WO2013084817A1 - 骨・組織再生誘導用メンブレン及びその製造方法 - Google Patents
骨・組織再生誘導用メンブレン及びその製造方法 Download PDFInfo
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- WO2013084817A1 WO2013084817A1 PCT/JP2012/081081 JP2012081081W WO2013084817A1 WO 2013084817 A1 WO2013084817 A1 WO 2013084817A1 JP 2012081081 W JP2012081081 W JP 2012081081W WO 2013084817 A1 WO2013084817 A1 WO 2013084817A1
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- bone
- membrane
- calcium phosphate
- hydrophilic polymer
- inducing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
- A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
- A61C8/0012—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy
- A61C8/0013—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools characterised by the material or composition, e.g. ceramics, surface layer, metal alloy with a surface layer, coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
- A61C5/00—Filling or capping teeth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
- A61C8/00—Means to be fixed to the jaw-bone for consolidating natural teeth or for fixing dental prostheses thereon; Dental implants; Implanting tools
- A61C8/0003—Not used, see subgroups
- A61C8/0004—Consolidating natural teeth
- A61C8/0006—Periodontal tissue or bone regeneration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
- A61F2/2846—Support means for bone substitute or for bone graft implants, e.g. membranes or plates for covering bone defects
-
- 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
- A61L27/14—Macromolecular 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
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
Definitions
- the present invention separates a granulation cell tissue from a site where bone is desired to be regenerated at a bone defect site, prevents the granulation tissue from entering the site where bone is desired to be regenerated, and generates a bone-like component at the bone defect site.
- the present invention relates to a membrane / guided bone / tissue regeneration membrane.
- An implant is a method in which a screw-like object called a fixture that is likened to a tooth is embedded in a hole formed in the alveolar bone after extraction and fixed, and then a prosthesis is mounted on the fixed fixture.
- a fixture that is likened to a tooth
- a prosthesis is mounted on the fixed fixture.
- the gap between the fixture and the alveolar bone is firmly filled with the regenerated bone.
- a bone guided regeneration method (Guided Bone Regeneration (GBR) method) has been established so far.
- fixation of the fixture and alveolar bone is one of the most important steps in implant treatment. In this step, after making a hole in the alveolar bone, it is necessary to generate regenerated bone in the alveolar bone using a membrane.
- the period of regeneration bone generation is a state in which the implant is not completed, and the patient is in a state where there is a burden on daily eating habits and the like, and thus it is required that the regeneration bone can be generated earlier. Normally, it takes 3 to 9 months to generate regenerated bone.
- Membranes used in the GBR method include an absorbent membrane and a non-absorbable membrane.
- Non-Patent Document 1 discloses a PET / collagen / hydroxyapatite membrane.
- Absorbable membranes include membranes made of collagen and membranes made of human skin.
- the non-absorbable membrane disclosed in Non-Patent Document 1 has an amide bond (peptide bond) with collagen on the surface of PET using water-soluble carbodiimide (WSC), then immobilized urease on the surface, urea, It is prepared by depositing hydroxyapatite with a calcium source and a phosphorus source.
- WSC water-soluble carbodiimide
- the manufacturing method of the membrane of Non-Patent Document 1 is very complicated. Furthermore, it is difficult to increase the thickness of the membrane produced by this method, and there is a drawback that the film is peeled off from the PET when the thickness is increased.
- the resorbable membrane cannot completely separate the regenerated bone formation site from the granulation tissue, the granulation tissue enters the regenerated bone formation site and prevents regenerated bone formation. Furthermore, in the case of an absorbable membrane, the bone, the membrane, and the granulation tissue cause adhesion, making it difficult to embed the fixture. In addition, it is difficult to confirm whether or not regenerated bone is formed from outside the mouth at the time of diagnosis with an absorbable membrane. Moreover, an absorptive membrane is very expensive, it is 2000 yen / cm ⁇ 2 > at a cheap thing, and 15000 yen / cm ⁇ 2 > or more at a high thing, and it becomes a burden on a patient also in terms of money.
- the present invention has been made in view of the above-described problems of the prior art, and provides a membrane for inducing bone / tissue regeneration that has excellent handleability and can shorten the time required for regenerating bone generation; and
- An object is to provide a method for producing the membrane.
- the present invention provides a membrane for inducing bone and tissue regeneration, comprising an organic base material and a new bone induction layer containing a hydrophilic polymer and calcium phosphate provided on one or both surfaces of the organic base material.
- the membrane for inducing bone / tissue regeneration of the present invention has the above configuration, it is excellent in handleability. In addition, the ability to induce the regeneration of bone tissue is high, and the time required to generate regenerated bone can be greatly shortened.
- regenerated bone refers to bone that is regenerated where bone has been lost, but “new bone” in the sense that new bone is created where there is no bone. It can also be replaced with the term.
- the thickness of the new bone induction layer is preferably 10 to 200 ⁇ m.
- the layer of the new bone induction layer is within this range, it is possible to further reduce the time required for the generation of regenerated bone, and in addition, the membrane is installed at a site (target site) where bone tissue is regenerated. At this time, it is possible to further suppress the detachment of the new bone induction layer from the organic base material, and the handleability is improved.
- the ratio of the content of the hydrophilic polymer and calcium phosphate in the new bone induction layer is preferably 40:60 to 10:90 in terms of mass ratio.
- the content ratio is in this range, the adhesion of the regenerated bone-inducing layer to the organic base material is improved, and the handling time is further improved, and the time required for regenerated bone generation Can be further shortened.
- the bone / tissue regeneration-inducing membrane can be suitably used for dental treatment including implants.
- the present invention also provides a method for producing a bone / tissue regeneration-inducing membrane comprising a step of applying a mixture containing a hydrophilic polymer and calcium phosphate to an organic substrate. According to the production method of the present invention, it is possible to produce the bone / tissue regeneration-inducing membrane. In addition, it becomes possible to manufacture a bone / tissue regeneration guiding membrane by a simple operation, and the manufacturing cost can be reduced.
- the manufacturing method may further include a step of roughening the surface of the organic substrate. Thereby, the coupling
- the bone / tissue regeneration-inducing membrane of the present invention is excellent in handleability and can easily reduce the time for implant establishment because regenerative bone generation is easily performed in a short period of time.
- it is possible to produce the bone / tissue regeneration-inducing membrane. Since the production method of the present invention is based on a technique in which a hydrophilic polymer and calcium phosphate are applied to the surface of an organic substrate, it is simple and can be reduced in cost.
- FIG. 1 is a schematic cross-sectional view showing a bone / tissue regeneration guiding membrane according to an embodiment.
- 1 is a schematic cross-sectional view showing a bone / tissue regeneration guiding membrane according to an embodiment.
- the membrane according to this embodiment includes an organic base material and a new bone induction layer provided on one or both surfaces of the organic base material.
- the new bone induction layer contains a hydrophilic polymer and calcium phosphate.
- the membrane according to the present embodiment can be used, for example, when bone regeneration is performed by the GBR method in implant treatment.
- FIG. 1 is a schematic cross-sectional view showing a bone / tissue regeneration-inducing membrane according to one embodiment.
- a bone / tissue regeneration induction membrane 100 shown in FIG. 1 includes an organic base material 1 and a new bone induction layer 2 provided on one surface of the organic base material 1.
- FIG. 2 is a schematic cross-sectional view showing a membrane for inducing bone / tissue regeneration according to another embodiment.
- a bone / tissue regeneration induction membrane 110 shown in FIG. 2 includes an organic base material 1 and two new bone induction layers 2 provided on both surfaces of the organic base material 1.
- the organic base material according to the present embodiment can be used without particular limitation as long as it is non-biologically absorbable and is made of an organic material. That is, the membrane according to this embodiment is a non-absorbable membrane.
- the shape of the substrate is not particularly limited, but is preferably a sheet or a film from the viewpoint of ease of handling as a membrane.
- PE polyethylene
- PS polystyrene
- PET polyethylene terephthalate
- PVC polyvinyl chloride
- PC polycarbonate
- PC polyamide
- PMMA polymethyl methacrylate
- epoxy resin epoxy resin
- urethane resin epoxy resin
- an organic base material that does not cause a big problem even if contained in the body is suitable for GBR membrane.
- those that are inexpensive and easily available are desirable in that the treatment cost is low.
- PET has the advantages that it is relatively easy to obtain, is inactive in the living body, has little adhesion to surrounding tissues, and is not a porous material, so that bacteria are difficult to enter and bacteria are difficult to immobilize. Therefore, it is more preferable to use PET among PE, PS and PET.
- These organic base materials may be used alone. Moreover, you may use the base material with which these organic base materials were piled up double or triple.
- the hydrophilic polymer according to this embodiment may be a hydrophilic polymer that is generally sold.
- Specific examples of the hydrophilic polymer include polysaccharides, proteins such as collagen, denatured proteins such as gelatin, peptides such as collagen peptides, and nucleic acids. Among these, gelatin, collagen or collagen peptide is preferable. Furthermore, it is more preferable to use a low endotoxin type, and a low endotoxin gelatin is more preferable.
- a hydrophilic polymer may be used individually by 1 type, and may use 2 or more types together.
- Collagen is an organic component of bone and has excellent biocompatibility. On the other hand, gelatin is cheaper and easier to obtain than collagen. Gelatin has a track record of being used for drug capsules in pharmaceutical applications.
- Gelatin is a modified form of collagen, an organic component of bone. That is, gelatin is a protein in which the three-stranded helix structure of collagen is broken by heat and acid or alkali to form a random coil. Gelatin has the same primary structure as collagen. Therefore, gelatin has a property that when applied to a living body as a medical material, it has a high affinity with tissue and excellent biodegradability like collagen. Gelatin usually contains a substantial amount of endotoxin from the raw materials and contamination during production. Endotoxin is a component of the outer membrane of Gram-negative bacteria and has no oral problems, but exhibits various physiological activities when it enters the blood.
- low endotoxin gelatin any commercially available one can be used, but the minimum calorific value is preferably 5 EU or less.
- hydrophilic polymer may be a polymer containing a phosphate residue.
- calcium phosphate As calcium phosphate, calcium phosphate having various forms can be used. Examples of calcium phosphate include simple calcium phosphate (Ca 3 (PO 4 ) 2 ; TCP), calcium monohydrogen phosphate (CaHPO 4 ), calcium dihydrogen phosphate (Ca (H 2 PO 4 ) 2 ), non- It may be crystalline calcium phosphate (Ca 3 (PO 4 ) 2 ⁇ nH 2 O; ACP), octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 ⁇ 5H 2 O; OCP). In addition to these, a compound having a calcium element and a phosphate group may be used.
- the apatite is preferably apatite represented by the formula (1) because it has properties close to teeth.
- M represents one or more divalent cations
- m represents an integer of 0 to 5
- X represents a monovalent anion.
- M may be a strontium ion, a barium ion, a magnesium ion or the like, or may be two hydrogen atoms (2H).
- the calcium phosphate may be a mixture of hydroxyapatite and apatite where X in the formula (1) is composed of fluorine ions, or apatite where M is composed of magnesium ions.
- Calcium phosphate may be any material having the same properties as bone, and other than artificial inorganic compounds, decalcified freeze-dried other bones and the like can be used.
- calcium phosphate may be used alone, or calcium phosphates having different compositions may be mixed and used.
- the average particle size of the calcium phosphate according to this embodiment is preferably 50 to 200 nm. Among these, the average particle size is more preferably 80 to 150 nm, and still more preferably 100 to 130 nm. When the average particle size of calcium phosphate is 50 to 200 nm, the dispersibility of calcium phosphate and hydrophilic polymer is good and the coating is easy.
- the average particle size means the particle size (median diameter D50) at an integrated value of 50% in the particle size distribution obtained by the laser diffraction / scattering method.
- the new bone induction layer containing a hydrophilic polymer and calcium phosphate preferably has a thickness of 10 to 200 ⁇ m.
- the thickness of the new bone induction layer is 10 to 200 ⁇ m, regenerative bone generation is performed more rapidly. If this layer is less than 10 ⁇ m, the time required for generating regenerated bone tends to be longer. If this thickness is greater than 100 ⁇ m, the hydrophilic polymer and calcium phosphate peel off when the membrane is placed in the mouth, It tends to be scattered inside and difficult to handle.
- the thickness of the new bone induction layer is more preferably 20 to 80 ⁇ m, and further preferably 30 to 60 ⁇ m. When the thickness is 20 to 80 ⁇ m, it is more effective for generating regenerated bone. Further, when the thickness is 30 to 60 ⁇ m, there is almost no peeling during handling, and the period of regenerated bone generation is also shortest.
- the ratio of the content of the hydrophilic polymer and calcium phosphate in the new bone induction layer is preferably 40:60 to 10:90 by mass ratio. More preferably, it is 30:70 to 15:85, and still more preferably 20:80.
- the adhesion of the new bone induction layer to the organic substrate tends to change. The better the adhesion, the better the handling.
- the ratio of the content of the hydrophilic polymer and calcium phosphate is 20:80 by mass, a membrane with good adhesion and a short regeneration bone formation period can be obtained.
- the membrane according to this embodiment can be suitably used for bone / tissue regeneration induction.
- it is preferably used for dental treatment, and for example, it is suitably used for bone regeneration by the GBR method in implant treatment. It can also be used for bone regeneration treatment in general surgical treatment.
- the biocompatibility of the membrane according to the present embodiment can be used to repair a local and fine fracture like a bandage.
- it is attached to the surface of the titanium alloy used for artificial bone, and can also be applied to a use as a member for imparting biocompatibility.
- the method for producing a bone / tissue regeneration-inducing membrane according to this embodiment includes at least a step of applying a mixture containing a hydrophilic polymer and calcium phosphate to an organic substrate.
- a hydrophilic polymer for example, the above-mentioned thing can be used as a hydrophilic polymer, calcium phosphate, and an organic base material.
- the method for manufacturing a bone / tissue regeneration-inducing membrane according to the present embodiment may further include a step of mixing a hydrophilic polymer and calcium phosphate to obtain a mixture containing the hydrophilic polymer and calcium phosphate.
- the mixing method is not particularly limited. For example, a hydrophilic polymer and calcium phosphate are weighed so that the ratio of their contents becomes a predetermined ratio, and then pure water or ion-exchanged water is added to the mortar. , Mixing with a stirrer, mechanical stirrer, magnetic stirrer, homogenizer or the like. When components other than the hydrophilic polymer and calcium phosphate are used, the components may be weighed before adding pure water or the like.
- the organic base material described above can be coated with a mixture of calcium phosphate (for example, calcium phosphate containing apatite) and a hydrophilic polymer (for example, gelatin) on the top, but the organic base material (for example, a film-shaped organic base) It is preferable to roughen the surface by coating the coating surface of the material in advance with sandblasting or corona treatment, or with a porous organic substrate. That is, the method for manufacturing a bone / tissue regeneration-inducing membrane according to the present embodiment may further include a step of roughening the coated surface of the organic base material.
- a surface roughening treatment method there is a method of treating the coated surface of the organic substrate with a strong alkali solution in addition to the sandblast treatment and the corona treatment. Further, after the sandblasting or corona treatment, the coated surface of the organic substrate may be treated with a strong alkali solution.
- a biocompatible substance may be applied on the organic base material (for example, a film-like organic base material) as a roughening treatment. It is valid. In that case, for example, sodium hyaluronate may be applied onto the organic substrate.
- the organic base material it is preferable to use a surface roughened on only one side of the organic base material. First, after bonding two organic base materials, the both surfaces are roughened. Then, it may be divided into two sheets to obtain an organic base material that has been subjected to a roughening treatment on only one side.
- the organic base material may be used by thermocompression bonding so that the hydrophilic polymer and calcium phosphate do not enter between the surfaces not subjected to the roughening treatment. .
- Example 1 (Roughening treatment of organic substrate) A PET film (Toyobo Co., Ltd .: E5100, 100 ⁇ m) was cut into a size of 10 cm ⁇ 10 cm and immersed in a 3 mol / L sodium hydroxide aqueous solution at a temperature of 70 ° C. for 3 hours. After immersion, the film was taken out from the aqueous sodium hydroxide solution, washed with pure water, and a PET film subjected to roughening treatment was obtained.
- a mixture of calcium phosphate and a hydrophilic polymer was applied on one surface of the PET film subjected to the roughening treatment with a gap of 100 ⁇ m using an applicator (the film thickness after application was 60 ⁇ m). After application, the membrane was dried at 60 ° C. for 1 hour to obtain a membrane.
- Adhesion evaluation The produced membrane was subjected to an adhesion test to evaluate the adhesion between the PET film and the coated material.
- the adhesion test was performed as follows. 11 lines were drawn with a cutter in a grid pattern at an interval of 1 mm with the coated surface of the membrane facing up.
- a 6 cm long cellophane tape (manufactured by Sumitomo 3M Co., Ltd., BK-18) was affixed to the end where the grid cuts were cut. After rubbed the cellophane tape sufficiently with an eraser, it was peeled off after 1 minute and evaluated by judging the presence or absence of peeling of the coating from the PET film.
- the evaluation criteria for adhesion were A: no peeling, B: slight peeling, C: most peeling.
- Example 2 A membrane was prepared in the same manner as in Example 1 except that the collagen peptide ratio was 30% by mass and the hydroxyapatite ratio was 70% by mass with respect to the total amount of the mixture, and an adhesion test and a new bone induction test were performed.
- Example 3 A membrane was prepared in the same manner as in Example 1 except that the ratio of the collagen peptide to the total amount of the mixture was 20% by mass and the ratio of hydroxyapatite was 80% by mass, and an adhesion test and a new bone induction test were performed.
- Example 4 A membrane was prepared in the same manner as in Example 1 except that the collagen peptide ratio was 15% by mass and the hydroxyapatite ratio was 85% by mass with respect to the total amount of the mixture, and an adhesion test and a new bone induction test were performed.
- Example 5 A membrane was prepared in the same manner as in Example 1 except that the collagen peptide ratio was 10 mass% and the hydroxyapatite ratio was 90 mass% with respect to the total amount of the mixture, and an adhesion test and a new bone induction test were performed.
- Example 6 A membrane was prepared in the same manner as in Example 1 except that gelatin was used in place of the collagen peptide, and the ratio of gelatin was 40% by mass and the ratio of hydroxyapatite was 60% by mass with respect to the total amount of the above mixture. A new bone induction test was performed.
- Example 7 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin to the total amount of the mixture was 30% by mass and the ratio of hydroxyapatite was 70% by mass, and an adhesion test and a new bone induction test were performed.
- Example 8 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin was 20% by mass and the ratio of hydroxyapatite was 80% by mass with respect to the total amount of the mixture, and an adhesion test and a new bone induction test were performed.
- Example 9 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin to the total amount of the mixture was 15% by mass and the ratio of hydroxyapatite was 85% by mass, and an adhesion test and a new bone induction test were performed.
- Example 10 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin to the total amount of the mixture was 10% by mass, the ratio of hydroxyapatite was 90% by mass, and the film thickness after coating was 80 ⁇ m. A bone induction test was performed.
- Example 11 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin to the total amount of the mixture was 20% by mass, the ratio of hydroxyapatite was 80% by mass, and the film thickness after coating was 120 ⁇ m. A bone induction test was performed.
- Example 12 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin to the total amount of the mixture was 20% by mass, the ratio of hydroxyapatite was 80% by mass, and the film thickness after coating was 10 ⁇ m. A bone induction test was performed.
- Example 13 A membrane was prepared in the same manner as in Example 6 except that the ratio of gelatin to the total amount of the mixture was 20% by mass, the ratio of hydroxyapatite was 80% by mass, and the film thickness after coating was 6 ⁇ m. A bone induction test was performed.
- the membrane according to the present invention can significantly reduce the period of new bone formation.
- collagen peptide or gelatin and hydroxyapatite are mixed and applied so as to have a mass ratio of 20:80 (see, for example, Example 3 and Example 8), the adhesion is good and new bone is formed. It can be seen that the period is short and it is effective as a membrane.
- SYMBOLS 1 Organic base material, 2 ... New bone induction layer, 100, 110 ... Membrane for bone / tissue regeneration induction.
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Abstract
Description
本実施形態に係る有機基材としては、生体非吸収性であって、有機材料から構成される基材であれば、特に制限なく用いることができる。すなわち、本実施形態に係るメンブレンは非吸収性のメンブレンである。基材の形状については特に制限されるものではないが、メンブレンとしての取り扱い易さの観点から、シート状、又はフィルム状であることが好ましい。
本実施形態に係る親水性ポリマーは、一般に販売されている親水性のポリマーであればよい。親水性ポリマーとしては、具体的には、例えば、多糖類、コラーゲン等のタンパク質、ゼラチン等の変性タンパク質、コラーゲンペプチド等のペプチド、及び核酸が挙げられる。これらの中でも、ゼラチン、コラーゲン又はコラーゲンペプチドが好ましい。さらに低エンドトキシン性のものを用いるのがより好ましく、低エンドトキシンゼラチンであればさらに好ましい。親水性ポリマーは一種を単独で使用してもよく、二種以上を併用してもよい。
リン酸カルシウムは、種々の形態を持つリン酸カルシウムを使用することができる。リン酸カルシウムとしては、例えば、単純なリン酸カルシウム(Ca3(PO4)2;TCP)のほか、リン酸一水素カルシウム(CaHPO4)、リン酸二水素カルシウム(Ca(H2PO4)2)、非晶質リン酸カルシウム(Ca3(PO4)2・nH2O;ACP)、リン酸八カルシウム(Ca8H2(PO4)6・5H2O;OCP)であってもよい。また、これら以外でもカルシウム元素とリン酸基を有する化合物であってもよい。
Ca(10-m)Mm(PO4)6X2・・・(1)
[式(1)中、Mは一種以上の2価の陽イオンを示し、mは0~5の整数を示し、Xは一価の陰イオンを示す。]
なお、平均粒径は、レーザー回折・散乱法によって求めた粒度分布における積算値50%での粒径(メディアン径D50)を意味する。
本実施形態に係るメンブレンは、親水性ポリマーとリン酸カルシウムとを含有する新生骨誘導層の厚みが10~200μmであることが好ましい。新生骨誘導層の厚みが10~200μmであると、再生骨生成がより迅速に行われる。この層みが10μm未満の場合、再生骨生成に要する時間が長くなる傾向にあり、この厚みが100μmより厚い場合、メンブレンを口腔内に設置する際に親水性ポリマーとリン酸カルシウムが剥がれ落ちて、口腔内に散らばってしまい、取り扱い性が困難となる傾向にある。さらに、新生骨誘導層の厚みが20~80μmであることがより好ましく、30~60μmであることが更に好ましい。この厚みが20~80μmであると、再生骨生成により有効である。また、この厚みが30~60μmであると、取り扱う際に剥がれはほぼ無く、再生骨生成の期間も最短となる。
本実施形態に係る骨・組織再生誘導用メンブレンの製造方法は、親水性ポリマー及びリン酸カルシウムを含有する混合物を有機基材に塗布する工程を少なくとも備える。ここで、親水性ポリマー、リン酸カルシウム及び有機基材としては、上述のものを使用することができる。
(有機基材の粗面化処理)
PETフィルム(東洋紡績株式会社製:E5100、100μm)を10cm×10cmの大きさに切断し、3モル/Lの水酸化ナトリウム水溶液に70℃の温度で3時間浸漬させた。浸漬後、水酸化ナトリウム水溶液からフィルムを取り出して純水で洗浄し、粗面化処理を施したPETフィルムを得た。
リン酸カルシウムとして、ハイドロキシアパタイト(和光純薬工業株式会社)を、親水性ポリマーとして、コラーゲンペプチド(和光純薬工業株式会社)を使用し、リン酸カルシウム:親水性ポリマーを質量比で60:40となるように混合し、固形分比が72%となるように純水を加え、乳鉢で混合し、リン酸カルシウムと親水性ポリマーとの混合物を得た。
粗面化処理を施したPETフィルムの一方の面上に、リン酸カルシウムと親水性ポリマーの混合物を、アプリケーターを用いてギャップ100μmで塗布した(塗布後の膜厚は60μm)。塗布後、60℃で1時間乾燥させ、メンブレンを得た。
作製したメンブレンは、密着性試験を行って、PETフィルムと塗布物との密着性を評価した。密着性試験は、以下のように行った。メンブレンの塗布面を上にし、1mmの間隔で碁盤目状に11本の線をカッターで引いた。碁盤目状の切り込みを入れた部分を端にし、6cmの長さのセロハンテープ(住友スリーエム株式会社製、BK-18)を貼り付けた。消しゴムでセロハンテープの上を十分に擦った後、1分後に剥がして塗布物のPETフィルムからの剥離の有無を判断することによって評価した。密着性の評価基準は、A:全く剥がれない、B:わずかに剥がれる、C:大部分剥がれる、とした。
豚の口腔にて、歯を抜歯した直後に、作製したメンブレンを歯槽骨を覆うように被せ、経過を観察した。2ヵ月後、2.5ヶ月後、3ヶ月後、4ヵ月後、6ヵ月後に経過を観察し、新生骨生成期間を求めた。
上記混合物全量に対する、コラーゲンペプチドの比率を30質量%、ハイドロキシアパタイトの比率を70質量%にした以外は実施例1と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、コラーゲンペプチドの比率を20質量%、ハイドロキシアパタイトの比率を80質量%にした以外は実施例1と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、コラーゲンペプチドの比率を15質量%、ハイドロキシアパタイトの比率を85質量%にした以外は実施例1と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、コラーゲンペプチドの比率を10質量%、ハイドロキシアパタイトの比率を90質量%にした以外は実施例1と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
コラーゲンペプチドの代わりに、ゼラチンを使用し、上記混合物全量に対する、ゼラチンの比率を40質量%、ハイドロキシアパタイトの比率を60質量%にした以外は実施例1と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を30質量%、ハイドロキシアパタイトの比率を70質量%にした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を20質量%、ハイドロキシアパタイトの比率を80質量%にした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を15質量%、ハイドロキシアパタイトの比率を85質量%にした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を10質量%、ハイドロキシアパタイトの比率を90質量%にし、塗布後の膜厚を80μmとした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を20質量%、ハイドロキシアパタイトの比率を80質量%にし、塗布後の膜厚を120μmとした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を20質量%、ハイドロキシアパタイトの比率を80質量%にし、塗布後の膜厚を10μmとした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
上記混合物全量に対する、ゼラチンの比率を20質量%、ハイドロキシアパタイトの比率を80質量%にし、塗布後の膜厚を6μmとした以外は実施例6と同様にメンブレンを作製し、密着性試験及び新生骨誘導試験を行った。
Claims (7)
- 有機基材と、該有機基材の片面又は両面に設けられた、親水性ポリマー及びリン酸カルシウムを含有する新生骨誘導層と、を備える、骨・組織再生誘導用メンブレン。
- 前記新生骨誘導層の厚みが10~200μmである、請求項1に記載の骨・組織再生誘導用メンブレン。
- 前記新生骨誘導層における、前記親水性ポリマーと前記リン酸カルシウムとの含有量の比が、質量比で40:60~10:90である、請求項1又は2に記載の骨・組織再生誘導用メンブレン。
- 歯科治療用である、請求項1~3のいずれか一項に記載の骨・組織再生誘導用メンブレン。
- 親水性ポリマー及びリン酸カルシウムを含有する混合物を、有機基材に塗布することにより製造される、請求項1~4のいずれか一項に記載の骨・組織再生誘導用メンブレン。
- 親水性ポリマー及びリン酸カルシウムを含有する混合物を有機基材に塗布する工程を備える、骨・組織再生誘導用メンブレンの製造方法。
- 有機基材の表面を粗面化処理する工程を更に備える、請求項6に記載の製造方法。
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