EP2010238A2 - Composition améliorée de colle à la fibrine et utilisation de cette dernière - Google Patents

Composition améliorée de colle à la fibrine et utilisation de cette dernière

Info

Publication number
EP2010238A2
EP2010238A2 EP07722567A EP07722567A EP2010238A2 EP 2010238 A2 EP2010238 A2 EP 2010238A2 EP 07722567 A EP07722567 A EP 07722567A EP 07722567 A EP07722567 A EP 07722567A EP 2010238 A2 EP2010238 A2 EP 2010238A2
Authority
EP
European Patent Office
Prior art keywords
composition according
fibrin
composition
based material
polyglucosamine
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07722567A
Other languages
German (de)
English (en)
Inventor
Niels Erik Holm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vivolution AS
Original Assignee
Vivolution AS
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 Vivolution AS filed Critical Vivolution AS
Publication of EP2010238A2 publication Critical patent/EP2010238A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0042—Fibrin; Fibrinogen
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/106—Fibrin; Fibrinogen

Definitions

  • the present invention relates to the field of homeostasis and tissue regeneration. More specifically, the invention pertains to improved fibrin sealant compositions and their application and uses.
  • the entire wound healing process is a complex series of events that begins at the moment of injury and may continue for months to years.
  • the first 2-5 days is called the inflammatory phase, during which first hemostasis is taking place by vasoconstriction, platelet aggregation and clot formation by thromboplastin, followed by inflammation characterized by vasodilation and phagocytosis.
  • the next approximately 3 weeks is called the proliferative phase, starting with granulation where fibroblasts lay bed of collagen, and defect capillaries are filled and new produced. During contraction wound edges pull together, and at epithelialization surfaces are covered with cells.
  • the remodeling phase may last for 3 weeks to 2 years. Here new collagen forms which increases tensile strength .
  • fibrin sealants also called fibrin adhesives or fibrin glues are based on the polymerization of fibrinogen monomers to an insoluble network (clot). The process is initiated when thrombin is cleaving fibrinogen to fibrin II acid-soluble monomers, and when thrombin in the presence of Ca++ is activating Factor XIII to Factor XIIIa. Fibrin II acid-soluble monomers are then converted by Factor XIIIa into an acid-insoluble cross linked fibrin II polymer.
  • fibrin sealant has been described for a variety of medical procedures, such as hemostatic agents, absorbent of excess fluid, surgical adhesion barrier, wound dressing and delivery vehicle of biologically active substances.
  • Numerous ways of applying fibrin sealant are known in the art. They are all developed with respect to the rapid polymerization of the fibrin sealant following mixing of the fibrinogen component and the thrombin component. In one method the mixture is drawn into an appropriate size syringe and must be rapidly applied to the de- sired site. In another method double barrel syringe is used. Other methods employ microdrop delivery systems or spray application systems. Some of the methods require special applicators. In yet other methods the components are fixed to a carrier material, alternatively one or more of the components may be in a non- liquid form, such as e.g. powder.
  • Biocompatible and biodegradable polymers have been identified as suitable carrier material for fibrin sealant components. Such polymers confer the advantages that a fibrin sealant fabric may be prepared in beforehand and is activated when placed on a wound site (US 6,503,527). Examples of useful polymers are polyglucosamin based material such as hyaluronic acid (HA) and chitin/chitosan. HA has also been described as a preferred viscosity enhancing polymer to keep fibrin sealants from dislocating from the application site (EP 0590015).
  • HA hyaluronic acid
  • HA has also been described as a preferred viscosity enhancing polymer to keep fibrin sealants from dislocating from the application site (EP 0590015).
  • Polyglucosamin based material may in addition to the above mentioned uses also possess other advantages.
  • HA is used in plastic surgery for removing of wrinkles, and physicians have for the past 20 years injected HA directly into the synovial fluid of the knee as a treatment for osteoarthritis.
  • the bioavailability of HA per se is limited due to its rapid turnover and short half life.
  • Chitosan which has been used as a dietary supplement for obtaining weight loss, has also been found to be useful in wound healing (US 4,532, 134).
  • fibrin sealant compositions have been employed wherein one or more of the components comprised are in a solid phase, like e.g. fiber, sheet or powder, or delivered by means of a solid phase carrier material. Such partly solid phase compositions may be prepared in good time before use due to the delay in initiation of the polymerization process.
  • the present invention relates to a liquid phase composition, wherein the liquid components of said composition upon application to a desired site is form- ing a fibrin sealant, comprising fibrin monomer or polymer, fibrinogen-cleaving agent and polyglucosamine based material.
  • a fibrin sealant comprising fibrin monomer or polymer, fibrinogen-cleaving agent and polyglucosamine based material.
  • the present invention relates to a method of preparing the composition, wherein the components of the composition are prevented from polymerizing by storage in a low pH buffer until use.
  • the present invention relates to a method of applying the composition comprising the steps of providing the components of the composition, providing an applicator device, wherein said device comprises at least two outlets for reagents and at least one outlet for air, and applying said components of the composition to the desired site using the applicator device.
  • the present invention relates to use of the composition for supporting cell growth.
  • Figure 1 is a chromatogram showing the result from SEC-MALLS-VISC analyses for extracts from clot with and without HA added (sample C and A, respectively). Legend: Sample A; lower line and sample C; upper line.
  • Figure 2 is a chromatograms showing the result from SEC-MALLS-VISC analysis for extract from clot with HA added (sample B).
  • Figure 3 is a picture of the ring for making the polymerized fibrin or platelet rich fibrin tablet.
  • FIG 4 are pictures of the Mueller Hinton agar plates plated with either S. aureus or E. coli
  • Figure 7 is an illustration of moulded clots.
  • Figure 8 is a figure illustrating the weight loss of moulded clots within the first 18 hours.
  • One embodiment of the present invention relates to the liquid phase composition, wherein the liquid components of said composition upon application to a desired site is forming a fibrin sealant comprising fibrin monomer or polymer, fibrinogen- cleaving agent and polyglucosamine based material, that is partially cross-linked or partially polymerized for at least 1 minute after application to a desired site.
  • the performance of a liquid fibrin sealant composition is determined by its physical properties, such as the ability to adhere to the site of application without dislocating, elasticity and tensile strength, which are formed during polymerization. In clinical use instant polymerization of fibrin sealant with defined physical properties is required. This must of cause be balanced with the time needed for handling the fibrin sealant.
  • Partially cross- linked or partially polymerized as used herein, means that the process of clot formation has not been fully completed.
  • the liquid composition of the present invention is suitable for most uses, as the fi- brin sealant conforms to the site of application.
  • the rapid polymerization secures that the fibrin sealant remains at the site of application and is not removed by bodily fluid or target movements. Therefore, the present invention does not need addition of components for providing an increased viscosity or a carrier material.
  • By one or more applications of said liquid phase composition it is possible to build up a fibrin sealant structure having the desired elasticity and tensile strength.
  • “Fibrin” as used herein, means fibrin, fibrin I or fibrin II.
  • Fibrinogen cleaving agent as used herein, means an enzyme capable of cleaving either peptide A or peptide B or both from fibrinogen.
  • Fibrinogen-cleaving agents commonly used in fibrin sealants are thrombin, which may be obtained from any suitable source such as e.g. human or bovine, enzymes from snake venom such as e.g. batroxobin, calobin, fibrozyme, and enzymes from the venom of Bothrops jara- racussu.
  • Polyglucosamine based material as used herein, means a molecule where the glucosamine is a repeated part of the molecule. It comprises biocompatible and bioab- sorbable materials such as hyaluronic acid, chitin/chitosan and derivatives thereof.
  • Chitin is widely distributed in both plant and animal kingdom, where its main func- tion is to provide structural and skeletal support.
  • Chitin is a linear homopolymer of beta-D(l-4) linked 2-acetamido-2-deoxy-D-glucopyranose (N-acetylglucosamine) units, of which a portion, typically about 15%, is N-deacetylated.
  • the fully acety- lated polymer is called chitan and the fully deacetylated polymer is called chitosan.
  • Hyaluronic Acid also called hyaluronan is a linear polymer of the disaccharide repeat unit, D-Glucuronic acid and N- Acetyl D- Glucosamine.
  • This mucopolysaccharide has shown to possess different biological properties depending on the molecular weight.
  • HA has an extraordinarily high rate of turnover in vertebrate tissues, with a half life of 2-5 mitutes, and is being removed by degradation with time, even with the highest molecular weight. Furthermore, viscosity of the high molecular weight solution confers a major problem during application.
  • the present invention demonstrates in example 1 that a polyglucosamin, such as HA surprisingly was trapped within fibrin sealants clots whereby its rapid turn-over and short half life were delayed.
  • a polyglucosamin such as HA
  • This provides for a broader employment in the selection and use of various molecular weight polyglucosamines.
  • the retention of HA in fi- brin clots may allow for use of low molecular weight polyglucosamines in combination with fibrin sealants, thereby making the delivery more continent due to the lower viscosity of the components.
  • Example 2 of the present application demonstrates the antibacterial effect of chitosan.
  • Other investigations have also reported this property of chitosan (US 4,532,134).
  • chitosan when applied alone decreased the tensile strength of the wound at an early stage of the wound healing process and did not provide any significant effect at a later stage.
  • An initial study has indicated that HA may help to decrease the incidence of bacterial infection in bronchitis (Venge, P., 1996 Am J Respir Crit Care Med 153(l):312-6). Therefore, the co-application of chitosan, HA or other polyclucosamines together with fibrin sealant, as proposed in the present invention, may confer the composition the addi- tional feature of anti-mi crobial activity.
  • High fibrin density may affect the proliferation and mobility of cells in the fibrin matrix, and thus affect the wound healing process.
  • Initial studies have shown that high fibrin density results in a compact network in which the in-growth of cartilage cells is prevented, whereas a relative lower fibrin density resulted in an HA expanded and thus more lose network in which said cells may grow.
  • a cellular compatible media such as po- lyglucosamine.
  • the polyglucosamine based material comprises at least 50% glucosamine monomers.
  • the polyglucosamine based material is selected from the group consisting of hyaluronic acid material, hyaluronic acid derivative material, chitin material, chitin derivative material, chitosan material and chitosan derivative material.
  • polyglucosamine based material also embraces materi- als comprising at least one modified monomer.
  • the modification may for example be chemically and non- limiting examples of the principal targets for modification is the carboxyl group present at N- Acetyl D-Glucosamine and the hydroxyl group present at D-Glucuronic acid, additional sites may be reducing end modification or N- acetyl.
  • monomers may be modified by numerous cross-linking strate- gies which are known in the art, many of which are described at www.glycoforum.gr.jp.
  • the polyglucosamine based material comprises a mixture of different materials.
  • the polyglucosamine based material comprises a mixture of different molecular sizes.
  • the polyglucosamine based material comprises a mixture of both different materials and different molecular sizes.
  • the combined use of chitosan and HA results in a protection of HA from enzymatic hydrolysis, and thus different material of different sizes may be selected for use depending on the requirement for resistance against degradation of the polyglucosamine based material.
  • the degree of acetylation of the polyglucosamine based material is from 0 to 100%.
  • compositions further comprising cells.
  • the cells may be included in a solution together with any other component or the cells may be kept in a separate solution. This may be determined depending on the origin of the cells and the selection of the best environment for viable cells. For example platelets may be isolated from the same source as the fibrin and is therefore already present in the fibrin containing solution. If cells are cultured the cells may be provided suspended in cell growth media, alternatively cells may be suspended in other suitable solutions further comprising one or more other components.
  • the cells are selected from the group consisting of platelets, stem cells, fibroblasts, keratinocytes, cartilage cells and bone cells.
  • One embodiment of the invention relates to the composition further comprising growth factors.
  • the growth factors may be included in a solution together with any other component or may be supplied in a separate solution. Such growth factor may aid in creating the best possible condition for the effector cells delivered to or already present at the wound site. Application of growth factors together with the fi- brin sealant saves a step in the wound treatment procedure.
  • the growth factors are selected from the group consisting of Epithelial Growth Factor (EGF), Fibroblast Growth Factor (FGF), Platelet Derived Growth Factor (PDGF), Transforming Growth Factor alpha (TGF ⁇ ), Transforming Growth Factor beta (TGF ⁇ ) and Interleukin- 1.
  • EGF Epithelial Growth Factor
  • FGF Fibroblast Growth Factor
  • PDGF Platelet Derived Growth Factor
  • TGF ⁇ Transforming Growth Factor alpha
  • TGF ⁇ Transforming Growth Factor beta
  • Interleukin- 1 Interleukin- 1.
  • One embodiment of the invention relates to a method of preparing the composition, wherein the components of the composition are prevented from polymerizing by storage in a low pH buffer until use, wherein the pH is 4.
  • the components of the composition are prevented from polymerizing by storage in two or more separate reservoirs until use.
  • One embodiment of the invention relates to a method of applying the composition to the desired site, comprising the steps, providing the components of the composition, providing the applicator device, wherein said device comprises at least two outlets for reagents and at least one outlet for air, and applying said components of the composition using the applicator device,
  • the device comprises three, four or five outlets for reagents and at least one outlet for air.
  • a spray applicator device such as e.g. Vivostat® application system (Dodd, R. A., 2002 Technology and Health Care 10:401-11) provides easy application and dosage, and a homogenous mixture of the components.
  • One embodiment of the invention relates to the use of the liquid phase composition for supporting cell growth. This may for example be done by adding to said composition additional (support) cells, growth factors, and the like for improving the conditions for cell proliferation, cell activation, cell migration or cell differentiation.
  • the composition is used as a delivery vehicle for biologically active substances.
  • biologically active substances Non-limiting examples may be anti-bacterial substances, drug substances, cells, growth factors, moist substances etc.
  • the composition is used as a surgical adhesion barrier.
  • the composition is used as an absorbent of excess fluid.
  • Hyaluronic acid is found in all connective tissue of the body where it per- formes special functions of lubrication.
  • HA is also called hydrogel due to its ability to bind and retain large amount of water.
  • the composition is used for reducing scar tissue formation.
  • Application of chitosan alone has been shown to prevent fibrosis formation by fibro- blasts, which is considered as scar tissue, and instead endothelial lining were ob- served (US 4,532,134).
  • inclusion of polyglucosamines such as e.g. chitosan, its derivatives or other polyglucosamines, may reduce the formation of scar tissue.
  • Example 1 Retention of Hyaluronic Acid (HA) in fibrin sealant.
  • the purpose was to determine the amount of HA extractable from the fibrin clot and thereby determine how much was retained. Furthermore, the molecular weight of the extractable HA was determined.
  • Sample A labeled "0,484g Fibrin” contained 20mg/ml fibrin.
  • Sample B labeled "0,568g Fibrin” contained approx. 10mg/ml fibrin and 1% HA
  • Sample C labeled "0,535g Fibrin” contained 20 mg/ml fibrin and 1% HA (v/v)
  • HA (MAG 30014 supplied by NovoZymes) with a molecular weight at 800 kDa was co-applied in a 1% solution with fibrin (fibrin:HA ratio 1:8). HA was extracted on the same day as preparation of clot. All samples were obtained from the same donor.
  • Extracts were crushed with a spatula against a glass wall before extraction in 10ml PBS buffer for 4x24h at 4°C with slight agitation. Extracts were collected by centrifuga- tion (lOmin, 3000rpm, 4 0 C), 5ml deionized milliQ H 2 O was added before passing through a 0.45 ⁇ m syringe filter. Extracts were stored at 4 0 C prior to analysis after 2 days. Quantification and characterization.
  • the extracts where analyzed by SEG-MALLS- VISG (mobile phase: 15OmM NaCl, 5OmM NaH 2 PO 4 , pH 7.0, 0.5ml/min) on a PL aquagel OH-40/0H-50/0H60 column.
  • System Waters Alliance HPLC system Waters 2410 RI detector and Wyatt MALLS detector.
  • Quantification was done by evaluating the RI signal. 0.5ml of each sample was injected on the column. The data was processed using the ASTRA V software from Wyatt Technology Corp. The samples were labeled: A: 14919-037-1, B: 14919-037- 2, and C: 14919-037-3.
  • Peak 1 The high molecular weight peak (peak 1) was identified as HA since it only appeared in sample B and C containing HA. Further, comparing molecular weight (Table 2), intrinsic viscosity (Table 3) and radius of gyration (Table 4) all indicate that peak 1 is indeed HA. Peak 2 and 3 are either proteins or protein fragments from the clots. Calculated quantities are summarized in Table 5.
  • Total amount of HA extractable seems to be proportional to the amount of fibrino- gen used. Apparently, a considerable amount of HA is contained/bound in the cloth (approx. 90-95%).
  • Example 2 Antibacterial properties of fibrin or platelet rich fibrin compositions further comprising chitosan.
  • the agar diffusion method used in this study is based on the diffusion of anti- microbial substances from a tablet or alike placed directly on agar plated with bacteria.
  • the plated microbes will grow on the entire plate, except for areas with micro- static concentrations of anti-microbial substance(s). This will lead to the formation of a ring around the tablet or substance, the diameter of this ring correlating with the potency of the added anti-microbial substance against the plated microbe.
  • a limita- tion of this method is the need for the anti-microbial substance to be able to diffuse in the used media (e.g. agar).
  • Fresh colonies of the bacteria S. Aureus strain S29 (sensitive to antibiotic originating from KVL) and E. coli strain ToplO/F'Tet R (resistant to tetracycline) were diluted in sterile 0,9% NaCl (Nycomed) to an OD 625 of approx. 0,1 (Spectrophotometer Cecil 2040) and seeded on agar plates by dipping a sterile cotton bud in the bacteria solution and wiping it several times across the agar plate. Test substances were added to the plates within 30 min.
  • Fibrin and PRF were obtained from donor BX051901 using RC Preparation Unit 05.17.003 or PRF Preparation Unit 05.17.003 (filters removed) respectively with Citrate buffer 04.41.002 (PRF) and 02.23.007 (RC).
  • the polymerized Fibrin or PRF tablets were transferred to a Mueller Hinton agar plate (batch no. 2105008) plated with either S. aureus or E. coli.
  • Example 3 Platelet rich fibrin with addition of chitosan or Hyaluronic Acid.
  • compositions comprising autologous platelet rich fibrin (PRF) further containing Hyaluronic Acid (HA) or Chitosan.
  • PRF autologous platelet rich fibrin
  • HA Hyaluronic Acid
  • Chitosan Chitosan

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Surgery (AREA)
  • Materials For Medical Uses (AREA)
  • Compositions Of Macromolecular Compounds (AREA)

Abstract

Le processus de guérison des plaies peut être amélioré par l'ajout d'une colle à la fibrine. En fonction de la composition de colle et de la procédure d'application, le processus de guérison des plaies et la régénération tissulaire peuvent être accélérés davantage. Cette invention concerne une composition de colle améliorée et l'utilisation de cette dernière.
EP07722567A 2006-04-20 2007-04-20 Composition améliorée de colle à la fibrine et utilisation de cette dernière Withdrawn EP2010238A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200600545 2006-04-20
PCT/DK2007/000188 WO2007121748A2 (fr) 2006-04-20 2007-04-20 Composition améliorée de colle à la fibrine et utilisation de cette dernière

Publications (1)

Publication Number Publication Date
EP2010238A2 true EP2010238A2 (fr) 2009-01-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP07722567A Withdrawn EP2010238A2 (fr) 2006-04-20 2007-04-20 Composition améliorée de colle à la fibrine et utilisation de cette dernière

Country Status (4)

Country Link
EP (1) EP2010238A2 (fr)
JP (1) JP2009534058A (fr)
CA (1) CA2648552A1 (fr)
WO (1) WO2007121748A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102011112955A1 (de) 2011-09-13 2013-03-14 Medizinische Hochschule Hannover Verfahren zur Herstellung eines biologischen Gewebekonstrukts und Verwendung spezifisch gewonnener autologer Zellen
WO2015172215A1 (fr) * 2014-05-12 2015-11-19 Universidade Estadual Paulista Júlio De Mesquita Filho - Unesp Scellant de fibrine à usage topique, procédé de formation de ce dernier et son utilisation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4532134A (en) * 1981-04-06 1985-07-30 Malette William Graham Method of achieving hemostasis, inhibiting fibroplasia, and promoting tissue regeneration in a tissue wound
US6440427B1 (en) * 1991-06-17 2002-08-27 Biovitrum Ab Tissue treatment composition comprising fibrin or fibrinogen and biodegradable and biocompatible polymer
US5510102A (en) * 1995-01-23 1996-04-23 The Regents Of The University Of California Plasma and polymer containing surgical hemostatic adhesives
ATE439150T1 (de) * 1997-11-17 2009-08-15 Haemacure Corp Ein hyaluronsäurederivat enthaltende fibrinsiegel-oder fibrinklebmasse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007121748A2 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102011112955A1 (de) 2011-09-13 2013-03-14 Medizinische Hochschule Hannover Verfahren zur Herstellung eines biologischen Gewebekonstrukts und Verwendung spezifisch gewonnener autologer Zellen
WO2013037349A1 (fr) 2011-09-13 2013-03-21 Medizinische Hochschule Hannover (Mhh) Procédé de fabrication d'un produit de synthèse tissulaire biologique et utilisation de cellules autologues obtenues de façon spécifique
US9655931B2 (en) 2011-09-13 2017-05-23 Medizinische Hochschule Hannover (Mhh) Method for producing a biological tissue construct and use of specifically obtained autologous cells
WO2015172215A1 (fr) * 2014-05-12 2015-11-19 Universidade Estadual Paulista Júlio De Mesquita Filho - Unesp Scellant de fibrine à usage topique, procédé de formation de ce dernier et son utilisation

Also Published As

Publication number Publication date
CA2648552A1 (fr) 2007-11-01
WO2007121748A3 (fr) 2008-05-29
JP2009534058A (ja) 2009-09-24
WO2007121748A2 (fr) 2007-11-01

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