CA1259266A - Method of producing a bone substitute material - Google Patents
Method of producing a bone substitute materialInfo
- Publication number
- CA1259266A CA1259266A CA000483643A CA483643A CA1259266A CA 1259266 A CA1259266 A CA 1259266A CA 000483643 A CA000483643 A CA 000483643A CA 483643 A CA483643 A CA 483643A CA 1259266 A CA1259266 A CA 1259266A
- Authority
- CA
- Canada
- Prior art keywords
- collagen
- cross
- apatite
- mineral component
- linking agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
Abstract:
For producing the bone substitute material from collagen and hydroxyl apatite, an aqueous solution of clean collagen is mixed with a cross-linking agent causing only a partial cross-linking, and the mixture is lyophilized. The quantity of the cross-linking agent is chosen such that the collagen retains its resorbability and its absorptivity vis-a-vis bodily fluids, the material further showing no undesirable side effects. Preferably less than 1% in weight of formaldehyde, one of the preferred cross-linking agents, is added, with reference to the dry weight of collagen, and sintered apatite grains with a diameter of 50-300 m are used. Such a bone substitute material is stronger and less tearable as previsouly known materials and insures a good promotion of the growth of own bone tissue and the substitution by it.
For producing the bone substitute material from collagen and hydroxyl apatite, an aqueous solution of clean collagen is mixed with a cross-linking agent causing only a partial cross-linking, and the mixture is lyophilized. The quantity of the cross-linking agent is chosen such that the collagen retains its resorbability and its absorptivity vis-a-vis bodily fluids, the material further showing no undesirable side effects. Preferably less than 1% in weight of formaldehyde, one of the preferred cross-linking agents, is added, with reference to the dry weight of collagen, and sintered apatite grains with a diameter of 50-300 m are used. Such a bone substitute material is stronger and less tearable as previsouly known materials and insures a good promotion of the growth of own bone tissue and the substitution by it.
Description
1;Z5~1266 Application for Patent Inventors: PETER RIES, FRANK BAUMGART and HEINZ MITTELMEIER
Title: A METHOD OF PRODUCING A BONE
SUBSTITUTE MATERIAL
Specificatio_ Back~round of The In~ention The patent application refers to a method of producing a bone substitute material, mainly of collagen and a mineral component consisting of apatite, tricalcium phosphate (a and ~) and/or hydroxyl apatite and/or calcium phosphate ceramics. Such a method is described in the U.S. patent no. 4,516,276 of the same assignee. Extensive clinical studies have been published in the German publication "Zeitschrift fur Orthopadie" 121 (1983), pages 115-123, H. Mittelmeier, B.D. Katthagen, from where it follows that an encouraging and satisfying success has been obtained.
These studies further showed that the material, in spite of a further termal treatment and chloric acid vaporization, was still relatively delispescent during clinical insertion into the tissue, in particular whilst soaking with blood and tissue fluids, and that the generation of bone tissue was not marked enough.
Accordingly, a more compact material would be desirable, which further would create a better~stimulation of the bone growth.
The PCT publication No. W 081/00963 discloses a method of producing a collagen material which, after Express Mail N~. B41947903 ~2S926~
admixing finely grained apatite,.served as bone substitute - material for the above-mentioned studies. As mentioned in said publication, an essential increase of the absorbency and the mechanical strength relative to previously known collagen fleeces has been obtained by subjecting the collagen material to a further heat treatment or a treatment with gaseous haloid acids.
From the same publication follows that it was known to improve the physico-chemical properties of collagen and gelatine products on chemical basis, for example by cross-linking with aldehydes, in particular formaldehyd or glutaraldehyd. It is stated that those methods have the drawback that the thus obtained products are resorbed only very slowly or not at all by the body when implantated and cause inflammations, defense reactions or the production of foreign substance macro cells. The cross-linking of the collagen products with aldehydes has been effectuted in an exhaustive manner, resulting in completely cross-linked, plastic material like products which are recognized by the organism as foreign substance and thus cause the mentioned harmful reactions. Rest quantities of free aldehyd in the implantate are also harming the tissue.
The publication Jap. Traumat. Surg. (1982) 99, pages 265-269 of K. Hayashi et al discloses a collagen-hydroxyl apatite preparation, which was freeze-dried after cross-linking. On one hand, relatively finely grained apatite has been used and on the other hand no hint has been given that the quantity of the admixed glutaraldehyd should be such that none of the above-mentioned reactions occurs.
Summary of The Invention Accordingly, it is an object of the present invention to provide a method for the ~roduction of a bone substitute material, which material is more compact and stronger and more tear resistant than previously known material, and which further stimulates the natural bone development to grow at and into the material, without causing the aforementioned undesirable effects.
According to the invention it has been found that a partial cross-linking with formaldehyd or glutaradehyd instead of a total, exhaustive cross-linking provides for a substantial improvement of the physico-chemical properties of the collagen without causing any negative effects to the organism after the implantation or any harm due to remaining quantities of aldehyd.
As mentioned above, finely grained apatite, resp.
tricalcium phosphate powder with particle sizes of 3-5 ~m has been used for performing the experiments with the ~nown material. It has been found that the osteogenetic efficiency can be increased substantially if the apatite is used in form of powder aggregates or as particles of a larger size. This increase of the particle size can be attained by sintering commercially available fine cristal-line apatite or tricalcium phosphate to grains of a diameter of 20-1000 ~m, preferably 50-300 ~m.
Experiments to this effect have shown that bone substitute material consisting of collagen partially cross-linked with ~ormaldehyd, and apatite resp. tricalcium phosophate in form of sintered grains which are added to the collagen solution before the freeze drying furnish substantial improved results over the previously known bone substitute material. Thus, this new material is suited for a larger indication range. It is particularly advantageous to distribute the apatite grains in the collagen analog to the cross points of the mineral structures in the natural bone, thus providing a matrix for the restitution of the bone, which is similar to the bone to be restituted.
In accordance with an aspect of the invention there is provided a method of producing a bone substitute material from collagen and a mineral component~ said mineral component comprising apatite and/or hydroxyl apatite and/or calcium phosphate ceramics, wherein an aqueous solution or a dispersion of cleaned collagen is mixed with A
1'~59'Z~6 ~3a a cross-linking agent with a quantity to result only in a partial cross-linking, whereby the quantity of said cross-linking agent is chosen such that the collagen is cross-linked only to such a degree that it retains its resorbability and its adsorptivity vis-a-vis bodily fluids and that the material does not generate undesirable side effects, and the mixture is lyophilized.
~escription of The Preferred Embodiments The starting material needed for carrying out the method of the invention can be ~btained according to the following process:
-4- lZ~ 6 1 kg bovine tendons were fr"eezed by -10 to -20C and reduced to very small pieces during 20 min. with a high speed knife homogenisator. The temperature of the ground stock was held below ~40C by adding ice bits. The thus obtained tenacious fibrous tissue pulp was suspended into 5 liters of a 10% NaCl-solution, which contained 2.5 g sodium azide and 50 ml of a 10% agueous solution of the non-lution of the non-ionic wetting agent NP 55/52*
(polyoxyethylen nonoylphenyl ether) under vigorous agitation. The suspension was agitated during two more hours by room temperature, than centrifuged. The gray to brownish colored supernatant so:Lution, containing grease and undesired water soluble ballast ~ubstances, was rejected. The remaining white skin fibers pulp was twice extracted in the same manner, whereby 0.1 mol disodium hydrogen phosphate was added per liter extraction solution.
It is also possible to use hog skin instead of bovine tendons.
A degreased and extracted fibrous tissue pulp, obtained from 1 kg bovine tendons as described above was suspended in the 5-fold volume of 0.5 M acetic acid. To the suspension was added a solution of 1 g technical pepsin in 100 ml 0.01 N HCl. The pH of the suspension was adjusted with HCl to 2.9. The suspension was digested under continuous agitation during 48 hours. The viscous collagen solution was filtrated through a suction filter Gl to eliminate non-digested rests. The collagen was precipitated by addition of 30% aqueous sodium hydroxyd solution from the suspension and separated by centrifuging. The collagen was purified by solving in 0.5 M acetic acid and precipitating by slow addition of 3%
sodium chloride. The purified collagen was solved in 0.5 M acetic acid and diluted with water. The rest of sodium chloride remaining in the collagen was removed by washing on an ultra filter. The ultra filtration was continued until no chloride ions could be detected in the eluate by * - Trade Mark ,i, ,.
` ` lZS~3~66 addition of nitrate of silver, and the collagen concentration attained ca. 1%. The collagen solution was filtrated and 0.2% in weight formaldehyd and 5 parts in weight of sintered apatite grains with a diameter of 20-1000 ~m, both with reference to the collagen content, were added to the collagen solution, agitated during ca.
20 min, molded into appropriate forms, resting several hours, lyophilized and sterilized by y-radiation Example 1 600 g of ultra-filtrated collagen solution obtained according to the above described process with a collagen content of 0.88% in weight were filtrated clear and mixed with 10.6 ml of a 0.1% aqueous formaldehyd solution and agitated. To the solution were added under agitation 26.4 g sintered apatite grains with a diameter of 50-150 ~m and stirred during 22 minutes. The pH of the solution rised during agitated from initial 3.5 to 6.35. The thus obtained solution was poured into portions of 70 g into polystyrol cups with the dimensions of 12 x 7.5 cm, kept standing over night, lyophilized the day after, then packed and sterilized by y-radiation with a dose of 2.5 Mrad.
Example 2 To 800 g of ultra-filtrated collagen solution obtained according to the above-described process with a collagen content of 1.07% in weight was added 6.83 ml of a 25% in weight, aqueous glutaraldehyd solution and 17.2 =
twice the guantity, with reference of the collgen content, of sintered apatite, resp. tricalcium phosphate grains with a diameter of 300-700 ~m, agitated for half an hour, kept standing for 10 hours and poured into portions of 18 g into cups with the dimensions of 6.3 x 3.8 cm, lyophilized, packed and sterilized by y-radiation with a dose of 2.5 Mrad.
Example 3 200 g of ultra-filtrated collagen solution obtained according to the above-described process with a collagen lZ~Z6~i content of 0.97% in weight were mixed with 5.82 g = the three fold quantity, with reference to the collagen content, of sintered apatite grains of a diameter of ca.
10~ ~m, agitated for half an hour, poured into portions of 40 g into circular cups with a diameter of 8 cm and lyophilized. The thus obtained material was unstable vis-a-vis aqueous solutions and was therefore partially cross-linked by exposing it to formaldehyd gases during two hours in a closed chamber charged with a 35% in weight formaldehyd solution. Afterwards, the formaldehyd solution was removed and the chamber was e~acuated and ventilated 6 times to remove the unbound formaldehyd gas from the collagen apatite material. At the third aeration the air was conducted through an aqueous ammonium hydroxyd solution to bond the last rest quantities of the formaldehyd to the incoming ammonia. The thus obtained bone substitute material was stable vis-a-vis aqueous solutions after this treatment and suited for the implantation by bone defects, after sterilization.
It follows from this example that good results can be obtained with a quantity of formaldehyd, which lies under 1% in weight, with reference to the dry weight of the collagen, preferably in a 0.05-0.5% in weight. For the use of other aldehydes, the corresponding quantity has to be taken.
Besides the mentioned form- and glutaraldehydes a saturated or unsaturated, mono- or polyfunctional aliphatic aldehyd, glyoxal, unsubstituted or substituted di- or tri- chlortriazine can be used. As gaseous cross-linking agent ethylen oxide can be used also.
It is preferable to increase the mechanical strength of the bone substitute material by combining it with honeycomb-, network-, layer like or textile tissue similar looking ~weaved, twisted, knitted) supporting elements of plastic material, textile, metal, alumina, ceramics, carbon fibers tissue, bone cement, glas fibers or bioglas fibers. Said supporting elements can have ~he form of the 61560/i8/1-1-1/ll iZ5~3Z6G
bone to be replaced. It is also possible to add antibiotics to the bone substitute material.
For compacting, the bone substitute material can be compressed in the dry or wet state, if needed under heating.
` The foregoing disclosure and description of the invention are illustrative and explanatory thereof and various changes in the size, shape and materials as well as in the details of the preferred embodiment may be made within departing from the spirit of the invention.
Title: A METHOD OF PRODUCING A BONE
SUBSTITUTE MATERIAL
Specificatio_ Back~round of The In~ention The patent application refers to a method of producing a bone substitute material, mainly of collagen and a mineral component consisting of apatite, tricalcium phosphate (a and ~) and/or hydroxyl apatite and/or calcium phosphate ceramics. Such a method is described in the U.S. patent no. 4,516,276 of the same assignee. Extensive clinical studies have been published in the German publication "Zeitschrift fur Orthopadie" 121 (1983), pages 115-123, H. Mittelmeier, B.D. Katthagen, from where it follows that an encouraging and satisfying success has been obtained.
These studies further showed that the material, in spite of a further termal treatment and chloric acid vaporization, was still relatively delispescent during clinical insertion into the tissue, in particular whilst soaking with blood and tissue fluids, and that the generation of bone tissue was not marked enough.
Accordingly, a more compact material would be desirable, which further would create a better~stimulation of the bone growth.
The PCT publication No. W 081/00963 discloses a method of producing a collagen material which, after Express Mail N~. B41947903 ~2S926~
admixing finely grained apatite,.served as bone substitute - material for the above-mentioned studies. As mentioned in said publication, an essential increase of the absorbency and the mechanical strength relative to previously known collagen fleeces has been obtained by subjecting the collagen material to a further heat treatment or a treatment with gaseous haloid acids.
From the same publication follows that it was known to improve the physico-chemical properties of collagen and gelatine products on chemical basis, for example by cross-linking with aldehydes, in particular formaldehyd or glutaraldehyd. It is stated that those methods have the drawback that the thus obtained products are resorbed only very slowly or not at all by the body when implantated and cause inflammations, defense reactions or the production of foreign substance macro cells. The cross-linking of the collagen products with aldehydes has been effectuted in an exhaustive manner, resulting in completely cross-linked, plastic material like products which are recognized by the organism as foreign substance and thus cause the mentioned harmful reactions. Rest quantities of free aldehyd in the implantate are also harming the tissue.
The publication Jap. Traumat. Surg. (1982) 99, pages 265-269 of K. Hayashi et al discloses a collagen-hydroxyl apatite preparation, which was freeze-dried after cross-linking. On one hand, relatively finely grained apatite has been used and on the other hand no hint has been given that the quantity of the admixed glutaraldehyd should be such that none of the above-mentioned reactions occurs.
Summary of The Invention Accordingly, it is an object of the present invention to provide a method for the ~roduction of a bone substitute material, which material is more compact and stronger and more tear resistant than previously known material, and which further stimulates the natural bone development to grow at and into the material, without causing the aforementioned undesirable effects.
According to the invention it has been found that a partial cross-linking with formaldehyd or glutaradehyd instead of a total, exhaustive cross-linking provides for a substantial improvement of the physico-chemical properties of the collagen without causing any negative effects to the organism after the implantation or any harm due to remaining quantities of aldehyd.
As mentioned above, finely grained apatite, resp.
tricalcium phosphate powder with particle sizes of 3-5 ~m has been used for performing the experiments with the ~nown material. It has been found that the osteogenetic efficiency can be increased substantially if the apatite is used in form of powder aggregates or as particles of a larger size. This increase of the particle size can be attained by sintering commercially available fine cristal-line apatite or tricalcium phosphate to grains of a diameter of 20-1000 ~m, preferably 50-300 ~m.
Experiments to this effect have shown that bone substitute material consisting of collagen partially cross-linked with ~ormaldehyd, and apatite resp. tricalcium phosophate in form of sintered grains which are added to the collagen solution before the freeze drying furnish substantial improved results over the previously known bone substitute material. Thus, this new material is suited for a larger indication range. It is particularly advantageous to distribute the apatite grains in the collagen analog to the cross points of the mineral structures in the natural bone, thus providing a matrix for the restitution of the bone, which is similar to the bone to be restituted.
In accordance with an aspect of the invention there is provided a method of producing a bone substitute material from collagen and a mineral component~ said mineral component comprising apatite and/or hydroxyl apatite and/or calcium phosphate ceramics, wherein an aqueous solution or a dispersion of cleaned collagen is mixed with A
1'~59'Z~6 ~3a a cross-linking agent with a quantity to result only in a partial cross-linking, whereby the quantity of said cross-linking agent is chosen such that the collagen is cross-linked only to such a degree that it retains its resorbability and its adsorptivity vis-a-vis bodily fluids and that the material does not generate undesirable side effects, and the mixture is lyophilized.
~escription of The Preferred Embodiments The starting material needed for carrying out the method of the invention can be ~btained according to the following process:
-4- lZ~ 6 1 kg bovine tendons were fr"eezed by -10 to -20C and reduced to very small pieces during 20 min. with a high speed knife homogenisator. The temperature of the ground stock was held below ~40C by adding ice bits. The thus obtained tenacious fibrous tissue pulp was suspended into 5 liters of a 10% NaCl-solution, which contained 2.5 g sodium azide and 50 ml of a 10% agueous solution of the non-lution of the non-ionic wetting agent NP 55/52*
(polyoxyethylen nonoylphenyl ether) under vigorous agitation. The suspension was agitated during two more hours by room temperature, than centrifuged. The gray to brownish colored supernatant so:Lution, containing grease and undesired water soluble ballast ~ubstances, was rejected. The remaining white skin fibers pulp was twice extracted in the same manner, whereby 0.1 mol disodium hydrogen phosphate was added per liter extraction solution.
It is also possible to use hog skin instead of bovine tendons.
A degreased and extracted fibrous tissue pulp, obtained from 1 kg bovine tendons as described above was suspended in the 5-fold volume of 0.5 M acetic acid. To the suspension was added a solution of 1 g technical pepsin in 100 ml 0.01 N HCl. The pH of the suspension was adjusted with HCl to 2.9. The suspension was digested under continuous agitation during 48 hours. The viscous collagen solution was filtrated through a suction filter Gl to eliminate non-digested rests. The collagen was precipitated by addition of 30% aqueous sodium hydroxyd solution from the suspension and separated by centrifuging. The collagen was purified by solving in 0.5 M acetic acid and precipitating by slow addition of 3%
sodium chloride. The purified collagen was solved in 0.5 M acetic acid and diluted with water. The rest of sodium chloride remaining in the collagen was removed by washing on an ultra filter. The ultra filtration was continued until no chloride ions could be detected in the eluate by * - Trade Mark ,i, ,.
` ` lZS~3~66 addition of nitrate of silver, and the collagen concentration attained ca. 1%. The collagen solution was filtrated and 0.2% in weight formaldehyd and 5 parts in weight of sintered apatite grains with a diameter of 20-1000 ~m, both with reference to the collagen content, were added to the collagen solution, agitated during ca.
20 min, molded into appropriate forms, resting several hours, lyophilized and sterilized by y-radiation Example 1 600 g of ultra-filtrated collagen solution obtained according to the above described process with a collagen content of 0.88% in weight were filtrated clear and mixed with 10.6 ml of a 0.1% aqueous formaldehyd solution and agitated. To the solution were added under agitation 26.4 g sintered apatite grains with a diameter of 50-150 ~m and stirred during 22 minutes. The pH of the solution rised during agitated from initial 3.5 to 6.35. The thus obtained solution was poured into portions of 70 g into polystyrol cups with the dimensions of 12 x 7.5 cm, kept standing over night, lyophilized the day after, then packed and sterilized by y-radiation with a dose of 2.5 Mrad.
Example 2 To 800 g of ultra-filtrated collagen solution obtained according to the above-described process with a collagen content of 1.07% in weight was added 6.83 ml of a 25% in weight, aqueous glutaraldehyd solution and 17.2 =
twice the guantity, with reference of the collgen content, of sintered apatite, resp. tricalcium phosphate grains with a diameter of 300-700 ~m, agitated for half an hour, kept standing for 10 hours and poured into portions of 18 g into cups with the dimensions of 6.3 x 3.8 cm, lyophilized, packed and sterilized by y-radiation with a dose of 2.5 Mrad.
Example 3 200 g of ultra-filtrated collagen solution obtained according to the above-described process with a collagen lZ~Z6~i content of 0.97% in weight were mixed with 5.82 g = the three fold quantity, with reference to the collagen content, of sintered apatite grains of a diameter of ca.
10~ ~m, agitated for half an hour, poured into portions of 40 g into circular cups with a diameter of 8 cm and lyophilized. The thus obtained material was unstable vis-a-vis aqueous solutions and was therefore partially cross-linked by exposing it to formaldehyd gases during two hours in a closed chamber charged with a 35% in weight formaldehyd solution. Afterwards, the formaldehyd solution was removed and the chamber was e~acuated and ventilated 6 times to remove the unbound formaldehyd gas from the collagen apatite material. At the third aeration the air was conducted through an aqueous ammonium hydroxyd solution to bond the last rest quantities of the formaldehyd to the incoming ammonia. The thus obtained bone substitute material was stable vis-a-vis aqueous solutions after this treatment and suited for the implantation by bone defects, after sterilization.
It follows from this example that good results can be obtained with a quantity of formaldehyd, which lies under 1% in weight, with reference to the dry weight of the collagen, preferably in a 0.05-0.5% in weight. For the use of other aldehydes, the corresponding quantity has to be taken.
Besides the mentioned form- and glutaraldehydes a saturated or unsaturated, mono- or polyfunctional aliphatic aldehyd, glyoxal, unsubstituted or substituted di- or tri- chlortriazine can be used. As gaseous cross-linking agent ethylen oxide can be used also.
It is preferable to increase the mechanical strength of the bone substitute material by combining it with honeycomb-, network-, layer like or textile tissue similar looking ~weaved, twisted, knitted) supporting elements of plastic material, textile, metal, alumina, ceramics, carbon fibers tissue, bone cement, glas fibers or bioglas fibers. Said supporting elements can have ~he form of the 61560/i8/1-1-1/ll iZ5~3Z6G
bone to be replaced. It is also possible to add antibiotics to the bone substitute material.
For compacting, the bone substitute material can be compressed in the dry or wet state, if needed under heating.
` The foregoing disclosure and description of the invention are illustrative and explanatory thereof and various changes in the size, shape and materials as well as in the details of the preferred embodiment may be made within departing from the spirit of the invention.
Claims (16)
1. A method of producing a bone substitute material from collagen and a mineral component, said mineral component comprising apatite and/or hydroxyl apatite and/or calcium phosphate ceramics, wherein an aqueous solution or a dispersion of cleaned collagen is mixed with a cross-linking agent with a quantity to result only in a partial cross-linking, whereby the quantity of said cross-linking agent is chosen such that the collagen is cross-linked only to such a degree that it retains its resorbability and its absorbing power vis-a-vis bodily fluids and that the material does not generate undesirable side effects, and the mixture is lyophilized.
2. The method according to claim 1, wherein said mineral component is apatite, in particular sintered hydroxyl apatite or calcium phosphate with a grain diameter of 20-1,000 µm.
3. The method according to claim 1, wherein the proportion of collagen to the mineral component is from 1:2 to 1:10.
4. The method according to claim 1, wherein an aqueous solution or dispersion of cleaned collagen is mixed with the mineral component grains, the mixture is lyophilized and the thus obtained lyophilisate is treated with a gaseous cross-linking agent.
5. The method according to claim 4, wherein the gaseous cross-linking agent is gaseous formaldehyde or ethylenoxide.
6. The method according to claim 1, wherein the cross-linking agent is a saturated or unsaturated, mono- or poly-functional aliphatic aldehyde.
7. The method according to claim 6, wherein said aldehyde is formaldehyde, glutaraldehyde or glyoxal.
8. The method according to claim 1, wherein the partial cross-linking of the collagen is effectuated with formaldehyde in a quantity below 1% in weight, with reference to the dry weight of the collagen, or the equivalent quantity of another aldehyde.
9. The method according to claim 1, wherein the cross-linking agent is an unsubstituted or substituted di-or trichlortriazine.
10. The method according to claim 1, wherein an antibiotic is added to the collagen and mineral component or to the material produced from it.
11. The method according to claim 1, wherein said bone substitute material is piled up on a honeycomb-like or porous basic structure.
12. The method according to claim 11, wherein the honeycomb-like basic structure is made of plastics material, textile, metal, ceramics, carbon fibers tissue or bone cement.
13. The method according to claim 1, wherein the bone substitute material is compressed in a dry or wet state, with or without heat treatment.
14. The method of claim 1, wherein said mineral component is apatite, in particular sintered hydroxyl apatite or calcium phosphate with a grain diameter of 50-300 µm.
15. The method of claim 1, wherein the proportion of collagen to the mineral component is from 1:3 to 1:5.
16. The method of claim 1, wherein the partial cross-linking of the collagen is effectuated with formaldehyde in a quantity below 0.05 to 0.5% in weight, with reference to the dry weight of the collagen, or the equivalent quantity of another aldehyde.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP84810288.5 | 1984-06-12 | ||
| EP84810288A EP0164483B1 (en) | 1984-06-12 | 1984-06-12 | Method of producing a bone replacement material |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1259266A true CA1259266A (en) | 1989-09-12 |
Family
ID=8193023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000483643A Expired CA1259266A (en) | 1984-06-12 | 1985-06-11 | Method of producing a bone substitute material |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4623553A (en) |
| EP (1) | EP0164483B1 (en) |
| JP (1) | JPS6145768A (en) |
| CA (1) | CA1259266A (en) |
| DE (1) | DE3479402D1 (en) |
Families Citing this family (90)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3325111A1 (en) * | 1983-07-12 | 1985-01-24 | Merck Patent Gmbh, 6100 Darmstadt | IMPLANTATION MATERIALS |
| DE3447583A1 (en) * | 1984-12-28 | 1986-07-10 | Battelle-Institut E.V., 6000 Frankfurt | METHOD FOR PRODUCING IMPLANTABLE BONE REPLACEMENT MATERIALS |
| CA1260391A (en) * | 1985-03-28 | 1989-09-26 | Karl A. Piez | Xenogeneic collagen/mineral preparations in bone repair |
| US5246457A (en) * | 1985-03-28 | 1993-09-21 | Collagen Corporation | Xenogeneic collagen/mineral preparations in bone repair |
| US4992226A (en) * | 1985-03-28 | 1991-02-12 | Collagen Corporation | Method of making molds with xenogeneic collagen/mineral preparations for bone repair |
| FR2585576B1 (en) * | 1985-07-30 | 1992-01-03 | Bioetica Sa | BONE MATRIX REPLACEMENT PROMOTING OSTEOGENESIS |
| US5904718A (en) * | 1986-03-27 | 1999-05-18 | Biocoll Laboratories, Inc. | Delayed drug delivery system |
| GB8616416D0 (en) * | 1986-07-04 | 1986-08-13 | Ethicon Inc | Polyurethane medical prostheses |
| FI80605C (en) * | 1986-11-03 | 1990-07-10 | Biocon Oy | Bone surgical biocomposite material |
| US4865602A (en) * | 1986-11-06 | 1989-09-12 | Collagen Corporation | Gamma irradiation of collagen/mineral mixtures |
| US4944754A (en) * | 1987-04-29 | 1990-07-31 | Vent-Plant Corporation | Method of manufacturing synthetic bone coated surgical implants |
| EP0322250B1 (en) * | 1987-12-23 | 1991-10-09 | Sumitomo Chemical Company, Limited | Coating liquor containing hydroxyapatite and method for forming hydroxyapatite coating film using the same |
| US5073114A (en) * | 1988-02-23 | 1991-12-17 | Detsch Steven G | Bone growing method and composition |
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|---|---|---|---|---|
| US3443261A (en) * | 1967-09-01 | 1969-05-13 | Fmc Corp | Prosthetic structures from microcrystalline collagen |
| DE2905878A1 (en) * | 1979-02-16 | 1980-08-28 | Merck Patent Gmbh | IMPLANTATION MATERIALS AND METHOD FOR THEIR PRODUCTION |
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| CA1190855A (en) * | 1980-09-03 | 1985-07-23 | Rolf W. Pfirrmann | Treatment of osteitis |
| US4430760A (en) * | 1981-12-18 | 1984-02-14 | Collagen Corporation | Nonstress-bearing implantable bone prosthesis |
-
1984
- 1984-06-12 DE DE8484810288T patent/DE3479402D1/en not_active Expired
- 1984-06-12 EP EP84810288A patent/EP0164483B1/en not_active Expired
-
1985
- 1985-06-04 US US06/741,170 patent/US4623553A/en not_active Expired - Lifetime
- 1985-06-11 JP JP60127014A patent/JPS6145768A/en active Granted
- 1985-06-11 CA CA000483643A patent/CA1259266A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| EP0164483B1 (en) | 1989-08-16 |
| EP0164483A1 (en) | 1985-12-18 |
| JPS6145768A (en) | 1986-03-05 |
| US4623553A (en) | 1986-11-18 |
| DE3479402D1 (en) | 1989-09-21 |
| JPH0522547B2 (en) | 1993-03-29 |
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