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WO2007025698A2 - Materiau osteoinductif et procede de fabrication - Google Patents

Materiau osteoinductif et procede de fabrication Download PDF

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Publication number
WO2007025698A2
WO2007025698A2 PCT/EP2006/008403 EP2006008403W WO2007025698A2 WO 2007025698 A2 WO2007025698 A2 WO 2007025698A2 EP 2006008403 W EP2006008403 W EP 2006008403W WO 2007025698 A2 WO2007025698 A2 WO 2007025698A2
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WO
WIPO (PCT)
Prior art keywords
bone
granules
calcium phosphate
xerogel
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2006/008403
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German (de)
English (en)
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WO2007025698A3 (fr
Inventor
Thomas Gerber
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Artoss GmbH
Original Assignee
Artoss GmbH
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Publication date
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Publication of WO2007025698A2 publication Critical patent/WO2007025698A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007025698A3 publication Critical patent/WO2007025698A3/fr
Ceased legal-status Critical Current

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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
    • A61L27/50—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
    • A61L27/40—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
    • A61L27/427—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of other specific inorganic materials not covered by A61L27/422 or A61L27/425
    • 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
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B38/00—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof
    • C04B38/009—Porous or hollow ceramic granular materials, e.g. microballoons
    • 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
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    • A—HUMAN NECESSITIES
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    • 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
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    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
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    • 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
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • A—HUMAN NECESSITIES
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    • 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
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
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    • A—HUMAN NECESSITIES
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    • 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
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30108—Shapes
    • A61F2002/30199—Three-dimensional shapes
    • A61F2002/30224—Three-dimensional shapes cylindrical
    • A61F2002/30235—Three-dimensional shapes cylindrical tubular, e.g. sleeves
    • 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
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30772—Apertures or holes, e.g. of circular cross section
    • A61F2002/30784—Plurality of holes
    • A61F2002/30785—Plurality of holes parallel
    • 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
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30772—Apertures or holes, e.g. of circular cross section
    • A61F2002/30784—Plurality of holes
    • A61F2002/30787—Plurality of holes inclined obliquely with respect to each other
    • 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
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • 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
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0017—Angular shapes
    • A61F2230/0019—Angular shapes rectangular
    • 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
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0063—Three-dimensional shapes
    • A61F2230/0069—Three-dimensional shapes cylindrical
    • 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
    • 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
    • A61F2310/00329—Glasses, e.g. bioglass
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
    • C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
    • C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications

Definitions

  • the invention relates to a hydroxylapatite / silica granules of defined morphology, a highly porous bone substitute material based on this granulate and a glass ceramic based thereon as a bone substitute material, which is characterized by a variable mechanical strength, and molded articles of this material, preference being given to the molded article Materials of different mechanical strength can be used.
  • the bone substitute materials according to the invention are characterized by a good resorbability in vivo.
  • the invention relates to the use of the bone substitute material for osteoinduction, in particular for ectopic osteoinduction.
  • Bone grafting is the second most common human transplantation mode after administration of blood components (Fox, R .: New bone The Lancet 339, 463f., (1992)). Thus, 250000 bone grafts were performed in the US in 1993 (Kenley et al., Biotechnology and Bone Graft Substitutes, Pharmaceut. Res., 10, 1393 (1993)). The replacement of congenital, posttraumatic and osteoporotic bone lesions as a result of osteomyelitis and tumor surgery is of clinically significant clinical importance, since only in this way is it possible to achieve a functionally comprehensive rehabilitation.
  • porous bone substitutes utilize the framework of natural corals (Pollick S, Shors, EC, Holmes RE, Kraut RA, Bone formation and implant degradation of coralline porous ceramics placed in bone and ectopic sites.) J Oral Maxillofac Surg 1995; 8): 915-23, White, EW, Calcium phosphate bone substitute materials, U.S. Patent 4,861,733, 1989) which have an ideal pore structure (size distribution, morphology) for bone tissue ingrowth.
  • Porous hydroxyapatite (HA) -based materials are an ideal bone substitute because they promote tissue regeneration through a special surface characteristic.
  • these ceramics are not intrinsically osteoinductive (Heymann D, Delecrin J, Deschamps C, Gouin F Padrines M, Passuti N.
  • Yuan et. al states that depending on the microstructure of the ceramic with the same chemical and crystallographic structure of the calcium phosphate osteoinductive properties can be caused.
  • osteoinductive properties bone formation in extraosseous sites
  • HA ceramics hydroxyapatite ceramics
  • BMPs bone morphogenetic proteins
  • ie purely inorganic materials can not cause this property (see For example, Sonobe J, Okubo Y, Kaihara S, Miyatake S, Bessho K .: "Osteoinduction by bone morphogenetic protein 2-expressing adenoviral vector: application of biomaterial to mask the host immune response.” Hum Gene Ther. 2004 JuI; 15 (7): 659-68).
  • Dagulsi describes the cell reaction, biodegradation and resorption as well as the transformation into carbonate hydroxyapatite of a biphasic material (HA / TCP) which was used as molding, coating as well as injectable bone substitute material (Dagulsi G. Biphasic calcium phosphate concept applied to artificial bone, implant coating and injectable bone substitute, 1998, 19 (16): 1473-8).
  • Oonishi et al. compare the ingrowth behavior of granules of bioglass and synthetic, temperature-treated hydroxyapatite in a study on adult rabbit femoral condyles (Oonishi H, Hench LL, Wilson J, Sugihara F, Tsuj i E, Matsuura M, Kin S, Yamamoto T, Mizokawa S. Quantitative comparison of Bone Growth Behavior in Granules of Bioglass, AW glass-ceramic, and hydroxyapatite J Biomed Mater Res 2000; 51 (1): 37-46). In contrast to bioglass, the synthetic hydroxyapatite is not completely absorbed.
  • Bioactive glasses are also described as bone replacement material (US 6,054,400, 2000, US 5,658,332, 1997).
  • the inorganic material is present here as a glassy solid. Pores of the order of the cancellous bone allow tissue ingrowth. Smaller pores are not present in the material.
  • Glass ceramics are also offered as bone substitutes (eg US 5,981,412, 1999). They are to be compared with the bioactive glasses, wherein in the glass matrix, which is generally a bioactive calcium silicate glass, crystalline components such as Na 2 O 2CaO 3SiO 2 are embedded. Calcium phosphate cements have been developed as a further group of substances for use as bone substitutes (US 5,997,624, 1999, US 5,525,148, 1996). A decisive disadvantage of this substance group is that no defined interconnecting pores are introduced into the material, whereby they are limited to very small bone defects.
  • an inorganic resorbable bone substitute material which has a loose crystal structure, ie the crystallites are not tightly joined together as in a solid (ceramic), but only interconnected by a few groups of molecules.
  • the volume occupied by the collagen in the natural bone is present in the material as interconnecting pores in the nanometer range.
  • a second pore size also interconnecting and in the range of a few micrometers, allows ingrowth of collagen fibers during tissue formation. These fibers are nucleating agents for the onset of biomineralization (formation of the body's own biological apatite).
  • the material contains a third interconnecting pore category, the cancellous bone is in the range of about lOO ⁇ m to lOOO ⁇ m and thus allows ingrowth of blood vessels, whereby the resorption and the formation of new bone is not only done as a front of the healthy bone, but happens from the entire defect out.
  • hydroxyapatite-based bone replacement materials are virtually non-resorbed and permanently present a foreign body.
  • the material described in DE 100 60 036 which consists essentially of hydroxyapatite, absorbs very well and simultaneously accelerates the formation of new bone tissue. This property is determined by the described loose crystal structure of calcium phosphates.
  • the mechanical strength of this material is relatively low. It can not take on a mechanical support function.
  • the potential for variation of the bone replacement material to be used for the replacement of whole bone fragments is very limited.
  • the present invention is based on the object to provide a bone replacement material that supports the formation of bone tissue (that is, osteoconductive or osteoinductive), which is absorbed through the natural processes of bone remodeling and has a mechanical strength corresponding to the various applications can be adjusted. Defects in the bones, such as those caused by inflammation, are usually surrounded by healthy bone on several sides. For these defects, the mechanical strength of the bone substitute material plays no role.
  • a replacement bone eg a hollow cylinder for a missing piece of tubular bone
  • osteosynthesis plates metal plates, which are removed after healing
  • Another object of the invention is to provide materials capable of effecting effective osteoinduction, i. a new bone formation in a much larger extent to the prior art.
  • the object is thus achieved according to the invention by a material which contains crystalline calcium phosphate embedded in a xerogel matrix.
  • This xerogel matrix is made of silicon dioxide.
  • a xerogel is a dry gel characterized by a high internal surface area and incomplete crosslinking of the assemblies.
  • the matrix containing the crystalline components is not a glass but a xerogel with its typical porous structure.
  • the xerogel matrix should preferably occupy a proportion by weight of 4 to 80% based on the total mass of the bone substitute material. Since a silica xerogel is a porous material, 2 tetrahedra are loosely connected in the SiO 4 / and has the high internal surface with -SiOH groups, depending on the size of the crystallites of the calcium phosphate matrix can already be constructed with low weight, the enclosing the crystalline components. Depending on the size of the crystallites, a reduction of the matrix fraction to less than 5% by weight is possible.
  • the xerogel matrix has different tasks. On the one hand, of course, it combines the crystalline components of the material. Due to the relatively loose linkage of the silicon dioxide, the mechanical strength of the material is limited. The breaking strength is typically in the range of 2 to 15 MPa (see Example 6). On the other hand Xerogel porosity allows resorption of the biomaterial and enhances bioactivity, which is, of course, primarily due to the calcium phosphate components, by accumulating endogenous proteins from the patient's blood during application to the high internal surface area. Therefore, the cells do not classify the biomaterial as foreign.
  • the invention thus relates to granules and a group of bone replacement materials based thereon, which will be described below.
  • the granules are based on calcium phosphate in which crystalline calcium phosphate is embedded in a silica-xerogel matrix, wherein the crystallites have an average diameter of about 10 nm to about 2000 nm, preferably from 10 nm to 200 nm, particularly preferably platelet-shaped crystallites having a thickness from 2.5 nm to 10 nm and a mean diameter of 10 nm to 200 nm.
  • the granules have an average diameter of about 1 micron to about 1000 microns and the silica content in the range of about 2 to about 80 wt .-%, preferably in the range of about 4 to about 50 wt .-%.
  • the pores in the xerogel have an average diameter in the range of 0.5 nm to 20 nm. In each case, they make up about 10% by volume to about 60% by volume, based on the volume of the granules, in the granules.
  • the calcium phosphate is hydroxyapatite.
  • the granulate may further comprise, in a particular embodiment, soluble calcium phosphate, wherein the soluble calcium phosphate is preferably present in an amount of about 5% by weight. to 50 wt .-% based on the calcium phosphate content is present.
  • the soluble calcium phosphate is especially ⁇ -tricalcium phosphate ( ⁇ TCP).
  • ⁇ TCP ⁇ -tricalcium phosphate
  • the xerogel of the granule may further comprise one or more network transducer oxides.
  • the network transducer oxide (s) is preferably present in an amount of from about 0.5 to about 35 mole percent, preferably at a level of about 17 mole. % to about 30 mole%, based on the silica before.
  • the network converter oxide is in particular Na 2 O.
  • Fig. 1 an inventive granule particles is exemplified schematically.
  • the crystallites (shown in black) in the granules are held together by the SiO 2 xerogel (shown in gray).
  • SiO 2 xerogel On the surface of the granules is SiO 2 xerogel.
  • a granular grain from the preferred size range with a diameter of eg 1 micron in the order of 10 4 crystallites, if these are, for example platelets with a diameter of 100 nm and a thickness of 10 nm and the xerogel 40 wt .-% of the granule takes.
  • the starting point is a highly porous bone substitute material, which is characterized in that the granules are connected to each other via the xerogel matrix and pores are formed by the packing of the granules, which are of the order of magnitude of the granules.
  • the highly porous Bone substitute material therefore has two pore categories. In addition to the pores just described, which come about through the packing of the granules and are thus in the micrometer range, the pores which are located inside the granulate and which have been described above are still present. It is the pores in the xerogel that have an average diameter in the range of 0.5 nm to 20 nm.
  • a porosity of preferably about 30% by volume to about 80% by volume is present in the highly porous bone replacement material.
  • the structure of the highly porous bone replacement material is shown schematically.
  • An essential difference to bone replacement materials in the prior art is that the interior of the granule particles (ie, the crystallites) defined by SiO 2 is held together.
  • the structure can be described so that each individual crystallite lies in a xerogel matrix.
  • the product is available by some conventional ceramic manufacturing processes using the described granules, as described in detail below.
  • the invention further relates to a highly porous bone substitute material which comprises granules of the aforementioned granules which form a three-dimensional structure which, in addition to the pores present in the granules, also has pores approximately the size of the granules.
  • the pore diameters are thus in the range from about 1 ⁇ m to about 1000 ⁇ m, preferably in the range from about 1 ⁇ m to about 50 ⁇ m.
  • Small pieces eg, shaped bodies, particles, bodies
  • this highly porous bone substitute material preferably in the form of cylinders with an average diameter of about 0.4 to about 2 mm and a length of about 1 to about 6 mm, are used to fill small bone defects, preferably up to a size of 10 cm 3 in particular, when the defects are limited to healthy bone on two sides.
  • the invention thus further relates to a highly porous bone substitute material characterized in that it further (ie, in addition to the pores within the individual granules and in addition to the pores formed by the (three-dimensional) granule package) interconnecting macropores in the range of about 100 microns to several 1000 microns, which have a volume fraction of about 10 vol .-% to about 60 vol .-%.
  • the highly porous bone substitute material preferably has a total porosity of about 30% to about 90% by volume, more preferably a total porosity of about 60% to about 80% by volume.
  • the fracture toughness of the highly porous bone replacement material without the described macropores is from about 2 MPa up to about 15 MPa, preferably from about 3 to about 10 MPa. Due to the macropores, the fracture strength of the material decreases and only reaches values of 0.1 MPa to 4 MPa.
  • the highly porous bone replacement material further comprises one or more network transducer oxides.
  • the network transducer oxide (s) are preferably present at a level of from about 0.5 to about 35 mole percent, preferably at a level of from about 17 to about 30 mole percent, based on the silica. Na 2 O is particularly preferred.
  • the invention further relates to a glass ceramic as
  • Bone replacement material (or, in other words, a bone substitute material comprising a glass matrix) that characterized in that crystalline calcium phosphate is embedded in a glass matrix, wherein the crystallites have a size of about 10 nm to about 2000 nra and the glass content in the range of about 4 to about 80 wt .-% (based on the total mass of the material) , preferably in the range of about 2 to about 50 wt .-%, the glass contains as a network former silica.
  • the bone replacement material may further comprise one or more network transducer oxides. To avoid repetition, with respect to the network transducer oxides, reference is made in full to the corresponding statements above, which apply equally to the bone substitute material described herein.
  • the glass ceramic according to the invention as a bone substitute material is obtainable from an aforementioned highly porous bone substitute material by converting the silica xerogel matrix into the glass state with the network converter, preferably sodium oxide.
  • the nanoporous xerogel becomes a fully interconnected glass network that increases the mechanical stability of the bone substitute material with a breaking strength of about 300 MPa to about 400 MPa.
  • the breaking strength of the described bone substitute material is dependent on the residual porosity described below, so that the theoretical values are not reached.
  • the invention thus also relates to a bone substitute material in which the glass matrix is sodium silicate. It preferably has a mechanical strength in the range of about 30 MPa to about 200 MPa, preferably about 50 MPa to about 120 MPa, and has a residual porosity of about 5 to about 35%, wherein the pores have a diameter in the range of about 1 micron to about 200 microns.
  • FIG. 3 schematically shows the structure of the glass ceramic.
  • the black-drawn calcium phosphate crystallites have the identical structure as in highly porous bone substitute material, but they are now in a glass matrix, which is shown in gray. The residual porosity was not shown in the schematic figure.
  • the process of converting gel into the glass involves sintering the highly porous bone substitute material.
  • the nanoporosity is completely eliminated and the described micron-sized porosity is reduced to maintain a residual porosity of from about 2 to about 35% by volume.
  • the material Due to the described proportion of calcium phosphates in the glass matrix, the material is biocompatible. However, the process of absorption has completely changed as there is no nanoporosity left.
  • the glass matrix is preferably sodium silicate glass
  • the sodium ions slowly dissolve, and the glass is converted back into a gel-like structure with nanopores.
  • the residual porosity in the micrometer range further enhances this effect. This process ultimately allows resorption of this bone replacement material.
  • a bone substitute material is available which continuously exhibits the mechanical properties and the resorption properties between the two extremes, the highly porous bone substitute material and the Glass ceramic as a bone substitute material, can be adjusted.
  • the invention relates (accordingly) to a bone substitute material characterized in that the crystalline calcium phosphate is embedded in a matrix, the crystallites having a size of about 10 nm to about 2000 nm, the matrix consisting of a xerogel and a glass which Glass content of the matrix between 0 and 100 vol .-%, preferably about 10 vol .-% to about 80 vol .-% and particularly preferably between about 60 vol .-% and about 80 vol .-%, is xerogel and glass Silicon dioxide and a network converter, preferably in a proportion of about 0.5 to about 35 mol .-%, preferably in an amount of about 17 mol .-% to about 30 mol .-%, based on the silica before, the network converter
  • sodium oxide is and the matrix is in the range of about 2 to about 80 wt .-%, preferably in the range of about 4 to about 50 wt.%, Of the bone substitute material.
  • the partial transition from the xerogel to the glass can be achieved by a heat treatment. Since the glass transition temperature of sodium silicate glass, depending on the sodium content in the range of about 460 0 C to about 800 0 C, it is clear that a heat treatment over this temperature range leads very quickly to the glass. If a temperature treatment is carried out at about 20% to about 5% below the glass transition temperature set for the composition, the process slows down and takes several hours and can be stopped at any time.
  • the bone substitute material according to a particular embodiment is a shaped body, in particular a cuboid, a plate, a hollow cylinder or a wedge.
  • the invention thus also relates to a shaped body made of the described highly porous bone substitute material comprising, on at least one side, a layer of an aforementioned bone substitute material having higher mechanical strength, preferably the described glass ceramic, wherein holes with a diameter of approximately 0.5 are contained to about 5 millimeters, which have a volume fraction of about 5 to about 80% based on the total volume of the layer and these holes are in turn filled with the aforementioned granules and / or with the aforementioned highly porous bone replacement material.
  • the starting point is the preparation of a calcium phosphate granulate, which is characterized in that the crystallites, as described, are in a xerogel matrix.
  • the highly porous bone substitute material is produced, which in turn is a prerequisite for the production of glass ceramic as a bone substitute material.
  • the preparation of the calcium phosphate is connected via a precipitation reaction, in which a so-called slip is formed, to a gelation process of the silicon dioxide. Only then can it be realized that separate nanocrystallites can be incorporated into a xerogel matrix.
  • the silica-containing calcium phosphate granules are preferably hydroxyapatite / silica granules, which optionally further comprise soluble calcium phosphate.
  • the synthesis is for the preparation of calcium phosphates and also, in particular, hydroxyapatite in aqueous solution (C.P.A.T. Klein, J.M.A. De Blieck-Hogerworst, J.G.C. Wolke, K. De Groot, Biomaterials, 11, 509 (1990)).
  • the hydroxyapatite synthesis can be carried out in alkaline medium and gives thermally stable phase-pure crystallites (M. Asada, Y. Miura, A. Osaka, K. Oukami, S. Nakamura, J.Mat.Sci.23, 3202 (1988), S. Lazic , J. Cryst.
  • Phosphorus of the starting materials is controllable, arises frequently
  • Dicalcium phosphate as a byproduct, which is undesirable. It is therefore advantageous to start from purely soluble starting materials and not to use lime milk (a dispersion).
  • the cited literature describes how the parameters pH value, homogeneity of the mixture of the starting materials and temperature influence the crystallite size and the degree of crystallinity of the end products.
  • the relationship between pH and temperature of the solution is important (M. Okido, R. Ichina, K. Kuroda, R. Ohsawa, O. Takai, Mat. Res. Soc. Symp. Proc. 599, 153 (2000 )).
  • hydroxyapatite is finely crystalline, i. as nanocrystallites, and for certain applications, e.g. As a cleaning body in the dental care is sought after process steps that lead to larger crystallites (DE 42 32 443 Cl).
  • the amounts of the starting materials are chosen so that a Ca / P ratio of 1.50 to 1.67 is formed.
  • the precipitated product in this area is always so-called "precipitated hydroxyapatite" (PHA.Cai 0-x (HPO 4 ) x (PO 4 ) 6-x (OH) 2 -x). arises at temperatures above about 65O 0 C from the precipitated hydroxyapatite "zT. completely hydroxyapatite, if the ratio of calcium to phosphate (Ca / P ratio) is exactly 1.67. At a Ca / P ratio of 1.5, almost all of the hydroxyapatite becomes ⁇ -tricalcium phosphate transformed.
  • a Ca / P ratio between 1.5 and 1.67 a mixture of ⁇ -tricalcium phosphate and hydroxyapatite is obtained, whose final composition is adjusted by the Ca / P ratio.
  • a Ca / P ratio of 1.67 is selected, preferably to obtain exclusively hydroxyapatite in the granules. If a soluble calcium phosphate (for the in vivo application, the pH value 7) is to be contained in the granules, a Ca / P ratio of less than 1.67 is selected and the soluble ⁇ -tricalcium phosphate is formed during the course of the process.
  • the crystals in the solution tend to agglomerate. If the solid is isolated after the precipitation, the agglomeration of the crystals, in particular of the nanocrystals, can not be avoided (DE 42 32 443 C1). This results in granules of calcium phosphate crystallites from which it is no longer possible to obtain the granules according to the invention in which the crystallites are in a xerogel matrix.
  • this problem is solved by the solution is homogenized with the precipitated calcium phosphate by stirring and a highly concentrated silicic acid solution, wherein preferably orthosilicic acid is used, is supplied.
  • a highly concentrated silicic acid solution wherein preferably orthosilicic acid is used.
  • TEOS tetraethyloxysilane
  • preference is given to mixing TEOS and 0.1 molar hydrochloric acid in a preferred ratio by volume of 30: 9 with vigorous stirring until hydrolysis takes place.
  • the water necessary for the hydrolysis gives the hydrochloric acid solution.
  • the ratio of calcium phosphate in the precipitated solution and the added silica is selected to provide the granule composition of the invention from about 2% to about 80% by weight silica.
  • silica from one liter of TEOS 270 g of silica arise. If, for example, granules containing 30% by weight of silicon dioxide are to be obtained, 43 g of silicon dioxide are necessary for a solution containing 100 g of calcium phosphate, which in turn means that about 160 ml of TEOS are used. This is independent of how much solvent the precipitated solution contains.
  • the pH of the mixture of the precipitated calcium phosphate and the silica is now adjusted in a range from about 2 to about 8, preferably in a range from about 5 to about 6.5.
  • the silica in the slurry begins to condense and thus increase the viscosity of the mixture.
  • a viscosity of preferably 2-10 5 cP sedimentation of the calcium phosphate is inhibited in the mixture by stirring.
  • the mixture Due to the onset of gelation of the silicon dioxide, the mixture is fixed.
  • the calcium phosphate crystallites are now in a matrix of a silica hydrogel.
  • the hydrogel matrix becomes the xerogel matrix according to the invention. Since a granulate according to the invention has a granule size of about 1 ⁇ m to about 1000 ⁇ m, comminution is necessary. This comminution preferably takes place in the state of the hydrogel.
  • the hydrogel is now in a sealed vessel, preferably at room temperature (ggf- even at temperatures of about 60 0 C to about 8O 0 C), stored, preferably over a period of about 24 h h to 48 hours. During this time, an aging of the silica gel takes place, ie in the solid gel more condensation reactions take place.
  • the gel is dried with the calcium phosphate to remove solvent.
  • the drying temperature is preferably at about 20 0 C to about 150 0 C, preferably at about 12O 0 C dried.
  • the wet hydrogel By freezing the wet hydrogel is obtained according to the invention also a calcium phosphate / silica granules (hydroxyapatite / silica granules).
  • the calcium phosphate and the silica of the hydrogel are pressed together to form granules, which are filtered off after the thawing of the ice.
  • the filtered granules are preferably dried at about 2O 0 C to about 150 0 C, preferably at about 120 0 C.
  • a particular embodiment of the preparation according to the invention of the granules is characterized in that the mixture of the precipitated calcium phosphate and the silica whose pH is adjusted in a range from about 2 to about 8, preferably in a range from about 5 to about 6.5 is spray-dried before gelation, which has the advantage that in a simple manner granule sizes in the range according to the invention are available.
  • Spray drying is a process known in the art (see, e.g., K. Masters, “Spray Drying", 2nd ed., John Wiley & Sons, New York, 1976).
  • liquid products are atomized into fine droplets at the top of a drying tower.
  • the drops are dried during their free fall by a stream of hot air in the tower.
  • the temperature of the hot air flow is between about 8O 0 C and about 200 0 C and acts only for a period of half to one second on the products.
  • spray-drying is the second-most-friendly industrially-used drying method, especially in the food industry. If a kinematic viscosity of preferably 0.5 to 50 cst is achieved by the onset of condensation of the silica, the mixture is spray-dried, the pressure being adjusted to the concentration and the viscosity so that granules of 10 .mu.m and smaller arise. (See Masters, Spray Drying Handbook, (1979) Georg Godwin Ltd;).
  • Evaporation of the solvent causes gel formation and initiates a transition from wet gel to xerogel.
  • Spray drying causes granules of appropriate size to form as the small droplets gel and the small droplets dry.
  • the granules are characterized in that the calcium phosphate crystallites (preferably HA crystallites) are held together by a porous silica gel.
  • the granules are characterized by electron microscopy and by photocorrelation spectroscopy. (E.R. Pike and J.B. Abbiss eds., Light Scattering and Photo Correlation Spectroscopy, Kluwer Academic Publisher, 1997).
  • a temperature treatment at about 700 0 C to about 900 0 C is preferred (about 800 0 C in the presence of oxygen (normal Air atmosphere)) removes any carbon present by oxidation.
  • a particular embodiment of the granulate according to the invention, as described above, contains about 0.5 mol% to about 35 mol% of a network converter in the xerogel, preferably Na 2 O.
  • the network converter is preferably introduced into the finished nanoporous granules by preferably using an aqueous solution.
  • a drying process at preferably about 120 ° C. to about 200 ° C. then removes the solvent.
  • 8 g of NaOH are dissolved in 50 ml of distilled water
  • the porous granules absorb this solution and are dried immediately to dissolve the xerogels in the basic solution prevent.
  • the network conversion oxide is present at 21 wt .-%, which corresponds to 19.3 mol% Na 2 O based on the xerogel.
  • the invention thus also relates to a process for the preparation of a granulate according to the invention in which, using appropriate orthophosphate compounds and calcium compounds (such as calcium nitrate and ammonium hydrophosphate), a hydroxyapatite is precipitated by the reaction of the orthophosphate group PO 4 3 " and calcium ions in aqueous solution, which has a Ca / P ratio of 1.50 to 1.67 due to the ion concentrations determined in the solution, with a preferred Ca / P ratio of 1.67 if the final product is to contain hydroxyapatite exclusively as calcium phosphate, and where a Ca / P ratio of less than 1.67 is selected, if in addition the soluble ⁇ -tricalcium phosphate should be present in the end product.
  • appropriate orthophosphate compounds and calcium compounds such as calcium nitrate and ammonium hydrophosphate
  • the process is further characterized in that the precipitated hydroxyapatite, without it forms agglomerates in the aqueous solution, is homogeneously embedded in a silicon hydrogel, which is realized by reacting the aqueous solution with silica, preferably orthosilicic acid, in particular hydrolyzed tetraethyloxysilane (TEOS). , and the pH is adjusted to be in the range of from about 2 to about 8, preferably from about 5 to about 6.5, so as to gel.
  • the amount of TEOS used is selected so that the silica content ranges from about 4 to about 80% by weight, preferably from about 2 to about 50% by weight, based on the total weight of the granules.
  • a drying process leads to a transition from the hydrogel to the xerogel, whereby the calcium phosphate crystallites are located in a xerogel matrix.
  • Hydroxylapatite optionally in combination with soluble calcium phosphate, preferably ⁇ -tricalcium phosphate, which contains silicon dioxide in a defined concentration and morphology, serves, as already mentioned, as starting material for the production of the highly porous bone replacement material.
  • soluble calcium phosphate preferably ⁇ -tricalcium phosphate, which contains silicon dioxide in a defined concentration and morphology
  • the parts which are in direct contact with the bone e.g. the shaft of a hip joint prosthesis coated with the material.
  • An application with dental implants is also possible.
  • the highly porous bone substitute material according to the invention is produced.
  • a slip from the described granules and preferably water is produced.
  • About 100 g of granules are preferably added about 100 ml to about 300 ml of water.
  • the pH is preferably adjusted to be in the range of about 5 to about 6.5, the slurry is poured into any shape and dried. This results in a highly porous bone replacement material.
  • the resulting shaped body is comparable with a green body, as is usually the case in ceramic processes (see: D. Richerson, Modern Ceramic Engineering, Dekker Publ., J. Reed, Principles of Ceramic Processing, Nanocrystalline Ceramics, M. Winterer, Springer 2002 ).
  • the surface of the granules is of course silicon dioxide, which in the chosen pH range tends to perform condensation reactions between the -SiOH groups of the surfaces of contacting granules. Due to the capillary pressure during the drying process, the surfaces of the granules are pressed together and connected by -SiOSi bonds. This gives the highly porous bone material its mechanical stability and the described properties of the invention.
  • Silica in particular orthosilicic acid, can be added to the slip as an additional binder.
  • TEOS with hydrochloric acid hydrolyzed and added to the slurry. In this case, preferably 3 ml to 15 ml TEOS are taken on 100 g granules.
  • the drying of the slurry is preferably carried out at a temperature between about room temperature and about 200 0 C, more preferably between about 80 0 C and about 130 0 C.
  • another temperature treatment for solidifying the highly porous bone substitute material at a temperature that the presence of of network transducers in the xerogel of the granule.
  • the temperature treatment is preferably carried out at about 700 0 C to about 900 0 C, preferably at about 800 0 C.
  • the temperature is preferably in the range between about 300 0 C and about 500 0 C.
  • the highly porous bone replacement material receives its described structure and thus the properties described.
  • a pore creep is formed, which is determined by the packing of the granules and their size.
  • Another pore structure in the size range of a few hundred microns to the mm range, which is to enable ingrowth of blood vessels, is produced in the molding by the slurry additionally preferably added organic powder having a particle size in the later desired pore size, which after the Burning process are burned out.
  • pores are generated by introducing organic fibers of the desired diameter in the slip, which are burned out after the drying process.
  • a drying of the material which always brings a low shrinkage, can be carried out at temperatures where the wax is soft and thus prevents cracking of the material.
  • a favorable drying temperature is thus about 40 0 C.
  • the wax can be removed by centrifugation at about 100 0 C from the pores. Remains of the wax are then burned out, and at about 800 0 C, the resulting carbon is removed.
  • the process for producing the described glass-ceramic according to the invention is based on the highly porous bone replacement material described.
  • the xerogel matrix of the ⁇ highly porous bone substitute material is converted into a glass matrix, without causing the calcium phosphate crystals to sinter together. This means that the connection of the silicon dioxide tetrahedra is completed
  • a gel-to-glass transition requires a relatively high temperature of about 900 ° C. to 1200 ° C. for pure silica. Since it is possible for the crystalline calcium phosphate components to undergo phase transition, a highly porous bone substitute material with a network transducer in the Xerogel used.
  • the network converters are either already in the highly porous bone replacement material through the original use of granules with a network converter, or the network converter are introduced into the finished highly porous bone substitute material by using the same method as the granules. This results in a gel-glass transition at much lower temperatures, and the calcium phosphate component does not change.
  • Network converter concentrations are from about 0.5 to about 35 mole percent, preferably from about 17 to about 30 mole percent, based on the silica content.
  • Na 2 O is suitable since the glass phase is therefore soluble in body fluid and thus can also be absorbed.
  • the glass goes the opposite way. That is, the glass becomes a gel-like structure again.
  • the bone replacement material according to the invention Many applications are possible with the bone replacement material according to the invention. For small defects, as z.T. occur in oral surgery, a granulate from the highly porous bone substitute material can be used for filling. For larger defects, where the remaining bone stabilizes the shape of the defect sufficiently, moldings made of the highly porous bone substitute material are used.
  • shaped body in a combination of mechanically stronger bone substitute materials (matrix is made of glass) and the highly porous bone substitute materials (matrix consists of xerogel) show interesting application, especially in larger defects or even in defects in which no native bone remains as a guide rail.
  • these moldings of at least one side have a layer of the inorganic resorbable bone substitute material with the glass as a matrix (increased strength) and holes in the order of 0.5 to 5 millimeters in this layer and these holes have a volume fraction in the layer of 5 to 80%.
  • the entire volume, including the holes in the more solid material, is occupied by the material having a xerogel as a matrix.
  • the hole structure in the solid layer should allow ingrowth of blood vessels.
  • the invention therefore furthermore relates to the use of the granules and bone replacement materials according to the invention for the production of shaped bodies, preferably a cuboid, a plate, a hollow cylinder or a wedge.
  • the invention allows the use of the aforementioned silica / calcium phosphate granules for coating implants (see above).
  • the coating is carried out by plasma spray coating.
  • the granulate according to the invention or the solid according to the invention is able to regenerate bone in a considerably larger size compared to the prior art, especially ectopically, ie outside of bone defects, eg in the Adipose tissue or muscle (ectopic osteoinduction).
  • the granules of the invention or the solid according to the invention thus for the production of a pharmaceutical Preparation or medical device for osteoinduction, in particular for ectopic osteoinduction.
  • the granulate is a calcium phosphate based granule in which crystalline calcium phosphate is embedded in a silica xerogel matrix, wherein the crystallites have a size of about 10 nm to about 2000 nm and the granules have a size of about 1 micron to about 1000 microns and the silicon dioxide content in the range of about 2 to about 80 wt .-%, preferably in the range of about 4 to about 50 wt .-%, based on the total mass of the granules).
  • the hydroxyapatite nanocrystallites are embedded in a Sio 2 xerogel matrix and allow interconnecting nanopores to be formed. Due to the high porosity and the loose packing of the granules, the solids content is about 5 to 70 vol .-%, preferably 10 to 30 vol .-% and preferably about 20 VoI. -%.
  • NanoBone ® According to the invention very particularly preferably used for osteoinduction.
  • NanoBone ® is a granulate containing 76% by weight of nanocrystalline, non - sintered hydroxyapatite (HA) and 24% by weight of silicon dioxide (SiO 2 ).
  • the nanocrystallites are embedded in a Sio 2 xerogel matrix and thus allow interconnecting nanopores to be formed. Due to the high porosity and the loose packing of the granules (see Fig. 19, "Pine cone structure”), the solids content is only about 20% by volume
  • the granule particles have a "pine cone structure" with an average diameter of 0.6 mm and a average length of 2 mm.
  • a shaped body according to the invention based on calcium phosphate, wherein the crystalline calcium phosphate is embedded in a silica xerogel matrix, wherein the crystallites have a size of 10 nm to about 2000 nm and the silicon dioxide content in the range from about 4 to about 50 wt.%, Based on the total mass of the shaped body, and the molded body has interconnecting macropores in the range of 100 microns to 3000 microns.
  • the pores in the xerogel preferably have an average diameter in the range of 0.5 nm to 20 nm.
  • the pores preferably make up from about 10% to about 60% by volume, based on the volume of material surrounding the macropores.
  • the invention further relates to the use of a granule or shaped article according to the invention for the production of a medicament or medical device for the healing of bone defects by osteoinduction and for ectopic osteoinduction.
  • Osteoinduction refers to new bone formation by differentiation of osteogenic cells from lower differentiated progenitor cells. It is thus the most effective form of defect healing of bone defects.
  • ectopic osteoinduction refers to bone regeneration outside of bone defects, including use in the production (growth) of bone, for example in the fat tissue of a patient, which microsurgically microsurgically, for example, in particularly severe cases of bone loss (such as by tumors) can be transplanted.
  • the invention further relates to the use of a granule or shaped body according to the invention for the manufacture of a medicament or medical device for the construction of osteoporotic bone by osteoinduction, for stimulating the Bone structure in the transition region to loosened metal implants or to stimulate the healing of periodontal defects.
  • the granules are preferably mixed with bone marrow fluid or blood.
  • the invention further relates to a pharmaceutical or medical device comprising a granulate according to the invention, which is mixed with bone marrow fluid or blood of the patient (thus autologous).
  • the invention further relates to a pharmaceutical or medical device which comprises a highly porous bone replacement material according to the invention or a glass ceramic as a bone substitute material, wherein the bone substitute material is brought into contact with bone marrow fluid or blood of the patient immediately before implantation (thus autologous) so that the pores of the patient Fill materials completely.
  • phase-pure hydroxyapatite which is not during the following process steps changes.
  • the precipitated hydroxyapatite solution is prevented from sedimenting by constant stirring and concentrated until 50 g of hydroxylapatite remain on 100 ml of solvent.
  • 60 ml of tetraethyloxysilane (TEOS) and 18 ml of 0.05 molar hydrochloric acid are stirred vigorously until the hydrolysis of the TEOS has taken place, which requires a time of about 15 minutes and can be detected by an increase in temperature from room temperature to about 50 ° C.
  • This solution is added to the solution with the precipitated, homogeneously distributed hydroxyapatite and the pH is adjusted to about 6.0 with NH 4 OH. This mixture is further stirred until a viscosity of about 2 * 10 A 5 cP is reached (by the onset of gelation of silicon dioxide, the solution becomes paste-like). After the onset of gelation, the batch is stored for 24 hours in a sealed vessel, then granulated.
  • the granules are rinsed in distilled water and then dried again. For this purpose, a temperature treatment of 120 0 C was selected for a period of two hours.
  • the subsequent heat treatment at 800 0 C claims a time of 1 hour.
  • the resulting granules consist of 75 wt .-% of calcium phosphate and 25 wt .-% of silica.
  • the resulting granules are characterized by scanning electron micrographs, such as it can be seen in Figure 5. It can be seen granules in the size range of 1 micron to 5 microns.
  • a slip is made from the granules with water and the size distribution of the granules is determined by dynamic light scattering (E.R. Pike and J.B. Abbiss eds., Light Scattering and Photo Correlation Spectroscopy, Kluwer Academic Publisher, 1997). The result is shown in Figure 6.
  • FIGS. 7 and 8 show transmission electron micrographs of sections through the granules.
  • the material was embedded in epoxy and about 60 nm thick sections were made.
  • the crystallites are platelets with a mean platelet diameter of 150 nm and a platelet thickness of about 10-20 nm. It is very nice to see how the crystallites are embedded in the xerogel matrix, although the contrast difference between the epoxide (potting material) and the silica xerogel only relatively weak.
  • Region A is an epoxide-filled pore
  • Region B is a typical region in which the hydroxyapatite is embedded in the xerogel.
  • An aqueous solution of calcium nitrate and ammonium hydrophosphate with a calcium to phosphate ratio of 1.67 is mixed homogeneously with a magnetic stirrer and adjusted to a pH of 10 with the aid of NH 4 OH.
  • the precipitated material is washed four times with distilled water and centrifuged and then dispersed in ethanol.
  • TEOS a 0.1 mol / l HCl solution
  • 9 ml of ethanol After hydrolysis of the TEOS, this mixture is added to the HA slip and homogeneously distributed and a pH of 6.0 is set.
  • the spray drying is carried out by the homogenized slurry is pressed through a nozzle with compressed air and a pressure between 50 and 100 kPa and the rapid drying is done in a coaxial air flow at a temperature of 100 0 C.
  • the subsequent temperature treatment at 800 0 C claimed a time of 1 hour.
  • the resulting granulate differs in the properties of the granules primarily by the size of the granules, which has a much narrower distribution and a maximum at a diameter of 18 microns.
  • a pH of 10 is adjusted with NH 4 OH.
  • the precipitated material is washed four times with distilled water and centrifuged and then dispersed in water leaving 50 g of calcium phosphate per 100 ml of solvent.
  • 30 ml of TEOS and 9 ml of 0.05 molar hydrochloric acid are stirred vigorously until the hydrolysis of the TEOS has taken place, which requires a time of about 15 minutes and can be detected by an increase in temperature from room temperature to about 50 ° C.
  • This solution is added to the solution with the precipitated, homogeneously distributed hydroxylapatite, and with NH 4 OH the pH is increased. Value set to approx. 6.0.
  • This mixture is further stirred until a viscosity of about 2-10 5 cP is reached (by the onset of gelation of silica, the solution becomes paste-like). After the onset of gelation, the batch is stored for 24 hours in a sealed vessel, then granulated.
  • the granules are rinsed in distilled water and then dried again. This was a
  • Temperature treatment selected from 120 0 C for a period of two hours.
  • the subsequent temperature treatment at 800 0 C claimed a time of 1 hour.
  • the resulting granules consist of 86 wt .-% of calcium phosphate and 14 wt .-% of silica.
  • Figures 9 and 10 show scanning electron micrographs of a granule.
  • Figure 9 shows the inside of a broken edge of a crushed granule.
  • Figure 10 shows the surface of a granule
  • ⁇ -tricalcium phosphate has relatively large crystallites about 1 ⁇ m in diameter.
  • the xerogel appears in the recordings as a compact material, which of course is due to the resolution of the scanning micrographs that do not completely dissolve the porosity of the xerogels. However, it is very easy to see how the xerogel forms a matrix in which the crystallites lie and in which the entire granular grain is surrounded by a xerogel layer.
  • Example 4 Production of highly porous bone substitute material
  • Example 1 100 g of the granules whose preparation is described in Example 1, which contains 25 wt .-% silica, is stirred with 150 ml of distilled water and poured into molds of 8 mm 15 mm 30 mm.
  • the bone substitute material has a porosity of about 60%.
  • FIG. 11 shows the scanning electronic image of the material.
  • the granules the original shape of which can be seen in FIG. 5, now form a continuous 3-dimensional structure with pores in the micrometer range.
  • the nanostructure inside the granules is unchanged.
  • 142 ml of water are mixed with 8 ml of hydrolyzed TEOS solution.
  • For the hydrolysis are added to 30 ml of TEOS 18 ml of 0.05 molar hydrochloric acid and stirred until the hydrolysis is completed, which can be seen in a temperature increase from room temperature to about 50 0 C.
  • Example 1 100 g of granules, the preparation of which is described in Example 1, are homogeneously distributed in this solution. There follows a further treatment as in Example 4. Due to the additional introduction of the silicon dioxide, the essential structure of the material (micrometer pores and nanometer pores) does not change. The granules are more strongly linked, which increases the overall strength of the highly porous bone substitute material by approximately 50%.
  • Wax threads of 0.2 mm in diameter are placed completely randomly in the molds of Example 4, so that they make up a volume fraction of 30% of the mold contents.
  • a slurry of silicon dioxide-containing calcium phosphate granules as described in Example 5 is added.
  • the drying is now carried out at 40 0 C, since the wax threads are soft and not yet liquid and thus do not spread in the resulting micron pores, over a period of 4 hours.
  • the macropores which were created in place of the wax threads, occupy about 30 vol .-%, so that a total porosity of 72% is formed, because the micrometer and nanometer structure has not changed compared to the example 5 or 6
  • the starting point for the production of the clad ceramic as a bone substitute material is the highly porous bone substitute material that was produced in Example 4.
  • a molding of this material has a density of 0.8 g / cm 3 and thus a porosity of about 60%.
  • a volume of 1000 ml of the shaped body contains 200 g of silica.
  • 50 g of NaOH are dissolved in 600 ml of water and placed in the pores of the molding.
  • the molding body absorbs the solution completely, and it is dried at 120 0 C.
  • the network converter oxide is present at 20 wt .-%, which corresponds to about 19 mol% Na 2 O based on the xerogel.
  • Silicon xerogel as a matrix. This is a
  • the curve B in the diagram represents a material of identical composition, in which case the xerogel matrix was converted into a glass.
  • the breaking strength has increased from about 3 to 50 MPa.
  • Göttingen minipigs were used for the animal experiments to test the properties of the material as a bone substitute.
  • the animals were adult (one year old) and weighed between 25 and 30 kg.
  • the bone defects exceeded the critical size of 5 cm 3 ; their dimensions are approx. 3.0 cm ⁇ 1.5 cm • 1.5 cm. They were in the Lower jaw set, completely filled with the bone substitute material and closed again with the periosteum. After 8 months, the pigs were sacrificed, and the mandibles were removed and radiographic, histological and scanning microscopic examinations were performed.
  • Figure 13 shows the lower jaw with the former defect filled with the material of the example 8 months after the operation.
  • the defect area has completely healed clinically. Histological studies show that averaged over several experimental animals less than 1% of the biomaterial is found in the defect area.
  • FIG. 14 shows a comparative study with an empty defect. This defect is encapsulated with connective tissue and does not heal.
  • FIG. 15 shows a comparative study with a commercial hydroxyapatite-based bone replacement material. The defect heals, but the biomaterial is not broken down and remains as a foreign body in the bone.
  • FIG. 16 shows a light micrograph of a histological section. It is a demineralized histological section of hemalum eosin
  • Biodegradation of the material is via osteoclasts, which is crucial for its application.
  • FIG. 17 shows a shaped body which has the properties of the two materials with different properties combined mechanical properties and intended for larger bone defects.
  • the material with the glass as matrix forms on one side a support layer which has a thickness of the order of two millimeters, which in turn is provided with a system of holes.
  • the volume of the shaped body as well as the holes in the stable layer are filled by the material with the xerogel as a matrix, since this material has the better bioactive properties.
  • FIG. 18 shows another possible shaped body.
  • the cylinder has a jacket of the material with the glass as a matrix. This mantle also has a system of holes that, like the entire volume, are filled with the material containing the xerogel as a matrix.
  • NanoBone ® For this example was used in one embodiment NanoBone ®. It consists of 76% by weight of nanocrystalline, non-sintered hydroxyapatite (HA) and 24% by weight of silicon dioxide (SiO 2 ). The nanocrystallites are embedded in a Sio 2 - xerogel matrix, thereby creating interconnecting nanopores. Due to the high porosity and the loose packing of the granules (see Fig. 19, "Pine cone structure”), the solids content is only about 20% by volume. The contact with the blood of the test animal results in about 80% by volume The granulate particles have a "pine cone structure" with an average diameter of 0.6 mm and a mean length of 2 mm (see Fig. 20).
  • the animals were 1 year old, the mean body weight was 27.4 kg.
  • the animals received a standard diet (Minipig maintenance food).
  • the miniature pigs were killed after 8 months according to the protocol of the experiment in pentobarbital overdose by means of a cardiac puncture.
  • a representative histological section is shown. It is recognizable by trabecular bone. It is physiologically completely intact bone tissue with osteocytes in a size of about 10 mm * 6 mm. Of the NanoBone ® granulate, only about 10% are still present, which is incorporated into the bone tissue. Most of the biomaterial was degraded by osteoclasts.
  • a macroscopic piece of bone about 1 cm 3 in size has developed in the fatty tissue, in which the mechanism of bone remodeling (bone formation and disassembly, constant renewal of the bone) takes place, as in the normal skeleton.
  • BMPs bone morphogenetic proteins
  • a ectopically formed bones piece is shown 4 months after subcutaneous administration of NanoBone ®, in two orientations. It is about half of a piece of bone cut into two parts when being dissected out.
  • the example is representative of the experimental series. Density differences in the preparation are represented by different colors. A slightly higher density can be recognized by the yellowing. The density of the newly formed bone is shown as a red color, the whole is transparent. This presentation distinguishes between NanoBone particles and newly formed bone. The density of NanoBone * is slightly higher than that of the newly formed bone. It can be seen in the figure that two larger separate pieces of bone have been created and that in one direction from these separate pieces of bone, inferior bone formation occurs. The granules are more or less separately visible.
  • FIG. 22 shows the sectional planes which were subsequently used for the precise examination of the tissue structure.
  • the with A, B, C designated sectional planes are shown as histological specimens in Fig. 23 also with the designation A, B, C.
  • HE hematoxylin-eosin stains
  • Cuts can be seen through hair follicles located in the connective tissue with sweat and sebaceous glands (3).
  • the epidermis is not included in this illustration.
  • a comparison of this section with the Mikrotomographieaufnähme shows that relatively low NanoBone ⁇ granules are present in this level, ie the biomaterial has already been largely biodegraded.
  • Fig. 24a shows a section of the edge of the newly formed bone. It belongs to the section A.
  • the capsule surrounding the bone consists of connective tissue, which has a very cell-rich layer towards the bone, which merges into an osteoblast fringe on which newly formed bone can be seen.
  • Fig. 24b shows from the section A the ectopic bone tissue.
  • the more blue colored bones are braid bones because there are many randomly distributed osteocytes.
  • Brain Bone is the initial, immature bone structure.
  • the figure shows osteons, suggesting that the mesh bone is already being rebuilt and replaced locally with lamellar bones.
  • Fig. 24c an osteon is shown at a higher magnification. Recognizable are the blood vessels in the Havers Canal and the Osteoblasttensaum at its edge. It is also noticeable that this newly formed lamellar bone structure reacts more strongly with the acid dye eosin of the HE stain. The process of remodeling can also be seen very well in Fig. 24d (section plane B). Here you can see a cement line between the older mesh bone and the lamellar bone layers attached to it. Towards the top, the trabeculae is strengthened. At the same time, on the lower side of the trabecula on the mesh bone, osteoclasts are seen, which degrade the older bone.
  • Fig. 24f a section of the sectional plane B is shown, and that in Fig. 23 sectional plane B to the left of the compact bone piece with (6) marked area.
  • FIG. 24f it can be seen that new bone tissue arises at a relatively large distance from NanoBone granules. This is unusual because the bone piece obviously enlarges.
  • the bone grows to the left.
  • Fig. 25 now details are shown, which belong to the cutting plane C, ie to the level with the lowest
  • Bone formation Here was in histological section in the immediate vicinity of the resulting bone tissue
  • Fig. 25a shows the bone formation on a NanoBone granule.
  • the bone develops mainly to the right.
  • an osteoblast layer can be seen directly on the NanoBone ® granule surface.
  • Fig. 25b shows an osteoclast from a NanoBone -
  • Fig. 25c to recognize.
  • the disordered mesh bone lies in the middle of an osteon, so newly formed lamellar
  • Bones including a newly emerging osteon can be found. Cartilage cells are recognizable in the lower left corner.
  • Fig. 25d shows this area at a lower magnification.
  • the cartilage cells are again arranged between two larger bone areas and separate them.
  • the point is marked with the (7).
  • Is NanoBone "implanted in the subcutaneous tissue, a strong osteoinductive effect can be detected. What implications does this Osteoinductivity, depends in which tissue the NanoBone ® granulate was implanted. Is NanoBone example, implanted into the connective tissue, which contains some of the fatty tissue and if the place of implantation ensures that the granules do not move against each other, large pieces of bone will result.After 4 months, the volume of the newly formed bone may be far greater than the volume of the implanted granules.
  • a piece of bone has a compact outer layer
  • This capsule is constructed like a normal periosteum, and its inner osteoblast layer deposits new matrix layers on the resulting bone.
  • the interior of the resulting Bone piece has a trabecular structure.
  • all cell types of a skeletal bone can be found, in particular osteoclasts, osteoblasts and osteocytes, as well as blood vessels.
  • the biomaterial is degraded via osteoclasts. In areas where much trabecular bone has formed, only a few granules are found.
  • the resulting bone which is in the early stages more or less braid bones, replaced over time by lamellar bone.
  • NanoBone ® granules are alike with the highly porous bone substitute material, wherein said granules form a three-dimensional structure, which in addition to those present in the granules void is also pores approximately in the size of the granules, as well as with the above described moldings from this bone substitute material receive.
  • an ectopic new bone formation ie ectopic osteoinduction, is observed.

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Abstract

L'invention concerne un granulat d'hydroxylapatite/dioxyde de silicium de morphologie définie, un matériau de remplacement osseux très poreux à base de ce granulat et une vitrocéramique à base de ce dernier, servant de matériau de remplacement osseux, caractérisée par une résistance mécanique variable, ainsi que des corps moulés réalisés dans ce matériau, des matériaux de résistances mécaniques différentes étant employés dans ledit corps moulé. Les matériaux de remplacement osseux selon l'invention sont caractérisés par une bonne résorbabilité in vivo. L'invention concerne également l'utilisation dudit matériau de remplacement osseux pour l'ostéoinduction, notamment pour l'ostéoinduction ectopique.
PCT/EP2006/008403 2005-08-29 2006-08-28 Materiau osteoinductif et procede de fabrication Ceased WO2007025698A2 (fr)

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US7568527B2 (en) 2007-01-04 2009-08-04 Rock Well Petroleum, Inc. Method of collecting crude oil and crude oil collection header apparatus
US7823662B2 (en) 2007-06-20 2010-11-02 New Era Petroleum, Llc. Hydrocarbon recovery drill string apparatus, subterranean hydrocarbon recovery drilling methods, and subterranean hydrocarbon recovery methods
CN103845756A (zh) * 2014-02-28 2014-06-11 中国科学院化学研究所 一种生物活性纳米粒子及其制备方法
US9492591B2 (en) 2010-06-25 2016-11-15 Sirakoss Limited Bone graft system
WO2017013440A1 (fr) * 2015-07-23 2017-01-26 Ucl Business Plc Système de greffe osseuse
EP3381479A1 (fr) * 2017-03-29 2018-10-03 ARTOSS GmbH Composition de support pour matériau de substitution osseuse
CN115337460A (zh) * 2022-06-30 2022-11-15 山东大学 聚磷酸钙/二氧化硅复合陶瓷材料及其制备方法与应用

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US11498880B2 (en) * 2019-07-26 2022-11-15 Warsaw Orthopedic, Inc. Calcium phosphate granules and methods of making them

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US7568527B2 (en) 2007-01-04 2009-08-04 Rock Well Petroleum, Inc. Method of collecting crude oil and crude oil collection header apparatus
US7823662B2 (en) 2007-06-20 2010-11-02 New Era Petroleum, Llc. Hydrocarbon recovery drill string apparatus, subterranean hydrocarbon recovery drilling methods, and subterranean hydrocarbon recovery methods
US9492591B2 (en) 2010-06-25 2016-11-15 Sirakoss Limited Bone graft system
CN103845756A (zh) * 2014-02-28 2014-06-11 中国科学院化学研究所 一种生物活性纳米粒子及其制备方法
WO2017013440A1 (fr) * 2015-07-23 2017-01-26 Ucl Business Plc Système de greffe osseuse
US11857698B2 (en) 2015-07-23 2024-01-02 Ucl Business Ltd Bone graft system
WO2018178266A1 (fr) * 2017-03-29 2018-10-04 Artoss Gmbh Composition porteuse pour matériaux substituts osseux
CN110650754A (zh) * 2017-03-29 2020-01-03 阿托斯有限责任公司 用于骨替代材料的载体组合物
KR20200021447A (ko) * 2017-03-29 2020-02-28 아르토스 게엠베하 골 대체물용 캐리어 조성물
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CN110650754B (zh) * 2017-03-29 2022-07-22 阿托斯有限责任公司 用于骨替代材料的载体组合物
KR102523981B1 (ko) 2017-03-29 2023-04-20 아르토스 게엠베하 골 대체물용 캐리어 조성물
EP3381479A1 (fr) * 2017-03-29 2018-10-03 ARTOSS GmbH Composition de support pour matériau de substitution osseuse
CN115337460A (zh) * 2022-06-30 2022-11-15 山东大学 聚磷酸钙/二氧化硅复合陶瓷材料及其制备方法与应用

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