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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


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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


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- pH,


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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,


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and then the calcium titanate formed at the

interface combined with phosphate ions,

consequently forming apatite nuclei.


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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.


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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


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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.


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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.


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The best quality (homogeneity and

stoichiometry) of HA coating was achieved when

the substrate was first coated with an intermediate

layer of CaTiO3.


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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.


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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.


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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.


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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.


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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.


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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


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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.


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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.


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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.


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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.


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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.


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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.


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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.


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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.


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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


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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.


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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.


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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.


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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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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


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TEM image of nano-TiO2 particles.

(A) TiO2 10 nm;

(B) TiO2 25 nm;

(C) TiO2 60 nm.


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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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