Materials Transactions, Vol. 59, No. 1 (2018) pp.

1 to 13
©2017 The Japan Institute of Metals and Materials OVERVIEW

Recent Progress in Research and Development of Metallic Structural Biomaterials

with Mainly Focusing on Mechanical Biocompatibility*1
Mitsuo Niinomi1,2,*2,*3
1
Graduate School of Engineering, Osaka University, Suita 565–0871, Japan
2
Graduate School of Science and Engineering, Meijo University, Nagoya 468–8502, Japan

The progress of metallic structural biomaterials, mainly titanium alloys, for implants with mainly focusing on mechanical biocompati-
bility is described. Mechanical biocompatibility includes not only Youngs modulus but also broad sense of mechanical biocompatibilities
such as balance of strength and elongation, fatigue endurance (fatigue strength) and fracture toughness. Specially, the present paper focuses on
developments of high fatigue strength of (α + β)-type titanium alloys composed of non-toxic elements, low Youngs modulus β-type titanium
alloys composed of non-toxic and allergy-free elements, Youngs modulus self-adjustable β-type titanium alloys composed of non-toxic ele-
ments, Ni-free β-type titanium alloys for biomedical applications. Ni-free stainless steels and Co-Cr-Mo alloys, cell viability of pure metals,
and some very recent research and development topics are also briefly introduced in the present paper.[doi:10.2320/matertrans.M2017180]

(Received October 10, 2017; Accepted October 23, 2017; Published December 25, 2017)
Keywords:metallic biomaterials, titanium and its alloys, stainless steels, cobalt-chromium-molybdenum alloys, zirconium alloys, Youngs
modulus, biodegradable metallic materials, surface modifications, additive manufacturing, groove design

1.Introduction tions. Furthermore, much attention has been paid to mechan-

ical biocompatibility, with focus on Youngs modulus, for the
Structural materials that show good mechanical biocom- design of metallic biomaterials1).
patibility (biomaterials) are required for use in implants that During above mentioned research and development on
substitute for failed hard tissue, such as failed bone. These metallic biomaterials with focusing on Ti and its alloys, re-
materials also need to show good stability under a high load. search and development of Ni-free stainless steels2) and Co-
The implants fabricated from these biomaterials must ex- Cr-Mo alloys3) for biomedical applications, biodegradable
hibit bone functionality. Mechanical reliability is a very im- metallic biomaterials including magnesium (Mg) alloys4),
portant attribute of structural materials used as bone substi- cell viability of pure metals5,6), and biofunctional surface
tute. From the viewpoint of mechanical reliability, metallic modifications7), etc. were progressed.
materials are superior to other materials because they exhibit Very recently, the design of mechanically biocompatible
an excellent balance of strength and ductility. They occupy metallic biomaterials, in which the user-friendliness during
almost of the structural materials for implants. In addition to implantation of the implants is taken into consideration, has
mechanical reliability, structural materials must fulfill the been proposed.
safety requirements for use in a living body. Therefore, bio- New trends of research and development of metallic bio-
materials must be composed of non-toxic and allergy-free materials including zirconium (Zr) based alloys for biomedi-
elements, and no dissolution of the constituent elements cal applications8,9), additive manufacturing (AM) by selected
must occur, that is, high corrosion resistance. In practice, laser melting (SLM)10) and electron beam melting (EBM)11)
stainless steels, cobalt (Co)-chromium (Cr)-molybdenum methods, and groove designing on the surface of the implant
(Mo) alloys, and titanium (Ti) and its alloys have been used to enhance the bone growth with the preferential direction12)
as representative implant materials. In the early stage of ap- are also raised in very recent years.
plications, mechanical reliability of these metallic biomateri- The progress in designing and developments of metallic
als was regarded as the most important factor; hence, gen- biomaterials are described in this paper, especially from the
eral structural metallic materials showing high corrosion view point of mechanical biocompatibility. Youngs modulus
resistance were applied in implants. Many of them are still is commonly used as the main indicator of the mechanical
used as structural biomaterials for implants. Subsequently, biocompatibility of biomaterials; however, the suitability of
with the increased concern regarding the safety require- mechanical characteristics (fatigue strength, balance of
ments, new alloys were designed for use as biomaterials to strength and ductility, and fracture toughness) to living tis-
circumvent problems related to toxicity and allergic reac- sue is also included into the broad sense of mechanical bio-
compatibility13) in this paper.
Some of very recent new topics including research and
development of Zr based alloys for biomedical applications,
*1
This Paper was Originally Published in Japanese in Materia Japan 56 AM for fabricating medical implants, and groove designing
(2017) 205–210. In order to introduce more recent topics on metallic
biomaterials, sections 4, 5, 9, and 10 were newly added. According to on the surface of the implant to enhance the bone growth
adding new sections, Tables 2 and 3, and Figs. 1–6, 8, 9, 13, and 19–25 with the preferential direction are also briefly described.
were newly added. The Refs. 1), 4–12), 14), 28–39), 51), and 57–72)
were also newly added. Following these changing, the numbers of ta-
bles, figures, and references were newly changed.
*2
Emeritus Professor, Visiting Professor, Tohoku University
*3
Visiting Professor, Nagoya University
2 M. Niinomi

2.Representative Practical Metallic Biomaterials for problems related to allergic reactions was initiated. Elements
Implants showing a high risk of allergic reactions were avoided in
metallic biomaterials: the addition of Ni, which is a high-
Ti and its alloys are superior in terms of biological bio- risk element from the viewpoint of allergic reactions25), has
compatibility, which is judged based on the chemical inter- been strongly avoided. Therefore, the development of Ni-
action of the material with living tissue and is evaluated by free metallic biomaterials was commenced. In the case of
cyto-toxicity or animal tests14–16). Ti and its alloys are gain- stainless steels, Ni was replaced with N, so that Ni-free
ing widespread importance due to their high stainless steel with a high N content was developed2). In the
biocompatibility. case of Co-Cr-Mo alloys, Ni- and carbon (C) free Co-Cr-Mo
Youngs moduli of SUS 316L stainless steel, which is the alloys were developed3). Ni in TiNi shape memory alloys
main stainless steel used for implants and Co-Cr-Mo alloys were pointed out, and so Ni-free shape memory Ti alloys
are approximately 180 and 210 GPa17), respectively. These were developed26,27).
values are much greater than that of cortical bone (hereafter,
referred to as bone), approximately 10–30 GPa18). In con- 4.Ni-Free Metallic Biomaterials
trast, Ti and Ti-6Al-4V ELI (Extra Low Interstitial), which
find practical applications in implants, show Youngs moduli As stated above, developments of Ni-free stainless steels,
of approximately 105–110 GPa18), which are much less than Co-Cr-Mo alloys, and titanium alloys were carried out. Ni-
those of SUS 316L stainless steel and Co-Cr-Mo alloys, but free titanium alloys will be described later in the section of
relatively comparable to that of bone. The use of Ti and its 8.2. Therefore, Ni-free stainless steels and Co-Cr-Mo alloys
alloys in implants can inhibit non-homogeneity of stress be- are introduced here.
tween the bone and the implant (referred to as stress shield- Ni-free austenitic stainless steels, that is, high nitrogen
ing) and is advantageous for bone remodeling according to stainless steels have been developed because of Ni allergy
the stress (referred to as bone remodeling). Therefore, the problem2). Deformation in wrought process of Ni-free stain-
mechanical biocompatibility of Ti and its alloys, considering less steel fabricated by ordinary fabricating process is not
Youngs modulus, is superior to those of SUS 316L stainless easy. The amount of its manganese (Mn) is also high. For
steel and Co-Cr-Mo alloys. This concept is connected to the solving these problems, new processing for making Ni-free
development of titanium alloys composed of non-toxic and stainless steel was developed. This new process fabricates
allergy-free elements and showing a low Youngs modulus the final products of Ni-free stainless steel without Mn28).
close to that of bone. This new process is shown in Fig. 128). Firstly, ferritic stain-
less steel is prepared and made into final shape of product
3.Development of Metallic Biomaterials by (in this case, wire). Then, ferritic stainless steel product is
Considering Safety to Living Tissue heated in nitrogen (N) gas atmosphere at high temperature.
N diffuses into ferritic stainless steel product and finally Ni-
Early metallic biomaterials contained toxic elements were free austenitic stainless steel product can be fabricated.
derived from general structural materials as stated above. Since the diffusion depth of N is limited to be several mm
Therefore, attempts were made to designing metallic bioma- from the surface of the product, the new process is applica-
terials composed of non-toxic elements. Firstly, the toxicity ble to make small products including wires with a small di-
of the β-stabilizing element vanadium (V), which is a con- ameter in the present state. Ni-free stainless steels developed
stituent element of Ti-6Al-4V ELI, was revealed19). are listed in Table 329).
Therefore, V in Ti-6Al-4V ELI was replaced by another Ni-free Co-Cr-Mo alloy has been already registered in
β-stabilizing element, iron (Fe) or niobium (Nb), both of
which are considered safer for living tissue than V. Ti-5Al-
2.5Fe20,21) and Ti-6Al-7Nb22), which are also (α + β)-type ti-
tanium alloys, were introduced17). Therefore, it can be said
that the development of titanium alloys, especially those in-
tended for use in living bodies began with the introduction
of these alloys. In addition, it has been reported that alumi-
num (Al) ions are neurotoxic and inhibit bone mineraliza-
tion23). Therefore, (α + β)-type titanium alloys that do not
contain V and Al, such as Ti-15mass%Zr (zirconium) and
Ti-15mass% Sn (tin) system alloys, were introduced24).
Then the mechanical biocompatibility focusing on
Youngs modulus was considered. The concept that similar
elastic deformation of the bone and implant is effective for
inhibiting bone resorption (stress shielding) and can allow
for efficient bone remodeling was considered. Specially,
since Youngs moduli of metallic biomaterials are greater
than that of bone, researchers have focused on lowering
these values.
Simultaneously, alloy design by taking into considering Fig. 1New process for making Ni- and Mn-free stainless steel.
 Recent Progress in Research and Development of Metallic Structural Biomaterials with Mainly Focusing on Mechanical Biocompatibility 3

ASTM standardization, but a small amount of Ni up to ap- II, and III) is shown in Fig. 43) with that of the cast Co-28Cr-
proximately 1 mass% is allowed to be contained, and a 5.4Mo-0.19Ni-0.24C annealed at 1503 K, which is equiva-
small amount of carbon (C) up to approximately lent to the Co-Cr-Mo registered in ASTM-F75 standardiza-
0.35 mass% is also allowed to be contained. It is effective to tion and stellite 6B. The wear rate of forged Ni- and C-free
improve the mechanical properties of the Ni-free Co-Cr-Mo Co-Cr-Mo alloy exhibits excellent wear resistance. The me-
alloy by utilizing hot forging process, but follows difficulty chanical properties and wear resistance are greatly improved
applying hot forging because the Ni-free Co-Cr-Mo alloy by grain refinement and deformation induced transformation
exhibits high work hardening, which causes brittleness. On of metastable γ phase to martensite.
the other hand, C also leads to brittleness of Co-Cr-Mo alloy Research and development of Co-Cr-Mo alloys for bio-
because the carbides form along with grain boundary. medical applications are being further energetically carried
Therefore, the improvement of mechanical properties and out.
wear resistance of Co-Cr-Mo with low Ni and C, whose
chemical composition is Cr: 28, Mo: 6, Ni: ≺0.01, C: 0.03– 5.Cell Biocompatibility of Pure Metals
0.07, Si: ≺0.01, O: 0.09–0.003, N: 0.0006–0.0009, Co: bal,
was investigated3). The fabrication process is shown in Data of cell viability of pure metals are useful to design
Fig. 23). The forging process is carried out in γ region fol- metallic biomaterials composed of non-toxic elements. The
lowed by rapid cooling because γ phase is ductile for easy widely known data of cell viability of pure metals are those
deformation and the following rapid cooling avoids the pre- reported by Kawahara et al.30). Further data of cell viability
cipitation of brittle ε phase. In this case, tensile gstrength of pure metals are needed. Then, cell viability evaluations of
and elongation of forged Ni- and C- free Co-Cr-Mo alloy various metal ion extract mediums5) or various metal salts6)
(Forged samples I, II, and III; I, II, and III indicate the dif- using L929, MC3T3-E1 or V79 cells were carried out. For
ferences of the lots.) are much higher than those of as-cast example, Fig. 56) shows compatibility of 21 kinds of metal
Co-28Cr-5.4Mo-0.19Ni-0.24C, which is equivalent to the salt with L929 cell. According to the results shown in Fig. 5,
Co-Cr-Mo alloy registered in ASTM-F75 standardization. as metal salts are grouped into low, intermediate and high toxic
shown in Fig. 33). The wear rate as a function of load of
forged Ni- and C- free Co-Cr-Mo alloys (Forged samples I,

Fig. 2Fabrication process of Ni- and C-free Co-Cr-Mo alloy.

Fig. 4Specific wear rate, w s of forged alloys I, II and III (Co-29Cr-6Mo)

vs. contact load, P in comparison with those of stellite 6B and Co-29Cr-
6Mo-1Ni-0.35C (F75).

Fig. 3Nominal stress-nominal strain curves of forged alloys I, II and III

(Co-29Cr-6Mo), and as-cast Co-29Cr-6Mo-1Ni-0.35C (F75). Fig. 5Compatibility of 21 kinds of metal salt with L929 cell.
4 M. Niinomi

categories; low toxicity: FeSo4, FeCl3, SnCl4, TiCl4, ZrCl4, 7.Mechanical Biocompatibility in (α + β)-Type
NbCl5, MoCl5, TaCl5, WCl6, and Al(NO3)3, intermediate Titanium Alloys
toxicity: CuCl, CoCl2, CuCl2, SnCl2, MnCl2, NiCl2, PdCl2,
ZnCl2, and Cr(NO3)3, and high toxicity: VCl3 and For Ti-15Zr-4Nb-4Ta-0.2Pd, a Ti-Zr system alloy, endur-
K2Cr2O75,6). ance, which is important factor as mechanical biocompati-
bility, namely fatigue strength was evaluated in addition to
6.Biodegradable Metallic Biomaterials the biological biocompatibility39). The fatigue strength of Ti-
6Al-4V was also evaluated for comparison. The fatigue
Since magnesium (Mg) and its alloys show similar strength of Ti-15Zr-4Nb-4Ta-0.2Pd (730 MPa) was reported
strength and Youngs moduli as those of bone and corrosive to be greater than that of Ti-6Al-4V (685 MPa). Effort have
property, and Mg is one of the essential elements, Mg and its been made to develop the fatigue strength of Ti-6Al-7Nb40).
alloys were studies as biodegradable metallic biomaterials For example, the fatigue strengths of Ti-6Al-7Nb subjected
with focusing on the stents applications although Mg is not to aging at 833 K for 4 h after solution treatment at 1273 K
so much safe element from the view point of cell viability. for 1 h followed by water quenching (WQ) or air cooling
The commercial Mg alloys such as AZ31 (Mg-Al-Zn-Mn (AC) and Ti-6Al-4V subjected to aging at 813 K for 4 h af-
system alloy), AZ91 (Mg-Al-Zn system alloy), AM60 (Mg- ter solution treatment at 1273 K for 1 h followed by AC
Al-Mn system alloy), AZ80 (Mg-Al-Zn-Mn system alloy), were evaluated and compared with each other. As a result,
WE43 (Mg-Y-RE-Zr system alloy), WE54 (Mg-Y-RE-Zr the fatigue strength of Ti-6Al-7Nb subjected to aging at
system alloy), and LAE442 (Mg-Li-Al-RE system alloy) 833 K for 4 h after solution treatment at 1273 K for 1 h fol-
were investigated as biodegradable Mg alloys31–35). lowed by AC was reported to be greater than that of Ti-
However, these commercial alloys have possibilities to con- 6Al-4V subjected to aging at 813 K for 4 h after solution
tain toxic elements. Therefore, biodegradable Mg alloys treatment at 1273 K for 1 h followed by AC as shown in
contains non-toxic elements were developed. Figure 631) Fig. 719,40).
shows relationship between yield stress and amount of dis- Hydrogenation and dehydrogenation process, which is re-
solved Mg ion into simulated body fluid of newly developed ferred to as thermochemical processing (TCP), is effective to
biodegradable Mg alloys and commercial extruded Mg al- improve fatigue strength of (α + β)-type titanium alloys be-
loys. Biodegradable Mg alloys showing various strength and cause their microstructures are refined significantly by TCP
41).
corrosion resistance levels were developed as shown in The basic TCP is schematically shown in Fig. 841).
Fig. 6. As newly developed biodegradable Mg alloys, Figure 941) shows the high-cycle fatigue strength of TCP
Mg-Ca alloy, Mg-Zn-Mn alloy, Mg-Nd-Zn-Zr alloy, Mg- treated and un-treated Ti-6Al-4V and Ti-5Al-2.5Fe for bio-
Zn-Ca bulk metallic glass were developed36).
Controlling of the dissolved rate (corrosion rate) is very
important factor for biodegradable Mg alloys. Surface modi-
fications using biopolymers or bioactive ceramics are inves-
tigating to control the corrosion rate of biodegradable Mg
alloys37,38).
Biodegradable iron (Fe) and its alloys such as Fe-Mn sys-
tem alloys were also developed34).

Fig. 7Ti-6Al-7Nb and Ti-6Al-4V ELI subjected to each heat treatment:

AC and WQ indicate air cooling and water quenching, respectively after
solution treatment.

Fig. 6Relationship between yield stress and amount of dissolved Mg ion

into simulated body fluid of newly developed biodegradable Mg alloys
and commercial extruded Mg alloys. Fig. 8Schematic drawings of thermochemical processing (TCP).
 Recent Progress in Research and Development of Metallic Structural Biomaterials with Mainly Focusing on Mechanical Biocompatibility 5

low Youngs moduli for biomedical applications. Many such

β-type Ti alloys have been developed to date, and some of
them have been standardized in ASTM, ISO, or JIS.
Since β-typeTi alloys with a low Youngs modulus gener -
ally contain a large amount of high-cost elements such as
Nb, Ta, Mo, and Zr, alternative alloys containing low cost el-
ements such as Fe, Mn or Cr are being developed. The rep-
resentative low Youngs modulus β-type Ti alloys developed
to date are listed in Table 142).
Youngs moduli of representative α-, (α + β)- and β-type
Ti alloys are shown in Fig. 1043,44). Youngs moduli of β-type
Ti alloys for biomedical applications are apparently lower
than those of α- and (α + β)-type Ti alloys. Although there is
a fairly large difference among Youngs moduli according to
the measurement methods, the corresponding values of
β-type Ti alloys are approximately 60–80 GPa under solu-
tionized conditions giving a single β phase. The Youngs
modulus values can be reduced further by severe cold work-
Fig. 9Comparison of high cycle fatigue strength of as-received, as-β ing after solution treatments45). These trends are seen in po-
transformed and TCP treated Ti-6Al-4V, and as-received and TCP ly-crystallineβ-type Ti alloys. However, in the case of a sin-
treated Ti-5Al-2.5Fe. gle crystal, the lowest Youngs modulus is, for example,
35 GPa in the <100> direction for Ti-29Nb-13Ta-4.6Zr (re-
ferred to as TNTZ) as shown in Fig. 1146). This value is
medical applications. The TCP treated Ti-6Al-4V and Ti- comparable to that of bone, which is approximately 10–
5Al-2.5Fe exhibits highly improved fatigue strength com- 30 GPa. Therefore, artificial bone made of single crystal
pared with untreated ones indicated by Ti-6AI-4V β-type Ti alloys with low Youngs modulus is highly desired
as-received, Ti-6A1-4V as-β transformed, and Ti-5Al-2.5Fe for biomedical applications.
as-received. The effectiveness of the low Youngs moduli of implants
for inhibiting stress shielding, namely bone resorption and
8.Mechanical Biocompatibility of β-Type Titanium facilitating bone remodeling was proved by evaluating bone
Alloys for Biomedical Applications fracture healing and bone remodeling situations, where in-
tramedullary rods and bone fracture fixation plates were im-
8.1Development of alloys with low Youngs modulus planted into fracture model made in tibia of Japanese white
The mechanical compatibility (mechanical biocompatibil- rabbits47,48). For example, in the study on bone remodeling,
ity) between the bone (living tissue) and the implant can be utilizing bone plates made of SUS 316L stainless steel, Ti-
given as the biocompatibility looking from both living body 6Al-4V ELI, and TNTZ, healing conditions were observed
and implant side. Namely, mechanical biocompatibility re- using X-ray photographs recorded at regular intervals over a
fers to the similarity in mechanical properties between the period of up to 48 weeks after implantation48). Following
bone and the implant. The main factors to be considered are this, both tibiae were extracted along with the bone plate,
prevention of failure or abnormalities, and homogeneous and the bone formation was externally observed. For all the
stress transfer. The latter is particularly regarded as an im- materials, callus formation was observed at 2 weeks, which
portant factor. This leads to a similar Youngs modulus be- became distinct at 3 weeks and then bone union was ob-
tween the bone and the implant, as already stated above. tained at 4 weeks after implantation, and the fracture line
Therefore, lowering Youngs modulus is imperative for de- was barely discernible at 8 weeks after implantation.
signing metallic biomaterials. Ti alloys are advantageous be- Moreover, there was no trace of the experimental fracture at
cause their Youngs moduli are lower than those of stainless 16 weeks to 20 weeks after implantation. However, bone at-
steels (SUS 316L) and Co-Cr-Mo alloys, as also stated rophy (thinning of the bone) was observed under the bone
above. Ti alloys are attracting much attention because they plate, and the time at which this occurred varied between the
exhibit excellent corrosion resistance, specific strength, and different materials. According to the X-ray images taken
good balance between the strength and the ductility in addi- from 4 weeks after implantation to 18 weeks after implanta-
tion to excellent biocompatibility. Ti alloys are roughly tion for each plate, for SUS 316L stainless steel, the thin-
grouped into α-, (α + β)- and β-types according to their con- ning of the bone was first observed at 7 weeks after implan-
stituent phases. The crystal structures of α- and β-type Ti al- tation, and the bone almost disappeared at 12 weeks after
loys are hexagonal close-packed (hcp) and body centered implantation. For Ti-6Al-4V ELI, the thinning was first ob-
cubic (bcc) structures, respectively. Since the packing ratio served at 7 weeks after implantation, and the bone almost
of atoms is less in the β-type Ti alloys than in the α-type Ti disappeared at 14 weeks after implantation. Finally, for
alloys, Youngs moduli of β-type Ti alloys are expected to be TNTZ, the corresponding times were 10 weeks and 18
lower than those of α- and (α + β)-type Ti alloys. Therefore, weeks after implantation. Furthermore, an increase in the di-
efforts have been devoted to developments of β-type Ti al- ameter of the tibia and the double wall structure in the intra-
loys composed of non-toxic and allergy-free elements with medullary bone tissue was observed only for the case of the
6 M. Niinomi

Table 1Representative β-type titanium alloys with low Youngs modulus developed to date.

β-type titanium alloys ASTM standard ISO standard JIS standard

Ti-13Nb-13Zr ASTMF F1713 --- ---
Ti-12Mo-6Zr-2Fe (TMZF) ASTM F1813 --- ---
Ti-12Mo-5Zr-5Sn --- --- ---
Ti-15Mo ASTM F2066 --- ---
Ti-16Nb-10Hf (Tiadyne 1610) --- --- ---
Ti-15Mo-2.8Nb-0.2Si --- --- ---
Ti-15Mo-5Zr-3Al --- ISO 5832-14 JIS T 7401-6
Ti-30Ta --- --- ---
Ti-45Nb --- --- ---
Ti-35Zr-10Nb --- --- ---
Ti-35Nb-7Zr-5Ta (TNZT: TiOsteum) ASTM Task Force 4.12.23 --- ---
Ti-29Nb-13Ta-4.6Zr (TNTZ) --- --- ---
Ti-35Nb-4Sn --- --- ---
Ti-11.5M0-6Zr-4.5Sn ASTM F 1713 ---
Ti-50Ta --- --- ---
Ti-8Fe-8Ta --- --- ---
Ti-8Fe-8Ta-4Zr --- ---
Ti-35Nb-2Ta-3Zr --- --- ---
Ti-22.5Nb-0.7Zr-2Ta --- --- ---
Ti-23Nb-0.7Ta-2.0Zr-1.2O (Gum Metal) --- --- ---
Ti-28Nb-13Zr-0.5Fe (TNZF) --- --- ---
Ti-24Nb-4Zr-7.9Sn (Ti2448) --- --- ---
Ti-7.5Mo --- --- ---
Ti-12Mo-3Nb --- --- ---
Ti-12Mo-5Ta --- --- ---
Ti-12Cr --- --- ---
Ti-30Zr-7Mo --- --- ---
Ti-30Zr-3Mo-3Cr --- --- ---
Ti-5Fe-3Nb-3Zr --- --- ---

Fig. 11Youngs modulus of single-crystal Ti-29Nb-13Ta-4.6Zr (TNTZ) in

Fig. 10Youngs moduli of representative α-type, (α+β)-type, and β-type directions between [100] and [110].
titanium alloys for biomedical applications.

Youngs modulus. Therefore, in the implant made of the

bone plate made of TNTZ, as shown in Fig. 1248). In this fig- β-type Ti alloy with low Youngs modulus for biomedical ap-
ure, the inner wall bone structure represents the original plications, stress transfer between the bone and the implant
bone, i.e., the remaining old bone, whereas the outer wall becomes homogeneous and good bone remodeling is
bone structure is the newly-formed part. This bone remodel- achieved although this has been proved only at the stage of
ing is the direct result of using a bone plate with a low animal testing.
 Recent Progress in Research and Development of Metallic Structural Biomaterials with Mainly Focusing on Mechanical Biocompatibility 7

8.2Development of shape memory and super elasticity 8.3Development of Youngs modulus self-adjustable
alloy alloys
For shape memory alloys, the practical applications of Development of Ti alloys has focused on the functionality
TiNi alloys are developing. TiNi alloys have been applied as with a low Youngs modulus, which is advantageous for pa-
guide wires of catheters and orthodontic wires. However, Ni tients because a low Youngs modulus inhibits stress shield-
is a high-risk element from the viewpoint of allergic reac- ing, between the bone and the implant, as previously de-
tions as stated above. Therefore, many Ni-free shape mem- scribed. The development of Ti alloys for biomedical
ory β-type Ti alloys for biomedical applications have been applications that are also advantageous for surgeons has re-
developed. The representative Ni-free β type titanium alloys cently progressed. For example, in operations for scoliosis
for biomedical applications are listed in Table 249). They are disease, the rods of the spinal fixation devices undergo bend-
roughly grouped into Ti-Nb, Ti-Mo, Ti-Ta, and Ti-Cr system ing when they are manually handled by surgeons within the
alloys. These show a low Youngs modulus. small space inside a patients body, to achieve in-situ spine
contouring50). The contoured shape of the rod should be
maintained. Therefore, reverse bending, known as spring-
back, of the bent rod should be prevented. For implant rods,
the degree of springback should be low to facilitate their
handling during operations. The degree of springback is
thought to depend on both the strength and Youngs modulus
of the implant rod. If two implant rods with the same
strength, but differing Youngs moduli, are used, the implant
rod with the lower Youngs modulus will exhibit greater
springback, as schematically shown in Fig. 1351). Therefore,
about the patients needs, low Youngs modulus is required to
prevent stress shielding, whereas to facilitate surgery, high
Youngs modulus is required to prevent springback. To sat-
isfy these conflicting demands simultaneously, it should be
possible to increase the Youngs modulus value of the bent
parts of the rod via deformation at room temperature, while
allowing Youngs modulus of the remainder of the rod to re-
main unchanged at a low value50). The metallic rods used in
spinal-fixation devices are required to have a low Youngs
modulus, good biocompatibility, and low springback.
Fig. 12CMRs (contact micro-radiographs) of cross sections of fracture Accordingly, it is necessary to develop novel Ti alloys that
models implanted with and without bone plates made of TNTZ at middle offer good biocompatibility and an adjustable Youngs mod-
and distal level at 48 weeks after implantation : (a) cross section of frac- ulus. To accomplish this, it should be possible to increase
ture model, (b) parts of of (a), namely high magnification CMR of
branched parts of bones formed outer and inner sides of tibiae, and (c) the local Youngs modulus to a high value at certain parts of
cross sections of unimplanted tibiae. the device via deformation at room temperature, while al-

Table 2Representative Ni-free shape memory and super elastic alloys.

Alloy system Shape memory alloy

Ti-Nb system Ti-Nb, Ti-Nb-O, Ti-Nb-Sn, Ti-Nb-Al, Ti-22Nb-(0.5-2.0)O (at%), Ti-Nb-Zr, Ti-Nb-Zr-Ta, Ti-Nb-Zr-Ta-O,
Ti-Nb-Ta-Zr-N, Ti-Nb-Mo, Ti-22Nb-6Ta(at%), Ti-Nb-Au, Ti-Nb-Pt, Ti-Nb-Ta, Ti-Nb-Pd
Ti-Mo system Ti-Mo-Ga, Ti-Mo-Ge, Ti-Mo-Sn, Ti-Mo-Ag, Ti-5Mo-(2-5)Ag (mol%), Ti-5Mo-(1-3)Sn (mol%), Ti-Sc-Mo
Ti-Ta system Ti-50Ta (mass%), Ti-50Ta-4Sn (mass%), Ti-50Ta-10Zr (mass%)
Others Ti-7Cr-(1.5, 3.0, 4.5)Al (mass%)
Super elastic alloy: alloy shows only elasticity
Ti3(Ta + Nb + V) + (Zr, Hf) + O (at%), Ti-29Nb-13Ta-4.6Zr (mass%)

Table 3Chemical compositions of several Ni-free stainless steels developed for biomedical applications, mass%.

Stainless steel C Cr Mn Mo Si Ni N Cu
PANCEA P558 0.20 17.4 10.18 3.09 0.43 ≤0.08 0.48 -
®
Biodur 108 0.08 21 23 0.7 0.75 ≤0.3 0.97 0.25
X13CrMnMoN18-14-3 (P2000) 0.13 18 14 3 - ≤0.05 0.75–1.0 ≤0.3
24Cr-1N - 24 - - - - 1.0 -
24Cr-2Mo-1N - 24 - 2 - - 1.0 -
BIOSSN4 0.043 17.9 15.3 2.02 0.02 ≤0.2 0.46 0.66
8 M. Niinomi

lowing the Youngs modulus of the remainder of the device fuse streaks are weakened. It is well known that the intensity
to remain unchanged at a lower value50). Figure 1450) sche- of the ω reflection is related to the amount of the ω phase.
matically shows the concept of self-adjustment of Youngs The amount of the athermal ω phase in the designed alloys
modulus in an implant rod, which has been proposed as a is found to be dependent on the stability of the β phase.
solution for the aforementioned problem. In the case of cer- Specifically, as the Cr content increased, the β phase became
tain metastable β-type titanium alloys, non-equilibrium more stable, so that the formation of the athermal ω phase
phases such as the α′, α′′, and ω phases appear in the β ma- during water quenching is suppressed. Therefore, the
trix during deformation52–55). Among these non-equilibrium amount of the athermal ω phase in Ti-11Cr-ST is lower than
phases, the ω phase has a higher Youngs modulus than the β that in Ti-10Cr-ST, and the athermal ω phase disappears al-
phase. Since the precipitation of the α′, α′′, and ω phases is most completely in Ti-12Cr-ST, Ti-13Cr-ST, and Ti-
significantly related to the stability of the β phase, the appro- 14Cr-ST. In order to achieve the largest amount of the ω
priate combination of Ti and its alloying element is import- phase induced by deformation, the amount of the athermal ω
ant to control the stability of the β phase. Ultimately, the phase should be as small as possible. Eventually, the Cr con-
β-type Ti-Cr system alloys for biomedical applications, in tent at which the circular diffuse streaks related to the ω
which the ω phase is induced, are being developed50,53). phase almost disappeared is found to be 12 mass%.
It is important to determine appropriate chemical compo- In contrast, Fig. 1655) shows the TEM diffraction patters
sitions of Ti-Cr system alloys, in which the ω phase is most of Ti-(10-14) Cr subjected to cold rolling (CR) with a reduc-
effectively induced by deformation and the degree of in- tion ratio of 10% as a simulation of bending deformation af-
crease in Youngs moduli is the greatest. ter ST (Ti-(10-14) Cr-CR). In contrast to the case of Ti-(10-
Figure 1555) shows the transmission electron microscope 14) Cr-ST, after CR, the ω reflections in Ti-10Cr-CR
(TEM) diffraction patters of Ti-(10-14) Cr subjected to solu- (Fig. 16 (a′)) are much sharper than those in Ti-10Cr-ST
tion treatment (ST) (Ti-(10-14)-ST). The electron diffraction (Fig. 15 (a)), indicating that the amount of the ω phase in-
patterns of Ti-10Cr-STshow weak extra spots, in addition to creases in response to cold rolling. Furthermore, the intensi-
the spots derived from the β phase, suggesting that a small ties of the ω reflections are higher in Ti-11Cr-CR and Ti-
amount of the athermal ω phase is formed in Ti-10Cr-ST 12Cr-CR (Fig. 16 (b′) and (c′)) when compared to those in
during water quenching (Fig. 15 (a)). For Ti-11Cr-ST, the Ti-11Cr-ST and Ti-12Cr-ST (Fig. 15 (b) and (c)). These
intensities of the ω reflections decrease, accompanied by a findings confirm that the deformation-induced ω phase
change to circular diffuse streaks. As shown in Fig. 15 (b)– transformation occurs in the Ti-10Cr, Ti-11Cr, and Ti-12Cr
(e), as the Cr content continues to increase, the circular dif- alloys during cold rolling. The amount of the ω phase in Ti-

Fig. 15TEM diffraction patters of Ti-(10-14)Cr subjected to solution

Fig. 13Relationship between Youngs modulus and springback. treatment (ST).

Fig. 14Schematic explanation of concept of spinal fixation rod with Fig. 16TEM diffraction patters of Ti-(10-14)Cr subjected to 10% cold
self-adjustable Youngs modulus. rolling (CR) after solution treatment (ST).
 Recent Progress in Research and Development of Metallic Structural Biomaterials with Mainly Focusing on Mechanical Biocompatibility 9

10Cr-CR, Ti-11Cr-CR, and Ti-12Cr-CR is too small to be The springback of Ti-12Cr is significantly lowered as com-
detected by X-ray diffraction (XRD) analysis, but the defor- pared with that of TNTZ, and is similar to that of Ti-6Al-4V
mation-induced ω phase is evident in TEM observation. ELI.
Specifically, as the Cr content increases, the intensities of To achieve more increase in Youngs modulus than that of
the ω reflections decreased. In addition, only diffuse streaks Ti-12Cr, which has an a thermal ω-phase, O is added to the
are observed in Ti-13Cr-CR and Ti-14Cr-CR (Fig. 16 (d′) alloy because O suppresses the formation of the athermal
and (e′)), suggesting that the amount of the ω phase does not ω-phase. FinallyTi-11Cr-0.2O, which exhibited a higher
change during cold rolling. These findings demonstrate that degree of increase in Youngs modulus than that of Ti-12Cr
deformation-induced ω phase transformation does not occur has been develop56).
in Ti-13Cr and Ti-14Cr alloys during cold rolling and that it
is dependent on the stability of the β phase. In lower stability 9.Surface Modifications
alloys such as Ti-10Cr, Ti-11Cr, and Ti-12Cr, deforma-
tion-induced ω phase transformation may occur, while with Ti and its alloys show the greatest biocompatibility among
increasing Cr content, the β phase can become more stable, metallic materials for biomedical applications. However,
thereby suppressing the deformation-induced ω phase they are grouped into bioinert materials as well as ceramics
transformation. like alumina, zirconia, etc., judging from the pattern of os-
Figure 1755) shows Youngs moduli of Ti-(10-14) Cr alloys teogenesis15) However, their biofunctionalities are poor.
subjected to solution treatment and cold rolling, where cold Therefore, surface modifications using bioactive ceramics
rolling at a reduction ratio of 10% was carried out to simu- such as calcium phosphate (Ca-P) and hydroxyapatite (HAp:
late deformation. The degree of increase in Youngs modulus Ca(PO4)3OH)7), or blood compatible polymers such as poly-
is the highest at a Cr content of 12 mass%. Therefore, the ethylene glycol (PEG)57) and segment polyurethane58) are
chemical composition that exhibits the lowest spring back, is carried out on Ti and its alloys to achieve high level biocom-
expected to be Ti-12Cr. patibility with living tissue.
Figure 1855) shows comparison profiles of the ratio of The biocompatible surface modifications are achieved, in
springback per unit stress as a function of the applied strain general, using dry process and wet process. There are vari-
for TNTZ, Ti-12Cr, and Ti-6Al-4V ELI (Ti64 ELI). The ra- ous dry and wet processes59).
tios of springback per unit stress of all the alloys show a Dry processes are, for example, plasma spray method, ion
similar trend; initially decreasing significantly and then re- plating, RF magnetron sputtering, pulse laser deposition
maining approximately stable with increasing applied strain. method, ion beam dynamic mixing method, super plastic
joining method, etc., where HAp is formed directly on Ti al-
loy surface, and calcium ion implantation, calcium ion mix-
ing method etc., where HAp are formed indirectly on Ti al-
loy surface7,59) Wet processes are, for example,
electrochemical treatment etc., which are direct HAp form-
ing methods, and alkali treatment, etc., which are indirect
HAp forming methods7,59).
There is another interesting method60) where the powder
of calcium phosphate invert glass mixed with distilled water
is coated on the surface of the Ti alloy followed by heating
at around 1073 K, and then phosphate calcium type ceram-
ics precipitate.
Figure 1961) shows the progress in research and practical
Fig. 17Youngs moduli of Ti-(10-14)Cr alloys subjected to solution treat- stage of surface treatment and modification for achieving
ment (ST) and 10% cold rolling (CR) after ST.

Fig. 19Progress in research and practical stage of surface treatment and

Fig. 18Ratio of springback per unit load as a function of applied strain modification for achieving bone formation function in dental implants as
for Ti-12Cr, Ti-6Al-4V (Ti64) ELI, and TNTZ. an example.
10 M. Niinomi

bone formation function in dental implants as an example. lective laser melting (SLM)10) or electron beam melting
The research stage of surface treatment and modification is (EBM)11).
progressed up to the 4th stage generation. The progress into The AM method of fabrication has attracted attention in
the 5th stage generation is desired. The practical stage is many fields including fabrication of implants, especially po-
progress up to the middle of the 3rd stage, and its further rous structural implants. The Youngs modulus of titanium
progress is required. and its alloys are easily controlled by making their porous
body (Fig. 21)68) by AM methods. As an example of the ani-
10.New Topics of Trends in Studies on Metallic mal test of Ti porous implant made by AM method (EBM
Biomaterials method), lateral X-ray and micro-computed tomography
(CT) images of porous Ti-6Al-4V without the bone graft
10.1Zr based alloys made by AM method (EBM) and PEEK cages with the bone
The magnetic susceptibilities of metallic biomaterials graft at 3 months and 6 months after implantation into the
such as Zr-1Mo8), Ti-6Al-4V, CP-Ti and Ti-6Al-7Nb, Co- spine of sheep are shown in Fig. 2269). At 3 months after im-
Cr-Mo alloy, and SUS 316L stainless steel are 0.98 × plantation (A1-3, B1-3), porous Ti-6Al-4V cages without
10−6 cm3·g−1, 3.5 × 10−6 62), 3.0 × 10−6 62), 7.7 × 10−6 62), and the bone graft exhibit better osteointegration with surround-
3380 × 10−6 cm3·g−1 63), respectively. Therefore, the mag- ing bone tissue as compared with PEEK (Polyether-ether-
netic susceptibilities of zirconium (Zr) alloys are lower than ketone) cages with the bone graft, as shown by the reduced
those of Ti and its alloys, Co-Cr-Mo alloy and SUS 316L. radiolucent region and smaller empty gap (white arrow
Magnetic resonance imaging (MRI) has become a power- head) around the edge of the cages. At 6 months after im-
ful diagnostic tool in orthopedics. MRI diagnostic is inhib- plantation (C1-3, D1-3), both cages achieve complete spine
ited by the presence of metallic implants in the body be- fusion. However, micro-CT shows that there are still small
cause they are magnetized in the intense magnetic field of empty gaps around PEEK cages with the bone graft whereas
the MRI instrument. That may cause image artifact leading porous Ti-6Al-4V cages without the bone graft are well inte-
to prevent exact diagnosis64). Therefore, Zr alloy implants grated with surrounding bone tissue. The growth of the bone
are advantageous to prevent the artifact of the MRI image. tissue into the porous Ti-6Al-4V cage is evident in the fig-
Therefore, Research and development of Zr alloys for bio- ure. The porous Ti-6Al-4V cage without the bone graft ex-
medical applications are nowadays energetically carried out. hibits better osteointegration as compared with that of the
Zr-Nb9,65), Zr-Mo8), Zr-Ti66), Zr-Cu67) alloys, etc. for bio- bone grafted PEEK.
medical applications have been reported.
Figure 209) shows Youngs moduli of Zr-5Nb, -10Nb, 10.3Bone orientation design
-20Nb, and -30Nb. The lowest Youngs modulus is obtained It has been recognized very recently that not only bone
to be approximately 40 GPa at a Nb content of 20 mass%. mineral density (BMD), but also bone orientation (biological
This value is lower than those of low Youngs modulus Ti al- apatite (BAp) crystal orientation) is important for the bone
loys as mentioned above. Therefore, Zr alloys are advanta- regeneration70).
geous from the view point of low magnetic susceptibilitiy Figure 2370) shows variations in the relative intensity ratio
and low Youngs modulus for biomedical applications. of the (002) diffraction peak to the (310) peak to evaluate
the orientation degree of the BAp c-axis orientation with dif-
10.2Additive manufacturing (AM)
Nowadays, additive manufacturing (AM), namely 3D
printing, wherein metal powders are accumulated layer by
layer to make products without a mold. In the AM methods,
laser or electron beam melting is used, which is called as se-

Fig. 20Youngs moduli and Vickers hardness of Zr-5Nb, -10Nb, -20Nb,

and -30Nb. Fig. 21Youngs modulus of porous Ti as a function of porosity.
 Recent Progress in Research and Development of Metallic Structural Biomaterials with Mainly Focusing on Mechanical Biocompatibility 11

ferent directions A, B, and C for the ulna, skull bone, and in vivo stress distribution and BAp c-axis tends to orient
mandible71,72). It can be concluded from this figure that the along the principal stress direction in the original bones
preferential orientation of the BAp c-axis corresponds to the Figure 2470) shows degree of BAp orientation intensity ra-
tio of (002)/(310) showing recovery of local BMD and BAp
c-axis alignment in the regenerated ulna. The diffracted in-
tensity ratio of (002)/(310) in the regenerated bone tissue in-
creases significantly Significant increases were observed
from 12 through 24 weeks in both local BMD and intensity
ratio. There are no significant differences from baseline (in-
tact bone) at 24 weeks in either local BMD or the intensity
ratio. Thus, in regeneration of rabbit ulnas, where controlled
release of rBMP-2 is carried out, recovery of the preferential
BAp c-axis orientation tends to follow that of BMD.
Above results leads to groove design of the surface of the
implant, which is favorable for the rapid bone fusion with
implant as shown in Fig. 2512). A maximum principle stress
is found to be distributed in 60 grooves by FEM: this align-
ment is favored for bone growth12).

Fig. 22Lateral X-ray and micro-CT images of porous Ti-6Al-4V fabri-

cated AM method and PEEK cages at 3 months (A1-3, B1-3) and 6
months. (C1-3, D1-3) after implantation.

Fig. 24Degree of BAp orientation intensity ratio of (002)/(310) showing

recovery of local BMD and BAp c-axis alignment in the regenerated
ulna.

Fig. 253D FEA (finite element analysis) model of the beagle femur–arti-
ficial hip joint implant used in this study. (A) Two types of groove angle
combinations on the surface of the proximal medial region ofthe femoral
Fig. 23Variations in the relative intensity ratio of the (002) diffraction stem: (60/0/−60) groove and (30/0/−30) groove. (B) Definition of
peak to the (310) peak to evaluate the orientation degree of the BAp the angle, θ, between groove wall and the maximum principal stress di-
c-axis orientation with different directions A, B, and C for the ulna, skull rection in the groove. (C) Loading and boundary conditions used for
bone, and mandible. FEA.
12 M. Niinomi

11.Summary Geneva, Switzerland.

22) ASTM F1295: Standard specification for wrought titanium-6alumi-
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