Note: Descriptions are shown in the official language in which they were submitted.
2111595 -
~'VO 95!17217 PCT1SE94101225
1
Metallic implant and process for treating a metallic
implant
Technical field of the invention.
The present application relates to biocompatible metallic
bone implants, preferably made of titanium or an alloy
thereof, and to a method for treating metallic implants
to enhance their biocompatibility.
Background to the invention.
A commonly used method for implanting metallic implants
into bone tissue is a two stage procedure involving in a
first operation surgically placing the implant into the
bone tissue, where it is then allowed to rest unloaded
and,immobile for a healing period of three months or more
in order to allow the bone tissue to grow onto the
implant surface so as to permit the implant to be well
attached to the bone tissue, the cut in the soft tissue
covering the implant site being allowed to heal over the
implant, and in a second operation opening the soft
tissue covering the implant and attaching the functional
parts to the implant. This two-stage procedure is often
used in connection with dental implants, one reason being
that it minimizes the risk of infection of the implant
site from the oral cavity. In some orthopaedic
applications the above two-stage surgery may not be
necessary since most orthopaedic implants do not
penetrate the soft tissue. A prolonged healing period is
however still considered necessary since any movements
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of the implant in the weeks and months following s~srgery
may endanger the final attachment of the implant to the
bone tissue.
The above procedure is for instance described in
Branemark et al: "Osseointegrated Implants in the
Treatment of the Edentulous Jaw, Experience from a 10-
year period", Almquist & Wiksell International, Stockholm
- Sweden.
However, the fact that the implant may not be loaded
means that the functional parts of the implant may not be
attached to the implant and/or used during the healing
period of three months or more. In view of the discomfort
associated with this, it is desirable to minimize t:he
time period necessary for the above-mentioned first stage
and in some cases, for instance in certain orthopaedic
applications, substantially dispense with said first.
stage and perform the entire implantation procedure in a
single operation.
The present invention provides an
implant with improved rate of bone tissue attachment: such
that the post-surgery healing period described above. may
be reduced.
Some of the metals or alloys used for bone implants are
capable of forming a strong bond with the bone tissue, a
bond which may be as strong as the bone tissue per se,
sometimes even stronger. The most notable example of this
kind of metallic implant material is titanium and alloys
of titanium whose properties in this respect have been
known since about 1950. This bond between the metal and
~fO 95117217 217 7 5 9 5 pCTISE94101225
3
bone tissue has been termed "osseointegration" by
Br~nemark et al.
Although this bond between titanium and bone tissue is
comparatively strong, in some applications it is
desirable to enhance the bond between metal and bone
tissue.
There are to date several methods for treating implants
made of titanium in order to obtain a better attachment
of the implant. Some of these involve altering the
topography of the implant, for example by creating
relatively large irregularities on the implant surface in
order to obtain a better mechanical retention and to
increase the area of attachment, by for example plasma
spraying, blasting or etching. Although the retention
may be improved, the time necessary for the
osseointegration process may be longer since the bone
tissue would have to grow into the irregularities in the
surface.
Other methods involve altering of the chemical properties
of the implant surface. For example one such method
involves the application of a layer of ceramic material
2$ such as hydroxyapatite to the implant surface, inter alia
in order to stimulate the regeneration of the bone
tissue. Ceramic coatings however may kze brittle and may
flake or break off from the implant surface, which may in
turn lead to the ultimate failure of the implant.
US Patent No. 4,330,891 could perhaps be said to combine
each of the above, in that the provision of an element
with a micro-pitted surface which micro-pits are within
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a certain diameter range, is said to effect improve=d
properties as regards acceptance of the carrier elEament,
and primarily improved durability of the healthy ingrowth
of the element due to its biological quality.
The invention also provides an
implant forming a stronger bond with the bone tissue.
Short description of the inventive concept.
It has been found that the desired metallic implant may
be obtained by treating a metallic surgical implant with
an aqueous solution of hydrofluoric acid.
Short description of the appended drawings
Fig 1 is a diagram illustrating the pushout force as well
as the fluorine and oxygen content of an implant surface
treated with 0.2$ HF as a function of the treatment t:me.
Fig 2 is a 5EM photograph of an implant surface treated
with 0.2$ HF for 30 seconds, in a magnification of 10 000
times,
Fig 3 is the implant surface in Fig 2, in 52 000 times
magnification,
Fig 4 is a SEM photograph of an implant, in 10 000 times
magnification, having been treated with 0.2~ HF fc~r 90
seconds,
Fig 5 is the surface of Fig 4 i:n 52 000 'times
magnification.
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Fig 6 is a SEM photograph of an untreated implant surface
in 52 000 times magnification.
5 Figs 7 - 9 are diagrams illustrating the effects of
different treatments by means of calcium precipitation
tests.
The invention
Accordingly, in a first aspect the present invention
provides a process for the treatment of a metallic
implant comprising treating the metallic implant with an
aqueous solution of-hydrofluoric acid, which solution is
of pH 1.6 to pH 3.
Alternatively stated in terms of concentration, the
present invention provides a process for the treatment of
a metallic implant comprising treating the metallic
implant with an aqueous solution of hydrofluoric acid of
concentration up to 3.0$.
Preferably the metallic implant is made of commercially
pure titanium or an alloy of titanium. The implants may
be standard, blasted or other.
Preferably, the concentration of hydrofluoric acid is
0.01$ to 3.0$ such as 0.1$ to 2.0 $. Most preferably the
concentration of hydrofluoric acid is about 0.2$ to about
2.0$ especially 0.2$ to 0.5$ and most preferably about
0.2$.
217 7 5 9 5 p~~gE9.11012~~
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The treatment of the present invention may be carried out
for any suitable length of time. Preferably the
treatment is carried out for at least 10 seconds such as
seconds to 6 hours, for example 10 seconds to 2
5 minutes such as lOs to SOs, or 30s, 60s, or 2 minutes.
The treatment may be carried aut in any suitable manner,
for example by immersing the implant in the treatment
solution for a period of time, and with or without
10 agitation. Varying temperatures may be employed:
parameters such as temperature and time may be selected
according to the concentration of the treatment solution
and the other process parameters. The treatment is
conveniently carried out at standard pressure, but
elevated pressures may be used where desired.
Preferably, treatment is carried out at around standard
temperature and pressure.
In a preferred embodiment the present invention provides
a process for the treatment of a metallic implant
comprising treating the metallic implant with a 0.1-2.0~
aqueous solution of hydrofluoric acid at room temperature
for a period of up to 3 minutes.
The treatment solution of the present invention may be
simply prepared, by diluting concentrated HF with
distilled water.
Prior to treatment, the implant material may be cleaned
by standard techniques such as are well known in the art.
After treatment, the implant material may be washed in
distilled water and kept under sterile conditions.
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Implants treated in accordance with the present invention
show a strong contact with bone, as demonstrated in
' "push-out" tests described herein, and a high degree of
bone contact in the spongiosa cancellous region. New bone
will form on the implant surface in the cancellous region
and will more or less cover the implant in this area.
Such a response is not observed in untreated control
groups. The degree of bone contact indicates bone growth
in the spongiosa cancellous region.
The process specified therefore beneficially effects the
surface of the implant so as to improve the
biocompatibility (specifically the rate of bone tissue
attachment and strength or bonding) of the implant.
While we do not wish to be limited to the expression of
theories herein, the improved biocompatibility is thought
to be due, at least in part, to fluoride being retained
on the surface of the implant. As such, treatments other
than with hydrofluoric acid, which provide fluoride ions,
could be expected to have some effect on the
biocompatibility of metallic implants. Treatment with
sodium fluoride is known from our prior application WO
94/13334. In a second aspect this invention therefore
5 provides a process for treating a metallic implant
comprising treating the implant with an aqueous solution
containing fluoride ions in a concentration of up to 3$,
said aqueous solution being free of sodium and sodium
ions. The preferred treatment parameters correspond to
those preferred in the hydrofluoric acid treatment
described herein.
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S
Preferably na significant etching of the implant surface
occurs with the present tr-eatment. Most preferably,
thereis substantially no etching of the implant surface.
Implants treated by the process of the present invention
are also provided herein.- Therefore in a third-aspect
the present invention provides a metallic implant which
has been treated with an aqueous solution of hydrofluoric
acid according to the processes described herein.
As stated hereinabove, the beneficial effect of the
present invention is thought to be related to fluoride
being retained on the surface of the treated implant.
The treatment described is a surface treatment which
affects the surface properties of the implant although at
this stage it is not possible to define the surface
characteristics of the treated implant more than to say
that the desired characteristics are provided by the
present process.
In a fourth aspect therefore the present invention
provides a metallic implant having a surface equivalent
to the surface of an implant which has been treated with
an aqueous solution of hydrofluoric acid according to the
processes described herein.
Another way of describing the effect of the present
treatment is by means of the induction of calcium phosphate
precipitation.-This is an in vitro test described in
"Damen, Ten Cate, Ellingsen, Induction of Calcium
Precipitation by Titanium Dioxide, Journal of Dental
Research, October 1991". In this method an implant is
immersed in a saturated solution of calcium phosphate.
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Depending on the surface, precipitation of calcium onto the
implant occurs. The concentration of Ca++ is monitored and
the time delay (the induction time) until precipitation
occurs is measured. The rationale behind this test is the
assumption that there is a correlation between the affinity
of the implant surface towards the calcium ions and the
biocompatibility of the implant surface in bone tissue.
Implants treated in accordance with the present invention
show an affinity to calcium ions in this test. Accordingly,
in a fourth aspect the present invention provides an implant
treated with hydrofluoric acid in accordance with the
present invention, which implant precipitates calcium ions
from a saturated solution of calcium phosphate.
The invention also provides a metallic implant having been
treated with HF, which implant causes precipitation of
calcium ions onto the implant surface when immersed in a
solution formed by adding 7.5 mM KHZPOø and 50 mM HEPES, at
pH 7.2, to 1 mM CaCl2 and 50 mM HEPES, at pH 7.2, the
temperature of the solution during said immersion of the
implant being 37 degrees centigrade, and the implant being
immersed in said solution for 5 hours.
The following Examples illustrate the invention.
Examples
Example 1
Seven surgical implants, of commercially pure (c. p.)
titanium, 5 mm in length and generally conical in shape
having a diameter at one end of 3 mm and at the other end
2 mm, were prepared by machining using a "Maximat super 11"
(TM) turning lathe. Therefore the area of the conical sides
of the implant, i.e. the part of the implant to be located
in the bone, is 39 mm2.
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Each implant was cleaned according to a well-known cleaning
procedure involving the following steps:
1. Treatment with trichloroethylene with ultrasonic
treatment, for 15 minutes.
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2. Rinsing in absoute ethanol, for 10 seconds.
3. Three successive treatments with ethanol with ultrasonic
treatment, each for 10 minutes.
Each cleaned implant was sterile packaged in a Mediplast
5 (TM) sterile envelope, and autoclaved in a Citomat 162 (TM)
(LIC Company) autoclave, at 120 C for 30 minutes.
A HF bath was prepared simply by diluting concentrated HF
with distilled water, to give a 0.2~ solution. The pH of
10 the bath was 2.1.
Seven implants, prepared, cleaned, sterile packaged and
autoclaved exactly as described above, were removed from
their sterile packages, placed in the HF treatment bai:h and
left there for two minutes. Thereafter each was washE~d
three times in a bath of distilled water, for periods of 30
seconds each wash. After being allowed to dry at room
temperature, each implant was transferred to a Mediplast
(TM) sterile envelope to await surgical implantation.
Implant study
Chinchilla rabbits were used as test animals. The rabbits
were randomly distributed regarding sex, but all had a.
weight of 2.5 kg at the start of the study. Each animal
was sedated by injection using a combination of
TM
fluanozonium 1.0 mg/kg and fentanylium 0.02 mg/kg (Hypnorm,
Jannsen Pharmaceuticals, Belgium) and locally anesthetised
with xylocaine/adrenaline (AB Astray. Two cavities were
drilled in each rabbit's right ulna, using standardised
bores designed to provide cavities into which the conical
implants would exactly fit. Treated and untreated implants
were placed in the cavities of each rabbit, using titanium
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tweezers so as to avoid the influence of other metals, and
left for sixty days.
At the end of sixty days the rabbits were sacrificed by
injection with pentobarbitol natrium, and the ulna's
removed and placed in sterile physiological saline to await
a "push-out" test the same day.
An Instron model 1121 tensile testing machine (Instron,
U.K.) inter alia comprising a support jig and a ram
adjusted for a load range of 0 - 200 N, was employed to
measure the force needed to separate each implant from
bone. Milling tracks, to fit the support jig, were made in
the specimen to be tested, in the bone surrounding the
larger end of the implant, and the specimen was placed on
the support jig. The ram was lowered at a speed of 1
mm/min., and the force required to separate the implant
from the bone was recorded.
This recorded force gives a direct assessment of the _
strength of connection of the implant and bone, the higher
the required force the stronger the connection.
The results are recorded in Table I.
Table I
Recorded force (N)
Untreated implants Treated implants
1 1s.1 1 84.1
2 59.2 2 96.0
3 44.7 3 64.2
4 39.2 4 62.7
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WO 95117217 PCfISE94101225
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59.5 5 64.9
6 6.0 6 89.5
7 8.5 7 89.5
mean 33.6 mean 78.7
5
The much greater strength of bone connection with implants
treated in accordance with the present invention is
apparant from the above.
Histological examination demonstrated that the implants
according to Example 1 were surrounded even in the ulna's
spongiosa by a.thick layer of newly formed bone which was
in close contact with the implants. In contrast the
untreated implants, i.e. those according to the comparative
Examples, were only partly covered, by a thin bone layer,
in the spongiosal area.
Example 2.
Reference implants were made of titanium grade 3, and were
made by turning at an average speed of about 7 meters per
minute. No cutting fluid was used. The cutting tool was
made of high speed steel.
The reference implant surface was cleaned by a standard
cleaning procedure involving the following steps:
1. Treatment with trichloroethylene with ultrasonic ,
treatment for 15 minutes.
2. Rinsing in absolute ethanol for 10 seconds.
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3. Three successive treatments with ethanol with ultrasonic
treatment, each for 10 minutes. Each cleaned implant should
then be sterile packaged in a Mediplast (TM) sterile
' envelope and autoclaved in a Citomat 162 (TNt) (LIC Company)
autoclave at 120 ° C for 30 minutes.
The result of an experiment in which the force necessary
for removing (pushing out) substantially conical,
unthreaded implants treated in 0.28 aqueous solution of -
hydrofluoric acid at room temperature for different time
periods is illustrated in the diagram in Fig I. The
implants had been manufactured to have a diameter of 2 mm
at one end, 3 mm at the other end and an overall length of
5 mm and were made from titanium grade 3 and cleaned and
sterilized in accordance with the above procedures for
treating the reference implant surface. The treatment times
were 10 seconds, 30 seconds, 60 seconds, 90 seconds, 120
seconds and 180 seconds. Pushout tests were made and the
pushout forces were marked in the diagram for each
treatment time except 90 and 180 seconds. The values for an
untreated control specimen are also given in the diagram as
having a treatment time of 0 seconds.
Each value for the pushout test results are a mean of the
values for four implants implanted in the tibia of a
respective rabbit and left to heal into the bone tissue for
two months.
The reference implants were also treated in the way
described above. The content of flourine and of oxygen as
measured in the surface of the treated implants are marked
in the diagram for each treatment time.
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An Instron model 1121 tensile testing machine (Instron,
U.K.) set to the same parameters as the machine in Example
1 was used and the contents of fluorine and oxygen were
measured by means of an Electron microprobe (CAMECA
camebax) at SINTEF/SI in Oslo. The results as measured with
this equipment were
F$ O$
0 sec O.OI 5.1
sec O.IS- 5.5
10 30 sec O.lI 5.8
60 sec 0.17 5.7
90 sec 0.2 - 9.4
120 sec 0.23 8.4
180 sec O.lfi I1.0
The diagram in Fig I illustrates higher values for the
pushout tests resulting from treatment times varying
between 10 and 50 seconds with a peak value at 30 seconds.
The values for the remaining treatment times and the
untreated control specimens are lower although the treated
implants generally have higher values than the untreated
ones. The values for the oxygen (5.5 to 5.8$) and fluorine
content (0.11 to about O.I5$) of the surface of the
implants for the treatment times between 10 and 50 seconds
are lower than the corresponding values for the other
treatment times.
The pushout tests were made after a time period which was
as short as two months. The rapid increase of the strength
of the bond results in that the healing period necessary
for reaching a given strength of the bone is shortened. The
use of the treatment according to the invention thus
facilitates the use of one-stage surgical procedures,
2177595
~O 95!17217 PCT/SE94/01225
particularly in orthopaedics, since the time the patient
must remain inactive is shortened.
Fig 2 illustrates how the implant surface seems to be
5 largely unaffected by the treatment involving a HF-
concentration of 0.2~ and a treatment time of 30 sec, no
effect being discernible in a magnification of 10 000 times
(the original tooling marks not being affected at all).
This photograph should be compared with the photograph in
10 Fig 4, in 10 000 times magnification, showing a surface
which has been treated longer (90 seconds) in 0.2$ HF and
in which the marked change in the surface by the treatment
in question is illustrated.
15 Fig 3, which shows the surface in Fig 2 in a magnification
of 52 000 times, should be compared with Fig 6, which shows
an untreated surface in a magnification of 52 000 times,
and with Fig 5, which shows the surface of Fig 4 in a
magnification of 52 000 times. As is evident, the surface
treated with 0.2~ solution is only slightly affected in
regard of the morphology, the tooling marks still being
discernible, whereas the surface treated for a longer
period of time is distinctly altered and covered with a
porous layer. It is believed that the best embodiment of
the invention involves surfaces whose morphology only are
slightly affected by the treatment although other treated
surfaces also may have the effect expected from the
invention.
In the above push out test implants manufactured and
treated in the same way as the reference implant surface -
were used. It should however be noted that the metallic
implants to be used in the clinical situation and/or in
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16
research of course can be_manufactured oi- any metal and
treated in any way within the scope of the claims provided
the implant surface is equivalent to the reference surface
in regard of the content of fluorine. -
S
Example 3.
Another way of describing the effect of the treatment is by
means of the induction of Calcium Phosphate Precipitation.
This is an in vitro test described in "Damen, Ten Cate,
Ellingsen, Induction of Calcium-Precipitation by Titanium
Dioxide, Journal of Dental Research, October~.991". In this
method an implant is immersed in a saturated solution of
calcium phosphate. Depending on the surface, precipitation
of calcium onto the implant occurs. The concentration of
Ca'" is monitored and the time delay (the induction time)
until precipitation occurs is measured.- The rationale
behind this test is the assumption that there is a
correlation between the affinity of the implant surface
towards the calcium ions and the biocompatibility of the
implant surface in bone tissue. The results of the tests
are illustrated in the appended diagrams, Figs 7 - 10.
The concentration of Ca'~ is given on the Y-axis t2.00e-1
means 2.OOxIO-' etc). The test time is given on the X-axis
in minutes.
The implants in the test had been treated as follows:
Concentration, HF Treatment time
0.05 $ 180 sec
0.15 $ 180 sec
0.2 $ 30, 60, I20 sec
0.5 $ 60 sec
2.0 $ 60 sec -.
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Untreated control implants were also tested.
The test solution was a solution comprising 7.5 mM KH2pp~
and 50 mM HEPES (pH 7,2) added to a solution comprising 1
mM CaClz and 50 mM HEPES (pH 7.2). HEPES is a standard
buffering solution. The temperature of the solution during
the tests was 37 degrees centigrade.
The concentration of the calcium in the solution after
immersion of the respective implant is measured at a
calcium selective electrode during a time period of 5
hours. As indicated in the diagrams, there is no
precipitation,in solutions in which the control implants
and implants treated with 0.15$ HF have been immersed
during the 5 hour immersion time, see fig 7.
For certain of the implants treated with 0.2 $ HF there
was precipitation in the test solution as early as 4
hours after the immersion. These implants had been
treated with HF for 60 and 120 sec. Implants having been
treated with 0.2$ HF for 30 sec caused precipitation, but
not until about 5 hours immersion time, see fig 8.
Implants treated with 0.5 $ HF for 60 sec caused
precipitation at about 4 hour immersion time, whereas the
implants treated with 2.0$ HF for 60 sec caused
precipitation both before and after 5 hour immersion
time.
According to these data there would seem to be ranges of
HF concentrations and treatment times giving the desired
result, with a central range around 0.2 - 0.5 $ giving
better results. These data to some extent complement the
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data in the previous examples, and it consequently is
believed that the implants according to the invention
also can be defined by means of this test, which is a
relatively simple one.
Accordingly, an implant according to the invention can be
defined as an implant having been treated with HF and
which causes precipitation of calcium ions onto the
implant surface from a solution comprising 7.5 mM KHZP04
and 50 mM HEPES (pH 7.2) added to a solution comprising 1
mM CaClz -and 50 mM HEPES (pH 7.2) , the temperature of the
solution during the tests being 37 degrees centigrade.
Example 4
Screwshaped implants having been implanted into bone
tissue in the ulna of rabbits for 2 months were removed
by torque and histological studies of the implant surface
were made.
For a standard implant treated in 0.2 $ HF for 120 sec,
the bone contact was 63.3$, whereas the bone contact for
a standard, untreated control implant was only 42.4 ~.
For an implant blasted with particles of titanium dioxide
and treated in 0.2 ~ HF for 90 sec the bone contact was
53.5$ whereas the bone contact for a similarly blasted,
but untreated implant was 37.38.
The above values are mean values for 4 - 8 implants.
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The bone contact was more pronounced in the spongiosa for
the treated implants.
The treated implants consequently show a pronounced
improvement in comparison with the untreated implants.
