Materials Science and Engineering C 62 (2016) 960–966

Contents lists available at ScienceDirect

Materials Science and Engineering C

journal homepage: www.elsevier.com/locate/msec

Review

Commercially pure titanium (cp-Ti) versus titanium alloy (Ti6Al4V)

materials as bone anchored implants — Is one truly better than the other?
Furqan A. Shah ⁎, Margarita Trobos, Peter Thomsen, Anders Palmquist
a
Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden
b
BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Göteborg, Sweden

a r t i c l e i n f o a b s t r a c t

Article history: Commercially pure titanium (cp-Ti) and titanium alloys (typically Ti6Al4V) display excellent corrosion resistance
Received 6 August 2015 and biocompatibility. Although the chemical composition and topography are considered important, the me-
Received in revised form 10 December 2015 chanical properties of the material and the loading conditions in the host have, conventionally, influenced mate-
Accepted 14 January 2016
rial selection for different clinical applications: predominantly Ti6Al4V in orthopaedics while cp-Ti in dentistry.
Available online 16 January 2016
This paper attempts to address three important questions: (i) To what extent do the surface properties differ
Keywords:
when cp-Ti and Ti6Al4V materials are manufactured with the same processing technique?, (ii) Does bone tissue re-
Commercially pure titanium spond differently to the two materials, and (iii) Do bacteria responsible for causing biomaterial-associated infections
Ti6Al4V respond differently to the two materials? It is concluded that: (i) Machined cp-Ti and Ti6Al4V exhibit similar sur-
Bacterial adhesion face morphology, topography, phase composition and chemistry, (ii) Under experimental conditions, cp-Ti and
Osseointegration Ti6Al4V demonstrate similar osseointegration and biomechanical anchorage, and (iii) Experiments in vitro fail
Biomechanics to disclose differences between cp-Ti and Ti6Al4V to harbour Staphylococcus epidermidis growth. No clinical com-
Bone parative studies exist which could determine if long-term, clinical differences exist between the two types of bulk
Implant
materials. It is debatable whether cp-Ti or Ti6Al4V exhibit superiority over the other, and further comparative
studies, particularly in a clinical setting, are required.
© 2016 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
2. Surface topography, morphology, chemistry and phase composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 961
3. Bone growth and osseointegration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
3.1. Histological evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
3.2. Biomechanical testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
3.3. Ultrastructural observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
3.4. Bone response to other titanium alloys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
3.5. Clinical performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
4. Bacterial interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
6. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965

1. Introduction

Commercially pure titanium (cp-Ti) and titanium alloys (typically

⁎ Corresponding author at: Department of Biomaterials, Sahlgrenska Academy at
Ti6Al4V), generally known for their excellent corrosion resistance, pas-
University of Gothenburg, Göteborg, Sweden. sivation capacity and biocompatibility [1], are used extensively in dental
E-mail address: furqan.ali.shah@biomaterials.gu.se (F.A. Shah). and orthopaedic reconstructive surgery. A gentle surgical technique

http://dx.doi.org/10.1016/j.msec.2016.01.032
0928-4931/© 2016 Elsevier B.V. All rights reserved.
 F.A. Shah et al. / Materials Science and Engineering C 62 (2016) 960–966
combined with sufficient healing time has long been considered the key
to osseointegration [2], and excellent long-term clinical outcome for
dental implants [3] thus validates the results of pre-clinical experimen-
tal studies. Alloying improves the mechanical properties of titanium [4]
for use in high load-bearing applications, e.g., total hip and total knee re-
placements. However, some concerns related to the toxicity of various
alloying elements do exist [5,6].
In simulated body fluid (SBF), OH− groups are adsorbed by Ti ions
in the oxide layer. The isoelectric point of rutile is pH 5–6. At physi-
ological pH (e.g., 7.4), TiO 2 gives up H+ ions forming negatively
charged Ti–O− groups. The negatively charged sites attract Ca 2+
ions from the solution to form a slightly positively charged calcium
titanate layer, which subsequently attracts PO 3− 4 ions resulting in
the formation of an unstable carbonated calcium phosphate (CaP)
phase. Thermodynamic stability is achieved by conversion of this CaP
phase into a crystalline structure that resembles poorly crystalline
bone-apatite [7,8].
Cell and tissue interactions with the surface of medical devices are
influenced by the choice of materials and their surface properties.
While the chemical composition and topography are recognised to be
important, the mechanical properties of the material and the loading
conditions in the host have, by convention, influenced the selection of
the material depending on the clinical use: predominantly Ti6Al4V in
orthopaedics and cp-Ti in dentistry.
Alloying elements stabilise either the α (hexagonal close-packed;
HCP) or the β (body-centred cubic; BCC) phase, resulting in an al-
tered phase composition and microstructure, and thereby the me-
chanical properties. While cp-Ti consists of the α phase, Ti6Al4V
consists of both the α and β phases stabilised by Al and V,
respectively. Other common alloying elements include Zr (neutral or
α stabilising), Sn (neutral), Ta, Mo, Zr, Ni, Nb (β stabilising), etc. The me-
chanical properties of the final alloy depend on the thermomechanical
treatment history including stress relieving, annealing, solution treat-
ment, and ageing, all of which will alter the microstructure and phase
composition. The interested reader is referred to Welsch et al. [9] and
Brunette et al. [10] for more information on the bulk properties of tita-
nium and titanium alloys.
The evaluation of implant performance in a clinical setting sets high
demands on the clinical protocol. It is extremely rare to find compara-
tive clinical studies on the performance of implants of identical
macro-design but different bulk chemical compositions. This, on the
other hand, is easier to achieve in a pre-clinical experimental model,
which reflects the higher number of published articles.
Clinical performance of cp-Ti and Ti6Al4V as the material compo-
nent in contact with tissues in different clinical situations is generally
quite successful. While most of the pre-clinical studies including indus-
trial developmental studies are performed in experimental in vivo
models with normal tissues, bone anchored implants and implant-
supported prostheses are often inserted in patients with compromised
conditions. Moreover, implanted devices often suffer the risk of infec-
tions, which involve colonisation of microorganisms on the implant sur-
face followed by the development of a biofilm.
Much progress is made to improve and optimise medical implant
materials; and extensive data is obtained by in vitro investigations
and in silico simulations. However, with few (if any), in vivo studies
confirming whether the biological response trends towards the two ma-
terials are observed consistently, it becomes increasingly critical to
question if one material is truly better than the other for clinical applica-
bility — beyond their mechanical properties.
For the purpose of the following review, three major questions were
asked explicitly in the context of biomedical grade bone-anchored de-
vices: (i) To what extent do the surface properties differ when cp-Ti and
Ti6Al4V materials are manufactured with the same processing technique?,
(ii) Does bone tissue respond differently to the two materials?, and (iii) Do
bacteria responsible for causing biomaterial-associated infections respond
differently to the two materials?
961
2. Surface topography, morphology, chemistry and
phase composition
The surfaces of both cp-Ti and Ti6Al4V are very similar in terms
of morphology, topography, phase composition and chemistry. The
machining process generates a minimally rough surface on both bulk
materials, with Sa values typically in the range of 0.2–0.5 μm [11], or
slightly higher depending on the evaluation technique and the machin-
ing conditions, for example 0.65 μm for cp-Ti vs. 0.53 μm for Ti6Al4V
[12]. Broadly speaking, Ti6Al4V surfaces frequently exhibit marginally
lower roughness than cp-Ti, attributable to the difference in the me-
chanical properties, e.g., microhardness, of the bulk materials. The sur-
face typically exhibits scratches, micro-grooves, pits and ridges aligned
along the rotational direction [11,13], with a smaller total height differ-
ence of the highest peak to lowest valley for the Ti6Al4V [14].
Auger Electron Spectroscopy (AES) shows the surface to be mainly
composed of Ti, O, and C. While Al is frequently found to be heteroge-
neously distributed in Ti6Al4V samples [14], similar levels of Al have
been reported on cp-Ti and Ti6Al4V, suggesting that impurities or con-
tamination of Al may also be detected by AES [15]. Other commonly
found contaminants include Ca, Si, Na, P, S and Cl. X-ray Photoelectron
Spectroscopy (XPS) has shown the surface of Ti6Al4V to be mostly com-
posed of TiO2 with small amounts of Al in the trivalent cation (Al3+)
configuration, while vanadium is not detected in spontaneously formed
surface oxides [16].
Transmission electron microscopy (TEM) demonstrates the sponta-
neously formed oxide layer to be approximately 10 nm thick, and while
mostly amorphous in the case of Ti6Al4V [17], crystalline rutile phases
are frequently found on cp-Ti [18]. The crystallisation temperature of
the oxide formed on Ti6Al4V is approximately 400 °C [16], which is a
temperature that may be reached during the machining process. There-
fore, the oxide on both cp-Ti and Ti6Al4V is likely to be of a mixture of
both amorphous and crystalline phases.
In experiments where cp-Ti and Ti6Al4V implants had been pre-
pared by the same machining process as the Brånemark Integration
Original Fixture, the surface morphology of both materials appears qual-
itatively similar by scanning electron microscopy (SEM), characterised
by scratches and ridges following a pattern along the machining direc-
tion [11]. Quantitatively, white-light optical interferometry shows a
slightly smoother surface for Ti6Al4V, which may be explained by the
difference in mechanical properties of the two materials. The relatively
thin surface oxide layer, found to be 5 nm (by AES depth profiling) to
10 nm thick (by cross-sectional TEM), consists mainly of TiO2 while
small amounts of the alloying elements are also detected in the oxide
for Ti6Al4V.
Both cp-Ti and Ti6Al4V are moderately wettable surfaces, and
hydrophilic, with similar water contact angles [19]. Surface micro-
structuring created by blasting, acid etching, or anodisation reduces
wetting of both cp-Ti [20] and Ti6Al4V [21]. The presence of microscale
structures and superimposed nanoscale features, as found on newly de-
veloped surface modifications, might also modulate wetting and the
corresponding biological response [22]. The spontaneously formed
oxide layer contains unsaturated ‘dangling’ bonds that allow impurities
such as hydrocarbons, SO2, NO and halogens to be adsorbed onto the
surface. Even a few molecular monolayers of such contamination may
influence the surface properties such as surface free energy and wetta-
bility [23]. New protocols have been introduced by manufacturers to en-
hance hydrophilicity [24] and bioactivity [25] of implant materials.
Although it is mainly the surface oxide layer that comes into direct
contact with the biological system, the microstructure of bulk cp-Ti
and Ti6Al4V is indeed different, leading to the considerable differences
in their mechanical properties (Table 1). Furthermore, the corrosion be-
haviour of the bulk materials may not be the same either. However, elu-
cidating the direct consequences of differences between the in vivo
corrosion behaviour of cp-Ti and Ti6Al4V is not only challenging — it
has neither been attempted, nor has it been reported in the literature.
962 F.A. Shah et al. / Materials Science and Engineering C 62 (2016) 960–966

Table 1
Minimum mechanical requirements of cp-Ti (Grade 4) and Ti6Al4V (Grade 5) specified in ASTM B265 [26].

Tensile strength (MPa) Yield strength, 0.2% offset (MPa) Elongation in 4D (%) Reduction of area (%)

cp-Ti 550 483–655 15 25

Ti6Al4V 895 828 10 25

This necessitates investigation of long-term healing, e.g., in human;
however, osseointegrated devices are rarely explanted for detailed anal-
ysis, and therefore analyses are restricted to non-invasive techniques
such as X-ray tomography with obvious technical limitations.
3. Bone growth and osseointegration
Upon in vivo implantation in the rabbit tibia, no qualitative or quan-
titative differences in bone growth are apparent from histological eval-
uation at eight weeks of healing. Both implant materials undergo
acceptable osseointegration, and high levels of direct bone-to-implant
contact are observed, without apparent adverse tissue response [11].
The potential clinical differences between cp-Ti and titanium based
alloys are difficult to determine since exceedingly few randomised con-
trolled trials (RCT) are performed and are often found to contain some
element of bias [27].
The following literature survey based on experimental studies inves-
tigates whether one material (cp-Ti or Ti6Al4V) is irrefutably superior
over the other or whether the null hypothesis holds true. Only compar-
ative in vivo studies have been considered where Grade-5 titanium alloy
(Ti6Al4V) and cp-Ti (as a reference material) were evaluated. Only a
handful of comparative studies of tissue reactions to pure titanium
and titanium alloys exist. Most studies have used other materials or sur-
faces in the same publication, and either accurate statistical evaluation
was not performed or the analysis failed to show statistical significance.
Most of the studies were performed in rabbit, baboon and rat
models. Healing periods of 3 days up to 12 months have been evaluated
with the following end-point analyses: (i) bone-implant contact (BIC);
(ii) bone area within the threads (BA); (iii) bone thickness; (iv) removal
torque (RTQ); (v) shear strength; (vi) resonance frequency analysis
(RFA); and (vii) ultrastructural analysis of the interface. Of the publica-
tions considered (Table 2), none indicate significant differences in BA or
BIC between cp-Ti and Ti6Al4V, while one study has demonstrated sig-
nificantly lower BIC for Ti6Al4V [28]. Three publications indicate higher
RTQ values for cp-Ti [12,29,30], two of which also show correspondingly
higher shear strength values [12,29] — a hybrid parameter based on RTQ
and BIC values, while the third did not consider this parameter [30]. On
the contrary, a few studies suggest higher RTQ values for Ti6Al4V im-
plants, but of no statistical significance [30,31]. Moreover, it is difficult
to compare the actual values obtained in the different studies since
measurements were not performed in a comparable or standardised
manner.
3.1. Histological evaluation
Quantitative histomorphometric analyses are usually performed on
thin (10–20 μm thick) ground sections [12,13,29,30,32], thick
(40–50 μm thick) ground sections [33,34], and polished blocks for
backscattered electron SEM [35]. However, the mean BA and BIC values
appear to be similar for both materials, as no statistically significant dif-
ferences have been demonstrated in most of the relevant published lit-
erature. While Dhert and co-workers [32] and de Maeztu and co-
workers [34] have reported larger differences in mean BIC values, sever-
al different surfaces were tested in the same study and lacked accurate
statistical analyses. Linder and co-workers also could not demonstrate
any differences between cp-Ti, Ti6Al4V, CoCr and stainless steel after 4
and 11 months in the rabbit tibia and no quantitative analyses were per-
formed [36]. Likewise, without any quantitative analysis, Johansson and
co-workers observed qualitatively that bone tissue adjacent to the
Ti6Al4V surface was less mineralised than cp-Ti [37], and concluded
that the leached aluminium ions may have been substituted for calcium
ions in the interfacial tissue, therefore affecting the mineralisation pro-
cess [38]. And although vanadium ions have been shown to inhibit apa-
tite formation in controlled in vitro conditions [39], taking the literature
collectively, there exists no histological evidence in support of differ-
ences between cp-Ti and Ti6Al4V in bone response at follow-up periods
of up to 1 year in rabbits (Fig. 1).
3.2. Biomechanical testing
The removal torque (RTQ) values (Table 3) generally appear to be
higher for cp-Ti than those for Ti6Al4V [12,29,30,40]. On the contrary,
using a different mechanical test, Mendes and co-workers reported a
higher retention capability of Ti6Al4V implants. However, the high
amount of ‘failed’ analyses (i.e., forces registered as 0 N; 67% for cp-Ti
and 50% for Ti6Al4V) precludes the reliability of the statistical data
[31]. Surface modification by 50% coverage with calcium phosphate
nanoparticles allowed significantly (p b 0.01) improved biomechanical
anchorage of Ti6Al4V (11.3 N) implants compared to cp-Ti (7.2 N) [31].
3.3. Ultrastructural observations
The ultrastructure of the bone implant interface has been investigated
using several different preparation techniques. Using a polycarbonate

Table 2
Relevant publications with the corresponding analyses performed.

Surface BA BIC RTQ Shear strength RFA Ultrastructure

Linder et al. [41] Machined X

Johansson et al. [37] Machined X
Johansson et al. [13]a Machined X X
Dhert et al. [32]a Blasted X
Johansson et al. [30] Machined X X X
Han et al. [29] Blasted X X X X
Mendes et al. [31]a Dual etched Xb
Palmquist et al. [11] Machined X X
Mendes et al. [35]a Dual etched X
Stenport et al. [12] Machined X X X X X
Saulacic et al. [28] Blasted, acid etched X X
Johansson et al. [40] Machined X X
a
Indicates that other surfaces were considered in the publication, as hydroxyapatite coatings or ion implantation, however, not considered in this review.
b
Traction test for bone bonding to a flat surface; and not removal torque.
 F.A. Shah et al. / Materials Science and Engineering C 62 (2016) 960–966 963

Fig. 1. Histological observation of the bone–implant interface. (a, c and e) Ti6Al4V, and (b, d and f) cp-Ti (Palmquist et al. [11]). At low magnification (a, b), similar amounts of bone are
observed around the implants and inside the threads, and appears to be remodelled, lamellar, and osteonal (c, d). Osteoclastic remodelling sites (arrowheads) are frequently observed at
the bone–implant interface demonstrating the dynamic nature of this region (e, f).

implant replica with a thin TiO2 coating to allow ultramicrotome sec- However, Linder et al., in line with their histological evaluation,
tioning, wider zones of unmineralised ground substance and irregularly failed to demonstrate differences in the interfacial tissue ultrastructure
arranged collagen preceding mature bone were found adjacent to between cp-Ti, Ti6Al4V, CoCr, and stainless steel implants [41]. The in-
Ti6Al4V implants compared to cp-Ti implants [37]. terfaces were composed of different structures described as indistinct
filamentous structures up to 100 μm from the implant surface. Others
have found mineralised bone in intimate contact with Ti6Al4V, without
Table 3 intervening unmineralised and/or indistinct structures [17,42].
A summary of the results of biomechanical analyses performed.
All of these studies were performed by sample preparation proce-
Time cp-Ti Ti6Al4V p value dures that necessitated, prior to ultrathin sectioning, physical or electro-
Johansson et al. [30] 1 month 13 Ncm 14 Ncm NS chemical removal, or a complete absence of bulk metal, followed by
6 months 30 Ncm 24 Ncm p = 0.01 prolonged decalcification of bone. Indeed, several kinds of preparation
12 months 38 Ncm 35 Ncm p = 0.01 artefacts associated with these techniques have been reported over
Stenport et al. [12] 3 months 24 Ncm 19 Ncm p = 0.01
the years. Ultrastructural investigations using TEM specimens prepared
Han et al. [29] 3 months 38 Ncm 27 Ncm p = 0.004
3 months 70 Ncm 50 Ncm p = 0.003 via the novel focused ion beam scanning electron microscopy (FIB-SEM)
Johansson et al. [40] 6 weeks 19.8 Ncm 13.2 Ncm Not tested in situ lift-out technique [18] to obtain electron transparent specimens
Mendes et al. [31]a 9 days b1 N ~2 N NS with the bone-implant interface intact have also demonstrated
The higher mean values are indicated with bold text. NS = not significant. comparable nanoscale 3D architecture for cp-Ti [43] and Ti6Al4V [44]
a
Tested in the rat femur, while the others are tested in the rabbit tibia. (Fig. 2).
964 F.A. Shah et al. / Materials Science and Engineering C 62 (2016) 960–966
Fig. 2. Ultrastructural observation of the bone–implant interface. (a) Ti6Al4V (Grandfield et al. [44]). (b) cp-Ti (Palmquist et al. [43]). In both cases, the bone–implant interface is
characterised by well-aligned collagen fibrils laid down parallel to the implant surface, as seen in both longitudinal (a) and transverse (b) directions.
3.4. Bone response to other titanium alloys
Alloys of titanium other than Ti6Al4V are not within the scope of the
present discussion. However some selected observations are considered
briefly, to underscore the fact that data in the published literature is in-
conclusive regarding whether titanium alloy performs better than cp-Ti,
and if so, which alloy performs best. Compared to the Ti6Al4V in vivo,
the Ti–7.5Mo alloy shows a two-fold increase in bone formation after
26 weeks of healing in the rabbit femur. This effect was explained to
be due to the low modulus of the Ti–7.5Mo alloy [45]. Ti–15Zr–4Nb–
4Ta, another novel alloy, shows bone formation similar to the Ti6Al4V
after 6–48 weeks of healing in the rat tibia. Ti6Al4V materials were how-
ever observed to suffer pitting corrosion in vivo [46].
In terms of BIC, the TiZr alloy has also been found to be superior to
Ti6Al4V [28] in mini-pigs, however with an outcome comparable to cp-
Ti in mini-pigs [28] and dogs [47]. The TiZr alloy, compared to cp-Ti, has
been implicated in a 5% BIC increase in the bone marrow at 4 weeks of
healing in rabbits — however, the authors present a p value of precisely
0.05225 considering it statistically significant [48]. The same study dem-
onstrates significantly higher RTQ for TiZr vs. cp-Ti at two weeks of
healing in the femur (although implants were also placed in the tibia),
and higher BA in the bone marrow at 4 weeks of healing [48].
More recently, a novel Ti–Ta–Nb–Zr alloy, designed to mimic the mi-
crostructure and phase composition of the α–β Ti–Al–V alloy but using
alloying elements of lower cytotoxicity than Al and V, has been investi-
gated in the rat [49]. RTQ tests demonstrated a significant increase in
implant stability of Ti–Ta–Nb–Zr between 7 and 28 days, which was
not observed for the cp-Ti [49].
3.5. Clinical performance
In an extensive review, Esposito et al. have identified a total of 81
comparative clinical studies for dental implants of which only 27 were
considered to strictly adhere to the inclusion criteria for RCT [27]. Of
these, only one directly compared different bulk materials, namely cp-
Ti and TiZr, with similar shape and surface treatment (SLActive®,
Institut Straumann AG, Basel, Switzerland) [50]. Different surface treat-
ments on different bulk materials, namely acid-etched Ti6Al4V (Steri-
Oss®, Nobel Biocare, California, USA) and sandblasted cp-Ti
(Southern®, Southern Implants, Irene, South Africa) were compared in
two studies: (i) conventional-loading at twelve weeks [51] and (ii)
early-loading at six weeks [52]. Although neither study was able to
demonstrate statistically significant differences in implant failure, a
trend towards lower risk of failure for cp-Ti (Southern®) vs. Ti6Al4V
(Steri-Oss®) was noted at 10-year follow-up. However, most of the
failed implants had been installed by the same surgeon, who exclusively
installed Steri-Oss® implants.
The mature dental implant market may be characterised by incre-
mental, step-wise changes in hardware solutions. Since it is highly likely
that implant manufacturers support most of the clinical trials, interest is
devoted to comparisons between a new technical modification and a
previous solution or that of a competitor. The final selection of a mate-
rial for dental and orthopaedic applications is based on multiple consid-
erations. And along with necessity, not only scientific rationale but also
risk assessment, tradition, branding, intellectual property rights, costs
and other considerations influence the decision-making process. A
shift to a new material is likely to involve greater effort and cost than
the introduction of, for example, modifications of the surface properties
of a material that is well embedded within the clinical community.
4. Bacterial interactions
There appears to be a gross lack of comparative in vivo infection
studies between cp-Ti and Ti6Al4V materials. The physical, chemical
and topographical properties of a biomaterial, as well as the bacterial
species and virulence properties of strains may influence bacterial adhe-
sion and biofilm formation in biomaterial-associated infections. In vitro,
the biofilm production ability of Staphylococcus epidermidis seems to be
related to a stronger adhesion of this bacterium to Ti6Al4V than non-
biofilm producing strains of S. epidermidis [53]. Ha KY et al. report stron-
ger adhesion and multiplication of biofilm producing strains of
S. epidermidis on nominally smooth-surfaced Ti6Al4V than rough-
surfaced Ti6Al4V whereas the growth of non-biofilm producing
S. epidermidis strains did not differ between differently roughened
Ti6Al4V [53]. While surface roughness increases the area for bacterial
adhesion, Ra values in the 5.6–22 nm range did not demonstrate differ-
ences in the adhesion of S. epidermidis on cp-Ti in vitro [54]. The mini-
mum roughness required for S. epidermidis adhesion differs depending
on the material used, since bacterial adhesion is a multi-factorial process
involving more than a single surface parameter [54,55].
The adherence of several Gram-positive (S. epidermidis and Strepto-
coccus sanguinis) and Gram-negative (Serratia species and Escherichia
coli) bacteria is reportedly comparable on both cp-Ti and Ti6Al4V [56].
Similar observations were made in a study on the adhesion of
S. epidermidis to Ti6Al4V alloy and to separate pure titanium, aluminium
and vanadium metal surfaces, where similar numbers of bacterial cells
adhered to pure titanium and Ti6Al4V [57]. Additional in vitro studies
on S. epidermidis adherence further confirm the similarity between
cp-Ti and Ti6Al4V [55,58].
Due to the intrinsic virulence traits of each strain (e.g., capsules,
adhesins, slime production), bacterial adhesion to surfaces is species
 F.A. Shah et al. / Materials Science and Engineering C 62 (2016) 960–966
and strain dependent [53]. While agreeing with the previous studies on
non-significant differences in S. epidermidis adhesion to cp-Ti and
Ti6Al4V, Schildhauer and co-workers observed higher Staphylococcus
aureus adherence to Ti6Al4V [58]. However, there was a correlation be-
tween the adherence of both staphylococcal species and the surface
roughness of cp-Ti (Ra = 0.32 μm) and Ti6Al4V (Ra = 0.69 μm). Another
study failed to find a correlation between corrosion-related increase in
surface roughness and Porphyromonas gingivalis attachment in vitro
[59]. In addition, the same study showed that electrochemically
corroded cp-Ti and Ti6Al4V surfaces promote more the attachment of
P. gingivalis than non-corroded controls. Furthermore, among the non-
corroded group, significantly more P. gingivalis attached to cp-Ti than
to Ti6Al4V.
High voltage (90–130 V) anodisation induces the development of
anatase on both cp-Ti and Ti6Al4V [60], and has been shown to decrease
bacterial attachment and biofilm formation of S. aureus, S. epidermidis,
Streptococcus mutans and P. gingivalis in vitro, but increased oral
plaque formation in vivo, and promoted in vitro proliferation of MG63
osteoblast-like cells and L929 murine fibroblasts [60]. Although the
study did not report statistical comparisons between cp-Ti and
Ti6Al4V, their data suggest possible differences in early in vitro bacterial
colonisation (3 h) with higher colony-forming units (CFU/cm2) of
S. epidermidis and S. mutans on Ti6Al4V than cp-Ti, but no differences
in bacterial proliferation at 24 h. In contrast, in vitro biofilm formation
of the four bacterial species (S. aureus, S. epidermidis, S. mutans and
P. gingivalis) at 24 h was reduced on Ti6Al4V vs. cp-Ti. In addition, qual-
itative SEM observation of cp-Ti and Ti6Al4V discs affixed to silicone
intraoral appliances, worn by human volunteers for 24 h, indicated
higher degree of bacterial plaque formation on Ti6Al4V [60].
Apart from a scarce number of in vitro studies, there is an evident
lack of comparative in vivo studies on infection between cp-Ti and
Ti6Al4V materials.
5. Conclusions
(i) Surfaces machined from cp-Ti and Ti6Al4V exhibit similar mor-
phology, topography, phase composition and chemistry.
(ii) Bacterial adhesion to surfaces is a multi-factorial, as well as spe-
cies and strain dependent process. Importantly, in vitro experi-
ments fail to disclose differences between cp-Ti and Ti6Al4V
in harbouring the growth of S. epidermidis (a common pathogen
in percutaneous medical devices) between cp-Ti and Ti6Al4V.
Other in vitro studies show contradictory results favouring one
material over the other depending on the bacterial species
under test and the methodological design. Nevertheless, careful-
ly designed studies need to be performed where the role of the
implant surface properties for host defence and colonisation of
bacteria are determined.
(iii) Experimental studies on the bone response of machined cp-Ti and
Ti6Al4V demonstrate similar osseointegration after 8 weeks in
rabbits. Although four publications (all from the same group)
demonstrate a higher biomechanical capacity of cp-Ti, results
from other research groups fail to present convincing evidence
of qualitative or quantitative differences between cp-Ti and
Ti6Al4V in bone healing and adaptation.
(iv) It is apparent that only a few clinical comparative studies have
been performed to determine if long-term, clinical differences
exist between cp-Ti and Ti6Al4V.
Based on the literature presently available, it may be concluded
that under experimental conditions, cp-Ti and Ti6Al4V demon-
strate similar osseointegration and biomechanical anchorage.
6. Future perspectives
The biocompatibility of titanium for bone-anchored applications
is indisputable. However, there is a strong disagreement within the
965
published literature as to which titanium type is more preferred for spe-
cific clinical settings. For instance, the extent of functional loading which
an implant is expected to withstand may guide the selection between
commercially pure or alloyed titanium. However, if tissue response
and bacterial adhesion, particularly in percutaneous applications and
conditions prone to periimplantitis, are similar for both types of mate-
rials, the selection is rooted firmly in the mechanical properties of the
implant material, rather than biology. Therefore, further comparative
clinical studies of cp-Ti, Ti6Al4V and new alloys are required. It is pro-
posed that correlative multi-scale analysis of retrieved clinical implants
[61], encompassing newer analytical approaches, for example the
molecular-scale composition of the bone-implant interface, and the
evaluation of changes in the osteocyte morphology [62] could be useful
in probing the differences in bone response to different bulk-materials.
Newer processing techniques, e.g., 3D printing, allow a substantial free-
dom in the macro-geometry of cp-Ti and Ti6Al4V constructs [63], for de-
signing materials with properties relevant to specific applications.
Acknowledgements
This study was supported by the Swedish Research Council (grant
K2015-52X-09495-28-4), the BIOMATCELL VINN Excellence Center of
Biomaterials and Cell Therapy, the Region Västra Götaland, an ALF/
LUA grant (ALFGBG-138721), the IngaBritt and Arne Lundberg Founda-
tion, the Dr. Felix Neubergh Foundation, the Wilhelm and Martina
Lundgren Foundation, Promobilia, the Hjalmar Svensson Foundation,
and the Materials Science Area of Advance at Chalmers and the Depart-
ment of Biomaterials, University of Gothenburg. The sponsors were not
involved in the study design, data acquisition, interpretation, writing
and submission of the article. The authors declare no conflict of interest.
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