Innovation and Development of Study Field
Nanomaterials at the Technical University of Liberec
nano.tul.cz
These materials have been developed within the ESF
project: Innovation and development of study field
Nanomaterials at the Technical University of Liberec
Technical University of Liberec
Calcium phosphate based
ceramics in medicine
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Outlook
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Apatites, bones and teeth
Calcium phosphate bioceramics - HAp and TCP
Dense and porous HAp and TCP bioceramics
Hydroxyapatite coatings
Requirements for hydroxyapatite bioceramics
Applications in medicine
Apatites, bones and teeth
 Biological apatites constitute a basic component of bones and teeth
and are part of pathologically calcified tissues such as urinary stones,
plaque and soft tissues,
 Bone apatites constitute very small crystals,
 The shape of the crystals can be acicular or lamellar with different
dimensions in the range of 40 – 60 nm long, 20 nm wide and 1.5 – 5
nm thick. They have very large surface area of about 100 – 200 m2/g,
 The mineral phase gives the bones stiffness and proper mechanical
strength.
4
Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Apatites, bones and teeth
• Very important role in bones is played by the organic substance. In bones
it is mostly collagen, proteins, polysaccharides and lipids,
• Organic compounds made bone in terms of mechanical parameters more
like polymer, by decreasing the Young’s modulus make it less fragile and
increase the resistance against failure under applied stresses,
• Such connection of organic and inorganic substances gives this natural
composite adequate properties not only biological but mechanical as
well,
• Such a combination makes the skeleton bones possible to serve as a
scaffold holding soft tissues and construction which allows for movement
of people and animals.
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Bone structure
● Structure of compact and cancellous bone
● SEM view of deproteinized trabecular bone
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http://en.wikipedia.org/wiki/File:Illu_compact_spongy_bone.jpg
Bone structure
7
Sadat-Shojai M et al. Synthesis methods for nanosized hydroxyapatite with diverse structures. Acta Biomater (2013),
http://dx.doi.org/10.1016/j.actbio.2013.04.012
Bone structure
• The hard outer layer of bones is composed of compact bone tissue. Its
porosity is 5–30%. This tissue gives bones their smooth, white, and solid
appearance, and accounts for 80% of the total bone mass of an adult
skeleton. Compact bone may also be referred to as dense bone.
• Filling the interior of the bone is the trabecular bone tissue (an open cell
porous network also called cancellous or spongy bone), which is
composed of a network of rod- and plate-like elements that make the
overall organ lighter and allow room for blood vessels and marrow.
Trabecular bone accounts for the remaining 20% of total bone mass but
has nearly ten times the surface area of compact bone. Its porosity is 30–
90%. The microscopic difference between compact and cancellous bone
is that compact bone consists of haversian sites and osteons, while
cancellous bones do not. Also, bone surrounds blood in the compact
bone, while blood surrounds bone in the cancellous bone.
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Calcium phosphate bioceramics
– HAp and TCP and BCP
Among modern implant materials, a special place is occupied
by calcium phosphate based bioceramic materials:
• hydroxyapatite Ca10(PO4)6(OH)2 HAp
• tricalcium phosphate Ca3(PO4)2 TCP
• biphase HAp + TCP
• Ca-def HAp + TCP*
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*
Resorbable calcium deficient hydroxtapatite
Compounds of CaO – P2O5 important
for medicine
Mark
Name
Chemical
formula
Oxide
composition
Ca/P
CP1
Ca-metaphosphate
Ca(PO3)3
CaOP2O5
0.5
C2P12
Di-Ca-phosphate
Ca2P2O7
2CaOP2O5
1.0
C3P 123
TCP
Tri-Ca-phosphate
Ca3(PO4)2
3CaOP2O5
1.5
C4P12
Tetra CP
TTCP
Tetra-Ca-phosphate
Ca4(PO4)2O
4CaOP2O5
2.0
1 – animal tests, 2 – clinical practice, 3 – used as biomaterial
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Compounds of CaO – P2O5 - H2O with
the importance for medicine:
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Mark
Name
Chemical formula
Ca/P
MCPA
Monocalcium phosphate anhydrous
Ca(H2PO4)2
0.5
MCPM
Monocalcium phosphate monohydrate
Ca(H2PO4)2H2O
0.5
DCPD
Dicalcium phosphate dihydrate
CaHPO42H2O
1.0
DCPA
Dicalcium phosphate andydrous
CaHPO4
1.0
OCP
Octocalcium phosphate
Ca8H2(PO4)6H2O
1.333
HAp
hydroxyapatite
Ca10(PO4)6(OH)2
1.667
Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Synthetic apatites
The most important meaning for medicine has commonly
used in implants manufacturing synthetic hydroxyapatite.
● Ophthalmic implants made
of synthetic HAp
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D.R. Jordan, Opthalmology 106 (1999) 505 - 512
http://www.networkmedical.co.uk
● Ophthalmic implant made
of synthetic HAp
Hydroxyapatite
 Hydroxyapatite is the calcium phosphate with the Ca/P molar ratio
1.667, which contain hydroxyl groups (OH-).
Ca10(PO4)6(OH)2
 Name apatite comes from the Greek word „he apáte” which means –
fraud or trick, and has been attributed in 1790 by Werner to newly
discovered group of minerals which caused a series of difficulties to the
scientists.
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Hydroxyapatite
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As a model compound corresponding to the crystalline inorganic
phase of bones and teeth is considered not stoichiometric
hydroxyapatite with Ca/P molar ratio varying from 1.67
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Ca/P molar ratio also depends on age, health condition and skeletal
fragment.
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Bone apatites also contain such elements like:
- magnesium
- sodium
- potassium
- chlorine
- fluorine
- trace elements:
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
0.7 % mass
0.9 % mass
0.03 % mass
0.13 % mas
0.03 % mass
Sr2+, Pb2+, Zn2+, Cu2+, Fe2+
Sources of hydroxyapatite biomaterials
– natural sources
15
Sadat-Shojai M et al. Synthesis methods for nanosized hydroxyapatite with diverse structures. Acta Biomater (2013),
http://dx.doi.org/10.1016/j.actbio.2013.04.012
Basic biological properties of
HAp and TCP
• Because of its chemical and mineralogical similarity to the
inorganic substance of bone and teeth, HAp and TCP doesn’t
show any cytotoxic or cancerogenic effects.
• They are characterized by the high biocompatibility in relation to
both soft and hard tissues.
• Due to their high biocompatibility calcium phosphate based
medical devices can be connected directly with the bone.
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Hydroxyapatite vs. bone
Structure of synthetic hydroxyapatite may
be similar to that of natural bone. Different
manufacturing methods enable the control
over the size and number of pores.
● Porous structure of bone
Porous surface of medical implant may
be overgrown by the new bone tissue
forming at the interface, which enables
durable and strong connection between
the bone and the implant.
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● Porous structure of hydroxyapatite
R. Mu¨ller et al. Bone 23 (1998) 59–66
A. Doostmohammadi et al. / Ceramics International 37 (2011) 1601–1607
Solubility – environmental conditions
Solubility of HAp and TCP is a very important parameter since those
materials are designed to fill cavities or to be overgrown by the surrounding
bone tissue. It depends on:
• pH and type of the solvent (hydroxyapatite is practically insoluble in
bases but soluble in acids). In salt solutions of potassium, sodium,
magnesium and strontium dissolves better than in distilled water
according to presented order:
Sr > Ba > Mg > Na > K
• presence of amino acids, proteins, enzymes and other organic
compounds.
• In saliva dissolves poorly.
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Solubility vs. properties
Solubility of HAp ceramics in in vivo conditions strongly depends on:
• crystallinity
• crystal size
• amount of defects
• stress level
• porosity
Porous implants due to a greater contact surface dissolve faster
than implants made of dense hydroxyapatite ceramics.
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Synthesis
Calcium phosphate based bioceramics is manufactured and applied in
medicine in the dense and porous forms as well as granules and powders
The process of production consists of the following steps:
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manufacturing of the initial powders
formation of shaped implants
burning (sintering)
final treatment ( grinding of sharp edges)
sterilization and packing
To some implants additionally can be introduced antibiotics, growth factors
and hormones or adequate cells (drug delivery, cell cultures)
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Dense and porous hydroxyapatite
ceramics:
Achieving a pure phase, dense hydroxyapatite ceramics with very high
mechanical properties is possible only by sintering powders with the Ca/P
molar ratio corresponding to the stoichiometric HAp. Any differences in
stoichiometry lead to formation of TCP and CaO as the secondary phases.
Manufacturing methods:
• Forming and free sintering
- uniaxial pressing
- CIP (Cold Isostatic Pressing)
- casting
- injection forming
- squeezing and burning
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
• HP (Hot pressing)
• HIP (Hot isostatic pressing)
Dense and porous hydroxyapatite
ceramics:
Size distribution and shape o pores
depend on applied synthesis technique
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•
•
•
•
Firing additive method
Steaming additive method
Sponge texture mapping method
Foaming method
Application of water soluble fillers
(NaCl, polyvinylalcohol fibres)
● SEM photographs of hydroxyapatite
granules showing the various pore sizes
and pore size distribution of different
granules
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S. Joschek et al. / Biomaterials 21 (2000) 1645}1658
D. Tadic et al. / Biomaterials 25 (2004) 3335–3340
Dense and porous hydroxyapatite
ceramics:
Compressive
strenght [MPa]
Bending
strenght
[MPa]
Tensile
strenght
[MPa]
Young’s
modulus
[GPa]
Dense HAp
120 - 900
38 - 196
38 - 300
35 - 120
Porous HAp
2 - 100
2 - 11
3
-
Dental
enamel
250 - 550
76
10 - 70
10 - 131
Cortical
bone
170 - 193
160 - 180
60 - 174
17 - 19
● Basic mechanical parameters of natural and synthetic hydroxyapatite materials
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Biomaterials 4, M. Nałęcz (ed), Polish Academy of Sciences
Hydroxyapatite coatings
Hydroxyapatite bioceramics has rather low mechanical properties, and
therefore it is not suitable for the production of load-bearing implants.
Nevertheless, a very good biological properties of this material, and above
all osteoconductivity make, that there is more and more technologies of
synthesis of hydroxyapatite in the form of thin coatings.
With the surface modification of the metal implant its good mechanical
properties are retained while its surface is characterized by significantly
improved biological parameters.
Since the main aim of this course is to make students familiar with possible
applications of nanotechnology in medicine, technologies of synthesis of
HAp coatings will be listed without further explanation. For more
information please refer to the references.
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D. Batory, et al. Surface & Coatings Technology 206 (2012) 2110–2114
Hydroxyapatite coatings
– methods of synthesis
• Pulsed Laser Deposition,
• sol-gel,
• electrophoresis,
● Schematic of the plasma spraying system
● Hip prosthesis surface modification
by plasma spraying technique
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http://www.sdbiocoatings.com
• plasma-spraying,
• Ion Beam Assisted Deposition,
• Radio Frequency magnetron sputtering.
Requirements for hydroxyapatite
bioceramics ISO 13779 – 1:2000 E
• Ca/P molar ratio 1.65 – 1.82
• Content of crystalline HAp phase 95%
• Compressive strength after sintering 1.5 MPa without the anisotropy
Other:
•
•
•
•
•
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Colour
Smell and taste
Grain and granule size
Porosity (share and size)
Sterilization method
Element
Max content
[mg/kg]
As
3
Cd
5
Hg
5
Pb
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Medical applications of HAp ceramics
Ceramic hydroxyapatite materials because of their high level of
biocompatibility, osteoinductivity and ability of creation of chemical
bonds with living tissues are considered as one of the leading material
in bone surgery. Dense hydroxyapatite materials are not restorable
however in the porous form they are biodegradable. The porous
material is gradually replaced by regenerating bone, which makes the
recovery process the same as the implantation of autologous
cancellous bone - there is a simultaneous elimination of the implant by
osteoclasts, and new bone mineralization
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A. Sobczak, Z. Kowalski, Hydroxyapatite materials applied in implantologyi, Biblioteka Cyfrowa Politechniki Krakowskiej
Medical applications of HAp ceramics
- cranial implants
● An implant with gradients in
● General view of the
implant bearing skull
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composition and spatially
different porosity.
● Stereolithographic model
reproducing the defects, perfectly
matching the HA based prosthesis
C. Schiller et al. / Biomaterials 25 (2004) 1239–1247
G. Staffa et al. / Journal of Cranio-Maxillo-Facial Surgery 40 (2012) 65 – 70
U. KLAMMERT et. al. Journal of Cranio-Maxillo-Facial Surgery (2010) 38, 565 - 570
Medical applications of HAp ceramics
- cranial implants
Number of implants
Between 1997 and 2010, 1549 patients underwent cranioplasty with the
implant of 1608 custom-made porous HA devices
400
350
300
250
200
150
100
50
0
378
325
270
232
170
114
63
1
1
2
6
4
19
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1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
● Number of cranial implants implanted each year
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Stefini R, Esposito G, Zanotti B, Iaccarino C, Fontanella MM, Servadei F. Use of "custom made" porous
hydroxyapatite implants for cranioplasty: postoperative analysis of complications in 1549 patients. Surg Neurol Int
2013;4:12
Medical applications of HAp ceramics
- bone filling
Hydroxyapatite implants may be used for filling bone defects in
orthopaedics and dentistry
● HAp implant press fitted into
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the medullar canal
.
D. Lakstein et al. / Acta Biomaterialia
5 (2009) 2258–2269
● Osseointegration of HAp
implant with surrounding tissue
.