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(19) 



J 



EuropSisches Patentamt 
European Patent Office 
Office europeen des brevets 



(12) 



(45) Date of publication and mention 
of the grant of the patent: 
30.07.2003 Bulletin 2003/31 

(21) Application number: 96916513.3 

(22) Date of filing: 21 .05.1 996 



(H) EP 0 831 884 B1 

EUROPEAN PATENT SPECIFICATION 

(51) int CI7: A61K38/18, A61P 19/00 



(86) International application number: 
PCT/US96/07282 

(87) International publication number: 

WO 96/039169 (12.12.1996 Gazette 1996/54) 



(54) USE OF BONE MORPHOGENIC PROTEINS FOR HEALING AND REPAIR OF CONNECTIVE 
TISSUE ATTACHMENT 

VERWENDUNG VON KNOCHENMORPHOGENESEPROTEINEN ZUR HEILUNG UND 
REPARATUR VON BINDEGEWEBEBEFESTIGUNG 

UTILISATION DE PROTEINES MORPHOGENIQUES OSSEUSES POUR SOIGNER ET REPARER 
LES INSERTIONS DU TISSU CONJONCTIF 



(84) Designated Contracting States: 

AT BE CH DE DK ES Fl FR GB GR IE IT LI LU MC 
NL PT SE 

(30) Priority: 05.06.1995 US 462497 

(43) Date of publication of application: 
01.04.1998 Bulletin 1998/14 

(73) Proprietors: 

• Genetics Institute, LLC 
Cambridge, MA 02140 (US) 

• NEW YORK SOCIETY FOR THE RELIEF OF 
THE RUPTURED AND CRIPPLED MAINTAINING 
THE HOSPITAL FOR SPECIAL SURGERY 
New York, N.Y. 10021 (US) 



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LU 



(72) Inventors: 

• WOZNEY, John, M. 
Hudson, MA 01749 (US) 

• WARREN, Russel, F. 
Greenwich, CT 06831 (US) 

♦ RODEO, Scott, A. 

New York, NY 10021 (US) 

♦ HANNAFIN, Jo, A. 

Greenwich, Connecticut 06830 (US) 

(74) Representative: VOSSIUS & PARTNER 
Postfach 86 07 67 
81634 MQnchen (DE) 



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(56) References cited: 
WO-A-88/00205 
WO-A-93/06872 
WO-A-96/36710 



WO-A-92/09697 
WO-A-95/16035 



Note: Within nine months from the publication of the mention of the.grant of the€uropean patent, any person may give 
notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in 
a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 
99(1 ) European Patent Convention). 



Printed by Jouve. 75001 PARIS (FR) 



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Description 

FIELD OF THE INVENTION 

[0001 ] The present invention relates to the field of tis- 
sue repair, specifically, the regeneration of a functional 
attachment between connective tissue, such as tendon, 
cartilage or ligament, to bone. This functional attach- 
ment may be destroyed by trauma or stress, or by de- 
generative or congenital disease. Thus, the present in- 
vention may be useful in reconstructive surgery or other 
procedures for the regeneration of a functional attach- 
ment between connective tissue and bone. 

BACKGROUND OF THE INVENTION 

Background of the incidence and etiology of need: 

[0002] Although several of reconstructive surgical 
procedures rely on the firm healing or attachment of con- 
nective tissue, particularly tendon or ligament, to bone, 
little is known about the healing process at the tendon- 
to-bone interface. Since the site of graft fixation to bone 
represents the weakest area in the early post-transplant 
period, methods to improve early graft fixation strength 
have significant clinical application. This is of particular 
importance in operations on the knee, shoulder, hip, 
hand, ankle and elbow. 

[0003] The development of tendon or ligament inser- 
tion into bone is poorly understood. The insertion site is 
mediated by collagen fibers, known as "Sharpey's fib- 
ers," which are continuous from tendon into bone. 
Sharpey's fibers are thought to form in the developing 
skeleton by progressive mineralization of ligament or 
periosteal collagen fibers by advancing bone during 
growth. Studies have indicated that bone heals to ten- 
don by bone ingrowth into the fibrovascular interface tis- 
sue which initially forms between the tendon and bone. 
There is progressive mineralization of the interface tis- 
sue with subsequent bone ingrowth into the outer ten- 
don. Despite the evidence that bone grows into colla- 
genous tissue, the mechanism of such bone ingrowth, 
and the effectiveness and strength of the attachment, 
remains uncertain. A previous study of tendon-to-bone 
healing demonstrated the formation of a fibrous tissue 
interface between the tendon and bone. Rodeo et al., J. 
Bone and Joint Surgery, 75-A: 1795-1803 (1993). 
[0004] Accordingly, despite substantial endeavors in 
this field, there remains a need for an effective method 
of repair of a functional attachment between connective 
tissue, such as tendon or ligament, and bone. 

SUMMARY OF THE INVENTION 

[0005] The present invention provides the use of one 
or more bone morphogenetic proteins (BMP) for the 
preparation of a pharmaceutical composition for regen- 
eration of a functional attachment between connective 



tissue or tendon and bone, with the proviso that said 
BMPs do not include BMP-12, BMP-13 or BMP-15. In 
particular, the present invention is useful in methods of 
treating patients with detached or degenerated attach- 
5 ments of the tendon or ligament to bone. Some exam- 
ples include reconstructive surgery on the knee, shoul- 
der, hand, ankle and elbow. Particular areas where the 
present invention may prove useful include reconstruc- 
tion of theanteriorcruciate ligament (ACL), or the rotator 
10 cuff. The compositions prepared according to the 
present invention are advantageous in that they utilize 
osteogenic proteins, which may be produced via recom- 
binant DNA technology, and therefore are of potentially 
unlimited supply. The compositions prepared according 
15 to the present invention are further advantageous in that 
regeneration of the attachment apparatus may be ac- 
celerated or may be of greater ultimate strength, and the 
attachment formed between connective tissue and bone 
may reach a functional strength sooner after surgery or 
repair is effected. The compositions prepared according 
to the present invention are further advantageous in that 
they induce the regeneration of the functional attach- 
ment between connective tissue and bone, while mini- 
mizing or avoiding formation of fibrous or granulation tis- 
sue at the interface between tissue types. 
[0006] The compositions prepared according to the 
present invention are particularly applicable to the fixa- 
tion of a round tendon in a bone tunnel or a flat tendon 
onto a bone surfabe. Several clinical examples are rel- 
evant. A common clinical example is reconstruction of 
the anterior cruciate ligament (ACL). Reconstruction 
may be performed by using the central third of the pa- 
tellar tendon with an attached bone block from both the 
tibia and patella, or by using the semitendinosus and 
gracilis tendons. Benefits of the use of patellar tendon 
include immediate bony fixation allowing aggressive 
post-operative rehabilitation and increased strength. 
However, the use of central third patellar tendon has 
been associated with adverse sequelae, including pa- 
tellar fracture, patellar ligament rupture, and degenera- 
tion of the patellofemoral joint. Benefits of the use of 
semitendinosus and gracilis tendons include easier 
graft harvest, no disruption of the -extensor mechanism 
of the knee, greater quadriceps strength one year post- 
operatively, and minimal loss of hamstring strength. The 
major pitfall is concern about the strength of fixation of 
the tendon within bone tunnels and risk of graft failure 
at the fixation site. The major difference between these 
two methods of ligament reconstruction is fixation of the 
graft. 

[0007] The use of BMP to augment tendon-to-bone 
healing may result in better methods to utilize-semitend- 
inosus and gracilis tendons for ACL reconstruction , thus 
obviating the patellar defect and concomitant extensor 
mechanism disruption inherent in patellar ligament har- 
vest. Preclinical evaluations indicate that rtiBMP-2 im- 
proves early healing of bone to a tendon graft, as -dem- 
onstrated by histologic and biomechanical evaluation. 



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Increased strength of tendon-to-bone fixation will allow 
earlier and more aggressive rehabilitation, resulting in 
earlier return to normal activities, work, or sport. 
[0008] Other common clinical examples for which the 
invention has direct application include the following: ro- 
tator cuff tendon repair to the greater tuberosity of the 
humerus, reattachment of the glenoid labrum to the 
scapular neck, reconstruction of the lateral ankle liga- 
ments using a tendon graft placed through bone tunnels, 
reconstruction of the medial collateral ligament of the 
elbow or knee using a tendon graft fixed to the surface 
of the bone or through bone tunnels, reconstruction of 
the ulnar collateral ligament of the thumb using a tendon 
graft placed in a bone tunnel, and repair of the flexor or 
extensor tendons of the digits into bone tunnels or to the 
surface of the bone of the phalanges. The invention is 
broadly applicable to any situation in which connective 
tissue (tendon, ligament, labrum, fascia, or joint cap- 
sule) is reattached to bone; either to the surface of the 
bone or into a tunnel in the bone. 

DETAILED DESCRIPTION OF THE INVENTION 

[0009] According to the present invention, means are 
provided for treatment of patients who require recon- 
structive surgery for repair of the functional attachment 
between connective tissue and bone. The compositions 
prepared according to the present invention are advan- 
tageous in that repair or improvement of the entire at- 
tachment apparatus may be effected: the tendon or lig- 
ament, the adjacent bone, as well as the functional at- 
tachment. The use of the compositions comprises ap- 
plying to the site in need of reconstructive surgery, or to 
the site of a defect, tear or detachment of connective 
tissue to bone, an amount of a composition comprising 
one or more purified osteogenic proteins which is effec- 
tive to regenerate the functional attachment of the con- 
nective tissue to the bone. The use of the compositions 
may further comprise the administration of a composi- 
tion comprising a purified or recombinant osteogenic 
protein to a site in need of regeneration of the connective 
tissue to bone attachment in a suitable carrier such that 
the connective tissue, the bone, and the functional at- 
tachment apparatus are regenerated, with reduced fi- 
brous or granulation tissue at the site of attachment oc- 
curring. The composition is preferably administered in 
combination with an effective carrier. One of the key ad- 
vantages of the present invention is that it allows for the 
controlled regeneration of connective tissue, bone and 
the functional attachment apparatus in an accelerated 
manner such that the attachment may attain greater 
functional strength, at an earlier time point than with a 
similar procedure performed without the addition of os- 
teogenic proteins. 

OSTEOGENIC PROTEIN 

[0010] The osteogenic protein is preferably from the 



subclass of proteins known generally as bone morpho- 
genetic proteins (BMPs), which have been disclosed to 
have osteogenic activity, and other growth and differen- 
tiation type activities. These BMPs include BMP-2, 

5 BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP- 
10, BMP-11, BMP-12, and BMP-13, and may also in- 
clude other members of the TGF-p superfamily of pro- 
teins, such as growth and differentiation factors, or 
GDFs, and MP52. The structures of a number of BMP 

10 proteins are disclosed in United States Patents 
4,877,864; 5,108,922; 5.013,649; 5,116,738; 
5,106,748; 5,187,076; 5,141,905; and in PCT applica- 
tions WO 91/18098; WO 93/00432; WO 94/26893; and 
WO 94/26892; and in United States Patent 5,658,882. 

15 WO 88/00205 disclosed human and bovine bone induc- 
tive factor products and their use for the treatment of 
bone and periodontal defects. WO 95/16035 showed 
BMP-12 and BMP-13 and tendon-inducing composi- 
tions thereof, whereas WO 96/3671 0 disclosed BMP-1 5 

20 compositions for treating bone and cartilage and/or oth- 
er connective tissue defects. The structure of a number 
of GDFs are disclosed in WO 94/15965, W094/15949; 
WO95/01801; WO95/01802; W094/21681; 
W094/15966. The structure of MP52 is disclosed in 

25 WO93/16099. The BMP is preferably BMP-2, the se- 
quence of which is disclosed in United States Patent 
5,013,649. Other BMPs known in the art can also be 
used. Presently, the most preferred BMP is BMP-2. 
[0011] The BMP may be recombinantly produced, or 

30 purified from a protein composition. The BMP may be 
homodimeric, or may be heterodimeric with other BMPs 
(e.g., a heterodimer composed of one monomer each 
of BMP-2 and BMP-6) or with other members of the 
TGF-p superfamily, such as activins, inhibins and TGF- 

35 pi (e.g., a heterodimer composed of one monomereach 
of a BMP and a related member of the TGF-p super- 
family). Examples of such heterodimeric proteins are 
described for example in Published PCT Patent Appli- 
cation WO 93/09229. 

40 [001 2] The amount of osteogenic protein useful here- 
in is that amount effective to stimulate increased osteo- 
genic activity of infiltrating progenitor cells, and will de- 
pend upon the size and nature of the defect being treat- 
ed, as well as the carrier being employed *Gene rally, the 

45 amount of protein to be delivered is in a range of from 
about 0.05 to about 1 .5 mg. 

[0013] In a preferred embodiment, the osteogenic 
protein is administered together with an effective 
amount of a protein which is able to induce the format ion 
so of tendon- or ligament-like tissue. Such proteins, include 
BMP-12, BMP-13, and other members of theeMP-12 
subfamily, as well as MP52. These-proteins and their 
use for regeneration of tendon and ligament-like tissue 
are disclosed in United States Patent 5,-658,882. 

55 

CARRIER 

[001 4] Materials which may be useful as the carrier in 



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practicing the present invention include pharmaceutical- 
ly acceptable materials having viscosity and polarity 
such that, when added to the bone morphogenetic pro- 
tein, form a composition that possesses appropriate 
handling characteristics (i.e., is neither too runny to re- 5 
main at the defect site) for application to the site of re- 
construction of the connective tissue to bone attach- 
ment. Adding the carrierto the bone morphogenetic pro- 
tein allows the protein to remain in the disease or lesion 
site for a time sufficient to allow the protein to increase 
the otherwise natural rate of regenerative osteogenic 
activity of the infiltrating mammalian progenitor celts, 
and to form a space in which new tissue can grow and 
allow for ingrowth of cells. The carrier may also allow 
the bone morphogenetic protein to be released from the 
defect or lesion site over a time interval appropriate for 
optimally increasing the rate of regenerative osteogenic 
activity of the progenitor cells. 

[0015] The most preferred family of carriers compris- 
es collagenous materials. Preferred collagen materials 
include Collastat* and Helistat R collagen sponges (In- 
tegra LifeSciences Corp., Plainsboro, N.J.). Other col- 
lagen materials which may be suitable for use in the 
present invention are described in United States Pat- 
ents 5,206,028; United States Patent 5,024,841 ; United 
States Patent 5,256,418. The collagen carrier is prefer- 
ably in the form of a sponge. The collagen sponge may 
be loaded with protein prior to administration by soaking 
the sponge in the desired volume and concentration of 
protein for a suitable time period. The collagen sponge 
is preferably soak loaded with protein in a range from 
about 10% to about 150%v/v[ml protein/cc dry sponge], 
more preferably about 10 to about 60% v/v. Alternative- 
ly, the protein may be adsorbed to the collagen sponge 
during production. In this case, bone morphogenetic 
protein is preferably added to the collagen sponge dur- 
ing production and tyophilized to form a unitary product. 
The protein is preferably added in a ratio of from about 
1 0 to about 1 50% v/v, more preferably in a range from 
about 60 to about 80% v/v. Other forms of collagen 
which may be useful in the present invention are colla- 
gen gel, and cross-linked polymeric collagen. 
[0016] Another preferred family of carriers for admin- 
istration of the bone morphogenetic proteins are porous 
particulate polymers, described in detail in United States 
Patent 5,171 ,579. Preferably the porous particulate pol- 
ymers are co-polymers of polylactic and polygtycolic ac- 
id. The protein and polymers are preferably sequestered 
by a sequestering agent, such as autologous blood. An 
alternative carrier useful for the present invention is a 
formulation of osteogenic protein, porous particulate 
polymers and another sequestering agent, such as cel- 
lulosic material. Other preferred sequestering agents in- 
clude hyaluronic acid, sodium alginate, poly(ethylene 
glycol), polyoxyethylene oxide, carboxyvinyl polymer 
and polyvinyl alcohol). Most preferred as the seques- 
tering agent for this embodiment is carboxymethylcellu- 
lose. These compositions are described in published 



PCT application WO 93/00050. The cellulosic protein 
sequestering agent is preferably present in a concen- 
tration of about 1 to about 1 0% (w/v implant) . The porous 
particulate polymer/cell ulosic sequestering agent may 
optionally be further combined with aqueous glycerol as 
a diluent, preferably in concentrations of about 10 to 
about 80% (v/v); and ratios of sequestering agent/liquid 
solution:porous particulate polymers are preferably 
from about 0.1 to about 0.9 (v/v). Alternatively, the po- 
rous particulate polymers may be formed into a fused 
sponge, as described in United States Patent 
5,520,923. The amount of osteogenic protein used with 
porous particulate polymers is generally in the range of . 

01 to 1 mg of protein, preferably .05 to .6 mg protein for 
each cubic centimeter of composition employed. 
[0017] Another preferred family of carriers is cellulosic 
materials such as alkylcellulose (including hydroxyalkyl- 
cellulose), including methyicellulose, ethylcellulose, hy- 
droxyethylcellulose, hydroxypropylcellulose, hydroxy- 
propylmethylcellulose, and carboxymethylcellulose, the 
most preferred being the cationic salts of carboxymeth- 
ylcellulose (CMC). 

[0018] In the case of cellulosic carriers and collagen 
gels, it is preferred that the carrier be in the form of a 
hydrated cellulosic viscous gel. Viscosity may be in- 
creased through mechanical means, such as high agi- 
tation for a suitable period of time, followed by autoclav- 
ing, or chemically. The BMP and cellulosic carrier is pref- 
erably in a solution of suitable buffer. One preferred buff- 
er solution is a composition comprising, in addition to 
the osteogenic protein, about 1 .0 to about 10.0% (w/v) 
glycine, about 0.1 to about 5.0% (w/v) of a sugar, pref- 
erably sucrose, about 1 to about 20 mM glutamic acid 
hydrochloride, and optionally about 0.01 to about 0.1% 
of a non-ionic surfactant, such as polysorbate 80. Pre- 
ferred solutions are from about 1% to about'20% w/v 
cellulosic carrier/buffer. If desired, a salt may be added. 
A preferred viscous gel carrier is described in Example 

2 below. The amount of osteogenic protein useful with 
viscous gel carrier is generally in a range of from about 
0.05 to about 1 .5 mg, preferably from about 0.1 to about 
1 .0 mg per cubic centimeter of implant material required. 
[001 9] Other materials which may be suitable for use 
as carriers for BMPs in the compositions prepared ac- 
cording to the present invention include hyaluronic acid, 
surgical mesh or sutures, polyglyconate, temperature- 
sensitive polymers, -demineralized bone, minerals and 
ceramics, such as calcium phosphates, hydroxyapatite, 
etc. , as well as combinations of the above described ma- 
terials. 

[0020] In one preferred embodiment of the present in- 
vention, however, no carrier is employed. Instead, the 
protein of the present invention, in a suitable buffer such 
as that described above, is applied directly to the site in 
need of tissue repair. For example, the protein may be 
applied using a brush or other suitable applicator, such 
as a syringe for injection . Alternatively, the protein may 
be directly applied to the site in need of tissue repair. 



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[0021] The following examples further describe the 
practice of embodiments of the invention with BMP-2 in 
a collagen sponge carrier. The examples are not limit- 
ing, and as will be appreciated by those skilled in the 
art, can be varied in accordance with the above speci- 5 
fication. 

EXAMPLES 

Example 1 : BMP-2 and Collagen Sponge Polymer 
Carrier In Surgically Created Tendon to Bone 
Detachment Defects 

[0022] Twenty adult mongrel dogs were used. The 
long digital extensor tendons of both knee joints were 
detached from their femoral insertion and transplanted 
through a drill hole in the proximal tibial metaphysis. The 
long digital extensor tendon of the knee joint of both hind 
limbs was detached from its femoral insertion and was 
transplanted, through a bone tunnel, into the proximal 
tibial metaphysis. Recombinant human BMP-2 (rhBMP- 
2) was applied to the tendon-bone interface in one limb, 
using a Type I collagen sponge as a carrier [Figure 1]. 
The contralateral limb received the collagen sponge 
with no rhBMP-2 [control]. 

[0023] The animals were anesthetized during sur- 
gery. The knee joint was approached through a lateral 
parapatellar incision; the long digital extensor tendon 
was identified and then was detached from its insertion 
on the lateral femoral condyle by sharp dissection. The 
fascia over the anterior tibialis muscle then was incised, 
and the muscle was retracted laterally. A drill-hole, 4.8 
mm in diameter, was made in the proximal tibial meta- 
physis at a 45-degree angle to the long axis of the bone. 
Helistat R collagen sponge was loaded with recombinant 
human BMP-2 (rhBMP-2), and the -sponge was then 
wrapped around the detached tendon. The free end of 
the tendon was pulled manually through the drill-hole 
and was fixed, under tension, on the medial aspect of 
the proximal tibial metaphysis with simple interrupted 
sutures of 4-0 stainless steel. The tendon fit snugly into 
the bone tunnel and was in contact with bone throughout 
the length of the tunnel. The joint capsule, fascia, and 
subcutaneous tissues were closed with interrupted su- 
tures of 3-0 chromic gut, and the skin was closed with 
interrupted sutures of 3-0 stainless steel. The procedure 
then was done on the contralateral knee. The limbs were 
not immobilized and the dogs were allowed exercise ad 
libitum in individual indoor runs. 
[0024] Eight dogs were sacrificed at two and four 
weeks; four dogs Were sacrificed at eight weeks. High 
resolution radiographs were made and microscopic sec- 
tions of the tendon-bone interface were examined under 
light and polarized light microscopy. Tetracycline-la- 
belled sections were examined under fluorescent micro- 
scopy. Biomechanical testing of ultimate load to failure 
was performed for the two and four week specimens on 
an MTS materials test machine at a strain rate of 50.8 



mm/second. The failure loads were averaged and the 
rhBMP-2 treated side was compared to the control side 
using a Students paired t-test. Results: Serial histolog- 
ic analysis revealed extensive proliferation of fibrob- 
lasts, plump osteoblast-like cells, and new bone trabec- 
ule in the tendon-bone interface in the rhBMP-2 treated 
limbs, compared with limbs that received the collagen 
carrier only. As healing progressed, the new bone 
trabeculae in the interface in the rhBMP-2 treated limbs 
matured and were in closer proximity to the tendon, 
while in the limb without rhBMP-2, there was a zone of 
fibrous or granulation tissue separating the tendon and 
the bone tunnel. Von Kossa stained sections and fluo- 
rescent microscopy of fluorochrome-labelled speci- 
mens demonstrated progressive mineralization of the 
newly formed bone in the tendon-bone interface. High 
resolution radiographs demonstrated that during the 
bone induction process, the pre-existing lamellar bone 
was resorbed and new bone was observed to progres- 
sively mineralize in the four and eight-week rhBMP-2 
specimens. There was no evidence of host immunologic 
response to the collagen implant. 
[0025] Paired comparisons of ultimate failure strength 
(N) demonstrated that the rhBMP-2 treated limbs were 
significantly stronger in both the two week specimens 
(p=0.035) and the four week specimens (p=0.05). There 
was a statistically significant increase in strength from 
two to four weeks in the rhBMP-2 treated limbs (p=0.02) 
and the control limbs (p=0.005). [Figure 2]. Discussion: 
Bone morphogenetic protein enhances the healing of a 
tendon graft in a bone tunnel. A previous study of ten- 
don-to-bone healing demonstrated a fibrous tissue in- 
terface between the tendon and bone. In the present 
study, rhBMP-2 induced extensive new bone deposition 
in this interface tissue, resulting in closer apposition of 
bone to the tendon at earlier time points and more reg- 
ular establishment of Sharpey's fibers between the ten- 
don and the bone in the rhBMP-2-treated limbs. The in- 
creased strength of fixation correlates with the histologic 
degree of bone ingrowth seen in the rhBMP-2 treated 
limbs. 



Claims 

1. Use of one or more bone morphogenetic proteins 
(BMP) for the preparation of apharmaceutical com- 
position for regeneration of a functional attachment 
between connective tissue ortendon and bone , with 
the proviso that said BMPs do not include BMP-12, 
BMP-13orBMP-15. 

2. The use of ~c\a\m 1 , wherein -said pharmaceutical 
compos itionfurthercomprises a protein which is ca- 
pable of inducing the formation of tendon- or liga- 
ment-like tissue. 

3. The use of claim 1 or 2, wherein said pharmaceuti- 



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cat composition comprises recombinant human 
BMP-2. 

4. The use of claim 2 or 3, wherein said protein capa- 
ble of inducing the formation of tendon- or ligament- 
like tissue is MP52. 

5. The use of any one of claims 2 to 4, wherein said 
BMP and said protein capable of inducing the for- 
mation of tendon- or ligament-like tissue form het- 
erodimers. 

6. The use of any one of claims 1 to 5, wherein said 
pharmaceutical composition further comprises a 
suitable carrier. 

7. The use of claim 6, wherein said carrier comprises 
collagenous materials, preferably in the form of a 
sponge, or porous particulate polymers and a se- 
questering agent. 

8. The use of claim 6, wherein the carrier is cellulosic 
viscous gel. 

9. The use of claim 7, wherein said sequestering agent 
is cellulosic material or autologous blood. 

Patentanspruche 

1. Verwendung eines Oder mehrerer morphogeneti- 
scher Knochenproteine (BMP) fur die Herstellung 
eines Arzneimittels zur Regeneration einerfunktio- 
nalen Bindung zwischen Bindegewebe Oder Sehne 
und Knochen, mit der MaBgabe, dass die BMPs 
nicht BMP-12, BMP-13 oder BMP-15 einschlieGen. 

2. Verwendung nach Anspruch 1 , wobei das Arznei- 
mittel weiterhin ein Protein umfasst, das in der Lage 
ist, die Bildung eines sehnen- oder bandahnlichen 
Gewebes zu induzieren. 

3. Verwendung nach Anspruch 1 oder 2, wobei das 
Arzneimittel das rekombinante menschliche BMP- 
2 umfasst. 

4. Verwendung nach Anspruch 2 oder 3, wobei das 
Protein, das in der Lage ist, die Bildung eines seh- 
nen- oder bandahnlichen Gewebes zu induzieren, 
MP52 ist. 

5. Verwendung nach einem der Anspruche 2 bis 4, wo- 
bei das BMP und das Protein, das in der Lage ist, 
die Bildung eines sehnen- oder bandahnlichen Ge- 
webes zu induzieren, Heterodimere bilden. 

6. Verwendung nach einem der Anspruche 1 bis 5, wo- 
bei das Arzneimittel weiterhin einen geeigneten 



Trager umfasst. 

7. Verwendung nach Anspruch 6, wobei der Trager 
kollagene Materialien umfasst, vorzugsweise in 

5 Form eines Schwammes, oder porose Polymerpar- 
tikel und ein Sequestriermittel. 

8. Verwendung nach Anspruch 6, wobei der Trager ein 
viskoses Cellulosegel ist. 

10 

9. Verwendung nach Anspruch 7, wobei das Seque- 
striermittel ein Cellulosematerial oder autologes 
Blut ist. 

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Revendications 

1 . Utilisation d'une ou plusieurs proteines mqrphoge- 
netiques de I'os (BMP) pour la preparation d'une 
20 composition pharmaceutique pour la regeneration 
d'un attachementfonctionnelentre le tissu conjonc- 
tif ou le tendon et I'os, a condition que lesdits BMP 
necomprennent ni BMP-12, ni BMP-13 ni BMP-15. 

25 2. Utilisation de la revendication 1 , ou ladite composi- 
tion pharmaceutique comprend de plus une proli- 
ne qui est capable d'induire la formation d'un tissu 
ressemblant a du tendon ou du ligament. 

30 3. Utilisation de la revendication 1 ou 2, ou ladite com- 
position pharmaceutique comprend BMP-2 humai- 
nes recombinantes. 

4. Utilisation de la revendication 2 ou 3, ou ladite pro- 
35 teine capable d'induire la formation de tissu res- 
semblant a du tendon ou du ligament est MP52. 

5. Utilisation de Tune quelconque des revendications 
2 a 4, ou lesdits BMP et ladite proteine capable d'in- 

40 duire la formation de tissu ressemblant a du tendon 
ou du ligament torment des hetero dime res. 

6. Utilisation de I'une quelconque des revendications 
1 a 5, ou ladite composition pharmaceutique con- 

45 tient de plus un support approprie. 

7. Utilisation de la revendication 6, ou ledit support 
comprend des matures collagenes de preference 
sous la forme d'une eponge ou de poly me res par- 

50 ticulaires poreux et un agent sequestrant. 

8. Utilisation de la revendication 6, ou le support est 
un gel visqueuxcellulosique. 

55 9. utilisation de la revendication 7, ou ledit agent se- 
questrant est une matiere cellulostque ou du sang 
autologue. 



6 



EP 0 831 884 B1 



Fig.1 




7 



EP 0 831 884 B1 



Fig-2 



Tendon Failure Strength 

mm Control ** 
= BMP "T" 

Mean±SD 

N=4 I 




2 Weeks 4 Weeks 



8 



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