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 50-150F2)) 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 Bio￾glass-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 becom￾ing 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 mechan￾ism provides the guidelines for designing novel bioactive materials with different mechanical properties. There￾fore, 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, bone￾producing 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