CN100435859C - Methods and compositions for healing and repair of articular cartilage - Google Patents
Methods and compositions for healing and repair of articular cartilage Download PDFInfo
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- CN100435859C CN100435859C CNB008055386A CN00805538A CN100435859C CN 100435859 C CN100435859 C CN 100435859C CN B008055386 A CNB008055386 A CN B008055386A CN 00805538 A CN00805538 A CN 00805538A CN 100435859 C CN100435859 C CN 100435859C
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- 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
Abstract
Methods and compositions are provided for the treatment of articular cartilage defects and disease involving the combination of the tissue, such as osteochondral grafts, with active growth factor. The active growth factor is preferably a composition containing at least one bone morphogenetic protein and a suitable carrier. The method results in the regeneration of functional repair of articular cartilage tissue.
Description
Invention field
The present invention relates to the tissue repair field, specifically, relate to stable functional articular cartilage reparative regeneration.Therefore, the present invention can be used for cerebral sursery or be used for other method that articular cartilage is regenerated or repaired.
Background of invention
The reparation of articular cartilage damage is still a challenge of current orthopedia.Present several therapeutic strategies are based on the transplanting of cartilaginous tissue and osteochondral tissue.Bone and cartilage autotransplantation provides only physiological material.Yet donor tissue is limited, need undergo surgery at second position usually, with the tissue that obtains to be used to transplant.Therefore, although carried out sizable effort in this field, but still the effective ways of a kind of articular cartilage defect of needs and injury repairing provide suitable physiology reparation, and do not need to collect autologous tissue from the patient.
Summary of the invention
The invention provides the method and composition of the functional organization's reparative regeneration that is used to conform with physiological requirement, be used for repairing articular cartilage damage and damaged.Specifically, the present invention includes treatment articular cartilage damage or damaged patient's method.The advantage of method and composition of the present invention is that they utilize bone morphogenetic protein (BMP), and described albumen is known to have osteogenesis and/or cartilage occurrence features, and can produce by recombinant DNA technology, therefore has the unlimited supply of possibility.Another advantage of method and composition of the present invention is: can quicken the regeneration of functional articular cartilage, or the regeneration of functional articular cartilage may have bigger final strength and stability, and conforms with physiological requirement at tissue damaged or that damage location forms.
The reparation of using BMP enhancement articular cartilage defect and damage may produce better osteoarthritis treatment method, therefore avoids, postpones or reduce artificial hip joint replacing and other needs of interfering commonly used.Assessment shows that rhBMP-2 has improved the damaged immediate union of rabbit articular cartilage through thickness before clinical.
Detailed Description Of The Invention
According to the present invention, be provided for treating the articular cartilage damage of suffering from some form or damaged patient's method and composition.Described damage may be the result of acute compressing or such as because caused damage takes place for the accident that maybe may tear, abrade or injure articular cartilage that joins into sports.
The advantage of described method and composition is: gentrify articular cartilage defect, particularly through thickness articular cartilage defect.Other damaged also can be with method and composition of the present invention treatment, particularly add described defect further to be increased the weight of so that arrives another kind of method as basic subchondral bone.
In the present invention, for example a kind of BMP of active growth factor is added in the suitable tissue source.Described tissue source or can be the osteochondral graft of this patient from body perhaps can comprise the tissue of alloplast or artificial preparation.In a preferred embodiment, described tissue source can be the cell culture of chondrocyte, for example by the isolated cells culture method and add or do not add the chondrocyte or the stem cell culture of extra somatomedin preparation.For example, referring to the description of US5226914, US5811094, US5053050, US5486359, US5786217 and US5723331.The description of all these applications all is attached to herein by reference.
Described organize also can be with traditional obtaining based on the acellular cultured method, adopt the technology of for example inlaying plasty (mosaicplasty), wherein use commercially available instrument for example Acufex7[Smith and Nephew, Inc., Andover MA], [InnovasiveTechnologies of COR system, Marlborough MA] or Arthrex7 bone cartilage autograft transfer system [Arthrex, Munich, Germany] collection cartilage.The tissue that is obtained can be directly used in the inventive method, or can combine with above-mentioned cell culture system based on tissue.
Somatomedin
The active growth factor that is used for the present invention is preferably from the albumen subclass that is commonly referred to bone morphogenetic protein (BMP), they be disclosed as have osteogenesis, cartilage takes place and the activity of other growth and differentiation type.These BMP comprise rhBMP-2, rhBMP-3, rhBMP-4 (being also referred to as rhBMP-2B), rhBMP-5, rhBMP-6, rhBMP-7 (rhOP-1), rhBMP-8, rhBMP-9, rhBMP-12, rhBMP-13, rhBMP-15, rhBMP-16, rhBMP-17, rhBMP-18, rhGDF-1, rhGDF-3, rhGDF-5, rhGDF-6, rhGDF-7, rhGDF-8, rhGDF-9, rhGDF-10, rhGDF-11, rhGDF-12, rhGDF-14.For example at United States Patent (USP) 5,108, disclosed BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 in 922,5,013,649,5,116,738,5,106,748,5,187,076 and 5,141,905; Disclosed BMP-8 in PCT description W091/18098; With disclosed BMP-9 in PCT description WO93/00432, at United States Patent (USP) 5,637, disclosed BMP-10 in 480, at United States Patent (USP) 5, disclosed BMP-11 or at United States Patent (USP) 5,658 in 639,638, disclosed BMP-12 or BMP-13 in 882, at United States Patent (USP) 5, in 635,372 disclosed BMP-15 and in the patent application serial number 08/715,202 of common pending trial disclosed BMP-16.Other compositions that also comes in handy comprises Vgr-2 and any growth and differentiation factor (GDF), is included in those disclosed factor in PCT application WO94/15965, WO94/15949, WO95/01801, WO95/01802, WO94/21681, WO94/15966, WO95/10539, WO96/01845, WO96/02559 and other application.In the present invention also usefully in WO94/01557 disclosed BIP, in JP publication No. 7-250688 disclosed HP00269 and in PCT application WO93/16099 disclosed MP52.The description of all these applications all is attached to herein by reference.The heterodimer of the albumen of above-mentioned albumen and modification or its excalation product also can be used for the present invention.These albumen can use individually, or use as two or more proteic mixture, preferably use rhBMP-2.
The BMP generation of can recombinating, also can be from protein composition purification.Described BMP can be a homodimer, perhaps can be with the heterodimer of other BMP (for example by BMP-2 and each heterodimer that monomer is formed of BMP-6) or with other member of TGF-beta superfamily heterodimer of activin, inhibin and TGF-β 1 (for example by the relevant member of a kind of BMP and a kind of TGF-beta superfamily respectively the heterodimer that monomer is formed) for example.The proteic case description of this class heterodimer is in disclosed PCT patent application WO 93/09229 for example, and its description is attached to herein by reference.Useful proteic amount of osteogenesis is the active amount that increases of osteogenesis of effective stimulus wellability CFU-GM in this, and this will depend on the carrier of damaged size to be treated and character and use.Generally speaking, protein content scope to be passed is that about 0.05mg is to about 1.5mg.
In a preferred embodiment, described osteogenesis albumen gives with the albumen of the effective dose that can induce tendon sample tissue or ligament sample tissue to form.This albuminoid comprises other member and the MP52 of BMP-12, BMP-13 and BMP-12 subfamily.These albumen and being disclosed in the application aspect tendon sample tissue and the tissue regeneration of ligament sample in the US application serial No. 08/362,670 of December in 1994 application on the 22nd, its description is attached to herein by reference.In another preferred embodiment, according to following method, give wherein a kind of monomer unit and be for example BMP-2 and another kind of monomer subunit is for example a kind of heterodimer of BMP-12 of tendon induced protein of a kind of osteogenesis albumen, form function between connective tissue and the bone and connect to induce.
The application of somatomedin
Somatomedin can be applied to tissue source with the form of buffer.A kind of preferred buffer be except that comprising described active growth factor, also comprise about 1.0 to about 10.0% (w/v) glycine, about 0.1 to about 5.0% (w/v) sugar preferably sucrose, about 1 to about 20mM glutamic acid hydrochloride and optional about 0.01 to about 0.1% non-ionic surface active agent compositions of Spheron MD 30/70 for example.Preferred solution is about 1% to about 20%w/v cellulose carrier/buffer.If needed, can add a kind of salt.
Other material applicable to the somatomedin application facet in the inventive method and the compositions comprises hyaluronic acid, operation net or suture, polyglyconate, temperature-sensitive polymers, demineralized bone, mineral and pottery, for example calcium phosphate, hydroxyapatite etc., and the combination of above-mentioned material.Yet do not use carrier in a preferred embodiment of the invention.
In for example above-mentioned suitable buffer or with the somatomedin of the present invention of suitable carriers combination, can directly apply to the tissue and/or the position that need tissue repair.For example, described somatomedin can by spraying or dipping or with brushing or other suitable applicator syringe for example, physical application be in described tissue.Perhaps, or in addition, described albumen can be directly applied to the position that needs tissue repair.
Following examples further describe the enforcement of embodiment of the present invention with BMP-2.Described embodiment is not restrictive, just as the skilled person will recognize, can change according to above-mentioned specific descriptions.
Embodiment
I. rabbit alloplast
Institute is undertaken by the IACUC approval in steps.Use 12 male New Zealand rabbits (6 monthly age).2 rabbits are as donor, and 10 rabbits are as receptor.Condyle obtains osteochondral graft (diameter is 3.5mm) from the coaster ditch (trochlear groove) of donor or femur, and it is transplanted in dark damaged of 3.5mm in the receptor coaster ditch.Before transplanting, with among graft or the immersion rhBMP-2 (0.5mg/ml) or in the contrast of immersion buffer.4 weeks of operation back are put to death rabbits, as Sellers etc.,
J.Bone Joint Surg., 79-A:1452-1463 (1997) describes, by histological histochemistry grade scale, and assessment graft and surrounding tissue.Also carry out the computer control image analysis of tissue slice.With non-paired Students t calibrating assessment result.
During macroscopy, the joint does not demonstrate the inflammation sign.All damaged equal filling repair tissues.Damaged appearance is variable, but acceptable, and irrelevant with processing form.(there are 2 in the experimental group, have 1 in the contrast buffer group) the middle hyperosteogeny of finding in 3 joints.
Between any damaged macroscopy outward appearance and histological appearance, there is not association.The clone that is dispersed in of the existence of chondrocyte and cell shows this tissue survival in the donor cartilage lacuna.The focal degeneration of donor cartilage all exists in all rabbits of matched group, but only exists in 1 rabbit in the rhBMP-2 processed group.Remarkable increase is compared in healing damaged in the rhBMP-2 processed group with matched group.The bone of rhBMP-2 processed group is integrated (bony integration) and is improved, and it is less to show as in the subchondral bone lacuna fibroid repair tissue.It is more to handle the cartilage also cause being higher than original tidemark (tidemark) with rhBMP-2, is made up of donor tissue and new regenerated receptor cartilage significantly.Observed bone total amount does not have significant difference between these two groups.
Table I
The histology's score of repair of cartilage and the measurement result of histomorphometricall, meansigma methods (SD)
| Parameter | rhBMP-2 | Contrast |
| Average score ** | 10.0(5.42) * | 20.6(5.18) |
| The bone % of not enough tidemark | 73.26(13.28) | 62.88(18.07) |
| The fibrous tissue % of not enough tidemark | 2.19(2.04) | 15.81(9.88) |
| The cartilage % that is higher than tidemark | 74.70(41.08) * | 18.17(26.70) |
| The damaged % that fills up | 96.53(4.86) * | 88.79(8.04) |
*With contrast statistically-significant difference (p＜0.05) is arranged.
*The modular system scope is that 0 (normal cartilage) be not to 31 (repairing).
Another histomorphometric data are further supported the useful effect of rhBMP-2 to graft healing.For example, show that the new organization that is higher than tidemark is 81.52% at the percentage ratio of rhBMP-2 processed group filling, and is 57.63% in contrast.(23.83%) graft cartilage degradation lacks than matched group (44.52%) in the rhBMP-2 processed group.Graft or new cartilage and being incorporated in the rhBMP-2 processed group (56.48%) of host's cartilage that forms make moderate progress than matched group (21.89%).Under the influence of rhBMP-2, perhaps form the cartilage that upgrades at the graft edge or at the graft top, at the graft edge, this has eliminated the gap between graft and the host, and at the graft top, makes graft and articular surface merge better.
The above results shows that the healing of the allogeneic osteochondral graft in the articular cartilage defect improves owing to adding rhBMP-2.Described active growth factor may have been quickened the healing of subchondral bone, for articular cartilage tissue provides support and nutrition.The adding of somatomedin also may stimulate in bone marrow and/or the synovial tissue and form new cartilage by the receptor interstital stem cell. and these results show, the active growth factor particularly combination of bone morphogenetic protein and bone cartilage alloplast may be provided for treating articular cartilage defect, the particularly available strategy of through thickness articular cartilage defect.
II. rabbit autograft
Obtain osteochondral graft (diameter is 2.7mm, long 3.0mm) from the coaster ditch of rabbit or condyle of femur, it is transplanted in the donor site of wide 2.7mm, long 3.5mm on the coaster ditch of this rabbit or the kneed condyle of femur.Before transplanting, buffer is added drop-wise to the described acceptor site of half animal, then this graft was immersed in buffer 2 minutes, place acceptor site then.Before transplanting, 5 μ g rhBMP-2 are added drop-wise to the acceptor site of second half animal, then this graft were immersed in the buffer that contains 500 μ g/ml rhBMP-2 2 minutes, be transplanted in the acceptor site then.4 weeks of operation back are put to death animal, and the quantitative Analysis machine control figure picture analysis with histological histochemistry grade scale [Sellers etc., J.Bone Joint Surg., 79-A:1452-63 (1997)] and tissue carries out tissue-estimating to acceptor site.Data show, handle the healing that has improved autograft with rhBMP-2.The most outstanding effect is that the graft cartilage degradation reduces (8.18% pair of contrast of rhBMP-2 36.25%) and graft edge and forms more cartilage (88.23% pair of contrast of rhBMP-2 50%).
III. non-human primates autograft:
The non-human primates that is used for the autograft experiment is South America macaque (cynomologousmacaques).Collect osteochondral graft (3.5mm diameter * 6mm is long) from the coaster ditches of 6 South America macaques, it is transplanted to the acceptor site in the condyle and femur side condyle in the femur that pierces same animal (n=12 graft altogether).Before transplanting, 25 μ g rhBMP-2 are splashed into 6 acceptor sites, will immerse from the graft of those 6 grafts then in the solution of 1.25mg/ml rhBMP-2 and reach 2 minutes.In other 6 grafts, only buffer is splashed into acceptor site, and before transplanting, graft immersed in the independent buffer 2 minutes.Used after operation plaster fixation limbs reached for 2 weeks, and operation 9 weeks of back are with sacrifice of animal.
The knee joint function of all animals is all normal.During macroscopy, the joint does not demonstrate the inflammation sign.In arbitrary joint, do not find hyperosteogeny.Though defect surfaces flushes with cartilage on every side when macroscopy, microscopic examination shows that in most of the cases graft sinks.The tissue of the covering surfaces that is observed visually is actually the new tissue that forms at the graft top.Carry out the computer control image analysis by unwitting evaluation personnel, carry out quantitatively so that the new organization type that is higher than original tidemark of damaged filling percentage ratio, formation and graft and cartilage are on every side integrated.In all these parameters of rhBMP-2 processed group, all observe good result.Between graft and host's cartilage, form the cartilage that upgrades, eliminated the gap, cause graft and integrate (88.59% pair of contrast 64.82% of rhBMP-2) on every side between the cartilage better.The relative cylinder charge matched group (86.68%) of cartilage defect in rhBMP-2 processed group (95.02%) will be got well.More fibrous tissue (11.90% couple of rhBMP-2 5.65%) is arranged in matched group, and find that in the rhBMP-2 processed group (36.38% pair contrasts 20.53%1 to more excessively type tissue.In overall histological histochemistry score, there is not significant difference between two groups.Periphery quantitative Analysis machine control tomoscan art (pQCT) shows that As time goes on bone density increases in the donor site.When performing the operation 6 weeks of back and 9 weeks, compare with the contrast position, obviously more fine and close with the tissue in the donor site of rhBMP-2 processing, agglutination more shifts to an earlier date.On the histology, the donor site all contains regenerated bone trabecula and surperficial fibrous tissue in all cases.
The in vitro reservation of IV.rhBMP-2:
Use graft, estimate the reservation of the rhBMP-2 of this technology of employing at osteochondral graft from non-human primates.Graft is immersed
125In the rhBMP-2 of I labelling and the mixture solution of unlabelled rhBMP-2.The result shows that the amount that is absorbed into the rhBMP-2 in the graft is proportional with this proteic concentration and soak time.Influence the existence that other factors that rhBMP-2 keeps comprises bone marrow composition between the size of graft and the bone trabecula.
Keep time-histories in the body of V.rhBMP-2:
In rabbit, estimate the reservation time-histories of rhBMP-2 in osteochondral graft.Before transplanting, will contain 5ug rhBMP-2 and 20 uCi
125I's
125The mixture solution application of sample of the rhBMP-2 of I labelling and unlabelled rhBMP-2 is to graft.In the 22 day time of after operation, continuing, with the described animal of γ-camera-scanning.With compare as the time-histories of carrier with collagen protein sponge, the half-life of rhBMP-2 in osteochondral graft increased to 3 days from 1 day.The radioactive maintenance of 10% starting point becomes 22 days of graft from 11 days of collagen protein sponge.
VI. non-human primates alloplast:
Take out donor site (3.5mm wide * 6mm is long) from the coaster ditches of 12 adult South America macaques, and it is transplanted in the acceptor site of 3.5 * 6mm in the condyle and side condyle in the femur of irrelevant individuality.Before transplanting, half graft is immersed among the 1.25mg/ml rhBMP-2 2 minutes, and second half graft is soaked in buffer.In 7 weeks of back of operation first, another limbs are implemented same step.After each operation, the operation back 9 weeks of operation back putting to death animal for the second time, is used for histologic analysis with Gypsum Fibrosum (in a cast) 2 weeks of fixed limb.
These results show, the combination of active growth factor (particularly bone morphogenetic protein) and bone cartilage autograft may provide a kind of articular cartilage defect, particularly efficient strategy of through thickness articular cartilage defect for the treatment of.In other embodiments, also BMP-2 is applied to refrigerated bone cartilage alloplast, is used for the treatment of focal articular cartilage defect.
Foregoing description describes the present embodiment preferred of the present invention in detail.Estimate that those skilled in the art when considering that these are described, can expect the many modifications and variations in the invention process.Those modifications and variations are believed to comprise in appended claims.
Claims (13)
1. preparation method to the osteochondral graft that needs the articular cartilage regeneration zone to give, wherein said method comprises the bone morphogenetic protein of at least a purification from the active amount that increases of osteogenesis of effective stimulus wellability CFU-GM to this osteochondral graft that use, and condition is the tissue that this osteochondral graft does not comprise artificial preparation.
2. the process of claim 1 wherein that described graft is an alloplast.
3. the process of claim 1 wherein that described graft is an autograft.
4. each method among the claim 1-3, described method comprises bone morphogenetic protein from 0.05mg-1.5mg to described osteochondral graft that use.
5. each method among the claim 1-3 also comprises the albumen of inducing the effective dose that tendon sample tissue or ligament sample tissue form, and wherein said albumen is selected from BMP-12, BMP-13 and MP-52.
6. each method among the claim 1-3, wherein said bone morphogenetic protein is BMP-2.
7. the bone morphogenetic protein of at least a purification is used for being administered to the purposes that can improve the medicine that osteochondral graft is integrated in patient's body when needing the articular cartilage regeneration zone in preparation, and condition is the tissue that this osteochondral graft does not comprise artificial preparation.
8. to the osteochondral graft that needs the articular cartilage regeneration zone to give, used the bone morphogenetic protein of the active amount that increases of osteogenesis of effective stimulus wellability CFU-GM in the described graft, condition is the tissue that this osteochondral graft does not comprise artificial preparation.
9. the osteochondral graft of claim 8, wherein said graft is an alloplast.
10. the osteochondral graft of claim 8, wherein said graft is an autograft.
11. each osteochondral graft among the claim 8-10 is wherein used the bone morphogenetic protein of 0.05mg-1.5mg to described graft.
12. each osteochondral graft among the claim 8-10, wherein said bone morphogenetic protein is BMP-2.
13. each osteochondral graft among the claim 8-10 has also been used the albumen of inducing the effective dose that tendon sample tissue or ligament sample tissue form in the described graft, wherein said albumen is selected from BMP-12, BMP-13 and MP-52.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11816099P | 1999-02-01 | 1999-02-01 | |
| US60/118160 | 1999-02-01 | ||
| US60/118,160 | 1999-02-01 |
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| CNA2008101693859A Division CN101385851A (en) | 1999-02-01 | 2000-01-31 | Methods and compositions for healing and repair of articular cartilage |
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| CN100435859C true CN100435859C (en) | 2008-11-26 |
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| CNA2008101693859A Pending CN101385851A (en) | 1999-02-01 | 2000-01-31 | Methods and compositions for healing and repair of articular cartilage |
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| KR (1) | KR100704537B1 (en) |
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| KR101012869B1 (en) * | 2008-02-05 | 2011-02-08 | 동국대학교 산학협력단 | Chondrogenesis of bone marrow mesenchymal stem cells |
| WO2016112176A1 (en) * | 2015-01-08 | 2016-07-14 | University Of Iowa Research Foundation | Methods for the regeneration of articular cartilage in vivo |
| CN106031792A (en) * | 2015-03-10 | 2016-10-19 | 西比曼生物科技（上海）有限公司 | Composition for treating defects of articular cartilage |
| EP3423121B1 (en) * | 2016-02-29 | 2022-11-02 | Cedars-Sinai Medical Center | Endogenous stem cell activation for tendon/ligament osseointegration |
| US11904006B2 (en) | 2019-12-11 | 2024-02-20 | University Of Iowa Research Foundation | Poly(diaminosulfide) particle-based vaccine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1064813A (en) * | 1991-01-31 | 1992-09-30 | 罗伯特弗朗西斯肖 | The method and composition of treatment and reparation cartilage defect or damage |
| WO1996039170A1 (en) * | 1995-06-06 | 1996-12-12 | Genetics Institute, Inc. | Cartilage induction by bone morphogenetic proteins |
| WO1998031788A1 (en) * | 1997-01-21 | 1998-07-23 | Genetics Institute, Inc. | Injectable formulations for treatment of osteoporotic bone |
| US5786217A (en) * | 1994-05-05 | 1998-07-28 | Genzyme Corporation | Methods and compositions for the repair of articular cartilage defects in mammals |
| CN1195295A (en) * | 1995-06-02 | 1998-10-07 | 加时R·格罗登多斯特 | Method and use of connective tissue growth factor as revellent |
-
2000
- 2000-01-31 CN CNB008055386A patent/CN100435859C/en not_active Expired - Fee Related
- 2000-01-31 KR KR1020017009650A patent/KR100704537B1/en not_active IP Right Cessation
- 2000-01-31 CN CNA2008101693859A patent/CN101385851A/en active Pending
-
2001
- 2001-07-25 ZA ZA200106113A patent/ZA200106113B/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1064813A (en) * | 1991-01-31 | 1992-09-30 | 罗伯特弗朗西斯肖 | The method and composition of treatment and reparation cartilage defect or damage |
| US5786217A (en) * | 1994-05-05 | 1998-07-28 | Genzyme Corporation | Methods and compositions for the repair of articular cartilage defects in mammals |
| CN1195295A (en) * | 1995-06-02 | 1998-10-07 | 加时R·格罗登多斯特 | Method and use of connective tissue growth factor as revellent |
| WO1996039170A1 (en) * | 1995-06-06 | 1996-12-12 | Genetics Institute, Inc. | Cartilage induction by bone morphogenetic proteins |
| WO1998031788A1 (en) * | 1997-01-21 | 1998-07-23 | Genetics Institute, Inc. | Injectable formulations for treatment of osteoporotic bone |
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| CN1345251A (en) | 2002-04-17 |
| CN101385851A (en) | 2009-03-18 |
| KR100704537B1 (en) | 2007-04-09 |
| ZA200106113B (en) | 2002-11-12 |
| KR20010101897A (en) | 2001-11-15 |
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