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Regulation of biodegradability of composite biomaterials

外国特許コード F110005189
整理番号 A122-35US
掲載日 2011年8月25日
出願国 アメリカ合衆国
出願番号 93773204
公報番号 20050042252
公報番号 7229971
出願日 平成14年12月11日(2002.12.11)
公報発行日 平成17年2月24日(2005.2.24)
公報発行日 平成19年6月12日(2007.6.12)
国際出願番号 JP2002012971
国際公開番号 WO2003094984
国際出願日 平成14年12月11日(2002.12.11)
国際公開日 平成15年11月20日(2003.11.20)
優先権データ
  • 特願2002-065831 (2002.3.11) JP
  • 特願2002-138989 (2002.5.14) JP
  • 2002JP008335 (2002.8.19) WO
  • 2002JP012971 (2002.12.11) WO
発明の名称 (英語) Regulation of biodegradability of composite biomaterials
発明の概要(英語) This invention relates to a method for regulating the biodegradability of composite biomaterials comprising calcium salt (particularly hydroxyapatite) and collagen, improved composite biomaterials obtained via such method, and a method for increasing bone mass with the use of such composite biomaterials.
従来技術、競合技術の概要(英語) BACKGROUND ART
In the field of orthopedics, bone defects used to be often reconstructed by transplanting a patient's own tissues in the past.
Use of a patient's own tissues, however, imposes a heavy burden on a patient, and supply source are limited.
Accordingly, it is necessary to reconstruct bone defects with artificial implants.
Such artificial implants are required to have bioadaptability and bone conductivity in addition to mechanical properties similar to those of natural bones.
That is, artificial implants need to be gradually absorbed after implantation in the body, involved into the bone regeneration cycle, and then substituted for the bones of the patient.
Bones of vertebrates are originally composed of an inorganic substance (hydroxyapatite (HAp)) and an organic substance (mainly collagen).
They form a specific nanocomposite structure in natural bones characterized in that the c-axis of HAp is oriented along collagen fibers (self-organization), and this structure imparts bone-specific mechanical properties.
Specifically, a simple combination of HAp and collagen cannot provide structures or properties similar to those of natural bones.
A variety of studies have been conducted in order to develop composite biomaterials that are more similar to natural bones with the use of HAp and collagen.
For example, Mehlisch et al. synthesized a mixture of HAp particles with collagen (Mehlisch, A. S. et al., Oral Surg Oral Med Oral Pathol, 70 (6), 1990, pp. 685-692), and Miyamoto et al. prepared collagen that had been reinforced with a HAp cement and evaluated its bioaffinity (Y.
Miyamoto et al., Biomaterials, 19, 1998, pp. 707-715).
Also, TenHuisen et al. employed calcium hydrogen phosphate as a precursor of HAp to allow a HAp crystal to grow on a collagen (Col) fiber to produce an HAp/Col nanocomposite (K. S. TenHuisen et al., J. Biomed Mater Res, 29 (7), 1995, pp. 803-810).
None of these techniques, however, were able to reproduce nanocomposite structures similar to those of natural bones.
The present inventors had successfully synthesized an HAp/Col composite having a nanocomposite structure similar to that of natural bones under biomimetic conditions (which is similar to the in vivo environment where osteogenesis takes place) with the utilization of HAp and Col self-organization (e.g., JP Patent Publication (Kokai) Nos. 7-101708 A (1995), 11-199209 A (1999), and 2000-5298 A).
This composite was found to have excellent bioaffinity, to be absorbed by osteoclasts, and to accelerate osteogenesis.
This composite was, however, disadvantageously absorbed and degraded immediately after implantation and thus was less useful for artificial bone materials and the like.
Osteoporosis refers to a clinical condition resulting from bone loss caused by an amount of bone absorption exceeding the amount of bone formation during the process of bone remodeling in which old bones are replaced with new bones.
In the past, a major treatment for osteoporosis used to be the use of medicines for internal application.
This was aimed at inhibiting bone absorption and accelerating bone formation.
At present, the most common treatment is the combined use of a hormone preparation (estrogen), a calcium preparation, vitamin D, a derivative thereof, or the like to improve the systemic bone metabolism with.
In this treatment, however, the dose of an agent is limited in view of side effects.
Accordingly, significant effects cannot be attained within a short period of time.
Such agent has the effect of preventing the bone trabeculae that have been thinned due to osteoporosis from being further absorbed, and also has the effect of thickening the thinned bone trabeculae to some extent.
However, it cannot newly form bone where bone trabeculae have been absorbed and lost.
Bone morphogenic proteins (BMP), which are currently in the experimental phase, are said to be capable of actively forming bone.
They, however, have problems in that they are expensive, continuous effects cannot be attained therefrom due to the absence of an ideal carrier, and frequent administration thereof is necessary.
A treatment for osteoporosis in which materials for topical application, such as biological implants, are used has not substantially been carried out in the past.
In fact, many of the existing bone filler materials are non-absorbable by the body, and thus effective bone formation cannot be expected.
For example, a commercially available bone filler material, i.e., a sintered apatite, does not have bioabsorbability.
If the granules thereof are used to fill in defective bones, therefore, they are considered to permanently remain in the body without being replaced by bone.
If a material for biological implantation having an excellent effect of bone mass increase were to be developed, such material would be very useful as a material for topically increasing bone mass at a desired site, such as a femur at risk of fracture of an osteoporosis patient who cannot be systemically treated with the use of an existing agent.

特許請求の範囲(英語) [claim1]
1. A method for regulating the biodegradation rate of a composite biomaterial comprising hydroxyapatite and collagen by introducing crosslinking to collagen in said composite biomaterial, wherein the composite biomaterial has a microstructure in which the c-axis of hydroxyapatite is oriented along the collagen fibers.
[claim2]
2. The method according to claim 1, wherein the crosslinking is introduced in at least 1% of reactive functional groups in collagen.
[claim3]
3. The method according to claim 1, wherein the crosslinking is introduced by a reaction utilizing glutaraldehyde.
[claim4]
4. The method according to claim 3, wherein 10 mu mol to 10 mmol of the glutaraldehyde is used per g of collagen in said composite biomaterial.
[claim5]
5. The method according to claim 1, wherein the crosslinking is introduced by using one or more crosslinking agent(s) selected from the group consisting of aldehyde crosslinking agents, isocyanate crosslinking agents, carbodiimide crosslinking agents, polyepoxy crosslinking agents, and transglutaminase.
[claim6]
6. The method according to claim 5, wherein the one or more crosslinking agent(s) is selected from the group consisting of glutaraldehyde, formaldehyde, hexamethylene diisocyanate, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, ethylene glycol diglycidyl ether, and transglutaminase.
[claim7]
7. The method according to claim 1, wherein the crosslinking is introduced in at least 5% of reactive functional groups in collagen.
[claim8]
8. The method according to claim 1, wherein 50% or more of the crosslinked composite biomaterial remains after 4 weeks in a natural bone.
[claim9]
9. A method for preparing a composite biomaterial by introducing crosslinking to collagen in said composite biomaterial, wherein the composite biomaterial comprises hydroxyapatite and collagen and has a microstructure in which the c-axis of hydroxyapatite is oriented along the collagen fibers.
[claim10]
10. The method according to claim 9, wherein the crosslinking is introduced in at least 1% of reactive functional groups in collagen.
[claim11]
11. The method according to claim 9, wherein the crosslinking is introduced in at least 5% of reactive functional groups in collagen.
[claim12]
12. The method according to claim 9, wherein the crosslinking is introduced by using one or more crosslinking agent(s) selected from the group consisting of aldehyde crosslinking agents, isocyanate crosslinking agents, carbodiimide crosslinking agents, polyepoxy crosslinking agents, and transglutaminase.
[claim13]
13. The method according to claim 12, wherein the one or more crosslinking agent(s) is selected from the group consisting of glutaraldehyde, formaldehyde, hexamethylene diisocyanate, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, ethylene glycol diglycidyl ether, and transglutaminase.
[claim14]
14. The method according to claim 9, wherein the crosslinking is introduced by a reaction utilizing glutaraldehyde.
[claim15]
15. The method according to claim 14, wherein 10 mu mol to 10 mmol of the glutaraldehyde is used per g of collagen in said composite biomaterial.
[claim16]
16. The method according to claim 9, wherein 50% or more of the crosslinked composite biomaterial remains after 4 weeks in a natural bone.
  • 発明者/出願人(英語)
  • TANAKA JUNZO
  • KIKUCHI MASANORI
  • ITO NORIICHI
  • MANDAI YOSHINOBU
  • MATSUMOTO HIROKO
  • KOYAMA YOSHIHISA
  • TAKAKUDA KAZUO
  • NITTA GELATIN
  • NATIONAL INSTITUTE FOR MATERIALS SCIENCE
国際特許分類(IPC)
米国特許分類/主・副
  • 514/16.7
  • 424/422
  • 514/17.2
  • 530/356
参考情報 (研究プロジェクト等) CREST Creation and Functions of New Molecules and Molecular Assemblies AREA
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