CA2075281A1

CA2075281A1 - Bioactive vitreous composition for bone implants, filaments made therefrom and method

Info

Publication number: CA2075281A1
Application number: CA002075281A
Authority: CA
Inventors: Emilio Vita Finzi Zalman; Bruno Locardi; Carlo Gabbi; Paolo Tranquilli Leali
Original assignee: Individual
Current assignee: Seipi Esportazione Importazione Prodotti Industriali SpA Soc
Priority date: 1990-02-08
Filing date: 1991-02-04
Publication date: 1991-08-09
Also published as: AU639981B2; EP0514401A1; FI923561A0; IT9067096A1; IT9067096A0; JPH05502603A; BR9106030A; HUT61899A; FI923561A; KR950008173B1; AU7149191A; IT1240938B; WO1991012032A1

Abstract

The invention relates to a bioactive vitreous composition for bone implantation which includes the following approximate percentages by weight of the following oxides: SiO2 from 40 to 55 %;
P2O5 from 5 to 8 %; Cao (MgO) from 20 to 40 %; Na2 (K2O) from 20 to 30 %. The composition can be reduced to filaments without becoming ceramic by virtue of the addition of a total of not more than 9 % by weight of K2O and Al2O3, the percentage of Al2O3 being from 0.5 % to 2.5 %. The filaments thus obtained can be used to prepare products for bone implantation in the form of bundles of filaments, gauzes, nets or other fabrics, felts, "cotton-wools" and the like. The filaments can be reduced to particles of powders for the application, inter alia, of a coating layer of the vitreous composition to a permanent metal prosthesis.

Description

t~''~ ;
207~2~1 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/EP91/0~201 207~281 - 2 -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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- 3 _ 2~7~281 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 : ~ , . : . :- -,,. . , ~ . .

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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' ' , ~ 5 ~ 2~75281 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 ~.i ., . ~ - - , . . .
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W O 91/12032 PC~rtEP91/00201 2 ~ ~ ~ 2 ~ 1 - 6 -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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` . ' . ,. : ' ~ , ~`''; 2a7~2~l 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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'' 2 3 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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9 2~75281 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 20~`2~1 10-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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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 , . , ... .. . . . , . - . - , -WO91~12032 PCT/EP91/00201 ,~; 207~281 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.

:: . : : - :

Claims

- 14 -

1. A bioactive vitreous composition for bone inplant-ation, including the following approximate percentages by weight of the following oxides: SiO2 from 40 to 55%;
P2O5 from 4 to 8%; CaO (MgO) from 20 to 40%; Na2O and/or K2O up to 30%, characterised in that it includes as anti-ceramising oxides a global percentage by weight between 2% and 9%
of K2O and Al2O3, the percentage of Al2O3 being from 0.5% to 2.5%, whereby the composition can be drawn into filaments or fibres from a fusion bath.

1.

2. A vitreous composition according to Claim 1 characterised in that it has the following constituents in percentages by weight: SiO2 50%; P2O5 6%? CaO 16%:
Na2O 20%; K2O 5%; MgO 1%; Al2O3 2%, with tolgerances of ? 7% in the percentage of each constituent.

3. A vitreous composition according to Claim 1, characterised in that it has substantially the following constituents in percentages by weight: SiO2 50%; P2O5 6%; CaO 16%; Na2O 15%; K2O 5%; MgO 1%; Al2O3 2%; B2O3 5% with tolerances of ? 7% in the percentage of each constituent.

4. A vitreous composition according to any of Claims 1 to 3, characterised in that it also includes at least traces of clacium fluoride and/or calcium fluorophos-phate.

5. The use of a vitreous composition according to any of Claims 1 to 4 for the formation of bone implants or parts thereof.

6. Filaments produced by the drawing of a vitreous composition according to any of Claims 1 to 4.

7. Filaments according to Claim 5, characterised in that their diameters are between 10 and 50 microns.

8. A bundle constituted by a plurality of filaments according to Claim 7 or Claim 8, for implantation in a bone defect.

9. A fabric, particularly a net or gauze, formed of filaments according to Claim 6 or Claim 7, for repairing a bone defect.

10. A felt or "cotton-wool" formed of filaments according to Claim 6 or Claim 7, for repairing a bone defect.

11. A particulate product produced from filaments according to Claim 6 or Claim 7, for implantation in a bone defect or for use in the preparation of products for bone implants.

12. A particulate product according to Claim 11, constituted by pieces or small cylinders produced by the shredding of the filaments.

13. A particulate product according to Claim 11. in the form of a powder produced by the grinding of the filaments.

14. A permanent bone prosthesis constituted by a solid body of biocompatible material, characterised in that the surface of the body is at least partially coated with a layer produced by the application of a parti-culate product according to any of Claims 11 to 13.

15. A prosthesis according to Claim 14, in which the coating layer is produced by the application of the particulate product by the "plasma spray" technique.

16. A method for the production of filaments of a bioactive vitreous composition for bone implantation, by drawing the molten composition through a die from a fusion bath, characterised in that use is made of a vitreous composition according to any of Claims 1 to 3.

17. A method according to Claim 16, characterised in that a crucible of substantially pure platinum is used for containing the fusion bath.