Periodontology 2000, Val.
17, 1998, 7-21
Printed in Denmark. All rights reserved
Titanium - the material of choice?
G. STEINEMANN
SAMUEL
The foreign body
Surgical fracture-treatment implants have the func-
tion of a temporary splint. In the form of a screw or
a plate or a pin, the implant stabilizes the fracture
and supports forces, including those of functional
load. Other types of implants, such as endoprosthes-
es, are permanent devices. In dental practice, the life
expectancy of a reconstruction or an implant should
at least be several decades. Yet any implant is a “for-
eign body”. The expression has a straightforward and
simple meaning. An implant is not like living tissue,
where no free electrons exist and where metals, such
as essential trace elements, occur in a bound and not
in an elemental state. Is this foreign body a chemical,
physiological or mechanical “insult” to the living
tissue?
Corrosion and soft tissue reaction
In the chemist’s view, corrosion is the visible de-
struction of metal. It may cause a structure to rup-
ture or lose function, such as by breakage of an im-
plant. That was before the 1960s. This aspect is not
important for modern metals in surgery because an
attack is so small that a material loss is not visible
and cannot be weighed. More sensitive electro-
chemical methods are needed to measure corrosion.
But experiments intended to reproduce the real con-
ditions for a surgical implant in tissue are not
simple.
The polarization resistance method has been used
for in vivo experiments (52);the results are shown in
Fig. 1. The method requires minimally invasive pro-
cedures, and a characteristic feature is that reduction
and oxidation reactions on the metal are not forced
and run in the open-circuit mode.
The noble metals silver and gold have a resistance
to corrosion that is about in the middle of a practical
scale. In the logarithmic scale of the polarization re-
sistance, the number is 5 to 6, and thus about 2
units, or a factor of 100, lower than high-grade stain-
C o m r i a h t 0 Munksaaard 1998
PERIODONTOLOGY 2000
ISSN 0906-6713
less steel and titanium. Gold and silver resist oxi-
dation in air but resist corrosion much less in sea
water and biological fluids. It is common experience
that these metals lose polish after some time.
Metals having lower corrosion resistance than sil-
ver and gold, such as aluminum, molybdenum and
iron, show visible attack or oxidation in living tissue
and abnormal cells are observed in their vicinity.
This tissue reaction is equivalent to a “chemical in-
sult”. In fact, the metals from iron through silver cor-
rode so rapidly that the supply and migration of oxy-
gen cannot keep up with the consumption of the
oxidant (this state is called the diffusion limit) so
that the contact tissue to the foreign body is starved
of oxygen. This direct effect of corrosion is not speci-
fic to the metal of the implant. However, metals are
released by the corrosion process and some of them
are toxic to cells; a sterile abscess and cell death are
[ohmcm*] CoCrNiMo
cw316LESRw
Toxicity
Ti alloys
Inertness
‘A1
Mo
Fe
Ic o Sequestration
I
Tissue reaction
I
Fig. 1. Data from in vivo corrosion experiments for various
metallic elements and for practical alloys. The diagram
has the two coordinates tissue reaction as abscissa and
polarization and corrosion resistance, as the ordinate.
Tissue reaction is grouped according to the three distinct
forms of “toxicity”,“sequestration”and “inertness”.Cor-
rosion resistance is roughly proportional to the measured
polarization resistance (to obtain corrosion current den-
sity, use j=0.03 Vlpolarization resistance). The useful
scale in chemistry and biology is always the logarithmic
one. Thus, differences over the series, such as from cobalt
(Co) to silver to titanium (Ti), amount to factors of 1 to
100 to 10,000 in corrosion resistance. CoCrNiMo is
wrought cobalt-base alloy, cw316LESR is cold-worked,
remelted stainless steel and the titanium alloys are
Ti&l,Mo, T i d 4 V , Ti15Mo.
7
Steinemann
Fig. 2. Micrographs of tissue in contact with implants
made of commercially pure titanium (left) and TiAlV alloy
(right)
observed. Among the four elements shown in Fig. 1,
vanadium is the most toxic and copper the least.
This reaction is equivalent to a major “physiological
insult”.
Stainless steel, cobalt-base alloy and titanium
have similar levels of polarization resistance, but
tissue reactions differ. High corrosion resistance is
apparently not sufficient to suppress the minor re-
jection reaction observed for the two classical alloys
that comprise the cell-toxic nickel and cobalt as es-
sential components. Another example is the Ti&14V
alloy, a standardized metallic biomaterial. Four per-
cent of toxic vanadium suffice to elicit a prominent
foreign body reaction (Fig. 2). These observations
suggest an alloy rule (53): avoid toxic components!
Corrosion is essentially an atomic process so that, in
principle, the interaction for all components of a
metal must be considered. On the other hand, path-
ologists question the existence of a threshold for lo-
cal and especially systemic (allergic) reactions.
The unwanted reaction of the
foreign body
The species of metal compounds ingested with nu-
trition and passing into the bloodstream, that is,
being metabolized, as well as those finally stored in
organs and tissue are incompletely known. But most
metals (other than alkali) in body fluids and tissue
are bound to organic matter and exist in a stable,
electrically uncharged form. Fig. 3 suggests that
metal release from implants involves a different
path; it can be associated with the entry of the metal
through a wound and then corrosion of the metal.
In that state, the metal is definitely in its elemental
form and in a different chemical state than the metal
bound in living matter.
Oxidation-reduction reactions (redox reactions)
play an important role in bioenergetics: the energy
transformations in living organisms. These reactions
8
involve electrons. Chemical reactions are the basis
of metabolic and growth processes; they involve the
second elementary particle of chemistry, the proton
or hydrogen ion, and the technical term for this is
acid-base reactions. The foreign body interferes with
these processes of life.
Redox reaction
In water and tissue fluid, corrosion occurs as an elec-
trochemical process in which oxidation of the metal is
coupled to reduction: an electron gain of electrolyte
components. The dominant form for the latter reac-
tion in neutral solutions is the oxygen reduction,
which yields a hydroxide that precipitates on the
metal surface. Other reduction reactions with inor-
ganic and organic components of tissue electrolytes
are possible. The crucial characteristic is that electron
exchange occurs at the metal surface (and only there,
but not in the liquid, where electrons do not exist as
free entities). It is a foreign body reaction of a chemi-
cal kind that can lead to denaturation of the tissue in
contact with metallic implants. The method for study-
ing these reactions is voltammetry, or a polarization
experiment. Interesting systems are electrolytes con-
taining complex formers, such as chloride, cyanide
and EDTA; gold shows massive reactions for any of
these complexes, whereas titanium is fully inert.
Dissolution of the corrosion product
The first-formed reaction products of corrosion are
hydroxides, hydrous oxides and oxides, that is, spar-
ingly soluble salts, and occasionally complexes (such
as halides). These salts can be soluble or not in the
tissue fluids (which are aqueous electrolytes) and
Internal fixation
a
Dental implant
Food 97 \
Metabolism
Foreign body
Fig. 3. Metals released from implants follow another reac-
tion path than metals entering metabolism with nutrition

MI
-6 mM-
.-
pM:
E nM
6 nM-
PM- , , , , , , , , , , , , , -
0 4 7 10
physiologicalu pH value
Fig. 4. Distribution of hydrolysis products in solutions
saturated with respect to nickel hydroxide [Ni(OH),]. The
full line is the solubility limit expressed as the total con-
centration of nickel. Data for the concentration of nickel
in serum (S), in muscle (M), in contact tissue around
stainless steel implants (I) and toxicity levels (T) are
added at right margin. Sources: Steinemann & Mausli (55)
and Steinemann (56).
they can be toxic or not (55, 56). To determine the
effects of this corrosion burden, the identity and sta-
bility of the hydrolysis products must be considered.
A question arises. What is the fate of the unwanted
reaction product of corrosion?
The word hydrolysis is applied to chemical reac-
tions in which a substance is split or decomposed by
water. New forms of precipitates and new species, as
bare ions and as charged and uncharged hydroxo-
(OH-containing) and 0x0- (0-containing) com-
pounds are found in solution. It is common experi-
ence that salts and oxides dissolve easily in strong
acids and in strong bases and that the solubility of
oxides is small for intermediate acidity (pH) values.
The mechanism behind this behavior is proton ex-
change. In solution, water molecules are attached to
metal ions and these aquaions tend to deprotonize.
The removal of a proton from the hydration sheath
results in a negatively charged hydroxyl, and thus a
reduction of electrical charge of the aquaion. The de-
protonized species become hydroxo complexes; Fig.
4 and 5 show these reactions in the case of nickel
and titanium. Hydrolysis data are best represented
as the solubility or distribution curves of the various
hydrolysis products. The diagrams have the coordi-
nates acidity (pH of the solution) as abscissa and the
molar concentration of dissolved and precipitated
species as the ordinate, both in logarithmic scale
what gives the straight lines.
Nickel. Nickel is a main component of stainless steel,
the metal largely used for fracture treatment im-
plants. The 2 + oxidation state of this metal is the
important one, and in an aqueous environment the
hydroxide is the first-formed corrosion product. Its
Titanium - the material of choice?
I dominant hydrolysis product under physiological
conditions (pH of about 7) is the unhydrolyzed
nickel cation, with a concentration of about 1 mM at
the limit of hydroxide precipitation. The unwanted
reaction product of corrosion is an ion.
S In serum, the nickel concentration is about 10 nM,
and in human skeletal muscle it is about 3 pM and
14 less than the solubility limit for physiological pH
values. The metal concentration in the contact tissue
around implants is strongly enhanced and far above
the content in normal muscle tissue; the concen-
tration is of the order of the toxicity threshold for
nickel. The sequestration reaction for stainless steel
implants is the consequence.
Titanium. Titanium is a reactive metal; in air and
aqueous electrolytes, it forms spontaneously a dense
oxide film at its surface. The unwanted reaction
product becomes a potent barrier against dissol-
ution of the metal.
The constant solubility of titanium dioxide above
pH 3 and up to pH 12 suggests that an electroneutral
species dominates in solution (Fig. 5). The core of this
dissolved neutral species Ti(OH),(aq) can be pictured
as a titanium ion with its four positive charges sur-
rounded by four negatively charged hydroxyl mol-
ecules. At physiological pH values, the first charged
species is the cation Ti(OHI3+with a concentration of
not more than 0.1 nM, which is three orders of magni-
tude lower than the concentration of the hydrogen
ion, which is always present in solution.
The unwanted reaction product of corrosion is not
an ion. This is an important finding because un-
charged hydrolysis products have no affinity for re-
action with organic molecules. Corrosion of titanium
Mi I
P M t , , , , , , , , \ , , , , , {
0 4 7 10 14
physiological U pH value
Fig. 5. Solubility behavior of hydrous titanium dioxide
measured in sodium chloride and chlorate electrolytes.
The full line is the solubility limit and dashed lines are
partial concentrationsfor the named species. Data for the
concentration of titanium in serum (S),in muscle (M) and
in contact tissue around implants (I) are added at right
margin. Sources: Steinemann & Mausli (55) and Steine-
mann (56).
9
Steinemann
becomes in fact no chemical burden, and its inert
reaction in tissue is a sign of the basically different
chemistry in solution.
In serum, the titanium concentration is about 0.1
pM, and in human skeletal muscle it is about 5 pM.
The muscle concentration of titanium equals the
upper limit of solubility for the aqueous hydroxide,
which is also about the lower limit for precipitation
of the solid oxide (about 3 pM). Solution chemistry
thus provides a stringent, even simple homeostatic
mechanism for the regulation of titanium in tissue:
titanium is at saturation in tissue! The concentration
of titanium in the contact tissue around implants is
about 100 times higher than that of muscle tissue.
These high concentrations seem representative for
larger and loaded implants and include fretting and
wear debris and residues from surface treatment.
These metal and oxide particles beyond the solu-
bility limit are just deposited in tissue, and retrieval
studies give no indication of any adverse reaction. A
statement is in order: no case of local or systemic
reaction for titanium has been documented.
Complexes in fluids and tissue
The contact between tissue and an implant raises
the local metal concentration by orders of magni-
tude. The capacity of homeostatic mechanisms can
be exceeded. Hydrolysis of the corrosion products
means proton exchanges in the tissue electrolyte and
pH shifts, which can cause denaturation of organic
matter. But binding of metal ions with other ligands
competes with hydrolysis and complexes can be
formed by substitution reactions. This substitution
is a third form of reaction, insidious in nature, of
how a foreign body interacts with living matter. The
distinction between ions or uncharged species as re-
action product of the corrosion becomes important.
Cell toxicity is well known for nickel, cobalt, copper
and vanadium, whose hydrolysis products are cat-
ions and anions respectively. Metals can act as hap-
tens: the ion can unite with a protein to form an
antigen, and nickel, cobalt and chromium are known
allergens (32). Titanium behaves totally different in
that no proton exchange and liganding with biologi-
cal molecules is possible.
Cell reaction in presence of metals
A small corrosion rate is not a sufficient condition
for tissue compatibility; the fate of the unwanted re-
action product (of corrosion) must be considered
10
(18, 55). The reaction products are available and can
be taken up by the cells. This may or may not be
toxic to the cells. Studying the effect of solid and dis-
solved metals on the development of embryonic
bone rudiments indicates that there is at least some
effect on skeletal development (13). The variety of
chemical interactions in tissue near the foreign body
and at the artificial interface is great.
Maurer et al. (33) investigated the chemical and
biochemical aspects of cell adhesion and cell pro-
liferation in the presence of many metals. Reactions
of fibroblast and osteoblast cultures were followed
for two modes of exposure in three experiments (Fig.
6): (i) fibroblasts cultured on metal discs, (ii) osteo-
blasts cultured on a neutral substrate in metal satu-
rated media, and (iii) osteoblasts cultured on metal
discs. An influence of the physical surface topogra-
phy was circumvented by preparing all metal
samples and the reference support made of a neutral
polymer to the same fine finish. The pure metal
samples included in experiments (i) and (iii) were
ground under water irrigation and then cleaned ul-
trasonically in deionized water and dried in a jet of
nitrogen gas. For the culture experiments, the metal
discs were rinsed with modified Eagle’s medium be-
fore cell seeding. For experiment (ii), the chlorides
of tin, aluminum, titanium, zirconium and tantalum
were added to water in concentrations somewhat
higher than the saturation limit of the oxide in water
(4, 5 5 ) . The solutions were titrated to a pH between
6.4 and 7.0 and served to make the supporting media
for the cell cultures. W o cell lines were used for the
three experiments, one rat fibroblastic line and one
rat osteoblastic line, and both were cultured with
modified Eagle’s medium as base. Cells were har-
vested at day 5 for cell counting.
The results of the three experiments are shown in
Fig. 7-9. In all figures, the abscissa is the polarization
resistance for the metals that had been measured in
a separate in vitro experiment. The polarization re-
sistance of a metal is proportional to its corrosion
resistance or the reciprocal of the corrosion current
density. Metals vary greatly (by a factor of lO,OOO),
and the logarithmic scale provides a good presen-
IMetal
In aqueous On metal
Fig. 6. Cell reactions are studied for two different modes of
exposure:the metal is dissolved in the supporting medium
and the cells are in direct contact with the solid metal.
 Titanium - the material of choice?

-
-
2
r
0

.-.>c
lrj
1-
0.5 -
- Control level -
Ta I
-
= 0.2 -
8
I 0.1 -
I

3
Iv
- Detection limit
.05 -
0
b

‘
!A

.02 I I I I
3 4 5 6
Polarization resistance, log ohmcmz
Fig. 7. Results from experiment (i): fibroblasts cultured on
metal discs. The abscissa is the logarithm of the polariza-
tion resistance of the metal considered and is a good scale
for its corrosion resistance. The ordinate is the normalized
cell count, also in logarithmic scale. Copper and va-
nadium are toxic to fibroblasts, and corroding molyb-
denum strongly reduces the proliferation rate. Titanium,
niobium, zirconium and tantalum do not interact.
I I .02 I I I I I I
? 3 4 5 6 7
Polarization resistance, log ohmcm2
Fig. 8. Results from experiment (ii): osteoblasts cultured
on a neutral substrate in metal-saturated media. The ab-
scissa is the logarithm of the polarization resistance of
the metal considered and is a good scale for its corrosion
resistance. The ordinate is the normalized cell count, also
in logarithmic scale. Osteoblasts cultured in modified
Eagle’s medium with dissolved metal hydroxides displayed
no inhibition of cell proliferation.

tation (see also the preceding section on corrosion

and soft tissue reaction). This scale also provides a
-
12
c
1- - - -,- Control level - - -
I - ZrI
-
good grading, as any metal located below number 5 E
0
0.5 - Ti
will show visible attack in chloride containing elec- >
Sn

-8=2 0.20.1 -- Fel

I
c
trolytes and a strong redox reaction, both processes Ta
equivalent to a ”chemical insult” in living tissue. The
Ni INb I
15 I
ordinate in the three figures, cell growth ratios, are 0
.05 - -
also drawn in a logarithmic scale for simplicity of 8 - -Detection limit

interpretation. The cell proliferation rate observed .“L

for the inert support and without metal salt is used
as the reference.
Fibroblast cells in contact with titanium, niobium,
zirconium and tantalum can proliferate but do not
in proximity with molybdenum, copper, vanadium
(Fig. 7 ) . These are reactions of “inertness” or
“sequestration” and “toxicity” on the other hand, as
they are found for soft tissue in contact with im-
planted metals (Fig. If. Osteoblasts cultured in
modified Eagle’s medium with dissolved metals dis-
played no inhibition of cell growth for the five metals
tested (Fig. 8). The metal concentrations in the cul-
ture medium ranged from 0.4 to 6 pM, equal to satu-
ration and a maximum possible level of dissolved
hydroxo compounds for pH values in the physiologi-
cal range. In the experimental series of osteoblasts
cultured on pure metal discs, growth inhibition is
absent for titanium and zirconium, relatively weak
for tin and aluminum, and strong or total for zinc,
iron, copper, molybdenum, vanadium, nickel, silver,
niobium and tantalum (Fig. 9). One experiment of
six with titanium resulted in unusually low cell
counts, but two others showed extreme proliferation
where the osteoblast layer reached confluence and
lifted off the surface.
3 4 5 6 7
Polarization resistance, log ohmcmZ
Fig. 9. Results from experiment (iii): osteoblasts cultured
on metal discs. The abscissa is the logarithm of the polar-
ization resistance of the metal considered and it is a good
scale for its corrosion resistance. The ordinate is the nor-
malized cell count, also in logarithmic scale. Growth inhi-
bition is absent for titanium and zirconium but strong for
the corrosion-resistant metals niobium and tantalum. In-
hibition is observed for all lesser corrosion resistant
metals, such as silver, molybdenum, aluminum, tin, iron,
zinc and the toxic metals nickel, vanadium, copper. The
compatible metals are titanium and zirconium.
Different modes of exposure, cells in a metal-satu-
rated electrolyte or cells in contact with solid metal,
elicit different responses. The conditions are not the
same. In the first case, the cells are in an environ-
ment of completely hydrolyzed metal species at low
concentration, what might be termed “weak interac-
tion”. Furthermore, it follows from basic principles
of chemistry that an interaction would be possible
only, and only when, the dissolved species is electri-
cally charged: an ion (55). This is the case for only
one, perhaps two of the elements considered in Fig.
8. Conversely, the direct contact of the cells with the

11
Steinemann
Fig. 10. Transmission electron micrograph of a nondemin-
eralized specimen showing the intimate contact between
the mineralized bone matrix (B) and the titanium coating
(T). Source: Listgarten et al. (31).
solid metal is sort of a “strong interaction” (Fig. 9).
Indeed, direct communication via cellular processes
between osseous cells and dental implants has been
documented (51).
A selective response is found whenever the cells
are in contact with the solid metal. Growth inhi-
bition is found for fibroblast cells (Fig. 7) and osteo-
blast cells (Fig. 9) if the polarization resistance of the
metal considered is below a logarithm of about 5 ,
that is, under conditions of strong corrosion and
strong redox activity. The observation of seques-
tration and toxicity is then an expected parallel situ-
ation for tissue reaction (Fig. 1). But the remaining
metals titanium, niobium, zirconium and tantalum
elicit different reactions for the two cell lines, even if
these elements have a same high corrosion resist-
ance. The biochemical interactions differ in the case
of niobium and tantalum. Fibroblasts are hardy cells
compared to the more differentiated osteoblasts.
The inhibition of osteoblast cell growth for any metal
other than titanium and zirconium suggests that
these elements only have the capacity for osseoin-
tegration, that is, a rather distinct property.
Osseointegration
Titanium has the surprising property that it can bind
to living tissue and to bone. It is interesting to read
Leventhal in 1951 (29):
Bone reaction was studied by the insertion of up
to 80 screws into the femora of rats ... At the end
12
of six weeks, the screws were slightly tighter than
when originally put in; at twelve weeks, the
screws were more difficult to remove and at the
end of sixteen weeks, the screws were so tight that
in one specimen the femur was fractured when
an attempt was made to remove the screw ...
From these studies it would appear that titanium
is a metal which may be useful in surgery, be-
cause of its strength and its failure to cause tissue
reaction. The fact that bone becomes attached to
titanium may be a disadvantage in cases where
screws or pins are placed temporarily. In the past,
the use of some prostheses has not become popu-
lar because it has been felt that these would re-
main separate from the bone and eventually
loosen. Since titanium adheres to bone, it may
prove to be an ideal metal for such prostheses.
A new form of prosthesis, tooth root analogues made
of titanium, become a reality in the late 1960s. This
was a major advance in clinical dental treatment and
engineering initiated by Brfinemark and collabor-
ators in Goteborg. The word “osseointegration” was
coined and defined as “a direct structural and func-
tional connection between ordered, living bone and
the surface of a load carrying implant” (6).
Structural aspects and cell reactions accompany-
ing osseointegration have been studied at all scales,
by light-optical histology through high-resolution
electron microscopy (1, 20, 30). Listgarten et al. (31)
comment on their transmission electron micro-
scopic image of the interface (Fig. 10) by saying that
“there is no evidence of any space between the met-
allic surface and the bone”. This finding suggests the
possibility of a direct chemical bond.
Osseointegration allows the efficient stress trans-
fer from implant to bone. It implies that no relative
motion occurs at the interface, and in case of a
chemical bond between the metallic implant and
bone, the displacement is restricted to atomic dis-
tances.
F
A ..$ Torque Pull - off
Fig. 11. Forces (F) on a dental implant have axial (A) and
transverse (T) components which generate shear and ten-
sile stresses at the interface between the metallic implant
(M) and the bone (B). The ultimate stresses for the bond
between metal and bone are measured as push-out load,
as release torque and as pull-off load.

Natural teeth and implants that support a dental
prosthesis will generally be loaded by both forces
and moments (torque). The mechanical force is a
vector quantity and it has a magnitude and a direc-
tion (Fig. 11). Mericske-Stern et al. (36-38) made
simultaneous force measurements on endosseous
implants along three axes and found that transverse
forces cannot be neglected. Using the Pythagorean
theorem, it is found that transverse components
reach 10-50% of the vertical force. The loading of an
implant is skewed, with angles up to 30”. In conse-
quence, different kinds of forces, shear, tension and
compression, will act in the implant-bone interface.
To determine the failure limit of the interface, “push-
out” tests of cylinders and “release torque” tests of
screws in bone are performed to give an interfacial
shear strength (Fig. 11).“Pull-off’’tests, on the other
hand give the interfacial tensile strength. Selected
examples of such measurements for various healing
times are shown in Fig. 12.
Mechanical aspects
An implant in the form of a screw will resist push-
out, but this shape requires a bond if it is to resist
torsion, which tends to loosen the implant along the
threads. The resistance to loosening is measured as
a removal torque (Fig. 12, left). It is noted that the
figure reports measurements without any normaliza-
tion for screw geometry and bone thickness. The re-
lease forces show a latency period of 2 to 3 weeks,
Time after insertion of implant, weeks
Fig. 12. Shear and tensile resistance of the titanium-bone
bond. Left.Raw data for the removal torque of screws (21,
54, 62); average values are shown. Surface preparation:
machine cut, titanium plasma-sprayed (TPS), corundum-
Titanium - the material o f choice?
followed by a rapid increase of torque and a maxi-
mum or leveling out of this torque after about 5
months. This timetable for incorporation of a dental
implant is similar to that of bone fracture healing,
whereby a short resorption period is followed by
bridging a gap with less organized bone and then
stabilization through generalized bone remodeling.
These processes can be followed by sequential label-
ing. Using this technique in the late healing-in phase
of a titanium implant, it was found that hard bone
formation occurs from the metal surface outwards,
a clear indication of total integration.
The removal torque and the push-out force are
proportional to the interfacial shear strength. The
length of the contact between implant and bone en-
ters the formula and in the case of a screw, this true
length can be expressed through an effective pitch
height leff=1.51, the factor being obtained from geo-
metric arguments or empirically (17).Representative
results from push-out and removal torque tests and
different surface preparations are collected in Table
1. At 12 weeks after insertion, the interfacial shear
strength ranges from 9 to 19 MPa for cortical bone
and from 2 to 6 MPa for trabecular bone. The results
clearly indicate that surface roughness and texture is
a primary factor in the anchorage of dental implants.
For longer times, as displayed in Fig. 12, the maxi-
mum interfacial shear strength reaches 24 MPa for
machined implants and nearly 50 MPa for special
preparations. These ultimate bond strengths are
high.
I I I
TPS and corundum blasted
Time after insertion of implant, weeks
blasted-etched (SLA).Right. Measurements of the pull-off
force for titanium plasma-sprayed (TPS)and blasted sur-
faces (44, 54).
13
Steinemann

I Table 1. Interfacial shear strength for bone-implant fixation made of commercially pure titanium
I

Experiment (12 weeks after insertion)

Implant Animal, bone removal torque push-out load shear strength References
Machined screw rabbit, corticalb 38N.cm 9.3 MPaa 60
Screw, blasted A120325 pm rabbit, corticalb 42 N.cm 10 MPaa 61
Screw, blasted A120375 pm rabbit, corticalb 50N.cm 12 MPaa 61
Cylinder, blasted A1203fine minipig, trabecular 130 N 1.9 MPaC 64
Cylinder, blasted A1203 rough minipig, trabecular 260 N 3.9 MPaC 64
Cylinder, blasted A1203 rough+etched minipig, trabecular 390 N 5.8 MPaC 64
Screw, titanium plasma-coated sheep and dog 200 N . cm 15 MPad 54, 62
Screw, blasted N203rough+etched sheep, corticale 250 N . cm 19 MPad 62
a The relationship between removal torque T and interfacial shear strength T is T=d/2 d x leff.T = C 7,. with c= 19 mm3 per pitch height (0.6 mm).
The thickness of bone is 1.25 mm.
The relationship between push-out load P and interfacial shear strength T is P=s T, with surface area s = d x .1=67 mm2,
The relationship between removal torque T and interfacial shear strength T is T=c T, with c=80 mm3 per pitch height (1.75 mm).
The thickness of bone is 3 mm.

I Table 2. Interfacial tensile strength for bone-implant fixation made of titanium

Experiment
Implant Animal, bone duration pull-off load tensile strength References
Titanium plasma-coated disc, 20 mm* Macacu sp., ulna 30 weeks 76 (30-120) N 2.7 MPa 54
Polished Ti&V disc, 39 mm' dog, cortical 43 weeks 25 (041) N 0.6 MPa 58
Hydroxyapatite-coated disc, 39 mm2 dog, cortical 43weeks 107N 2.7 MPa 58
Commercially pure titanium, blasted
and plasma coated rabbit, epiphysis 24 weeks 107 N 1.6-3.1 MPa 44
The relationship between pull-off load P and interfacial tensile strength a is P=s a, where s is surface area.

Interestingly, the pull-out interfacial shear
strengths for freshly inserted BrHnemark (Nobel Bi-
ocare AB, Goteborg, Sweden) screw implants (7, 8)
and small bone fixation screws (49) are less than the
above-reported results: 31 MPa and 34-39 MPa re-
spectively. These latter figures can represent a
"notched shear strength' and a practical limit when
acute threads engender high local stresses. Likewise,
an implant inserted in the mandibula or maxilla will
be subject to similar effects that limit the anchorage.
For comparison, human bone has a shear strength
of 68 MPa when measured in torsion along the bone
axis, but the property falls strongly for other orien-
tations (45).
Pull-off tests have the characteristic feature that a
strong interaction between the metallic implant and
living hard tissue, that is, the adhesion reaction, is
observed only beyond about 10 weeks (Fig. 12, right).
Perfect immobilization of the test implant is always
required. Table 2 collects data for conditions when
bonding is completed. For titanium, the interfacial
tensile strength is 2.5 MPa on average, and hydroxy-
apatite-coated titanium does not fare better. The
figure is of the order of the compressive strength of
human trabecular bone (2-10 MPa). Fragments of
bone are commonly observed on the fractured test
pieces, which indicates a less dense bone in the con-
tact zone.
To give an idea how strong this bond is, reference
can be made to a classical work in physics. The Mag-
deburg half-spheres experiment measured the force
necessary to break vacuum; it needs the (negative)
pressure of 1 atmosphere, equal to 0.1 MPa. The ad-
hesion between two bodies can never exceed this
stress if there is empty space or free water present in
the bond region. The interfacial tensile strength of
the metal-bone bond is 25 times larger than this
limit. Thus, one may ask what is the glue?
Material aspects
Corrosion can be the cause of a tissue reaction. An
example is gold, which has a strong redox activity
in the chloride-containing tissue fluids and whose
corrosion current density is not far above a practical
limit for visible attack (see earlier). Sequestration of

14
 Titanium - the material of choice?

the foreign body is observed in soft tissue, and im-
plants made of gold provoke bone resorption (59).
Stainless steel, CoCrMo (vitallium) and Ti&14Vhave
much better corrosion resistance; nevertheless,
sequestration and a local reaction are observed in
soft tissue because of leaching, even in minute quan-
tities, of toxic components from the alloys. Bone
screws made of stainless steel loosen after some
weeks, and screw implants made of vitallium and ti-
tanium alloy have reduced removal torque (Table 3).
Push-out tests in trabecular bone all show the effect
of surface texture, but the enhancement of anchor-
age by etching pure titanium is absent for the alloys
(compare with Table 1). It is concluded that vitallium
and all titanium alloys used for bone surgery have no
capacity or a reduced capacity for total integration. A
chemical effect of the metal is manifest. On the other
hand, zirconium and niobium have interfacial shear
strength values not less than that of titanium.
Chemistry of osseointegration
Titanium is a reactive metal. This means that, in air,
water or any other electrolyte, an oxide is spon-
taneously formed on the surface of the metal (Fig.
13).The native oxide film has a thickness of about 4
nm, or 20 times the interatomic distance. Its mode
of growth is specific in that the oxygen ions migrate
towards the metal and react with the counter-ion ti-
Metal ion J, J Oxygen ion
0 . 0 0 .
0 0 . 0 . .
Fig. 13. Surface oxide on a metal. In the case of titanium,
the oxide grows by the transport of oxygen from the exter-
nal surface towards the metal-oxide interface where the
oxidation reaction proper takes place.
tanium at the base of the oxide (35).This mechanism
is unique for titanium and some other elements of
valency IV, such as silicon and zirconium. Ordinarily,
both the oxygen anion and the metal cation migrate
when a metal undergoes oxidation, or corrosion. The
specific mode of oxide growth on titanium has the
positive effect that no metal ion will reach the sur-
face and be released into the electrolyte.
Titanium oxide is a good insulator even in the
form of a very thin surface film, which may be in a
crystalline or in a glassy state and which can occlude
anionic impurities such as chlorine, fluorine or
phosphates (12, 34). This behavior differs from that

Table 3. Interfacial shear strength for bone-implant fixation made of titanium alloys and other materials
Experiment (12 weeks after insertion)
removal push-out shear
Implant Animal, bone torque load strength References
Vitallium, machined screw rabbit, corticalg 12 N . cma 3.4 MPae 24
Zirconium, machined screw rabbit, corticalg 26 N . cmb 6.5 MPae 26
Niobium, machined screw rabbit, corticalg 33 N . cmc 9.1 MPaf 25
Ti&14V,machined screw rabbit, corticalg 16 N.cmd 4.3 MPae 22
Ti&14V,cylinder, blasted A1203,fine minipig, trabecular 120 N 1.8 MPah 64
rough
Ti&14V,cylinder, blasted A1203, minipig, trabecular 230 N 3.4 MPah 64
Ti&14V,cylinder, blasted rough+etched minipig, trabecular 230 N 3.4 MPah 64
Ti&17Nb,cylinder, blasted A1203, fine minipig, trabecular 110 N 1.6 MPah 64
Ti&17Nb,cylinder, blasted A1203, rough minipig, trabecular 280 N 4.2 MPah 64
Ti&17Nb,cylinder, blasted rough+etched minipig, trabecular 230 N 3.4 MPah 64
Hydroxyapatite-coatedTi, cylinder minipig, trabecular 830 N 12 MPah 64
a The measurement for commercially pure titanium gives 25 N . cm.
Commercially pure titanium has 26 N cm.
Commercially pure titanium has 25 N cm.
Commercially pure titanium has 23 N . cm.
The relationship between removal torque T and interfacial shear strength T is T=d/2 . d n I,#' T = C . T, with (9 c=17 mm? per pitch height (0.6 mm), and
(f) c=19 mm3 per pitch height (D.6 mm).
8 The thickness of bone is 1.25 mm.
The relationship between push-out load P and interfacial shear stress I[ is P=s .I[,with surface area s=d . B . 1=67 mm'.

15
Steinemann
of the passive film on gold, stainless steel and vitalli-
um, which is an electron conductor. The availability
of electrons at the outer interface towards the elec-
trolyte or living contact tissue implies that redox pro-
cesses, that is, electron exchange processes, can pro-
ceed. Or, this is one mechanism leading to denatura-
tion of macromolecules and sequestration at a larger
scale. Gold, stainless steel and cobalt-chromium al-
loy show this response; titanium does not.
Most metal oxides are hydroxylated at room tem-
perature and when water or its vapor has access to
the surface (5, 39). In fact, a water molecule adsorb-
ed on a bare metal site loses a proton, which jumps
to the neighboring surface oxide ion, leaving a hy-
droxyl (OH) on the metal ion (Fig. 14). These reac-
tions lead to two types of hydroxyl groups. In the
case of titanium dioxide, one is bound to one ti-
tanium-ion site (terminal OH), and the other to two
such sites (bridging OH), and these would be ex-
pected to exhibit quite different types of chemical
behavior. The bridging groups must be strongly po-
larized by the cations and therefore be acidic in
character, whereas the terminal OH group can be
predominantly basic and exchangeable with other
anions. This surface has an amphoteric nature: it has
the ability to bind with both acids and bases. The
acid groups react, for example, with amines (such as
ammonia and methylamine), and basic OH groups
r-r
H ionic chemical bonds. The necessary proof that such
H Oxygen ion H H H
Fig. 14. Surface of a metal oxide. Top. Naked surface of
oxide. Middle. In the presence of water, the surface metal
ions bind water molecules. Bottom. Dissociation and
chemisorption of the water molecules leads to an ap-
parent monolayer of OH groups, a “hydroxylatedsurface.
Source: Schindler (47).
16
exchange with phosphates. Further, alcohols react
fairly easily with the acidic OH groups to form esters.
The amphoteric or zwitterionic nature of the oxide
surface can be weighed by counting the effective
positive and negative charges at all surface sites, and
this can be measured by potentiometric titration. A
characteristic value for which the positive and nega-
tive charges at the surface cancel each other is called
the zero point of charge. For TiO, in the two struc-
ture variants of rutile and anatase zero point of
charge =pH 6, that is, near to neutrality (9, 40). For
other oxides of interest, A1203 and ZrO,, zero point
of charge =pH 9, and for Si02 zero point of charge
=pH 2 (39). At physiological pH values, the surface
of titanium oxide has no charge, whereas aluminum
oxide and zirconium oxide have negative and quartz
has positive charges. Zeta potentials, connected to
the zero point of charge, have also been measured
for natural and synthetic apatites, giving a pH of 6-
7 (50), similar to that of titanium oxide.
Schindler et al. (14, 47, 48, 63) have studied the
adsorption of amino acids and some metal ions on
crystalline titanium oxide and give a complete pic-
ture of how the surface hydroxyls exchange charges,
that is, their protons, with the dissolved ligands.
These exchanges are controlled by the pH of the sol-
vent, that is, the environment. Strong interactions
are involved. In fact, the energy calculated from re-
action constants derived from adsorption coverage
numbers (63) for amino acids amounts to 20-50
kJ/mole, and the energy necessary for thermal de-
sorption of glycine on platinum indicates binding
energy values of roughly 100 kJ/mole (11). These
numbers are characteristic of real chemisorption
processes involving the formation of covalent or
bonds exist comes from photoelectron diffraction
experiments with adsorbed glycine on single-crystal
rutile, which show the correct distances and angles
among carbon atoms of the amino acid (41).
The spontaneously formed thin surface oxide film
on titanium metal is apparently in an amorphous or
glassy state (35). But photoelectron spectroscopy in-
dicates that the stoichiometry of the crystalline oxide
is preserved and that the amorphous oxide film is
also hydroxylated at its surface (34). Adsorption and
desorption experiments with the oxidized metal by
Gold et al. (15, 16) showed a similar amphoteric re-
action, as displayed by crystalline oxides (5, 14, 63).
In a first series of experiments (Fig. 15), the adsorp-
tion of cysteine in a salt solution of variable pH was
monitored by X-ray excited photoelectron spec-
troscopy. In a second series of experiments (Fig. 16),

d in soft tissue is of the order of mm, and the size of
0 I
I
0 4 7 10 pH
Fig. 15. Cysteine adsorption on titanium vs pH as deter-
mined by photoelectron spectroscopy. Proton exchange
reactions on the amino acid occur at pH=2 and = l l .
Source: Gold et al. (15).
- oo l
P I
.-
-0.4 0.0 E-E (H*/Oz),V
Fig. 16. Desorption of soft tissue residues on titanium
after exposure to solutions of variable pH (top) and of
variable redox potential (bottom). The thickness of the or-
ganic films before the experiments was 6.3-8.7 nm. Posi-
tive potential differences correspond to oxidizing electro-
lytes. Source: Gold et al. (16).
the adherent tissue on retrieved titanium implants
was examined by controlled desorption treatments
in solutions of variable pH and of variable oxidation
strength (redox potential); again, the organic matter
at the surface was monitored by photoelectron spec-
troscopy. Adsorption and desorption show a type of
mirror response, as expected (compare Fig. 15 with
Fig. 16). The proton exchanges on carboxyl and
amino groups of the amino acids favor binding in
the first experiments, but the opposite, that is, a re-
lease of proteinaceous residues in the second series
of experiments. The results further indicate a strong
influence of the redox reaction on desorption; strong
oxidizers such as potassium permanganate, hydro-
gen peroxide and chloric acid can remove adherent
Titanium - the material of choice?
organic matter, probably by destroying a primary
structure.
The strong adhesion between bone and tissue is
quite a puzzle. The structure of a tissue and interac-
tion in cohesion occur at rather different scales. In
fact, the space between bone trabeculae or vessels
cells is of the order of pm, whereas the interaction
14
distance of chemical forces, the Debye length, is only
in the nm range. One wonders how the chemistry
at the substrate relatively remote from a cell surface
“protrudes” through to influence interaction that re-
sults in binding.
Organic compounds comprise various groups of
atoms that account for the compounds’ character-
istic reactions (3).These groups, about 15 in number,
are called functional groups. Among them, the rela-
tively simple chemical groups such as hydroxyl (OH),
carbonyl (CO), carboxyl (COOH), amine (NH,) and
sulfonate (S03H) can change the surface properties
of organic matter, including rendering these surfaces
hydrophobic or hydrophilic, and they can modulate
cell adhesion on polymers and on metals (10,27, 57).
The ground substance identified in the near con-
t tact zone of bone toward titanium, zirconium, ni-
obium, tantalum metals (2,23,30)has the properties
Ti O2 f + - f
I .o
+- I 2- I
Arg .R I ;f+ I ?+ I 20 I-
OOJ
OxidexG [ q I
Oxidex D 1 1
OxidexR 7 1
1 I I
PH 0 7 14
Fig. 17. Affinity for surface complex formation between
titanium oxide and the RGD series of amino acids (argi-
nine-glycine-aspartic acid). Bar 1. Surface charge of the
oxide. Bars 2-4. Charge of glycine, aspartic acid, arginine.
Bars 5-7. Binding, as represented by folding the surface
charges of the oxide with the charges on the binding sites
of the amino acid, for the whole molecule and for the side
chain only (cross-hatched). No charged aqueous titanium
hydroxide species do exist for pH between 2.5 and 11.2.
The signature of charges for the carboxyllamino and for
the side group of the amino acid is shown (+ positive,
- negative, 0 uncharged). The dissociation constants are
from Lehninger (28).
17
Steinemann
Ti02 f + - f 1 the carboxyl group can only bind with the basic site
Ca (11) Caz+
OxidexCa
OxidexPh 1 1
I I
I
PH 0 7 14
Fig. 18. Affinity for surface complex formation between ti-
tanium oxide and inorganic calcium and phosphate. Bar 1.
Surface charge of the oxide. Bars 2,3. Charge of dissolved
Ca(I1) and P (V) species. Bars 4,5. Binding as represented
by folding the surface charges on the oxide with the charges
of the chemisorbed ligand. No charged aqueous titanium
hydroxide species do exist for pH between 2.5 and 11.2.The
hydrolysis data are from Pourbaix et al. (43).
of a general “glue” and certainly comprises adhesion
proteins having the ability to promote cell adhesion
and to interact with matrix molecules and with a for-
eign material. A simple electrostatic model of the in-
teraction of an adhesion protein with an oxide sur-
face having receptor sites will now be given.
Fibronectin has emerged as a prototype adhesion
protein, and the identification of the tripeptide se-
quence arginine-glycine-aspartic acid (RGD) as the
focal domain where cells attach to the surface of the
large molecule was a major breakthrough in molecu-
lar biology (42, 46). The charge structure of the three
amino acids and their apparent dissociation con-
stants, that is, the pH values at which protonation
and deprotonation of the functional groups occur,
are shown in Fig. 17. If the organic molecule adheres
to the surface, its charges will interact with the am-
photeric oxide in a strictly local manner. A proton
is exchanged and electrostatic energy is gained. The
mechanism is selective for the functional group of
the amino acid and for the surface site of the oxide;
Table 4. Mechanical data for a dedicated metal
Material Yield strength
316L stainless steel, cold-worked 730 MPa
Commercially pure titanium, grade 2 330 MPa
Commercially pure titanium grade 4, cold-worked 690 MPa
Titanium alloys ( T a V Ti&Nb) 920 MPa
Cortical bone
!8
(terminal OH) and the amino group can only bind
with the acidic site (bridging OH), whereas the side
chain functional groups will exchange protons with
one or the other surface site matching in character.
The latter case corresponds to the molecular state
with the intact peptide links. This great selectivity of
interactions is the consequence of the zwitterionic
property of both reactants.
Experiments indicate that titanium oxide has four
or five reactive groups of acidic and basic character
per nm2 of surface (5). On the other hand, the vol-
ume of an amino acid molecule in the Arg-Gly-Asp
tripeptide is 0.1 to 0.2 nm3; thus, if these amino acids
are spread on a surface, about 4 molecules will cover
an area of 1 nm2. This number of molecules matches
well with the number of available bonds on the inor-
ganic substrate.
It is known from photoelectron spectroscopy that
calcium and phosphate ions chemisorb on the ox-
ide-covered titanium (19). A binding mechanism can
also be modeled by electrostatic interaction (Fig. 18).
It is not calcium phosphate that precipitates on the
metallic substrate; the 2-valent Ca ion binds to oxy-
gen after deprotonation, and the phosphate makes a
bidentate link to surface atoms. As in the case of the
organic ligand, these selective interactions are the
consequence of the zwitterionic behavior of the
oxide.
The simple electrostatic force model proved to be
a versatile tool in understanding the true mechanism
of osseointegration. It turns out that the native oxide
on titanium is a receptor of short- and perhaps also
long-range interactions for adhesion-promoting fac-
tors of living tissue.
Conclusion - the dedicated metal
For modern metals, the surgeon expects full tissue
compatibility. Unalloyed titanium is the reference.
Yield strength to Notched tensile strength
elastic modulus to (plain) tensile strength
0.38% 1.7
0.32% 1.8
0.66% 1.6
0.84% 1.4
0.67%

But that metal has limited mechanical strength. High
mechanical properties are needed for structural ef-
ficiency in surgical and dental implants. Their vol-
ume is in fact restricted by anatomic realities, which
require good yield and fatigue strength of the metal.
On the other hand, an implant “bridges” the forces
in bone: it may reduce the normal physiological level
of forces. This should give advantage to a “less-rigid’
bone plate or hip prostheses so as to retain a func-
tional load on bone. Frequently this suggestion is as-
sociated with a low elastic modulus, comparable to
bone. The conjecture is misplaced; the implant must
“guide, transport and distribute” forces, and to do
this it must be stiff. The useful comparison of prop-
erties refers to functional aspects (Table 4). The yield
strength has to do with load capacity and possible
distortion failure of the implant and associated ele-
ments. A second quantity is the elastic modulus, re-
lated to the stiffness of the implant. The ratio of
these two properties, a dimensionless quantity, is the
permissible strain, which has to do with deformation
capacity of a mechanical construct. It equals 0.67%
for human cortical bone. Differences between ma-
terials are substantial. High yield stress and permiss-
ible elastic strain do characterize the “forgiving
metal” in the clinic; in fact, implants should have
spare strength to overcome an unfavorable anatomic
situation and lack of cooperation by the patient. The
penalties associated with implant failure are always
great. Another entry in the table has to do with the
safety of the implant. The notch sensitivity is import-
ant for design; this parameter must exceed 1.2, to
avoid cracks in the shape variations of common im-
plants. It is found that the properties of titanium
metals are favorable for making surgical implants in-
trinsically safe and damage tolerant.
The metal titanium must not be a foreign body in
living tissue, at least regarding a chemical and
physiological “insult”. For integration, it has unique
properties among all metals in the periodic table.
The question at the outset of this work can be
answered: yes - titanium is the material of choice!
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