WO1993024155A1 - Dispositif pour reparer des nerfs et son utilisation - Google Patents

Dispositif pour reparer des nerfs et son utilisation Download PDF

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Publication number
WO1993024155A1
WO1993024155A1 PCT/FI1993/000231 FI9300231W WO9324155A1 WO 1993024155 A1 WO1993024155 A1 WO 1993024155A1 FI 9300231 W FI9300231 W FI 9300231W WO 9324155 A1 WO9324155 A1 WO 9324155A1
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WIPO (PCT)
Prior art keywords
laminin
nerve
neurite outgrowth
peptide
collagen
Prior art date
Application number
PCT/FI1993/000231
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English (en)
Inventor
Päivi LIESI
Timo Kauppila
Original Assignee
Liesi Paeivi
Timo Kauppila
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liesi Paeivi, Timo Kauppila filed Critical Liesi Paeivi
Publication of WO1993024155A1 publication Critical patent/WO1993024155A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/044—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1128—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of nerves
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction

Definitions

  • the present invention relates to a medical device useful as a graft in repairing injured nerve tissues. It is a graft device composed of a collagen filter coated with neurite outgrowth promoting substances. The invention also comp- rises the preparation of the said device, and its use as a graft for repairing injured nerve tissues.
  • tubulization techniques have also been disclosed. These methods apply tubular grafts or implants fabricated from various biological materials. These grafts bring the stumps of the severed nerve close to each other as well as provide a suitable environment for nerve regeneration.
  • the ⁇ se grafts may also contain additives, such as growth fac ⁇ tors.
  • the PCT application WO 84/03035 discloses a longitudinally openable, porous, rough-surfaced tube of a natural or synthetic absorbable polymer. This polymer is said to support nerve regeneration as a tube but not as a membrane wrapped around the nerve. The tube is compared with resutu- ring, which is, however, done without sufficient numbers of animals to allow a reliable interpretation of the data. It is described that the nerve becomes bonded to the porous inner surface of the tube. It remains, however, unclear if the graft remains in its place merely due to this effect.
  • European patent application No. 277 678 discloses a graft for use in reconstructive surgery to repair e.g. damaged nerve tissue.
  • the graft comprises porous matrix of an organic polymeric material incorporating optionally addi- tives, such as growth factors.
  • the application does not, however, contain any information about the use of the said graft.
  • PCT-application WO 89/10725 discloses a method for produ- cing a biodegradable polymer having a preferentially oriented pore structure, and a method for using this poly ⁇ mer to regenerate damaged nerve tissue.
  • Navarro et al . (1991) disclose a comparative study of nerve regeneration using collagen conduits optionally coated with laminin. The conduits must, however, be sutured in their place. Furthermore, the results obtained showed that lami ⁇ nin did not exert any positive effect in the reinnervation.
  • the prior art does not provide a method that would be an improvement as compared to the methods in use at pre ⁇ sent.
  • the degree of the regeneration is un- clear in most cases, as only few investigators have inclu ⁇ ded an adequate control, e.g. resuturing, to compare the efficiencies of their resuturing applied in restorative surgery.
  • the PCT application WO 84/03035 is the only one in which resuturing is replaced by a graft. However, this method does not significantly reduce autotomy as compared to the resuturing. Furthermore, regeneration was only assessed by histological examination, without testing of a functional recovery. Many factors that promote nerve growth are known in the art. One of the factors, known to enhance outgrowth of axons of cultured neurons is laminin. Laminin is a 1000 kDa extracellular matrix protein that promotes neurite out- growth in vitro (Baron van Evercooren et al. 1982), and correlates with regenerative CNS systems in vivo (Liesi, 1985).
  • Laminin has been used in the form of a gel (Madison et al. 1985), a soluble agent (Muller et al. 1987, Muller 1988) or a molecule attached to silicone fibres (Yoshii et al. 1985).
  • a 12 amino acid peptide from the C-terminal region of the B2-chain of mouse laminin has been shown to promote neurite outgrowth of cultured neurons in both soluble and substrate bound forms (Liesi et al. 1989).
  • the present invention thus provides a new kind of device for use as a graft in nerve repair, the device comprising a collagen filter coated with at least one of the neurite outgrowth promoting substances selected from the group consisting of laminin, a peptide of a neurite outgrowth promoting domain of laminin, and an antibody raised against said domain of laminin.
  • a preferable peptide for the device of this invention is the 10 amino acid peptide of a neurite outgrowth promoting domain of the B2 chain of mouse laminin, or its human analogue.
  • the graft of the invention comprising pure protein or peptide, is sticky when wetted and remains in its place like a "fly-paper". Thus, use of this graft is rapid and minimizes manipulation of the nerve as no suturing is required.
  • Collagen used in this invention may be any type I collagen, but preferably type I collagen suitable for medical use.
  • type I collagen suitable for medical use.
  • clinically acceptable bovine tendon type I collagen was used as a back-bone for the filters.
  • the laminin used in the grafts of the experiments is pu ⁇ rified from the mouse EHS tumor using published methods (Timpl et al . , 1979). Human laminin or recombinant mamma ⁇ lian laminin may also be used.
  • the 12 amino acid neurite outgrowth promoting peptide from the C-terminal region of the B2-chain of mouse laminin was identified by Liesi et al. 1989.
  • the published peptide has an amino acid sequence Arg-Asn-Ile-Ala-Glu-Ile-Ile-Lys-Asp- Ile-Glv-Cvs.
  • the 10 amino acid form excluding the two last amino acids, is preferable.
  • the 10 amino acid peptide is called p20.
  • this peptide can be prepared according to Liesi et al . 1989, except that Gly-Cys present in the published form can be omitted.
  • the corresponding human analogue of the said mouse neurite outgrowth promoting peptide has an amino acid sequence Arg- Asp-Ile-Glu-Glu-Ile-Met-Lys-Asp-Ile.
  • This peptide can be produced as the mouse peptide and it is called p20-HU.
  • the peptides are prepared in the C-terminal acid form.
  • the antibodies against the neurite outgrowth promoting pep- tide of the mouse B2 chain is produced in rabbits by met ⁇ hods known as such, i.e. by immunizing the animals with sequential injections of the peptide antigen.
  • soluble collagen is spread onto an aluminium block having suitable dimensions, another block is located onto the said first block, and even pressure is subjected to the material in the apparatus.
  • the apparatus is quick frozen on dry ice whereby the collagen layer in it also freezes.
  • the apparatus is then located in a lyofilizer whereby the material forms a filter.
  • a layer of laminin and/or desired peptides or antibodies is conse ⁇ cutively pressed on top of the collagen filter.
  • grafts of the invention can be fabricated by coating commercially available collagen filters (Helisert V301 or V166, Helitrex, Princeton, NJ, USA) with laminin and/or the desired peptides or antibodies using the above described apparatus.
  • commercially available collagen filters Helisert V301 or V166, Helitrex, Princeton, NJ, USA
  • a process for the repair of an injured nerve is also described, wherein the graft defined above is provided, the said graft is wrapped around the stumps of the injured nerve, and the nerve is allowed to regenerate.
  • Fig. 2 The degree of autotomy using the laminin graft vs. resuturation.
  • a significant diffe ⁇ rence between the groups is indicated by an asterisk (p ⁇ 0.05; Mann-Whitney U-test).
  • Fig. 4 Double immunocytochemistry for the NGF receptor (A,C,E) and neurofilaments (B,D,F) in the proximal areas of the resutured (A-B), and laminin (C-D) or its neurite outgrowth promoting peptide (E-F) grafted nerves 20 days after operation.
  • NGF receptor immunoreactivity in the distal stump areas (A-B) of the resutured (A) or laminin grafted (B) animals and double immunostaining for NGF receptor (C,E), and neurofilaments (D,F) in the distal stumps of the neuri- te outgrowth promoting peptide grafted animals 20 days after operation.
  • FIG. 6 Immunocytochemical demonstration of the neurite outgrowth promoting domain of the B2 chain of laminin (A,C,D), and its free peptide antigen (B) in the peptide grafted animals in the graft area (A,B,D), and in the proximal stump (C).
  • A-B the same photographic field is immunostained with an antibody that recognizes both the free decapeptide as well as this domain in the B2 chain of laminin.
  • Fig. 7 The ability of the p20-HU to promote neurite out ⁇ growth in vitro .
  • Fig. 8 The ability of the antibody against the p20 to promote neurite outgrowth in vivo is verified.
  • A the preimmune serum of the rabbit immunized with p20 is used.
  • B the antibody to p20 is applied onto the filter.
  • C the resuturing of the nerve.
  • a graft of laminin, collagen alone, or a graft comprising the mouse neurite outgrowth promoting peptide p20, its human analogue or antibody against the mouse peptide were inserted to join a 10 mm long gap between the stumps of a transected sciatic nerve, immunohistochemistry was applied to verify nerve regenera ⁇ tion, and resuturing of the cutted piece of nerve served as a control.
  • the grafts supported a short term regeneration of the sciatic nerve across the gap as effectively as resuturing. This was apparent by the demonstration of outgrowth of neurofilament positive nerve fibres from the proximal stump into the graft, and to the distal stupm area (Fig. 3-5). This nerve fibre outgrowth occured within 20 days after the operation, whereas in the collagen grafted animals the neurites did not grow into the graft areas.
  • NGF receptor As the low affinity NGF receptor has been linked to pe- ripheral nerve regeneration (Taniuchi et al . , 1986; Heumann et al., 1987), we used antibodies directed against this receptor to monitor regeneration in grafted or resutured sciatic nerves.
  • the NGF receptor was weakly ex ⁇ pressed by groups of the presumptive Schwann cells in the proximal nerve stump (Fig. 3).
  • 3A the NGF receptor is expressed by scattered Schwann cells in the nerve, and neurofilament immunoreactive nerve fibre bundles grow in between the NGF receptor positive areas (3B).
  • 3C-D a similar distribution of the NGF receptor is apparent in the laminin grafted animal.
  • 3E-F the proximal stump of a neurite outgrowth promoting domain grafted animal show scattered NGF receptor immunoreactivity (E), and neurofila- ment positive nerve fibre bundles (F).
  • E scattered NGF receptor immunoreactivity
  • F neurofila- ment positive nerve fibre bundles
  • 3G the NGF receptor immunoreactivity is markedly increased in the collagen grafted animal.
  • 3H double immunostaining shows neurofilament positive nerve fibre bundles slightly swollen and disorganized.
  • the NGF receptor expressed at high levels by all Schwann cells (Fig. 5).
  • 5A intense immunoreactivity for the NGF receptors is shown in all the Schwann cells.
  • 5B a similar distribution of the NGF immunoreactivity is demonstrated in the laminin grafted nerve.
  • 5C the NGF receptor expression in the distal stump is elevated also in the peptide grafted nerve.
  • 5D double immunocytochemical demonstration of neurofilaments reveals massive regeneration.
  • the Schwann cells are immunoreactive for the NGF receptor (5E), and double im ⁇ munocytochemistry for neurofilaments (5F) shows that the Schwann cells are in close contact with regenerating nerve fibres that have varicosities (5F).
  • a pattern of the low affinity NGF receptor expression was thus detected in the nerves restored using grafts of la ⁇ minin or the neurite outgrowth domain of the B2 chain of laminin.
  • the NGF receptor activity was highest in the distal stump area, low in the graft and scattered in the proximal stump area.
  • the B2 chain immunoreactivity was present in a few scattered Schwann cells, whereas this immunoreactivity was markedly increased in the proximal graft areas (6D), and in the distal stump of the peptide grafted nerves (not shown).
  • the B2 chain immunoreactivity was identical to that of the peptide grafted nerves (Fig.6), whereas the collagen grafted nerves showed low levels of the B2 chain immunoreactivity in the proximal graft areas (not shown). The ability of an antibody against the p20 to promote neurite outgrowth in vivo was also verified.
  • a 1 cm gap was reconnected with a graft containing 200 ⁇ l of 10 ⁇ g/ml concentration of the preimmune serum (Fig. 8 A), or the antibody against p20 (8B) . Resuturing of the cut 1 cm piece of the nerve (8C) was used as a control.
  • the 200 kDa neuro ⁇ filament protein is demonstrated in the distal part of the nerve using monoclonal antibodies (Boehringer, Germany, RT 97). Note that in 8A no nerve fibres are growing. The only neurofilament positive structures are accumulations of depri, typical in Wallerian degeneration.
  • the ability of the p20-HU to promote neurite outgrowth was investigated as described in the experimental section. It was shown that addition of 100 ⁇ g/ml of the peptide p20-HU into the culture medium of cerebellar neurons grown on a laminin substrate support significantly the neurite out- growth of cerebellar neurons p ⁇ 0.005 (Fig. 7).
  • Laminin and its neurite outgrowth promoting domain may also function as both soluble and substrate bound trophic fac- tors in a regenerating peripheral nerve. This idea is supported by the three lines of evidence:
  • mice Female Han-Wistar rats (age 3 months, weights 250-300 g) were used in all experiments. The rats were housed in groups of six, having food and water ad libitum. The animal house had lights on 6.00-18.00 h, and humidity in the room was 35-55percent. All the experimentation was performed under an approved animal licence from the Provincial Go- vernment of Uusimaa, Finland.
  • a graft was produced by first laying down 1 mg/ml con- centration of bovine tendon collagen on an aluminium block having a space of about 0.3 mm thick and 1 cm wide. This was closed by another aluminium block having lines of about 0.3 mm thick and 0.1 mm wide crossing each other. These two aluminium blocks were placed towards one another and a constant pressure was created by pressing them firmly against each other. The apparatus containing the bovine tendon collagen was then quick frozen in powdered dry ice, and the material was lyophilized overnight in a standard lyophilizer.
  • the mouse EHS-tumor laminin was purified according to published methods (Timpl et al., 1979), and 400 ⁇ l of 100 ⁇ g/ml concentration of laminin sprayed onto the collagen filter placed in the same device on dry ice. The aluminium block was sealed again with its upper part after which the frozen materials were lyophilized.
  • the mouse peptide p20 or its human analogue were prepared in the C-terminal acid form as described (Liesi et al., 1989) or supplied by Multiple Peptide Systems, Inc. (San Diego, CA). These materials were applied at 100 ⁇ g/ml concentration. Each filter obtained 200 ⁇ l of such solu ⁇ tion.
  • Rabbit antibodies to the mouse peptide p20 were prepared as described (Murtomaki et al., 1992), i.e. by immunizing rabbits with 10 sequential injections of a 100 ⁇ g/injection of the 10 amino acid peptide antigen, and the IgG fraction purified by a protein A Sepharose column. The antibody obtained (anti-1543) was applied on top of the collagen filter at a final concentration of 10 ⁇ g/ml.
  • the other grafts used in the described experiments were prepared by lyophilizing the described concentrations of laminin, the mouse peptide p20 or its human analogue or antibodies to the mouse peptide on top of the collagen filters purchased by Helitrex.
  • Example 2 Nerve regeneration in vivo
  • mice Four months after surgery the rats were anesthetized with pentobarbital (60 mg/kg). The restoration of muscle rein- nervation was evaluated by comparing the amplitude of the maximal twitch and tetanic tensions of the operated ex ⁇ tensor muscles of the ankle with those of the contralateral unoperated control side, (Brunetti et al. 1987). In the end of the tests the rats were sacrified with an overdose of pentobarbital, the muscles were dissected free and weighed immediately (Sartorium, USA). The statistical analysis of the data was carried out with the Student's t-test.
  • cryostat sections were fixed in 0.4% p-benzoquinone in PBS for 15 min, washed in PBS and dehydrated and rehydrated as desc ⁇ ribed (Liesi and Silver, 1988).
  • Rabbit antibodies to neu ⁇ rofilaments (Dahl and Bignami, 1977), the neurite outgrowth promoting domain of laminin (Murtomaki et al . , 1992), or mouse monoclonal antibodies to NGF receptor (Yan and Johns- son, 1988) were applied at 1:1000, 10 ⁇ g/ml and 1:2000 dilutions, respectively. After an overnight incubation with the first antibodies, the sections were washed in PBS and exposed to second antibodies for 1 hour.
  • the ability of the p20-HU to promote neurite outgrowth was investigated in vitro by comparing the numbers of neurons with long neurites (>10 times the cell soma) on a laminin substrate with or without 100 ⁇ g/ml of the peptide p20-HU included in the culture medium.
  • cerebellar tissue from 5 day old rats was dissected aceptically, and the cells dissociated as described (Liesi et al., 1989). They were plated on LAMININ substrate at a density of 1 x 10 5 and cultured overnight in a serum-free RPM medium.
  • the p20- HU was added to the cells simultaneously with the plating.

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Abstract

L'invention concerne un dispositif médical utile comme greffe pour réparer des tissus nerveux meurtris. Ce dispositif servant de greffe est constitué d'un filtre de collagène enrobé d'une substance favorisant la croissance des axones choisie dans le groupe de la laminine, d'un peptide du domaine de la laminine favorisant la croissance des axones et d'un anticorps dirigé contre ledit domaine. L'invention concerne également la préparation dudit dispositif et son utilisation comme greffe pour réparer des tissus nerveux meurtris.
PCT/FI1993/000231 1992-05-29 1993-05-28 Dispositif pour reparer des nerfs et son utilisation WO1993024155A1 (fr)

Applications Claiming Priority (2)

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FI922517 1992-05-29
FI922517A FI922517A (fi) 1992-05-29 1992-05-29 Nervrepareringsmedel och dess anvaendning

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014135A1 (fr) * 1996-10-04 1998-04-09 Regents Of The University Of Minnesota Tiges d'equivalents de tissus et de biopolymeres a orientation magnetique
US6194182B1 (en) 1994-10-06 2001-02-27 Regents Of University Of Minnesota Magnetically oriented tissue-equivalent and biopolymer tubes
WO2003035675A1 (fr) * 2001-10-26 2003-05-01 Liesi Paeivi Peptides actifs biologiquement et leur utilisation dans la reparation de nerfs endommages
WO2009039973A2 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984003035A1 (fr) * 1983-02-02 1984-08-16 Minnesota Mining & Mfg Procede et dispositif absorbables pour la reconstitution des nerfs
EP0286284A1 (fr) * 1987-03-30 1988-10-12 Brown University Research Foundation Voie de guidage semi-perméable pour des nerfs
US5026381A (en) * 1989-04-20 1991-06-25 Colla-Tec, Incorporated Multi-layered, semi-permeable conduit for nerve regeneration comprised of type 1 collagen, its method of manufacture and a method of nerve regeneration using said conduit

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984003035A1 (fr) * 1983-02-02 1984-08-16 Minnesota Mining & Mfg Procede et dispositif absorbables pour la reconstitution des nerfs
EP0286284A1 (fr) * 1987-03-30 1988-10-12 Brown University Research Foundation Voie de guidage semi-perméable pour des nerfs
US5026381A (en) * 1989-04-20 1991-06-25 Colla-Tec, Incorporated Multi-layered, semi-permeable conduit for nerve regeneration comprised of type 1 collagen, its method of manufacture and a method of nerve regeneration using said conduit

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 110, No. 19, 8 May 1989, (Columbus, Ohio, USA), LIESI, PAIVI et al., "Identification of a Neurite Outgrowth-Promoting Domain of Laminin Using Synthetic Peptides", Abstract No. 170843j; & FEBS LETT., 1989, 244(1), 141-148. *
NEURO REPORT, Volume 2, 1991, XAVIER NAVARRO et al., "Effects of Laminin on Functional Reinnervation of Target Organs by Regenerating Axons", pages 37-40. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057137A (en) * 1994-10-06 2000-05-02 Regents Of The University Of Minnesota Tissue-equivalent rods containing aligned collagen fibrils and schwann cells
US6194182B1 (en) 1994-10-06 2001-02-27 Regents Of University Of Minnesota Magnetically oriented tissue-equivalent and biopolymer tubes
US6461629B1 (en) 1994-10-06 2002-10-08 Regents Of The University Of Minnesota Method of nerve regeneration using biopolymer rods with oriented fibrils
US6544762B1 (en) 1994-10-06 2003-04-08 Regents Of The University Of Minnesota Magnetically oriented tissue-equivalent and biopolymer tubes and rods
WO1998014135A1 (fr) * 1996-10-04 1998-04-09 Regents Of The University Of Minnesota Tiges d'equivalents de tissus et de biopolymeres a orientation magnetique
WO2003035675A1 (fr) * 2001-10-26 2003-05-01 Liesi Paeivi Peptides actifs biologiquement et leur utilisation dans la reparation de nerfs endommages
AU2002336124B2 (en) * 2001-10-26 2008-07-03 Paivi Liesi Biologically active peptides and their use for repairing injured nerves
US7659255B2 (en) 2001-10-26 2010-02-09 Paivi Liesi Methods of inhibiting glutamate receptors by administering the tripeptide KDI
US7741436B2 (en) 2001-10-26 2010-06-22 Liesi Paeivi Biologically active peptides and their use for repairing injured nerves
WO2009039973A2 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009039973A3 (fr) * 2007-09-11 2009-07-23 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique

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AU4072393A (en) 1993-12-30
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