CA2237148A1 - Bioactive composite material for repair of hard and soft tissues - Google Patents
Bioactive composite material for repair of hard and soft tissues Download PDFInfo
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- CA2237148A1 CA2237148A1 CA002237148A CA2237148A CA2237148A1 CA 2237148 A1 CA2237148 A1 CA 2237148A1 CA 002237148 A CA002237148 A CA 002237148A CA 2237148 A CA2237148 A CA 2237148A CA 2237148 A1 CA2237148 A1 CA 2237148A1
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- Prior art keywords
- composite
- bioactive glass
- soft tissue
- bioactive
- prosthesis
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C4/00—Compositions for glass with special properties
- C03C4/0007—Compositions for glass with special properties for biologically-compatible glass
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- 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
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C1/00—Ingredients generally applicable to manufacture of glasses, glazes, or vitreous enamels
- C03C1/006—Ingredients generally applicable to manufacture of glasses, glazes, or vitreous enamels to produce glass through wet route
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C11/00—Multi-cellular glass ; Porous or hollow glass or glass particles
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C12/00—Powdered glass; Bead compositions
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C14/00—Glass compositions containing a non-glass component, e.g. compositions containing fibres, filaments, whiskers, platelets, or the like, dispersed in a glass matrix
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
- C08K3/20—Oxides; Hydroxides
- C08K3/22—Oxides; Hydroxides of metals
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L23/00—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
- C08L23/02—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers not modified by chemical after-treatment
- C08L23/04—Homopolymers or copolymers of ethene
- C08L23/06—Polyethene
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/924—Material characteristic
Abstract
Composites suitable for use as prostheses for attachment to soft tissues, such as cartilage, tendons, skin, tympanic membrane and gingiva, as well as to cancellous or trabecular bone, are based on combination of a polyolefinic binder with certain bioactive glass materials. The composites bond actively with soft tissues and are readily formulated to achieve mechanical properties comparable to those of the soft tissue of interest.
Description
CA 02237148 1998-0~-08 BIOACTIVE COMPOSITE MATERIAL FOR REPAIR
OF HARD AND SOFT TISSUES
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to composite materials, and in particular to materials suitable for surgical implantation as replacements for various hard and soft tissue structures.
Description of the Related Art Historically, materials used in endoprosthesis (i.e., the replacement of internal anatomical structures with artificial appliances) have largely been "bioinert". Metallic alloys, such as stainless steel or cobalt chro,l,iul-l, are typically superior in strength to the structures they replace but do not interact chemically or interfacially with surrounding tissue. Although they avoid the many problems arising from tissue incompatibility, bioinert materials can never become fully integrated within their in vivo environment. As a consequence, the prosthesis frequently detaches from the tissue to which it was originally affixed, resulting in prosthetic loosening. Moreover, modulus mismatching between the appliance and the replaced structure can lead to stress shielding, resulting in poor mechanical compatibility. Bioinert ceramics such as alumina, for example, are stiffer than bone and also exhibit inferior fracture toughness.
An alternative approach is disclosed in U.S. Patent No. 5,017,627, which sets forth various compositions that, when fabricated and CA 02237148 1998-0~-08 W O 97/17401 PC~US96/17939 im~l~nte-l as prosthetic devices, remain anchored to :juliuu~ding tissue.
The composite materials described in the '627 patent are based on a polyolefinic binder cont~ining a particulate inorganic solid. Disclosed particulate solids include calcium salts such as hyd~ y~patite (HA) or s fluor~p~tite, chalk, flyash and silica. Tn~te~cl of rem~ining biologically inert, the composite materials instead exhibit "bioactive" behavior, establishing interfacial bonds to compact bone. The ratio of polyolefin to particulate material can be varied to obtain different values of Young's modulus and strain-to-failure and different amounts of o interfacial bonding. Importantly, the composite can be made ductile.
While versatile, this type of material exhibits certain lirnitations.
In particular, the range of mechanical properties obtainable according to the '627 patent is relatively limited due to the high HA loading levels necessary to achieve bioactivity. The available values of Young's modulus, for example, tend to be comparable with compact (cortical) bone, but not cancellous bone or soft tissues.
Moreover, soft tissues (such as tendons, ligaments, cartilage and skin) tend to be among the most resistant to adhesion altogether. Even composites containing very high HA concentrations do not stimulate significant interfacial bonding in such tissues. Thus, current materials are both mechanically and chemically unsuited as prostheses for repair of soft-tissue structures.
CA 02237148 1998-0~-08 DESCRIPI ION OF THE INVENI ION
Objects of the Invention Accordillgly, it is an object of the present invention to provide c~ po~i~e materials that eYhibit high degrees of bioactivity and rapidly s establish interfacial bonds with ~u~ unding tissue.
It is another object of the invention to achieve, with synthetic bioactive materials, mechanical compatibility with a range of hard and soft tissues.
It is still another object of the invention to provide prosthetic 10 replacements whose bioactivity level can be selected to achieve a wide range of predetermined, in vivo ~tt~-~hment durations.
Other objects will, in part, be obvious and will, in part, appear hereinafter. The invention accordingly comprises an article of manufacture posses~ing the features and properties exemplified in the lS constructions descAbed herein and the several steps and the relation of one or more of such steps with respect to the others and the apparatus embodying the features of construction, combination of elements and the arrangement of parts that are adapted to effect such steps, all as ~-Y~mplified in the following summary and detailed description, and the 20 scope of the invention will be indicated in the claims.
Bnef Summary of the Invention We have found, quite ~u~ lgly, that a polyolefinic binder can be combined with certain bioactive glass materials to produce CA 02237148 1998-0~-08 WO 97/17401 PCT~US96/17939 p~c.lt5 that not only retain high bioactivity levels, but may also be r formulated to achieve mechanical properties comparable to various soft and hard tissues over a variety of parameters, including tensile strength, fracture strain, and Young's modulus.
Bioactive glasses are well-known compositions that elicit specific physiological responses, including the provision of surface-reactive silica, calcium and phosphate groups and alkaline pH levels at interfaces with tissues. In particular, glasses composed of SiO2, Na20, CaO and P2OS
exhibit substantial bioactivity, with compositions having SiO2 levels ranging from 42% to 52% bonding to bone much more rapidly than HA.
See, e.g., Hench, "Bioceramics: From Concept to Clinic," 74 J. ,4mer.
Ceram. Soc. 1487 (1991). Such compositions also bond with exceptional efficacy to soft connective tissues.
These advantageous characteristics arise as a result of chemical reactions occurring at the surface of the glass when exposed to ambient body fluids. Ion exchange and irregular surface dissolution forms a hydrated silica gel layer that increases the presented area and enhances fc,~ alion of a microcrystalline biological apatite layer on the roughened glass. This layer, which can form in as little as a few hours in vivo, bonds not only to bone but also to collagen fibrils. The latter type of bonding, which cannot be achieved by materials such as HA or polymeric compositions (or, obviously, by bioinert materials), is required for soft-tissue bonding. Furthermore, bioactive glass in buL~c form bonds to bone with significantly greater rapidity and completeness than does HA.
By retaining the interfacial and chemical properties of bioactive gl~es, the composites of the present invention offer unique advantages as soft-tissue prostheses and for prostheses that bond to cancellous or CA 02237148 1998-0~-08 W O 97/17401 PCT~US96/17939 trabecular bone or cartilage. Our composites can be col,lplession or injection molded into appliances for replacement of or bonding to a variety of soft tissues. As used herein, the term "soft tissue" is intended to embrace cartilage, tendons, ligaments, skin, tympanic membrane, s gingiva, subcutaneous tissue, and all collagen-based connect*e tissue.
BnefD~sc ,i~lion of the Drawings The foregoing discussion will be understood more readily from the following detailed description of the invention, when taken in conjunction with the accoll-panying drawings, in which:
FIG. 1 graphically compares ductility for composites having bioactive-glass volume loading fractions of 0%, 10%, 20%, and 40%;
FIG. 2 graphically illustrates the dependence of Young's Modulus on bioactive-glass volume loading fraction;
F~G. 3 graphically illustrates the dependence of tensile strength on bioactive-glass volume loading fraction;
FIG. 4 graphically illustrates the dependence of fracture strain on bioactive-glass volume loading fraction;
FIG. S is an inked rendition of a Fourier-transform infrared spectroscopy (F~IR) spectrum that illustrates the formation of biological apatite layers on various samples in a simulated body fluid containing no calcium or phosphate ions;
FIG. 6 is an inked rendition of an FTIR spectrum that illustrates CA 02237148 1998-0~-08 the formation of biological apatite layers on various samples in a simulated body fluid that does contain calcium and phosphate ions; and ~;IG. 7 illustrates the dependence of composite bioactivity on the bioactive-glass volume loading fraction.
Detailed Descnption of the Preferred Embodiments The preferred embodiment of the present invention is a composite material comprising a particulate bioactive glass dispersed in a solid-phase polyolefin binder. The bioactive glass formula should contain 42-52% SiO2, and a suitable material is the 45S5 BIOGLASS~
product (45 wt% SiO2, 6 wt% P2Os, 24.5 wt% CaO, 24.5 wt% Na2O) marketed by U.S. Biomaterials Corp., Baltimore, MD 21236. However, other bioactive glass formulations with up to 52 wt~ SiO2 can be used in~te~cl l~he polyolefin binder is preferably a homo- or copolyolefin having a weight-average molecular weight, <Mw~, greater than 20,000, suitably greater than 100,000, and preferably in excess of 300,000, and suitably below 3,000,000 but preferably below 1,000,000. Binders with cMw> below 20,000 may not exhibit sufficient biocompatibility, while those with cMw> above 3,000,000 present processing difficulties. High-density polyethylene (HDPE) in linear form is the preferred binder material, although advantageous results can also be obtained using linear or branched polypropylene, polybutylene, or a copolymer of - 25 ethylene and at least one of propylene, bu~lene and hexene.
CA 02237148 1998-0~-08 WO 97/17401 PCTrUS96/17939 As ~ cll~ce~ in greater detail below, the glass loading fraction detel ~i"es both the mechanical properties and bioactivity level of the resulting composite, and is thelefole carefully chosen to achieve both tissue compatibility and a desired extent of attachment. Loading fractions in the range of 10% to 40% by volume are plefel,ed; however, lo~ling fractions of 5 to 50% by volume are acceptable. The bioactive glass is present in the form of ground particles. Size U~ O~ ity is not necessary to the present invention; partides having sizes ranging from 1.5 ~Lm to 150 ~m are preferred, sizes from 0.5 ~m to 500 ~Lm are o acceptable.
1. Material Preparation The composite materials of the present invention may be prepared first by compounding the polyolefin, preferably at a temperature above the softening point (in the case of HDPE, suitably between 200~ to 260~ C, and preferably between 200~ and 240~ C) with the bioactive glass in dry, particulate form. The polyolefin is advantageously introduced into the compounder first, and the bioactive glass thereafter added in small quantities until the desired volume fraction is obtained. The compounding time depends on the identities and volume fractions of the binder and bioactive glass, but for a 0.5 kg charge a period of 1-2 hours is typical. Two-stage compounding may be utilized for relatively high particulate volume fractions. Alternatively, ~ the composites may be blended by extrusion and re-extrusion, as well as 2s by other suitable solid-phase mixing techniques.
The compounded composite is then molded by compression or injection to its final shape as a prosthesis, and at least a portion of its CA 02237148 1998-0~-08 W O 97/17401 PCTrUS96/17939 s~ ce ground or m~fhined to ensure adequate exposure of the glass particles. DiL~e,~.lL particle sizes or volume fractions of bioactive glass can be used during the molding or injection step to produce gradients in mechanical properties.
s Using the compounding terhnique described above, we prepared composite materials from HDPE and 45S5 BIOGLASS0 particles ranging in size from 1.5 ~Lm to 150 ~m, and with an average size of 45.7 ~m, in particle/binder volume ratios of 10%, 20%, and 40%.
Subsequent processing of the composites into specific compression-molded shapes preserved the dispersion of the bioactive glass phase, which was also undisturbed by machining, grinding, polishing or sand-blasting of the surfaces to expose the particles. For comparative ~ul~oses, we also prepared unfilled (0% bioactive glass) HDPE samples in a similar manner. The following analyses were then performed on these materials.
OF HARD AND SOFT TISSUES
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to composite materials, and in particular to materials suitable for surgical implantation as replacements for various hard and soft tissue structures.
Description of the Related Art Historically, materials used in endoprosthesis (i.e., the replacement of internal anatomical structures with artificial appliances) have largely been "bioinert". Metallic alloys, such as stainless steel or cobalt chro,l,iul-l, are typically superior in strength to the structures they replace but do not interact chemically or interfacially with surrounding tissue. Although they avoid the many problems arising from tissue incompatibility, bioinert materials can never become fully integrated within their in vivo environment. As a consequence, the prosthesis frequently detaches from the tissue to which it was originally affixed, resulting in prosthetic loosening. Moreover, modulus mismatching between the appliance and the replaced structure can lead to stress shielding, resulting in poor mechanical compatibility. Bioinert ceramics such as alumina, for example, are stiffer than bone and also exhibit inferior fracture toughness.
An alternative approach is disclosed in U.S. Patent No. 5,017,627, which sets forth various compositions that, when fabricated and CA 02237148 1998-0~-08 W O 97/17401 PC~US96/17939 im~l~nte-l as prosthetic devices, remain anchored to :juliuu~ding tissue.
The composite materials described in the '627 patent are based on a polyolefinic binder cont~ining a particulate inorganic solid. Disclosed particulate solids include calcium salts such as hyd~ y~patite (HA) or s fluor~p~tite, chalk, flyash and silica. Tn~te~cl of rem~ining biologically inert, the composite materials instead exhibit "bioactive" behavior, establishing interfacial bonds to compact bone. The ratio of polyolefin to particulate material can be varied to obtain different values of Young's modulus and strain-to-failure and different amounts of o interfacial bonding. Importantly, the composite can be made ductile.
While versatile, this type of material exhibits certain lirnitations.
In particular, the range of mechanical properties obtainable according to the '627 patent is relatively limited due to the high HA loading levels necessary to achieve bioactivity. The available values of Young's modulus, for example, tend to be comparable with compact (cortical) bone, but not cancellous bone or soft tissues.
Moreover, soft tissues (such as tendons, ligaments, cartilage and skin) tend to be among the most resistant to adhesion altogether. Even composites containing very high HA concentrations do not stimulate significant interfacial bonding in such tissues. Thus, current materials are both mechanically and chemically unsuited as prostheses for repair of soft-tissue structures.
CA 02237148 1998-0~-08 DESCRIPI ION OF THE INVENI ION
Objects of the Invention Accordillgly, it is an object of the present invention to provide c~ po~i~e materials that eYhibit high degrees of bioactivity and rapidly s establish interfacial bonds with ~u~ unding tissue.
It is another object of the invention to achieve, with synthetic bioactive materials, mechanical compatibility with a range of hard and soft tissues.
It is still another object of the invention to provide prosthetic 10 replacements whose bioactivity level can be selected to achieve a wide range of predetermined, in vivo ~tt~-~hment durations.
Other objects will, in part, be obvious and will, in part, appear hereinafter. The invention accordingly comprises an article of manufacture posses~ing the features and properties exemplified in the lS constructions descAbed herein and the several steps and the relation of one or more of such steps with respect to the others and the apparatus embodying the features of construction, combination of elements and the arrangement of parts that are adapted to effect such steps, all as ~-Y~mplified in the following summary and detailed description, and the 20 scope of the invention will be indicated in the claims.
Bnef Summary of the Invention We have found, quite ~u~ lgly, that a polyolefinic binder can be combined with certain bioactive glass materials to produce CA 02237148 1998-0~-08 WO 97/17401 PCT~US96/17939 p~c.lt5 that not only retain high bioactivity levels, but may also be r formulated to achieve mechanical properties comparable to various soft and hard tissues over a variety of parameters, including tensile strength, fracture strain, and Young's modulus.
Bioactive glasses are well-known compositions that elicit specific physiological responses, including the provision of surface-reactive silica, calcium and phosphate groups and alkaline pH levels at interfaces with tissues. In particular, glasses composed of SiO2, Na20, CaO and P2OS
exhibit substantial bioactivity, with compositions having SiO2 levels ranging from 42% to 52% bonding to bone much more rapidly than HA.
See, e.g., Hench, "Bioceramics: From Concept to Clinic," 74 J. ,4mer.
Ceram. Soc. 1487 (1991). Such compositions also bond with exceptional efficacy to soft connective tissues.
These advantageous characteristics arise as a result of chemical reactions occurring at the surface of the glass when exposed to ambient body fluids. Ion exchange and irregular surface dissolution forms a hydrated silica gel layer that increases the presented area and enhances fc,~ alion of a microcrystalline biological apatite layer on the roughened glass. This layer, which can form in as little as a few hours in vivo, bonds not only to bone but also to collagen fibrils. The latter type of bonding, which cannot be achieved by materials such as HA or polymeric compositions (or, obviously, by bioinert materials), is required for soft-tissue bonding. Furthermore, bioactive glass in buL~c form bonds to bone with significantly greater rapidity and completeness than does HA.
By retaining the interfacial and chemical properties of bioactive gl~es, the composites of the present invention offer unique advantages as soft-tissue prostheses and for prostheses that bond to cancellous or CA 02237148 1998-0~-08 W O 97/17401 PCT~US96/17939 trabecular bone or cartilage. Our composites can be col,lplession or injection molded into appliances for replacement of or bonding to a variety of soft tissues. As used herein, the term "soft tissue" is intended to embrace cartilage, tendons, ligaments, skin, tympanic membrane, s gingiva, subcutaneous tissue, and all collagen-based connect*e tissue.
BnefD~sc ,i~lion of the Drawings The foregoing discussion will be understood more readily from the following detailed description of the invention, when taken in conjunction with the accoll-panying drawings, in which:
FIG. 1 graphically compares ductility for composites having bioactive-glass volume loading fractions of 0%, 10%, 20%, and 40%;
FIG. 2 graphically illustrates the dependence of Young's Modulus on bioactive-glass volume loading fraction;
F~G. 3 graphically illustrates the dependence of tensile strength on bioactive-glass volume loading fraction;
FIG. 4 graphically illustrates the dependence of fracture strain on bioactive-glass volume loading fraction;
FIG. S is an inked rendition of a Fourier-transform infrared spectroscopy (F~IR) spectrum that illustrates the formation of biological apatite layers on various samples in a simulated body fluid containing no calcium or phosphate ions;
FIG. 6 is an inked rendition of an FTIR spectrum that illustrates CA 02237148 1998-0~-08 the formation of biological apatite layers on various samples in a simulated body fluid that does contain calcium and phosphate ions; and ~;IG. 7 illustrates the dependence of composite bioactivity on the bioactive-glass volume loading fraction.
Detailed Descnption of the Preferred Embodiments The preferred embodiment of the present invention is a composite material comprising a particulate bioactive glass dispersed in a solid-phase polyolefin binder. The bioactive glass formula should contain 42-52% SiO2, and a suitable material is the 45S5 BIOGLASS~
product (45 wt% SiO2, 6 wt% P2Os, 24.5 wt% CaO, 24.5 wt% Na2O) marketed by U.S. Biomaterials Corp., Baltimore, MD 21236. However, other bioactive glass formulations with up to 52 wt~ SiO2 can be used in~te~cl l~he polyolefin binder is preferably a homo- or copolyolefin having a weight-average molecular weight, <Mw~, greater than 20,000, suitably greater than 100,000, and preferably in excess of 300,000, and suitably below 3,000,000 but preferably below 1,000,000. Binders with cMw> below 20,000 may not exhibit sufficient biocompatibility, while those with cMw> above 3,000,000 present processing difficulties. High-density polyethylene (HDPE) in linear form is the preferred binder material, although advantageous results can also be obtained using linear or branched polypropylene, polybutylene, or a copolymer of - 25 ethylene and at least one of propylene, bu~lene and hexene.
CA 02237148 1998-0~-08 WO 97/17401 PCTrUS96/17939 As ~ cll~ce~ in greater detail below, the glass loading fraction detel ~i"es both the mechanical properties and bioactivity level of the resulting composite, and is thelefole carefully chosen to achieve both tissue compatibility and a desired extent of attachment. Loading fractions in the range of 10% to 40% by volume are plefel,ed; however, lo~ling fractions of 5 to 50% by volume are acceptable. The bioactive glass is present in the form of ground particles. Size U~ O~ ity is not necessary to the present invention; partides having sizes ranging from 1.5 ~Lm to 150 ~m are preferred, sizes from 0.5 ~m to 500 ~Lm are o acceptable.
1. Material Preparation The composite materials of the present invention may be prepared first by compounding the polyolefin, preferably at a temperature above the softening point (in the case of HDPE, suitably between 200~ to 260~ C, and preferably between 200~ and 240~ C) with the bioactive glass in dry, particulate form. The polyolefin is advantageously introduced into the compounder first, and the bioactive glass thereafter added in small quantities until the desired volume fraction is obtained. The compounding time depends on the identities and volume fractions of the binder and bioactive glass, but for a 0.5 kg charge a period of 1-2 hours is typical. Two-stage compounding may be utilized for relatively high particulate volume fractions. Alternatively, ~ the composites may be blended by extrusion and re-extrusion, as well as 2s by other suitable solid-phase mixing techniques.
The compounded composite is then molded by compression or injection to its final shape as a prosthesis, and at least a portion of its CA 02237148 1998-0~-08 W O 97/17401 PCTrUS96/17939 s~ ce ground or m~fhined to ensure adequate exposure of the glass particles. DiL~e,~.lL particle sizes or volume fractions of bioactive glass can be used during the molding or injection step to produce gradients in mechanical properties.
s Using the compounding terhnique described above, we prepared composite materials from HDPE and 45S5 BIOGLASS0 particles ranging in size from 1.5 ~Lm to 150 ~m, and with an average size of 45.7 ~m, in particle/binder volume ratios of 10%, 20%, and 40%.
Subsequent processing of the composites into specific compression-molded shapes preserved the dispersion of the bioactive glass phase, which was also undisturbed by machining, grinding, polishing or sand-blasting of the surfaces to expose the particles. For comparative ~ul~oses, we also prepared unfilled (0% bioactive glass) HDPE samples in a similar manner. The following analyses were then performed on these materials.
2. Mechanical Properties We prepared tensile test specimens from compression-molded co~ osiLe plates 1.75 mm thick, with a gauge length of 25 mm, acco~ g to ISO Standard 527. We then conducted conventional tensile tests under ambient conditions with an Instron 6025 testing machine at a crosshead speed of 0.5 mm/min or 5.0 mm/min. The results appear in l;lG. 1, and indicate that composites having bioactive-glass volume fractions of 30% or below exhibit considerable ductility.
- 2s FIGS. 2-4 illustrate the effect of varying volume fractions on Young's modulus, tensile strength and fracture strain, respectively. As CA 02237148 l99X-05-08 _ 9 inrlic~fed in the following tables, c~ o~;Les with bioactive-glass volume fractions of 30% or below exhibit levels of elastic compliance, tensile strength and fracture strain comparable to those of soft connective tissues such as tendon, ligaments, articular cartilage, skin, tympanic s membrane, and gingiva. Composites with bioactive-glass volume fractions in excess of 30% exhibit mechanical characteristics comparable to cancellous bone.
-r , ~ d Mate~ial S Particle Volumc Fraction Particlc Weight Percentage Young's Tensile Fracture (%) (%) Modulus Strength Strain (GPa) (MPa) (%) 0 0 0.65+0.02 17.89+0.29 >360 22.7 1.05+0.04 1434+0.11 105.1+56.6 39.8 1.21+0.02 12.69+0.07 6A0+9.4 63.8 254+0.16 lO.lS+0.71 8.5+2.8 Table 1 ~0 Property Cortical Cancellous Articular Tendon Bone Bone Cartilage 25 Young's 7-30 05-0.05 0.001-0.01 Modulus (GPa) Tensile 50-150 10-20 1040 80-120 Strength (~a) Fracture Strain (%) 1-3 5-7 15-50 10 Table 2 3. Bioactivi~r In a first experiment, we evaluated the bioactivi~y of composites having bioactive-glass volume fractions of 10%, 20%, and 40% by 40 subjecting the samples at 37~ C to a simulated body fluid (SBF-tris) that does not contain calcium or phosphate ions. The rate of formation of a biological apatite layer on the surface, which can be measured using CA 02237148 1998-0~-08 W O 97/17401 PCT~US96/17939 F~IR, is directly correlated with the level of bioactivity. FIG. 4 depicts three FIIR spectra obtained in the diffuse reflection mode for the 45S5 BIOGLASS~ particles in isolation (a), the composite cont~inin~ 40%
bioactive glass particles (b), and the composite Cont~ining 10% bioactive s glass particles (c) after reaction for 20 hours. The 20-hour time period is ~linirz~lly significant, and is used for quality-assurance testing of bioactive glasses intended to bond with bone and soft connective tissue.
The shaded regions correspond to the molecular vibrational modes characteristic of a microcrystalline biological apatite layer. The spectra indicate that only the 40% composite and the pure bioactive glass particles developed the biological apatite layer in SBF-tris within 20 hours.
In a second experiment, identical composites and the isolated particles were exposed for 20 hours at 37~ C to a simulated body fluid (SBF-9) that does contain calcium and phosphate ions. The resulting FIIR spectra, shown in FIG. 6, demonstrate that all of the composites develop surface biological apatite layers equivalent to that of the isolated glass particulate.
The rate of apatite formation (i.e., the actual level of bioactivity), 20 however, depends on the volume percentage of the bioactive glass phase.
This is shown in FIG. 7, which graphically depicts the dependence of the composite's bioactivity on its bioactive-glass loading fraction. Bioactivity is ~ "~ressed as the parameter IB~ defined as 100/to.5bb, where to5bb is the time necessary for 50% of the composite surface to bond to tissue. The CA 02237148 1998-0~-08 WO 97/17401 PCTrUS96/17939 range r re~. es_.lb preferred bioactive-glass loading fractions.
- 2s FIGS. 2-4 illustrate the effect of varying volume fractions on Young's modulus, tensile strength and fracture strain, respectively. As CA 02237148 l99X-05-08 _ 9 inrlic~fed in the following tables, c~ o~;Les with bioactive-glass volume fractions of 30% or below exhibit levels of elastic compliance, tensile strength and fracture strain comparable to those of soft connective tissues such as tendon, ligaments, articular cartilage, skin, tympanic s membrane, and gingiva. Composites with bioactive-glass volume fractions in excess of 30% exhibit mechanical characteristics comparable to cancellous bone.
-r , ~ d Mate~ial S Particle Volumc Fraction Particlc Weight Percentage Young's Tensile Fracture (%) (%) Modulus Strength Strain (GPa) (MPa) (%) 0 0 0.65+0.02 17.89+0.29 >360 22.7 1.05+0.04 1434+0.11 105.1+56.6 39.8 1.21+0.02 12.69+0.07 6A0+9.4 63.8 254+0.16 lO.lS+0.71 8.5+2.8 Table 1 ~0 Property Cortical Cancellous Articular Tendon Bone Bone Cartilage 25 Young's 7-30 05-0.05 0.001-0.01 Modulus (GPa) Tensile 50-150 10-20 1040 80-120 Strength (~a) Fracture Strain (%) 1-3 5-7 15-50 10 Table 2 3. Bioactivi~r In a first experiment, we evaluated the bioactivi~y of composites having bioactive-glass volume fractions of 10%, 20%, and 40% by 40 subjecting the samples at 37~ C to a simulated body fluid (SBF-tris) that does not contain calcium or phosphate ions. The rate of formation of a biological apatite layer on the surface, which can be measured using CA 02237148 1998-0~-08 W O 97/17401 PCT~US96/17939 F~IR, is directly correlated with the level of bioactivity. FIG. 4 depicts three FIIR spectra obtained in the diffuse reflection mode for the 45S5 BIOGLASS~ particles in isolation (a), the composite cont~inin~ 40%
bioactive glass particles (b), and the composite Cont~ining 10% bioactive s glass particles (c) after reaction for 20 hours. The 20-hour time period is ~linirz~lly significant, and is used for quality-assurance testing of bioactive glasses intended to bond with bone and soft connective tissue.
The shaded regions correspond to the molecular vibrational modes characteristic of a microcrystalline biological apatite layer. The spectra indicate that only the 40% composite and the pure bioactive glass particles developed the biological apatite layer in SBF-tris within 20 hours.
In a second experiment, identical composites and the isolated particles were exposed for 20 hours at 37~ C to a simulated body fluid (SBF-9) that does contain calcium and phosphate ions. The resulting FIIR spectra, shown in FIG. 6, demonstrate that all of the composites develop surface biological apatite layers equivalent to that of the isolated glass particulate.
The rate of apatite formation (i.e., the actual level of bioactivity), 20 however, depends on the volume percentage of the bioactive glass phase.
This is shown in FIG. 7, which graphically depicts the dependence of the composite's bioactivity on its bioactive-glass loading fraction. Bioactivity is ~ "~ressed as the parameter IB~ defined as 100/to.5bb, where to5bb is the time necessary for 50% of the composite surface to bond to tissue. The CA 02237148 1998-0~-08 WO 97/17401 PCTrUS96/17939 range r re~. es_.lb preferred bioactive-glass loading fractions.
4. Clinical Applicaffons In accordance with a further aspect of the invention, the s cc,lllpo~es are molded into prostlleses for use in surgery. The ranges of bioactivity and mechanical properties of the composites facilitates the production of implants tailored for highly specific medical requirements.
The invention is particularly well suited to implants requiring intimate contact with soft tissue (e.g., aeration tubes for the middle ear, which o protrude through the tympanic membrane).
For example, present-day aeration tubes are frequently extruded within a year; because these devices must typically remain implanted for several years, patients often undergo multiple implantation surgeries to replace the failed tubes. The present invention not only provides tubes lS that will remain in place for the clinically indicated period, but also, through judicious selection of bioactivity level, allows the clinician to match this period with the degree of soft-tissue bonding most compatible therewi~l,. Thus, as shown in FIG. 7, bioactive glass fractions of 10-20%
by volume would be expected to exhibit little soft-tissue bonding, and 20 therefore resemble most present-day aeration tubes; accordingly, composite formulations with this range of bioactive glass fraction are ., suitable for 1-2 years of use. By contrast, implants suitable for 2-4 years of use can be obtained using bioactive glass fractions in the range of 20-CA 02237148 1998-0~-08 W O 97/17401 PCT~US96/17939 40%. The low elastic modulus of the composites of the present invention, particularly those having particulate volume fractions of 10-30%, discuu-dges mechanical deterioration of the interface between the aeration tube and the ~y~lpallic ~nembrane, while bioactivity provides s adherence to the collagen fibrils of the membrane to hinder extrusion.
The low Young's modulus, high fracture strain and soft-tissue bonding characteristics associated with our composites (particularly those with particulate volume fractions of 10-30%) renders them uniquely well suited to use as percutaneous leads (e.g., to accommodate o perfusion, in-dwelling catheters, electrodes for auditory or neuromuscular stimulation, etc.). The interfacial adhesion that results from soft-tissue bonding reduces the chance of infection, while high flexibility inhibits the formation of interfacial stresses, which can deteriorate the junction between the lead and ~ulloullding tissue.
lS Repair of cartilage or cancellous bone or fixation of traditional orthopedic prostheses against such tissues can require establishment of an interface therebetween. Bioinert prostheses typically exhibit values of Young's modulus in excess of 100 GPa and sometimes several orders of magnitude above the corresponding values for cancellous bone (see Table 2). Prostheses fabricated from the composites of the present invention offer values of Young's modulus far more compatible with " those of cancellous bone and cartilage, while providing a bioactively derived tissue bond across the interface. Composites used in such - prostheses may desirably be formulated with a gradient in the volume W O 97/17401 PCT~US96/17939 fraction of bioactive glass in order to achieve an optimal gradation in elastic ~lope,Lies, thereby m~X;.~ .g fracture toughness without loss of nt ~ l bioactivity.
Prostheses may be fabricated from the cc,.l.posiles of the present s invention by co.,~ ession or injection molding. In the former case, the solid composite is remelted, suitably, in the case of HDPE, at a temperature from 190~ to 250~ C, and preferably between 200~ to 230~ C;
~hen charged to the prosthesis mold cavity under load untiI the cavity is filled; and finally cooled under load. In the case of injection molding, similar temperatures are used, but care is taken to employ an injection pressure and speed low enough to avoid scorching.
It may prove desirable, especially with polyolefins having <Mw>
below 500,000, to gamma-irradiate the fabricated prosthesis, both for sterilization and to impart resistance to creep and el,vh~llll,ental stress cracking. Where processing difficulties are encountered or expected, it is often desirable to employ a polyolefin of relatively low <Mw>, to facilitate convcl.ient production of the composite, and then to irradiate.
It will therefore be seen that the foregoing represents a highly advantageous approach to production of bioactive composites and prostheses having unique and easily varied mechanical properties. The terms and c~.cssions employed herein are used as terms of description and not of limitation, and there is no intention, in the use of such terms and e,~re~ions, of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various mo-liffr~ffons are possible within the scope of the invention claimed.
What is claimed is:
The invention is particularly well suited to implants requiring intimate contact with soft tissue (e.g., aeration tubes for the middle ear, which o protrude through the tympanic membrane).
For example, present-day aeration tubes are frequently extruded within a year; because these devices must typically remain implanted for several years, patients often undergo multiple implantation surgeries to replace the failed tubes. The present invention not only provides tubes lS that will remain in place for the clinically indicated period, but also, through judicious selection of bioactivity level, allows the clinician to match this period with the degree of soft-tissue bonding most compatible therewi~l,. Thus, as shown in FIG. 7, bioactive glass fractions of 10-20%
by volume would be expected to exhibit little soft-tissue bonding, and 20 therefore resemble most present-day aeration tubes; accordingly, composite formulations with this range of bioactive glass fraction are ., suitable for 1-2 years of use. By contrast, implants suitable for 2-4 years of use can be obtained using bioactive glass fractions in the range of 20-CA 02237148 1998-0~-08 W O 97/17401 PCT~US96/17939 40%. The low elastic modulus of the composites of the present invention, particularly those having particulate volume fractions of 10-30%, discuu-dges mechanical deterioration of the interface between the aeration tube and the ~y~lpallic ~nembrane, while bioactivity provides s adherence to the collagen fibrils of the membrane to hinder extrusion.
The low Young's modulus, high fracture strain and soft-tissue bonding characteristics associated with our composites (particularly those with particulate volume fractions of 10-30%) renders them uniquely well suited to use as percutaneous leads (e.g., to accommodate o perfusion, in-dwelling catheters, electrodes for auditory or neuromuscular stimulation, etc.). The interfacial adhesion that results from soft-tissue bonding reduces the chance of infection, while high flexibility inhibits the formation of interfacial stresses, which can deteriorate the junction between the lead and ~ulloullding tissue.
lS Repair of cartilage or cancellous bone or fixation of traditional orthopedic prostheses against such tissues can require establishment of an interface therebetween. Bioinert prostheses typically exhibit values of Young's modulus in excess of 100 GPa and sometimes several orders of magnitude above the corresponding values for cancellous bone (see Table 2). Prostheses fabricated from the composites of the present invention offer values of Young's modulus far more compatible with " those of cancellous bone and cartilage, while providing a bioactively derived tissue bond across the interface. Composites used in such - prostheses may desirably be formulated with a gradient in the volume W O 97/17401 PCT~US96/17939 fraction of bioactive glass in order to achieve an optimal gradation in elastic ~lope,Lies, thereby m~X;.~ .g fracture toughness without loss of nt ~ l bioactivity.
Prostheses may be fabricated from the cc,.l.posiles of the present s invention by co.,~ ession or injection molding. In the former case, the solid composite is remelted, suitably, in the case of HDPE, at a temperature from 190~ to 250~ C, and preferably between 200~ to 230~ C;
~hen charged to the prosthesis mold cavity under load untiI the cavity is filled; and finally cooled under load. In the case of injection molding, similar temperatures are used, but care is taken to employ an injection pressure and speed low enough to avoid scorching.
It may prove desirable, especially with polyolefins having <Mw>
below 500,000, to gamma-irradiate the fabricated prosthesis, both for sterilization and to impart resistance to creep and el,vh~llll,ental stress cracking. Where processing difficulties are encountered or expected, it is often desirable to employ a polyolefin of relatively low <Mw>, to facilitate convcl.ient production of the composite, and then to irradiate.
It will therefore be seen that the foregoing represents a highly advantageous approach to production of bioactive composites and prostheses having unique and easily varied mechanical properties. The terms and c~.cssions employed herein are used as terms of description and not of limitation, and there is no intention, in the use of such terms and e,~re~ions, of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various mo-liffr~ffons are possible within the scope of the invention claimed.
What is claimed is:
Claims (20)
1. A bioactive composite material comprising a solid-phase homo- or copolyolefin binder having dispersed therein an effective in vivo bonding amount of particulate bioactive glass material sufficient to achieve in vivo attachment by in vivo formulation of hydroxyapatite from said bioactive glass material, the composite material exhibiting a Young's modulus comparable to, a soft tissue.
2. The material of claim 1 wherein the soft tissue is selected from the group consisting of cartilage, tendons, ligaments, skin, tympanic membrane, gingiva, subcutaneous tissue and collagen-based connective tissue.
3. The material of claim 1 wherein the material is further capable of bonding to cancellous or trabecular bone.
4. The material of claim 1 wherein the polyolefin comprises polyethylene, polypropylene, polybutylene, or a copolymer of ethylene and at least one of propylene, butylene and hexene.
5. The material of claim 4 wherein the polyolefin comprises linear polyethylene.
6. The material of claim 1 wherein the polyolefin has a weight-average molecular weight greater than 100,000 and less than 1,000,000.
7. The material of claim 1 wherein the Young's modulus lies in the range 0.5-4.0 GPa.
8. The material of claim 1 wherein the particulate bioactive glass material ranges in size from 0.5-500 µm.
9. The material of claim 8 wherein the particulate bioactive glass material has an average size ranging from 25-75 µm.
10. The material of claim 1 wherein the bioactive glass material is a composition comprising SiO2, Na2O, CaO and P2O5.
11. The material of claim 9 wherein the SiO2 in present in proportions ranging from 42% to 52%.
12. The material of claim 1 wherein the bioactive glass material constitutes from 5% to 50%, by volume, of the composite.
13. The material of claim 1 wherein the bioactive glass material is dispersed along a concentration gradient within the binder.
14. The material of claim 1 wherein the material also exhibits a tensile strength comparable to that of a soft tissue.
15. The material of claim 1 wherein the material also exhibits a fracture strain comparable to that of a soft tissue.
16. The material of claim 1 wherein the material also exhibits a Young's modulus comparable to that of a soft tissue.
17. A prosthesis for the replacement of or attachment to cancellous bone or cartilage formed by compounding, in the solid phase, a homo- or copolyolefin binder with an effective amount of particulate bioactive glass material to form a composite, the composite being capable of bonding with, and exhibiting a Young's modulus comparable to, a soft tissue.
18. The prosthesis of claim 17 wherein the composite material is molded into an orthopedic prosthesis.
19. The prosthesis of claim 17 wherein the composite material is molded into an aeration tube.
20. The prosthesis of claim 17 wherein the composite material is molded into a percutaneous lead.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/556,016 | 1995-11-09 | ||
| US08/556,016 US5728753A (en) | 1995-11-09 | 1995-11-09 | Bioactive composite material for repair of hard and soft tissues |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2237148A1 true CA2237148A1 (en) | 1997-05-15 |
Family
ID=24219536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002237148A Abandoned CA2237148A1 (en) | 1995-11-09 | 1996-11-08 | Bioactive composite material for repair of hard and soft tissues |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US5728753A (en) |
| EP (1) | EP0859813B1 (en) |
| JP (1) | JP2000500174A (en) |
| CN (1) | CN1207753A (en) |
| AT (1) | ATE252134T1 (en) |
| AU (1) | AU7724696A (en) |
| CA (1) | CA2237148A1 (en) |
| DE (1) | DE69630389D1 (en) |
| WO (1) | WO1997017401A1 (en) |
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| WO1997041079A1 (en) * | 1996-05-01 | 1997-11-06 | Usbiomaterials | Bioactive ceramics and method of preparing bioactive ceramics |
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| US6756060B1 (en) | 1996-09-19 | 2004-06-29 | Usbiomaterials Corp. | Anti-inflammatory and antimicrobial uses for bioactive glass compositions |
| WO1999032280A1 (en) | 1997-12-19 | 1999-07-01 | Usbiomaterials Corporation | Tape cast multi-layer ceramic/metal composites |
| US6423343B1 (en) * | 1998-01-23 | 2002-07-23 | Usbiomaterials Corporation | Bioactive glass treatment of inflammation in skin conditions |
| AU6244799A (en) * | 1998-09-10 | 2000-04-03 | Us Biomaterials Corporation | Anti-inflammatory and antimicrobial uses for bioactive glass compositions |
| US6274159B1 (en) | 1998-10-28 | 2001-08-14 | University Of Florida | Surface modified silicone drug depot |
| US6147135A (en) * | 1998-12-31 | 2000-11-14 | Ethicon, Inc. | Fabrication of biocompatible polymeric composites |
| US6517863B1 (en) * | 1999-01-20 | 2003-02-11 | Usbiomaterials Corporation | Compositions and methods for treating nails and adjacent tissues |
| US6383519B1 (en) * | 1999-01-26 | 2002-05-07 | Vita Special Purpose Corporation | Inorganic shaped bodies and methods for their production and use |
| US6190643B1 (en) * | 1999-03-02 | 2001-02-20 | Patricia Stoor | Method for reducing the viability of detrimental oral microorganisms in an individual, and for prevention and/or treatment of diseases caused by such microorganisms; and whitening and/or cleaning of an individual's teeth |
| CA2372384C (en) | 1999-04-29 | 2009-04-07 | Usbiomaterials Corporation | Anti-inflammatory bioactive glass particulates |
| CA2377402C (en) | 1999-06-14 | 2011-01-18 | Imperial College Innovations | Silver-containing, sol-gel derived bioglass compositions |
| US6458162B1 (en) * | 1999-08-13 | 2002-10-01 | Vita Special Purpose Corporation | Composite shaped bodies and methods for their production and use |
| US6495168B2 (en) | 2000-03-24 | 2002-12-17 | Ustherapeutics, Llc | Nutritional supplements formulated from bioactive materials |
| US20020115742A1 (en) * | 2001-02-22 | 2002-08-22 | Trieu Hai H. | Bioactive nanocomposites and methods for their use |
| US7206639B2 (en) * | 2002-03-15 | 2007-04-17 | Sarcos Investments Lc | Cochlear drug delivery system and method |
| US7066962B2 (en) * | 2002-07-23 | 2006-06-27 | Porex Surgical, Inc. | Composite surgical implant made from macroporous synthetic resin and bioglass particles |
| US7067169B2 (en) * | 2003-06-04 | 2006-06-27 | Chemat Technology Inc. | Coated implants and methods of coating |
| US7189263B2 (en) | 2004-02-03 | 2007-03-13 | Vita Special Purpose Corporation | Biocompatible bone graft material |
| US9220595B2 (en) | 2004-06-23 | 2015-12-29 | Orthovita, Inc. | Shapeable bone graft substitute and instruments for delivery thereof |
| US20060199876A1 (en) * | 2005-03-04 | 2006-09-07 | The University Of British Columbia | Bioceramic composite coatings and process for making same |
| WO2006110393A1 (en) | 2005-04-04 | 2006-10-19 | The Regents Of The University Of California | Inorganic materials for hemostatic modulation and therapeutic wound healing |
| US9326995B2 (en) | 2005-04-04 | 2016-05-03 | The Regents Of The University Of California | Oxides for wound healing and body repair |
| ES2726355T3 (en) | 2005-11-14 | 2019-10-03 | Biomet 3I Llc | Deposition of discrete nanoparticles on an implant surface |
| US20070258916A1 (en) * | 2006-04-14 | 2007-11-08 | Oregon Health & Science University | Oral compositions for treating tooth hypersensitivity |
| CA2656050C (en) | 2006-06-29 | 2015-02-03 | Orthovita, Inc. | Kit for bone graft comprising collagen,calcium phosphate,and bioactive glass |
| US9034456B2 (en) * | 2006-12-28 | 2015-05-19 | Boston Scientific Scimed, Inc. | Medical devices and methods of making the same |
| US9433704B2 (en) * | 2007-03-09 | 2016-09-06 | Novabone Products, Llc | Osteostimulative settable bone graft putty |
| WO2009097218A1 (en) | 2008-01-28 | 2009-08-06 | Biomet 3I, Llc | Implant surface with increased hydrophilicity |
| US8994666B2 (en) * | 2009-12-23 | 2015-03-31 | Colin J. Karpfinger | Tactile touch-sensing interface system |
| US8641418B2 (en) | 2010-03-29 | 2014-02-04 | Biomet 3I, Llc | Titanium nano-scale etching on an implant surface |
| US8877220B2 (en) | 2010-08-05 | 2014-11-04 | Collagen Matrix, Inc. | Self-expandable biopolymer-mineral composite |
| US8551525B2 (en) | 2010-12-23 | 2013-10-08 | Biostructures, Llc | Bone graft materials and methods |
| WO2013142118A1 (en) | 2012-03-20 | 2013-09-26 | Biomet 3I, Llc | Surface treatment for an implant surface |
| CN104446386B (en) * | 2014-11-10 | 2016-05-18 | 新昌县镜岭镇康柳电子元件厂 | Be used for aluminium oxide ceramics of hip joint and preparation method thereof |
| CN106139255A (en) * | 2015-04-17 | 2016-11-23 | 天津市赛宁生物工程技术有限公司 | A kind of collagen protein combines new material and the preparation method of the medical sponge support of calcium phosphate |
| CN110170007B (en) * | 2019-03-28 | 2021-08-31 | 北京刷新活力健康科技有限公司 | Composition for inhibiting pigmentation in skin healing process and preparation method and application thereof |
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| JPS5116064B2 (en) * | 1972-10-12 | 1976-05-21 | ||
| US5017627A (en) * | 1980-10-09 | 1991-05-21 | National Research Development Corporation | Composite material for use in orthopaedics |
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| JPH0629126B2 (en) * | 1989-03-29 | 1994-04-20 | 京都大学長 | Coating method of bioactive hydroxyapatite film |
| US5074916A (en) * | 1990-05-18 | 1991-12-24 | Geltech, Inc. | Alkali-free bioactive sol-gel compositions |
| NL9001847A (en) * | 1990-08-21 | 1992-03-16 | Stamicarbon | POLYETHENE PROSTHESIS FILLED WITH AN INORGANIC FILLER. |
| JP3472970B2 (en) * | 1993-12-10 | 2003-12-02 | 株式会社アドバンス | Method for producing bioimplant material |
| AU3795395A (en) * | 1994-11-30 | 1996-06-06 | Ethicon Inc. | Hard tissue bone cements and substitutes |
| JPH0959870A (en) * | 1995-08-14 | 1997-03-04 | Toyobo Co Ltd | Ultraviolet light absorbing polyester fiber structure and its production |
-
1995
- 1995-11-09 US US08/556,016 patent/US5728753A/en not_active Expired - Fee Related
-
1996
- 1996-11-08 AU AU77246/96A patent/AU7724696A/en not_active Abandoned
- 1996-11-08 DE DE69630389T patent/DE69630389D1/en not_active Expired - Lifetime
- 1996-11-08 EP EP96940339A patent/EP0859813B1/en not_active Expired - Lifetime
- 1996-11-08 AT AT96940339T patent/ATE252134T1/en not_active IP Right Cessation
- 1996-11-08 CN CN96199574A patent/CN1207753A/en active Pending
- 1996-11-08 JP JP9518342A patent/JP2000500174A/en active Pending
- 1996-11-08 CA CA002237148A patent/CA2237148A1/en not_active Abandoned
- 1996-11-08 WO PCT/US1996/017939 patent/WO1997017401A1/en active IP Right Grant
-
1997
- 1997-12-09 US US08/987,469 patent/US5962549A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997017401A1 (en) | 1997-05-15 |
| EP0859813B1 (en) | 2003-10-15 |
| EP0859813A4 (en) | 2001-01-24 |
| US5962549A (en) | 1999-10-05 |
| DE69630389D1 (en) | 2003-11-20 |
| EP0859813A1 (en) | 1998-08-26 |
| AU7724696A (en) | 1997-05-29 |
| ATE252134T1 (en) | 2003-11-15 |
| JP2000500174A (en) | 2000-01-11 |
| US5728753A (en) | 1998-03-17 |
| CN1207753A (en) | 1999-02-10 |
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| EEER | Examination request | ||
| FZDE | Discontinued |