JP2005518409A - 心筋および末梢血管新生を促進する組成物および方法 - Google Patents
心筋および末梢血管新生を促進する組成物および方法 Download PDFInfo
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Abstract
Description
近年、1型フィブロネクチンモジュールの成分であるイソロイシン−グリシン−アスパラギン酸(Ile−Gly−AspすなわちIGD)トリペプチド配列が、皮膚繊維芽細胞の細胞遊走を誘導できることが報告されている(ショーら(非特許文献3)。以前は、生物活性はフィブロネクチン中の保存されたIGD配列だとされてはいなかったが、以前の研究は、細胞外フィブロネクチンマトリクスの集合体中の9番目の1型反復が、IGDS配列を含むことを示唆していた(非特許文献4)。特許文献3(ショーら/ダンディー大学(Schor et al./University of Dundee))では、IGDを含むある種のペプチドが記載され、そのIGDSペプチドは、ラット創傷治癒モデルにおいてある条件下で繊維芽細胞遊走および血管数を増加させることが示された。
ZZIGDZZ (式1)
式中、Iはイソロイシンを表し、Gはグリシンを表し、Dはアスパラギン酸を表し、Zは20種の生物学的アミノ酸のうち任意のものを表す。配列番号1〜4のペプチド、およびその他の代表的なIGDペプチドは、ヒト上皮細胞、ヒト繊維芽細胞およびヒツジ核細胞(nucleus cells)を含むさまざまな細胞型において遊走を誘導する能力による評価では、驚くほど優れた生物活性を示すことが見出されている。
配列番号1〜6に特定されたIGDペプチドの滅菌製剤は、ペプチドをペプチド合成装置で合成し、結果として得られる溶液を0.22ミクロンフィルターを用いて濾過滅菌して調製することができる。ペプチドは濾過滅菌後に凍結乾燥することができ、これと共に同時に出願された、全体が参照によって開示に含まれる「ポリペプチド増殖因子のためのポビドン含有担体」(POVIDONE−CONTAINING CARRIERS FOR POLYPEPTIDE GROWTH FACTORS)と題する同時係属の特許文献4に記載の通り、1%ポリビニルピロリジノン水溶液または他のポビドン化合物中で再構成することができる。あるいは、希HCl(10mmol)といった別の既知の担体を使用することができる。ポビドンは細胞毒性がないため、in vitro 分析を実施する際の担体として好ましい。
本発明に記載のIGDモチーフペプチドがヒト内皮細胞および平滑筋細胞の細胞遊走を促進する能力を、その遊走は血管新生に特徴的な過程であるが、配列番号1および2のペプチド、およびDIG配列で特徴づけられるIGDペプチドのスクランブルについて細胞遊走分析を実施することによって評価した。GGDIGGG配列によって特徴づけられる、そのスクランブルの末端に結合させたものもまた試験した。
本発明に記載のIGDモチーフペプチドの、ヒト大動脈上皮細胞の細胞遊走を促進する能力を、配列番号1および2のペプチド、DIGスクランブルペプチド、およびスクランブルの末端結合付きであるGGDIGGGについてin vitro細胞増殖分析を実施することによって評価した。〜95%密集状態まで増殖したヒト大動脈上皮細胞を増殖培地に播種し(5000細胞/ウェル)、4時間で細胞を接着させた。細胞をその後、実施例1で記載した飢餓培地に移し、約18時間飢餓状態にした。細胞を次いで被験ペプチドを含む飢餓培地に移し、細胞をさらに48時間増殖させた。培地をその後除去し、ウェルをPBSで洗浄した。細胞を次いで1回の凍結乾燥サイクルに供した。サイクォント(CyQuant)(商標)試薬(モレキュラー・プローブズ(Molecular Probes)、オレゴン州ユージーン)をその後細胞に取扱説明書に従って加え、細胞を暗所で5分間インキュベートした。色の強度−細胞の数と直接比例する−を励起波長485nm、検出波長を535nmに合わせて測定する。
IGDモチーフペプチドがin vitroウズラ漿尿膜(CAM)モデル中の内皮細胞および平滑筋細胞の細胞遊走および増殖を誘導するする活性を、その開示が引用によって援用される、パーソンズ−ウィンガーサーら(非特許文献5)によって記載されたのと同様の方法で分析した。要約すると、ニホンウズラの受精卵(coturnix coturnix japonica)を培養3日後にシャーレに開けた。培養7日後、それぞれ37℃に予温した1%ポリビニルピロリジンに溶解した、実施例1および2で試験した4種類のIGDモチーフペプチド(IGD、GGIGD、DIG、GGDIGGG)を、別々のシャーレ内のCAMの表面上に均一に撒いた。培養24時間後、CAMを固定し、切開して、終末期血管を含む樹状の動脈が見えるように倍率10倍で撮影した。3連のCAM標本のデジタル像を倍率10倍でグレースケール、白黒に二値化、およびスケルトン化して得た。血管分岐パターンを、フラクタル次元によって分析し定量した。
Claims (19)
- GGIGDGG[配列番号4]の配列を有する単離ペプチド。
- IGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチド、ならびに前記少なくとも1つのペプチド以外の少なくとも1つの血管新生増殖因子を含む血管新生組成物。
- 前記少なくとも1つの血管新生増殖因子が、骨由来血管新生タンパク質(BDAPs)、血管内皮細胞増殖因子(VEGF)、塩基性繊維芽細胞増殖因子(bFGF)、アンジオゲニン、内皮増殖因子(EGF)、血小板由来増殖因子(PDGF)、形質転換増殖因子α(TGF−α)、形質転換増殖因子β(TGF−β)および腫瘍壊死因子α(TNF−α)より成る群から選択されることを特徴とする請求項2記載の血管新生組成物。
- IGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つの細胞遊走刺激ペプチドペプチド、ならびに少なくとも1つの組み換え血管新生増殖因子を含む血管新生組成物。
- 細胞増殖促進条件下で細胞遊走および/または血管新生を促進する活性を有する組成物であって、IGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチド、ならびにマトリクス材料を含む組成物。
- 医薬として受容可能な担体を含むことを特徴とする請求項5記載の組成物。
- 滅菌されていることを特徴とする請求項6記載の組成物。
- 治療を必要とする個体の心臓の虚血領域に、生理学的に受容可能な担体中のIGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチドを含む組成物を、血管内皮細胞遊走および/または増殖を促進するのに有効な量で心筋内投与する工程を含む、心筋血管新生を促進する方法。
- 前記組成物が:
IGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチド;
骨由来血管新生タンパク質(BDAP)、血管内皮細胞増殖因子(VEGF)、塩基性繊維芽細胞増殖因子(bFGF)、アンジオゲニン、内皮増殖因子(EGF)、血小板由来増殖因子(PDGF)、形質転換増殖因子α(TGF−α)、形質転換増殖因子β(TGF−β)および腫瘍壊死因子α(TNF−α)より成る群から選択される少なくとも1つの増殖因子;ならびに
生理学的に受容可能な担体;を含むことを特徴とする請求項8記載の方法。 - 前記生理学的に受容可能な担体が、ポリビニルピロリジノンを含むことを特徴とする請求項8記載の方法。
- 前記投与工程が、前記組成物を虚血領域に皮下注射によって投与することを含む請求項8記載の方法。
- 治療を必要とする人の末梢血管によって維持される器官または組織の虚血領域に、生理学的に受容可能な担体中のIGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択されるペプチドを、前記虚血領域において血管内皮細胞遊走および/または増殖を促進するのに有効な量で投与する工程を含む、末梢血管新生を促進する方法。
- 前記投与工程が、
IGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチド;
骨由来血管新生タンパク質(BDAPs)、血管内皮細胞増殖因子(VEGF)、塩基性繊維芽細胞増殖因子(bFGF)、アンジオゲニン、内皮増殖因子(EGF)、血小板由来増殖因子(PDGF)、形質転換増殖因子α(TGF−α)、形質転換増殖因子β(TGF−β)および腫瘍壊死因子α(TNF−α)より成る群から選択される少なくとも1つの増殖因子;ならびに
生理学的に受容可能な担体;を含む組成物を、前記虚血領域に送達することを含む請求項12記載の方法。 - 前記生理学的に受容可能な担体が、ポリビニルピロリジノンを含むことを特徴とする請求項12記載の方法。
- 前記投与工程が、虚血領域に皮下注射によって前記組成物を投与することを含む請求項12記載の方法。
- 身体の虚血組織への血流を高める方法であって、生理学的に受容可能な担体中のIGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチドを、虚血組織への血流を回復または増加させるのに十分血管内皮細胞遊走および/または増殖を促進するのに有効な量で、前記虚血組織の特定領域に投与する工程を含む方法。
- 前記投与工程が、アテローム硬化性疾患が原因で狭窄した天然の血管に隣接する部位に前記組成物を送達することを含む請求項16記載の方法。
- 前記投与工程が、バイパス移植片に隣接する部位に前記組成物を送達することを含む請求項16記載の方法。
- 前記投与工程が、
IGD[配列番号1]、IGDS[配列番号2]、IGDQ[配列番号3]およびGGIGDGG[配列番号4]より成る群から選択される少なくとも1つのペプチド;
骨由来血管新生タンパク質(BDAPs)、血管内皮細胞増殖因子(VEGF)、塩基性繊維芽細胞増殖因子(bFGF)、アンジオゲニン、内皮増殖因子(EGF)、血小板由来増殖因子(PDGF)、形質転換増殖因子α(TGF−α)、形質転換増殖因子β(TGF−β)および腫瘍壊死因子α(TNF−α)より成る群から選択される少なくとも1つの増殖因子;ならびに
生理学的に受容可能な担体;を含む血管新生組成物を、アテローム硬化性疾患が原因で狭窄した天然の血管に隣接する部位に送達することを含む請求項16記載の方法。
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Cited By (4)
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JP2011046637A (ja) * | 2009-08-26 | 2011-03-10 | Nagoya Univ | 細胞特異的ペプチド及びその用途 |
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Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US7972337B2 (en) | 2005-12-28 | 2011-07-05 | Intrinsic Therapeutics, Inc. | Devices and methods for bone anchoring |
EP1624832A4 (en) | 1999-08-18 | 2008-12-24 | Intrinsic Therapeutics Inc | DEVICES AND METHOD FOR AUGMENTING A WINDOW NUCLEUS |
US7998213B2 (en) | 1999-08-18 | 2011-08-16 | Intrinsic Therapeutics, Inc. | Intervertebral disc herniation repair |
WO2009033100A1 (en) | 2007-09-07 | 2009-03-12 | Intrinsic Therapeutics, Inc. | Bone anchoring systems |
US7717961B2 (en) | 1999-08-18 | 2010-05-18 | Intrinsic Therapeutics, Inc. | Apparatus delivery in an intervertebral disc |
US8323341B2 (en) | 2007-09-07 | 2012-12-04 | Intrinsic Therapeutics, Inc. | Impaction grafting for vertebral fusion |
US20080159604A1 (en) * | 2005-12-30 | 2008-07-03 | Allan Wang | Method and system for imaging to identify vascularization |
GB0813659D0 (en) | 2008-07-25 | 2008-09-03 | Smith & Nephew | Fracture putty |
US8349325B2 (en) | 2008-12-23 | 2013-01-08 | Abbott Laboratories | Soluble FMS-like tyrosine kinase-1 (sFLT-1) antibody and related composition, kit, methods of using, and materials and method for making |
Family Cites Families (118)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5831210B2 (ja) | 1973-04-09 | 1983-07-05 | 武田薬品工業株式会社 | アンテイナスイセイケンダクエキノセイゾウホウ |
US4172128A (en) | 1975-03-26 | 1979-10-23 | Erhard Thiele | Process of degrading and regenerating bone and tooth material and products |
US4761471A (en) | 1980-08-04 | 1988-08-02 | The Regents Of The University Of California | Bone morphogenetic protein composition |
US4619989A (en) | 1981-05-05 | 1986-10-28 | The Regents Of The University Of Cal. | Bone morphogenetic protein composition |
US4455256A (en) | 1981-05-05 | 1984-06-19 | The Regents Of The University Of California | Bone morphogenetic protein |
JPS57144756A (en) | 1981-03-04 | 1982-09-07 | Koken Kk | Impermeable laminated film |
US5705477A (en) | 1982-09-24 | 1998-01-06 | The United States Of America As Represented By The Department Of Health And Human Services | Compositions of transforming growth factor β(TGF-β) which promotes wound healing and methods for their use |
US5656587A (en) | 1982-09-24 | 1997-08-12 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Promotion of cell proliferation by use of transforming growth factor beta (TGF-β) |
US4529590A (en) | 1982-12-27 | 1985-07-16 | Leveen Robert F | Production of angiogenetic factor |
US5328695A (en) | 1983-03-22 | 1994-07-12 | Massachusetts Institute Of Technology | Muscle morphogenic protein and use thereof |
US4801299A (en) | 1983-06-10 | 1989-01-31 | University Patents, Inc. | Body implants of extracellular matrix and means and methods of making and using such implants |
US4596574A (en) | 1984-05-14 | 1986-06-24 | The Regents Of The University Of California | Biodegradable porous ceramic delivery system for bone morphogenetic protein |
US4620327A (en) | 1984-07-05 | 1986-11-04 | Caplan Arnold I | Process of adapting soluble bone protein for use in stimulating osteoinduction |
US4699788A (en) | 1984-08-20 | 1987-10-13 | Trustees Of Boston University | Angiogenic factor methods of extraction and method for producing angiogenesis |
JPH0678460B2 (ja) | 1985-05-01 | 1994-10-05 | 株式会社バイオマテリアル・ユニバース | 多孔質透明ポリビニルアルユールゲル |
US4678470A (en) | 1985-05-29 | 1987-07-07 | American Hospital Supply Corporation | Bone-grafting material |
US4774227A (en) | 1986-02-14 | 1988-09-27 | Collagen Corporation | Collagen compositions for bone repair containing autogeneic marrow |
US5459047A (en) | 1986-07-01 | 1995-10-17 | Genetics Institute, Inc. | BMP-6 proteins |
US5013649A (en) | 1986-07-01 | 1991-05-07 | Genetics Institute, Inc. | DNA sequences encoding osteoinductive products |
US5631142A (en) | 1986-07-01 | 1997-05-20 | Genetics Institute, Inc. | Compositions comprising bone morphogenetic protein-2 (BMP-2) |
US5543394A (en) | 1986-07-01 | 1996-08-06 | Genetics Institute, Inc. | Bone morphogenetic protein 5(BMP-5) compositions |
US6150328A (en) | 1986-07-01 | 2000-11-21 | Genetics Institute, Inc. | BMP products |
US6432919B1 (en) | 1986-07-01 | 2002-08-13 | Genetics Institute, Inc. | Bone morphogenetic protein-3 and compositions |
US5187076A (en) | 1986-07-01 | 1993-02-16 | Genetics Institute, Inc. | DNA sequences encoding BMP-6 proteins |
ZA874681B (en) | 1986-07-01 | 1988-04-27 | Genetics Inst | Novel osteoinductive factors |
US4743259A (en) | 1986-10-29 | 1988-05-10 | The University Of Virginia Alumni Patents Foundation | Use of demineralized bone matrix in the repair of segmental defects |
US4902296A (en) | 1986-10-29 | 1990-02-20 | The University Of Virginia Alumni Patents Foundation | Use of demineralized bone matrix in the repair of segmental defects |
US4834757A (en) | 1987-01-22 | 1989-05-30 | Brantigan John W | Prosthetic implant |
US4952404A (en) | 1987-06-19 | 1990-08-28 | President And Fellows Of Harvard College | Promotion of healing of meniscal tissue |
US5258043A (en) | 1987-07-20 | 1993-11-02 | Regen Corporation | Method for making a prosthetic intervertebral disc |
US5681353A (en) | 1987-07-20 | 1997-10-28 | Regen Biologics, Inc. | Meniscal augmentation device |
US5108438A (en) | 1989-03-02 | 1992-04-28 | Regen Corporation | Prosthetic intervertebral disc |
US4772287A (en) | 1987-08-20 | 1988-09-20 | Cedar Surgical, Inc. | Prosthetic disc and method of implanting |
US4863732A (en) | 1987-12-16 | 1989-09-05 | Collagen Corporation | Injectable composition for inductive bone repair |
US4895838A (en) | 1988-03-09 | 1990-01-23 | Trustees Of Boston University | Method for provoking angiogenesis by administration of angiogenically active oligosaccharides |
US4900673A (en) | 1988-03-28 | 1990-02-13 | President And Fellows Of Harvard College | Mutant human angiogenin (angiogenesis factor with superior angiogenin activity) genes therefor and methods of expression |
US4950483A (en) | 1988-06-30 | 1990-08-21 | Collagen Corporation | Collagen wound healing matrices and process for their production |
US5219576A (en) | 1988-06-30 | 1993-06-15 | Collagen Corporation | Collagen wound healing matrices and process for their production |
US5545229A (en) | 1988-08-18 | 1996-08-13 | University Of Medicine And Dentistry Of Nj | Functional and biocompatible intervertebral disc spacer containing elastomeric material of varying hardness |
US5510418A (en) | 1988-11-21 | 1996-04-23 | Collagen Corporation | Glycosaminoglycan-synthetic polymer conjugates |
US5936035A (en) | 1988-11-21 | 1999-08-10 | Cohesion Technologies, Inc. | Biocompatible adhesive compositions |
US5356630A (en) | 1989-02-22 | 1994-10-18 | Massachusetts Institute Of Technology | Delivery system for controlled release of bioactive factors |
US5015255A (en) | 1989-05-10 | 1991-05-14 | Spine-Tech, Inc. | Spinal stabilization method |
US5100422A (en) | 1989-05-26 | 1992-03-31 | Impra, Inc. | Blood vessel patch |
CA2022480C (en) | 1989-08-02 | 2001-02-27 | Gerald L. Mechanic | Process for cross-linking collagenous materials and resulting product |
GB8927546D0 (en) | 1989-12-06 | 1990-02-07 | Ciba Geigy | Process for the production of biologically active tgf-beta |
FR2659226B1 (fr) | 1990-03-07 | 1992-05-29 | Jbs Sa | Prothese pour disques intervertebraux et ses instruments d'implantation. |
US5342394A (en) | 1990-05-16 | 1994-08-30 | Olympus Optical Co., Ltd. | Apparatus for blocking a vein branch and method of blocking a vein branch |
DE69111021T2 (de) | 1990-10-31 | 1996-01-04 | Gendler El | Flexible Membrane hergestellt aus organischer Knochenmatrix zum Ausbessern und Wiederherstellen von Knochen. |
AU651421B2 (en) | 1990-11-30 | 1994-07-21 | Celtrix Pharmaceuticals, Inc. | Use of a bone morphogenetic protein in synergistic combination with TGF-beta for bone repair |
DE69129121T2 (de) | 1990-12-21 | 1998-11-19 | Curative Tech Inc | Angiogene peptide |
US5047055A (en) | 1990-12-21 | 1991-09-10 | Pfizer Hospital Products Group, Inc. | Hydrogel intervertebral disc nucleus |
US5192326A (en) | 1990-12-21 | 1993-03-09 | Pfizer Hospital Products Group, Inc. | Hydrogel bead intervertebral disc nucleus |
US5206023A (en) | 1991-01-31 | 1993-04-27 | Robert F. Shaw | Method and compositions for the treatment and repair of defects or lesions in cartilage |
US5390683A (en) | 1991-02-22 | 1995-02-21 | Pisharodi; Madhavan | Spinal implantation methods utilizing a middle expandable implant |
US5171278A (en) | 1991-02-22 | 1992-12-15 | Madhavan Pisharodi | Middle expandable intervertebral disk implants |
US5972884A (en) | 1991-03-11 | 1999-10-26 | Creative Biomolecules, Inc. | Morphogen treatment of gastrointestinal ulcers |
US5290763A (en) | 1991-04-22 | 1994-03-01 | Intermedics Orthopedics/Denver, Inc. | Osteoinductive protein mixtures and purification processes |
US5563124A (en) | 1991-04-22 | 1996-10-08 | Intermedics Orthopedics/ Denver, Inc. | Osteogenic product and process |
EP0516901A1 (en) | 1991-06-06 | 1992-12-09 | Richard L. Lindstrom | Method and apparatus of a serumfree medical solution |
US5661007A (en) | 1991-06-25 | 1997-08-26 | Genetics Institute, Inc. | Bone morphogenetic protein-9 compositions |
US5741429A (en) | 1991-09-05 | 1998-04-21 | Cardia Catheter Company | Flexible tubular device for use in medical applications |
CA2117088A1 (en) | 1991-09-05 | 1993-03-18 | David R. Holmes | Flexible tubular device for use in medical applications |
US5270300A (en) | 1991-09-06 | 1993-12-14 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone |
US5304194A (en) | 1991-10-02 | 1994-04-19 | Target Therapeutics | Vasoocclusion coil with attached fibrous element(s) |
WO1993009229A1 (en) | 1991-11-04 | 1993-05-13 | Genetics Institute, Inc. | Recombinant bone morphogenetic protein heterodimers, compositions and methods of use |
US5147374A (en) | 1991-12-05 | 1992-09-15 | Alfredo Fernandez | Prosthetic mesh patch for hernia repair |
US6120760A (en) | 1992-02-12 | 2000-09-19 | Biopharm Gesellschaft Zur Biotechnologischen Entwicklung | Growth/differentiation factors of the TGF-β family |
DE4210334A1 (de) | 1992-03-30 | 1993-10-07 | Stoess & Co Gelatine | Biologisch abbaubares, wasserresistentes Polymer-Material |
US5413571A (en) | 1992-07-16 | 1995-05-09 | Sherwood Medical Company | Device for sealing hemostatic incisions |
JPH0648955A (ja) | 1992-07-29 | 1994-02-22 | Morinaga Milk Ind Co Ltd | 消化管細胞賦活化剤 |
US5800537A (en) | 1992-08-07 | 1998-09-01 | Tissue Engineering, Inc. | Method and construct for producing graft tissue from an extracellular matrix |
US5318957A (en) | 1992-09-02 | 1994-06-07 | The United States Of America As Represented By The Department Of Health And Human Services | Method of stimulating angiogenesis |
US5437288A (en) | 1992-09-04 | 1995-08-01 | Mayo Foundation For Medical Education And Research | Flexible catheter guidewire |
US5478739A (en) | 1992-10-23 | 1995-12-26 | Advanced Tissue Sciences, Inc. | Three-dimensional stromal cell and tissue culture system |
US5616490A (en) | 1992-12-07 | 1997-04-01 | Ribozyme Pharmaceuticals, Inc. | Ribozymes targeted to TNF-α RNA |
US5595722A (en) | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
US5637480A (en) | 1993-05-12 | 1997-06-10 | Genetics Institute, Inc. | DNA molecules encoding bone morphogenetic protein-10 |
IL110589A0 (en) | 1993-08-10 | 1994-11-11 | Bioph Biotech Entw Pharm Gmbh | Growth/differentiation factor of the TGF- beta family |
US5425772A (en) | 1993-09-20 | 1995-06-20 | Brantigan; John W. | Prosthetic implant for intervertebral spinal fusion |
US5370660A (en) | 1993-11-01 | 1994-12-06 | Cordis Corporation | Apparatus and method for delivering a vessel plug into the body of a patient |
US5514180A (en) | 1994-01-14 | 1996-05-07 | Heggeness; Michael H. | Prosthetic intervertebral devices |
US5556429A (en) | 1994-05-06 | 1996-09-17 | Advanced Bio Surfaces, Inc. | Joint resurfacing system |
US5681310A (en) | 1994-07-20 | 1997-10-28 | Yuan; Hansen A. | Vertebral auxiliary fixation device having holding capability |
US5707962A (en) | 1994-09-28 | 1998-01-13 | Gensci Regeneration Sciences Inc. | Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof |
US5824093A (en) | 1994-10-17 | 1998-10-20 | Raymedica, Inc. | Prosthetic spinal disc nucleus |
US5562736A (en) | 1994-10-17 | 1996-10-08 | Raymedica, Inc. | Method for surgical implantation of a prosthetic spinal disc nucleus |
US5674296A (en) | 1994-11-14 | 1997-10-07 | Spinal Dynamics Corporation | Human spinal disc prosthesis |
US5846770A (en) | 1994-11-22 | 1998-12-08 | Genetics Institute, Inc. | DNA molecules encoding human chordin |
US5677276A (en) | 1994-12-23 | 1997-10-14 | La Jolla Cancer Research Foundation | Immobilization of peptides to hyaluronate |
US5733337A (en) | 1995-04-07 | 1998-03-31 | Organogenesis, Inc. | Tissue repair fabric |
US5635372A (en) | 1995-05-18 | 1997-06-03 | Genetics Institute, Inc. | BMP-15 compositions |
EP0830381A4 (en) | 1995-06-09 | 2000-11-22 | William N Drohan | CHITINE HYDROGELS, PRODUCTION METHOD AND USE |
DE59509135D1 (de) | 1995-10-11 | 2001-05-03 | Sulzer Markets & Technology Ag | Verfahren zu einer photooxidativen Behandlung von kollagenhaltigen Geweben |
US6048964A (en) | 1995-12-12 | 2000-04-11 | Stryker Corporation | Compositions and therapeutic methods using morphogenic proteins and stimulatory factors |
ES2420106T3 (es) | 1995-12-18 | 2013-08-22 | Angiodevice International Gmbh | Composiciones de polímeros reticulados y métodos para su uso |
US5645597A (en) | 1995-12-29 | 1997-07-08 | Krapiva; Pavel I. | Disc replacement method and apparatus |
US5800550A (en) | 1996-03-13 | 1998-09-01 | Sertich; Mario M. | Interbody fusion cage |
US6498142B1 (en) | 1996-05-06 | 2002-12-24 | Curis, Inc. | Morphogen treatment for chronic renal failure |
US5981489A (en) | 1996-07-18 | 1999-11-09 | Alza Corporation | Non-aqueous protic peptide formulations |
US5716416A (en) | 1996-09-10 | 1998-02-10 | Lin; Chih-I | Artificial intervertebral disk and method for implanting the same |
US5965403A (en) | 1996-09-18 | 1999-10-12 | Genetics Institute, Inc. | Nucleic acids encoding bone morphogenic protein-16 (BMP-16) |
US5928940A (en) | 1996-09-24 | 1999-07-27 | Creative Biomolecules, Inc. | Morphogen-responsive signal transducer and methods of use thereof |
US5827328A (en) | 1996-11-22 | 1998-10-27 | Buttermann; Glenn R. | Intervertebral prosthetic device |
US5776142A (en) | 1996-12-19 | 1998-07-07 | Medtronic, Inc. | Controllable stent delivery system and method |
US5815904A (en) | 1997-03-13 | 1998-10-06 | Intratherapeutics, Inc. | Method for making a stent |
US5800549A (en) | 1997-04-30 | 1998-09-01 | Howmedica Inc. | Method and apparatus for injecting an elastic spinal implant |
GB9714276D0 (en) | 1997-07-08 | 1997-09-10 | Univ Dundee | Peptides and related compounds |
JP2002508173A (ja) | 1997-12-17 | 2002-03-19 | クリエイティブ バイオモレキュールズ, インコーポレイテッド | 軟部組織細胞の組織に適切な表現型を維持または回復するための方法。 |
US6211157B1 (en) | 1998-05-01 | 2001-04-03 | Sulzer Biologics, Inc. | Protein mixtures to induce therapeutic angiogenesis |
US7087577B2 (en) | 1998-10-16 | 2006-08-08 | Zimmer Orthobiologies, Inc. | Method of promoting natural bypass |
US6992066B2 (en) | 1998-10-16 | 2006-01-31 | Zimmer Orthobiologics, Inc. | Povidone-containing carriers for polypeptide growth factors |
WO2000055206A1 (en) | 1999-03-18 | 2000-09-21 | The Hope Heart Institute | Endothelial cell stimulation by a complex of fibronectin and vascular endothelial growth factor |
CA2371046A1 (en) | 1999-04-23 | 2000-11-02 | Eugene Lukanidin | Therapeutic compositions and methods for enhancing angiogenesis |
US20030104977A1 (en) | 2000-03-31 | 2003-06-05 | Ugo Ripamonti | Methods for inducing angiogenesis using morphogenic proteins and stimulatory factors |
US7081240B1 (en) | 2000-06-28 | 2006-07-25 | Zimmer Orthobiologics, Inc. | Protein mixtures for wound healing |
US20020025340A1 (en) | 2000-08-30 | 2002-02-28 | Dyer Wallace K. | Methods and compositions for tissue augmentation |
US20020173453A1 (en) | 2000-12-15 | 2002-11-21 | Rama Akella | Method of treating renal injury |
-
2001
- 2001-12-21 US US10/027,015 patent/US7232802B2/en not_active Expired - Fee Related
-
2002
- 2002-12-23 AU AU2002367033A patent/AU2002367033B2/en not_active Ceased
- 2002-12-23 EP EP02806521A patent/EP1478383A4/en not_active Withdrawn
- 2002-12-23 WO PCT/US2002/041484 patent/WO2003059436A2/en active Application Filing
- 2002-12-23 CA CA002470503A patent/CA2470503A1/en not_active Abandoned
- 2002-12-23 JP JP2003559596A patent/JP2005518409A/ja active Pending
-
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- 2007-06-13 US US11/762,219 patent/US7579322B2/en not_active Expired - Fee Related
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2007151608A (ja) * | 2005-11-30 | 2007-06-21 | Med Solution Kk | 器官の形状および走行の複雑さを定量的に評価する装置およびプログラム |
JP2011046637A (ja) * | 2009-08-26 | 2011-03-10 | Nagoya Univ | 細胞特異的ペプチド及びその用途 |
JP2013523720A (ja) * | 2010-03-26 | 2013-06-17 | インダストリー―アカデミック コオペレーション ファウンデーション、 スンミョン ウィメンズ ユニバーシティー | 血管新生促進用ペプチド及びその使用 |
EP2578246A2 (en) | 2011-09-29 | 2013-04-10 | Fujifilm Corporation | Scaffold for vascular endothelial cell migration |
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AU2002367033A1 (en) | 2003-07-30 |
US7232802B2 (en) | 2007-06-19 |
WO2003059436A2 (en) | 2003-07-24 |
AU2002367033B2 (en) | 2008-04-17 |
EP1478383A4 (en) | 2006-05-10 |
US7579322B2 (en) | 2009-08-25 |
US20050143312A1 (en) | 2005-06-30 |
CA2470503A1 (en) | 2003-07-24 |
US20070287671A1 (en) | 2007-12-13 |
EP1478383A2 (en) | 2004-11-24 |
WO2003059436A3 (en) | 2004-09-23 |
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