared by the sol–gel method show apatite-forming ability as well as stability in SBF when they are immersed in water at 80C for 7 d, or 95C for 2 d, respectively. This is because nano-sized anatase particles are precipitated homogeneously in the hybrids by the hot water treatment, as shown in Fig. 17 [89,90]. These hybrids show bending strength and Young’s modulus that are almost equal to human cancellous bone as well as high deformability, as shown in Fig. 18. It is expected that their mechanical strengths could be increased up to the level of human cortical bone if they were reinforced with some fibrous material. 3.3. Bioactive composites with bone-like mechanical properties As is well known, bone is a composite in which nanosized crystals of apatite are deposited on collagen fibers Fig. 15. SEM photographs of the surface of titanium metal after anodic oxidation in 1 m H2SO4 under 155 V for 1 min (A), and after subsequent soaking in an SBF for 3 d (B). Fig. 16. Schematic drawing of the structure of a bioactive inorganic– organic hybrid. Fig. 17. TEM photograph of the PTMO–TiO2 hybrid. (* center of the electron diffraction). 2170 T. Kokubo et al. / Biomaterials 24 (2003) 2161–2175
