WO2003075971A1 - Controle de la biodegradabilite d'un biomateriau composite - Google Patents

Controle de la biodegradabilite d'un biomateriau composite Download PDF

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Publication number
WO2003075971A1
WO2003075971A1 PCT/JP2002/008335 JP0208335W WO03075971A1 WO 2003075971 A1 WO2003075971 A1 WO 2003075971A1 JP 0208335 W JP0208335 W JP 0208335W WO 03075971 A1 WO03075971 A1 WO 03075971A1
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WIPO (PCT)
Prior art keywords
collagen
composite
cross
composite biomaterial
hydroxyapatite
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PCT/JP2002/008335
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English (en)
Japanese (ja)
Inventor
Junzo Tanaka
Masanori Kikuchi
Noriichi Ito
Yoshinobu Mandai
Original Assignee
Japan Science And Technology Agency
National Institute For Materials Science
Nitta Gelatin Inc.
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Application filed by Japan Science And Technology Agency, National Institute For Materials Science, Nitta Gelatin Inc. filed Critical Japan Science And Technology Agency
Publication of WO2003075971A1 publication Critical patent/WO2003075971A1/fr
Priority to US10/937,732 priority Critical patent/US7229971B2/en

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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
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • 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 calcium salts (in particular, hydroxyapatite) and collagen
  • the present invention relates to a method for controlling the biodegradability of a composite biomaterial containing a biotin, and an improved composite biomaterial field provided by the method.
  • Vertebrate bone is originally a complex of inorganic hydroxyapatite (HAp) and organic collagen. They form a unique nanocomposite structure in which HAp is oriented along the collagen fiber in the c-axis direction in living bone (self-organization), and this structure gives the bone a unique mechanical property. . In other words, simply combining HAp and collagen cannot achieve the same structure and properties as living bone.
  • HAp inorganic hydroxyapatite
  • the present inventors have utilized the self-assembly of HAp and Col to have a nanocomposite structure similar to a living bone under biomimetic conditions (similar to the in vivo environment in which osteogenesis occurs).
  • the HAp / Col composite was successfully synthesized (JP-A-7-101708, JP-A-11-199209, JP-A-2000-5298, etc.). It was confirmed that this complex had excellent biocompatibility, was absorbed by osteoclasts, and promoted osteogenesis. However, the composite is absorbed and decomposed immediately after transplantation, and thus has a problem that it is not practical as an artificial aggregate or the like. Disclosure of the invention
  • the present invention relates to a complex containing a calcium salt (particularly, hydroxyapatite) having a structure similar to that of a living bone and collagen, while maintaining the mechanical strength thereof, controlling the rate of in vivo degradation, and suitable for practical use. It is an object of the present invention to provide a composite biomaterial.
  • the present inventors have conducted intensive studies in order to solve such a problem, and as a result, have found that the introduction of crosslinks into the collagen fibers constituting the complex can control the mechanical strength and the rate of in vivo degradation of the complex. Completed. That is, the present invention provides the following (1) to (9).
  • a method for controlling the rate of biodegradation of a composite biomaterial in a composite biomaterial containing a calcium salt and collagen by introducing crosslinks into the collagen by introducing crosslinks into the collagen.
  • the composite biomaterial of the present invention can provide a composite containing a calcium salt (particularly, a hydroxyapatite in the form of a hide) and collagen by introducing cross-linking into the collagen to improve the mechanical strength and the in vivo degradation rate suitable for the biomaterial. It has been realized.
  • the calcium salt contained in the composite biomaterial of the present invention is preferably calcium phosphate or calcium carbonate, and most preferably hydroxyapatite.
  • this composite biomaterial containing collagen and hydroxyapatite it is preferable that hydroxyapatite and collagen be oriented in a self-organizing manner to form a complex similar to living bone.
  • self-assembly refers to “the same or different kinds of atoms, molecules, fine particles, etc., gathering through non-covalent interactions to form a specific tissue (Tokyo Chemical)
  • calcium phosphate (a hydroxyapatite: HAp) having an apatite structure is oriented along a collagen fiber in the present invention. It means to form a microporous structure in which the c-axis of HAp is oriented along the collagen fiber.
  • Hydroxyapatite compounds der to the general composition Ca 5 (P0 4) 3 0H , and is, by non-stoichiometry of the reaction, CaHPO have Ca 3 (P0 4) 2, Ca 4 0 (P0 4) 2, referred to as Ca 10 (P0 4) 6 ( 0H) 2, CaP 4 0 1 P Ca (P0 3) 2, Ca 2 P 2 0 7, Ca (3 ⁇ 4P0 4) 2 ⁇ 0 , phosphoric acid strength Rushiumu Contains a group of compounds.
  • hydroxyapatite It is for the Ca 5 (P0 4) 3 0H or Ca lfl (P0 4) 6 ( 0H) basic ingredient a compound represented by the second formula, a portion of the Ca component, Sr, Ba, MG, It may be substituted with one or more selected from Fe, Al, Y, La, Na, K, H and the like. Further, (P0 4) a portion of the component, V0 4, B0 3, S0 4, C0 3, S i0 may be substituted with one or more selected from 4 like. Further, a portion of the (0H) component, F, C 0, C0 may be substituted on 1 or more kinds selected from 3 or the like. In addition, some of these components may be defective. Because some of the P0 4 and 0H components Apataito of biological bones is replacement to a normal C0 3, some substitutions in the manufacture of the composite biomaterial into C0 3 of contamination and the components from the atmosphere (About 0 to 10% by mass).
  • the hydroxyapatite may be an isomorphous solid solution, a substitutional solid solution, or an interstitial solid solution, in addition to ordinary microcrystals / amorphous crystals, and may contain non-quantitative defects. You may.
  • the atomic ratio of calcium and phosphorus (Ca / P) is preferably in the range of 1.3 to 1.8, particularly 1.5 to 1.7. More preferred. If the atomic ratio is in the range of 1.3 to 1.8, the composition and crystal structure of apatite (calcium phosphate compound) in the product will be similar to that of apatite in vertebrate bone. This is because the structure can be adopted, and the biocompatibility and bioabsorbability are increased.
  • collagen used in the present invention it is known that about 20 different molecular species of collagen are present not only in mammals but also in biological tissues of a wide range of animals including fish, Are collectively referred to as the collagen used in the present invention, the species, tissue site, age and the like of the animal used as the starting material are not particularly limited, and any collagen can be used. Generally, collagen obtained from the skin, bones, cartilage, tendons, organs, etc. of mammals (eg, porcupines, bushes, magpies, magpies, rats, etc.) and birds (eg, chickens, etc.) is used. .
  • mammals eg, porcupines, bushes, magpies, magpies, rats, etc.
  • birds eg, chickens, etc.
  • Fish eg cod, flounder, flounder, salmon, trout, tuna, mackerel, Thailand, sardines, Collagen-like proteins obtained from the skin, bone, cartilage, fins, scales, organs, etc. of sharks
  • collagen obtained by genetic recombination technology may be used.
  • type I collagen is the most abundant and well studied among the molecular species of collagen. Usually, simply referring to collagen often refers to type I collagen. Although the molecular species of the collagen used in the present invention is not particularly limited, it is preferable that the type I collagen is a main component. Further, collagen may be used after appropriately modifying amino acid residues of collagen protein by acetylation, succination, maleylation, phthalation, benzoylation, esterification, amidation, guanidinolation, and the like.
  • a method for preparing collagen for example, a method of extracting from the above-mentioned starting materials (excluding the genetic recombination technique) with a neutral buffer or a dilute acid such as hydrochloric acid, acetic acid, or citric acid may be mentioned.
  • the former is called neutral salt-soluble collagen, and the latter is called acid-soluble collagen.
  • the amount of extracted collagen is small, and most remains as insoluble collagen.
  • an enzyme solubilization method and an alkali solubilization method are known.
  • the former is called enzyme-solubilized collagen, and the latter is called alkali-solubilized collagen, but both can be solubilized as molecular collagen in almost 100% yield.
  • the method for preparing collagen (extraction type) used in the present invention is not particularly limited. However, if the molecular weight is large when the collagen is solubilized, the strength of the complex becomes insufficient due to steric hindrance. It is preferable to use a monomeric (monomolecular) collagen.
  • the enzyme-solubilized collagen and the alkali-solubilized collagen have a high monomeric content, Since the non-helical portion (telopeptide) having most of the antigenicity of collagen at the floor is selectively decomposed and removed, it is suitable for the organic-inorganic composite biomaterial of the present invention.
  • the collagen from which the non-spiral portion has been decomposed and removed is called atelocollagen.
  • the isoionic point is the pH at which both the positive and negative charges originating from the dissociation group inherent in the protein molecule cancel each other out.In the case of collagen, it becomes solubilized as it approaches the pH region at the isoionic point. It is known that what has been turned into fibrosis. Generally, the isoionic point of enzyme-solubilized collagen is pH 8-9, and the iso-ionic point of alkaline solubilized collagen is pH 4-5.
  • enzyme-solubilized collagen in which fibrosis of collagen proceeds in a reaction vessel in which the pH is maintained at 7 to 11, and self-organization is easy.
  • solubilizing enzyme include, for example, pepsin, trypsin, chymotrypsin, papain, and pronase. Pepsin and pronase are preferably used because of the ease of treatment after the enzymatic reaction.
  • a complex containing a calcium salt and collagen which is a base of the composite biomaterial of the present invention
  • a method for producing a complex containing hydroxyapatite and collagen will be described.
  • Complexes containing hydroxyapatite and collagen can be prepared, for example, by the method of Kikuchi et al. (Kikuchi, S. et al, J., Biomater., 22 (13) (2001), 1705-1711, S. Itoh et al. al, J. Biomed Mater Res, (2001), 445-453).
  • the complex is produced using at least three components, collagen, phosphate, and calcium salt as starting materials. Note that strictly speaking, although it does not fall under "salt", in the present invention, the above phosphate includes phosphoric acid, and the calcium salt includes calcium hydroxide.
  • Examples of the phosphoric acid source of the aqueous phosphate solution used include ninadium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and phosphoric acid.
  • the aqueous phosphate solution dissolves the above-mentioned collagen and is used for the reaction.
  • Examples of the calcium source of the aqueous calcium salt solution used include calcium carbonate, calcium acetate, calcium hydroxide and the like.
  • the calcium salt aqueous solution may be a suspension as long as it is in a homogeneous state.
  • calcium carbonate is calcined and then crushed in a mortar or the like to obtain calcium hydroxide, and water obtained by adding water thereto is obtained.
  • a suspension of calcium oxide can be suitably used.
  • the aqueous calcium salt solution and the aqueous phosphate solution containing collagen are simultaneously dropped into a reaction vessel.
  • the term “simultaneously” does not refer only to the form of dropping exactly at the same time, but also includes the form of dropping alternately in small amounts (about 0.01 to 5 ml).
  • the two solutions may be continuously dropped as long as they are simultaneous, or may be dropped intermittently.
  • the amount of the pure water is not particularly limited, but is preferably substantially the same as the amount of the aqueous calcium salt solution used.
  • the calcium ion concentration in the reaction vessel is maintained at 3.75 ⁇ or less and the phosphate ion concentration is maintained at .25 mM or less. If the concentration of calcium ion-phosphate ion exceeds the above range, suitable self-assembly of the complex is hindered. This is because if the concentration of the ions convection in the reaction vessel exceeds their concentration in the body fluid Probably due to spontaneous nucleation. If the calcium ion concentration is maintained at 2.5 and the phosphate ion concentration is maintained at 1.5 mM or less, a composite having an average fiber length of one thigh or more can be obtained, which is more preferable.
  • the hydroxyapatite and collagen produced in the reaction vessel are present in a weight ratio of 3: 2 to 9: 1, preferably 70:30 to 85:15. This is because it is important for self-organization that the weight ratio of hydroxyapatite to collagen when the ideal reaction occurs is closer to the composition of living bone (75:25).
  • the ratio of the aqueous solution of phosphoric acid containing collagen to the aqueous solution of calcium salt is preferably in the range of 3: 1 to 1: 3. If the amount of the aqueous solution of phosphoric acid containing collagen is small, the composition becomes excessive and the strength is reduced. If the amount of the aqueous solution containing potassium salt is small, calcium deficiency occurs and Young This is because the rate may decrease and the strength may decrease (see JP-A-11-199209).
  • the pH of the reaction solution is dropped in the range of 7 to 11 and that the range of change is within 1 or less. More preferably, the pH is in the range of 7 to 9, and the range of change is within 0.5. This is because native collagen precipitates at the isoelectric point in the pH range of 7 to 11 to regenerate fibers, and calcium phosphate tends to precipitate in this pH range. This is because self-organization of calcium phosphate and collagen is promoted. If the pH exceeds 11, the water molecules are hydrated around the collagen molecules, making it difficult for the water molecules to separate in the subsequent pressure molding step, so that the water content of the complex increases and self-organization is hindered. The strength may also decrease.
  • the pH controller is provided with a means for measuring the pH of the reaction solution and a means for adjusting the amount of the two solutions to be dropped.
  • the pH controller is provided with a predetermined value (for example, pHIO). In order to maintain a certain range (for example, ⁇ 0.3), the drop amount of both solutions is adjusted based on the pH value of both solutions.
  • a predetermined value for example, pHIO
  • the pH controller is one manufactured by NISSIN. It is preferable to carry out the reaction while constantly stirring both the solution and the reaction solution so that the pH of the reaction solution is not biased.
  • the temperature of the reaction solution is preferably maintained at 35 ° C. to 4 ° C. (TC is preferable. If the temperature is within this range, it is expected that complex formation is performed under the same conditions as in vivo.
  • the precipitate formed from the reaction solution is filtered, dried, and then press-molded to obtain a composite in which hydroxyapatite and collagen are self-organized and oriented and bonded.
  • a cross-link is introduced into collagen fibers constituting the complex.
  • Crosslinking is preferably performed directly without isolating the complex from the reaction solution.
  • a small amount (1 to 100 mol% based on the amount of collagen of the complex) of collagen or polysaccharide may be added to increase the number of crosslinking points.
  • Cross-linking may be performed by any method such as chemical cross-linking using a cross-linking agent or a condensing agent, physical cross-linking using r-ray, ultraviolet light, thermal dehydration, electron beam or the like.
  • cross-linking agent examples include aldehydes such as dal aldehyde and formaldehyde. Hydrome cross-linking agents; Isocyanate cross-linking agents such as hexamethylene diisocyanate; 1-ethyl-3- (3-dimethylaminopropyl) carpoimide cross-linking agents such as carbodiimide hydrochloride; ethylene glycol getyl Polyepoxy-based cross-linking agents such as ether; The amount of these cross-linking agents is preferably about lO ⁇ mol to lOmmol with respect to collagen lg in the complex.
  • the cross-linking may be any cross-linking between collagens, but it is particularly preferable to cross-link lipoxyl groups and hydroxyl groups, lipoxyl groups and ⁇ -amino groups, and ⁇ -amino groups.
  • the use of excess bridging agent introduces cross-links between the fibers forming the composite, thereby increasing the water content of the composite, inhibiting the bonding between particles and reducing the strength of the composite. Attention is needed.
  • crosslinking method using a crosslinking agent such as datalaldehyde is particularly preferable from the viewpoint of controllability of crosslinking degree and biocompatibility of the obtained composite.
  • a cross-linking method using glutaraldehyde will be described as a preferred embodiment of the present invention.
  • reaction solution of the complex containing hydroxyapatite and collagen obtained in the preceding section is reacted immediately after synthesis of the complex, or after aging for up to 3 hours, by adding daltaraldehyde with vigorous stirring for 10 minutes. After the crosslinking reaction, the complex is immediately filtered and washed with pure water three times to remove excess glutaraldehyde.
  • Daltaraldehyde reacts with collagen lg in the composite biomaterial. Then, it is preferable to add 10 z nio l to 10 marl ol, particularly 10 mol to lm mol.
  • the temperature of the reaction solution is preferably maintained at 0 ° C to 40 ° C.
  • the crosslinked composite biomaterial thus obtained has higher mechanical strength and a lower biodegradation rate in comparison with an uncrosslinked composite biomaterial, and thus has the necessary in-vivo retention properties for artificial aggregates and the like. That is, the present invention provides a method for controlling the rate of biodegradation of a composite biomaterial in a living body while maintaining mechanical strength by introducing a bridge between hydroxyapatite and collagen.
  • the biodegradation rate can be evaluated, for example, by implanting the composite biomaterial in bones of mice, rats, and egrets, and observing the in vivo retention.
  • the mechanical strength can be evaluated, for example, by a three-point bending strength or a Young's modulus obtained from the value.
  • an organic-inorganic composite biomaterial obtained by adding 10 inol to 10 nmol of glucanaldehyde to 1 g of collagen to introduce a crosslink has a mechanical strength of 7 MPa (uncrosslinked) to 15 MPa or more. (After crosslinking). The uncrosslinked sample was absorbed in the living bone almost completely (over 90%) in 4 weeks, whereas about 50% of the crosslinked composite biomaterial remained in the living bone even after 4 weeks. .
  • the crosslinked composite biomaterial obtained by the above method can be appropriately press-molded and used as an implant such as an artificial aggregate.
  • the pressure molding is preferably performed in a temperature range of 0 ° C. or more and 110 ° C. or less and a pressure range of 10 MPa to 5 GPa. If pressure molding is performed in this temperature range, most of the water contained in the precipitate will rapidly It is because it is released to.
  • the temperature is preferably in the range of 25 ° C. or more and 60 ° C. or less where the amount of released water is large, and particularly preferably in the range of 35 ° C. or more and 45 ° C. or less.
  • the treatment while applying ultrasonic waves, because self-organization can be further promoted.
  • Examples of the pressure processing apparatus that can be used for pressure molding in the present invention include CIP manufactured by Kobe Steel.
  • the shape and shape of the composite biomaterial of the present invention are not particularly limited, and the composite biomaterial can be formed into any shape and shape such as a block shape, a paste shape, a film shape, a granular shape, a sponge shape, and the like according to the use.
  • the composite biomaterial of the present invention has elasticity like a sponge when absorbing water, and has excellent biocompatibility, osteoinductive ability or osteoconductive ability. Therefore, when the composite biomaterial is used as an implant, it may be used after being immersed once in a suitable liquid such as physiological saline.
  • the composite biomaterial implanted in this way can quickly bind to the bone tissue and integrate with the hard tissue on the donor side.
  • the composite biomaterial of the present invention may contain, in addition to the essential components calcium salt, phosphate and collagen, other components as long as the object and effects of the present invention are not impaired.
  • Such components for example St, inorganic salts such as Mg and C0 3, Kuen acids and organic phospholipid such as bone morphogenetic proteins, drugs such as anticancer agents.
  • the composite biomaterial of the present invention has a strength and a composition close to that of a living bone, and has a sustained drug release effect, or an osteoinductive or osteoconductive ability because both of its constituent components, collagen and calcium phosphate, are biosoluble. In addition, due to crosslinking, it has excellent mechanical strength and in-vivo retention (moderate in-vivo degradation rate).
  • the composite biomaterial of the present invention contains a high bioactive site force in, By using this as a substrate and performing tissue culture in a biologically similar environment or in vivo with the addition of dynamics and electricity, the effect of tissue reconstruction of bone marrow, liver, etc. is also expected.
  • tissue reconstruction of bone marrow, liver, etc. is also expected.
  • an anticancer agent for reconstruction of resected bone such as osteosarcoma
  • the composite biomaterial obtained according to the present invention may be used as a bone-replacement type bone reconstruction material having osteoinduction and osteoconductivity, tissue engineering containing amino acids, carbohydrates, and cytokines.
  • the method include the use as a bioactive base material used as a base material and a sustained-release base material for a biocompatible drug such as an anticancer agent.
  • Specific examples include artificial bones, artificial joints, bonding materials between tendons and bones, Examples include dental implant materials, percutaneous terminals for catheters, sustained drug release substrates, bone marrow induction chambers 1, tissue reconstruction chambers 1 and base materials.
  • FIG. 1 is a graph showing the relationship between the crosslinking agent concentration and the three-point bending strength of the crosslinked composite.
  • A shows the three-point bending strength of the crosslinked daryl aldehyde
  • B shows the three-point bending strength of the water-soluble carbodiimide crosslinked body
  • C shows the three-point bending strength of the transdaltaminase bridge.
  • FIG. 2 is a graph showing the cross-linking agent concentration and the degree of swelling of the cross-linked complex (normalized by the amount of collagen).
  • A indicates the degree of swelling of the cross-linked glutaraldehyde
  • B indicates the degree of swelling of the cross-linked water-soluble carbodiimide
  • C indicates the degree of swelling of the cross-linked transdaltaminase.
  • FIG. 3 is a photograph of each darthal aldehyde cross-linked complex two weeks after implantation in the tibiae of the egret.
  • numeral Dar glutaraldehyde concentration thigh ol 'g c. 1 Is shown.
  • the Hap / Col complex was prepared according to the method of Kikuci et al. (M. Kikuchi, et al., Biomater., 22 (13) (2001), 1705-171 1).
  • calcium carbonate for alkali analysis, Wako Pure Chemical
  • phosphoric acid special grade, Wako Pure Chemical
  • atelocollagen Na Gelatin
  • the pH in the reaction vessel was controlled to PH9 by a controller, and the temperature was controlled to 40 ° C by a hot water bath.
  • reaction solution was allowed to stand for 3 hours while being suspended, and a crosslinking agent: dartaldehyde was added thereto with vigorous stirring, and the reaction was allowed to proceed for 10 minutes. After the crosslinking reaction, the complex was immediately filtered and washed three times with pure water. For comparison, water-soluble carbodiimide, Cross-linking reaction is similarly carried out using -ze (condensation agent) 1.
  • the cross-linking reaction was carried out with respect to collagen lg in the complex by adding Daltaraldehyde: 0.019 to 13.5 ⁇ 01 / g, water-soluble carbodiimide: 0.0191-8.8, 01 / g, and trans-Dalminase: 19.1-1910 mg / g.
  • the test was carried out by changing the range. In the case of dal aldehyde, 0.191 nmol / g theoretically allows all ⁇ -amino groups in the collagen molecule to be crosslinked.
  • the crosslinked complex was dispersed in pure water and observed using a transmission electron microscope Rapid-VueR (manufactured by Beckman-Colter).
  • the crosslinked composite was subjected to dehydration molding by uniaxial pressing at 2 OMPa for 24 hours, and the three-point bending strength was measured using a universal testing machine (Autograph AGS-lkN, manufactured by Shimadzu). The measurement was performed using a cross-linked composite piece of 5 ⁇ 3 ⁇ 20 mm at a crosshead speed of 500 zm and a span of 15 mm.
  • the degree of swelling mainly depends on the amount of collagen. Therefore, the degree of swelling was normalized by the amount of collagen to reflect the amount of cross-linking (Figure 2). The results suggested that the degree of swelling decreased with the concentration of daltonaldehyde, and that cross-linking could control the biodegradability of the complex in living tissue.
  • the biodegradability of the cross-linked HAp / Col complex was examined by implanting the cross-linked product (2 ⁇ 2 ⁇ 2 mm) obtained in Example 1 with various concentrations of dartaldehyde in the tibiae of the egret. Evaluation was performed by performing gross findings ( Figure 3) and histological examination (hematoxylin-eosin staining) after 1, 2, and 4 weeks.
  • the absorption / decomposition rate of the HAp / Col complex cross-linked product decreases with glutaraldehyde concentration, and 70-80% remains in bone even after 4 weeks with high-density cross-linking (over 191 x mol) Was. Approximately 50% of those crosslinked with 19.1 zmol of glutaraldehyde per lg of collagen remained, and about 85% or more of those crosslinked with 675 mol remained. Furthermore, in the case of cross-linking with 1.35 mol of dal aldehyde per lg of collagen, only the surface is absorbed and more than 95% remains. Existed. The residual amount of ⁇ -amino group in each crosslinked sample was 80-95%, 0-10%, and 0%. In particular, with 1.35 mmol of glutaraldehyde, it was considered that in a cross-linking process, excessive dartal aldehydes formed a cross-linking network in the complex, further reducing the absorbency of the complex.
  • the rate of in vivo degradation is controlled while maintaining its mechanical strength.
  • a calcium salt particularly, hydroxyapatite

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Abstract

L'invention porte sur un procédé de contrôle de la vitesse de décomposition d'un biomatériau composite contenant un sel de calcium (notamment hydroxyapatite) et du collagène dans un organisme vivant, ce procédé consistant à introduire des liaisons transversales dans le collagène ; et sur un biomatériau préparé au moyen de ce procédé. Ce procédé permet d'obtenir l'absorptivité dans un organisme vivant du biomatériau composite susmentionné qui convient à un os artificiel ainsi que la rétention d'une force mécanique satisfaisante.
PCT/JP2002/008335 2002-03-11 2002-08-19 Controle de la biodegradabilite d'un biomateriau composite WO2003075971A1 (fr)

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JP2007050084A (ja) * 2005-08-17 2007-03-01 National Institute For Materials Science 骨再建材の製造方法および骨再建材ならびに骨組織誘導方法
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