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RSC AdvancesView Article OnlineView Journal
Ti
bone
bone
Polymer
MuBiNaF
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Recent progress in the field of multicomponent bioactive nanostructured films
Dmitry V. Shtanskya, Evgeny A. Levashova, Irina V. Bateninaa, Natalia A. Gloushankovab,
Natalia Y. Anisimovab, Mikhail V. Kiselevskyb, and Igor V. Reshetovc
a National University of Science and Technology “MISIS”, Leninsky prospect 4, Moscow 119049,
Russia b Blokhin Russian Cancer Research Center of the Russian Academy of Medical Sciences,
Kashirskoe shosse 24, Moscow 115478, Russia c Hertsen Moscow Oncological Research Institute, 2nd Botkinsky driveway 3, Moscow 125284,
Russia
E-mail: [email protected]
Tel.: +7-499-236-6629
Multicomponent bioactive nanostructured films (MuBiNaFs) with an excellent
combination of chemical, mechanical, tribological, and biological properties were
developed and deposited by sputtering of composite targets produced via the self-
propagating high-temperature synthesis method. Reviewed substrate materials included
Ti-, Ni-, and Co-based alloys, insoluble polymers, and deimmunized donor’s bones. Our
results showed that the MuBiNaF deposition can be effectively combined with either a bulk
material modification to improve its mechanical properties, or a surface modification to
control surface roughness and blind porosity. Among other promising applications, the
fabrication of hybrid materials incorporated with stem cells or medicine is mentioned.
1. Present state-of-the-art
Bone and joint degenerative and inflammatory problems affect millions of people
worldwide and the development of patient-friendly biomaterials is a challenge that biological
community has faced for many years. However, the materials of dream were not yet developed.
The main efforts are focused on the design of new biomaterials with accelerated self-adaptation
in human body, which would reduce the patient’s rehabilitation period, and with improved
chemical and mechanical properties, which would markedly increase the implant lifetime. This,
however, is not easy because the sought advanced biomaterials should possess a combination of
properties such as biocompatibility, bioactivity, wettability, corrosion resistance, good
mechanical and tribological properties, which cannot be found in one single material.
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Surface engineering is an effective tool to modify surface characteristics of various
materials (e.g. metals and polymers, as those widely used in biomedical applications), while
retaining their bulk properties. Most of the materials currently used in medicine, have certain
drawbacks. For instance, titanium and its alloys have been well known as one of the best choices
for load-bearing implants for many years, which is explained by their high strength combined
with excellent plastic characteristics, high chemical stability, and good biological compatibility.1
At the same time, they demonstrate insufficient wear- and corrosion resistance, high friction
coefficient, and poor bioactivity, thus implying the necessity of surface modification. In addition,
the formation of wear debris and metal ion release may cause loosening of implant fixation and
toxic response, respectively. In turn, insoluble polymers and polytetrafluoroethylene (PTFE) in
particular attracted much attention as nonporous materials and porous scaffolds for load carrying
and supporting implants, fixation devices, bulk space fillers, prostheses, artificial blood vessels,
pericardium and vascular grafts, and heart valves.2 The shortcomings of PTFE include its
hydrophobicity, which prevents the attachment of cells to its surface, and insufficient interfacial
bonding between the polymer surface and the surrounding bone.3
An effective way to improve the surface properties of bulk biomaterials and to promote the
interaction between the implant surface and surrounding tissue is the deposition of
multifunctional bioactive films. Hydroxyapatite (HA), Ca10(PO4)6(OH)2, and calcium phosphate
(CaP) ceramics are widely used as a bioactive interface between the bulk metal implant and the
surrounding tissue because of their close similarity to the chemical and mineral components of
teeth and bones. However, these pure compounds cannot be used as load-bearing components
due to their poor mechanical properties.4 The properties of HA and CaP ceramics can be further
improved by doping with other elements, e.g. Ti,5,6 Si,7,8 and Mg.9 These dopants may
demonstrate a positive affect either on the coating mechanical properties (adhesion strength (Ti)
or viscosity (Mg)) or on material biological characteristics (Si). Another interesting application
of the CaP-based materials is a fabrication of composite coatings consisting of CaP and
biodegradable polymers.10-12 These biodegradable composite materials have some advantages
over pure biodegradable polymers due to the presence of a bioactive substance with pH-
stabilizing effect, which prevents the surrounding tissue damage.11
Plasma-assisted methods for CaP-based coating fabrications were recently reviewed by
Surmenev.13 The review shows that different plasma-assisted methods, e.g. plasma spraying (PS),
radio-frequency (RF) magnetron sputtering, pulsed laser deposition (PLD), and ion beam-
assisted deposition (IBAD), are well suitable for the deposition of dense, homogeneous, pore-
free and highly adherent biocompatible coatings. Plasma immersion ion implantation and
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deposition (PIII&D) is another effective technique to enhance the surface bioactivity of
materials.14-16
In the design of new multicomponent bioactive films, particular attention should be paid to
elemental and phase composition, and, in this context, Ti, Ta, Zr, Ca, P, C, N, and O are suitable
elements to optimize surface chemistry and promote fast osseointegration. Using the concept of
nanocomposite materials it is possible to produce films in which some of the phase constituents
provide mechanical strength and wear resistance, while others are bioactive. In this work, our
recent progress and results in the field of multicomponent bioactive nanostructured films
(MuBiNaFs) with an excellent combination of chemical, mechanical, tribological, and biological
properties for load-bearing implants is reviewed.
A new approach to design MuBiNaFs involves two main technological steps: (i)
development and fabrication of composite targets and (ii) film deposition using sputtering of the
composite targets. The capabilities of ion-plasma technology can be substantially extended
through the use of composite targets produced by the self-propagating high-temperature
synthesis (SHS).17 The SHS-technology allows one to produce a wide spectrum of targets based
on ceramics, metal ceramics, and intermetallic compounds.18 SHS is an alternative method to
various powder-metallurgy based approaches (cold pressing, hot extrusion, hot isostatic pressing,
etc.) and provides a highly dense, uniform structure that exhibits required mechanical, thermal,
and electrical properties needed for composite PVD target materials.19 Various multicomponent
films (to date, up to six elements) can be deposited using a single SHS-fabricated composite
target, which allows the use of a simple sputtering unit. During the magnetron sputtering of
composite targets, a multicomponent uniform flow of both metal and nonmetal atoms and ions is
realized from the target to substrate, which is particularly beneficial for the deposition of
MuBiNaFs and in which both metal (Ca, Ti, Ta, Zr) and nonmetal (C, N, O, Si, P) elements are
present.20 During the last decade various SHS-composite targets have been developed and
synthesized for the deposition of MuBiNaFs, such as TiC0.5 + CaO, TiC0.5 + ZrO2, TiC0.5 + CaO
+ TiO2, TiC0.5 + Ca10(PO4)6(OH)2, TiC0.5 + Ca3(PO4)2, (Ti,Ta)C + Ca3(PO4)2, and (Ti,Ta)C +
CaO).21,22 The type and amount of various inorganic additives in the TiC- and (Ti,Ta)C-based
composite targets permitted to control biological characteristics of films without compromising
their mechanical and tribological properties. In order to enhance the toughness and thermal
resistance (resistance to thermal cycling during high-power magnetron sputtering) required for
PVD targets, functionally graded targets have been also developed, manufactured, and used.
The chemical reactions in various systems have been investigated.21,23 Only one chemical
reaction between Ti and C was observed during SHS of TiC-based targets with various inorganic
additives such as (Ti+0.5C)+CaO, (Ti+0.5C)+ZrO2, (Ti+0.5C)+Ca3(PO4)2, and
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(Ti+0.5C)+Ca10(PO4)6(OH)2.23 For Ta-doped targets, the synthesis process was more complex
and depended on the charging parameter x: (90% – x)(Ti + 0.5C) + x(Ta + C) + Ca3(PO4)2.21 For
small x, two well resolved combustion waves propagated though the green mixture within a short
interval resulting in the formation of TiC and TaC phases with a short delay relative to each
other. When the charging parameter x was increased to 45% and the initial heating temperature
increased to 420 °C, the chemical reactions proceeded in one step, the combustion rate being the
same. The observed differences in the combustion modes can be explained as follows. At low Ta
concentrations at the combustion front, Ti melts and flows over the surface of C particles. The
formation of TiC occurs either on the surface of ash particles or during the crystallization of Ti-C
melt. In this case, Ta reacts with carbon in the afterburning zone. Such a combustion mode is
usually called the “detached mode”. As the Ta content increases, the intensity of the second
reaction increases, while that of the first reaction between Ti and C substantially decreases, and
the combustion gradually transforms into the coalescence mode.
For MuBiNaFs deposition, different methods were employed. The films were obtained by
magnetron sputtering24-26, ion implantation-assisted magnetron sputtering (IIAMS),27-29 and а
hybrid process involving sputter deposition and either inductively-coupled plasma (ICP)30-32 or
an RF system for an additional ionization.33 IIAMS was used to enhance film adhesion to the
metal substrate via high-energy ion bombardment several minutes before and after the beginning
of deposition. In ionized physical vapor deposition processes using ICP or RF systems, the
sputtered species were highly ionized, which led to highly-dense films. A similar dense
homogeneous structure was also observed when a high bias voltage (-250 V) was applied during
dc magnetron sputtering.27
For the first generation of MuBiNaFs, composite targets TiC0.5+X [X=CaO, ZrO2, TiO2,
Ca3(PO4)2, and HAP(Ca10(PO4)6(OH)2)] were manufactured by means of SHS.24-27 All the films
deposited in a gaseous mixture of Ar+N2 had a nanocomposite structure with cubic B1 NaCl-
type crystallites, with sizes smaller than 20 nm, embedded in an amorphous matrix (Fig. 1). Fig.
2 shows the Ti-L2,3, O-K, C-K, Ca-L2,3, N-K, and P-L2,3 energy-loss near-edge structures of the
TiCaPCON film deposited using the target TiC0.5+Ca3(PO4)2. The Ti-L2,3, N-K, and C-K spectra
exhibited peak shapes and positions similar to those of TiC and TiN. The presence of
characteristic Ca-L2,3, P-L2,3, and O-K edge structures indicates that Ca and P are in oxidized
states, probably in an amorphous matrix. The elemental composition of the TiCaPCON film was
determined from EELS data and is shown in Table 1.
The MuBiNaFs demonstrated a combination of mechanical and tribological properties
superior to those of Ti-, Ni-, and Co-based alloys, which are widely used as orthopedic and
dental implants, as well as to those of their binary TiC and TiN thin film counterparts. The
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MuBiNaFs were characterized by high hardness 25-40 GPa combined with a high percentage of
elastic recovery (up to 75%) and reduced Young’s modulus of 230-350 GPa, which are lower
than those of bulk ceramics (TiN – 440 GPa, TiC – 480 GPa, SiC - 450 GPa, Al2O3 - 390 GPa)
and closer to the modulus of stainless steel (200 GPa) and Ti (120 GPa). The benefits of a
moderately low Young’s modulus in implant applications are well known: (i) a better transfer of
functional loads to the bone and (ii) a reduced interfacial stress between the film and substrate
materials. The MuBiNaFs also showed high resistance to plastic deformation (up to 0.9 GPa) and
long elastic strain to failure, which was previously reported as a good indicator of high film
durability and wear resistance.34 Other mechanical characteristics of the films included a high
fatigue limit of 350 MPa (MuBiNaFs on a Grade 4 Ti substrate), high adhesion strength (up to
50 N), and excellent impact resistance. In general, the MuBiNaFs demonstrated a hydrophilic
nature, a negative surface charge at pH 5-8.5, and positive values of corrosion potential with low
current density under various biological solutions. It should be noted that for the Ca- and P-
doped TiCON films the proliferation of MC3T3-E1 osteoblastic cells was visibly higher than on
the surface of control samples.24 In addition, MC3T3-E1 osteoblasts cultivated for 14 days on the
surface of TiCaCON films showed a two-fold higher alkaline phosphatase (ALP) activity than
those on the control sample.
The in vivo investigations included three types of tests using the rat (i) calvarian defect
model, (ii) hip defect model, and (iii) subcutaneous model. Implantation studies indicated early
signs of bone formation on coated titanium implants. After one month, a close contact between
the implant surface and cortical bone was observed without any bone losses at the interface (Fig.
3). The biocompatibility of the MuBiNaFs was also confirmed in biological tests using larger
animals (rabbits and pigs).35
In 2008, clinical studies initiated with metallic implants for cranial-jaw-face surgery, spine
surgery, and hip joints coated with TiCaCON and TiCaPCON films. These types of MuBiNaFs
were evaluated at the P.A. Hertsen Moscow Research Oncological Institute and the Central
Institute of Traumatology and Orthopeadics, Moscow and subsequently were approved for
medical applications on the territory of the Russian Federation.
More recently, we have explored novel advanced approaches to MuBiNaFs by doping the
Ti-Ca-P-C-O-N films with Ta and Si.28,29,36 This second generation of MuBiNaFs was shown to
possess a nanocomposite structure with various functional groups on the film surface that
stimulate accelerated osseointegration. For instance, the Si-doped TiCaCO(N) films sputter-
deposited using composite TiC0.5+CaO+Si and TiC0.5+CaO+Si3N4 targets consisted of TiC(N) as
a main phase with a minor amount of TiOx, SiNx, SiOx, SiC, and CaO phases, which were
probably mainly in an amorphous state at the grain boundaries, and carboxyl groups on the film
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surface among others. Excess carbon atoms precipitated in the TiSiCaCON film as amorphous
carbon or diamond-like carbon (DLC) phase. The Si-doped TiCaCON films possessed improved
osteoconductive characteristics during the early stages of cell/material interaction. The ALP
level of MC3T3-E1 cells grown on the Si-doped films was significantly higher than that on an
uncoated coverslip and coverslips coated with Ti and TiN films. The Ta-doped Ti-Ca-(P)-C-O-
(N) films deposited in argon consisted of (Ti,Ta)C, TixOy, and CaO phases in an amorphous
matrix with P-O, C-O, and O-H bonding.29 The films reactively sputtered in an Ar+N2
atmosphere exhibited (Ti,Ta)(C,N), TixOy, and CaO phases, DLC, bcc Ta and trace amounts of
P-O bonding. The Ta-doped films also showed a high rate of osteoblastic cell proliferation and
high level of ALP.
It was also shown that the modification of a PTFE surface by the deposition of TiCaPCON
films with and without adipose-derived stem cells (ASCs) is an effective way to improve the
chemical and mechanical characteristics of polymer implants and provide them with a high
osseointegration potential.37 The TiCaPCON/PTFE samples demonstrated a hardness of 0.6 GPa,
Young’s modulus 4.8 GPa, and percentage of elastic recovery 61%, which are significantly
higher than those of the uncoated PTFE (H=0.04 GPa, E=0.9 GPa, and We=30%). After film
deposition, the water contact angle decreased from 100 to 18o, indicating that the surface became
hydrophilic, which is believed to be favorable for good cell attachment, spreading and
proliferation.38,39 In vivo tests clearly demonstrated that the porous PTFE plates with TiCaPCON
films induced the formation of a mature bone tissue, which filled in all the area of the critical
bone defect of the rabbit’s calvaria. This can be regarded as an indication of a very high
osseoinduction potential of such films. Particular attention was paid to studying the influence of
ion etching and ion implantation, which are widely used in surface treatment to improve film
adhesion, on the cytotoxicity of PTFE.40 It was demonstrated that, unlike the ion implantation,
the ion etching resulted in the destruction of the polymer and appearance of the cytotoxicity.
The interaction between an implant and surrounding tissues is a complex dynamic
process whose efficiency largely depends not only on the implant surface chemistry but also on
the surface topography and roughness. The possibility to produce biocompatible materials with
controllable surface roughness, blind porosity, and desired chemical composition opens new
avenues for the design of novel metal-ceramic implants. Yet the question arises as to whether it
is possible to obtain a synergetic effect by a proper choice of both surface chemistry and
roughness. To address this question, the influence of elemental composition and surface
roughness on the osteoblastic MC3T3-E1 cell behavior was recently investigated.41 Four groups
of Ti samples, as-supplied Ti and sandblast-treated Ti with and without TiCa(P)CON films, were
used in the test. The obtained results show that surface chemistry was important at different
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stages of the osteoblast/implant interaction, while surface roughness (root-mean-square
roughness Sq in the range of 0.4-1.0 m) was not observed to have any significant influence on
adhesion, proliferation and differentiation of osteoblasts.41
The investigation revealing the role of surface chemistry and topography, both separate and
in synergy, was extended further to samples with porosity in the range of 100-300 m and
average roughness Ra=1-100 m. To achieve this goal, a new combined approach using cold
spray (CS), selective laser sintering (SLS), pulsed electro-erosion treatment (PEET), and
magnetron sputtering methods was developed to fabricate metal-ceramic materials with
controlled topography, blind porosity, and desired surface chemistry.42 The results indicated that
the change of surface porosity and roughness may influence the adhesion, spreading, growth, and
differentiation of osteogenic cells. It was also shown that the bioactivity of Ti surfaces can be
well controlled by a proper choice of surface chemistry and topography. The ALP level of
MC3T3-E1 cells growing on the PEET-treated sample with Ra=8 m was 1.6 times higher than
that of cells on a flat Ti control. This result implies that the bioactivity of Ti alloys can be well
controlled by a proper choice of surface topography. The deposition of the TiCaPCON coating
resulted in a further increase of ALP activity, but the difference was not significant. Our results
also clearly indicated that the deposition of the TiCaPCON film on the surface of PEET-
modified sample with Ra=3 m improved its bioactivity, whereas surface roughness itself did not
affect the ALP activity (Table 2). Additional studies are needed to reveal the synergetic role of
surface chemistry and topography. The obtained metal-ceramic materials with high surface
roughness and blind porosity were also shown to be suitable as orthopedic implants with
microcontainers for medicine.42
It is worth noting that safety and reliability of the medical systems, especially load-bearing
ones, should be addressed with special attention. The adhesion and deformation characteristics of
MuBiNaFs deposited on different substrates were studied using the scratch test.43 Depending on
the type of substrate material, three cases were treated: (i) hard film on hard substrate, (ii) hard
film on soft substrate with a low value of E/H ratio (mostly elastic contact), and (iii) hard film on
soft substrate with a high value of E/H ratio (mostly plastic deformation). It was shown that
critical loads responsible for different types of adhesion and cohesion failure of the films could
be determined from a set of parameters recorded during their scratching.
2. Undergoing scientific research
A key MuBiNaFs property that can be improved further is their antibacterial effect.
Implant-related microbial infections remain a serious problem in orthopedic and dental surgery.
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One of effective ways to overcome this problem is a deposition of an antibacterial film which
minimizes the risk of bacterial contamination without compromising the implant bioactivity and
biocompatibility. Ag-doped TiCaPCON films, which are thereafter referred as third generation
of MuBiNaFs, were tested against Saccharomyces cerevisiae yeast and gram-positive
Lactobacillus acidophilus bacteria and the obtained results are summarized in Table 3. Our
preliminary data showed that doping of TiCaPCON films with 1.2 at.% of Ag resulted in a
decrease of the number of L. acidophilus colonies by 71% after 2 days of incubation and the
bacteriostatic effect reached 100% after 4 days. The absolute concentration of the L. acidophilus
was also decreased. The biocompatibility of the Ag-doped films was evaluated in vitro using
МС3Т3-E1 osteoblastic cells (the results being presented in Table 3). It can be seen that cultured
МС3Т3-E1 cells were well spread on the both tested surfaces (film and control). The МС3Т3-E1
cells cultured on the Ag-doped surface exhibited, however, a reduced level of ALP activity.
Additional studies are in progress to elucidate the observed phenomena in more detail. Note that
recent studies by Greulich et al.44 showed that the toxic effect of silver occurs in a similar
concentration range for both bacteria and human cells, raising doubts about the widespread use
of silver as an antibacterial agent in medical applications.
Nanostructured (nc) titanium alloys exhibit unique characteristics compared with
commercially pure titanium (cp-Ti). The mechanical properties of metals and alloys can be
drastically improved upon a decrease in their mean grain size down to 100 nm by using the
methods of severe plastic deformation.45 The properties of nc-Ti can be further improved by the
deposition of MuBiNaFs. An important issue is, however, that film/substrate fatigue and creep
properties can be different for micro- and nanocrystalline metallic substrates. The impact test is
commonly used to characterize film contact fatigue under repetitive dynamic loading.46 Figure 4
compares diagrams of the impact force vs. the number of impacts leading to the TiCaPCON film
failure on two different substrates, i.e. cp-Ti and nc-Ti. It can be seen that the fatigue limit for
the TiCaPCON/nc-Ti system was drastically increased compared with that on the cp-Ti substrate.
The last, but not least, exciting application of the above discussed films is the fabrication of
bioengineered constructions based on the deimmunized donor’s bone coated with MuBiNaFs and
further colonized by recipient’s mesenchymal stromal cells (Fig. 5). According to our
preliminary results, this complex hybrid structure provides a configuration, which, on one hand,
is anatomically adequate to the original bone, and, on the other hand, promotes both accelerated
tissue fixation and revascularization of the implant (Fig. 6). These two effects are achieved by
the deposition of MuBiNaFs on the bone surfaces. The film was shown to promote cellular
adhesion, cultivation, and proliferation. This approach provides the delivery of a large number of
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mesenchymal stromal cells to the implantation zone. Such cells are capable of differentiating to
certain connective tissue cells including, e.g., endotheliocytes.
Conclusions
Recent progress in the field of multicomponent bioactive nanostructured films (MuBiNaFs)
is briefly reviewed in the article. The films were obtained by sputtering of specially designed and
fabricated SHS composite targets on different metal, polymer, and deimmunized donor’s bone
substrates. An excellent combination of properties makes such MuBiNaFs very attractive
materials for bioengineering and modification of metal and polymer surfaces, as well as
deimmunized donor’s bones:
- Nanocomposite structure with various functional surface groups
- High hardness in the range of 25-40 GPa; lower hardness 15-20 GPa for Ag-doped films
- Reduced Young’s modulus in the range of 230-350 GPa
- High resistance to plastic deformation and long elastic strain to failure
- High fatigue limit about 350 MPa
- High adhesion strength up to 50 N
- High percentage of elastic recovery up to 75%
- Low coefficient of friction 0.12-0.22 in normal saline
- Low wear rate 10-6 - 10-7 mm3N-1m-1
- Negative surface charge at pH of 7
- Positive values of corrosion potential with low current density values in biological solutions
- Good wettability (hydrophilicity)
- Bioactivity
- Biocompatibility
- Antibacterial activity.
To get even better synergetic effect of implant modifications, the MuBiNaFs deposition
can be combined with either a bulk material modification, for instance by a severe plastic
deformation to improve mechanical properties, or a surface modification to control surface
roughness and blind porosity. Another promising application is the fabrication of hybrid
materials incorporated with stem cells or medicine.
Acknowledgements
The authors acknowledge the funding from the Ministry of Science and Education of the
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Russian Federation during the course of this work. In vivo tests have been conducted with the
ethical approval by the Animal Care and Use Committees of the Blokhin Russian Cancer
Research Center of RAMS and the Hertsen Moscow Oncological Research Institute. We thank
Dr. C. Rojas (ICMS, Seville, Spain) for help with EELS studies and K.A. Kuptsov (MISIS,
Moscow, Russia) for assistance with impact tests.
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(a) (b)
Fig. 1 (a) TEM and (b) high-resolution TEM micrographs (cross-section) of the TiCaPCON film
obtained by magnetron sputtering of a TiC0.5 + Ca3(PO4)2 target.
.
Si 5 nm
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Fig. 2 EELS spectra of the TiCaPCON film deposited using a TiC0.5+Ca3(PO4)2 target.
O-K
Inte
nsity
, a.u
.
450 500 550 600 Energy loss, eV
Inte
nsity
, a.u
.
300 350 400 450 Energy loss, eV
Inte
nsity
, a.u
.
150 200 250 300 Energy loss, eV
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Fig. 3 SEM image of interface between bone and TiCaPCON coated cylindrical Ti rod implanted
in the artificial hip defect of rat for 30 days showing that the surrounding bone comes into close
contact with the implant surface.
Ti
bone
0.02 mm
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(a) (b)
Fig. 4 Fatigue limit for TiCaPCON/substrate systems. (a) – cp-Ti and (b) – nc-Ti substrates.
104 5104 105 Number of cycles
104 5104 105 Number of cycles
Impa
ct fo
rce,
N
Impa
ct fo
rce,
N
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Fig. 5 TiCaPCON coating colonized with dog’s mesenchymal stromal cells. Light microscopy,
×400.
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Fig. 6 Deimmunized dog’s bone coated with a TiCaPCON film after implantation for 3 months:
a) recipient’s tissue; b) the deimmunized donor’s bone coated with a TiCaPCON film.
Hematoxylin and Eosin staining, light microscopy, ×1000.
a b
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Table 1
Film elemental composition as determined by EELS.
Elemental composition, at.% Ti C N Ca P O 39.6 37.4 13.0 1.0 0.5 8.5
Table 2
ALP activity in MC3T3-E1 cells.
Sample Ra, m ALP activity (nmol/mg protein/min)
control (F12) 62.5±20.1 control (α-MEM+β-glycerophosphate and ascorbic acid)
505.1±14.3
Ti 0.3 329.6±24.0
Control
Ti + TiCaPCON 0.3 368.5±15.2 Ti 3.0 326.8±7.4 Ti + TiCaPCON 3.0 537.9±22.2* Ti 8.0 520.6±15.7*
PEET
Ti + TiCaPCON 8.0 612.6±50.6* Asterisk indicates the values that differ significantly from those of Ti controls (t-test, p<0.01). Table 3
Results of in vitro tests.
Sample
Measured characteristic Incubation time, days
Control TiCaPCON-1.2%Ag
1 9 (8-12)* 6 (6-7) 2 7 (1-8) 2 (0-4) 3 5 (2-7) 2 (0-2)
Number of L. acidophilus colonies
4 4 (2-5) 0 (0-0) L. acidophilus concentration in 1 ml, ×106
3 20.2±1.6** 10.6±2.4
Area of MC3T3-E1 cells, m2 ×103
1 1.7±0.1** 1.5±0.1
ALP activity of MC3T3-E1, nmol/mg protein/min
14 330±24** 205±15
* Median (min-max). Number of colonies was counted in 5 Petri dishes. ** Average value ±SD.
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