EP0191086A1

EP0191086A1 - Bone-replacing material

Info

Publication number: EP0191086A1
Application number: EP19850904297
Authority: EP
Inventors: Gerrit Johannes Brinks; Jan Cornelis Brinks
Original assignee: Individual
Current assignee: Individual
Priority date: 1984-08-17
Filing date: 1985-08-15
Publication date: 1986-08-20
Also published as: WO1986001113A1; NL8402534A

Abstract

Une composition est utile comme matériau pour implants chez des êtres humains et des animaux, afin de remplacer un tissu osseux absent. Le matériau comprend un matériau céramique particulaire biocompatible comme composant de remplacement du tissu osseux, et un matériau polymère biodégradable. Le matériau céramique n'est pas résorbé, et le matériau polymère biodégradable agit comme liant dudit matériau céramique, la composition étant formée d'un mélange intime de 4-30% en poids dudit matériau polymère, 15-30% d'eau et le reste de matériau céramique. Ce mélange intime est pétrissable et a une consistance à viscosité élevée. La composition est préparée en mélangeant intimement un mélange gélifié composé du matériau polymère biodégradable et d'eau avec le composant céramique à l'aide d'un malaxeur à grand puissance et à vitesse réduite, à une température ne dépassant pas 60oC, et un soumettant le mélange ainsi obtenu à une pression élevée d'au moins 10 MPa à la température ambiante pendant au moins 5 minutes environ.A composition is useful as an implant material in humans and animals to replace absent bone tissue. The material includes a biocompatible particulate ceramic material as a replacement for bone tissue, and a biodegradable polymeric material. The ceramic material is not absorbed, and the biodegradable polymer material acts as a binder of said ceramic material, the composition being formed from an intimate mixture of 4-30% by weight of said polymer material, 15-30% of water and the remains of ceramic material. This intimate mixture is kneadable and has a high viscosity consistency. The composition is prepared by intimately mixing a gelled mixture composed of the biodegradable polymeric material and water with the ceramic component using a high power mixer and at low speed, at a temperature not exceeding 60oC, and a submitter the mixture thus obtained at a high pressure of at least 10 MPa at room temperature for at least 5 minutes approximately.

Description

Bone-replacing material.

This invention relates to a composition suitable for use as an impant material in human beings and animals to replace absent bone tissue, and comprising a biocompatible particulate ceramic material as a bone-replacing component and a biodegradable polymeric material.

A similar material is disclosed in NL-A-7704659. In this known material, however, the inorganic component or both the inorganic and the organic components are resorbable. Other known materials consist virtually entirely of a calcium phosphate compound, for example, hydroxylapatite in the form of hard shapes which prior to use have to be subjected to all sorts of complicated operations, or of a mixture of a calcium phosphate compound with polymers which for example have to harden in the site of implantation, or of loose granulate of, for example, hydroxylapatite . One disadvantage of these known materials is that owing to their form of presentation they are difficult to process, and in some cases are even poorly processable, because for example they are presented at a loose granulate, which first must be mixed with venous blood or with physiological saline, or require being ground into shape. The often hardening polymers have the disadvantage that they may contain toxic monomer residues or harmful catalyst or initiator residues. In addition, the polymer content is often predominant, so that the polymer is the actual implant material rather than the calcium phosphate compound. The disadvantage of this is that the breakdown time of such polymers is often long and that there is no direct contact between the calcium phosphate or hydroxylapatite and the bone tissue. It is an object of the present invention to provide an improved composition of the above kind which has a good processability and is bio-active, that is to say, fully integrable in the human and animal body and, in a general sense, suitable for surgical purposes, and in which, at the site of implantation in the body, the ceramic component is maintained and integrated in the bone tissue.

According to the present invention, there is provided a composition suitable for use as an implant material in human beings and animals to replace absent bone tissue, comprising a biocompatible, particulate ceramic material as a bone-replacing component and a biodegradable polymeric material, characterized in that the ceramic material is a non-resorbable material, and the biodegradable polymeric material functions as a binder for said ceramic material, the composition being an intimate mixture of, by weight,

4-307o of said polymeric material, 15-307_o of water and balance the ceramic material, said intimate mixture having a highly- viscous kneadable consistency.

The invention is based on the insight that, after the implantation of the composition according to the invention in the human or animal body the biodegradability of the polymeric material functioning as a binder will ensure that it is broken down in the course of time, and will disappear, leaving a microporous structure of the (bio)ceramic material into which new blood vessels and connective tissue can grow. Examples- of biodegradable polymeric materials suitable for use in the composition according to the invention are the reticulating polymers gelatin A or B, carboxymethyl ^"cellulose and dextran, which are all polymers of natural origin, but polyethylene glycol, for example, is also suitable Generally speaking, any biodegradable organic compound capable of forming a network or reticulation, and hence capable of functioning as a binder for the biocompatible ceramic material, and which further satisfies the general requirements as imposed in the pharmacopeias, for example, The Netherlands, European and North-American pharmacopeias is suitable for use as an adjuvant in the material according to the present invention.

The above gelatin A or B is a polymer made from skin or bones, and satisfies the requirements imposed in the various pharmacopeias. It is a mixture of protein molecules, is biocompatible and biodegradable, and is already being widely applied in injection compositions.

Carboxymethyl cellulose is a polysaccharide of vegetable origin with a molecular weight of lθ -lθ6. in the form of the sodium salt this polymer is water-soluble. It satisfies the above requirements and is also frequently being used in injection compositions.

The polyethylene glycol is a white to off-white viscous composition with a molecular weight of 200-6000 and is also already, being used in pharmaceutical compositions.

The biocompatible, non-resorbable ceramic material for use in the implant material according to this invention will naturally also have to satisfy the general requirements as defined in the pharmacopeias, in particular the above Netherlands, European and North-American pharmacopeias.

Examples of ceramic materials of the above type, which already have found application in practice as an implant material and are also suitable for use as a bone-replacing component in the implant material according to this invention are hydroxylapatite » referred to hereinbefore and, in general a calcium phosphate compound.

The hydroxylapatite is a white to off-white calcium phosphate compound having the chemical formula Ca o(Pθ )6(OH) _ The compound is a solid and consists of approximately spherica particles with a porosity of between 1 and 50%. Its particle size is about 0.07-0.2 mm. The compound is normally purified by treatment with hydrogen peroxide, followed by intensive washing with distilled water. The compound is fully biocompati and not resorbable after implantation in human and animal bone tissues.

The.more general calcium phosphate compound refers to a compound which is available in the form of a white powder and can be represented by the generic chemical formula Ca_x(H_yPO_z) .nH2θ, in which x represents 1, 2 or 3, y is 0, 1 or 2 ; z is 3 or 4; m is 1 or 2; and n represents 0, 1 or 2. The compound is a non-toxic, biocompatible material which is often being used as an adjuvant in the pharmaceutical industry and has recently been found to be suitable for use as an implant material.

Aluminum oxide with the chemical formula Al2θ3.nH2θ also has known applications as an implant material, and is therefore suitable for use in the implant material accordi to the present invention.

In summary, it can be concluded with regard to the ceramic material to be used as the bone-replacing component in the implant material according to this invention that any inorganic or ceramic compound that is biocompatible and non-resorbable and can be processed for preparing the implant material of the invention is suitable for this purpos Further examples are Siθ2-nH2θ, GeO and GaS.

For the preparation and application of the implant material according to the invention, the particle size of the ceramic material should not be too large. Preferably, the particle size should not be larger than about 1.5 mm.

As a result of the way in which the implant material of this invention is prepared, to which we will revert herein- after, this material has a highly viscous consistency so that it is mouldable by kneading or modelling, but it can also be provided as a shaped material in the form of plates, rods or bars. Thus shaped, the material according to the invention can be used as such in the case of a bone defect where bone tissue is locally absent and this void is in a form corresponding to the shape of the material. For that matter, the plates, rods or bars are by themselves deformable or breakable.

The composition according to the invention comprises, by weight, 4-307, of biodegradable polymer and 15-307, water and balance bone-replacing ceramic component. The use of less water in the composition increases the risk of the composition being less easy to handle and process, because the binder function of the biodegradable polymeric material is suboptimal.

For that matter, the composition according to the invention may incorporate more biodegradable polymeric materia

With a content of about 187, or more of polymeric materia in the composition according to the invention, the implant material has such a viscosity that it can be introduced by means of an injection syringe.

The invention also relates to a method of producing the composition for use as an implant material, said method being characterized in that a gelled mixture, prepared from the biodegradable polymeric material and water is intimately mixed with the ceramic component, using a high-power, low-spe kneader at a temperature of no more than 60°C, and subjecting the mixture thus produced to an- elevated pressure of at least 10 Mpa at room temperature for at least about 5 minutes. In carrying out the method according to the invention, it is efficient to adopt a sequence in which the quantity of the ceramic material required for the contemplated batch of the implant material to be made is previously purified. For this purpose, the particulate ceramic material is treated with an aqueous solution of hydrogen peroxide. During this process step, impurities which are oxidizable, and after implantation could have a pyrogenic effect are converted. Pyrogenics may cause immunochemical reactions and are hence undesirable. As the particles of ceramic material are not soluble in this solution, or to a very small extent only, a suspension is formed. This suspension is filtered and washed on the filter with distilled water. Thereafter, a treatment with a 707, ethanol solution in water may be given on the filter, whereby the ceramic material is sterilized. Subsequently the material is dried at 110-130°C (material A) . In addition distilled water, in the required quantity calculated, is brought to a temperature of 60°C. Onto this water, the required amount of the biodegradable polymeric material is sprinkled. This biodegradable polymeric material, e.g. gelatin, carboxymethyl cellulose, or dextran, has first been treated with a 807. ethanol solution in water and dried at 110-120°C. (The treatment with a 807, ethanol solution in water is given because when a less concentrated solution is used, e.g. a 707, ethanol solution in water, the polymeric material may swell unduly) . In the course of time, a gel material is formed, which may take about 2 hours. This process step is completed by homogenizing the gel (material B) . Subsequently, material A is slowly added to material B in discrete portions with careful stirring, mixing or kneading. In this way the mixing operation can be well controlled, and the production of a homogeneous product is ensured. The use of a mixer whose operation is base.d on the occurrence of high shear forces is not recommended by reason of the danger of metal contaminat For this reason, in the method according to the present invention, a kneader with a low speed and, by reason of the highly-viscous character of the mixture formed, high power is used, which also prevents the temperature of the mixture from being unduly elevated from internal friction. Too high a temperature is undesirable in connection with the risk of premature decomposition of the polymer and evapora of the water. A temperature of up to 60°C is permissible, operation at elevated temperature being generally beneficial inasmuch as it facilitates kneading by decreasing the viscosit Taking this circumstance into account, therefore, the mixing operation is preferably carried out at elevated temperature. The product produced by the mixing operation described already exhibits a certain coherence, but is in many cases nevertheless too brittle. In a next step, therefore, the ultimate composition, produced by mixing with the bone- replacing component, is subjected, in a mould, to an elevated pressure of at least about 10 MPa for at least about 5 minutes to produce an end product of sufficient coherence.

In this pressure stage, the amount of the pressure and the time for which the pressure is applied are important parameters. It has been found that this stage can be carried out at room temperature, and further that when a given pressur is used it is possible to determine a duration for this treatment after which no appreciable changes in the nature of the material under pressure take place any longer. It can be assumed that the interaction between the particles of ceramic material and the biodegradable polymer, which partly causes the formation of an adsorption bond between the polymer and the ceramic particles, no longer has any effect, or that the bonding process is completed. The product thus obtained is then ready to be packaged and subsequently sterilized, whereafter it can be used.

The amount of the pressure to be used depends partly upon the nature of the biodegradable adjuvant used. Thus when gelatin is used a preferred pressure range is from 10 to 30 MPa, and in the case of carboxymethyl cellulose a pressure of 75-150 MPa.

The amount of the pressure to be applied is also selecte with a view to the desired consistency of the implant material When a pressure of about 455 MPa is used, a product is obtaine which is excellently suitable for being shaped into the implant material in the form of plates, rods or bars. A pressure of less than about 150 MPa ensures the production of a product having a good plasticity. When a pressure is used with a value in the intermediate range of about 150-455 M the plastic properties of the resulting product are not unequivocal or insufficiently so, and such a product is less suitable for use in practice.

The composition according to the invention is highly viscous and kneadable and can easily be applied with a spatula Accordingly, it is ready for use as an implant material. Owing to the selection of the formulation, the composition according to the invention is hydrophilic and slowly absorbs wound fluid from its surroundings. Owing to the relatively low concentration of polymer, there is a direct contact between the ceramic material and wound fluid, while yet, owing to the pressure step, the ceramic particles, for example apatite particles, are densely packed.

Preliminary keeping tests have shown that the product will keep for at least 1 year, provided it is stored in sterile conditions and at 2-6°C (refrigerator) .

The implant material according to the invention, which has a specific mass ranging from 1.2 x 10³ and 3.5 x 10³ kg/m³ is a product having a greatly improved processabilit , which amply satisfies the requirements imposed thereon in practice. Examples of fields of application are surgery, traumatology, implantology, orthopedics, paradontology, dental surgery and general dentistry.

Once implanted in, for example, the human body, accordi to expectations, a gradual decomposition of the biodegradable matrix, such as the biodegradable polymer matrix, takes place, leaving a microporous structure consisting of the ceramic material, which offers the possibility of 'the ingrowt of new blood vessels and connective tissue. The result is that the ceramic particles are embedded and integrated in the bone tissue, and also that new bone tissue is initiated. The invention is illustrated in and by the following examples. Example I

Preparation of 50 g implant material on the basis of hydroxylapatite and gelatin.

34 g hydroxylapatite was stirred at room temperature for 1 hour in a 307, H2O2 solution in water (50 cm³, 100 ^*cm³ glass beaker, magnetic stirrer) . Thereafter the resulting suspension was filtered and washed on the filter with distill water (4 x 100 cm³) . Subsequently the material was dried at liooc. 2.7 g gelatin was sprinkled onto 13.3 cm³ distilled water which had. been brought to 60°C. After 2 hours the resulting gel was homogenized. Subsequently, the hydroxylapati was added in portions of about 5 g to the gel with kneading by means of a suitable kneader. Kneading was continued until a homogeneous mixture had formed, and all of the hydroxylapati had been added. The material thus obtained was placed in a mould and subjected to a pressure of about 15.2 MPa for 5 minutes. The material thus obtained was ready for further processing. Example II Preparation of 100 g implant material on the basis of calcium phosphate and carboxymethyl cellulose.

74 g calcium phosphate (anhydrous) was treated in the manner described in Example I with H2O2 in distilled water. 4 g of the sodium compound of carboxymethyl cellulose was sprinkled onto 22 cm³ distilled water having a temperature of 60°C. After 2 hours the gel was homogenized. The remainder of the procedure was similar to Example I, except- that the pressure applied was about 152 MPa. Example III

50 g hydroxylapatite was stirred in ^'80 cm³ of a 307, H2O2 solution in water for 20 minutes. This suspension was filtered and washed on the filter with 100 cm³ of distilled water and then washed with 100 cm³ of a 707, ethanol solution in water. Thereafter the apatite was dried at 120-130°C. 5 g carboxymethyl cellulose was stirred in a glass beaker with a 807, ethanol solution in water and then filtered. This was repeated 2x. The carboxymethyl cellulose was then dried at 110-120°C. 9 cm³ of distilled water of a temperature of 60°C was placed in a Teflon mixing beaker. 5 g of the above carbox methyl cellulose was sprinkled on the water. After being allowed to stand at ambient conditions, the gel was homogeniz A total amount of 45 g, in discrete portions of about 5 of the hydroxylapatite treated as described above was added with kneading. The total kneading process lasted about 30 min After about 1 minute, after the first portion, 1 cm³ of distilled water was added, after 3 minutes another 1 cm³, and finally after 5-6 minutes another 1 cm³ of distilled water. After termination of the kneading process (approximately

30 minutes) , the mass thus obtained was introduced into a disinfected mould and pressed for 5 minutes using room temperature and a pressure of 110 MPa.

Thus resulting product was then ready for use and was packaged in sterile containers.

Example IV

1.6 g gelatin was sprinkled onto 2 cm³ of distilled water brought to 60°C. After 2 hours the resulting gel was homogenized. 16.4 g hydroxylapatite was stirred in a 307, H2O2 solution in water at room temperature for 1 hour. This suspens was subsequently filtered and washed on the filter with

707, ethanol solution- in water. The slurry was then dried- at 120-130^OC. The resulting hydroxylapatite was added to the gel in portions of about 4 g, at room temperature, with kneading.

Kneading was continued until a homogeneous mixture had been obtained.

2 g of the resulting mixture was introduced into a mould and pressed at room temperature at a pressure of 455 MPa for 5 minutes.

The resulting plates exhibited a brittle fracture when pressed with a spatula.

Example V Similarly to Example IV, 2 g carboxymethyl cellulose was sprinkled onto 4.3 cm³ of distilled water, and 13.7 g hydroxylapatite was mixed with the gel.

2 g of the resulting product was subjected to a pressure of 455 MPa, at room temperature, for 5 minutes. Solid, deformable plates were produced which permitted being shaped in a simple manner by breaking pieces from them with a spatula or by hand. Example VI; apex restoration.

Using the product prepared in accordance with Example I (but with 87, gelatin) and Example III (CMC), a clinical study was made into its applicability in the case of apex resections (removal of tooth root extremity) . In this study attention was paid to processability and acceptance in the bone tissue. Results were qualitativel ^"evaluated clinically and radiologicall . In this examination 13 patients participated over a period of 1 year. Evaluation took place after 1, 3, 6 and 12 months. In 5 patients the product with 87, gelatin was implanted, and in 8 patients the product of Example III. Processability turned out to be good for the product of Example I to very good for the product of Example III. Except two, all patients exhibited the desired clinical and radiological picture. Both with the product of Example I and with the product of Example III, there was a case of relapse of the inflammation. In both patients the product was --removed after 1 month, and further recovery was without any problem. Example VII: use in capping dental implants.

In the same manner as in Example VI, a clinical examinat was made, but now regarding the capping of dental implants. Evaluation etc. was as in Example VI.

8 patients participated in the examination. In 3 patient the product of Example I (87. gelatin) was used, and in 5 patients the product of Example III (CMC) . Applicability and processability were found to be very good in all cases. In all cases the patients showed the desired clinical and radiological picture.

Example VIII: filling alveolus after extraction.

In the same way as in Examples VI and VII a clinical examination was made, but now into the applicability for filling the alveolus after extraction. Three patients took part in the examination. In one patient the product of Example I (87, gelatin) was used, and in two patients the product of Example III.

Processability could be called good to very good in all cases.

In all cases the expected clinical and radiological picture was obtained.

In one case in which the product of Example III was used, the results were even so good (as regards maintaining and building jaw bone) that after 6 months a dental implant could be, and was, placed in the site of implantation and hence in the newly-formed bone tissue. Evaluation after a total period of 12 months gave the desired clinical and radiological picture. Example IX

Using two products, an examination was made into the clinical applicability of the implant material of this invention. Both products were based on hydroxylapatite as the ceramic material, while one product contained 107, carboxymethyl cellulose and the other 87 gelatin as the biodegradable polymeric matrix.

In the examination, attention was paid to the processabi and the acceptance of the product in human tissue. The materia had been implanted subcutaneously during medically indicated operations. A total of 10 patients were treated over a period of 3 months. In two patients, a bone defect was filled after an apex resection (removal of tooth root extremity) , in six patients a dental implant was capped with the product, and finally, in two patients, after paradontal surgery the interdental gap was filled with the product. The products turned out to meet expectations: all patients except one showed the desired clinical and radiological picture.

Claims

1. A composition suitable for use as an implant material in human beings and animals to replace absent bone tissue, comprising a biocompatible, particulate ceramic material as a bone-replacing component and a biodegradable polymeric material, characterized in that the ceramic material is a non-resorbable material, and the biodegradable polymeric material functions as a binder for said ceramic material, the composition being an intimate mixture of, by weight, 4-307, of said polymeric material, 15-30% of water and balance the ceramic material, said intimate mixture having a highly- viscous kneadable consistency.

2. A composition according to claim 1, characterized in that the composition is a shaped material in the form of plates, rods or bars.

3. A method of producing a material as claimed in claim 1, characterized in that a gelled mixture, prepared from the biodegradable polymeric material and water is intimately mixed with the c^eramic component, using a high-power, low-spee kneader at a temperature of no more than 60°C, and subjecting the mixture thus produced to- an elevated pressure of at least 10 MPa at room temperature for at least about 5 minutes.

4. A method as claimed in claim 3, characterized in that the pressure is higher than about 455 MPa or lower than about 150 MPa.

5. A method as claimed in claim 3, wherein gelatin is used as the biodegradable polymeric material, characterized in that the pressure is 10-38 MPa.

6. A method as claimed in claim 3, wherein carboxymethyl cellulose is used as the biodegradable polymeric material, characterized in that the pressure is 75-150 MPa.