WO2001023013A1 - Implant material - Google Patents

Implant material Download PDF

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Publication number
WO2001023013A1
WO2001023013A1 PCT/GB2000/003131 GB0003131W WO0123013A1 WO 2001023013 A1 WO2001023013 A1 WO 2001023013A1 GB 0003131 W GB0003131 W GB 0003131W WO 0123013 A1 WO0123013 A1 WO 0123013A1
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WO
WIPO (PCT)
Prior art keywords
carbon dioxide
bone ash
dioxide gas
removal process
impurity removal
Prior art date
Application number
PCT/GB2000/003131
Other languages
French (fr)
Inventor
John Joseph Cooper
Original Assignee
Biocomposites Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Biocomposites Limited filed Critical Biocomposites Limited
Priority to AU64606/00A priority Critical patent/AU6460600A/en
Publication of WO2001023013A1 publication Critical patent/WO2001023013A1/en

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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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • 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
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking

Definitions

  • This invention concerns a method of producing an implant material, and also a material made by such a method.
  • An effective bone graft material such as for use in orthopaedic and dental surgical procedures is required to elicit no adverse tissue response, pose no threat of transmissible diseases and promote the formation of new bone tissue through either osteoconduction or osteoinduction. To satisfy all these requirements the graft material is required to possess certain chemical and physical characteristics.
  • the ideal graft material is autograft which is the patients own bone.
  • its availability is limited and its harvesting involves a second surgical procedure which is time consuming and costly.
  • donor site morbidity is a significant problem.
  • Allograft material such as from a bone bank has been a popular alternative.
  • Its clinical outcome is variable and unpredictable, while its availability is being restricted by the increasing stringency of processing and testing required to help minimise the risk of transmissible diseases. A finite risk however, still remains which can pose a serious threat to the health of recipients.
  • Any natural bone graft material whether of animal (xenograft), or human (allograft) origin which contains any residual organic matter can elicit an adverse tissue response, in addition to being potentially a carrier of serious transmissible disease.
  • Synthetic bone graft materials which include hydroxyapatite and tri- calcium phosphate can have acceptable levels of bioactivity while at the same time be readily available and safe in use. A predictable clinical response is important and this is helped by ensuring consistent chemical and physical characteristics of the graft material. Both microporosity, (1-10 microns) and macroporosity, (100-1000 microns) are very important to the performance of a graft material. These parameters are vital for cell attachment, colonisation and vascularisation of the graft site.
  • the natural mineral constituent of bone is hydroxyapatite with the chemical formula Ca ⁇ o (PO 4 ) 6 (OH) 2 .
  • Animal bone is a convenient source of this material and when prepared as an anorganic material i.e. one that is devoid of all organic matter, has certain desirable properties.
  • an ashing procedure is usually adopted. Due to the variable nature of bone in terms of chemical composition and the presence of chemical impurities such as carbonate, sodium and magnesium ions, during ashing these are released from the hydroxyapatite and give alkaline oxides of sodium, calcium and magnesium.
  • this ashed bone, ceramic hydroxyapatite is exposed to an aqueous environment the pH becomes very alkaline and can rise to 12 or more.
  • various washing treatments have been proposed. These usually involve the use of copious amounts of water or certain dilute acids. However, because of the low solubility of some of the chemical species these treatments are not always fully effective, and in addition, the handling of acids can have environmental and safety issues.
  • a method of producing an implant material comprising subjecting bone ash to an impurity removal process, which process comprises introducing the bone ash to an aqueous environment which contains carbon dioxide gas, or into which environment carbon dioxide gas is introduced.
  • the carbon dioxide gas may be provided in the impurity removal process by any of introduction of carbon dioxide gas direct, addition of dry ice or introduction of relatively large volumes of air.
  • the carbon dioxide gas or air may be bubbled through an aqueous suspension of bone ash.
  • the impurity removal process may be carried out until a particular pH level is reached.
  • the material formed may be filtered and/or washed.
  • the washing may be with water which may have been slightly acidified with carbon dioxide.
  • the material formed may subsequently be dried, and perhaps by spray drying.
  • the material formed may be sintered, and preferably at a temperature of between 1000 and 1400°C.
  • the bone ash may be in the form of a powder.
  • the bone ash may be formed from animal bones.
  • the bone ash may be formed by heating bones to a temperature of between 600 and 1000°C.
  • the bones may be boiled with water prior to heating, and the supernatant liquid may be removed during and/or after boiling.
  • the invention also provides an implant material made by a method according to any of the preceding eight paragraphs.
  • Raw beef bones were mechanically freed from extraneous soft tissue. They were reduced in size to dimensions of a few centimetres and boiled in water for 1-2 hours. The supernatant liquid was removed and the process repeated.
  • the boiled bone was dried and powdered in a comminuting mill.
  • the resulting bone meal powder was placed into a refractory crucible, in a kiln and ashed by subjecting to a temperature of 650°C for ten hours.
  • the resulting white bone ash powder was then suspended in distilled water, 200gms of powder to 1 litre of water, in a glass beaker. The suspension was stirred and the pH was 11.8. While stirring, CO 2 gas was bubbled gently through the suspension with continuous monitoring of pH.
  • the bone meal powder from Example 1 was placed in a refractory crucible in a kiln and heated to 800°C for a period of six hours.
  • the resulting white bone ash powder was suspended in distilled water, 200gms per litre of water, in a plastic bucket and copious quantities of air were bubbled through the suspension over a period of seven days, at which point the pH had fallen from an initial value of .12.2 to a final value of 7.8.
  • the suspension was Buchner filtered, washed with a dilute carbonic acid solution and dried.
  • the powder thus formed is further processed as outlined above. X-ray diffraction analysis of the powder revealed only hydroxyapatite.
  • Cuboids 1 x 1 x 2cm of spongious bone from the ephyseal humerous of beef bones were cut with a saw. These were boiled twice in distilled water and the resulting solution discarded. These degelatinised and defatted pieces were carefully dried and then heated at 50°C/hr to 800°C and maintained at this temperature for six hours to render the material anorganic. After cooling the pieces were put into a container with a carbonic acid solution and the pH was maintained at 6-7 with gentle bubbling of CO 2 gas and gentle agitation of the vessel for a period of 24 hours.
  • the pieces were removed from solution, washed with deionised water, dried and then sintered by heating at 60°C/hr to 1200°C and maintained at this temperature for three hours.
  • the resulting porous, ceramic hydroxyapatite had maintained the porous structure of the original bone and by X-ray diffraction consisted of only hydroxyapatite.
  • bone ash may be produced differently.
  • Carbon dioxide gas could be introduced in a different manner, for instance as dry ice, or by bubbling through relatively large quantities of air. Conditions could be used other than those described in the above examples.

Abstract

A method of producing implant material from bone ash. The bone ash is suspended in an aqueous environment which has carbon dioxide gas introduced therein to remove impurities in the bone ash until a predetermined pH is reached. The resulting material in then filtered and/or washed, dried and then processed to form a usable implant material.

Description

IMPLANT MATERIAL
This invention concerns a method of producing an implant material, and also a material made by such a method.
An effective bone graft material such as for use in orthopaedic and dental surgical procedures is required to elicit no adverse tissue response, pose no threat of transmissible diseases and promote the formation of new bone tissue through either osteoconduction or osteoinduction. To satisfy all these requirements the graft material is required to possess certain chemical and physical characteristics.
The ideal graft material is autograft which is the patients own bone. However, its availability is limited and its harvesting involves a second surgical procedure which is time consuming and costly. In addition, donor site morbidity is a significant problem. Allograft material such as from a bone bank has been a popular alternative. However, its ability to promote the formation of new healthy bone tissue is less than ideal. Its clinical outcome is variable and unpredictable, while its availability is being restricted by the increasing stringency of processing and testing required to help minimise the risk of transmissible diseases. A finite risk however, still remains which can pose a serious threat to the health of recipients.
Any natural bone graft material whether of animal (xenograft), or human (allograft) origin which contains any residual organic matter can elicit an adverse tissue response, in addition to being potentially a carrier of serious transmissible disease.
Synthetic bone graft materials which include hydroxyapatite and tri- calcium phosphate can have acceptable levels of bioactivity while at the same time be readily available and safe in use. A predictable clinical response is important and this is helped by ensuring consistent chemical and physical characteristics of the graft material. Both microporosity, (1-10 microns) and macroporosity, (100-1000 microns) are very important to the performance of a graft material. These parameters are vital for cell attachment, colonisation and vascularisation of the graft site.
The natural mineral constituent of bone is hydroxyapatite with the chemical formula Caιo(PO4)6(OH)2. Animal bone is a convenient source of this material and when prepared as an anorganic material i.e. one that is devoid of all organic matter, has certain desirable properties.
To render the bone anorganic i.e. completely free of all organic residues, an ashing procedure is usually adopted. Due to the variable nature of bone in terms of chemical composition and the presence of chemical impurities such as carbonate, sodium and magnesium ions, during ashing these are released from the hydroxyapatite and give alkaline oxides of sodium, calcium and magnesium. When this ashed bone, ceramic hydroxyapatite, is exposed to an aqueous environment the pH becomes very alkaline and can rise to 12 or more. To counteract this high pH and at the same time remove the offending impurities to give a high purity hydroxyapatite, various washing treatments have been proposed. These usually involve the use of copious amounts of water or certain dilute acids. However, because of the low solubility of some of the chemical species these treatments are not always fully effective, and in addition, the handling of acids can have environmental and safety issues.
According to the present invention there is provided a method of producing an implant material, the method comprising subjecting bone ash to an impurity removal process, which process comprises introducing the bone ash to an aqueous environment which contains carbon dioxide gas, or into which environment carbon dioxide gas is introduced.
The carbon dioxide gas may be provided in the impurity removal process by any of introduction of carbon dioxide gas direct, addition of dry ice or introduction of relatively large volumes of air. The carbon dioxide gas or air may be bubbled through an aqueous suspension of bone ash.
The impurity removal process may be carried out until a particular pH level is reached.
Following the impurity removal process, the material formed may be filtered and/or washed. The washing may be with water which may have been slightly acidified with carbon dioxide. The material formed may subsequently be dried, and perhaps by spray drying.
Following the impurity removal process, the material formed may be sintered, and preferably at a temperature of between 1000 and 1400°C.
The bone ash may be in the form of a powder. The bone ash may be formed from animal bones.
The bone ash may be formed by heating bones to a temperature of between 600 and 1000°C. The bones may be boiled with water prior to heating, and the supernatant liquid may be removed during and/or after boiling.
The invention also provides an implant material made by a method according to any of the preceding eight paragraphs.
Embodiments of the present invention will now be described by way of example only:-
Example 1
Raw beef bones were mechanically freed from extraneous soft tissue. They were reduced in size to dimensions of a few centimetres and boiled in water for 1-2 hours. The supernatant liquid was removed and the process repeated. The boiled bone was dried and powdered in a comminuting mill. The resulting bone meal powder was placed into a refractory crucible, in a kiln and ashed by subjecting to a temperature of 650°C for ten hours. The resulting white bone ash powder was then suspended in distilled water, 200gms of powder to 1 litre of water, in a glass beaker. The suspension was stirred and the pH was 11.8. While stirring, CO2 gas was bubbled gently through the suspension with continuous monitoring of pH. When the pH had fallen to a value of 6.8 after three hours, the bubbling was stopped. The resulting suspension was then filtered on a Buchner Filter and washed through twice with distilled water which had been slightly acidified with CO.,. The filter cake was dried. Spray drying could be used to form spherical particles. The powder thus formed is further processed by any conventional route such as sintering to form a usable implant material. X-ray diffraction analysis identified hydroxyapatite as the only phase detected.
Example 2
The bone meal powder from Example 1 was placed in a refractory crucible in a kiln and heated to 800°C for a period of six hours. The resulting white bone ash powder was suspended in distilled water, 200gms per litre of water, in a plastic bucket and copious quantities of air were bubbled through the suspension over a period of seven days, at which point the pH had fallen from an initial value of .12.2 to a final value of 7.8. The suspension was Buchner filtered, washed with a dilute carbonic acid solution and dried. The powder thus formed is further processed as outlined above. X-ray diffraction analysis of the powder revealed only hydroxyapatite. Chemical analysis by X- ray fluorescence spectroscopy gave the result shown in the table below in column b. This is compared to bone ash which had not been subsequently treated - column a, and also to bone ash which had been washed with a citric acid solution - column c.
By way of comparison, the ashed only beef bone was examined by X-ray diffraction and found to contain 1.296 magnesium oxide, 2.396 calcium oxide and minor amounts of other, unidentified, phases. Hydroxyapatite content was 9696.
CaO 53.94 55.18 55.64 pA 40.97 42.16 41.77
MgO 1.02 0.10 0.15
Na2O 0.91 0.24 0.35 κ2o 0.02 <0.01 <0.01
SiO2 <0.02 <0.02 0.05
Al2O3 <0.02 <0.02 0.03
ZnO 0.01 <0.01 0.02
BaO 0.01 0.02 0.06
SrO 0.02 0.02 0.02 loss on Ignition 2.49 1.51 0.90
Total 99.39 99.23 98.99
Ca: P Molar Ratio 1.666 1.656 1.686
(Theoretical = 1.667)
Example 3
Cuboids 1 x 1 x 2cm of spongious bone from the ephyseal humerous of beef bones were cut with a saw. These were boiled twice in distilled water and the resulting solution discarded. These degelatinised and defatted pieces were carefully dried and then heated at 50°C/hr to 800°C and maintained at this temperature for six hours to render the material anorganic. After cooling the pieces were put into a container with a carbonic acid solution and the pH was maintained at 6-7 with gentle bubbling of CO2 gas and gentle agitation of the vessel for a period of 24 hours. The pieces were removed from solution, washed with deionised water, dried and then sintered by heating at 60°C/hr to 1200°C and maintained at this temperature for three hours. The resulting porous, ceramic hydroxyapatite had maintained the porous structure of the original bone and by X-ray diffraction consisted of only hydroxyapatite.
There is thus described a method for making implant material, which method gives a high purity hydroxyapatite having low levels of alkalinity. The method is much safer to use than previous arrangements and also cost effective, efficient, highly controllable and environmentally friendly.
Various modifications may be made without departing from the scope of the invention. For example the bone ash may be produced differently. Carbon dioxide gas could be introduced in a different manner, for instance as dry ice, or by bubbling through relatively large quantities of air. Conditions could be used other than those described in the above examples.
Whilst endeavouring in the foregoing specification to draw attention to those features of the invention believed to be of particular importance it should be understood that the Applicant claims protection in respect of any patentable feature or combination of features hereinbefore referred to and/or shown in the drawings whether or not particular emphasis has been placed thereon.

Claims

Claims
1. A method of producing an implant material, the method comprising subjecting bone ash to an impurity removal process, characterised in that the process comprises introducing the bone ash to an aqueous environment which contains carbon dioxide gas, or into which environment carbon dioxide gas is introduced.
2. A method according to claim 1, characterised in that the carbon dioxide gas is provided in the impurity removal process by any of introduction of carbon dioxide gas direct, addition of dry ice or introduction of relatively large volumes of air.
3. A method according to claims 1 or 2, characterised in that the carbon dioxide gas or air is bubbled through an aqueous suspension of bone ash.
4. A method according to any of claims 1 to 3, characterised in that the impurity removal process is carried out until a particular pH level is reached.
5. A method according to any of the preceding claims, characterised in that following the impurity removal process, the material formed is filtered and/or washed.
6. A method according to claim 5, characterised in that the washing is with water.
7. A method according to claim 6, characterised in that the water has been slightly acidified with carbon dioxide.
8. A method according to any of claims 5 to 7, characterised in that the material formed is subsequently dried.
9. A method according to claim 8, characterised in that the material formed is subsequently dried by spray drying.
10. A method according to any of the preceding claims, characterised in that following the impurity removal process, the material formed is sintered.
11. A method according to claim 10, characterised in that the material formed is sintered at a temperature of between 1000 and 1400°C.
12. A method according to any of the preceding claims, characterised in that the bone ash is in the form of a powder.
13. A method according to any of the preceding claims, characterised in that the bone ash is formed from animal bones.
14. A method according to claim 13, characterised in that the bone ash is formed by heating bones to a temperature of between 600 and 1000°C.
15. A method according to claim 14, characterised in that the bones are boiled with water prior to heating.
16. A method according to claim 15, characterised in that the supernatant liquid is removed during and/or after boiling.
17. An implant material made by a method according to any of the preceding claims.
18. Any novel subject matter or combination including novel subject matter disclosed herein, whether or not within the scope of or relating to the same invention as any of the preceding claims.
PCT/GB2000/003131 1999-09-24 2000-08-11 Implant material WO2001023013A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64606/00A AU6460600A (en) 1999-09-24 2000-08-11 Implant material

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9922562.5 1999-09-24
GBGB9922562.5A GB9922562D0 (en) 1999-09-24 1999-09-24 Implant material

Publications (1)

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WO2001023013A1 true WO2001023013A1 (en) 2001-04-05

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GB (1) GB9922562D0 (en)
WO (1) WO2001023013A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1931399B1 (en) * 2005-08-29 2010-05-26 Sanatis GmbH Bone cement composition and method of making the same
US20150335785A1 (en) * 2014-05-20 2015-11-26 Reed Ayers Constructs containing bone tissue and methods for making the same
US10118827B2 (en) 2013-05-10 2018-11-06 Reed A. Ayers Combustion synthesis of calcium phosphate constructs and powders doped with atoms, molecules, ions, or compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB184206A (en) * 1921-11-10 1922-08-17 John Guilfoyle Williams Improved process of manufacturing soluble phosphates
US5306302A (en) * 1990-09-10 1994-04-26 Merck Patent Gesellschaft Mit Beschrankter Haftung Implant material

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB184206A (en) * 1921-11-10 1922-08-17 John Guilfoyle Williams Improved process of manufacturing soluble phosphates
US5306302A (en) * 1990-09-10 1994-04-26 Merck Patent Gesellschaft Mit Beschrankter Haftung Implant material

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1931399B1 (en) * 2005-08-29 2010-05-26 Sanatis GmbH Bone cement composition and method of making the same
US10118827B2 (en) 2013-05-10 2018-11-06 Reed A. Ayers Combustion synthesis of calcium phosphate constructs and powders doped with atoms, molecules, ions, or compounds
US20150335785A1 (en) * 2014-05-20 2015-11-26 Reed Ayers Constructs containing bone tissue and methods for making the same

Also Published As

Publication number Publication date
GB9922562D0 (en) 1999-11-24
AU6460600A (en) 2001-04-30

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