Artificial bone applications with porous hydroxyapatite

Prince George (513CH1070)

1. Introduction
There has been considerable research in developing synthetic hydroxyapatite as a material for bone
replacement, as natural bone contains hydroxyapatite. Hydroxyapatite (HA) ceramics has been widely
applied as bone substitutes. Together with b-tricalcium phosphate, they have been for nearly three
decades the most extensively used substitution materials for artificial bone grafts. Their chemical
composition close to the mineral phase of bone is an origin of their excellent biocompatibility to tissue
bone. This meets the requirement of any materials designed for bone repair and augmentation. To this
aim, a high degree of crystallinity and chemical stability have been included among the desirable
properties of an ideal HA. Although many problems concerning infective risk, mechanical and biological
stability, compatibility, storage and costs still remain, HA materials have been applied in orthopedics as
block implants, granules or coating, either dense or porous. In recent years, particular attention has been
paid to the preparation of HA bio ceramics with porous morphology. Porous HA exhibits strong bonding
to the bone; the pores provide a mechanical interlock leading to a firm fixation of the material. Bone tissue
grows well into the pores, increasing strength of the HA implant.

It was comprehended that dimension and morphology of pores are vital factors for an excellent osteo-
integraton. Minimum pore size is vital to enable ingrowth of the surrounding bone together with blood
supply, is about 100-150 mm for macro pores, and even at pores of as small as 50 mm osteo-conduction
is still likely. Some reports stated that it should be 200500 mm for establishment of osteoblastic the
pores, fibro-vascular ingrowth and finally the deposition of new bone. Other important requirements for
porous grafts are interconnectivity of the pores for the dissemination of the osteoblast-like cells inside
the pores as well surface roughness for the attachment of cells. With larger pores strength of the implant
decreases significantly. Therefore, normally porous HA implants cannot be heavy loaded and are used to
fill only small bone defects.

The obtained physical characteristics in development of porous ceramics for bone substitutes depend on
the porous volume of the biomaterials, as well as the mean pore and interconnection sizes. A successful
development of porous bone substitutes with optimal properties requires perfect control of these
parameters. Furthermore, HA powders have been used as coatings on metal implants in order to make
them compatible with the body and to promote stronger bone to implant bonding and increase longevity
of the implant for instance in the case of femoral hip implants.

Porous HA granulates have already been developed in the quest to develop implants comprising HA alone.
It is believed that a 3D porous synthetic structure in its most perfect form will fulfil the following needs:

Bioactivity this is followed by cell proliferation/differentiation and new cell-induced bone growth
Anti-bacterial properties
Suppression of hostile immune system responses
Excellent mechanical properties to minimize (i) failure and (ii) stress shielding (the latter has
potential to alter the stresses experienced in areas away from any insert and so induce distorted
bone growth or high osteoclast activity)
 Porosity that is designed to enable the impregnation of vascular and new bone-mineral / collagen
structures

An ability to create bespoke shaped 3-D sections of bone, ideally via some form of Additive Layer
Manufacturing, to cut down on waste created by machining.

The following article explores the role of (multi-element) substitution in HA and how this can impact on
behavior of HA in aqueous physiological environments.

2. Adaptation of HA Chemistry
The HA lattice can be altered by the specific inclusion of target ions. It is possible to distort the HA lattice
to a lesser or a greater extent based on the properties of the ion substituting into the lattice (ionic radius
and charge simply, however access to different electron orbits may be important).

The dissolution method works in three steps:

The HA crystal consists of two distinct ion channels running down the c-axis of the lattice, one channel
being filled by OH- and lined by Ca2+ in a helix, the other being formed by Ca2+ surrounded by PO43- groups.
The primary ion channel is that of the OH- with a diameter of approximately 3 .

Dissolution occurs by first acidic neutralization of the OH- leading to removal of H2O and the opening up
of the channel. This is followed by the migration of Ca2+ out of this channel.

The removal of Ca2+ leads to the formation of the PO43- rich layer, which then dissolves due to a lack of
cross linking between PO43- tetrahedral. Substitutions can alter these processes by either restricting the
primary ion channel (F-), replacing the Ca with an easier to remove cation (Mg2+), or by providing a salting
out ion (SO42-).

Present work at Ceram involves investigations into and developments of multi-substituted HAs.

Figure 1 shows the mean deviation in ionic volume because of substitution from the original lattice against
the HA yield. Generation of data was achieved by modification of the data set from a Factorial
Experimental Design (FED) experimental group to include true values for the substitutions (values
gathered by X-Ray Fluorescence XRF). This graph suggests that the HA lattice will readily form through
wet precipitation when the substituents it is attempting to incorporate lead to a positive volume deviation
rather than a negative deviation.

Figure 1. Volume Deviation Vs HA Yield Figure 2. Charge Deviation Vs HA Yield

Along with looking at ionic volume changes, Lucideon has also studied the impact of mean ionic charge
variations arising from substitutions. In order to fully study the data in Figure 2, further work is needed
and there is certain information that can be gathered. On completion of studies on the impact of ion
substitution on retention of a HA crystalline structure, Ceram will focus on how this data correlates to
bioactivity.

3. HA preparation methods

Fig 3: HA synthesis via different preparation methods, Spherical HA, HA synthesized via polymeric
method, Endobons method, ceramic foaming method, ad mixing method.

Formation of porous structure using pore-creating volatile particles which burn away during sintering
Various kinds of pore making agents including paraffin, naphthalene, carbon, starch, flour, hydrogen
peroxide, or synthetic polymers (for example polyvinyl butyral) are admixed to HA powders or slurries.
After molding, the organics burn away from the molding body during sintering. This approach allows direct
control over the pore characteristics since their fraction, size, morphology, and distribution are controlled
by type, amount and properties of the added volatile phase. Removal of pore-creating organics can either
be conducted by physical processes like evaporation and sublimation or chemical reactions like
combustion and pyrolysis. Obtained porous ceramics frequently have closed macro pores with a wide-
ranging pore size of 0.15000 mm diameter.

Formation of porous structure via admixture of water soluble poro gens with HA powders without
sintering process
It consists of mixing salt crystals and water soluble polymers as pore creating agents with calcium
phosphate powders followed by cold-isostatic pressing. Since poro gens are easily water soluble they can
be detached without any heat treatment. Pores are formed by the salt crystals and channels between
these pores are formed by the polymeric fibers. The obtained porous HA showed respectable pore
interconnectivity with the pore diameters in the range of 250400 mm

Conversion of marine coral skeleton and natural bone

The three-dimensional skeletal structure of certain marine corals mimics human cancellous bone and can
be used as a pattern for making any porous structures. A commercially available porous HA, Endobon
(Biomet UK Ltd), is manufactured from natural cancellous bones by removal of the organic component
while preserving the trabecular structure. With pore size of 100-1500 mm and excellent interconnecting
pore system

Ceramic foaming technique

This technique involves foaming of ceramic suspensions or swelling of ceramic green bodies via gas
evaporating chemical reactions from organic and inorganic sources. This technique involves a crosslinking
polymerization step that gelatinizes the foam-like HA slurry in a speedy manner, thus encouraging the
formation of an interconnected porous structure. The wall surface of the device obtained is very smooth
and HA particles are affiliated closely to one another and bound tightly. With average pore size 150 mm
and average inter pore connections 40 mm, this device is advantageous for inter pore cell migration or
tissue ingrowth. Gel casting of foams can be functional to produce ceramic scaffolds with high mechanical
strength. The disadvantage of this procedure is that it typically results in a structure of poorly
interconnected pores and non-uniform pore size distribution.

Polymeric sponge method

The polymeric sponge method, is achieved by saturating porous polymeric substrates (sponges) with HA
slurry. Porous HA prepared via the polymeric sponge method have shown well- interconnected pores but
poor mechanical strength for load bearing applications. It was shown that the polymeric sponge method
results in a proper pore size distribution, as osteoconduction necessitates. This is characterized by the
existence of micro/meso/macropores with adequate degree of interconnection.

Some of the above-mentioned methods have been combined to produce porous HA with
improved properties. Ramay and Zhang prepared HA porous frameworks by combining the gel-casting
technique with polymer sponge method. This novel technique resulted in porous HA with upgraded
mechanical strength and controllable pore structure. The frameworks prepared were found to have a
consistent microstructure, and an open, uniform and interconnected porous structure with a pore size of
200400 mm.

4. Applications
Ceramic micro carriers

Micro carrier culture technique is one of the methods developed for cell cultivation. Owing to high surface
area for cells to adhere and grow, micro carrier culture offers a practical high yield culture of anchorage-
dependent cells and thus it is possibly suitable for large-scale operations. A variety of micro carriers,
including those based on dextran, polystyrene or cellulose, and collagen or gelatin- based macro porous
beads have been developed. Ceramic micro carriers, on the other hand, introduces new possibilities for
the culture of animal cells. Ceramic micro carrier is predicted to meet the special requirements of a micro
carrier technique due to good mechanical, chemical and thermal resistances

Drug delivery systems

In drug delivery systems, it has been recognized that a system for the slow, local and continuous release
of drugs would be a decided advantage for the treatment of many ailments. One of potential candidates
for such controlled drug delivery systems is porous ceramics; much attention has been paid to porous HA.
Owing to their physicochemical and biological properties, porous HAs have been proven as a potential
candidate for bone drug delivery system.

5. Conclusion
In the generation of synthetic bone solutions, the successful preparation of multi-substituted HAs is just
the first step. The applications of porous HA in the biomedical field are massive; they have been used for
hard tissue frameworks, cell packing, and drug releasing agents. In bone tissue engineering, porous HA
are used as filling material for bone faults and extension, false bone graft, prosthesis adjustment surgery.

The high surface area leads to excellent osteo conductivity and resorbability advantageous for fast bone
in growth. A number of methods have been used to prepare porous HA are admixture of pore-creating
organics which burn away during sintering, ceramic foaming technique, conversion of marine coral
skeleton and natural bone, and polymeric sponge method.

Variation in synthesis methods allowed design and production of porous HA with controlled porosity,
good pore interconnectivity, mechanical strength, and surface properties as demanded by clinical
reconstructive requirements.

There is still need of extensive research to establish correlations to bioactivity and propose mechanisms
behind enhanced bioactivity and to convert HA powders into shaped porous structures that surgeons can
work on.

6. References
B.D. Ratner, A.S. Hoffman, Biomaterials Science: An Introduction to Materials in Medicine, Elsevier Science &
Technology, 2004.

W. Frieb, J. Warner, in: F. Schuth, K.S.W. Sing, J. Weitkamp (Eds.), Handbook of Porous Solids, Wiley-VCH, Weinheim,
2002, 2923pp.L.L. Hench, Biomaterials 19 (1998) 1419.

A. Bigi, E. Boanini, K. Rubini, J. Solid State Chem. 177 (2004) 3092.

L.L. Hench, J. Wilson, An Introduction to Bioceramics, World Scientific, Singapore, 1993.