• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates in particular to an artificial ligament prosthesis remarkable in that it comprises a ply consisting entirely or partly of PCL fibers. The ligament prosthesis according to the invention is a biodegradable artificial ligament and "biointegrable" to remove all the apprehensions and uncertainties due to non-degradable synthetic supports. It is a prosthetic structure inspired and close to the native fabric, biodegradable while being sterilizable. It can be seeded or not to facilitate the formation of functional tissues by controlled cell and tissue activity, and having the required mechanical properties. The prosthesis according to the invention is slowly resorbable in order to be progressively replaced by a functional tissue identical to that of the native ligament.
    公开号:FR3013584A1
    申请号:FR1361522
    申请日:2013-11-22
    公开日:2015-05-29
    发明作者:Bernard Brulez；Veronique Migonney；Roger Guilard
    申请人:L A R S LABORATOIRE D APPLIC ET DE RECH SCIENT；
    IPC主号:
    专利说明:

    [0001] TECHNICAL FIELD The present invention relates to a resorbable biomimetic prosthetic ligament and its method of obtaining. PRIOR ART Anterior cruciate ligament (ACL) rupture of the knee is a common condition with an incidence estimated at 1 per 3,000 population per year in the United States and Europe. It occurs mainly in sporting subjects: thus, the history of the rupture of the ACL begins in more than 65% of the cases by a sporting accident (ski, football, rugby, combat sports). The average age at the time of the accident is between 20 and 29 years, and 70% of the patients are between 20 and 40 years old. ACL is an essential component of knee stabilization. Once broken, because of its intraarticular localization and poor vascularization, it does not heal spontaneously and the evolution is towards retraction and degeneration of the broken ends. The resulting laxity of the knee causes a functional repercussion with instability that will hinder or prevent the practice of sports activities or even current life. Moreover, this laxity favors the long-term occurrence of meniscal lesions followed by osteoarthritic deterioration of the knee, which is observed at 30 years of age in 85% of the subjects affected (HAS report, June 2008). For all these reasons, recourse to surgical intervention is frequent, particularly in young subjects. In France, 35,732 patients underwent LSS001-FR-9_TEXTE DEPOSE_SO / GE - 2 - surgery in 2010 following a rupture of the ACL (Source PMSI 2010). The usual surgical techniques are based on the replacement of the ACL by an autologous transplant: the patellar tendon (Kenneth Jones technique) or the tendons of the internal right and semi-tendinous muscles (DIDT technique). The use of an autograft is, however, not without drawbacks (morbidity related to tissue sampling, lack of graft anchorage to bone level and rupture rate still too high with a failure rate estimated at about 15%). %) and induces significant recovery times for the resumption of sports activities (> 6 months). The alternative is to replace the disrupted ligament with a synthetic ligament prosthesis which decreases the iatrogenicity of the surgical procedure and provides immediate mechanical support. The latter solution is proposed by some surgeons to high-level athletes for whom the functional recovery must be rapid and to patients with less frequent but more serious multi-ligamentous lesions. In the latter case, the absence of a sufficient number of transplants may lead to the use of allografts presenting a risk of viral transmission or to use, for the posterior cruciate ligament, a synthetic ligament prosthesis as a healing tutor. There is also an economic interest in this use by reducing the indirect costs associated with periods of functional rehabilitation and cessation of activity. The purpose of the development of artificial ligaments in the 1970s and 1980s was to overcome the shortcomings and complications associated with autografts and ligament allografts. Many artificial ligaments have been proposed, firstly in carbon, then in polyethylene, in polyethylene terephthalate (Leeds-Keio ligament), in polypropylene. (Kennedy Ligament Augmentation Device), or poly (tetrafluoroethylene) (Gore-tex, or ABC Surgicraft). If the results of these ligaments in the treatment of ACL fractures were good in the short term, the choice of materials was totally inadequate and therefore their low resistance to abrasion, their high rate of fatigue failure and their low integration naturally favored failures in the medium term. Lung debris fragmentation was the source of inflammatory synovitis and permanent chondral lesions. Histological examination of the explanted ligaments further showed that the tissue colonization was inhomogeneous and that it was more of a destructuring element than a mechanical reinforcing element. After a phase of initial enthusiasm, the use of these ligaments has thus gradually been limited to use as reinforcing material of an autologous ligamentous structure rather than as a true substitute. The poor results of these first ligaments led to their non-recommendation as part of the first-line ligamentoplasty of the anterior cruciate in France.
    [0002] During the years 1990 to 2000, a second generation of synthetic ligament was born and allowed to propose an innovative solution in this specific field (LARS Ligaments). The LARS prosthesis (artificial ligament made of PET) which, by its innovative structure, constitutes the second generation of ligamentary prostheses is one of the most used artificial ligaments for fifteen years. However, since no one knows today the long-term impact of the presence of a synthetic structure in the knee joint, artificial ligaments of the third generation have also been proposed. These artificial bioactive ligaments usable without hostile reaction of the host, described in FR0300495 patent, improve tissue colonization and tissue functionality and bone anchoring. In order to overcome these shortcomings, the present application proposes to develop a bioactive and biodegradable ligament (bio-hybrid) which has none of the defects of current ligaments and which constitutes a medical device easily manipulated by the practitioner and inducing a true regeneration damaged tissue.
    [0003] SUMMARY OF THE INVENTION Thus, the present invention relates in particular to an artificial ligament prosthesis that is remarkable in that it comprises a ply consisting entirely or partly of biodegradable fibers and advantageously PCL fibers.
    [0004] According to a preferred embodiment of the invention, said artificial ligament is an articular or periarticular ligament. According to a most preferred embodiment, said artificial ligament is anterior or posterior cruciate ligament.
    [0005] Advantageously, said ligament prosthesis consists of said rolled or folded sheet on itself, which sheet advantageously comprises two intraosseous end portions and an intra-articular intermediate portion. Said intermediate portion is preferably constituted by a skein of longitudinal weft son, adjacent and not interconnected transversely. At the ligament assembly, each active wire is twisted longitudinally, resulting in a dextrorotary or levorotatory ligament reproducing the natural twisting of the flexion ligaments. SUMMARY OF THE INVENTION In the context of the present invention, the term "biodegradable" refers to materials capable of degrading once in place in the body. According to a preferred embodiment of the invention, the term "biodegradable" refers to fibers capable of losing between 1 and 100% of their constituents in a period of exposure to physiological conditions of between 1 month and 4 years. According to a most preferred embodiment of the invention the term biodegradable refers to materials selected from the group consisting of poly s-caprolactone (PCL), copolymers of s-caprolactone and lactic acid (L and D ) or glycolic acid, copolymers of lactic and glycolic acids (L and D), polydioxanone, polyhydroxyalkanoate and copolymers of these different molecules. Most preferably, said biodegradable fibers are PCL fibers. This type of PCL ligament, a material whose biocompatibility is well known, has an extremely high resistance to tensile, flexural and torsional stresses. Polycaprolactone (PCL) has been widely used in the 70s-80s in the field of biodegradable sutures, and its use has gradually decreased in favor of faster absorbable polyesters, such as PLGA. PCL is a semi-crystalline polymer with a high degree of crystallinity (-50%) which has a glass transition temperature Tg of -60 ° C and a melting temperature Tf of 60 ° C. Thus, when used at 37 ° C, PCL macromolecular chains are in a highly "flexible" state allowing its use for soft tissue tissue engineering. In addition, its use in the biomedical field is already validated since a large number of drug delivery devices have received FDA approval and CE marking.
    [0006] PCL degrades slowly (up to 4 years depending on the molar mass and the morphology of the material) and does not generate an extreme acidic environment during its degradation contrary to PLGA. Thus, PCL undergoes degradation in two stages: first, hydrolytic degradation to a decrease in molecular weight at 3000 gmol-1; then the intracellular degradation that occurs after phagocytosis of small fragments of PCL. The ligament prosthesis according to the invention is a biodegradable artificial ligament and "biointegrable" to remove all the apprehensions and uncertainties due to non-degradable synthetic supports. It is a prosthetic structure inspired and close to the native fabric, biodegradable while being sterilizable. It can be seeded or not to facilitate the formation of functional tissues by controlled cell and tissue activity, and having the required mechanical properties. The prosthesis according to the invention is slowly resorbable in order to be progressively replaced by a functional tissue identical to that of the native ligament. According to a preferred embodiment of the invention, said biodegradable fiber has a diameter of between 1 and 400 μm. According to a preferred embodiment of the invention, said fiber has a molar mass of between 1 and 200,000 g / mol. According to a preferred embodiment of the invention, said web consists entirely of PCL fibers. In another preferred embodiment of the invention, said biodegradable fibers are rendered biologically active by grafting a polymer. Thus, said biodegradable fibers comprise biologically active polymers. According to another preferred embodiment of the invention, said biologically active polymer is poly (sodium styrene sulfonate). Thus, the ligament prosthesis according to the invention is conducive to adhesion, proliferation, colonization, cell differentiation and the production of an extracellular matrix to re-create a functional tissue. In order to ensure a good fibroblastic "rehabitation" of the prostheses according to the invention, the present invention proposes a process for biomimetic functionalization of said prostheses, a process that confers them, in particular, the ability to mimic living materials in order to improve their biological integration. Thus, the present invention also relates to a method for treating artificial prostheses made of biodegradable fibers, in order to give them the capacity to mimic living materials, said biomimetic functionalization process being remarkable in that it comprises at least one grafting step of biologically active polymers or copolymers on the surface of the fiber of said prostheses, which grafting step consists in performing a peroxidation of the surface by ozonation followed by a radical polymerization of a solution of at least one monomer. According to a preferred embodiment of the invention, the ozonation time for an ozone content of the order of 50 g / cm 3 is between 5 and 90 min. According to another preferred embodiment of the invention, the monomer is sodium styrene sulphonate. DETAILED DESCRIPTION OF THE INVENTION According to another preferred embodiment of the invention, the monomer solution has a concentration of monomer (s) of between 5% and k%, where k is a concentration close to the limiting solubility of the monomer (s) in the solution. According to another preferred embodiment of the invention, the grafting step is preceded by an additional step of preparing the surface of the fiber in a solvent medium capable of modifying the surface by swelling only, or in a solvent medium and then in a medium aqueous. According to another preferred embodiment of the invention, the solvent medium consists of ethyl ether, DMSO, hexane and / or ethyl ether. In the case of PCL fibers, the solvent medium is advantageously constituted by ethyl ether. According to another preferred embodiment of the invention, the solvent medium consists of at least one solvent capable of modifying the surface by swelling. According to another preferred embodiment of the invention, the solvent capable of modifying the surface by swelling is of the cyclic or aliphatic ether type having little or no toxicity. According to another preferred embodiment of the invention, the solvent capable of modifying the surface by swelling is chosen from the following group of solvents: tetrahydrofuran (THF), dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). According to another preferred embodiment of the invention, the step of preparing the aqueous LSS001-FR-9_TEXTE DEPOSE_SO / GE surface consists in treating the hot polyester surface with an aqueous solution of sodium salts. alkali or alkaline earth carbonates, such as for example Na2CO3 or CaCO3, in order to eliminate the polyester production residues present on its surface. According to another preferred embodiment of the invention, said method comprises an additional step of impregnating the prosthesis after the grafting step with one or more biochemical agents promoting colonization by fibroblasts. Finally, according to another preferred embodiment of the invention, the biochemical agent is a protein of the family of fibronectins and / or collagen type I and / or III.
    [0007] The method according to the invention is here applied to ligament prostheses already formed or to the webs comprising biodegradable fibers used in the manufacture of said prostheses. Other advantages and features will become more apparent from the description which follows, of the complete embodiment variant, given by way of non-limiting example, of the ligament and the method according to the invention. DESCRIPTION OF EMBODIMENTS Preparation of PCL biodegradable webs PCL fibers may preferentially be obtained by extrusion and especially by extrusion blow molding, extrusion forming and / or extrusion spinning. The biodegradable fibers of PCL can also be obtained by the so-called "electrospinning" technique for obtaining fibers from a solution of LSS001-FR-9_TEXTE DEPOSE_SO / GE - 10 - polymer and finally polycaprolactone sheets (PCL). The principle of this technique lies in the application of a high voltage on a polymer solution then generating the formation of a jet which, once deposited on a collector, forms a fibrous mat. The versatility of this technique makes it possible to manufacture fibrous structures whose fiber diameter is adjusted by influencing the concentration, composition and flow rate of the solution.
    [0008] Step 1: Preparation of the PCL surface LA) In a solvent medium: This so-called de-image step is necessary in order to eliminate the greases and impurities incorporated during the manufacture of the PCL frame serving as a ligament structure. It thus makes it possible to avoid pathological reactions of the acute synovitis type during implantation in the patient. In addition, this step makes it possible to ensure growth of the fibroblasts on this surface of PCL thus cleaned, growth not observed on uncleaned surfaces. There are three variants of this preparation in a solvent medium, depending on the nature of the solvent and / or the surfactant chosen. Variation 1: Descaling with a solvent capable of swelling the PCL surface: The use of a solvent capable of swelling the surface of the PCL offers the advantage of improving the grafting by increasing the number of peroxides on the treated surface during of the ozonation step. In addition, it will be selected from the following solvent group: tetrahydrofuran (THF), chloroform and dichloromethane. These solvents have the advantage of having little or no toxicity and thus allow easy use in an industrial environment. The treatment is by immersion of the PCL in the solvent for a period of about 5 minutes to an hour, preferably 10 to 25 minutes. Thus, by way of example, a time of 15 minutes at room temperature will be chosen for immersion in tetrahydrofuran (THF). - Variation 2: Drying with a solvent and a surfactant. This desizing is preferably carried out in the presence of hexane at a temperature below 60 ° C. Variation 3: Descaling without surface swelling: A minimum of 12 extraction cycles are applied in a SOHXLET apparatus and a control of the fat body residues after the 12th hexane cleaning cycle. These hexane cleaning cycles are followed by ethyl ether wash cycles (EPR), three minimum washes with residue control after the third wash. 1B) In an aqueous medium: The purpose of this optional step of preparing the surface in an aqueous medium is to remove the manufacturing residues of the PCL present on its surface. This gives a perfectly prepared surface before ozonation. The treatment consists in washing the PCL in a solution of sodium carbonate (Na2CO3) at 5% by weight in distilled water. This washing is carried out hot, that is to say at more than 60 ° C. and less than 120 ° C. and preferably at slightly boiling, ie 100 ° C. ± 5 ° C. ° C, for about ten minutes. Of course, any other alkali or alkaline earth carbonate such as K 2 CO 3 or CaCO 3 may be used. The washing is followed by successive rinsings with distilled water until the pH of the rinsing water has returned to 7. 1C) Cleaning: Whatever the steps previously carried out (variant 1 or 2 of the step 1A, then step 1B, or only step lA), the PCL product is then cleaned, for example by rinsing with absolute ethanol or tetrahydrofuran (THF) followed by drying in a drying cabinet. a duration of 30 minutes, for example. Step 2: Grafting Biologically Active Polymers or Copolymers to the PCL Surface: 2A) Choice and Preparation of the Monomers: The monomers used according to the invention are monomers capable of polymerization and radical copolymerization giving rise to organic polymers. -compatibles stimulating cell proliferation and differentiation and more particularly that of fibroblasts. Such monomers containing hydroxyl, carboxylate, phosphonate, sulphonate and sulfate groups are, for example, described in US Pat. No. 6,365,692 and may be used according to the invention alone or in admixture. It is possible, for example, to use methacrylic acid and styrene sulphonate, as well as their mixtures. Before using them for the polymerization, these monomers will be purified beforehand. For example, for sodium styrene sulfonate, it is purified by recrystallization from a mixture of bidistilled water / alcohol (10/90, v: v), and then dissolved at 70 ° C in this solution.
    [0009] It is then vacuum filtered with a sintered glass disk of porosity index 3 and stored at 4 ° C. The formed sodium sulfonate crystals are recovered by filtration and the solid obtained is dried under vacuum at 50 ° C. until a constant weight is obtained. 2B) Ozonation: The PCL prostheses or frames constituting these prostheses previously treated according to step 1 are introduced into an ozonation device as conventionally used. For example, it will be possible to use a tubular reactor of 500 cm 3 containing 100 cm 3 of bidistilled water, which reactor is provided with a dip tube for supplying ozone. For example, a gas flow equivalent to ozone at 50 g / m 3 of oxygen may be used. For such an amount of ozone, the optimal ozonation time of the PCL is 5 to 90 minutes. The measurements of the peroxide level show that the optimal rate is obtained between 10 and 30 minutes of ozonation, again for this same ozone stream. It will also be appreciated that an ozonation time greater than 90 minutes strongly degrades the PCL surface. We will also note the contribution of variant 2 of step 1A. Indeed, the use of a surface swellable solvent increases the peroxide level by a factor of 5, compared with the use of a non-swelling solvent. Once the ozonation is complete, the prostheses or PCL frames introduced into the ozonation device are rinsed and cleaned, for example according to the following protocol: rinse three times at the same time. doubly distilled water, then three times with absolute alcohol. Then dry in a vacuum oven for 30 minutes at 25 ° C. 2C) Polymerization: The monomer (s) chosen and prepared according to step 2A are dissolved in water, preferably bidistilled. Any concentration compatible with the implementation of the radical polymerization reaction can be chosen with a minimum of 2% by weight. Concentrations close to the limiting solubility of the monomer (s) in the solution are advantageously chosen, with a viscous medium thus favoring radical polymerization reactions with respect to termination reactions. This amounts to choosing a weight concentration k = s - E, where s is the limiting solubility and E is 1 to 7% by weight. For example, in the case of polystyrene sulfonate whose solubility limit is 20% by weight, a concentration of 15% will be chosen.
    [0010] The duration of the polymerization step depends on the nature of the monomer. It is estimated at the time necessary for the gelation of the medium at the reaction temperature. Thus, for example, it will be remembered for the polystyrene sulfonate at 50 ° C, the polymerization will last 1 hour and at 30 ° C, it will last 15 hours. The polymerization reaction is conducted in a hermetically sealed enclosure free of all oxygen, for example, by bubbling with argon. The monomer or comonomer solution that is to be reacted and the previously ozonated PCL tissue prostheses or strips of tissue are introduced into this chamber. The sealed container is heated in a waterbath to the temperature and time determined as previously discussed. At the end of the reaction, the PCL elements which have been grafted are extracted from the reactor. These grafted materials can then be washed to remove unreacted monomer residues. For example, the functionalized surface can be washed several times with a suitable solvent of the monomer (s), for example double-distilled water, and the wash can be optionally finished with any suitable solvent, absolute ethanol by for example, to remove any traces of ungrafted monomers and polymers. Step 3: Impregnation with Biochemicals: This step is optional. It aims to strengthen the biological integration capacity of the ligament which has previously been grafted biomimetic polymers as described in steps 1 and 2. Thus, the impregnation of the prosthesis with one or more biochemical agents aims at increasing these properties. adhesion and cell proliferation. These biochemical agents promoting colonization by fibroblasts are a protein of the family of fibronectins and / or collagen type I and / or III. Advantageously, a mixture of the preceding proteins, ie a mixture of fibronectins and collagen of type I and / or III, will be used: a synergistic effect on the adhesion of the fibroblasts is observed. The impregnation of the prosthesis by these agents may, for example, be carried out by dipping in a bath containing collagen. It goes without saying that this impregnation step does not necessarily follow the grafting step and that it can be inserted and interposed between other steps of preparation of the LSS001-FR-9_TEXT DEPOSE_SO / GE - 16 - ligament depending on its stage of manufacture. In addition, this impregnation step will advantageously be followed by a ligament sterilization step.
    [0011] Sterilization of PCL webs and ligaments The choice of the sterilization method is crucial in the development of biomaterials based on hydrolyzable polyesters and particular attention must be paid to them. Aliphatic polyesters being sensitive to moisture and heat, sterilization methods by autoclave or dry heat are not possible. In addition, in this sterilization mode, there are added toxicity problems related to the difficulty of completely eliminating the ethylene oxide residues of the biodegradable scaffold. Three sterilization methods are preferably used ethanol sterilization, UV radiation and beta radiation. LSS001-EN-9_TEXT DEPOSE_SO / GE
    权利要求:
    Claims (20)
    [0001]
    CLAIMS1 - Artificial ligament prosthesis characterized in that it comprises a web consisting wholly or partly of biodegradable fibers.
    [0002]
    2 - Artificial ligament prosthesis according to the preceding claim characterized in that said biodegradable fiber comprises a material selected from the group comprising PCL, copolymers of PCL and lactic acid (L and D) or glycolic acid, copolymers lactic and glycolic acids (L and D), polydioxanone, polyhydroxyalkanoate and copolymers of these different molecules.
    [0003]
    3 - artificial ligament prosthesis according to the preceding claim characterized in that said biodegradable fiber comprises PCL.
    [0004]
    4 - Artificial ligament prosthesis according to the preceding claim characterized in that said web is made entirely of PCL fibers.
    [0005]
    5 - artificial ligament prosthesis according to one of the preceding claims characterized in that said biodegradable fibers comprise biologically active polymers.
    [0006]
    6 - Artificial ligament prostheses according to the preceding claim characterized in that said biologically active monomer is sodium styrene sulfonate. LSS001-EN-9_TEXT DEPOSE_SO / GE- 18 -
    [0007]
    7 - Artificial ligament prostheses according to one of the preceding claims characterized in that said artificial ligament is an articular ligament or peri-articular.
    [0008]
    8 - Artificial ligament prostheses according to one of the preceding claims characterized in that said artificial ligament is anterior or posterior cruciate ligament.
    [0009]
    9 - Process for the treatment of artificial prostheses made of biodegradable fibers, in order to give them the capacity to mimic living materials, said biomimetic functionalization process characterized in that it comprises at least one step of grafting biologically active polymers or copolymers to the surface of said prostheses, which grafting step consists in performing a peroxidation of the surface by ozonation followed by a radical polymerization of a solution of at least one monomer.
    [0010]
    10 - Process according to claim 9 characterized in that the ozonation time for an ozone content of the order of 50g / m3 is between 5 and 90 min.
    [0011]
    11 - Process according to any one of claims 9 or 10 characterized in that the monomer is sodium styrene sulfonate.
    [0012]
    12 - Process according to any one of claims 9 to 10 characterized in that the monomer solution has a concentration of monomer (s) between LSS001-FR-9_TEXT DEPOSE_SO / GE- 19 - 5% and k%, where k is a concentration close to the limiting solubility of the monomer (s) in the solution.
    [0013]
    13 - Process according to any one of claims 9 to 11 characterized in that the grafting step is preceded by an additional step of preparing the surface in a solvent medium only, or in a solvent medium and then in an aqueous medium.
    [0014]
    14- The method of claim 13 characterized in that the solvent medium is hexane or ethyl ether.
    [0015]
    15- The method of claim 13 characterized in that the solvent medium is constituted by at least one solvent capable of modifying the surface by swelling.
    [0016]
    16. The process as claimed in claim 15, characterized in that the solvent capable of modifying the surface by swelling is ether.
    [0017]
    17. The process as claimed in claim 15, wherein the solvent capable of modifying the surface by swelling is chosen from the following group of solvents: tetrahydrofuran (THF), dimethylsulfoxide (DMSO), N, N- dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). 30
    [0018]
    18- The method of claim 13 characterized in that the step of preparing the surface in LSS001-EN-9_TEXTE DEPOSE_SO / GE aqueous medium is to treat the hot polyester surface with an aqueous solution of carbonate salts alkaline or alkaline-earth metals, such as for example Na2CO3 or CaCO3, in order to eliminate the polyester production residues present on its surface.
    [0019]
    19 - Method according to one of claims 9 to 18 characterized in that it comprises an additional step of impregnating the prosthesis after the grafting step with one or more biochemical agents promoting colonization with fibroblasts.
    [0020]
    20 - Process according to claim 19 characterized in that the biochemical agent is a protein of the family of fibronectins and / or collagen type I and / or III. LSS001-EN-9_TEXT DEPOSE_SO / GE
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    AU2014351652A1|2016-06-16|
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    AU2018229431A1|2018-10-04|
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    引用文献:
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    CN103239300B|2013-03-29|2015-02-25|西安交通大学|Ligament-bone bionic support with initial self-fixing function and forming method of support|
    CN103315827B|2013-06-25|2016-01-20|周婕|A kind of preparation method of artificial ligament|CN108744052B|2018-05-08|2021-04-23|广东职业技术学院|Composite scaffold for tissue engineering ligament and preparation method thereof|
    FR3089784B1|2018-12-12|2020-12-18|Les Laboratoires Osteal Medical|Polymer fiber membrane|
    FR3092988B1|2019-02-22|2021-12-03|Les Laboratoires Osteal Medical|Membrane|
    FR3109162A1|2020-04-14|2021-10-15|Les Laboratoires Osteal Medical|Manufacturing process of a non-woven textile structure|
    CN111821517A|2020-07-08|2020-10-27|花沐医疗科技有限公司|Temperature-sensitive bionic ligament and preparation method thereof|
    法律状态:
    2015-10-05| PLFP| Fee payment|Year of fee payment: 3 |
    2016-09-29| PLFP| Fee payment|Year of fee payment: 4 |
    2017-09-29| PLFP| Fee payment|Year of fee payment: 5 |
    2018-09-14| PLFP| Fee payment|Year of fee payment: 6 |
    2019-08-30| PLFP| Fee payment|Year of fee payment: 7 |
    2020-08-21| PLFP| Fee payment|Year of fee payment: 8 |
    2021-10-28| PLFP| Fee payment|Year of fee payment: 9 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1361522A|FR3013584B1|2013-11-22|2013-11-22|BIOMIMETIC PROOFHETIC RESISTANCE LIGAMENT|FR1361522A| FR3013584B1|2013-11-22|2013-11-22|BIOMIMETIC PROOFHETIC RESISTANCE LIGAMENT|
    RU2016122733A| RU2683264C1|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    AU2014351652A| AU2014351652A1|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    EP14824505.3A| EP3071246B1|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    CA2931224A| CA2931224A1|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    PL14824505T| PL3071246T3|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    US15/038,259| US20160287746A1|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    CN201480063973.8A| CN105828846A|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    PCT/FR2014/052992| WO2015075397A1|2013-11-22|2014-11-21|Resorbable biomimetic prosthetic ligament|
    HK16111593.0A| HK1223308A1|2013-11-22|2016-10-05|Resorbable biomimetic prosthetic ligament|
    AU2018229431A| AU2018229431A1|2013-11-22|2018-09-11|Resorbable biomimetic prosthetic ligament|
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