Chapter 6 Implants and biomaterials (hydroxyapatite)
Chief Researcher of Biomaterials Center, National Institute for Materials Science
Yasushi Suetsugu
Medical Engineering Coordinator and Emeritus Fellow of Biomaterials Center, National
Institute for Materials Science
Tetsuya Tateishi
I. Hydroxyapatite1) 2)
The mineral apatite, can be represented by the formula, M10(ZO4)6X2 (or M5(ZO4)3X), as a general termthat can be applied to the crystal structures that will be mentioned later on in this chapter. The name“apatite” comes from the Greek spelling “apate” (απαταω) which means deceit. The reason for this wasthat the mineral appeared in different colors with a variety of crystal habits, and was thus often mistaken
for precious minerals such as aquamarine or amethyst. This variation arises from the fact that theapatite structure has a particularly complex solid system.

Each component (M, ZO4, and X) of thecommon equation M10(ZO4)6X2 can be replaced by a large number of different elements or solid states aslisted in Table 3-6-1. M or X can also be absent. The most common form found in nature is calcium
phosphate apatite, whereby the M and ZO4 are Ca2+ and PO43- groups. If the X is F, it is given the namefluorapatite, the main source of phosphorus, used as the standard mineral for hardness level 5 on the
Mohs scale, making it an invaluable source for rock-forming minerals. When the X is OH-, i.e.
Ca10(PO4)6(OH)2, it is given the name hydroxyapatite, HA, which is the main subject of this report (Table
3-6-1 artificially synthesized hydroxyapatite crystal). HA is the key inorganic component of the hardtissues of vertebrae, and is an important substance in bioactive ceramic materials.
HA is one of many types of calcium phosphate (or calcium orthophosphate), but there are several others inthis class. The main compounds of calcium phosphate are listed in Table 3-6-2. The simplest way toarrange these into order is by the calcium-phosphorus composition ratio. At physiological pH (7.2-7.6), HA
is most stable. MCPM, DCPA, DCPD and TeCP are used as the ingredients of calcium phosphate cement.
OCP is an intermediate that appears during extraction of the HA phase. Within TCP, α-TCP shows astable phase between 1180 and 1430°C and transforms into itsα’-phase at higher temperatures. β-TCP,
a hypothermic phase material, is often used in the same way as HA, in bioactive ceramics. Its absorptivity
when implanted into the body is significantly higher than that of HA. A material composed of a mixture of
HA and β -TCP has also been developed, called biphasic calcium phosphate (BPC). A metastable
amorphous phase material known as amorphous calcium phosphate (ACP) exhibits a significantly higher
bioresorbable property than other crystalline calcium phosphate compounds.

Table 3-6-1 The main ions that can be consisted in the formula M10(ZO4)6X2

1

Fig. 3-6-1
Artificially synthesized hydroxyapatite crystals

II. The crystal structures of hydroxyapatite2) ,3)
Fig. 3-6-2 shows a schematic diagram of the structure of HA. The structure shown here is the
stoichiometric composition of HA whereby the unit cell is composed of Ca20(PO4)12(OH)4. The coreframework of the structure is constituted mainly of the PO43- tetrahedron, with two types of channel
structures that lie parallel to the c -axis at the positions, (x, y) = (0, 1/4) and (x, y) = (1/3, 1/12). The OHion (z = 0 ± 0.2, 1/2 ± 0.2) and Ca2+ ion (z = 0, 1/2) lie within each of these structures. Eight of the 20 Ca2+in the unit cell are located at the Ca2+ site (Ca I), with the remaining 12 Ca2+ located on the second site
(Ca II, z = 1/4, 3/4), which is also the peak of the equilateral triangle that is constructed from the OH- ionchannels. This Ca2+ is exposed on the crystal surface, thus playing a large role in the physical properties
of HA, such as surface charge, and in interactions with organic compounds.
The stoichiometric crystal structure of HA has a monoclinic system with P21/b as its space group, andlattice constants of a = 0.942 nm, b2a, c = 0.688, r = 120° However, if this unit cell is divided into two at

the plane y = 1/2, the two halves become equivalent, so that this structure essentially has the symmetryof a hexagonal crystalline structure. The factor that defines the symmetry of a unit cell is thearrangement of OH- ions. The OH- ions are aligned on the y = 1/4 plane facing the same direction withregards to the c axis, but the OH- ions on the y = 3/4 plane all face in the opposite direction, thus resulting
in repetition in the b -axis direction that is double that of a. However, at high temperatures (>211°C), or if
the structure is non-stoichiometric, with inclusion of impurities or holes, this neat arrangement becomes
disordered, and the space groups become hexagonal P63/m. The structure of HA is broadly determined by
the positions of Ca (as M) and PO4 (as ZO4) creating space group of P63/m, and is often represented by thechemical formula M10(ZO4)6X2, in accordance with b = a as the unit cell.
Biological apatite is a non-stoichiometric form of HA, characterized by Ca2+ deficiency but containing
trace elements. The trace elements include positively charged ions, Mg2+, Na+, K+; and negatively charged
ions, Cl- and F-. The most common replacement is with the CO32- ion which constitutes 5-8% of apatite inbone, by weight. The CO32- ion can replace all of the OH- and certain PO43- within the HA structure,termed A-type and B-type replacement, respectively. B-type replacement is common in bones, and is an
essential factor in altering the melting point of the biological apatite. Increases in positive charge withthe replacement of PO43- by CO32- are balanced out either by the loss of Ca2+ sites or by the introduction of
Na+ ions.

2

Table 3-6-2 The major calcium phosphates

Fig. 3-6-2 The crystal structure of hydroxyapatite
The c-axis is perpendicular to the plane of the paper. The x, y, z that are mentioned in the text correspondto the direction of a, b, c in the diagram with defining the repetitive cycle as 1. The numbers in thisdiagram are the coordinates of the z-axis. The hydrogen atom of OH- ions on the y = 3/4 plane are hidden
behind the oxygen atom

III. Synthesis and applications of hydroxyapatite ceramics4),5)
The raw material powder used in simple HA ceramics can be synthesized using the wet method. Wet
methods can largely be divided into neutralization reactions and reactions between calcium andphosphorous salts. In neutralization reactions, phosphoric acid solution is steadily added into a solution
where calcium hydroxide is suspended in water. The chemical equation for this is shown below,
10Ca(OH)2 +6H3PO4 +H2O → Ca2(PO4)6(OH)2 + 18H2O
3

Meanwhile, an example of the reaction between the calcium salt and the phosphorous salt is given as,
6Ca(NO3)2 + 6(NH4)3PO4 + H2O → Ca10(PO4)6(OH)2 + 18NH3 +20HNO3
There are other methods of synthesis, such as the dry method whereby calcium and phosphorouscompounds are directly reacted and heated to complete the reaction, or by the removal of organic matterfrom bones extracted from fish or cows. As an example of the dry method,
6CaHPO4⋅2H2O + 4CaCO3 → Ca10(PO4)6(OH)2 + 14H2O +4CO2
The above reaction is conducted at temperatures above 1000°C. In the extraction from bone, the crushedbone undergoes enzymatic treatment to break down the proteins, and is rinsed before heat treatment at
800°C. The product of this method contains trace elements such as Mg.
Sintered bodies are generally formed by the adding organic polymer binding agents to the raw powderedmaterials, which are then compacted and heated under atmospheric pressure to temperatures of roughly
1200°C. Sintering aids are not usually required under normal circumstances.
High pressure techniques can be applied for the preparation of compact bodies. By using techniques suchas hot-press methods where a piston is used to press from above and below uniaxially, or the hot isostaticpress (HIP) method where an inert gas acts as the pressure catalyst, generation of a transparent sinteredbody with a relative density of 100% is possible. The mechanical properties of a sintered compact of HA
and that of cortical bone are shown in Table 3-6-3. The manufacture of porous material usually requires
mixing of beads that decompose on heating or foaming of a slurry that consists of raw materials dispersed
throughout a liquid. The porous material created with this foaming method is unstable and is therefore
commonly stabilized by cross-linking with the polymer that was initially added to the slurry. Other
methods include hydrothermal treatment of skeletal structures of natural coral (calcium carbonate as themain ingredient) in a phosphoric acid-containing solution 7); there are also examples of manufacture of aporous body with unidirectional pores oriented by growth of thin ice columns within an HA slurry 8), 9).
HA ceramics are remarkable for their marked ability to absorb certain organic compounds, and therefore
have been used widely as adsorption separation agents for proteins and nucleic acids, in chromatography
column resins, toothpaste additives and gas sensor element components. Most significant of all is theirbiocompatibility when used in osteoimplants. HA ceramics not only have low biological effects, but wheninserted closely to bone, promote regenerative growth and facilitate direct chemical bonding with bone,
without any need for the presence of other connective tissue. HA has become referred to as a “bioactive
ceramic” because of its ability to actively and physiologically stimulate the surrounding cells.
Osseointegration is a term commonly used in this field to describe an interaction where there is absenceof connective tissue on the interface between material (typically titanium) and bone. However, as thisdoes not have a strict definition with regards to connectivity, it can only be used as a general term. Theinteraction between bioactive ceramics and bone can be described as biointegration to differentiate thisinteraction from osseointegration, an umbrella term.
HA ceramics have already been used as filling agents in bone defects in the form of a sintered body, a4porous body, granules (agglomerates), and cement. Improvements to these materials are being made withregards to their mechanical properties and bioactivity by compounding with organic polymers. A numberof promising materials are currently under development for use as regenerative medicines, (e.g. cell
scaffolds), or as vehicles for sustained release of drugs.
Typical HA ceramics in current use have a coating material over titanium-based implants, as this has
been discovered to be invaluable due to its mechanical strength characteristics.
The introduction of HA coatings will be explored later in this manuscript.

Fig. 3-6-3

Table 3-6-3

Transparent sintering body of

The comparison of the mechanical properties of the sinteredhydroxyapatitecompact of hydroxyapatite and cortical bone

IV. Hydroxyapatite coating of titanium10)-12)
HA-coated implants constructed of pure titanium or coated titanium alloy are rapidly able to bond withbone that is very rigid, without the need for bone cement. For this reason, stability can be expected to be
maintained for a long period of time. In this chapter, the course of development of HA coating methods
and those in current practice are described, under the following headings: the wet method, theelectro-chemical method, the vapor growth method and the thermal spraying method.

A. Wet methods
In neutral or alkaline solution, HA is the most stable of the calcium phosphate compounds. By immersing
a titanium plate into a solution that contains calcium and phosphate, it is possible to precipitate HA onto
its surface. In many research examples, pseudo-body fluids have been used as the immersion liquid; thisis also referred to as the biomimetic method. These pseudo-body fluids such as Kokubo solutions andHanks solutions that contain concentrations of inorganic ions, and pH and temperature similar to thoseof natural body fluids, are supersaturated with HA in its ionic concentrations. Once titanium is placed in
the solution, the surface becomes covered with amorphous ACP, which gradually converts to HA,
becoming increasingly crystalline. In order to boost the rate of formation of the HA membrane, several
methods may be used, such as increasing the ionic concentrations of pseudo-body fluids, treating thetitanium surface with acid or alkali, or by injecting ions using the “dry process”.
In acid treatment, the titanium plate acts as the anode in electrolysis in solution, and its surface becomescoated with HA 13). Alkaline treatment is also effective whereby, after immersing the titanium plate insodium hydroxide solution, an amorphous layer of sodium titanate is formed by heat treatment. If thisproduct is soaked in the pseudo-body fluid, the Na+ ions are removed from the same layer, increasing thepH adjacent to the titanium surface. This effectively increases HA saturation levels, forming Ti-OH
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groups on the plate surface, and inducing the nucleation of HA 14), 15).
An example of ion injection is where, by driving Ca2+ into the titanium plate, a calcium titanate layer isformed 16), and HA layer formation occurs rapidly in the pseudo-body fluid. The coating layer formed by
the pseudo-body fluid is fairly even and has the advantage that its composition is close to that of
biological HA. However, problems arise such as difficulty in controlling the shape, amount andcomposition of the layer of HA that is deposited, and the fact that that this layer can come off easily.
In the wet method, other fluids may be used apart from pseudo-body fluid, including fluid that contains
colloidal HA, used in a direct coating method that is also known as the sol-gel process. Dip-coating is themost common method whereby once immersed in the solution, the layer is fixed further by heat treatment.
Calcium nitrate and dibasic ammonium phosphate 17), calcium nitrate and triethyl phosphate18), or
commercially available HA powder are commonly used as sources of calcium phosphate. Typically, thecalcium titanate phase or titanium oxide phase are coated on the interface of titanium and HA.

B. Electro-chemical methods
It is also classed under the wet method since the film is formed in solution. The distinction lies in that theelectrical energy is utilized as a more efficient means of membrane formation, and a method withimproved adhesive ability.
Here, the titanium plate is very often used as the cathode for deposition. Using the titanium plate,electric current is passed through the acidic calcium phosphate solution, increasing the pH of the solution
surrounding the plate, and forming an HA layer20). Depending on the reaction conditions, H2PO42- ions or
HPO42- ions are reduced in the vicinity of the cathode releasing hydrogen and becoming PO43- ions, andsubsequently reacting with Ca2+ to finally yield HA21). There are reports of methods to control theparticles to nanodimensions by application of ultrasound22).
The solubility of HA above room temperature declines as the temperature increases; and a thermal
substrate method has been developed to utilize this property. Here, the temperature in the vicinity of thetitanium plate is increased by electrical heating, passing an alternating current through the plate in aphosphate- and calcium-containing solution23), 24).
There are also reports of experiments that used electrophoresis25). Electrophoresis is the dispersing
movement of charged particles in fluid under the influence of a spatially uniform electric field, created byapplication of a voltage. The charged particles then accumulate at the electrode. The two factors thatmust be considered are the size of the particles, which must be small enough to avoid precipitating out
during electrophoresis, and the choice of the dispersion medium, with suitable stability and conductivity.
Even though this electrochemical method is simple and does not require complex equipment, the rate oflayer formation is much faster than with the dip-coating method, and this approach has the added
advantage that the coating can be applied to complex shaped objects. Further, it permits control of factors
such as temperature, ionic concentration of the solution and current density, enabling control of the
thickness and structural properties of the layer 26), 27). There are cases where heat treatment is stillnecessary as the final step.

C. Vapor growth method
There are two types of vapor growth method, physical vapor deposition (PVD) and chemical vapor
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deposition (CVD), but PVD has been the more popular of the two for application of HA coatings. PVD canbe further divided into vacuum deposition, ion spraying and spattering.
In the vacuum deposition method, the solid state is vaporized by heating under conditions of high vacuum.
The vapor accumulates on the plate, is maintained at a certain temperature, and formation of a thin film
occurs on the plate. Laser light is often used to evaporate the raw material to be deposited (laser
abrasion) 28), 29).

Laser abrasion uses laser light with a high energy density, and evaporates the materialusing its photochemical abilities. This method is also referred to as the pulse laser deposition (PLD)
method. In a similar manner to vacuum deposition, the ion-plating method uses plasma to ionize or excite
the evaporated particles, plating the material with highly energetic particles. This method is yet to be
widely applied in HA coating.
Sputtering has been applied in various industrial fields as a technique for forming thin layers. Ion-guns
or electric discharges are used to ionize inert gases such as argon. These inert gas ions are thenaccelerated to bombard the target raw materials to cause evaporation, and the target atom or clusters areforcefully ejected from the surface. In HA coating, radio-frequency magnetron-sputtering is often used 30),31). When an insulator such as HA is used as the target of raw material to be evaporated, this method is aneffective means for preventing the target from being charged by using high-frequency wave as the power
to gain ions through discharge of electricity. Furthermore, when a magnetic field is applied to the area ofelectric discharge, the electrons emitted from the target surface rotate in response to the Lorenz force
received, increasing the discharge current and stimulating ionization of the sputtered gas, thus
accelerating the formation of the film coating.
The PVD method has the advantage of not only allowing the chemical composition of the coating layer tobe controlled, but also regulating its crystalline and orientation properties through setting of theconditions for deposition32). The thickness of the coating formed by this method is less than a few
micrometers and its most notable advantage is firm adhesion to the titanium plate.

D. Thermal spraying methods
The most popular method in current practice for coating titanium with HA is the plasma spray method,
one of the thermal spraying methods. Here, the HA particles are melted with plasma flame at extremely
high temperatures of over 10,000°C, and repeatedly sprayed onto the titanium plate at a speed of 100-200m/s for layer formation. The plasma spraying method was one of the first HA film coating methods to be
used, and therefore many industrial examples have been reported. However, the process of solidification
requires rapid cooling from a critically high temperature, and it is not easy to control the thickness of thefilm layers. Generally, the HA coating formed by the plasma spray method is thick (tens of micrometers),
and contain impurities such as calcium oxide and TeCP in an amorphous matrix, mixed in with highly
crystalline HA, resulting in an inconsistently distributed structure33) with uneven density and unevenadhesive properties. The stability upon implantation becomes problematic. In order to overcome theissues, treatments are continuously renovated to increase the smoothness and to improve stability. Heat
treatment in solutions such as pseudo-body fluid is the main method in current procatice, and therecrystallization of an HA coating mentioned in this text, falls under this heading.

V. Final word7

In this report, use of HA as a coating material was summarized. HA ceramics exhibit prominent biologicalactivity and show efficacy as artificial bone material, however, for these to replace physiological bone,
obstacles still remain, in particular, with regards to mechanical strength. Brittleness has been noted to bea problem associated with the simplex form of the materials that fully utilize the excellent biologicalactivity of HA ceramics. The most successful material so far to solve this problem has been HA-coatedtitanium. All of the current methods of coating have their advantages and disadvantages, from unevenlayers that are close to the amorphous phase, to highly pure, highly crystalline layers. There have beenreports of improvements in proliferation and differentiation of osteoblasts on highly crystalline HA layersof calcium phosphate from that observed on the surface of amorphous substrates34).
Conversely, in the biologically active process whereby the HA layer binds with normal bone, HA needs tosolubilize partially, therefore a coating that is less crystalline and highly soluble is more advantageouswhen it comes to fusing with bone. Nevertheless, a highly soluble coating lacks stability and may bequickly eliminated after installation, which is inappropriate for the success of the implant.
As titanium itself does not have any physiological adhesive property, the HA coating is expected to act as
a long-term mediator to stabilize and aid the function of the titanium implant.
In attempts to find an optimum coating method that is most practical, the most rational method currently
available may be the application of after-treatment to convert, a calcium phosphate layer formed initiallywith an inexpensive method, to a highly pure, highly crystalline HA, to gain high adhesiveness.

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