WO2009119935A1 - Procédé et composition pour induire la régénération de cartilage endommagé en utilisant des microfractures et l’acide hyaluronique - Google Patents
Procédé et composition pour induire la régénération de cartilage endommagé en utilisant des microfractures et l’acide hyaluronique Download PDFInfo
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- WO2009119935A1 WO2009119935A1 PCT/KR2008/002417 KR2008002417W WO2009119935A1 WO 2009119935 A1 WO2009119935 A1 WO 2009119935A1 KR 2008002417 W KR2008002417 W KR 2008002417W WO 2009119935 A1 WO2009119935 A1 WO 2009119935A1
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- Prior art keywords
- cartilage
- hyaluronic acid
- composition
- microfracture
- damaged
- Prior art date
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- 210000000845 cartilage Anatomy 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 34
- 208000013201 Stress fracture Diseases 0.000 title claims abstract description 29
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 28
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 28
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 28
- 230000008929 regeneration Effects 0.000 title claims abstract description 25
- 238000011069 regeneration method Methods 0.000 title claims abstract description 25
- 230000001939 inductive effect Effects 0.000 title claims abstract description 20
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- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 9
- 210000001612 chondrocyte Anatomy 0.000 claims description 6
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- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
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- TYJOQICPGZGYDT-UHFFFAOYSA-N 4-methylsulfonylbenzenesulfonyl chloride Chemical compound CS(=O)(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 TYJOQICPGZGYDT-UHFFFAOYSA-N 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
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- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
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- 229960003957 dexamethasone Drugs 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 238000011587 new zealand white rabbit Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- 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
- A61L27/20—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
- A61B2017/564—Methods for bone or joint treatment
-
- 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
- A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
Definitions
- the present invention relates to a method, a composition and use thereof for inducing regeneration of damaged cartilage. Specifically, the invention relates to a method, a composition and use thereof for inducing regeneration of damaged cartilage by applying hyaluronic acid to damaged area of cartilage after microfracture formation.
- Hunziker 2002 Prakash et al. 2002. Since articular cartilage has neither vascular supply nor easy access to stem cells, repair is often unsuccessful. Partial thickness defects cannot heal spontaneously because stem cells found in the bone marrow cannot be accessed (Buckwalter 1998). Full thickness defects, however, do have access to these cells and thus can heal spontaneously (Wei et al. 1997). However, the regenerated cartilage is fibrocartilage rather than hyaline cartilage (Frisbie et al. 2003) and, being mechanically weaker than hyaline cartilage, it gradually degenerates over time (Shapiro et al. 1993).
- Microfracture used to treat articular cartilage injuries can facilitate the intrinsic healing response of stem or progenitor cells recruited by subchondral penetration to the marrow and can stimulate cartilage regeneration. Multiple drilling, arthroplasty, microfracture surgery, or the like may be used in this method. However, microfracture has been shown to result in regeneration of fibrocartilage, with inferior mechanical properties, rather than the desired hyaline cartilage. Microfracture has been failed to regenerate cartilage that maintains its functional integrity of articular cartilage.
- Cartilage transplantation has limitations. Various problems result at the area where the graft has been provided and the method cannot be used when the chondral lesion is too large. Furthermore, margins are generated between the original tissues and healed regions.
- the present inventors found that application of hyaluronic acid to the area including a microfractured site for treating damaged cartilage resulted in regeneration of hyaline-like cartilage rather than fibrocartilage by the stem or progenitor cells recruited by subchondral penetration to the marrow.
- the present invention provides a method for inducing regeneration of cartilage in a mammal comprising:
- Hyaluronic acid is a type of complex polysaccharide composed of N-acetyl glucosamine and glucuronic acid.
- the present invention provides the present method for inducing regeneration of cartilage is provided, wherein the hyaluronic acid being in a cross-linked form or the carboxyl group or alcohol group of the hyaluronic acid being chemically modified.
- the present invention provides the present method for inducing regeneration of cartilage, wherein bone marrow-derived stem cells flowing over the damaged area of cartilage as a result of the formation of microfracture(s).
- the present method for inducing regeneration of cartilage one forms one or more microfractures and confirms that bone marrow- derived stem cells flow over the damaged area of cartilage before applying biomaterial containing hyaluronic acid.
- Biomaterial' means material which is generally allowed to be implanted, injected or applied to human and whose biocompatibility is verified.
- Biomaterial may comprise pharmaceutically acceptable buffer, injection or the like including saline solution.
- the biomaterial may also comprise one or more carrier, vehicle, excipient for efficient delivery of an effective component.
- any type of biomaterial containing hyaluronic acid may be used as long as that can be applied to a damaged area of cartilage including microfracture(s).
- the biomaterial containing hyaluronic acid is gel-type.
- the method for inducing regeneration of cartilage of the present invention does not comprise transplantation of cells including chondrocytes.
- the method for inducing regeneration of cartilage of the present invention may be used in combination with other method for inducing cartilage regeneration.
- the method that can be used with the present method include any surgical or drug administering methods known in the art.
- the present invention provides a composition for applying to a mi- crofractured site for inducing regeneration of damaged cartilage comprising hyaluronic acid.
- the molecular weight of hyaluronic acid is greater than 10,000 Da.
- the present composition for applying to a microfractured site for inducing regeneration of damaged cartilage further comprises one or more inducers of chondrogenic differentiation.
- inducers of chondrogenic differentiation may be selected from the group consisting of transforming growth factor - ⁇ (TGF- ⁇ ), BMPs, IGF, Wnt proteins. More preferably, the inducer of chondrogenic differentiation is TGF- ⁇ or BMP-2.
- the present invention provides a use of hyaluronic acid for applying to a microfractured site for inducing regeneration of damaged cartilage.
- composition of the present invention may be applied to an damaged area of cartilage after microfrature formation in that area.
- Bone marrow-derived stem cells flowed over the damaged area of cartilage facilitate regeneration of hyaline-like cartilage, which is more natural, rather than fibrocartilage thereby improve remedial results.
- FIG. 1 shows photographs of rabbit knee articular cartilage defects immediately after creation (A) and after microfracture surgery (B).
- A A full-thickness cartilage defect (2.5 x 5 mm, depth 1-2 mm) was created on the patellar groove. The dotted line indicates the defect.
- B Four holes of subchondral penetration (arrows) were made in the defects.
- FIG. 2. shows photographs of rabbit knee articular cartilage defects three months after treatments.
- A Treatment with microfracture only (group A).
- B Treatment with microfracture and hyaluronic gel (group B).
- C Treatment with microfracture and Hyaluronic gel containing TGF- ⁇ (group C). The dotted lines indicate the defects.
- FIG. 3 illustrates H&E-stained histological sections of defects three months after treatments.
- A Treatment with microfracture only (group A).
- B Treatment with microfracture and HA gel (group B).
- C Treatment with microfracture and HA gel containing TGF- ⁇ (group C).
- the arrows indicate defect edge.
- the scale bars indicate 1 mm.
- FIG. 4 illustrates Alcian blue-stained histological sections of defects three months after treatments.
- A Treatment with microfracture only (group A).
- B Treatment with microfracture and HA gel (group B).
- C Treatment with microfracture and HA gel containing TGF- ⁇ (group C).
- the arrows indicate defect edge.
- the scale bars indicate 1 mm.
- Halim Animal Laboratory Co. Seoul, Korea were anesthetized with an intramuscular injection of 250 mg ketamine hydrochloride (Yuhan Co., Seoul, Korea), 35 mg xylazine hydrochloride (Bayer, Seoul, Korea), and 5 mg of acepromizine (Yuhan Co., Seoul, Korea)
- ketamine hydrochloride Yuhan Co., Seoul, Korea
- xylazine hydrochloride Bayer, Seoul, Korea
- acepromizine Yuhan Co., Seoul, Korea
- a full-thickness cartilage defect (2.5 x 5 mm, depth 1-2 mm) was created on the patellar groove by controlled drilling without violation of the subchondral bone ( Figure IA).
- Using a fine 0.03-inch Kirschner wire (Sanatmetal Co., EGER, Hungary), meticulous subchondral penetration (microfracture method) was introduced to the defects ( Figure IB).
- Four holes were made in each defect without violation of neighboring holes. The debris was completely removed and hemostasis was achieved.
- the cartilage defects in the knee joints of group A were not treated with HA(hyaluronic acid) and served as controls.
- the cartilage defects in the knee joints of group B were filled with commercially available, medical grade 4% (w/v) HA in phosphate buffered saline (50 ⁇ l/site, Hyruan plus, LG Pharmacological Co., Chunbuk, Korea).
- Example 4 histological analysis
- specimens were fixed in 10 % (v/v) buffered formalin, decalcified with decalcifying agent (Decal RapidTM, National Diagnostics, Georgia, USA), dehydrated with a series of graded alcohol, and embedded in paraffin.
- Tissue sections (4 ⁇ m thick) were stained with hematoxylin and eosin (H&E) for morphologic analysis and with alcian blue staining for glucosaminoglycan production.
- H&E hematoxylin and eosin
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Surgery (AREA)
- Biomedical Technology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Medical Informatics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Transplantation (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un procédé, une composition et l’utilisation de ceux-ci pour induire la régénération de cartilage endommagé. Spécifiquement, l’invention concerne un procédé, une composition et l’utilisation de ceux-ci pour induire la régénération de cartilage endommagé en appliquant de l’acide hyaluronique sur la zone de cartilage endommagée après formation de microfracture. Les présents procédé et composition pour induire la régénération de cartilage endommagé peuvent régénérer du cartilage de type hyalin avec une procédure chirurgicale plus simple. L’absence de toute étape de transplantation rend le présent procédé plus utile.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2008-0028065 | 2008-03-26 | ||
| KR1020080028065A KR20090102552A (ko) | 2008-03-26 | 2008-03-26 | 히알루론산을 포함하는 연골 손상 질환 치료용도의미세천공 부위 도포용 조성물 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009119935A1 true WO2009119935A1 (fr) | 2009-10-01 |
Family
ID=41114104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2008/002417 WO2009119935A1 (fr) | 2008-03-26 | 2008-04-29 | Procédé et composition pour induire la régénération de cartilage endommagé en utilisant des microfractures et l’acide hyaluronique |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20090102552A (fr) |
| WO (1) | WO2009119935A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017062493A1 (fr) * | 2015-10-05 | 2017-04-13 | Board Of Regents, The University Of Texas System | Micro-dispositif et nano-dispositif pour détection et traitement de lésions du cartilage |
| JP2017518315A (ja) * | 2014-06-06 | 2017-07-06 | ヴィヴォスクリプト，インコーポレイテッド | 軟骨損傷を修復する方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6645945B1 (en) * | 1996-03-05 | 2003-11-11 | Depuy Acromed, Inc. | Method of treating diseased, injured or abnormal cartilage with hyaluronic acid and growth factors |
| WO2005073365A1 (fr) * | 2004-01-29 | 2005-08-11 | Japan Tissue Engineering Co., Ltd. | Procédé de traitement de cellules destinées à une transplantation, suspension cellulaire, prothèse pour transplantation et procédé de traitement d’un site lésé |
| JP2008037770A (ja) * | 2006-08-02 | 2008-02-21 | Nippon Barrier Free:Kk | 抗加齢剤 |
-
2008
- 2008-03-26 KR KR1020080028065A patent/KR20090102552A/ko not_active Application Discontinuation
- 2008-04-29 WO PCT/KR2008/002417 patent/WO2009119935A1/fr active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6645945B1 (en) * | 1996-03-05 | 2003-11-11 | Depuy Acromed, Inc. | Method of treating diseased, injured or abnormal cartilage with hyaluronic acid and growth factors |
| WO2005073365A1 (fr) * | 2004-01-29 | 2005-08-11 | Japan Tissue Engineering Co., Ltd. | Procédé de traitement de cellules destinées à une transplantation, suspension cellulaire, prothèse pour transplantation et procédé de traitement d’un site lésé |
| JP2008037770A (ja) * | 2006-08-02 | 2008-02-21 | Nippon Barrier Free:Kk | 抗加齢剤 |
Non-Patent Citations (1)
| Title |
|---|
| SUN-WOONG KANG ET AL.: "Articular cartilage regeneration with microfracture and hyaluronic acid.", BIOTECHNOL LETT., 31 October 2007 (2007-10-31), pages 436 - 439 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017518315A (ja) * | 2014-06-06 | 2017-07-06 | ヴィヴォスクリプト，インコーポレイテッド | 軟骨損傷を修復する方法 |
| EP3151848A4 (fr) * | 2014-06-06 | 2018-01-24 | Vivoscript, Inc. | Méthode de réparation de lésion cartilagineuse |
| WO2017062493A1 (fr) * | 2015-10-05 | 2017-04-13 | Board Of Regents, The University Of Texas System | Micro-dispositif et nano-dispositif pour détection et traitement de lésions du cartilage |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20090102552A (ko) | 2009-09-30 |
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