WO2003047645A1 - Composite d'apatite-collagene poreux ou superporeux de type eponge et son procede de production - Google Patents

Composite d'apatite-collagene poreux ou superporeux de type eponge et son procede de production Download PDF

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Publication number
WO2003047645A1
WO2003047645A1 PCT/JP2002/012782 JP0212782W WO03047645A1 WO 2003047645 A1 WO2003047645 A1 WO 2003047645A1 JP 0212782 W JP0212782 W JP 0212782W WO 03047645 A1 WO03047645 A1 WO 03047645A1
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Prior art keywords
collagen
apatite
sponge
porous
complex
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PCT/JP2002/012782
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English (en)
Japanese (ja)
Inventor
Masayuki Okazaki
Yasuhiro Yoshida
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Japan Science And Technology Agency
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Publication of WO2003047645A1 publication Critical patent/WO2003047645A1/fr

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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
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers

Definitions

  • the present invention relates to a novel superporous biomaterial for the purpose of developing a scaffold for replacing hard tissue, that is, a superporous composite of collagen and carbonate apatite.
  • a superporous composite having excellent cell infiltration properties comprising a metabolic carbonate abatite having a composition and a crystal structure similar to that of a living bone or a tooth, and collagen, and a method for producing the same.
  • Japanese Patent Application Laid-Open Publication No. 2000-266628 discloses orthopedic, neurosurgery and plastic surgery comprising various bioabsorbable organic materials including collagen and calcium phosphate compounds including carbonate-containing apatite.
  • a composite type bone filling material used for repairing a bone defect in a subject or the like is described.
  • Japanese Patent Application Laid-Open No. 8-187254 in accordance with the invention of the present inventors discloses that a collagen layer and an apatite / collagen layer are appropriately formed so as to be able to cope with both soft and hard tissues.
  • a laminated composite film formed by laminating in combination is described. Further, Japanese Patent Application Laid-Open No.
  • 8-336559 discloses a container for an artificial organ for newly generating an autologous organ tissue for treating a lesion of the organ tissue, and at least the container. It describes an artificial organ container whose inner wall is made of a material mainly composed of apatite containing an organic substance such as collagen.
  • U.S. Pat. No. 5,071,4,336 describes that a sponge having hydroxyapatite and gel-like collagen is used as a bone replacement material for plastic surgery.
  • U.S. Patent Nos. 5,776,193 and 6,187,047 state that porosity is imparted in the design of bone replacement materials. Have been. Further, U.S. Pat. No.
  • 6,201,039 describes various medical artificial bones comprising a hydroxyapatite starting from a hydroxypatite precursor, which is treated with collagen, and which is similar to a living bone tissue. It states that the organization will be obtained.
  • apatite is used as a material constituting the composite, and although carbonate apatite is exemplarily described therein, carbonate apatite is described therein.
  • the chemical composition is very similar to the biological bone tissue, and the crystallographic relationship is also very similar (this point will be described later with reference to FIGS. 3 and 4).
  • the material to be used has properties as a high-level biofunctional material. That is, bioactive substances and stem cells must be maintained for a certain period of time, sustained release should be exhibited, and they should have excellent cell invasiveness and be metabolized and replaced by new tissues. For various demands, those with characteristics that can meet these requirements are required.
  • the conventional composite is as described above, and it cannot be said that it is a material that can sufficiently respond to the various requests as described above.
  • the present invention seeks to develop and provide a scaffold material for hard tissue replacement that meets the above-mentioned demands, and as a result of intensive research, among various known apatites, carbonate apatite is particularly close to living bone tissue.
  • the material has a composition and crystallinity and is excellent in affinity for living tissue, and in addition, this apatite is complexed with collagen, so-called bioregenerating medical apatite.
  • the material design of the composite can be designed to be porous and high porosity sponge-like, it is excellent in terms of, for example, enhancing the infiltration of new tissues.
  • the sponge-like high porosity, porous composite was successfully obtained by treating both the carbonate carbonate and collagen materials by a specific process. It has been confirmed that the composite material obtained as a result of the above can be sufficiently used as a regenerative medical engineering material, and that the intended purpose can be achieved by this. is there.
  • the present invention solves the above-mentioned problems, and provides the following sponge-like porous apatite-collagen composite, sponge-like superporous apatite.collagen composite, and methods for producing them.
  • a sponge-like porous body for replacing living hard tissue which is a composite for replacing living hard tissue, comprising a carbonate carbonate and collagen, wherein the tissue structure of the complex is a porous sponge. Carbonated abatite-collagen complex.
  • Collagen is dissolved in acid to prepare an acidic collagen solution, gelled by adding alkali, and then mixed with apatite carbonate particles to obtain a water-containing composite gel composed of apatite and collagen.
  • the water-containing composite gel thus obtained is centrifuged to remove water appropriately, frozen, and freeze-vacuum-dried to obtain a sponge-like porous carbonated apatite-collagen complex, which is a substitute for living hard tissue.
  • spongy porous carbonated apatite / collagen composites for producing spongy porous carbonated apatite / collagen composites.
  • Collagen is dissolved in acid to prepare an acidic collagen solution, gelled by adding alkali, and then mixed with apatite carbonate particles to form a hydrous composite gel composed of apatite and collagen.
  • the resulting hydrous composite gel is centrifuged to remove water as appropriate, frozen, freeze-dried and vacuum-dried to obtain sponge-like porous apatite collagen, and then insolubilized.
  • a first solution of the present invention is a living hard tissue replacement complex comprising carbonate apatite and collagen, characterized by exhibiting a porous sponge shape. This is a sponge-like porous carbonated apatite / collagen composite.
  • a second solution of the present invention is a sponge-like porous material for replacing a living tissue, wherein the composite according to the first solution has a porosity of 5 to 90 vol%. It is a carbonate apatite / collagen complex.
  • a third solution of the present invention is a sponge-like ultraporous material for substituting a living hard tissue, wherein the composite according to the second solution has a porosity of 50 to 90 vol%. This is a complex of carbonic acid apatite and collagen.
  • a fourth solution of the present invention is characterized in that the complex according to the first solution contains 95% by weight or less of carbonate apatite and has a porosity of 5 to 90% by volume.
  • a fifth solution of the present invention is the substitute for living hard tissue, characterized in that the carbonate apatite in the first solution contains a trace component similar to that contained in the living body apatite. Sponge-like porous carbonate It is a patite-collagen complex.
  • a sixth solution of the present invention is a sponge-like porous material for substituting a living hard tissue, wherein the trace component in the fifth solution is Mg, Fe, Zn, F, or CI. It is a carbonate apatite / collagen complex.
  • the seventh solution of the present invention is to prepare an acidic collagen solution by dissolving collagen in an acid, gelling by adding an alkaline solution, and then mixing the carbonated apatite particles, A water-containing composite gel consisting of collagen and collagen is obtained. The obtained water-containing composite gel is centrifuged to remove water as needed, and then frozen and freeze-vacuum dried to form a sponge-like porous material.
  • the eighth solution of the present invention is to prepare an acidic collagen solution by dissolving collagen in an acid, gelling by adding an alkaline solution, then mixing the carbonated apatite particles, and mixing with the carbonated apatite.
  • a water-containing composite gel comprising collagen was obtained, and the obtained water-containing composite gel was centrifuged to appropriately remove water, and then frozen and freeze-vacuum-dried to form a sponge-like porous carbonate.
  • This is a method for producing a sponge-like porous carbonate-collagen complex for replacing living hard tissue, which comprises obtaining an apatite-collagen complex and then insolubilizing the complex.
  • a ninth solution of the present invention is a sponge-like porous carbon dioxide for replacing living hard tissue, wherein the eighth insolubilization treatment is performed by irradiation with UV light.
  • This is a method for producing a patite-collagen complex.
  • a tenth solution of the present invention is a method for producing a sponge-like porous carbonated apatite-collagen complex for substituting a living hard tissue, wherein the eighth insolubilization treatment is a chemical treatment.
  • the usual apertype is C ai.
  • ( ⁇ ⁇ 4) 6 (OH) is represented by 2, carbonate Apatai you want to use in the present invention, the chemical composition of the general formula; C a 10 one X (PO 4) 6- ⁇ ( CO s) ⁇ ( OH) 2-z, where 0 ⁇ X ⁇ 3 to 5, 0 ⁇ Y 2 to 4, 0 ⁇ Z ⁇ 1 to 2, and its crystallinity is very similar to the crystal structure of living bone ing.
  • FIGS. 3 and 4 a comparison of the synthetic carbonate apatite with the bones of the human body by X-ray diffraction patterns is as shown in FIGS. 3 and 4.
  • the crystal structures of both are almost similar and cannot be distinguished.
  • the requirement for setting the complex to be sponge-like porous or sponge-like super porous is that, by this, the bioactive substance to be introduced and osteoblasts can be retained, and the cells can be infiltrated. And ensure landing It has an action.
  • the sponge-like porous composite is defined by the porosity and is selected according to the porosity in use.However, the range in which the porosity is set or selected depends on the purpose of use. The decision will be taken into account. The selection will be clarified through further experiments.
  • the complex of the present invention is unique in that it is set in a sponge-like state as compared with the conventional complex, and thus the complex is recognized.
  • the composite based on the previous design, as described in the present invention may be described as being porous even if the description is actually porous, or a description suggesting this or a guide to that effect.
  • the present invention has a sponge shape and a porosity of 5 to 90 vol%.
  • the lower limit of 5 vol% is that if it is less than 5 vol%, it will not be possible to meet the above-mentioned requirements such as cell invasiveness.
  • the reason for setting the upper limit to 90 vol% is beyond this—in this case, the strength of a biomaterial support is the limit. This is what we stipulated. INDUSTRIAL APPLICABILITY
  • the present invention can freely set the porosity in a wide range, thereby meeting a wide range of usage modes and demands.
  • the void portion plays an important role in regenerative medical engineering as a void for holding a bioactive substance and a living cell, or as a void for implantation and infiltration of cells.
  • the composite set at 50 to 90 vol% has a porosity that accounts for more than half of the volume of the composite, and can be said to be a superporous composite. Which range of porosity is to be set or selected depends on its use in regenerative medical engineering, that is, a support for bone regeneration (for osteoblast culture), a support for cell culture, and an artificial organ. It is set appropriately according to various uses such as a tissue culture support or a bone filling material, and referring to clinical examples.
  • collagen will be described.
  • Collagen is commercially available, and the collagen used in the present invention is usually commercially available and sufficient, and there is no particular limitation on its quality and the like.
  • the significance of collagen in the present invention is that, in producing a sponge-like porous composite, it plays a role as a binder for carbonic acid apatite crystal particles and also adjusts porosity. Also plays an important role together with other factors.
  • the sponge-like porous composite is produced by the above-described process, but depends on various conditions in a series of processes such as the concentration of the collagen solution, the amount of mixed carbon apatite, and the centrifugation operation for separating water.
  • the porosity, etc., of the resulting composite varies and is affected.
  • collagen Is dissolved in an acid and then neutralized to neutrality or alkalinity in order to dissolve and gelate. That is, collagen is dissolved by an acid and gelled when an alkali is added to the acidic solution and the pH is adjusted to 7 or more.
  • the mixing operation of carbonated apatite is performed after neutralization, because if mixed at the stage when the solution is acidic, the apatite crystals may be partially eluted or altered, or the crystal structure of the particles may be altered. This may have some effect on the situation, and this should be avoided. In the region having a pH of 7 or more, the collagen in the acidic collagen solution gels. Mix apatite immediately after neutralization.
  • the gelation progresses due to the neutralization, the viscosity increases due to the gelation and it becomes difficult to mix, so it is preferable to carry out immediately after the neutralization.However, the gelation is adjusted to an appropriate viscosity, and As an embodiment, the mixing amount of the apa-titer particles is appropriately controlled and agitated, thereby controlling the dispersion state and the like of the two in the composite. It is not something that must be done. After the mixing operation is completed, centrifugation operation and freeze-vacuum drying treatment are performed. The significance is that the hydrogel composite obtained by mixing has not yet formed a porous state in this state, and this operation process As a result, water is removed, and the gel body becomes a sponge-like porous body.
  • the complex may be a carbonate apatite.
  • the point that the content was 95% by weight or less and the complex was specified only based on the upper limit of carbonate apatite is not limited to the lower limit, that is, when carbonate apatite S is substantially close to 0 wt%. (Collagen 100 wt%) is also possible.
  • the upper limit set at 95 wt% when the carbonate apatite exceeds 95 wt%, the composite becomes dense and it becomes difficult to obtain the desired porosity.
  • FIG. 1 is an electron micrograph showing the structure of the sponge-like superporous carbonate apatite / collagen complex of the present invention.
  • Fig. 2 is an electron micrograph showing the structure of a conventional apatite-collagen complex.
  • FIG. 3 is an X-ray diffraction diagram of the synthetic carbonate apatite.
  • FIG. 4 is an X-ray diffraction pattern of a human bone.
  • Fig. 5 is an electron micrograph showing the bone tissue of the sample not irradiated with UV.
  • FIG. 6 is an electron micrograph showing the bone tissue of the sample irradiated with UV.
  • the sponge-like porous carbonated abatite-collagen composite of the present invention has a sponge shape and a high porosity.
  • it when used as a cell culture support, it has good retention of the introduced bioactive substance and good cell infiltration and metabolism, as described above. Not only can it be used for the same purpose as the normal apatite-collagen complex, but it can also be used in the fields, applications, or cell invasiveness that were previously considered difficult by taking advantage of the characteristics shown above.
  • composition of carbonate apatite as shown in the general formula, has values of x, y, and z each within a predetermined range. It is possible.
  • the pH value is set to 7 or more, that is, to the near side.
  • the reaction temperature may be in the range of about 40 ° C. to 80 ° C., but keeping the temperature as low as possible at 60 ° C. is particularly preferable for obtaining uniform crystals.
  • 0.05 N NaOH solution was added dropwise, and when the whole amount was neutralized, the above carbonate abatite was immediately mixed. Further, NaOH solution was added dropwise to gel the collagen, and the collagen was gelled. As a result, a sponge-like porous carbonate and collagen precursor, which is a precursor of the collagen complex, was obtained.
  • This gelation reaction is caused by the acidity of the acidic collagen solution, regardless of the presence or absence of apatite. In other words, the phenomenon is based on the change in the molecular structure of the collagen itself.
  • the concentration of the collagen solution prepared for the production of the complex is preferably 0.1 to 2.0% by weight.
  • the state of the hydrous composite gel obtained after gelation differs in viscosity and water content. That is, the moisture content can be freely controlled by the difference in the concentration.
  • the water content can be freely controlled by the difference in the concentration.
  • a composite having a high porosity can be obtained, and conversely, from the water-containing composite gel having a low water content, the porosity can be obtained.
  • a material having a low porosity can be obtained, thereby controlling the porosity and the porosity in a target state.
  • 0.1 to 2.0 wt% is used.
  • the lower limit was set because the desired composite could not exhibit its function and the shape and strength of the target composite were too weak, which hindered use. 2. If it exceeds O wt%, the viscosity at the time of gelation becomes strong, and the amount suitable for forming a bulky porous body for carbonated apatite particles is uniformly dispersed and mixed. In this case, the mixing operation and the subsequent dehydration operation for making the material porous are also difficult.
  • the gelation reaction was performed in a mold having a predetermined shape, whereby a water-containing composite gel having a certain shape was obtained, and then processed into a predetermined shape by separating and removing water.
  • Obtaining a sponge-like porous composite is also one of the embodiments.
  • the operation of separating and removing water in the composite sponge preparation process is as follows. First, the water-containing composite gel obtained in the previous step is centrifuged to preliminarily remove water that has liberated in a substantial amount, and then removes it. The unretained water is removed by freezing the gel as it is at 180 ° C. or with liquid nitrogen for 2 hours, followed by freeze vacuum drying, and sublimation and separation of the frozen water. By performing this moisture separation operation, the mixture becomes porous, and when pressed with a finger, an elastic sponge-like porous composite having a high porosity can be obtained.
  • the sponge-like porous composite obtained by the above-mentioned process dissolves and swells in the living tissue as it is, gradually loses its form, and can no longer maintain the desired form. And may cause inconvenience.
  • the sponge-like porous composite has a large surface area as compared to a solid one, and is in a state where solubility is easily promoted. Therefore, it is desirable to perform insolubilization.
  • the insolubilization treatment include ultraviolet irradiation and chemical treatment. The result does not change much.
  • Example of insolubilization treatment Place the apatite-collagen complex obtained by the above-mentioned process in a sterile box at a distance of 10 cm under a UV lamp (10 W, ultraviolet light with a wavelength of 253.7 nm). And irradiated with UV light for 2 hours on both sides.
  • a UV lamp (10 W, ultraviolet light with a wavelength of 253.7 nm).
  • the insolubilization means other than the UV irradiation a treatment using a chemically treated gamma ray using Daltar aldehyde 0.1 to 5 wt% is also used.
  • the porosity and the pore diameter can be freely adjusted by controlling the water content, thereby obtaining a sponge-like composite having an extremely high porosity. Can be done.
  • the pore diameter has not been described in detail, it is generally said that the invasiveness of cells depends on the pore diameter, and the pore diameter into which cells can easily enter is 200 to 3 • 0 microns. In other words, this value serves as a reference index, but the optimal range will be awaiting further research.
  • Another feature of the present invention is that, since the present invention is in the form of a sponge, it can be easily formed.
  • the biological apatite has trace elements of trace elements such as Mg, Fe, Zn, F, CI, etc., and it is possible to approach this in the present invention.
  • trace elements such as Mg, Fe, Zn, F, CI, etc.
  • the addition of trace elements during production is included as an embodiment of the present invention.
  • carbonate apatite having a very similar chemical composition and crystal structure to the bone of a living body is used, and this is composited with collagen, so that it has an affinity for biological tissue.
  • the structure of the complex is made of sponge-like porous or ultra-porous, so that physiologically active substances and stem cells can be effectively and reliably retained for a certain period of time, and cell infiltration It provides a metabolic complex with excellent properties, and its significance is extremely large.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Dispersion Chemistry (AREA)
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  • Materials For Medical Uses (AREA)

Abstract

Dans le domaine du génie thérapeutique de régénération, des activités de recherche et de développement de composites d'apatite-collagène ont été effectuées de manière efficace. Les composites existant ne peuvent pas toujours répondre au différentes demandes, telles que support d'une substance physiologiquement active ou de cellules souches telles que des ostéoblastes pendant une durée définie, accélération de l'infiltration de cellules et remplacement par un nouveau tissu via un métabolisme spontané. De ce fait, les composites précités sont destinés à remplir ces demandes. L'invention concerne essentiellement la formation de composites de carbonate d'apatite très proches la composition chimique et de la structure cristalline de l'os et de collagène possédant une excellente compatibilité avec les tissus biologiques. Ces composites possèdent une structure poreuse ou superporeuse de type éponge permettant de supporter de manière sûre une substance physiologiquement active ou des cellules souches pendant une durée définie. De ce fait, on peut obtenir un composite présentant d'excellentes propriétés d'infiltration de cellule et de métabolisme.
PCT/JP2002/012782 2001-12-07 2002-12-05 Composite d'apatite-collagene poreux ou superporeux de type eponge et son procede de production WO2003047645A1 (fr)

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JP2001374469A JP2003169845A (ja) 2001-12-07 2001-12-07 スポンジ状多孔質アパタイト・コラーゲン複合体、スポンジ状超多孔質アパタイト・コラーゲン複合体及びそれらの製造方法

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WO2006046414A1 (fr) * 2004-10-28 2006-05-04 National Institute For Materials Science Procédé pour la fabrication d’un objet poreux comprenant des fibres composites d’apatite et de collagène
WO2008026634A1 (fr) * 2006-08-31 2008-03-06 Osaka University Stimulateur de proliferation de cellule mesenchymateuse et biomateriau du systeme squelettique
US9976011B2 (en) 2010-07-14 2018-05-22 The Curators Of The University Of Missouri Polymer composites and fabrications thereof
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JP5024780B2 (ja) * 2005-09-09 2012-09-12 独立行政法人物質・材料研究機構 一方向性多孔質複合体の製造方法および一方向性多孔質複合体
EP2596764B1 (fr) 2006-08-22 2016-07-13 Mitsubishi Electric Corporation Appareil de traitement laser, procédé osséo-intégration, matériau d'implant et procédé de fabrication de matériau implant
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Publication number Priority date Publication date Assignee Title
WO2006046414A1 (fr) * 2004-10-28 2006-05-04 National Institute For Materials Science Procédé pour la fabrication d’un objet poreux comprenant des fibres composites d’apatite et de collagène
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WO2008026634A1 (fr) * 2006-08-31 2008-03-06 Osaka University Stimulateur de proliferation de cellule mesenchymateuse et biomateriau du systeme squelettique
US8222216B2 (en) 2006-08-31 2012-07-17 Osaka University Mesenchymal cell proliferation promoter and skeletal system biomaterial
US9976011B2 (en) 2010-07-14 2018-05-22 The Curators Of The University Of Missouri Polymer composites and fabrications thereof
US11883302B2 (en) 2021-11-22 2024-01-30 Warsaw Orthopedic, Inc. Spinal implant having a compressible insert

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