Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/42—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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/02—Inorganic materials
• • 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
  • A61L27/02—Inorganic materials
  • A61L27/12—Phosphorus-containing materials, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/30—Inorganic materials
  • A61L27/32—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
• • 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
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/02—Inorganic materials
  • A61L31/026—Ceramic or ceramic-like structures, e.g. glasses
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/08—Materials for coatings
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/08—Materials for coatings
  • A61L31/082—Inorganic materials
  • A61L31/086—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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L31/121—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
  • A61L31/123—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of 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
  • 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
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
• • 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), 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, osteoinductive 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 osteoinductive 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 ⁇ -TCP/HAP by heating a powder mixture of ammonium phosphate and HAP at 1200-1500 Q C.
• 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.
• the 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 sintered CAP core may comprise tricalcium phosphate (TCP), notably ⁇ - TCP ( ⁇ -Ca 3 (PO 4 )2) or ⁇ -TCP ( ⁇ -CastPO ⁇ ), and/or tetracalcium phosphate (TTCP) Ca ⁇ PO ⁇ O.
• TCP tricalcium phosphate
• ⁇ -TCP ⁇ -Ca 3 (PO 4 )2
• ⁇ -TCP ⁇ -CastPO ⁇
• TTCP tetracalcium phosphate
• the sintered CAP core essentially consists of TCP, ⁇ -TCP being preferred.
• 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 nanpcrystals 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 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 ⁇ m.
• the sintered CAP core material may comprise tricalcium phosphate (TCP), notably ⁇ -TCP ( ⁇ -Ca 3 (P ⁇ 4) 2 ) or ⁇ -TCP ( ⁇ -Ca3(PO ⁇ ), and/or tetracalcium phosphate (TTCP) Ca 4 (PO 4 J 2 O.
• TCP tricalcium phosphate
• ⁇ -TCP ⁇ -Ca 3 (P ⁇ 4) 2
• ⁇ -TCP ⁇ -Ca3(PO ⁇
• TTCP tetracalcium phosphate
• a bulk sintered TCP core material may thus be obtained by mixing powders of calcium hydrogen phosphate (CaHP ⁇ 4), calcium carbonate and/or calcium hydroxide in stoichiometric ratio, calcining and sintering the mixture at a temperature in the range of 1200-1450 2 C, preferably about 1400°C.
• a bulk sintered TTCP core material may also be obtained by the above described process.
• 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 prototyping techniques such as CNC milling or 3D printing (see for example Bartolo P. et al., 2008, Bio-Materials and Prototyping Applications in Medicine, Springer Science New York, ISBN 978-0-387-47682-7; Landers R. et al., 2002, Biomaterials 23(23), 4437; Yeong W.-Y. et al., 2004, Trends in Biotechnology, 22 (12), 643; and Seitz H. et al., 2005, Biomed. Mater. Res. 74B (2), 782).
• the aqueous solution of step b) may 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.
• 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.
• 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 temperature range in step b) is generally between 10°C and 50°C, preferably between 25 and 45 0 C, more preferably between 35 0 C and 40 0 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.
• 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 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.
• the 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 humane 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.
• CAP/HAP system enables the prediction of the phase transition of CAP into HAP and the thickness of the layer such that the epitactic layer of HAP can be prepared in a stable and reproducible manner.
• 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.
• the invention also concerns the use of the above defined CAP/HAP bone substitute material, generally in the form of a particulate 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 or a shaped body.
• Crystal size analysis has been performed by using TEM (transmission electron microscopy), SPM (scanning probe microscopy techniques) as well as refinement of X-ray diffraction data by using the Bragg method .
• the constant concentration of calcium ions results in an improved adhesion of osteoblasts and osteoclasts to the HAP surface in the correct ratio for the osteogenesis and thus to a steady state in the cycle of bone regeneration.
• a surface is provided to which osteoblasts and osteoclasts readily attach in the correct ratio for bone regeneration.
• the CAP/HAP bone substitute material of the invention can function as a matrix for bioactive molecules such as extracellular matrix proteins such as notably growth factors for bone regeneration.
• bioactive molecules such as extracellular matrix proteins such as notably growth factors for bone regeneration.
• phase purity was performed using powder X-ray diffraction analysis.
• the work piece was placed and fixed into a 4-axis CNC milling machine equipped with a round-head hard metal milling cutter tool with a diameter of 3 mm.
• the cylinders were milled by using a helical milling route with a radius of 3 mm and a slope of 0.25 mm.
• the main speed of the work piece during the CNC milling process was 1700 rotations per minute, the maximum rotation speed of the helical milling route was calculated by an integral process within the CNC equipment and averages 10 rotations per minute.
• the cylindrical preforms were rinsed 2 times by using purified water for separating fine powder residuals adsorbed to the cylinder surface.
• the porous cylinders were dried for 10 hours at 12O 0 C in a cabinet dryer.
• the cleanness of the preform surface after rinsing was controlled by surface observation using scanning electron microscopy.
• the correctness of the preform dimensions was controlled by using a slide gauge.
• Example 4 Preparation of an epitactically grown nanocrystalline HAP coating on the granules of sintered ⁇ -TCP from Example 2
• a buffered solution (1000ml) adequate for the coating and phase transformation process was prepared by using 1.82 mol/1 sodium, 4.68 mol/1 hydrogen, 0.96 mol/1 phosphorus, 5.64 mol/1 oxygen, 0.01 mol/1 calcium and 0.71 mol/1 chlorine.
• the solution will be adjusted to a pH of 7.4 at a temperature of 4O 0 C.
• the granules produced according to example 1 and 2 were immersed into the prepared solution and stored within a well tempered water bath (40 0 C) for a time calculated according a layer thickness at an average of 250 nm (10 hours) which equates to a phase composition of (w/w) 75 % alpha-TCP and 25% hydroxyapatite.
• the porous granules were dried for 4 hours at 120°C in a cabinet dryer.
• the phase composition of the granules were analyzed by Rietveld analysis of powder X-ray diffraction data, the crystal sizes of crystalline phases obtained by the coating process were analyzed by size-strain refinement of X- ray diffraction data according to the Bragg technique.
• the porosity of the granules was controlled by using mercury intrusion porosimetry, the surface morphology after coating was controlled by using scanning electron microscopy.
• Example 5 Preparation of an epitactically grown nanocrystalline HAP coating on the cylinders of sintered ⁇ -TCP from Example 3
• a buffered solution (1000 ml) adequate for the coating and phase transformation process was prepared by using 1.82 mol/1 sodium, 4.68 mol/1 hydrogen, 0.96 mol/1 phosphorus, 5.64 mol/1 oxygen, 0.01 mol/1 calcium and 0.71 mol/1 chlorine.
• the solution was adjusted to a pH of 7.4 at a temperature of 4O 0 C.
• porous cylinders produced according to example 1 and 3 were immersed into the prepared solution and stored within a well tempered water bath (40°C) for a time calculated according a layer thickness at an average of 20 ⁇ m (60 hours) which equates to a phase composition of approximately 85% (w/w) alpha-TCP and 15%
• Tables 2 and 3 show experimental data for an example showing the influence of the immersing time on the layer thickness and the phase composition, respectively, for porous ⁇ -TCP particles with nearly spherical geometry and size from 10 to 20 ⁇ m, a porosity 25-40 vol.-%, a specific (inner) surface area of 50-60 m 2 /g/ a bulk density of 0.6-0.8 g/ml.

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