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M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept 2011
TiO2 - 1 -
M1 Science des matériaux -
matériaux pour la médecine -
Sept 2011
Chapitre 2 – Partie C
L’oxyde de Titane TiO2
D. Bazin
Laboratoire de Physique des Solides UMR 2502,
Université Paris Sud, Bât 510 91405 Orsay Cedex, France.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 2
PLAN Chapitre 0 Introduction
Chapitre 1 Sondes & Polymères
Chapitre 2 - Prothèse en alliage à base de titane Partie A Chapitre 2.1 Aspect médical Chapitre 2.1a La Hanche
Chapitre 2.1b Le disque intervertébral
Chapitre 2.1c Implants dentaires
Chapitre 2.2 Métallurgie - La raideur des alliages
Chapitre 2.3 Surface d’une prothèse en titane Chapitre 2.3a Nature de la surface d’une prothèse en titane.
Chapitre 2.3b La structure de l’oxyde TiO2.
Chapitre 2.3c Taille et stabilité des particules de TiO2.
Partie B Diffraction des rayons X
Chapitre 2.4a Généralités
Chapitre 2.4b Aspects expérimentaux
Chapitre 2.4c Complémentarité Neutrons – Rayons X
Chapitre 2.4d Equation de Debye
Chapitre 2.4e Diffraction de nanomatériaux
Chapitre 2.4f Formule de Scherrer
Chapitre 2.4g Le cas de nanocristaux anisotropes
Chapitre 2.4h Application aux apatites
Partie C Chapitre 2.5 Revêtement d’apatite Chapitre 2.5a Mécanismes de formation de l’apatite
Chapitre 2.5b Régularité de la couche de TiO2
Chapitre 2.5c Composition chimique de l’interface Ti/HA
Chapitre 2.5d Porosité
Chapitre 2.5e Optimisation de la couche d’apatite
Chapitre 2.6 Etude de la surface d’un implant réel
Chapitre 2.7 Autres applications Chapitre 2.7a TiO2 comme agent anticancéreux
Chapitre 2.7b TiO2 comme agent antibactérien (Ag/TiO2)
Chapitre 2.7c TiO2 Pour stopper les hémorragies
Chapitre 2.8 Toxicité des nanoparticules de TiO2
Chapitre 2.8a Réponse cellulaire
Chapitre 2.8b Par inhalation
Chapitre 2.8c A travers la peau
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Chapitre 2.4 Revêtement d’apatite
Chapitre 2.4a Mécanismes de
formation de l’apatite1
Apatite formation induced by negatively
charged nanocrystalline TiO2 coatings soaked
in simulated body fluid (SBF) is affecting by
factors such as
- pH,
- size of TiO2 particles
- thickness of TiO2 coatings,
1. Yang et al., Mechanism and kinetics of apatite formation on nanocrystalline TiO2 coatings:
A quartz crystal microbalance study, Acta Biomaterialia 4 (2008) 560–568
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 4
- pH,
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 5
Two different stages were clearly
observed in the process of apatite
precipitation, indicating two different
kinetic processes.
At the first stage, the Ca2+ ions in
SBF were initially attracted to the
negatively charged TiO2 surface,
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 6
and then the calcium titanate formed at the
interface combined with phosphate ions,
consequently forming apatite nuclei.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 7
After the nucleation, the calcium
ions, phosphate ions and other minor ions
(i.e. CO2-3
and Mg2+
) in supersaturated
SBF deposited spontaneously on the
original apatite coatings to form apatite
precipitates.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 8
Chapitre 2.4b Régularité de la couche de TiO22
TiO2 thin films were prepared on NiTi surgical alloy by sol–gel method.
Tetrabutyl titanate (Ti(C4H9)4, or Ti(OBu)4, from Zhejiang, China) was used as
TiO2 precursor.
The forming process, surface morphology and structure of the films were
studied by X-ray diffraction and atomic force microscopy.
2. Liu et al., Sol–gel deposited TiO2 film on NiTi surgical alloy for biocompatibility
improvement, Thin Solid Films 429 (2003) 225–230
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 9
Chapitre 2.4b Régularité de la couche de TiO23
SEM morphologies of the HA/ TiO2 double layer coating on the Ti substrate.
3. H.W. Kim et al., Hydroxyapatite coating on titanium substrate with titania buffer
layer processed by sol–gel method Biomaterials 25 (2004) 2533–2538.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 10
Chapitre 2.4c Composition chimique de l’interface Ti/HA4
Influence du protocole de preparation: The sol gel
technique employed in this work is based on hydrolysis
and condensation of metal alkoxides such Ti(OR) where
R is an organic ligand.
Following the crystallisation through XRD (TiO2,
CaTiO3 and HA).TiO2 was crystallized in the single
phase of anatase at T= 550°C whereas rutile was the
predominant phase at T=750°C.
4. Kaciulis et al., Surface analysis of biocompatible coatings on titanium, J. of electron
Spectroscopy 95 (1998)61-69.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 11
The best quality (homogeneity and
stoichiometry) of HA coating was achieved when
the substrate was first coated with an intermediate
layer of CaTiO3.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Chapitre 2.4d Porosité5
Titanium (Ti) and some of its alloys have been
extensively applied as orthopaedic implant materials
under load-bearing conditions due to their outstanding
mechanical properties and biocompatibility6,7.
However, the mismatch of Young’s modulus between Ti and its alloys (90–110 GPa) and bones (0.3–
30 GPa) causes severe ‘‘stress shielding”, leading to
bone resorption8.
One way to solve this problem is to reduce the
Young’s modulus of Ti-based biomaterials by
introducing a porous structure, thereby
minimizing or eliminating the stress-shielding to the
tissues adjacent to the implant materials and eventually
prolonging the implant lifetime9.
5. Xiao-Bo Chen, The importance of particle size in porous titanium and nonporous
counterparts for surface energy and its impact on apatite formation Acta Biomaterialia 5
(2009) 2290–2302
6. Brunette DM, Tengvall P, Textor M, Thomsen P. Titanium in medicine. Heidelberg:
Springer-Verlag; 2001.
7. Long M, Rack HJ. Titanium alloys in total joint replacement—a materials science
perspective. Biomaterials 1998;19:1621–39.
8. Uhthoff HK, Finneagan M. The effects of metal plates on posttraumatic remodelling and
bone mass. J Bone Joint Surg Br 1983;65:66–71.
9. Gibson LJ, Ashby MF. Cellular solid: structure and properties. Cambridge: Cambridge
University Press; 1997.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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10
A porous structure encourages
osteointegration and prevents implantation
failure by providing spaces for bone cells, vascular
and bone tissue in growth to form mechanical
interlocking11
. It has been proposed that the
optimal pore size for the cell attachment,
differentiation and ingrowth of osteoblasts and
vascularization is approximately 200–500 µm12.
10. http://www.covalent.co.jp/eng/rd/new_technologies/bio.html 11. Park JB, Lakes RS. Biomaterials: an introduction. New York: Plenum; 1992.
12. Clemow AJT, Weinstein AM, Klawitter JJ, Koeneman J, Anderson J. Interface mechanics
of porous titanium implants. J Biomed Mater Res 1981;15:73–82.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 14
Chapitre 2.4e Optimisation de la couche
d’apatite13
Il est possible de modifier les caractéristiques
structurales de la couche d’apatite en choisissant
des précurseurs différents:
- organic sol–gel of Ca(NO3)2 4H2O and
PO(CH3)3 ,
- inorganic sol of Ca(NO3)2 4H2O and (NH4)2
HPO4.
13. L. Guo et al., Fabrication and characterization of thin nano-hydroxyapatite coatings on
titanium Surface & Coatings Technology 185 (2004) 268– 274.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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On remarque par SEM des différences
importantes de la surface de HAP.
- Haut: Organic sol– gel coating,
- Bas: Inorganic sol coating.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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On remarque par SEM des différences
importantes de l’interface HAP/TiO2.
- Haut: Organic sol –gel coating
- Bas: Inorganic sol coating.
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From the XRD pattern, CaTiO3 did not form
on Ti surface or the interface after firing at 400–
600 °C.
For all coatings after firing over 400 °C, the
main crystalline phase of coatings was calcium
phosphate with apatite structure, and no obvious
tricalcium phosphate (-TCP and -TCP) and
calcium oxide were found in the XRD patterns.
Taille des cristalites : Precursor types of HA
coating significantly affected the aggregating size
of particles of nano-HA coatings, which were 25–
40 nm for organic sol–gel and approximately
100 nm for inorganic sol.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Chapitre 2.4e Optimisation de la couche d’apatite14
Hydroxyapatite (HA) coatings were deposited on
commercially pure titanium plates using a
hydrothermal–electrochemical deposition method in an
electrolyte containing calcium and phosphate ions. The
deposition conditions used in this study were the
followings: electrolyte temperature (33–20 °C), current
density (1–2 mA/cm2), and deposition time (10–120
min).
14. Yousefpour et al., Nano-crystalline growth of electrochemically deposited apatite coating
on pure titanium, Journal of Electroanalytical Chemistry 589 (2006) 96–105
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Needle-like and granular crystals of apatite coating were created
with different concentrations of calcium (0.0021–0.042 M) and phosphate
(0.00125–0.025 M) salts.
The size of HA crystals of the coating was considerably changed with
different concentration of calcium and phosphate salts, temperature of the
electrolyte, and deposition time.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 20
Chapitre 2.5 Etude de la surface d’un implant
réel15
15. Schrooten et al., Adhesion of bioactive glass coating to Ti6Al4V oral implant,
Biomaterials 21 (2000) 1461-1469.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 21
SEM-micrograph of the coating cross-section of a BAG-
coated moment test sample, tested beyond its functionality.
SEM-micrograph of the BAG-Ti6Al4V interface after
adhesion testing.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Chapitre 2.6 Autres applications
Chapitre 2.6a TiO2 comme agent anticancéreux16
The photocatalytic properties of TiO2-mediated
toxicity have been shown to eradicate cancer
cells17,18. It is now well established that TiO2 particles,
on exposure to ultraviolet (UV) light, produce
electrons and holes leading subsequently to the
formation of reactive oxygen species ROS such as
hydrogen peroxide, hydroxyl radicals, and
superoxides19.
These oxygen species are highly reactive with cell
membranes and the cell interior, with damaged areas
depending on particle location upon excitation. Such
oxidative reactions affect cell rigidity and chemical
arrangement of surface structures, leading to cell
toxicity20.
16. Thevenot et al., Surface chemistry influences cancer killing effect of TiO2 nanoparticles,
Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 226–236
17. Huang N-P, Xu M-H, Yuan C-W, Yu R-R. The study of the photokilling effect and
mechanism of ultrafine TiO2 particles on U937 cells. J Photochem Photobiol A: Chem
1997;108(2-3):229-33.
18. Zhang AP, Sun YP. Photocatalytic killing effect of TiO2 nanoparticles on LS-174-T
human colon cancer cells. World J Gastroenterol 2004; 10(21):3191-3.
19. Ogino C, Farshbaf Dadjour M, Takaki K, Shimizu N. Enhancement of sonocatalytic cell
lysis of Escherichia coli in the presence of TiO2. Biochem Eng J 2006;32(2):100-5.
20. Blake DM, Maness P-C, Huang Z,Wolfrum EJ, Huang J. Application of the photocatalytic
chemistry of titanium dioxide to disinfection and the killing of cancer cells. Sep Purif
Methods 1999;28(1):1-50.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Despite promising outcomes in killing cancer
cells, such treatments would be difficult to
implement in clinical settings for the following
reasons.
- First, UV light cannot penetrate deeply
into human tissues, thus limiting this technique
to superficial tumors21.
- Second, UV-mediated production of ROS has
a very short life span and thus would not be able
to provide a continuous prolonged cancer-killing
effect.
21. Cai R, Kubota Y, Shuin T, Sakai H, Hashimoto K, Fujishima A. Induction of cytotoxicity
by photoexcited TiO2 particles. Cancer Res 1992;52(8):2346-8.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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In the present study the nonphotocatalyic
anticancer effect of surface-functionalized
TiO2 was examined. Nanoparticles bearing
-OH, -NH2, or -COOH surface groups were tested for their effect on in vitro survival
of several cancer and control cell lines.
High-resolution TEM picture of a 5-nm plasma-
generated film deposited on a 25-nm nanoparticle,
illustrating the uniform and highly conformal aspect of
the coating.
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(A) Nonexposed cells appear normal,
(B) exposed cells show collection of particles on the cell membrane.
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Conclusion
Cell viability was observed to depend on
particle concentrations, cell types, and
surface chemistry. Specifically, -NH2 (AA)
and -OH (EO2V) groups showed significantly
higher toxicity than –COOH (VAA).
Microscopic and spectrophotometric
studies revealed nanoparticle-mediated cell
membrane disruption leading to cell death.
The results suggest that functionalized
TiO2, and presumably other nanoparticles, can
be surface engineered for targeted cancer
therapy.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 27
Chapitre 2.6b Ag-TiO2 comme agent
antibactérien22
TiO2 nanoparticles containing Ag+ have been widely used as
a filler in the manufacture of antibacterial plastics, coatings, functional fibers,
dishware and medical facilities, because Ag+ has a strong antibacterial
activity against many kinds of bacteria even at lower
concentrations23,24.
The basic material used for this study – antibacterial TiO2/Ag+
nanoparticles – is a commercial product (Shanghai Weilai Company, China)
with the primary particle size of about 70 nm and the Ag+ content approximately
0.4% by weight.
22. Cheng et al., Surface-modified antibacterial TiO2/Ag+ nanoparticles: Preparation and
properties, Applied Surface Science 252 (2006) 4154–4160
23. N. Edwards, S.B. Mitchell, A. Pratt, European Patent Application EOS251.783 (1987).
24. M. Kawashita, S. Tsuneyama, F. Miyaji, et al. Biomaterials 21 (2000) 393.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Conclusions
Surface treatment of the particles does not deteriorate
antibacterial properties of TiO2/Ag+ nanoparticles.
Surface modification can assure better affinity of the particles to
organic matrix, in our case PVC.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 29
Chapitre 2.6c TiO2 pour stopper des
hémorragies25
The ability to rapidly stem hemorrhage in
trauma patients significantly impacts their chances
of survival, and hence is a subject of ongoing
interest in the medical community. Herein, we
report on the effect of biocompatible TiO2
nanotubes on the clotting kinetics of whole blood.
25. Roy et al., The effect of TiO2 nanotubes in the enhancement of blood clotting for the
control of hemorrhage, Biomaterials 28 (2007) 4667–4672
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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FESEM images of a 10 mm long TiO2 nanotube array achieved by
anodization of a Ti foil sample in a 2% HF in dimethyl sulfoxide
(DMSO) electrolyte; shown are cross-section, top, and bottom. The
DMSO fabricated tubes are loosely bound, and could be separated by
sonication of the sample (ethanol–water mixture) for approximately
10 s.
Figure (lower right) shows some dispersed tubes.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 31
Chapitre 2.7 Toxicité des
nanoparticules de TiO226,27
Under mechanical stress or altered
physiological conditions such as low pH,
Ti-based implants can release large
amounts of particle debris, both in the
micrometer and nanometer size range 28,
29,30.
26. C. Vamanu et al., Induction of cell death by TiO2 nanoparticles: Studies on a human
monoblastoid cell line Toxicology in Vitro 22 (2008) 1689–1696.
27. Wang et al., Potential neurological lesion after nasal instillation of TiO2 nanoparticles in
the anatase and rutile crystal phases, Toxicology Letters 183 (2008) 72–80.
28. Brien, W.W., Salvati, E.A., Betts, F., Bullough, P., Wright, T., Rimnac, C., Buly, R.,
Garvin, K., 1992. Metal levels in cemented total hip arthroplasty. A comparison of well-fixed
and loose implants. Clinical Orthopaedics and Related Research, 66–74.
29. Buly, R.L., Huo, M.H., Salvati, E., Brien, W., Bansal, M., 1992. Titanium wear debris in
failed cemented total hip arthroplasty. An analysis of 71 cases. The Journal of Arthroplasty 7,
315–323.
30. Arys, A., Philippart, C., Dourov, N., He, Y., Le, Q.T., Pireaux, J.J., 1998. Analysis of
titanium dental implants after failure of osseointegration: combined
histological, electron microscopy, and X-ray photoelectron spectroscopy approach. Journal of
Biomedical Materials Research 43, 300–312.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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Chapitre 2.7a Toxicité des nanoparticules de TiO2 – Réponse cellulaire
The cellular responses to degradation products from titanium (Ti) implants are
important indicators for the biocompatibility of these widely used implantable
medical devices. The potential toxicity of nanoparticulate matter released from
implants has been scarcely studied.
Electron micrographs of U937 cells after 42 h exposure to (A) 4 mg/ml nano-
TiO2 – note pseudopodia (black arrow) embracing small nano-TiO2 aggregates
(white arrow), (C) the same vacuole at higher magnification – note presence of
nano-TiO2 inside the vacuole and outside the cell (arrows).
TiO2 nanoparticles induced both
apoptotic and necrotic modifications in
U937 cells.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 33
Chapitre 2.7b Par inhalation31
This study was designed to determine whether ultrafine-TiO2 particles
impart significant toxicity in the lungs of rats, and more importantly, how the
activity of different TiO2 formulations compares with other reference particulate
materials, such as anatase/rutile ultrafine-TiO2 particles.
Thus, the aim was to assess in rats, using a well-developed short-term
pulmonary bioassay, the pulmonary toxicity effects of two intratracheally
instilled, ultrafine-TiO2 particle samples and to compare the lung toxicity
responses of these samples with
31. Warheit et al., Pulmonary toxicity study in rats with three forms of ultrafine-TiO2
particles: Differential responses related to surface properties, Toxicology 230 (2007) 90–104
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M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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The responses to uf-1, uf-2 or F-1 TiO2 particles were substantially less active in
terms of inflammation, cytotoxicity, and fibrogenic effects when compared to
the quartz, or to the uf-3 TiO2 particles.
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Chapitre 2.7c A travers la peau32
Skin is the largest organ of the body and serves as a primary outer layer of
environmental and/or occupational exposure. It is also an important route of
entry for foreign articles including nanomaterials into the body.
The exposure of nanoscale TiO2 to the skin can be either intentional or
accidental.
For example, in certain lotions or creams, nanoscale TiO2 is
incorporated as a sunscreen component or used to coat fibrous materials and
enhance water or as a stain repellent property. Therefore the application of the
nanoparticles to human skin is intentional.
On the other hand, dermal contact with anthropomorphic
substances during nanomaterial manufacture or combustion can be accidental.
Due to the extremely small size of nanoparticles, assessment of health risks and
toxicity of nanoscale TiO2, in particular, following a long term dermal exposure,
is a key area of study in nanotechnology.
Control des tailles par TEM
32. Wu et al.,Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin
after subchronic dermal exposure, Toxicology Letters 191 (2009) 1–8
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
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TEM image of nano-TiO2 particles.
(A) TiO2 10 nm;
(B) TiO2 25 nm;
(C) TiO2 60 nm.
M1 Science des matériaux - matériaux pour la médecine - D. Bazin - Sept
2011 TiO2 38
Histopathological evaluation of the organ of hairless mice after dermal exposure
to different sized TiO2 nanoparticles for 60 days. Samples were stained with
hematoxilin and eosin (H&E) and observed at 100×. The arrows points at
pathological changes in various tissue sections.
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