Note: Descriptions are shown in the official language in which they were submitted.
WO91/12032 PCT/EP91/00201
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BIOACTIVE VITREOUS COMPOSITION FOR BONE IMPLANIS.
FIL,AI~NrS MADE THEREFROM AND M~D
The present invention relates to so-called bio-
active vitreous compositions or glasses for bone
implantation according to the preamble of Claim 1.
Glasses of this kind have been the subject of
investigations since the '70s and are described by Larry
L. Hench in an article entitled 'Ceramic Implants for
Humans" in ADVANCED CERAMIC MATERIALS, ~ol. 1, No. 4,
1986. pp. 306-310 and 324.
Examples of such known glzsses may be found in the
following patent documents: FR-A-2 243 915; US A-4 159
358: US-A-4 171 544; US-A-4 234 972; GB-A-2 080 281;
DE-A-3 248 649; EP-A-0 145 210; EP-A-0 154 513.
As well as being biocompatible, these known
glasses are also biodegradable by means of an inter-
action mechanism which is explained below.
When a glass of the type in question is pu intocontact with the in~erstitial liauids of a human or
animal body, it creates a gel having an ionic composi-
tion similar to that of the ossification front observed
in the natural bone-remodelling process. The gel thus
formed is recognized by the osteoblasts as a substrate
for the deposition of an osteoid matrix. The inter-
action between the collagen fibrils, the mucopoly-
saccharides of the matrix and the gel is characterised
by the precipitation of hydroxylapa~ite crystals which
enable a stable bond to be formed be~ween the giass and
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WO91~12032 PCT/EP91/0~201
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the newly-added bone matrix.
In many cases, it is desirable for the glass
implant to degrade until it disappears completely as the
bone gradually reforms and/or is remodelled to leave
room for the latter.
From experiments carried out. it has been found
that, with the known bioactive glasses specified above.
this does not take place completely. These glasses
cannot be reduced to filaments by being drawn through a
die startlng from a bath of fused glass. that is, if one
tries to draw them. they become ceramic at the output of
the die and give rise to a fragile product whose
properties are quite different from those required for a
biodegradable glass filament or fibre.
For this reason, the only way to use these known
glasses for prosthetic implants is to grind them to
produce a powder. In most applications the bone defects
are packed with this powder which is made into a paste
with a binder. The particles of the powder are far from
uniform in size. however, and are irregular in shape
with dimensions ranging from a few microns to several
hundreds of microns. Because of the non-uniform sizes of
the particles, most of the smallest particles are
reabsorbed completely during the bone reconstitution
process, whilst the largest particles are not reabsorbed
or degraded and cause undesirable vitreous inclusions in
the reconstituted bone. constituting corresponding
discontinuities. The random arrangement of the
particles of different sizes encourages the bone fibres
to grow in a similarly random arrangement when for the
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WO91/12032 PCT/EP91/00201
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purposes of the mechanical strength of the bone, it is
desirable for the fibres to be reconstituted in a
regular arrangement.
In certain applications, the use of a powder in a
prosthetic implant is even dangerous since, on the one
hand, the blood can form a kind of mixture with the
powder which constitutes a barrier against the growth of
bone and, on the other hand, the powder particles may be
entrained in the bloodstream and form thromboses.
The problem behind the present invention, in the
first place, is that of providing a glass which can be
used to produce bone implants without the aforementioned
disadvantages.
According to the present invention, this problem
lS is resolved by means of a vitreous composition substan
tially as defined in the characterising part of Claim l.
The invention also relates to filaments or fibres
obtained by the drawing of said vitreous composition, to
products obtained from said filaments. and to a method
for the production of said filaments.
It has been found experimentally that both K~0 and
Al203 have the property of preventing a vitreous
composition from ceramising, by keeping it in an
amorphous condition when it is drawn into a filament.
The amorphous condition then persists during the life of
the filament.
The presence of K2O in a bioactive vitreous
composition is beneficial as regards bioactivity. In
this regard K20 also constitutes an advantageous
substitute for Na20 in implants destined to patients
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WO9l/1~032 PCT/EPg1/~0201
2~752~1 4 _
suffering, or liable to suffer from hypertension.
However, increasing amounts of K20 have the
property of rendering a vitreous composition more and
more soluble in water. This means that a vitreous
composition containing a too high percentage of K20 will
soften or even be converted to a gel if it is kept under
normal ambient conditions, due to hydrolysis of K20 by
interaction with atmospheric humidity. Thus, filaments
of vitreous compositions having a too high percentage of
K20 could be stored and handled, e.g. woven, only in a
perfectly dry atmosphere, but this would be quite
impractical from an industrial point of view.
The undesirable effects of K20 can be successfully
mitigated by the addition of Al203 to the vitreous
composition. However, increasing amounts of A1203 have
the drawback of lessening the reactivity of the
composition, i.e. its affinity to bone tissues.
It has been found that a vitreous composition
including proportions of K20 and Al203 within the
claimed ranges performs well under both aspects of fully
preventing ceramising of the drawn filaments and fully
preserving their affinity to the bone tissues.
FR-A-2 243 915 GB-A-2 080 281, DE-A-3 248 649 and
EP-A-0 145 210 all disclose bioactive vitreous composi-
tions containing K20 in indeterminate percentages from
zero (from 0.4% in FR-A-2 243 915) to 20%. Such
documents do not teach the use of K20 as an anti-
ceramising agent. GB-A-2 080 281 and US-A 4 708 652
both disclose bioactive vitreous compositions containing
indeterminate amounts from zero to 8% of AL203+ZrO2+
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WO91/12032 PCT/EP91/00201
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Nb2O5. The percentage of A12O3 is not specified. On the
one hand, A12O3 ZrO2 and Nb2O5 are described in such
documents as reaction controllers in respect of bio-
activity. On the other hand, A12O3, ZrO2 and Nb205 are
known to be inhibitors in respect of bioactivity.
Further, the compositions disclosed by GB-A-2 080 281
and US-A-4 708 652, and containing A12O3 in indetermin-
ate amounts, are mainly of the ceramic type. In other
words, such documents do not teach the use of A12O3 as
an anti-ceramising agent
According to the invention it is possible to
produce filaments or fibres even with diameters of the
order of 10-50 microns. From such filaments or fibres
one may obtain products, such as bundles of fibres,
fabrics. particularly gauzes and nets, felts. and
"cotton-wools" as well as particulate products made of
shredded filaments and powders made by grinding of the
filaments.
~ bundle of filaments or fibres of a vitreous
composition as claimed can be used as an implant by
being inserted in a bone defect with the filaments
oriented in the direction in which it is envisaged that
the bone fibres will grow. thus encouraging their
regular development to the benefit of the mechanical
strength of the reformed bone.
The small diameters of the filaments or fibres
ensure that they are completely degraded, that is, that
they are completely replaced by the bone tissue as it is
gradually reformed and remodelled.
The fabrics, particularly the nets and gauzes, as
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well as the felts and "cotton-wools" produced from the
glass filaments of the invention behave in the same way
as the bundles of fibres as regards degradation but
enable the growth of bone in several preferred direc-
tions to be planned. Thus, a net or a gauze canencourage the bone tissue to form a network similar to
that of the original bone tissue.
Nets and gauzes can be used in the form of
bandages for binding the broken region of a bone.
The filaments of the vitreous composition accord-
ing to the invention can be bro~en into pieces or small
cylinders whose lengths are of the same order of
magnitude as their diameters. For example, cylinders
can be produced with diameters and lengths of the order
of twenty microns.
A particulate product thus obtained, possibly made
into a paste with a binder, can be implanted as it is by
the same technique as that by which the prior-art ground
glasses were implanted but with the difference that the
bone defect is filled with uniformly sized particles,
ensuring the degradation of the implant and its complete
replacement by bone tissue over a period of time.
Naturally, this application is justified only if there
is no danger of the ~ormation of clots with the blood
and/or of the entrainment of the powder particles by the
blood.
Preferably, however, a particulate material of the
vitreous composition according to the invention is
inten~ed to be applied as an at least partial coating,
for example, by the "plasma spray" technique, to a
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WO91/12032 PCT/EP91/Q0201
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permanent prosthesis, for example of titanium, to
improve its anchorage to the surrounding bone by virtue
of the progressive, and finally complete, replacement of
the coating by bone tissue. In this application,
S uniform and homogenous coatings are produced because of
the uniform dimensions of the glass particles. This was
impossible with known biocompatible glass powders.
partly because of their non uniform particle size but
particularly because these known glasses became ceramic
if they were applied by spraying at the high tem-
peratures of the "plasma spray" process.
Glass filaments or fibres, as well as fabrics
produced from these fibres, are ~nown from the document
; FR-A-2 548 658 and include calcium phosphate as the main
lS constituent and not less than 80% by weight of CaO+P2O5,
possibly with the addition of an inorganic oxide
selected from alumina, silica, sodium oxide, iron oxide,
magnesium oxide, ~aolin and mixtures thereof.
Although they are wholly biocompatible and "recog-
nised" as hydroxylapatite by the osteoblasts, theseglass fibres are not biodegradable so that fabrics made
of these fibres remain incorporated permanently in the
reformed bone tissue.
The following are two currently preferred vitreous
compositions according to the invention.
Composition I
This composition is characterised essentially in
that it has the following constituents in percentages by
weight:
SiO2 50%; P2O5 6%; CaO 16%; Na2O 20%; K2O 5%; ~gO 1%;
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Compos sion l_
Lhis eom~os ~ or. ;a charac~-ria2d esse.~rlally
tha~ it i..cluces the _ollowi-.g cons~'tuen~s '-. percen-
5 tages by weigr.t:
SiO2 50%; P205 5~ CaO 1~%; Na20 15~/o: ~'{2 5~/; MgO i%;
2 3 ; 2 3
ToleYances of 7% in the ?er-en~age ~1 weignt of
eac-i ^onst1'uer.. are ?ermi~.e~ for both com?os tions.
B~rom a b~logicai ?oin~ o~ view, the behaviour of
both compositio~.s is the same.
~ he comDosltions are -educed ~o ~ilaments 'oy
melti-.~g them ~ a crucible ?rovided w~t~, a ~ie a~ ~he
bot~cm æ~d d-aw'n.g ~.e moitsn compos'~ on throu~n the
1~ die. 2re eraol~, to a~roid he inclusion of` mr,urit-es
into the 'oa~h and the f`ilamer.~s, the cr-~c~bl- s of`
substantially pure platinum.
Com?osit~'on ~ ^an be drawr. into f'ilaments very
easily but wi~hin a fair'y narrow temDerature r~nge of
between about ~00C and lOSC3C ~ l.. w~.ic'h t~e vitreous
mass is very Lluid. The or.ly oroblem, therefore, is
that the temcerature of t~e fusion bat~ must be
'.controlled very Drecisely.
In composition Il, the ~resence of B203 widens the
125 temperature range within ~hich the COmDosition can be
;drawn into filaments withou~ becoming ceramic to between
aoo3c and loso3c~ Within this temoerature range,
howeve~, the vitreous mass is yet more fluid than
comoosition'~' I so ~hat t~.e draw~'ng rat- must oe
controlled precisely.
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WO91tl2032 PCT/EP91/00201
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At least traces of calcium fluoride and/or calcium
fluorophosphate may be added to the compositions in
small proportions to catalyse certain biological proces-
ses. Compositions including these fluorides are
particularly suitable for making implants for dental
surgery.
Tests have been carried out in vivo on rats and
rabbits, using compositions I and II both in fibre and
powder form, according to an experimental protocol which
provided for the insertion of the fibres and the powders
in the marrow cavity of the tibia of each animal.
After periods varying from lO days to 7 months,
the portions of bone concerned in the test were removed
from animals which had been killed and were then
prepared for ex~mination by optical microscope or
electron scanning microscope and for X-ray micro-
analysis.
In the inspections after lO days, optical micro-
scopic examination of the specimens obtained revealed
that they had cells with basophilous cytoplasm which
adhered to the surfaces of the fibres and the particles
and were starting to produce a bony matrix. Inter alia,
this confirmed an absence of rejection.
In subsequent inspections at 20 and 30 days, both
the fibres and the particulate material appeared to be
completely surrounded by a bony matrix without the
interposition of a connective membrane or capsule
between the vitreous composition and the biological
substrate. Moreover, some cells similar in appearance
to primary bone cells appeared to be incorporated in the
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WO91/12032 PCT~EP91/00201
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matrix near the vitreous composition. This confirmed
the absence of a barrier which could arrest the growth
of bone between the vitreous composition and the
biological substrate.
At 30 days, the cortical bone defect was complete-
ly filled with newly-formed bone. The fibres of the
vitreous composition incorporated in the bony matrix
retained their individuality and appeared circular in
histological sections taken in planes perpendicular to
the major axes of the fibres and rectangular in
histological sections taken in planes parallel to the
major axes of the fibres.
Still at 30 days, the particles of the vitreous
composition formed aggregations with irregular profiles
which, nevertheless, were incorporated in the bony
matrix without the interposition of connective mem-
branes.
In the sections of the tibiae examined at
subsequent time intervals (from 2 to 7 months) no
changes were observed in the vitreous compositions as
long as they remained incorporated in the bony matrix.
As a result of the remodelling of the bone, the
inspections at 4, 5, 6 and 7 months showed resorption
lacunae which extended to the bone surrounding the
implanted material and exposed its surface. These
lacunae constituted a similar number of regions which,
as is desirable, were susceptible to vascularisation.
The inspections made at the same time intervals showed
that the aggregations of particles of the vitreous
composition and the fibres released from the bony matrix
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WO91/12032 PCT/EP91/00201
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appeared irregular and broken and were absorbed progres-
sively by giant multinucleate cells, that is, they were
progressively removed from the matrix.
The vitreous material which had not come into
contact with the osteogenic bone cells, for example, the
material which had migrated out of the periosteum,
appeared to be surrounded by an inflammatory infiltrate
constituted mainly by neutrophilous polymorphonucleates
and giant multinucleate cells. The presence of the
inflammatory infiltrate was evidence of a favourable
intensification of the blood circulation.
As well as confirming the surface characteristics
of the vitreous compositions according to the invention,
the experiments carried out appear to have demonstrated
their osteoconductive properties, documented histo-
logically by fact that the material was incorporated in
the bony matrix without the interposition of connective
tissue, provided that a sufficient number of cells
differentiated towards osteogenic activity were present
a~ the site of the implant. The fibres and particles of
the vitreous composition inserted in the cortical bone
defect both showed this property. In the case of the
fibres, when these were bathed in blood, they formed a
three-dimensional networ~ or "felt" which defined empty
spaces between the fibres so that, as a whole, they
offered an extensive surface for the attachment of
osteogenic cells. The particles of the vitreous
composition of the invention, however, formed compact
aggregations upon contact with the blood and only the
outer surface was available for bonding. Thus, although
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the chemical surface characteristics of the two forms of
the composition, that is, the fibres and the particles.
are identical, their biological responses can vary
according to their physical properties such as their
shape and size. In general, in the experiments, the
fibres were ~ore easily manipulated than the particles
and were more evenly distribued in the bone defect.
In the experiments carried out, it was observed
that, once they were incorporated in the bony matrix,
the fibres or the aggregations of particles of the
vitreous compositions of the invention showed no further
changes in the inspections up to 7 months and did not
cause any cell reaction. This can be attributed to the
fact that the incorporated material was no longer in
contact with the interstitial liquids, or at any rate
that the interstitial circulation in the bone was not
sufficient to trigger a significant degradation process.
The presence of the siliceous residue in the bony
matrix did not appear to interfere with the bone
remodelling process so that, in the inSpections made at
4 months, resorption lacunae were already observed in
the region of the cortical defect which by that time was
completely repaired. The osteoclasts appear to cause
the resorption of the matrix but do not seem to attac~
the fibres of the particles incorporated therein so
that, when the whole of the matrix which surrounds it
has been reabsorbed, the vitreous composition is, in the
lacunae, in contact with the vasal and cellular
components. The histological appearance of the fibres
at this stage showed fragmentation. suggesting that the
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WO91~12032 PCT/EP91/00201
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process of dissolution of the vitreous composition was
progressing and that the fragments were being absorbed
by giant polynucleate cells.
Since the remodelling of the bone consists of
successive resorption and addition, the dissolution of
the vitreous composition or its reincorporation in the
newly-added matrix would seem to be affected by two
factors:
1) the number of osteogenic cells available in the
lacuna;
2) the shape and size of the vitreous material: in
fact, whilst the fibres showed generalised dissolution,
the aggregations of several particles also had surfaces
with newly-added material.
These results appear to confirm that~ as well as
being affected by the chemical characteristics of the
material, the nature of the biological response is also
affected by the shapes and sizes of the fibres and
particles and, in particular, that the uniformity of
; 20 their dimensions is beneficial.
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