WO2019115704A1 - Bone substitute material - Google Patents
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- WO2019115704A1 WO2019115704A1 PCT/EP2018/084783 EP2018084783W WO2019115704A1 WO 2019115704 A1 WO2019115704 A1 WO 2019115704A1 EP 2018084783 W EP2018084783 W EP 2018084783W WO 2019115704 A1 WO2019115704 A1 WO 2019115704A1
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- WIPO (PCT)
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- hap
- cap
- hydroxyapatite
- bone substitute
- nanocrystalline
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- 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
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L24/0052—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with an inorganic matrix
- A61L24/0063—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
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
- A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, 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
- A61L27/40—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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
- A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
- A61F2310/00005—The prosthesis being constructed from a particular material
- A61F2310/00179—Ceramics or ceramic-like structures
- A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
-
- 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
-
- 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
- A61L27/28—Materials for coating prostheses
- A61L27/30—Inorganic materials
- A61L27/32—Phosphorus-containing materials, e.g. apatite
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y80/00—Products made by additive manufacturing
Definitions
- the invention relates to a new biphasic bone substitute material with a bilayer structure based on calcium phosphate/hydroxyapatite (CAP/HAP) which has a homogeneous coarse external surface, a process for preparing that material and the use thereof as implant or prosthesis to support bone formation, bone regeneration, bone repair and/or bone replacement at a defect site in a human or animal.
- CAP/HAP calcium phosphate/hydroxyapatite
- a well-known natural, osteoconductive bone substitute material that promotes bone growth in periodontal and maxillofacial osseous defects is Geistlich Bio-Oss®, commercially available from Geistlich Pharma AG. That material is manufactured from natural bone by a process described in US Patent No. 5,167,961, which enables preservation of the trabecular architecture and nanocrystalline structure of the natural bone, resulting in an excellent osteoconductive matrix which is not or very slowly resorbed.
- Tricalcium phosphate / hydroxyapatite (TCP/HAP) systems and their use as bone substitute materials are described, for example, in US-6,338,752 disclosing a process for preparing a biphasic cement of a-TCP/HAP by heating a powder mixture of ammonium phosphate and HAP at 1200-1500 2 C.
- European Patent EP-285826 describes a process for the production of a layer of
- HAP on metallic and non-metallic bodies for implants by application of a layer of cx- TCP and completely converting the a-TCP layer into HAP by reaction with water of pH 2 to 7 at 80-100 2 C.
- the product obtained is a metallic or non-metallic body covered with a layer of HAP.
- WO 97/41273 describes a process for coating a substrate such as notably hydroxyapatite (HAP) or other calcium phosphates (CAP) with a coating of carbonated hydroxyapatite, i.e. hydroxyapatite wherein phosphate and/or hydroxyl ions are partially replaced by bicarbonate ions, by a process comprising (a) immersing the substrate in a solution of pH 6.8 to 8.0 containing calcium ions, phosphate ions and bicarbonate ions at a temperature lower than 50 °C, (b) heating the portion of the solution in contact with the substrate to a temperature of 50 to 80 °C until having a pH greater than 8, (c) maintaining the substrate in contact with the alkali solution obtained in step (b) to form a carbonated hydroxyapatite coating, and (d) taking the substrate off the solution and subjecting the coating to drying.
- HAP hydroxyapatite
- CAP calcium phosphates
- bicarbonate ions are disclosed to act as inhibitors of hydroxyapatite crystal growth, resulting in non-stoichiometric crystals containing defects and having rather small dimensions, namely 10-40 nm in length and 3-10 nm in width (see page 7, lines 1-7).
- the components of calcium phosphate / hydroxyapatite (CAP/HAP) systems, especially TCP/HAP systems differ in their thermodynamic stability. Due to this difference, when CAP/HAP systems are implanted into a mammal, in particular a human patient, the solubility of TCP and other calcium phosphates is higher in the body fluid than the solubility of HAP.
- the difference in solubility between calcium phosphates and HAP causes a breakdown of the unordered sinterstructure of the CAP/HAP system because the better soluble compound CAP (e.g. TCP) is removed quicker than HAP.
- the sintered interconnection between CAP and HAP produced at high temperatures will also make a remarkable contribution to higher solubility of the device in the physiological environment.
- osteoclast activity and therefore to an accelerated ill-controlled resorption of the ceramic material and a risk of adverse inflammation reactions, especially when using a large amount of synthetic bone substitute material.
- EP-B1-2445543 discloses a highly advantageous calcium
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material which, like bone substitute material Gottlich Bio-Oss®, after being set in vivo enables the concentration of calcium ions on the surface of the material and within the local environment thereof to remain almost constant and thus does not lead to an increased osteoclast activity.
- CAP/HAP phosphate/hydroxyapatite
- EP-B1-2445543 relates to a biphasic calcium
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and at least one uniform and closed epitactically grown layer of nanocrystalline HAP deposited on top of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, i.e. a length of 30 to 46 nm and a width of 14 to 22 nm.
- the sintered CAP core may comprise tricalcium phosphate (TCP), notably a- TCP (a-Ca 3 (P0 4 ) 2 ) or
- TCP tricalcium phosphate
- 3-TCP
- TTCP tetracalcium phosphate
- the sintered CAP core essentially consists of TCP, a-TCP being preferred.
- the epitactically grown layer of nanocrystalline HAP is structurally and chemically nearly identical to the natural human bone mineral.
- the epitactically grown layer of nanocrystalline HAP generally has a thickness of at least from 15 to 50 nm, preferably at least from 20 to 40 nm, more preferably at least from 25 to 35 nm. That minimum thickness corresponds to one layer of HAP nanocrystals in epitaxial orientation.
- the epitactically grown layer of nanocrystalline HAP may comprise a single or multiple layers of HAP nanocrystals in epitaxial orientation.
- the thickness of the epitactically grown layer of nanocrystalline HAP which is related to the number of such layers of HAP nanocrystals in epitaxial orientation, will be selected according to the intended application of the bone substitute material as implant or prosthesis in differently loaded parts of the body.
- the bone substitute material of that invention is indeed designed to function in vivo as a living-like system progressively
- the sintered CAP core into hydroxyapatite similar in size and morphology to human bone mineral, the rate of that transformation being dependent on the rate of calcium release by the sintered CAP core, which is to a large extent controlled by the thickness of the epitactically grown layer of nanocrystalline HAP.
- the properties of the CAP/HAP bone substitute material are to a large extent controlled by the thickness of the epitactically grown layer of crystalline HAP.
- the term "properties" includes the ability of the CAP/HAP bone substitute to release a constant concentration of calcium ions to the local environment in vitro and in vivo.
- the thickness of the epitactically grown layer of nanocrystalline HAP is related to the ratio of the sintered CAP core material to HAP, said ratio being generally between 5:95 and 95:5, preferably from 10:90 to 90:10.
- the CAP/HAP bone substitute material may be a particulate or a granulate, the particles or granules having a desired size and shape. Generally, the particles or granules are approximately spherical and have a diameter of 250 to 5000 pm.
- the CAP/HAP bone substitute material may also be a shaped body, e.g. a screw, a nail, a pin or a structure having the profile of an osseous body part such as notably a hip, a clavicle, a rib, a mandible or a skull part.
- a screw, a nail or a pin may be used in reconstructive orthopedic surgery for fixing a ligament to a bone, for example in the knee or the elbow.
- Such a structure having the profile of an osseous body part may be used in orthopedic surgery as prosthesis for replacing a missing or defective bone or bone part.
- That CAP/HAP bone substitute material of EP-B1-2445543 is taught to be obtained by a process comprising the steps of
- step d) optionally sterilizing the separated material coming from step c).
- the preparation of the sintered CAP core material may be performed by methods known in the art comprising first mixing powders of calcium hydrogen phosphate (CaHPCk), calcium carbonate and/or calcium hydroxide, then calcining and sintering the mixture within an appropriate temperature range, thereby giving a bulk sintered CAP core material (see e.g. Mathew M. et ak, 1977, Acta. Cryst. B33: 1325; Dickens B. et ak, 1974, J. Solid State Chemistry 10, 232; and Durucan C. et ak, 2002, J. Mat. Sck, 37:963).
- CaHPCk calcium hydrogen phosphate
- CaHPCk calcium carbonate
- calcium hydroxide calcium hydroxide
- a bulk sintered TCP core material may thus be obtained by mixing powders of calcium hydrogen phosphate (CaHP0 4 ), calcium carbonate and/or calcium
- a bulk sintered TTCP core material may also be obtained by the above described process.
- the bulk sintered CAP material prepared by such methods may be porous with a porosity of 2 to 80 vol % and a wide distribution of pores.
- the porosity parameters will be selected according to the intended application of the CAP/HAP bone substitute material.
- the sintered CAP core material used in step b) may be
- a preform of sintered CAP core material having a desired shape and size, e.g. a screw, a nail, a pin or a structure having the profile of an osseous body part.
- a preform of any desired shape and size may be obtained from the bulk sintered core material prepared as described above, by using well known
- the aqueous solution of step b) is taught to be pure water, a simulated body fluid or a buffer. Important is that the pH value of the immersing solution of step b) is nearly neutral and remains stable throughout the transformation process, preferably within a pH range from 5.5 to 9.0.
- simulated body fluid refers to any solution that mimics a body fluid.
- the simulated body fluid has an ion concentration similar to that of blood plasma.
- the buffer may be any buffer in the above pH range but is preferably a phosphate buffer with or without calcium, magnesium and/or sodium.
- the buffer used in the Examples is an aqueous phosphate buffer.
- the temperature range in step b) is generally between 10°C and 50°C, preferably between 25 and 45 °C, more preferably between 35°C and 40°C.
- the immersing step b) induces in a first phase a first-order phase transition of the CAP core material and therefore the nucleation of HAP nanocrystal precursors.
- a first-order phase transition of the CAP core material and therefore the nucleation of HAP nanocrystal precursors.
- the resulting HAP precursors from the first phase will grow and establish a closed (i.e. completely coating) epitactic nanocrystalline composite layer.
- the first HAP nanocrystal layer must be uniform and closed and epitaxially connected to the sintered CAP core material.
- the first-order phase transition may proceed within the newly formed bilayer composite to further transform the sintered CAP core material (TCP or TTCP) into nanocrystalline HAP.
- the epitactically grown nanocrystalline HAP layer of appropriate thickness will be prepared in vitro, the transformation of CAP into HAP being stopped before it is completed.
- transformation process of CAP into HAP will be reactivated by contact with the body fluids and the bone substitute material will function as a living-like system forming new hydroxyapatite similar in size and morphology to human bone mineral.
- Step c) is therefore a very critical step.
- the exposure time in the aqueous solution of step b) is based upon the thickness of the HAP layer desired. At least one layer of nanocrystalline HAP in epitaxial orientation is necessary. It is essential that the transformation of CAP into HAP is not finished.
- the proper exposure time according to the thickness desired can be calculated by using several thermodynamic differential equations well known to the skilled person in the art of calcium phosphates, cement and concrete chemistry.
- Separating the solid material from the aqueous solution at the end of step c) is usually performed by filtration, washing and drying, using techniques well known in the art.
- washing is performed by washing the separated granules 3 times with purified water to remove residuals from the buffered solution.
- the optional sterilizing step d) may be performed by techniques well known in the art such as gamma-irradiation or X-ray radiation.
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and a closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, , i.e.
- the closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core has a non-homogeneous external surface comprising individual (separated) clusters of flat crystal platelets consisting of epitactically grown HAP nanocrystals and smooth areas between the individual clusters of flat crystal platelets, the % of the external surface occupied by the smooth areas between the individual clusters of flat crystal platelets depending on the transformation time in given transformation conditions.
- Fig. 1 A represents a SEM (scanning electron microscopy) picture of prototype 1 (1-2 mm granule) having a transformation time of 30 min wherein the smooth areas represent about 70 % of the total external surface as measured by SEM
- Fig. IB represents an SEM picture of prototype 2 (1-2 mm granule) having a transformation time of 40 min wherein the smooth areas represent about 50 % of the total external surface as measured by SEM.
- WO 2015/009154 discloses a method for producing an osteoconductive material with improved osteoinductive capacity, which comprises subjecting a sintered biphasic calcium phosphate/hydroxyapatite (CAP/HAP) material having a surface topography consisting of grains to a hydrothermal treatment under a pressure of 2-4 bars at a temperature equal to or higher than 125 °C without controlling the pH for a duration sufficient to change calcium phosphate grains on the surface of the starting material into calcium phosphate needles of a diameter 10- 1500 nm.
- CAP/HAP sintered biphasic calcium phosphate/hydroxyapatite
- a temperature of at least 125 °C and a pressure of at least 2 bars is far from the (close to the human body physiological) conditions used in EP-B1-2445543 (temperature 35-40 °C, pH 5.5-9.0, ambient pressure) which enable epitactic growth of HAP nanocrystals.
- Those needles are not epitactically grown but attached to or deposited on the core material base and only partially (usually 40-90 %) coat the latter, thereby increasing its specific surface and capacity of harboring proteins, thus enhancing its osteoinductive potential.
- That homogeneous coarse external surface generally comprises epitactically grown nanocrystalline hydroxyapatite platelets forming an interlocked network of platelets with individual platelet sizes of 0.2 to 20 pm, preferably 0.5 to 5 pm, as determined by SEM, depending on the amount of aliphatic alcohol used.
- the in vivo osteogenic response is likely to be stronger for the biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material having that homogeneous coarse external surface comprising flat crystal platelets than for the biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material taught by EP-B1-2445543 which has a non-homogeneous external surface comprising individual clusters of flat crystal platelets and smooth areas in between.
- CAP/HAP biphasic calcium phosphate/hydroxyapatite
- the invention thus concerns a biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material comprising a sintered CAP core and a closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core, whereby the epitactically grown nanocrystals have the same size and morphology as human bone mineral, wherein the closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core has a homogeneous coarse external surface comprising flat crystal platelets.
- CAP/HAP biphasic calcium phosphate/hydroxyapatite
- That biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material shows an increased osteogenic differentiation of fetal human mesenchymal stem cells (hMSCs), which is a strong indication of an enhanced in vivo osteogenic response.
- CAP/HAP biphasic calcium phosphate/hydroxyapatite
- the term "closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core” means that the epitactically grown layer of nanocrystalline HAP completely covers the entire external surface of the sintered CAP core.
- homogeneous coarse external surface comprising flat crystal platelets means that macroscopically the coarseness of the external surface caused by the flat crystal platelets is statistically evenly distributed on the surface of the CAP core without individual crystal clusters of flat crystal platelets. See Fig. 2 which represents SEM pictures of prototypes 3 to 7 of the biphasic calcium
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material of the invention with a homogeneous coarse external surface with a varying degree of coarseness.
- flat crystal platelets means crystal assemblies where the height (thickness) is considerably smaller than the width and length with respect to the three perpendicular directions. Such flat crystal platelets are clearly visible in Fig. 3B.
- the homogeneous coarse external surface comprises epitactically grown nanocrystalline hydroxyapatite platelets forming an interlocked network of platelets with sizes (width and length) of 0.2 to 20 pm as determined by SEM.
- the homogeneous coarse external surface comprises epitactically grown nanocrystalline hydroxyapatite platelets forming an interlocked network of platelets with sizes of 0.5 to 5 pm as determined by SEM
- homogeneous coarse external surface comprises epitactically grown hydroxyapatite platelets forming an interlocked network containing pores between 0.03 and 2 pm as determined by Mercury Intrusion Porosimetry (MIP).
- MIP Mercury Intrusion Porosimetry
- homogeneous coarse external surface may be characterized by AFM (Atomic Force Microscopy) with an AFM-derived root mean square roughness (R q ) in a range of 50 to 400 nm and an average maximum height of the profile (Rz) in a range of 500 to 2000 nm.
- AFM Anatomic Force Microscopy
- the homogeneous coarse external surface may be characterized by an AFM-derived root mean square roughness (Rq) in a range of 110 to 150 nm and an average maximum height of the profile (Rz) in a range of 550 to 750 nm.
- Rq AFM-derived root mean square roughness
- Rz average maximum height of the profile
- phosphate/hydroxyapatite (CAP/HAP) bone substitute material is from 1 to 90 %, as measured by XRD.
- That percentage is from 1.5 to 30%, more preferably from 2 to 15 %, as measured by XRD.
- the sintered CAP core comprises tricalcium phosphate (TCP), notably a-TCP (a-Ca 3 (P0 4 ) 2 ) or
- TCP tricalcium phosphate
- the sintered CAP core essentially consists of TCP, a-TCP being preferred.
- the epitactically grown layer of nanocrystalline HAP is structurally nearly identical to the natural human bone mineral.
- the CAP/HAP bone substitute material may be a particulate or a granulate, the particles or granules having a desired size and shape. Generally, the particles or granules have a size of 250 to 5000 pm, preferably 1000 to 2000 pm.
- the CAP/HAP bone substitute material may also be a shaped body, e.g. a screw, a nail, a pin or a structure having the profile of an osseous body part such as notably a hip, a clavicle, a rib, a mandible or a skull part.
- a screw, a nail or a pin may be used in reconstructive orthopedic surgery for fixing a ligament to a bone, for example in the knee or the elbow.
- Such a structure having the profile of an osseous body part may be used in orthopedic surgery as prosthesis for replacing a missing or defective bone or bone part.
- the invention also relates to a putty comprising particles or granules of the above defined CAP/HAP bone substitute in a suitable matrix, generally comprising natural or synthetic polymers.
- a putty comprising particles or granules of the above defined CAP/HAP bone substitute in a suitable matrix, generally comprising natural or synthetic polymers.
- the particles or granules have a size of 250 to 5000 pm, preferably 1000 to 2000 pm.
- the invention further relates to a process of preparing the above defined
- step d) optionally sterilizing the separated material coming from step c).
- a suitable short-chain aliphatic alcohol may be selected from the group consisting of methanol, ethanol, propanol and butanol.
- the short-chain aliphatic alcohol is ethanol.
- the buffer solution of step b) contains 20 to 60 %, more preferably 30 to 50 %, of a short-chain aliphatic alcohol.
- the coarseness parameters of the homogeneous coarse external surface of the closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core notably
- the AFM parameters the AFM-derived root mean square roughness (R q ) and the average maximum height of the profile (Rz),
- the buffer solution of step b) containing 10 to 90 % of a short-chain aliphatic alcohol is obtained by mixing an aqueous buffer solution with varying amounts of a short-chain aliphatic alcohol.
- the aqueous buffer solution is chosen such that the pH value of the immersing solution of step b) which further contains 10 to 90 % of a short-chain aliphatic alcohol is nearly neutral and remains stable throughout the transformation process, preferably within a pH range from 5.5 to 9.0, more preferably from 7.0 to 8.0.
- the buffer may be any buffer in the above pH range but is preferably a phosphate buffer with or without calcium, magnesium and/or sodium.
- a suitable buffer solution is e.g. a 0.05-0.3 M aqueous solution of sodium dihydrogen phosphate (NaH 2 P0 4 ) with a pH value of 7.3 to 7.6.
- the temperature range in step b) is generally between 10°C and 50°C, preferably between 25 and 45 °C, more preferably between 35°C and 40°C.
- step b) is carried out at a temperature of 35 to 40 °C in a phosphate buffer solution of pH from 7.0 to 8.0 containing 20 to 60 % of a short-chain aliphatic alcohol.
- the preparation of the sintered CAP core material may be performed by methods known in the art comprising first mixing powders of calcium hydrogen phosphate (CaHP0 4 ), calcium carbonate and/or calcium hydroxide, then calcining and sintering the mixture within an appropriate temperature range, thereby giving a bulk sintered CAP core material (see e.g. Mathew M. et ak, 1977, Acta. Cryst. B33: 1325; Dickens B. et ak, 1974, J. Solid State Chemistry 10, 232; and Durucan C. et ak,
- a bulk sintered TCP core material may thus be obtained by mixing powders of calcium hydrogen phosphate (CaHP0 4 ), calcium carbonate and/or calcium hydroxide in stoichiometric ratio, calcining and sintering the mixture at a
- a bulk sintered TTCP core material may also be obtained by the above described process.
- the bulk sintered CAP material prepared by such methods may be porous with a porosity of 2 to 80 vol% and a wide distribution of pores.
- the porosity parameters will be selected according to the intended application of the CAP/HAP bone substitute material.
- the sintered CAP core material used in step b) may be
- a preform of sintered CAP core material having a desired shape and size, e.g. a screw, a nail, a pin or a structure having the profile of an osseous body part.
- Such a preform of any desired shape and size may be obtained from the bulk sintered core material prepared as described above, by using well known
- the immersing step b) induces in a first phase a first-order phase transition of the CAP core material and therefore the nucleation of HAP nanocrystal precursors.
- the resulting HAP precursors from the first phase will grow and establish a closed (i.e. completely coating) epitactic nanocrystalline composite layer.
- the first HAP nanocrystal layer must be uniform and closed and epitactically connected to the sintered CAP core material.
- the first-order phase transition may proceed within the newly formed bilayer composite to further transform the sintered CAP core material (TCP or TTCP) into nanocrystalline HAP.
- the sintered CAP core material TCP or TTCP
- calcium ions will be released for a controllable time by a slow diffusion controlled process until a part of the sintered CAP core material has been transformed into nanocrystalline HAP.
- the thickness of the HAP layer and therefore the rate of calcium release can be controlled by variation of the transformation time.
- the epitactically grown nanocrystalline HAP layer of appropriate thickness will be prepared in vitro, the transformation of CAP into HAP being stopped before it is completed.
- transformation process of CAP into HAP will be reactivated by contact with the body fluids and the bone substitute material will function as a living-like system forming new hydroxyapatite similar in size and morphology to human bone mineral.
- Step c) is therefore a very critical step.
- the exposure time in the aqueous solution of step b) is based upon the thickness of the HAP layer desired. At least one layer of nanocrystalline HAP in epitaxial orientation is necessary. It is essential that the transformation of CAP into HAP is not finished.
- the proper exposure time according to the thickness desired can be calculated by using several thermodynamic differential equations well known to the skilled person in the art of calcium phosphates and cement and concrete chemistry.
- Separating the solid material from the aqueous solution is usually performed by filtration and drying, using techniques well known in the art.
- the optional sterilizing step d) may be performed by techniques well known in the art such as gamma-irradiation or X-ray radiation.
- the invention also concerns the use of the above defined CAP/HAP bone substitute material, generally in the form of a particulate, a putty or a shaped body as an implant or prosthesis for supporting bone formation, bone regeneration, bone repair and/or bone replacement at a defect site in a human or animal.
- the invention also relates to a method of promoting bone formation, bone regeneration and/or bone repair at a defect site in a human or animal by implanting the above defined CAP/HAP bone substitute material, generally in the form of a particulate, a putty or a shaped body.
- That biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material of the invention with a homogeneous coarse external surface comprising flat crystal platelets shows an increased osteogenic differentiation of fetal human mesenchymal stem cells (hMSCs), in particular a higher expression of differentiation markers osteopontin (OPN) and osteocalcin (OCN), compared with the biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material taught by EP-B1 -2445543 which has a non-homogeneous external surface comprising individual clusters of flat crystal platelets and smooth areas in between. This is a strong indication of an enhanced in vivo osteogenic response.
- hMSCs fetal human mesenchymal stem cells
- OPN osteopontin
- OCN osteocalcin
- the process of preparation of the biphasic calcium phosphate/hydroxyapatite (CAP/HAP) bone substitute material of the invention allows to conveniently adjust the coarseness parameters of the homogeneous coarse external surface of the closed epitactically grown layer of nanocrystalline HAP deposited on the external surface of the sintered CAP core, notably
- Fig. 1A represents an SEM picture of prototype 1 (1-2 mm granule) of a bone substitute material disclosed by EP-B1 -2445543 and prepared in Example 1 having a transformation time of 30 min wherein the smooth areas represent about 70 % of the total external surface as measured by SEM.
- Fig. IB which represents an SEM picture of prototype 2 (1-2 mm granule) of a bone substitute material disclosed by EP-B1-2445543 and prepared in Example 1 having a transformation time of 40 min wherein the smooth areas represent about 50 % of the total external surface as measured by SEM.
- Figs. 2A-2E represent SEM pictures of prototype 3 (Fig. 2A): 20 % ethanol, 1-2 mm granule), prototype 4 (Fig. 2B): 30 % ethanol, 1-2 mm granule), prototype 5 (Fig. 2C): 40 % ethanol, 1-2 mm granule), prototype 6 (Fig. 2D): 50 % ethanol, 1-2 mm granule) and prototype 7 (Fig. 2E): 60 % ethanol, 1-2 mm granule) of bone substitute materials according to the invention.
- Fig. 3A represents a SEM picture of a cross-section of prototype 5 (40 % ethanol, 1-2 mm granule) at low magnification (1000 x).
- the bottom-right corner shows the outer surface of the granule and the center of the granule is located towards the top-left corner.
- Fig. 3B represents a SEM picture of a cross-section of prototype 5 (40 % ethanol, 1-2 mm granule) at higher magnification (14' 000 x).
- Fig. 4 represents SEM pictures (the two upper pictures) and AFM pictures (the other four pictures) of prototypes 3a (left: 20 % ethanol) and 6a (right: 50 % ethanol) of non-porous discs of bone substitute materials according to the invention prepared in Example 2.
- Figs. 5A-5B represent the osteocalcin (OCN, Fig. 5A) and the osteopontin (OPN, Fig. 5B) responses of fetal human mesenchymal stem cells (hMSCs) in contact with bone substitute materials according to the invention compared to prior art bone substitute materials in an in vitro test.
- OCN osteocalcin
- OPN osteopontin
- hMSCs fetal human mesenchymal stem cells
- Fig. 6 represents MIP diagrams of 1-2 mm granules of prototypes 3 (20 % ethanol), 5 (40 % ethanol) and 7 (60 % ethanol) of the 1-2 mm granules of bone substitute materials according to the invention prepared in Example 2 and pure a- TCP produced as described in Example 1.
- a bulk sintered material of lph -TCP, porous granules thereof with a particle size of 1.0-2.0 mm and transformed granules having an epitactically grown HAP coating were prepared similarly to Examples 1, 2 and 4 of EP-B1-2445543.
- the bulk product was crushed by using a jaw crusher (jaw distances varied from 10 to 1 mm).
- the produced granules were sieved by using a sieving machine and sieve inserts with mesh apertures of 2 mm and 1 mm. After sieving, the granules were rinsed with ethanol for separating fine powder residuals adsorbed to the granules.
- the porous granules were dried for 1 h at 80°C in a cabinet dryer. The cleanness of the particle surfaces after rinsing was controlled by surface observation using scanning electron microscopy.
- a buffered solution adequate for the coating and phase transformation process was prepared by dissolving 0.4 mol/l sodium dihydrogen phosphate (NaThPO ⁇ in distilled water. The pH of the solution was adjusted to 7.45 at room temperature by using sodium hydroxide (NaOH).
- the granules produced according to the previous paragraphs were immersed into the prepared solution and stored within a well- tempered water bath (40°C) for 30 min (prototype 1) respectively 40 min (prototype 2). After immersing, the granules were rinsed 3 times with distilled water to stop the phase transformation process and remove residuals from the buffered solution. The porous granules were dried at 100°C in a cabinet dryer for 2 hours.
- Figs. 1A and IB which represent SEM pictures of prototypes 1 and 2, the external surface of the granules is non-homogeneous comprising individual (separated) clusters of flat crystal platelets consisting of epitactically grown HAP nanocrystals and smooth areas between the crystals.
- the phase transformation and coating step was performed in glass flasks placed in a water bath set to 40°C.
- the transformation buffer was an aqueous solution of sodium dihydrogen phosphate (NaEEPO ⁇ mixed with different proportions of ethanol.
- the molarity of the aqueous solution of sodium dihydrogen phosphate was varied between 0.05 M and 0.3M and the content of ethanol between 20 and 60 w/w %.
- the pH of the transformation solution was between 7.3 and 7.6.
- the glass flasks were filled with the transformation buffer and alpha-TCP granules were added with a ratio between 1:40 to 1:80 (granules to transformation solution).
- the granules were immersed in the transformation solution at 40°C for a period between 24 and 72 hours. After immersing, the granules were rinsed 5 times with deionised water (granules to water ratio being 1:10 with respect to weight) and 2 times with Ethanol (99.9%, granules to ethanol ratio being 1:10 with respect to weight) to stop the phase transformation process and remove residuals from the buffered solution.
- the porous granules were dried at 100°C in a cabinet dryer for 2 hours.
- Fig. 2 represents SEM pictures with a 3500 x magnification of prototype 3 (20 % ethanol), prototype 4 (30 % ethanol), prototype 5 (40 % ethanol), prototype 6 (50 % ethanol) and prototype 7 (60 % ethanol) of bone substitute materials according to the invention. It can be seen by comparing Figs. 1 A and IB to Fig. 2, that the non- homogeneous external surface of prototypes 1 and 2 with the individual clusters of flat crystal platelets and smooth areas in between is replaced by a homogeneous coarse external surface without any individual crystal clusters. The homogeneous coarse external surface is built up of an interlocked network of epitactically grown hydroxyapatite platelets. The individual platelet sizes are decreased by increasing the ethanol content in the transformation solution as observed by the SEM analysis thus decreasing the coarseness or roughness of the external surface.
- Fig. 3A represents a SEM picture of a cross-section of prototype 5 (40 % ethanol, 1-2 mm granule) at low magnification (1000 x).
- the bottom-right corner shows the outer surface of the granule and the center of the granule is located towards the top-left corner.
- Fig. 3B represents a SEM picture of a cross-section of prototype 5 (40 % ethanol, 1-2 mm granule) at higher magnification (14 ⁇ 00 x) where one can clearly see the individual flat crystal platelets which are the building blocks of the coarse surface. There is no difference between the coarse external surface in the center of the granule and the coarse external surface on the outer surface of the granule.
- MIP mercury intrusion porosimetry
- Fig. 6 represents MIP diagrams of prototypes 3, 5 and 7 of bone substitute materials according to the invention compared to pure a-TCP (produced according to example 1 and core material of the prototypes 3, 5 and 7). All measurements were performed with 1-2 mm granules. It can be seen that the pure a-TCP sample does not have any pores in the range of 0.03 to 2 pm because of its smooth surface. All the bone substitute materials according to the invention contain pores in the range of 0.03 to 2 pm due to the porous nature of the homogeneous coarse external surface which is built up of an interlocked network of epitactically grown hydroxyapatite platelets.
- the pore volume of the coarse external surface which corresponds to the area under the MIP curve in the range of 0.03 to 2 pm, depends on the individual platelet sizes of the interlocked network. The bigger the individual platelets are, the higher is the included pore volume of the interlocked network. Thus, the included pore volume of the interlocked network can directly be correlated to the coarseness of the surface. The higher the pore volume in the range of 0.03 to 2 pm in the MIP diagram is, the higher is the coarseness of the surface.
- Prototype 3 has the largest pore volume (area under the curve) in the range of 0.03 to 2 pm of the shown prototypes, followed by prototype 5 and 7. It is confirmed by the SEM analysis in Figs. 2A-2E that the coarseness of the prototypes is decreasing from prototype 3 to prototype 5 and 7.
- the 1-2 mm sized granules of phase pure a-TCP produced as described in above Example 1 were milled with a planetary mill during 20 hours with 150 rpm to obtain a fine powder.
- the fine powder was filled in a pressing mold and compacted with a hand press with a load of 1 ton.
- the green body was removed from the mold and transferred to a high temperature furnace.
- the furnace was heated to 1450°C by using a heating rate of 250°C per hour. This temperature was kept for 24 hours and afterwards the furnace was cooled down to 800°C with a cooling rate of 500°C per hour and then cooled down to room temperature with a cooling rate of 150°C per hour.
- phase pure a-Ca 3 (P0 4 ) 2 was removed from the furnace.
- the control of phase purity was performed using powder X-ray diffraction analysis and the surface characteristics were analysed by using SEM.
- the phase transformation and coating of the prepared discs was performed as described above under 1), with the only difference that the weight ratio of a-TCP to transformation solution was 1 to 3.5.
- Prototypes 3a (20 % ethanol) and 6a (50 % ethanol) of bone substitute materials according to the invention were thus prepared.
- the surface morphology after the coating and phase transformation process was observed using SEM.
- the corresponding roughness parameters were determined using atomic force microscopy AFM.
- AFM analyses were conducted under ambient atmosphere using non-porous cylindrical discs with a diameter of 11 mm and a height of 1 mm. A resonance frequency of 190 kHz and a tip radius of up to 10 nm were used. Each AFM analysis was performed over a 50 pm x 50 pm area and three samples of every group were scanned. The original data was plane-leveled to remove tilt by applying a numerical correction and mean values of root mean square roughness (R q ) and average maximum height of the profile (Rz) were determined using the Gwyddion software.
- R q root mean square roughness
- Rz average maximum height of the profile
- Fig. 4 represents AFM pictures of the prototypes 3a (20 % ethanol, left hand side) and 6a (50 % ethanol, right hand side) of non-porous discs prepared according to the invention.
- the AFM-derived roughness values for the prototypes 3a and 6a can be found in following Table 1.
- the mean value of the root mean square roughness (R q ) decreased from 237 nm to 130 nm and the average maximum height of the profile (Rz) decreased from 1391 nm to 630 nm by increasing the ethanol content from 20% to 50%.
- Example 3 in vitro test of osteogenic differentiation of fetal human mesenchymal stem cells (hMSCs).
- osteogenic differentiation markers osteopontin (OPN) and osteocalcin (OCN) was measured for all bone substitute material prototypes in granular form (1-2 mm) prepared in Examples 1 and 2.
- Example 4 Comparison of the crystal size and morphology for the HAP nanocrystals of the biphasic CAP/HAP bone substitute material of the invention and human bone mineral.
- Crystal size analysis was performed by using as in EP-B 1-2445543 a refinement of X- ray diffraction data by applying the Bragg method on samples of prototype 3 and on natural human bone mineral.
- biphasic CAP/HAP bone substitute material of the invention and human bone mineral have the same morphology and the same crystal size.
Abstract
Description
Claims
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IL275203A IL275203B2 (en) | 2017-12-14 | 2018-12-13 | Bone substitute material |
CN201880080248.XA CN111465418B (en) | 2017-12-14 | 2018-12-13 | Bone substitute material |
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KR1020207016840A KR102233325B1 (en) | 2017-12-14 | 2018-12-13 | Bone substitutes |
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WO2020249716A1 (en) | 2019-06-14 | 2020-12-17 | Geistlich Pharma Ag | Collagen matrix or granulate blend of bone substitute material |
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