WO1993017976A1

WO1993017976A1 - Bioactive glass as a bone substitute

Info

Publication number: WO1993017976A1
Application number: PCT/FI1993/000081
Authority: WO
Inventors: Juha Kaarlo Peltola; Örjan Helmer ANDERSSON
Original assignee: Turku Implant Team Oy
Priority date: 1992-03-09
Filing date: 1993-03-09
Publication date: 1993-09-16

Abstract

The present invention refers to bioactive glasses or glass-ceramics, in granular form, as bone substitutes. They find use for filling of e.g. infected or non-infected forehead, sinus, alveolar and bone cyst.

Description

Bioactive glass as a bone substitute

FIELD OF THE INVENTION

The present invention describes glasses for replacement of bony tissue in obliteration of bone defects. The described materials have been found to perform successfully in infected sites as well as in non-infected sites. The glass can be used as such or in its partially crystallized form (glass-ceramic) . Glasses of this kind are known in the art, as is their bone bonding behaviour. According to the invention a narrow optimal compositional range has been found wherein the glass can be used as a granulate, i.e. with a large surface area. The granules possess a good ability to conduct bone growth and are used alone or in combination with bulk glass (blocks, plates etc.) or other implants, such as titanium tooth root implants, for filling of bone defects or for stabilizing dental or surgical implants in the bone. The granules are easy to apply and provide for a complete filling of defects of irregular shape.

BACKGROUND OF THE INVENTION

Many types of materials are presently used for replacement of human tissue. The materials used can be divided into three groups on the basis of their stability in the tissue, i.e. nearly inert materials, resorbable materials and surface reactive or bioactive materials. The first group of materials relies on a mechanical fixation in the tissue. Examples are titanium and alumina. Typically these materials are used as prostheses or for attachment of prostheses in the bone, i.e. not as bone substitutes and fillers. The resorbable materials, e.g. tricalcium phosphate, have largely been replaced by the bioactive material hydroxylapatite (HA) in clinical use. The inert and the resorbable materials do not achieve bone bonding and are therefore proned to infection. The risk of infection is a recognized problem in implant surgery and the presently used inert or resorbable materials have not shown stable results in infected tissue since the lack of a direct bonding of bone to implant makes it posssible for soft-tissue mediated infection to occur. The healing after implantation of these materials is slow. Therefore an existing infection or a later occurring one is often the reason for failure.

Surface reactive or bioactive materials are such to which living bone not only can achieve contact (like titanium) , but can attach firmly. This firm fixation can be seen as a several times higher interfacial strength than that which is achieved with the inert materials. These materials to which glasses, glass-ceramics and HA belong, are known in the art. Presently the use of synthetic HA is fairly wide¬ spread. For a well defined HA, the production costs are high. It is considerably easier to produce a well-defined glass and the production costs are lower. The high price and the poor handling properties probably explain why the use of HA has not become very wide-spread. In addition to this our studies show that bioactive glass is more rapidly bonded to bone. HA is used in reconstruction of bony tissue and for example in dental sites which are proned to infection. HA gives a good roentgenological contrast and has, when studied in this way, been considered to achieve extensive bone contact. Still the clinical results have often been unsatisfactory.

In designing a material for bone replacement, certain aspects must be considered. Rapid healing is important. In order to avoid any infiltration of soft tissue the material should form a direct bond with the bone tissue. The bond should also be self-repairing in case of damage. Thus, if detached, the bone should due to its normal healing ability reattach to the implant surface without the need for surgery. The establishment of stable contact of bone is important in avoiding infection.

A bioactive glass that has proved to be a successful candidate for bone replacement is the 45S5 Bioglass^® composition (see e.g. US-patent 4,171,544, column 1), which comprises 45 % by weight Si0₂, 24.5 % by weight Na₂0, 24.5 % by weight CaO and 6 % by weight P 0₅. The 45S5 glass has received FDA approval for use in a middle ear transplant. This glass is, however, not used as granules, but as bulk. In a recent paper (Gatti, A.M. & Zaffe, O. Biomaterials 1991, Vol. 12. pp 345-350)) it was reported that the bone growth around granules of the 45S5 glass is unsatisfactory. In a later patent (US 4,775,646) the 45S5 composition has been improved by substituting 40 % of CaO by CaF₂. This glass is according to the patent intended for use as bulk implants or for coating of implants. The US-patent 4,851,046 (=EP 206 726) describes the use of bioactive glass in periodontal osseous defects. The glasses are used as granules in sizes from 90 to 710 μm. Our results, however, show that a more extensive bone infiltration is achieved with less reactive glass granules.

SUMMARY OF THE INVENTION

The present invention relates to bioactive glass in granular form with a composition to be specified hereinafter, as such or in crystalline form as a glass- ceramic. The invention also relates to the use, in humans and non-humans, of the said materials as a bone substitute for infected and non-infected sites for use in dental and orthopaedic implants.

The invention is based on the discovery that too high ion release rates, i.e. reactivity, of the glass may disturb the bone formation around the implant. According to the invention it has now been found that within a fairly narrow range the reactivity of the material is low enough to make it possible for it to be used as a granulate, which application form has many advantages over bulk form, as will be explained later. The invention also contemplates the use of bulk implants together with the granules of the invention.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention we have thus discovered that for optimal performance other aspects than those presented above need to be taken into account as well. The dissolution or release rate for elements from the implant material must not be too high, since the flux of released ions can interfere with the biological processes as well as with the implant surface chemistry. In the case of glass, too high a dissolution rate can cause the local pH at the glass surface to increase to a biologically unacceptable level. On the other hand, a certain release of ions at the surface might stimulate the healing process and the bone formation. This conclusion can be drawn on basis of studies by us and others, showing that a bioactive glass usually is more rapidly bonded to and surrounded by new bone, than is for example HA. The release of ions from HA is slower than from bioactive glass. Thus our conclusion is that too low or too high ion release rates do not give the best possible result in terms of healing. A controlled reactivity (ion release rate) is therefore required. We have discovered that when using glasses as bulk samples excellent results are achieved, but if the glass is to be used as a granulate the reactivity must be reduced.

The above mentioned and other objects of the invention are achieved by a bioactive glass in granular form and having - the following composition, wherein percentages are by weight:

It is to be noted that the addition of B₂0₃ to the glass increases the reactivity, but small additions might be tolerated. The addition of A1₂0₃ decreases the reactivity and also affects the bone bonding process. Our results, however, show that small amounts can be tolerated.

The material according to the invention may be used as such or in partly crystallized form as glass-ceramics as a bone substitute for the obliteration of bone defects, such as for filling of bone defects and cavities, and for bone augmentation. According to the present invention the glass may be used as such as a granular implant, in the form of a mix with e.g. a physiological saline solution, or together with bulk implants. Specific applications or treatments included in the present invention are the use as dental or surgical implants including granules of controlled reactivity in a variety of sites, such as filling of forehead, sinus, alveolar, bone cysts, and in ozena treatment. The granulate can also be used around metal or ceramic implants for stabilizing purpose. A common feature of all these applications is that granules are needed to achieve a complete filling of the bone defect.

In many applications granules are thus preferred over bulk specimens since granules can readily be applied in bone pockets of very irregular shape. Granules are also preferred since the size of the filling cannot always be established before the operation. Thus from the point of view of the surgeon and the patient, a granulate is preferred. We have shown that bioactive glasses have the ability to conduct bone growth along their surfaces. This is known to the art. When used as granules, the material however provides an efficient scaffold for the bone growth. When filling a bone defect with a bioactive granulate, for example, the bone can under beneficial circumstances grow from one granule to another, eventually filling up the gap. A gap in the bone can in the absence of a osteoconductive material close only when the width of the gap is not too large. By using a granulate filler, considerably larger spaces can be closed. From the surgeons point of view, easy handling of the material during the operation is of importance. It should be possible to apply the material rapidly in a controlled way. The material should be such that it does not migrate from the place of application. According to our experience the handling properties (reology) of glass granules are excellent, whereas those of e.g. HA are not. The advantage of glass is that it, when soaked in a physiological saline solution, forms a porridge-like mass that can easily be applied. This behaviour is not shown by HA which results in that HA granules do not always stay at the site of application, but float away.

The granulate is produced by mixing the raw materials (e.g. Si0₂, Na₂C0₃, CaC0₃ etc) and heating them at about 1350 °C for several hours. After this the melt is poured on a graphite plate and annealed at about the glass transition temperature of the glass for one to several hours. Alternatively the glass can be quenched and left annealed to facilitate the crushing. The glass is crushed mechanically e.g. in a ball mill and sieved to appropriate grain sizes. Glass-ceramics are produced by heating the base glass to about 650-1000 °C for several hours.

Thus according to the invention it has been discovered that comparable to having a very reactive glass (such as the 45S5 bulk glass) and an intermediate surface area is having a glass of intermediate reactivity and a very large surface area. In both cases the bone pocket will be filled with new bone more slowly than if the reactivity-to-surface area ratio had been lower. Thus there is no one optimal glass composition but the composition must be seen in relation to the total surface area of the implanted material. Therefore the highly reactive glass composition 45S5 can be used with a small specific surface area, whereas a less reactive glass composition is needed if the glass is to be used as a granulate. The glass defined in the Example 1 (S53P4) is an intermediate reactive glass and thus a fairly large surface area can be tolerated, but if the surface area is very large, this glass will not perform satisfactorily. Our studies show i.a. that grains smaller than about 200 μm (microns) give a surface area that is too large in relation to the reactivity of the glass. Consequently a glass of even less reactivity is needed if a grain size of less than 200 μm is to be used. However, from a practical point of view there is no need for so small grains in obliteration of bone defects. We have successfully performed clinical tests with grains ranging from 300 μm to several millimeters. Thus e.g. glass S53P4 can due to its optimized composition and controlled reactivity be used in all practically interesting sizes, i.e. from granules of about 300 μm up to bulk size, i.e. to about 5 to 10 mm. Larger pieces can be considered as bulk specimens.

Our extensive in vitro and in vivo studies have made it possible to optimize the above defined bioactive compositional ranges according to the invention within which the compositions are suited for use as granules.

EXPERIMENTAL

To reduce the number of animal experiments needed for this study we have used a method not previously reported for bioactive glasses. An experimental plan containing 16 glass compositions was made using the Placket and Burman method (δ. H. Andersson et al "In vivo behaviour of glasses in the Si0₂-Na₂0-CaO-P₂0₅-Al₂0₃-B₂0₃-system" J. Mater. Sci.

Materials in Medicine; D.C. Montgomery, "Design and analysis of experiments, 2nd ed. New York, Wiley 1984) . All these 16 compositions fell within the following wider range:

The 16 glasses were studied by implantation in rabbit tibia. The glasses were classified according to their reaction behaviour as well as according to the type of bone response (i.e. no contact, contact, bonding) . By linear regression analysis of the results a phenomenological model was developed. The model describes the relationship between the behaviour in vivo and the glass composition. Thus it is possible to use the model to predict (interpolate) results for unknown glass compositions within the specified limits and to calculate a bioactive compositional range. In both cases the bioactivity was established on basis if implantation of bulk specimens. As discussed above, the reactivity or ion release rate must not be too high if the glass is to be used not only as bulk but also as granules. By a number of in vitro-tests (e.g. ion release, neutralization, weight-loss) we have been able to define the compositional ranges within which the reactivity is high enough for bone bonding but low enough to allow the use of granules. Glass undergoes in contact with water two main reactions, ion exchange (leaching) and glass network breakdown. A measure of the latter reaction is the Si-release from the glass. A standard method is carried out at 98 °C and was therefore modified and performed at 36.5 °C, i.e. body temperature. A number of compositions were tested and compared with factual in vivo data as well as with data predicted by the model. A narrower compositional range having a low enough reactivity (ion release rate) but a sufficient bone bonding ability was found within the known broader bioactive ranges. The optimized compositional ranges suited for use also as granules, i.e. at high specific surface area, is the composition of the invention given above.

Of the possible compositions within the above compositonal ranges the composition given in the Example 1 was chosen for extensive testing in vivo and in vitro. It was found that the glass behaves as expected, i.e. that it shows a relatively low solubility/reactivity as compared with composition 45S5 and that its behaviour when implanted is good.

EXAMPLES

Example 1: A glass (S53P4) of the following composition was studied

The glass was implanted in rabbit tibia as bulk specimens (cones) and granules and was found to perform well, with a large amount of infiltration of bony tissue. The minimum acceptable grain size for this glass appeared to about 300 μm. Smaller grain sizes are according to our findings not desirable from the handling point of view. Therefore the above composition performs as desired in the practically interesting grain size, i.e. from about 300 μm grains up to bulk size.

• Based on this finding it was decided to use the same glass as a bone filler for clinical testing. The applications chosen were filling of a cavity in the forehead, for sinus lifts, for filling of bone cysts and alveolar pockets. In all cases the fillings were performed using granules alone or in combination with bulk glass (blocks) . The grain sizes used were of the following fractions 300-500, 630-800, 1000-2000 μm and up to 10 mm. Specimens larger than about 10 mm may with respect to the ion release rate be regarded as bulk specimen.

In the filling of some of the foreheads the need for material was extensive and in these cases a combination of glass plates and granules were used. The granules made it possible for the surgeon to achieve a total filling of the hollow space. Due to the good handling properties, i.e. suitable reology, of the granules, the filling was easy. No infections occured and good bone contact developed.

Example 2: A glass having the same composition as in the Example 1 was used. It was used in the same manner as in the Example 1, but in infected, wet sites. Together with antibiotic treatment the result was very good and better than usually achieved with antibiotic treatment together with other implant materials, such as polymers, metals and bone or fat autografts.

Example 3: The same glass as in Example 1 was implanted to lift the bottom of the maxilla sinus. Granules and a plate of the glass were used in this application. After 3 months bone had surrounded the granules and thus lifted the bottom of the sinus 12 to 17 mm. A titanium implant was inserted at the time of the operation and thanks to the increased thickness of the the bone, the titanium implant was stable.

Claims

1. Bioactive glasses and glass-ceramics in granular form for use as a bone substitute for obliteration of bone defects and cavities and for bone augmentation, and having the following composition:

2. Glasses and glass-ceramics according to the Claim 1 wherein the granules are of a size of at least about 300 μm.

3. Glasses and glass-ceramics according to the Claim 2 wherein the granules are of a size of up to about 10 mm.

4. Glasses and glass-ceramics according to the Claim 2 wherein the granules are of a size of about 300 μm - 2 mm.

5. Glasses and glass-ceramics according to anyone of the Claims 1 to 4 having the following composition

6. Use of a glass and glass-ceramic of the composition

in the form of granules as such or together with bulk specimens as a bone substitute for the obliteration of bone defects and cavities and for bone augmentation.

7. Use according to the Claim 6 wherein the granules are of a size of at least about 300 μm.

8. Use according to the Claim 7 wherein the granules are of a size of up to about 10 mm.

9. Use according to the Claim 7 wherein the granules are of a size of about 300 μm - 2 mm.

10. Use according to any one of the claims 6 to 9 wherein the glass has the following composition

Si0₂ 53.0 % by weight Na₂0 23.0 -••-

CaO 20.0 -"-

P₂0₅ 6.0 -"-

11. Use according to the Claim 6 for the filling of infected or non-infected forehead, infected or non-infected sinus, infected or non-infected alveolar, infected or non- infected bone cysts, and ozena treatment.

12. Use according to the Claim 6 wherein the granules are used together with dental or orthopeadic implants for the stabilization thereof.