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WO2014126326A1 - Echafaudage de gel comprenant des peptides bioactifs auto-assemblés et son procédé de préparation - Google Patents

Echafaudage de gel comprenant des peptides bioactifs auto-assemblés et son procédé de préparation Download PDF

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Publication number
WO2014126326A1
WO2014126326A1 PCT/KR2013/010210 KR2013010210W WO2014126326A1 WO 2014126326 A1 WO2014126326 A1 WO 2014126326A1 KR 2013010210 W KR2013010210 W KR 2013010210W WO 2014126326 A1 WO2014126326 A1 WO 2014126326A1
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Prior art keywords
support
gel
seq
self
substituted
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Ceased
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English (en)
Korean (ko)
Inventor
정종평
박윤정
이주연
김정민
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Nano Intelligent Biomedical Engineering Corp Co Ltd
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Nano Intelligent Biomedical Engineering Corp Co Ltd
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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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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

Definitions

  • the present invention relates to a support in the form of a gel self-associated with a physiologically active peptide, and more particularly, to a support in the form of a gel capable of differentiating mesoderm-derived stem cells into bone tissue and self-association with the physiologically active peptide. It's about how
  • Tissue engineering is a treatment that can regenerate or replace damaged tissue when a tissue or organ is damaged by a disease or accident.
  • cells or stem cells constituting damaged tissue are transplanted into a porous polymer support having a three-dimensional structure, and then cultured in a bioreactor for a certain period of time, and then surgically implanted into the damaged area.
  • the polymer support used here uses proteins, ceramics and medical synthetic polymers that make up the extracellular matrix.
  • tissue growth factors eg, bone morphogenic proteins
  • tissue regeneration ability e.g., tissue growth factor 1
  • the molecular weight is several tens of Kda
  • the activity is likely to be lost unless the tertiary structure is maintained.
  • the activity is reduced by proteolytic enzymes in the body, there is a possibility of causing an immune response.
  • a technology has been developed that can form cells in a gel or porous nanofiber structure by self-association of a hydrophilic physiologically active peptide and a hydrophobic carbon chain to cultivate cells (Korea Patent No. 10-A). 0630903).
  • the support by the self-association has a structure that mimics the characteristics of the extracellular matrix.
  • Hydrophilic bioactive peptides can increase the adhesion and differentiation of cells or can significantly increase the therapeutic effect by using peptides specific for specific tissue regeneration.
  • the hydrophilic and hydrophobic moieties must first be synthesized with chemically bonded substances, and the composites must be applied to the aqueous solution above the critical micelle concentration to cause self-association.
  • the present inventors do not need to introduce a hydrophobic carbon chain into the physiologically active peptide, and find a peptide to form a support by self-association by controlling the arrangement of hydrophilic or hydrophobic amino acids constituting the physiologically active peptide.
  • Peptides were self-assembled to prepare a support in the form of a gel, seeding the mesoderm-derived stem cells on the prepared support, and culturing without a growth factor, and confirming that the mesoderm-derived stem cells were differentiated into bone tissue. The invention has been completed.
  • Another object of the present invention is to provide a support in the form of a gel capable of differentiating mesoderm-derived stem cells into bone tissue by self-association of physiologically active peptides.
  • Still another object of the present invention is to provide a method of preparing a support in the form of a gel capable of differentiating mesoderm-derived stem cells into bone tissue by self-association of a physiologically active peptide.
  • the present invention provides a bioactive peptide in which at least one of R and K, S and P are each substituted with A in the amino acid sequence of SEQ ID NO: 1.
  • the present invention also provides a bioactive peptide in which at least one of K and S are each substituted with A, and at least one of R is substituted with F in the amino acid sequence of SEQ ID NO: 1.
  • the present invention also provides a physiologically active peptide in which at least one of R is substituted with F in the amino acid sequence of SEQ ID NO: 1 and P and I are each substituted with A.
  • the present invention also provides a support in the form of a gel, characterized in that the bioactive peptide is self-associated.
  • the present invention also provides a method for preparing a gel-type support, characterized in that the bioactive peptide forming the support by self-assembly is dissolved in a solvent and then left at room temperature.
  • the present invention also provides a support in the form of a nano-shaped gel prepared by the above method and having a viscosity of 1000 cps to 3000 cps and a diameter of 20 nm to 60 nm.
  • 1 is a support in the form of a gel formed by self-association.
  • Example 2 is a microstructure of the support in the form of a gel with a differential scanning electron microscope (SEM), (a) is a gel form of the support prepared in Example 2, (b) is a gel form prepared in Example 3 The support of and (c) corresponds to the support of the gel form prepared in Example 4.
  • SEM differential scanning electron microscope
  • Figure 3 is cultured in mesenchymal stem cells (Mesenchymal stem cells) in a gel-like support after differentiation into bone tissue, the degree of calcium deposition was observed with a confocal microscope (a) is the untreated group ( no treatment, NT), (b) poly glutamic acid, (c) the support prepared in Example 2, (d) the support prepared in Example 3 and (e) the support prepared in Example 4 Intracellular calcium deposition (green: calcium, blue: nucleus, red: actin) is shown.
  • a is the untreated group ( no treatment, NT)
  • poly glutamic acid poly glutamic acid
  • Intracellular calcium deposition green: calcium, blue: nucleus, red: actin
  • Figure 4 is a support implant implanted in the skull defect of the rabbit, and after 4 weeks the degree of bone regeneration was observed under an optical microscope, (a) and (d) is the untreated group (no treatment, NT), (b) and (e) ) Is a poly glutamic acid and (c) and (f) is a group transplanted with the support prepared in Example 2, tissue photograph 4 weeks after transplantation (OB: old bone, NB: new bone, arrow: bone margin, CT: connective tissue). (a), (b) and (c) are the results of observation at 20 magnification, (d), (e) and (f) at 100 magnification.
  • a gel-like support that can differentiate the mesoderm-derived stem cells into bone tissue, characterized in that the bioactive peptide having bone differentiation ability to self-associate.
  • bioactive peptides 1 to 3 were prepared by modifying a part of the amino acid sequence GLRSKSKKFRRPDIQYPDA (SEQ ID NO: 1) of the protein constituting the extracellular matrix.
  • Bioactive Peptide 1 GLAAKAAFARADIQYADA (SEQ ID NO: 2)
  • Bioactive Peptide 2 GLRSKSKKFFRADAQYADA (SEQ ID NO: 3)
  • Bioactive Peptide 3 GLRAKAKAKFFRPDIQFPDA (SEQ ID NO: 4)
  • Protein constituting the extracellular matrix in the present invention is a peptide derived from human osteopontin disclosed in the Republic of Korea Patent No. 10-0739528, and has a feature that can be changed to a gel form by self-combination have. In addition, it may be used a bone-forming protein-derived peptide disclosed in Republic of Korea Patent No. 10-0757241.
  • the hydrophilic and hydrophobic amino acids are maintained in a repeating pattern to form a self-association
  • the P of the existing peptide is replaced with A to remove the bending structure to facilitate the self-association reaction.
  • the present invention relates to a bioactive peptide wherein at least one of R and at least one of K, S and P are each substituted with A in the amino acid sequence of SEQ ID NO: 1.
  • the physiologically active peptides may be represented by the amino acid sequence of SEQ ID NO: 2.
  • the N-terminal portion causes the hydrophilic and hydrophobic amino acids to be repeated, and the C-terminal portion He added a sequence of positive and negative charges to the side branches to facilitate the self-association reaction.
  • the present invention relates to a bioactive peptide in which at least one of K and S are each substituted with A, and at least one of R is substituted with F in the amino acid sequence of SEQ ID NO: 1.
  • the bioactive peptide may be represented by the amino acid sequence of SEQ ID NO: 3.
  • the N-terminal part is repeatedly inserted into a sequence consisting of a positive charge and a negative charge, and the C-terminal part.
  • P By replacing P with A to remove the folding structure and repeating the sequence consisting of a positive charge and a negative charge again, the self-association reaction was facilitated.
  • the present invention relates to a bioactive peptide in which at least one of R is substituted with F in the amino acid sequence of SEQ ID NO: 1, and P and I are each substituted with A.
  • the bioactive peptide may be represented by the amino acid sequence of SEQ ID NO: 4.
  • the self-association reaction by pi bond can occur.
  • bioactive peptides 1 to 3 of SEQ ID NOS: 2 to 4 do not need a hydrophobic carbon chain, do not need to add any chemical components, and self-association may occur due to the arrangement of hydrophilic and hydrophobic amino acids.
  • Gel support formed by self-association can be used for cell culture for tissue engineering, and since the support itself can differentiate mesoderm derived stem cells into bone tissue, it is not necessary to add additional tissue growth factor.
  • bioactive peptides 1 to 3 represented by SEQ ID NOS: 2 to 4 were dissolved in a solvent, and left to prepare a support in the form of a gel.
  • the solvent may be purified water, cell culture medium, phosphate buffer (phosphate buffer, pH 7.4), and organic solvents such as methanol, ethanol, and acetonitrile may be used, but it is preferable to use purified water.
  • phosphate buffer phosphate buffer, pH 7.4
  • organic solvents such as methanol, ethanol, and acetonitrile may be used, but it is preferable to use purified water.
  • the viscosity of the support in the form of a gel can be adjusted by the content of the peptide, the peptide is preferably dissolved in 50mg to 100mg per 1ml solvent. If the bioactive peptide is dissolved at less than 50 mg / ml, the gel is not formed, and if it exceeds 100 mg / ml, there is a disadvantage in that the fluidity of the gel is high due to its high viscosity.
  • a support in the form of a gel it is preferable to dissolve the physiologically active peptide in a solvent and then leave it at room temperature for 5 to 15 minutes. If it is left for less than 5 minutes, the gel is not formed, if it exceeds 15 minutes, there is a disadvantage that the fluidity of the gel is high due to the high viscosity. Therefore, More preferably, it can be left for 10 minutes at room temperature.
  • the present invention relates to a method for preparing a gel-type support, characterized in that the bioactive peptide forming the support by self-assembly is dissolved in a solvent and then left at room temperature. will be.
  • the microstructure of the support in the gel form was observed. As a result, it was found that the diameter is 20mm to 60mm and is in the form of nanofibers. In addition, it was confirmed that the structure can support the stem cells.
  • the bioactive peptide was dissolved in 50 mg to 100 mg per 1 ml of solvent to obtain a gel form support having a viscosity of 1000 cps to 3000 cps.
  • the support of the gel form has the ability to promote bone tissue differentiation of stem cells.
  • the sample was taken by implanting and suturing the support of the gel form was observed with an optical microscope .
  • the support in the form of a gel containing a physiologically active peptide differentiated mesoderm-derived stem cells into bone tissue was confirmed that there is a bone regeneration effect in vivo.
  • Gel-type scaffolds composed of the bioactive peptides of the present invention can be used alone or transplanted by culturing cells. In addition, it can be applied to the surface of a variety of medical devices, such as implants, or can be used in combination with the particulate bone graft material, the particulate bone graft material is a bio-derived bone mineral powder and its porous block, the synthetic apatite powder and its porous block , Tricalcium phosphate powder and its porous block, monocalcium phosphate powder and its porous block, bone grafting material containing silicon dioxide (silica) as a main ingredient, bone filler graft material containing a mixture of silica and polymer, chitosan, biocompatibility And particulates based on the polymer and titanium.
  • the particulate bone graft material is a bio-derived bone mineral powder and its porous block, the synthetic apatite powder and its porous block , Tricalcium phosphate powder and its porous block, mono
  • the gel-type support consisting of a bioactive peptide and 0.1g to 1.0g bone graft material.
  • the bioactive peptide per 1.0 g of bone graft material is preferably contained 40mg / ml to 400mg / ml.
  • the present invention relates to a support prepared in the form of a nano-shaped gel prepared by the above method, having a viscosity of 1000 cps to 3000 cps and a diameter of 20 nm to 60 nm.
  • a physiologically active peptide a peptide derived from human osteopontin, which is a protein constituting the extracellular matrix represented by SEQ ID NO: 1, is modified as shown in Table 1, and the physiology represented by SEQ ID NOs: 2 to 4 Active peptides 1-3 were prepared.
  • the biologically active peptides 1 to 3 represented by SEQ ID NOS: 2 to 4 were synthesized by F-moc solid-phase chemical synthesis in order from the C terminus of the human osteopontin protein constituting the extracellular matrix. It was synthesized using Rink resin (0.075 mmol / g, 100-200 mesh, 1% DVB crosslinking) combined with Fmoc- (9-Fluorenylmethoxycarbonyl) as a blocking group, and 50mg of Rink resin was added to the synthesizer. After swelling the resin with DMF, 20% piperidine / DMF solution was used to remove the Fmoc-group.
  • 0.5 M amino acid solution (solvent: DMF), 1.0 M DIPEA (solvent: DMF & NMP), and 0.5 M HBTU (solvent: DMF) were added in 5, 10, and 5 equivalents, respectively, for 1 to 2 hours under a nitrogen stream. Each time the deprotection and coupling steps were completed, washing was performed twice with DMF and NMP. After coupling the last amino acid (coupling), deprotection (deprotection) to remove the Fmoc-group.
  • the synthesized peptide sequence was cleaved from the resin, washed, lyophilized and separated and purified by liquid chromatography. Purity and molecular weight of the purified peptide were confirmed in Table 2, and the mobile phase gradient conditions of the analytical HPLC are shown in Table 3.
  • Analysis wavelength Analysis wavelength: 214 nm
  • Example 1 the purified biologically active peptide 1 of SEQ ID NO: 2 was dissolved in purified water at a concentration of 10, 20, 50 mg / ml, and when left at room temperature, it was observed to change into a gel form. After about 8-10 minutes a support in the form of a gel was formed (FIG. 1).
  • the biologically active peptide 2 of SEQ ID NO: 3 purified in the Example was dissolved in purified water at a concentration of 50 mg / ml, and then left at room temperature for 10 minutes to obtain a gel-like support.
  • the biologically active peptide 3 of SEQ ID NO: 4 purified in the Example was dissolved in purified water at a concentration of 50 mg / ml, and then left at room temperature for 10 minutes to obtain a gel-like support.
  • the microstructure of the gel-shaped support prepared in Examples 2 to 4 was observed using a scanning electron microscope (SEM).
  • SEM scanning electron microscope
  • Gel support was treated with 2.5% glutaraldehyde for 3 hours, post-fixed in 1% osmium tetroxide and then with 70%, 80%, 90%, 95% and 100% alcohol. Dehydration was made to the specimen of the microscope.
  • the gel-formed support prepared in Example 2 (a), the gel-formed support prepared in Example 3 (b) and Example 4 Gel support prepared in the (c) all composed of nanofibers, the diameter of the nanofibers was observed to be 25-50nm. It is about the diameter of 20-30 collagen molecules that make up the extracellular matrix.
  • the supports of Examples 2 to 4 can provide an environment similar to the extracellular matrix to provide suitable conditions for cell culture.
  • mesenchymal stem cells (Lonza) were seeded on the gel-like support prepared in Example 2, and 14 in hard tissue-forming medium containing calcein (calcein, sigma, calcium staining). Incubated for days. The cultured mesoderm derived stem cells were fixed with 2% glutaraldehyde solution. The immobilized cells were treated with 1% triton X-100, followed by nuclei with DAPI (Sigma), and cytoplasmic actin with Rhodamine phalloidin (Molecular Probe, red). Stained. Calcium (green) deposited on the extracellular matrix was observed with a Confocal Laser Scanning Microscope (FIG. 3).
  • negative control is incubation of cells in 24 wells.
  • the control group is a peptide consisting of poly glutamic acid and has no activity on cells.
  • (a) is an untreated group (no treatment, NT)
  • (b) is a poly glutamic acid
  • (c) a support prepared in Example 2
  • (d) a support prepared in Example 3
  • ( e) shows the degree of calcium deposition in the cells by the support prepared in Example 4.
  • the support prepared in Example 2 (c) As shown in Figure 3, compared to the untreated group (a) and poly glutamic acid (b), the support prepared in Example 2 (c), the support prepared in Example 3 (d) and prepared in Example 4 More calcium fluorescence appeared in the support (e).
  • it was found that the supports of Examples 2 to 4 promote differentiation into bone tissue of mesenchymal derived stem cells.
  • a 8 mm diameter defect was formed in the skull of a New Zealand white rabbit (former name: cuniculus), 0.2 mL of the support prepared in Example 2 was implanted, and the periosteum and the skin were double-sealed. Animals were sacrificed 4 weeks after transplantation, and the collected samples were fixed in formalin solution and embedded in tissue to prepare specimens having a thickness of 20 ⁇ m. The prepared specimens were stained with basic fuchsin and toluidine blue to prepare non-limeous specimens. The prepared specimens were observed with an optical microscope.
  • a bioactive peptide is synthesized, a gel-like support is prepared by self-association, and the mesoderm-derived stem cells are transplanted into the support to differentiate into bone tissue and transplant into bone defects of animals, thereby regenerating bone.
  • the support of the mesenchymal-derived stem cells increased the differentiation into bone tissue, it was confirmed that the bone regeneration effect in vivo.
  • the support according to the present invention can be applied to the surface of various medical devices, such as implants, and can be applied by mixing with the bone graft material, so that not only in the dental area but also in the bone tissue repair, orthopedic and plastic surgery areas of tumor patients Increasing the therapeutic effect of medical devices has the effect of maximizing tissue regeneration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne un échafaudage de gel dans lequel des peptides bioactifs sont auto-assemblés et son procédé de préparation, et plus spécifiquement, un échafaudage en forme de gel dans lequel des peptides bioactifs sont auto-assemblés, ce qui permet la différenciation de cellules souches mésenchymateuses dans un tissu osseux. L'invention concerne également un procédé de préparation. L'échafaudage selon la présente invention peut être appliqué sur la surface de divers dispositifs médicaux, tels qu'un implant et analogue(s), et peut être mélangé avec un matériau de greffe osseuse particulaire devant y être appliqué. Il peut ainsi maximiser la régénération tissulaire en augmentant l'effet du traitement des dispositifs médicaux classiques dans les domaines de l'odontologie, la régénération du tissu osseux chez un patient atteint d'une tumeur, la chirurgie orthopédique et la chirurgie plastique.
PCT/KR2013/010210 2013-02-14 2013-11-12 Echafaudage de gel comprenant des peptides bioactifs auto-assemblés et son procédé de préparation Ceased WO2014126326A1 (fr)

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KR10-2013-0015954 2013-02-14
KR1020130015954A KR101501436B1 (ko) 2013-02-14 2013-02-14 생리활성 펩타이드가 자기회합된 젤 형태의 지지체 및 그 제조방법

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062969A2 (fr) * 2001-02-06 2002-08-15 Massachusetts Institute Of Technology Reprogrammation cellulaire dans un hydrogel peptidique et ses applications
KR20090107199A (ko) * 2008-04-08 2009-10-13 대한민국(관리부서:농촌진흥청장) 마늘에서 유래된 ｓｓｒ 프라이머 및 이의 용도
KR20100021567A (ko) * 2007-04-17 2010-02-25 제임스 훌밧 개선된 용해도를 갖는 신규한 펩티드 양친매성 물질 및 그의 이용방법
WO2011131671A1 (fr) * 2010-04-19 2011-10-27 Universita' Degli Studi Di Milano Bicocca Nouveaux peptides auto-assembleurs et leur utilisation dans la formation d'hydrogels

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KR100894265B1 (ko) * 2007-06-05 2009-04-21 재단법인서울대학교산학협력재단 골형성 촉진 펩타이드를 함유하는 주입형 골재생재

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WO2002062969A2 (fr) * 2001-02-06 2002-08-15 Massachusetts Institute Of Technology Reprogrammation cellulaire dans un hydrogel peptidique et ses applications
KR20100021567A (ko) * 2007-04-17 2010-02-25 제임스 훌밧 개선된 용해도를 갖는 신규한 펩티드 양친매성 물질 및 그의 이용방법
KR20090107199A (ko) * 2008-04-08 2009-10-13 대한민국(관리부서:농촌진흥청장) 마늘에서 유래된 ｓｓｒ 프라이머 및 이의 용도
WO2011131671A1 (fr) * 2010-04-19 2011-10-27 Universita' Degli Studi Di Milano Bicocca Nouveaux peptides auto-assembleurs et leur utilisation dans la formation d'hydrogels

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Title
ZHANG, S. ET AL.: "Designer self-assembling peptide nanofiber scaffolds for 3D tissue cell cultures", SEMIN. CANCER BIOL., vol. 15, no. 5, October 2005 (2005-10-01), pages 413 - 420 *

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KR20140102514A (ko) 2014-08-22

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