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2 Titanium for Medical Applications

David F. Williams

University of Liverpool, Liverpool, UK

Introduction ..................................................
The Role of Titanium in Current Medical Devices. . . . . . . . . . . . . . . . ..
The Validity of the Concept of Biostability and Biological Safety ........
Titanium and Tissue Engineering ..................................
Bioactivity and Titanium ........................................
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

D. M. Brunette et al., Titanium in Medicine


Springer-Verlag Berlin Heidelberg 2001

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2 Titanium for Medical Applications

2.1
Introduction
In a review of the biocompatibility of clinical implant materials some twenty years
ago [1] I referred to a statement given in the preface of the Proceedings of an International Conference on the Science, Technology and Applications of Titanium in
1968 which stated that:
Never has there been, as in the case of titanium, the concentration of scientific
and technical devotion to a single metal, with so much money, over such diversified areas, both technical and geographical. Never has a metal invited and
received such attention, not only from the technical viewpoint, but also from the
political arena and the world offinance. Never has metal, normally considered
so mundane, been so extravagantly described as the wonder metal, the glamour
metal and the metal of promise.

After considering the properties and characteristics of titanium and its alloys with
respect to biocompatibility and applications in implanted devices, I then concluded
that this excitement about this metal in general engineering was reflected in the
specific situation in the medical field, with the following comment:
The extensive list of clinical uses of titanium and the titanium-aluminium-vanadium alloy is a clear indication of the suitability of these materials for implant
applications. There is no doubt, of course, that both stainless steel and cobaltchromium alloys are widely used and generally accepted as good biomaterials.
However, the fact that titanium is being used preferentially in many of the more
recent applications in maxillofacial and oral surgery, neurosurgery and cardiovascular surgery, indicates a slight superiority. There is a clear advantage in
corrosion resistance, and probably the titanium-aluminium-vanadium alloy has
the best combination of mechanical and physical properties, corrosion resistance and general biocompatibility of all metallic biomaterials.

Twenty years is a long time in the history of biomaterials and medical devices and
it is appropriate and opportune to consider whether this superiority exists today and
whether titanium and its alloys can still be regarded as exceptionally good biomaterials. This chapter represents an attempt to update this analysis of titanium in the
context of medical devices. It does so partly with an attempt to review the performance of current medical devices that employ titanium and its alloys and partly
with an analysis of the requirements of medical devices today, and indeed tomorrow. The latter point shall be dealt with first.

2.2 The Role of Titanium in Current Medical Devices

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2.2

The Role of Titanium in Current Medical Devices


Whenever titanium is mentioned in the context of medical applications, it is usually
assumed that it is long term implantable devices that are under consideration since,
as noted above, it is the combination of corrosion resistance and biocompatibility
with mechanical performance that is the principal attribute of the metal. This chapter, and indeed the whole of this book, assumes the same fundamental position,
although this is without prejudice to the excellent properties in general, which
make these alloys very attractive, if expensive, engineering alloys for non-implantation medical applications.
The list of past and current applications of titanium (which, in this section of the
chapter will be taken to mean titanium or any titanium-rich alloy, but not any shape
memory alloy), as reviewed in detail in the later chapters of the book, are varied
and wide ranging in their function and expectations. Nevertheless, a relatively
small number of generic applications can be identified. The reader will readily see
that these applications and expectations are consistent with the general principles
upon which materials selection for medical devices are founded.
First, there are those situations where a tissue or organ has suffered from some
disease or condition that has resulted in pain, malfunction, structural degeneration,
or any combination of these, and which can only be alleviated by replacement, or
possibly augmentation, of the affected part. The causative agent or factor could be
bacterial, viral or fungal, autoimmunity, sclerosis, neoplasia, or simply age-related
degeneration. The patients are often elderly, but need not necessarily be so, and
require that any pain be reduced or eliminated and the offending tissue circumvented by an alternative structure that is able to provide a degree of function equivalent to that which might be expected in such a person without the condition. It
may well be that this is best achieved by excision of the tissue and its replacement,
but the objective may be best satisfied by introducing an additional functional component into the body that takes on the role of the affected tissue. For example, the
best solution to the arthritic hip may be to remove the affected bone and cartilage
and replace them in their entirety with a total joint prosthesis, but with an atherosclerotic artery, the objective may be more easily satisfied with a by-pass rather
than a replacement. The important thing is that function is restored. It is, with a few
exceptions, not necessary to make the prosthetic component look like or otherwise
physically resemble the tissue that it is replacing, as long as it carries out the appropriate function. It follows from this that it is a further requirement that this prosthetic component is able to continue to perform this function for as long as the
patient is alive. This is obviously where titanium comes in, because, as noted
above, it has very good mechanical properties that are more than adequate for most
stress systems in the body and has excellent biostability and biocompatibility characteristics. Examples where titanium has been used to good effect here are replacements for teeth (dental implants) and bones (maxillofacial devices, components of
hip and knee replacements).

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Secondly, there are those situations in which there is a malfunction of a tissue or


organ and where relief may be obtained by the implantation of an engineering
device which can assist that tissue or organ in its normal function. Typically such
devices will be active, or powered, and will supply mechanical or physical energy
to the affected part. Implantable electronic devices such as cardiac pacemakers,
cochlear implants and defibrillators form a major group in this category, but this
also includes the powered systems that assist cardiac function such as the experimental heart pumps. Such devices generally have three sections, the internal functional components such as signal generators, power sources and pumping
chambers, the parts that contain such components and the active interface between
the device and the relevant tissues. The materials used for the internal functional
components are not generally considered to be biomaterials since, by definition,
they do not contact tissues. However, the containment materials are crucial and
require to be diffusion barriers as well as mechanically robust and biostable, with
excellent biocompatibility. The attributes of titanium can again be seen positively
here.
Thirdly, there are situations in which control is required over regeneration processes in tissues and where a device is used to either enhance or repress tissue
growth or proliferation. Two examples may be cited here. The first is the stent that
is used within a tubular system in order to maintain patency through the control of
shape and the restriction of endothelial and muscle tissue proliferation, such as
with the intravascular stent. The second is the structure, such as a cage, which is
used to direct the process of new bone growth in attempts to repair defects or produce bony fusion, such as in the spinal cage systems used in inter-body fusion. The
requirements here will not be dissimilar to those of the first type of application.
The fourth type of application is transient and directed towards the temporary
support of traumatized or deformed tissues. Generically this could include sutures,
clips, adhesives and staple for soft tissue, haemostatic and sealant devices and
materials in the vascular system, plates, screws, pins and fixators for bone fracture
repair and wires, brackets and other devices for orthodontic applications. The
requirements here will be varied depending upon the stress transfer systems
required in the device-tissue complex, and on the desire for biostability or biodegradation.
It is self evident from the above brief analysis of the generic nature of implantation applications that involve, or could involve titanium, that there are just a few
generic requirements of titanium in order to perform the desired function. The first
is that the material must have the appropriate mechanical properties, taking into
account the stress levels and frequencies that will be encountered, and the expectations for stress transfer within the relevant part of the body. The second is that the
material must be sufficiently corrosion resistant, taking into account the duration of
implantation and the consequences of any corrosion process should it take place in
that particular situation. The third is that the material should have adequate biological safety, which will be predicated upon the lack of cytotoxicity, mutagenicity,
carcinogenicity, immunogenicity and thrombogenicity.

2.2 The Role of Titanium in Current Medical Devices

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When considering these requirements, it is not surprising that titanium has been
used so much, and indeed has, for most applications, become the clear metallic
material of choice for implantation. Titanium has, in fact, become the archetypal
biomaterial, the uses of which are based upon the classical foundations of inertness, biological safety and adequate mechanical performance. If the actual contributions that the titanium makes to an implantable medical device are analyses, it
will become obvious that titanium is not a great deal different to other real and
potential biomaterialsexcept that it gives marginally better performance in a number of areas and probably gives better complete performance when taking all factors into account.
With respect to mechanical performance in implanted devices, a number of
parameters may be considered and used in the selection process and risk analysis,
but these do narrow to a very small number of critical factors for most structural
applications, representing the need to resist fracture or permanent deformation over
a sustained period of dynamic stress and the need for an appropriate elastic modulus taking into account the stress transfer mentioned earlier. Making an assumption
that a metallic material has to be used for a given application, an assumption that
sometimes may be intuitive but may not always be valid, bearing in mind the qualities of many engineering polymers, ceramics and composites, this means that a
high fatigue endurance limit (or more correctly corrosion fatigue endurance limit),
a high elastic limit, proof strength or yield strength, and a low elastic modulus represent the optimal mechanical property characteristics for general use. In certain
applications, other mechanical attributes become important, such as wear resistance whenever any abrasion is anticipated and superelasticity when recoverable
elastic strain is desired as in some orthodontic and fracture fixation applications. It
will be shown later in this book that titanium is very satisfactory in this respect.
There will be other alloys known to the metallurgist, however, that will have superior absolute mechanical properties than titanium alloys, and certainly many have
better wear resistance. The usefulness of titanium is dependent on the combination
of these properties with other important characteristics.
Turning now to the question of biostability and corrosion resistance, there can
be no doubt that if a synthetic material is intended to be implanted in the human
body for a long period of time with the intention of replacing permanently a part of
the body or the function of that part, the material must be sufficiently resistant to
the very hostile environment of the body. Leaving aside those transient applications
where degradability might be desirable, maximum corrosion or degradation resistance is a prime requisite for a long-term implantable biomaterial. This should take
into account all potential mechanisms by which a material might adversely interact
with the physiological environment, including conjoint mechanical - environmental phenomena and highly specific biodegradation processes. Thus, with a metallic
material, maximal resistance to dissolution / metal ion release, crevice corrosion,
pitting corrosion, fretting corrosion, galvanic corrosion, corrosion fatigue, stress
corrosion cracking, protein and inflammatory cell induced corrosion, accelerated
corrosion and microbiological corrosion are all important. There can be no doubt

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that if the requirement for inertness is paramount, titanium would be one of the
most attractive alternatives.
With respect to biological safety, adverse events associated with an implantable
material (ignoring any adverse events attributed to the physical presence of the
device) can be caused by either a surface interaction or a release of some material
component. Taking the latter point first, it has already been concluded above that
titanium excels in corrosion resistance, including the straightforward metal ion
release, and so there are few opportunities for any metal ions to be released in any
quantity into the body under normal operating circumstances. It is well known [2,3]
that some titanium is released into tissues over a period of time and, indeed, can
give rise to a characteristic discoloration of the tissue, but the amounts seem to be
very small in most clinical applications. However, this condition is predicated on
the stability of the oxide film on the titanium and it is possible, for example under
extreme conditions of abrasion or fretting, for the oxide film to be compromised,
such that elemental or particulate products are released.
The biological activity of titanium ions or compounds, if released has been a
matter of some controversy. The vast majority of the evidence [for example 2,4]
has indicated that the titanium that is present in the tissue, and associated with this
discoloration, has very little effect, a position that is confirmed by abundant in vitro
studies [for example 5] that demonstrate an absence of cytotoxic effects, or at least
a minimal cytotoxicity in comparison with other metallic elements. I have often
referred to titanium as physiologically indifferent, it being tolerated by cells and
tissues without being an essential element and, therefore, without any positive
effect but also without any negative effect. Some studies have appeared to show a
more marked biological response, including a putative immunogenicity but these
are in a considerable minority. It must also be mentioned, of course, that with a titanium alloy, ions other than those of titanium may be released, and this again has
been a source of some controversy. The most commonly used alloy contains 6%
aluminium and 4% vanadium. There have been many claims that vanadium is an
element with certain toxicological characteristics and that this should be a reason
for seeking alternatives. It is true that, although there are undoubted positive roles
for vanadium as an essential trace element, cytotoxic effects can be observed with
this element under some circumstances, but the evidence would suggest that the
risks of such events at the levels likely with the clinical use of the alloy are very
low. If anything there should be a greater concern with the aluminium content of
the alloy, since this element has clearly identified toxicological characteristics, but
unfortunately the aluminium is required to act as the alpha stabilizer and provide
the alpha-beta structure that is the basis of the mechanical properties of the alloy. In
practice, some marginally better performance mechanically may be achieved by
using alternatives to Ti-AI-V, but the toxicological or biocompatibility arguments
for change are rather weak.
As far as the possibility of a biomaterial causing adverse events through surface
reactivity is concerned, there is little reason to assume that a titanium surface has
any possibility of engaging in any specific interactions with cells or proteins that

2.3 The Validity of the Concept of Biostability and Biological Safety

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could cause harmful effects. More will be said of this later in the context of the positive aspects of biocompatibility but few would argue with the premise that, if a
smooth surface biomaterial was required for direct contact with either soft tissue or
blood, with minimal activation of any biological component (contact phase activation of the clotting cascade, platelet adhesion and activation, complement activation, protein adsorption and denaturation), titanium would be a natural choice, as it
is for the frame of many heart valves and the casing of most implantable electronic
devices.
It has to be concluded from this analysis that, unless specific and unique properties are required, titanium should be considered as the material of choice for any
implantable medical device for which the mechanical properties of a metal are
deemed necessary and where biostability and freedom from biological risk are
required.

2.3
The Validity of the Concept of Biostability and Biological
Safety
In the light of the above comments, and on the understanding that titanium is a very
valuable biomaterial at the present time, it is appropriate to consider the validity of
this whole approach so that the future position of titanium can be assessed.
The reason that titanium is so useful is that it does not react with the body. We
will discuss arguments about bone bonding and so-called osseointegration a little
later, but this has to be the underlying rationale for the widespread use of the material. Titanium is much more corrosion resistant than stainless steel and has therefore, slowly over the years, replaced it in many areas of surgery. Cobalt-chromium
alloys are still used in many situations of course, and display very good corrosion
resistance, although not as good as titanium, and has excellent biocompatibility,
although again arguably not so good as titanium. In some circumstances these
alloys are superior to titanium mechanically, as with some of the bearing surfaces
in joint replacement devices, whilst in other situations the elasticity of titanium is
preferred, as with bone support or replacement. It is also relevant to point out that
the other group of metallic biomaterials that are widely used, although under different circumstances, are the platinum group metals and these again rely upon biological inertness and biological safety.
If this is true, that titanium is successful because it reacts minimally with the
body, we must ask the question of whether this is the best approach. It certainly
may be argued that this situation with metallic materials has been replicated elsewhere with biomaterials, since some of the most successful biomedical polymers
and bioceramics have been those that are inert and which display excellent biocompatibility. PTFE, polyethylene, silicone elastomers, polymethylmethacrylate, pyrolytic carbon and alumina are all used because they also react minimally with the
tissues of the body. Many polyurethanes would be useful as thermoplastic elas-

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tomers but their lack of biostability compromises their long term suitability, as it
does with otherwise useful materials such as certain polyesters and polyamides.
The situation is, therefore, that the majority of the implanted medical devices of
today rely upon materials chosen for their inertness. It is a consequence of this that
these materials do not have any intrinsic capacity to become incorporated into the
tissues of the body either physically or biologically and will always have to act as
an adjunct to the body, performing such functions as are desired but never being
part of the body and always being at risk of a separation from the body at some
future time.
Heart valves may be made of inert materials, for example a titanium frame, carbon leaflets and expanded PTFE sewing ring. These materials do not incorporate
themselves within the heart muscle but the device is sewn in pace. Tissue ingrowth
into the pores of the sewing ring or pannus overgrowth may occur but these are not
processes of material induced incorporation. A pacemaker can remain in place
without incorporation but its exact location is not important; however, the pacemaker electrode has to be firmly fixed to the heart muscle and there is no hope of
achieving this with a metal unless a porous surface is used. Most hip replacements
have to be cemented in place because they cannot otherwise be retained. Dental
implants achieve stability by protective surgery (i.e. a procedure that minimizes
loading on the implant during the early post-operative stages) and a threaded root
for mechanical integration.
In other words, the search for inertness has led to a group of implantable devices
which may function mechanically and may be biologically safe, but which cannot
be integrated into the body. This places a serious constraint on the uses of inert
materials for reconstructive surgery. We may have some useful devices that save
lives, provide pain relief and generally improve the quality of life, but it may prove
impossible to extend their performance in terms of reliability and the range of conditions these procedures address.
It is also true that the search for inertness itself may not ultimately be successful.
Many of us have argued that there is no such thing as an absolutely inert biomaterial, and inertness and biostability have to be considered in relative terms. The failure of most polyurethanes to demonstrate biostability and the corrosion failures of
stainless steels testify to the fact that otherwise very good biomaterials may eventually be shown to fail the strictest tests for inertness. Alumina has been shown to
loose strength on implantation, polyethylene oxidizes and Dacron hydrolyzes in the
presence of lysosomal enzymes. Notwithstanding all of the favorable comments
above about the exceptional corrosion resistance of titanium, it can corrode under
some conditions. For example, if lessons are not learnt about galvanic and fretting
corrosion, the titanium stems of modular hip replacements, in contact with a cobalt
alloy surfaced head may well corrode, with disastrous clinical consequences [6].
Thus, it could be argued that not only is inertness a concept of limited applicability, it is an aspiration that is extremely difficult to achieve. It may be concluded,
therefore, that titanium has provided an extremely good solution to a number of
medical device issues, but that its uses have probably reached a peak, and that

2.4 Titanium and Tissue Engineering

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these are likely to decline in the future as different concepts and different materials
emerge. Whether this is correct will depend on a number of factors, concerning first
the relationship between tissue engineering and medical devices, and secondly the
validity of the theories about the putative bioactivity of titanium surfaces.

2.4
Titanium and Tissue Engineering
At the present time, tissue engineering is under intense discussion and scrutiny.
According to some sources, tissue engineering could negate the need for implantable, conventionally engineered devices, in which case the future for titanium, or
indeed any other inert biomaterial would be in doubt. What is tissue engineering,
and is this likely? I have defined tissue engineering as "the persuasion of the body
to heal itself, through the delivery to the appropriate site of cells, molecular signals
and supporting structures" [7]. There will be many situations where the ability to
address a clinical condition by tissue engineering has no counterpart in conventional medical devices since, for the reasons alluded to above, the latter approach
has been entirely inappropriate, one example being the treatment of neurodegenerative diseases such as Parkinson's Disease. A comparison may be seen, however, in
cases of diseases of the skeletal system, where there are implantable prostheses at
the moment and where the ability to cause regeneration of bone and cartilage
implies rapid progress in the tissue engineering approach. In the latter case, it will
be the ability to diagnose cartilage degeneration at an early stage, coupled with the
ability to harvest and grow chondrocytes and produce new cartilage that can be
implanted into the early lesion in order to restore joint structure, that is so attractive, in which case the total joint replacement, currently used as a last resort with
severely damaged cartilage and sub-chondral bone, will largely become redundant.
It may well be that scientific, technical, regulatory and logistics hurdles delay the
progress in this area, and total joint replacements will still be required for a long
time yet, but it does appear that these uses have peaked. The same may be said of
heart valves, where it is unlikely that the mechanical valves, already losing ground
to the bioprosthetic valve, will be able to compete with tissue engineered or other
more natural valve forms in the future.
The above definition did indicate that there would still be a need for support systems in some cases. The delivery of cells and biologically active molecules to sites
of tissue damage where they are intended to effect a regenerative process is not a
trivial process. Most scaffolds and matrices are being made of biodegradable polymers for the obvious reason that there is usually little point in persuading tissue to
repair itself around a permanent un-natural object. In some situations, however, the
need to achieve rapid and effective stability with continued support from a stable
structure, as in some situations with the treatment of spinal defects, suggests that
the most stable and inert of all engineering structures may still have a role alongside tissue engineered bone grafts.

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2.5
Bioactivity and Titanium
Much of the discussion about titanium performance in the literature during the last
decade or so has been focussed on the manner in which titanium interacts with
bone. Ever since Branemark and his colleagues demonstrated good success with
dental implants made of titanium with respect to attachment to bone, and the socalled osseointegration phenomenon [8] arguments have been put forward, and
refuted, about the special qualities of titanium that allowed for a positive interaction at the bone titanium interface. Mechanistically there are two issues with
respect to the bone-biomaterial interface. First, is it bone that forms at the interface
or is it a variable combination of bone and soft tissue. Secondly, if bone does form
at the interface without any detectable soft tissue layer, is the material actually
bonded to the surface. The conclusions that I draw from the literature and my own
observations is that there is a great variability in the way in which bone and soft tissue compete for the biomaterial surface after the latter is implanted in a bony site.
There are some materials that come close to 100% contact with bone and some that
develop little or no bone contact. Taking into account the many experimental variables that are involved, such as mechanical stability, surface roughness and so on, it
is a clear impression that the extent of bone contact increases with inertness. It is
possible to see essentially the same level of bone contact in a transcortical rabbit
model with implants made of alumina, high density polyethylene and titanium,
with decreasing levels as less and less inert metals, ceramics, composites and thermoplastics are used. In the vast majority of circumstances, apposition to bone and
clinical stability of devices, which is considered by many to be the effective meaning of osseointegration, is achieved through the route of maximizing inertness, the
lack of reactivity meaning minimal stimulus to inflammation and the resulting soft
tissue formation.
On the other hand, apposition of a material to bone does not signify adhesion or
bonding. There is a clear indication that so-called bioactive materials based on calcium phosphates, particularly calcium hydroxyapatite, do actively permit bone
bonding, hence their use as coatings on many orthopaedic and dental implants. The
coating of titanium implants with hydroxyapatite in order to achieve bone bonding
implicitly states that this bonding does not occur so readily or so well with
uncoated titanium. Intuitively it is not easy to see why a bond should form between
titanium and new bone. As Davies points out [9], the important thing about the
interface is that the associated environment permits expression of osteoblast phenotype. However, these cells should produce a calcium phosphate cement-like substance and if, as shown to be feasible by Hanawa [10], the phosphorus and calcium
are adsorbed to a surface such as titanium oxide, a bond could form. It is possible,
therefore, that titanium has a little more to offer than exceptional corrosion resistance.

2.6 Conclusions

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Whether this proves to be the case and provides titanium, in any of its forms (i.e.
alloys), with a clinically significant advantage over other conventional biomaterials
remains to be seen.

2.6
Conclusions
This review has demonstrated that titanium and several of its alloys have been confirmed as one of the most effective groups of traditional biomaterials and are still
the materials of choice for many structural implantable device applications. It has
to be recognized, however, that this situation has arisen almost exclusively because
titanium has exceptional corrosion resistance in the physiological environment, a
characteristic which itself, along with physiological indifference, imparts excellent
soft and hard tissue biocompatibility. There is no reason for this position to change
in the short, or probably medium term. However, it is necessary to be cognizant of
the radical change that is currently underway in reconstructive surgery, with the
emergence of tissue engineering and its associated products. On this basis, it may
well be that the clinical uses of titanium will peak soon. A great deal will depend
on the competitive edge that some titanium alloys may have with respect to overall
performance in those situations where metallic devices or components will still be
required irrespective of the developments in tissue engineering, and on the outcome
of the controversial aspects of so-called bioactivity of titanium, especially with
respect to bone.

References
1. Williams DF (1981) Titanium and titanium alloys. In: Williams DF (ed) Biocompatibility of
Clinical Implant Materials. CRC Press, Boca Raton
2. Meachim G, Williams DF (1973) Changes in non-osseous tissue adjacent to titanium
implants. J Biomed Mater Res 7:555-572
3. Black J, Sherk H, Bonini J, Rostoker WR, Schajowicz F, Galante JO (1990) Metallosis associated with a stable titanium alloy femoral component in total hip replacement. J Bone Joint
Surg 72A (1):126-130
4. Bardos D (1990) Titanium and titanium alloys. In: Williams DF (ed) Concise Encyclopedia of
Medical and Dental Materials. Pergamon Press, Oxford New York, pp 360-364
5. Maurer AM, Merritt K, Brown SA (1994) Cellular uptake of titanium and vanadium from
addition of salts or fretting corrosion in vitro. J Biomed Mater Res 28:241-246
6. Williams DF (1999) Unpublished observations
7. Williams DF (1999) The Williams Dictionary of Biomaterials. Liverpool University Press,
Liverpool
8. Bn"tnemark PI, Hansson BO, Adell R, Breine U, Lindstrom J, Hallen 0, Ohman A (1977)
Osseointegrated implants in the treatment of the edentulous jaw. Scand J Plast Reconstr Surg
52:1-132

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9. Davies JE, Ottensmeyer P, Shen X, Hashimoto M, Peel SAP (1991) Early extracellular matrix
synthesis by bone cells. In: Davies JE (ed) The Bone-Biomaterial Interface, University of
Toronto Press, Toronto, pp 214-228
10. Hanawa T (1991) Titanium and its oxide film; a substrate for formation of apatite. In: Davies
JE (ed) The Bone-Biomaterial Interface. University of Toronto Press, Toronto, pp 49-61