Implantable device made from umbilical cord wall.

Abstract

Implantable device consisting of umbilical cord wall. The present invention relates to the field of implantable devices usable as allografts in surgery. It relates in particular to a method for manufacturing an implantable device consisting of a reticulated umbilical cord wall, said implantable device being selectable from the group comprising a biological lens, an intracorneal implant consisting of a ring or a ring segment, a nerve, ligament, and / or tendon regeneration guide, and / or an artificial heart valve. The invention also relates to the devices thus obtained and their surgical uses. Figure for the abstract: Fig. 3

Description

Title of the invention: Implantable device made of umbilical cord wall.

[0001] The present invention relates to the field of implantable devices usable as allografts in surgery.

[0002] In the context of the constant evolution of grafting techniques, the use of implantable devices derived from biological tissues as allografts in surgery presents significant advantages, particularly in terms of biocompatibility and tissue regeneration.

[0003] However, manufacturing these devices presents a real challenge. Indeed, it is particularly difficult to reproduce shapes and structures as precise and regular as those obtained from synthetic composite materials.

[0004] In addition, the processes of processing and preserving biological tissues pose additional challenges, making the production of reliable and uniform devices even more complex.

[0005] A primary challenge lies in identifying the starting biological tissue to be used, as many essential characteristics of the final implantable devices, such as strength, size, and in particular thickness, are determined by the very nature of this tissue. Furthermore, this tissue must be available in sufficient quantities to allow for its large-scale use, while respecting current bioethical standards.

[0006] These difficulties are exacerbated by compatibility and immunological tolerance problems, which can lead to rejection reactions or premature degradation of the implanted tissue.

[0007] Another major challenge lies in the preparation of the biological tissue. This process must primarily reduce the likelihood of graft rejection by minimizing potential immune reactions. At the same time, the preparation must allow for the precise shaping of the device so that it can be used directly and easily by the surgeon during the procedure. This includes the need to maintain the structural and functional integrity of the tissue while modifying it to meet the specific requirements of the surgical application, which represents a delicate balance to achieve.

[0008] Thus, the present application aims at the development of implantable devices usable as allografts in surgery, in particular as a biological lens, an intracorneal implant consisting of a ring or a segment of a ring, a nerve, ligament and / or tendon regeneration guide and / or a heart valve artificial, produced from biological tissues and addressing all the issues outlined above.

[0009] In this context, the amniotic membrane, obtained from the placenta after childbirth, is a tissue that has been used for over a hundred years in the treatment of burns and wounds. Indeed, as early as 1909, Davies (Davis JS. II. Skin Grafting at the Johns Hopkins Hospital. Ann Surg. 1909 Sep;50(3):542-9. doi: 10.1097 / 00000658-190909000-00002. PMID: 17862406; PMCID: PMC1407162.) used fetal membranes on both burns and ulcerated tissue. In 1972, the work of Trelford et al. (Trelford JD, Anderson DG, Hanson FW, Mendel V, Sawyer RH. Amniotic autografts and allografts as a cover for skin defects in sheep. A preliminary report. J Med. 1972;3(2):81-7. PMID: 4507072.) confirmed this fact. Fénelon et al. (Fénelon M, Catros S, Meyer C, Fricain JC, Obert L, Auber F, Louvrier A, Gindraux F. Applications of Human Amniotic Membrane for Tissue Engineering. Membranes (Basel). 2021 May 25;11(6):387. doi: 10.3390 / membranes 11060387. PMID: 34070582; PMCID: PMC8227127.)) report that from 1972, and especially since its rediscovery in 1995, other authors have confirmed all the clinical applications presented previously, and have also reported new indications such as the genitourinary tract, stomach, larynx, oral cavity, head and neck, whether in clinical trials or case reports.

[0010] Application EP4209200A1 discloses a method for manufacturing a device usable as a lens from a placental amniotic membrane comprising a reticulated annular structure at its periphery so as to have a rigid external structure less fragile than the placental amniotic membrane alone and simpler to place on the patient, having excellent biocompatibility.

[0011] Indeed, due to its thickness of between 30 and 50 µm, the placental amniotic membrane is fragile and too flexible to be manipulated without supports. This thinness also limits the creation of other devices using the same process.

[0012] Application WO2008042441 discloses a process for obtaining biomaterials from umbilical cord membrane and their use as an adjunct to eye surgeries. The process disclosed in this application does not include a prolonged treatment step with a strong base. The disclosed process aims to preserve the biomechanical and structural properties of the membrane's components, particularly collagen. The materials obtained therefore do not possess the rigidity required for the various applications targeted by the present invention.

[0013] Application WO2008060377 discloses the use of a composition preferably in the form of a solution, suspension, gel, or paste. Conversely, the process according to the present invention allows for the preservation of a the structural integrity of the amniotic membrane thus ensuring better shape retention over time.

[0014] US patent application 2019192734 discloses a method for dehydrating placental tissues for the production of placental tissues usable for tissue healing. In particular, it describes a method for dehydrating umbilical cords, not including the steps according to the present invention, for forming a structure described as thin and pliable, contrary to the desired thickness and rigidity.

[0015] Application KR20090006256 discloses a method for treating a collagen matrix to make it transparent for use as a corneal graft. This matrix is ​​obtained from skin tissue or umbilical cord tissue. However, this application does not disclose the use of amniotic membrane from the umbilical cord. The method comprises a first step of enzymatic treatment of the target tissue with a collagenase and / or a protease to denature and then reconstitute a new collagen matrix, which is subsequently cross-linked.

[0016] It therefore proposes a process whose purpose is the opposite of that according to the present invention. Indeed, in the process according to the invention, the native structure of the extracellular matrix proteins, and in particular of the collagen of the umbilical cord wall, is not altered and is, on the contrary, preserved by cross-linking. The product obtained exhibits a native structural organization of the collagen fibers, conferring sufficient thickness as well as resistance qualities compatible with the various intended applications.

[0017] US application US2017049928A1 discloses a human umbilical cord-derived transplantation product intended for use as a soft tissue barrier, wound covering, or other internal or external wound-healing accessory. The manufacturing process for this transplantation product consists of washing and drying the umbilical cord derivative prior to implantation. The product obtained according to this application is therefore very flexible and requires a suturing step to be held in place around the treated areas and organs.

[0018] Conversely, the product according to the present invention, in particular when used as a guide for nerve, ligament and / or tendon regeneration, has sufficient rigidity to maintain a tubular shape compatible with this use and therefore does not require suturing to be held on the treated areas and organs.

[0019] There is therefore a need to have structures having a size, in particular a thickness, and mechanical properties, in particular rigidity, compatible with the applications intended.

[0020] In a particularly surprising manner, the applicant has succeeded in developing a device consisting of cord walls whose thickness is between 0.5 mm and 2 mm. The manufacturing process steps give the device sufficient strength to be handled and used without risk of deterioration without a support structure.

[0021] The said process according to the present invention therefore allows the manufacture of thicker devices in particular than devices obtained from placental amniotic membrane and also usable for the manufacture of the various implantable devices mentioned above.

[0022] In a particularly surprising way, the applicant has in particular developed a prolonged treatment step with a strong base to improve the resistance properties of the biomaterial, in particular following the crosslinking step.

[0023] The method according to the present invention has the advantage of preserving the integrity of the umbilical cord wall surface. In particular, it does not cause random disruption of the continuity of the umbilical cord wall or decellularization of said wall, giving it superior mechanical properties compared to those known in the prior art.

[0024] It also allows the native organization of the extracellular matrix molecules of the umbilical cord wall to be preserved, in particular collagen.

[0025] Fig. 1 is a photograph of an implantable device consisting of a lens obtained by the process according to the invention.

[0026] Fig. 2 is a photograph of an implantable device consisting of a nerve, ligament and / or tendon regeneration guide obtained by the process according to the invention.

[0027] Fig. 3 is a photograph of an implantable device consisting of an artificial heart valve obtained by the process according to the invention.

[0028] Figures [Fig.4] and [Fig.5] are a schematic representation of step w') of shaping the implantable device made of umbilical cord wall, said implantable device being an artificial heart valve.

[0029] The present invention relates to a method for manufacturing an implantable device characterized in that it comprises the steps of:

[0030] a) We have an umbilical cord wall,

[0031] b) The umbilical cord wall is treated with a strong base for a period of at least one hour,

[0032] c) At least one crosslinking step is carried out,

[0033] d) An implantable device is obtained consisting of a reticulated umbilical cord wall,

[0034] said process not comprising a step of treating the umbilical cord wall with proteases and / or collagenases.

[0035] In one embodiment, the implantable device is chosen from the group comprising a biological lens, an intracomeal implant consisting of a ring or a ring segment, a nerve, ligament and / or tendon regeneration guide and / or an artificial heart valve.

[0036] In one embodiment, the method according to the present invention is characterized in that it allows the integrity of the surface of the umbilical cord wall to be preserved.

[0037] For the purposes of the present invention, "maintaining the integrity of the surface" means the absence of random disruption of the continuity of the surface, in particular by grinding, homogenizing, fragmenting and / or pulverizing the umbilical cord wall, it being understood that the wall may in particular be cut to fit the dimensions and shape of the implantable device.

[0038] In one embodiment, the process according to the present invention does not include a step resulting in the decellularization of the amniotic wall of the umbilical cord.

[0039] In one embodiment, the process includes at least one step of cutting the wall to bring it to the dimensions and shape of the implantable device.

[0040] For the purposes of the present invention, "umbilical cord wall" means an umbilical cord free of vessels, comprising at least the amniotic membrane of the umbilical cord.

[0041] In one embodiment, the umbilical cord wall available in step a) is essentially free of Wharton's jelly.

[0042] In one embodiment, the umbilical cord wall available in step a) is free of Wharton's jelly.

[0043] In one embodiment, the umbilical cord wall available in step a) comprises Wharton's jelly.

[0044] In one embodiment, the umbilical cord wall available in step a) comprises a Wharton jelly thickness of between 0.3 and 3 millimeters.

[0045] In one embodiment, the umbilical cord wall available in step a) comprises a Wharton jelly thickness of between 0.3 and 1 millimeter.

[0046] In one embodiment, the umbilical cord wall available in step a) comprises a Wharton jelly thickness of between 1 and 3 millimeters.

[0047] In one embodiment, the process includes a preliminary step of preparing an umbilical cord wall by obtaining an umbilical cord and mechanically removing the vessels.

[0048] In one embodiment, the umbilical cord wall available in step a) is of animal or human origin.

[0049] In one embodiment, the umbilical cord wall available in step a) is of human origin.

[0050] In one embodiment, the umbilical cord wall available in step a) is obtained according to the protocol as described in application WO2017140914A1.

[0051] The umbilical cord wall according to the present invention is obtained after the delivery of a properly informed and consenting donor in accordance with the requirements of European directives and the Bioethics Law. This delivery may have taken place by cesarean section or vaginally.

[0052] Due to health requirements related to donations of human tissues and cells, a socio-clinical and biological pre-donor assessment is systematic. This assessment includes testing for HIV, hepatitis B, C, HTLV, and the Treponema pallidum bacterium responsible for syphilis.

[0053] In one embodiment, the umbilical cord wall available in step a) is previously frozen.

[0054] In one embodiment, the umbilical cord wall available in step a) is first placed in a sterile box, frozen and transported at a temperature of -20°C, then stored at -80°C.

[0055] In one embodiment, the umbilical cord wall available in step a) is transported to +4 °C.

[0056] In one embodiment, the umbilical cord wall available in step a) was not initially frozen; the cutting and separation of the umbilical cord wall are carried out after transport at +4°C.

[0057] In one embodiment, the umbilical cord wall available in step a) is stored at -80°C.

[0058] In one embodiment, the umbilical cord wall available in step a) is virus-inactivated.

[0059] In one embodiment, the method according to the invention is characterized in that it further comprises a step a') of viro-inactivation of the umbilical cord wall following step a).

[0060] In one embodiment, the viro-inactivation step a') includes a viro-inactivation step i) comprising the application to the umbilical cord wall of a wash and / or the latter remaining in a bath, composed of a first viro-inactivating agent.

[0061] In one embodiment, the first viro-inactivating agent is ethanol.

[0062] In one embodiment, the first viro-inactivating agent is ethanol at a alcohol content of 50% to 80% (v / v) (50% < alcohol content < 80%).

[0063] In one embodiment, the first viro-inactivating agent is ethanol with an alcohol content of 70% (v / v).

[0064] In one embodiment, step i) of viro-inactivation is carried out for a duration within an interval of 30 minutes to 120 minutes (30 min < duration < 120 min).

[0065] In one embodiment, step i) of viro-inactivation is carried out for a duration within an interval of 45 minutes to 100 minutes (45 min < duration < 100 min).

[0066] In one embodiment, step i) of viro-inactivation is carried out for a period of approximately 60 minutes.

[0067] In one embodiment, step i) of viro-inactivation is carried out by treating the umbilical cord wall with ethanol at an alcohol content of 70% (v / v) for a period of approximately 60 minutes.

[0068] In one embodiment, step i) is followed by a step i') of washing the umbilical cord wall with purified water or staying in a purified water bath.

[0069] In one embodiment, the viro-inactivation step a') includes a second viro-inactivation step ii) following step i) or i') comprising the application to the umbilical cord wall of a wash and / or the latter remaining in a bath, composed of a second viro-inactivation agent.

[0070] In one embodiment, the second viro-inactivating agent is hydrogen peroxide.

[0071] In one embodiment, the second viro-inactivating agent is hydrogen peroxide in a form chosen from an aqueous solution and a gas.

[0072] In one embodiment, the second viro-inactivating agent is hydrogen peroxide in aqueous solution in a concentration within a range of 1% to 30% (w / v) (1% < w / v concentration < 30%).

[0073] In one embodiment, the second viro-inactivating agent is hydrogen peroxide in aqueous solution in a concentration within a range of 3% to 10% (w / v) (3% < w / v concentration < 10%).

[0074] In one embodiment, step ii) of viro-inactivation is carried out for a duration within an interval of 30 minutes to 120 minutes (30 min < duration < 120 min).

[0075] In one embodiment, step ii) of viro-inactivation is carried out for a duration within an interval of 45 to 100 minutes (45 min < duration < 100 min).

[0076] In one embodiment, step ii) of viro-inactivation is carried out for a period of approximately 60 minutes.

[0077] In one embodiment, the process is characterized in that the second viro-inactivation step ii) of the umbilical cord wall comprises two sub-steps of treatment by the second viro-inactivation agent chosen from the peroxide family.

[0078] For the purposes of the present invention, "peroxides" means any chemical compound containing a functional group of general formula ROOR' (two neighboring oxygen atoms bonded together) where R and R' are hydrogen atoms or any alkyl radicals.

[0079] According to one embodiment, the second step of viro-inactivation ii) of the umbilical cord wall comprises two sub-steps of treatment with hydrogen peroxide:

[0080] a first sub-treatment step ii') carried out with a hydrogen peroxide solution at a concentration greater than 10% w / v for a period of at least 20 minutes; and

[0081] a second sub-treatment step ii”) carried out with a hydrogen peroxide solution at a concentration of less than 5% w / v for a period of more than 50 minutes.

[0082] According to another embodiment, the second step of viro-inactivation ii) of the umbilical cord wall comprises two sub-steps of treatment with hydrogen peroxide:

[0083] a first sub-treatment step ii') carried out with a hydrogen peroxide solution at a concentration of 30% w / v for a period of approximately 15 minutes; and

[0084] a second sub-treatment step ii')' carried out with a hydrogen peroxide solution at a concentration of 3% w / v for a period of approximately 60 minutes.

[0085] In one embodiment, the viro-inactivation step a') includes a third step iii) following step ii) comprising at least one neutralization step, by application to the umbilical cord wall, comprising washing and / or soaking the latter in a bath, composed of at least one basic buffer.

[0086] In one embodiment, the basic buffer is added in sufficient quantity to neutralize the pH in third step iii).

[0087] In one embodiment, step a') of viro inactivation includes a final step iv) comprising the application to the umbilical cord wall includes a wash and / or a stay in a bath, composed of at least one buffer solution ensuring physiological rebalancing.

[0088] In one embodiment, the last step iv) comprises two baths carried out in phosphate saline buffer (PBS) solution.

[0089] In one embodiment, the thawing, viro-inactivation, washing, pH adjustment and buffering steps are carried out at room temperature.

[0090] In step b) of the process, the wall is treated with a strong base, in the sense of the present invention, "strong base" means an aqueous solution of an alkali salt whose pKa is greater than 14.

[0091] In one embodiment, step b) is characterized in that the strong base is an aqueous solution of an alkali salt selected from the group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, barium hydroxide and / or strontium hydroxide.

[0092] In one embodiment, step b) is characterized in that the alkali salt is sodium hydroxide.

[0093] In one embodiment, step b) is characterized in that the concentration of alkali salt is within a range from 0.1M to 5M.

[0094] In one embodiment, step b) is characterized in that the concentration of alkali salt is within a range of 0.5M to 3M.

[0095] In one embodiment, step b) is characterized in that the concentration of alkali salt is within a range from IM to 2M.

[0096] In one embodiment, step b) is characterized in that the concentration of alkali salt is approximately IM.

[0097] In one embodiment, step b) is characterized in that it is carried out over a period of one hour to 48 hours.

[0098] In one embodiment, step b) is characterized in that it is carried out for a period of at least 2 hours.

[0099] In one embodiment, step b) is characterized in that it is carried out for a duration within an interval of 8h to 48h at a temperature of about 4°C.

[0100] In one embodiment, step b) is characterized in that it is carried out for a duration within an interval of 12h to 36h at a temperature of about 4°C.

[0101] In one embodiment, step b) is characterized in that it is carried out for a duration within an interval of 16h to 24h at a temperature of about 4°C.

[0102] In one embodiment, step b) is characterized in that it is carried out for a period of about 16h, 17h, 18h, 19h, 20h, 21h or 22h at a temperature of about 4°C.

[0103] In one embodiment, step b) is characterized in that it is carried out for a duration within an interval of 1h to 4h at a temperature between 20°C and 27°C.

[0104] In one embodiment, step b) is characterized in that it is carried out for a duration within an interval of 1h to 3h at a temperature between 20°C and 27°C.

[0105] In one embodiment, step b) is characterized in that it is carried out under weak agitation.

[0106] In one embodiment, the process according to the invention is characterized in that it further comprises a step b') of pH neutralization before step c) of crosslinking.

[0107] In one embodiment, the process according to the invention is characterized in that the neutralization step b') is carried out by washing with water.

[0108] In one embodiment, the crosslinking step c) is characterized in that it is carried out according to the protocol as described in application EP4209200A1.

[0109] In one embodiment, the crosslinking step c) is characterized in that it is carried out by non-enzymatic glycation, irradiation by UV rays with or without a photosensitizing agent and / or by aldehyde reaction.

[0110] In one embodiment, the crosslinking step c) is characterized in that it is carried out by irradiation with UV rays with or without a photosensitizing agent.

[0111] In one embodiment, the crosslinking step c) is characterized in that it is carried out by irradiation with UV-A and / or UV-C rays with or without a photosensitizing agent.

[0112] In one embodiment, the crosslinking step c) is characterized in that it is carried out by irradiation with UV rays with a photosensitizing agent.

[0113] In one embodiment of any of the processes according to the invention, step c) of crosslinking is carried out by irradiation with UV rays in the presence of riboflavin or one of its salts.

[0114] In one embodiment, step c) of crosslinking is carried out by irradiation with UV-A rays in the presence of phosphated sodium salt of riboflavin.

[0115] Riboflavin and riboflavin sodium phosphate are photosensitizing and photopolymerizing molecules with low diffusion capacity. Riboflavin is an essential constituent of living cells and is non-cytotoxic; therefore, its use will have no impact on the toxicity of the devices thus manufactured.

[0116] In one embodiment, the crosslinking step c) is characterized in that the concentration of riboflavin or riboflavin salt is within a range of 0.01 g / L to 2 g / L.

[0117] In one embodiment, the crosslinking step c) is characterized in that the concentration of riboflavin or riboflavin salt is within a range of 0.1 g / L to 0.5 g / L.

[0118] In one embodiment, the crosslinking step c) is characterized in that the concentration of riboflavin or riboflavin salt is approximately 0.1 g / L.

[0119] In one embodiment, the crosslinking step c) is characterized by the application of UV radiation of between 10 and 20 joules for 15 to 60 minutes.

[0120] In one embodiment, the crosslinking step c) is characterized by the application of UV-A radiation of between 10 and 20 joules for 2 times 15 minutes.

[0121] In one embodiment, the crosslinking step c) is characterized by the application of UV radiation of between 12 and 16 joules for 20 to 40 minutes.

[0122] In one embodiment, step c) of crosslinking is characterized by the application of UV radiation of 14.4 joules for 30 minutes

[0123] In one embodiment, the process according to the invention is characterized in that it further comprises a rinsing step c') following step c).

[0124] This step ensures the elimination of all the crosslinking agent.

[0125] In one embodiment, step c') of rinsing is carried out with water.

[0126] In one embodiment, step c') of rinsing is carried out with a mixture water and macromolecules chosen from dextran, carboxymethyl cellulose and / or polyvinylpyrrolidone (PVP).

[0127] In one embodiment, step c') of rinsing is carried out with a mixture of water and dextran.

[0128] In one embodiment, step c') of rinsing is carried out with a mixture of water and dextran at a concentration in the range of 0.1% to 10%.

[0129] In one embodiment, step c') of rinsing is carried out with a mixture of water and dextran at a concentration in the range of 1% to 8%.

[0130] In one embodiment, step c') of rinsing is carried out with a mixture of water and dextran at a concentration in the range of 3% to 7%.

[0131] In one embodiment, step c') of rinsing is carried out with a mixture of water and carboxymethyl cellulose.

[0132] In one embodiment, step c') of rinsing is carried out with a mixture of water and carboxymethyl cellulose at a concentration in the range of 0.1% to 10%.

[0133] In one embodiment, step c') of rinsing is carried out with a mixture of water and carboxymethyl cellulose at a concentration in the range of 1% to 5%.

[0134] In one embodiment, the process according to the invention is characterized in that it further comprises a drying step y) following step c), or alternatively following step c') when this step is implemented.

[0135] In one embodiment, the drying step y) is characterized in that it comprises at least one desiccation and / or freeze-drying step.

[0136] In one embodiment, the drying step y) is characterized in that it comprises at least one desiccation step.

[0137] For the purposes of the present invention, "desiccation" means the removal of water contained in a substance by vaporization, using heat, vacuum and / or a hygroscopic material.

[0138] In one embodiment, the desiccation step y) includes the application of heat, vacuum and / or a hygroscopic material.

[0139] In one embodiment, the desiccation step y) includes the application of heat on the one hand and vacuum and / or a hygroscopic material on the other.

[0140] In one embodiment, the desiccation step y) includes the application of heat and vacuum.

[0141] In one embodiment, the desiccation step y) does not include freezing and / or deep-freezing of the umbilical cord wall.

[0142] In one embodiment, in the desiccation step y), the minimum temperature is chosen so as to avoid the formation of water crystals depending on the pressure applied.

[0143] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C (0°C < temperature).

[0144] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 2°C (2°C < temperature).

[0145] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 4°C (4°C < temperature).

[0146] In one embodiment, the drying step y) is carried out by gradually raising the temperature up to 35°C.

[0147] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 35°C.

[0148] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C to 35°C (0°C < temperature < 35°C).

[0149] In one embodiment, the drying step y) is carried out by progressively raising the temperature in an interval from 4°C to 35°C (4°C < temperature < 35°C).

[0150] In one embodiment, the drying step y) is carried out by progressively raising the temperature in steps from 1 to 10°C (1°C < temperature < 10°C).

[0151] In one embodiment, the drying step y) is carried out by progressively increasing the temperature in stages from 1 to 10°C.

[0152] In one embodiment, the drying step y) is carried out by progressively increasing the temperature in stages from 2 to 8°C.

[0153] In one embodiment, the drying step y) is carried out by progressively increasing the temperature in stages from 3 to 7°C.

[0154] In one embodiment, the drying step y) is carried out by progressively increasing the temperature in 5°C increments.

[0155] In one embodiment, the drying step y) is carried out by progressively raising the temperature by 5°C.

[0156] In one embodiment, the drying step y) is carried out for a duration within an interval of 1 hour to 12 hours.

[0157] In one embodiment, the drying step y) is carried out for a duration within an interval of 2 hours to 10 hours.

[0158] In one embodiment, the drying step y) is carried out for a duration within an interval of 3 hours to 7 hours.

[0159] In one embodiment, the drying step y) is carried out for a duration within an interval of 4 hours to 6 hours.

[0160] In one embodiment, the desiccation step y) is carried out under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0161] In one embodiment, the desiccation step y) is carried out under pressures within a range of 100 to 800 microbars (100 microbars < pressures < 800 microbars).

[0162] In one embodiment, the desiccation step y) is carried out under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0163] In one embodiment, the desiccation step y) is carried out under pressures of approximately 600 micro-bars.

[0164] In one embodiment, the desiccation step y) is carried out under pressures of approximately 400 micro-bars.

[0165] In one embodiment, the drying step y) is carried out by progressively raising the temperature up to 35°C and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0166] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 50°C and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0167] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 2°C up to 45°C and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0168] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 4°C up to 40°C and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0169] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 8°C up to 35°C and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0170] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 35°C and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0171] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C to 35°C (0°C < temperature < 35°C) and under pressures within a range of 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0172] In one embodiment, the drying step y) is carried out by progressively raising the temperature in a range from 4°C to 35°C (4°C < temperature < 35°C) and under pressures in a range from 50 to 900 microbars (50 microbars < pressures < 900 microbars).

[0173] In one embodiment, the drying step y) is carried out by progressively raising the temperature up to 35°C and under pressures within a range of 100 to 800 micro-bars (100 micro-bars < pressures < 800 micro-bars).

[0174] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 50°C and under pressures within a range of 100 to 800 micro-bars (100 micro-bars < pressures < 800 micro-bars).

[0175] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 2°C up to 45°C and under pressures within a range of 100 to 800 microbars (100 microbars < pressures < 800 microbars).

[0176] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 4°C up to 40°C and under pressures within a range of 100 to 800 microbars (100 microbars < pressures < 800 microbars).

[0177] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 8°C up to 35°C and under pressures within a range of 100 to 800 microbars (100 microbars < pressures < 800 microbars).

[0178] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 35°C and under pressures within a range of 100 to 800 micro-bars (100 micro-bars < pressures < 800 micro-bars).

[0179] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C to 35°C (0°C < temperature < 35°C) and under pressures within a range of 100 to 800 microbars (100 microbars < pressures < 800 microbars).

[0180] In one embodiment, the drying step y) is carried out by progressively raising the temperature in a range from 4°C to 35°C (4°C < temperature < 35°C) and under pressures in a range from 100 to 800 microbars (100 microbars < pressures < 800 microbars).

[0181] In one embodiment, the drying step y) is carried out by progressively raising the temperature up to 35°C and under pressures within a range of 400 to 600 micro-bars (400 micro-bars < pressures < 600 micro-bars).

[0182] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 50°C and under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0183] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 2°C up to 45°C and under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0184] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 4°C up to 40°C and under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0185] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 8°C up to 35°C and under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0186] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C up to 35°C and under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0187] In one embodiment, the drying step y) is carried out by progressively raising the temperature from at least 0°C to 35°C (0°C < temperature < 35°C) and under pressures within a range of 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0188] In one embodiment, the drying step y) is carried out by progressively raising the temperature in a range from 4°C to 35°C (4°C < temperature < 35°C) and under pressures in a range from 400 to 600 microbars (400 microbars < pressures < 600 microbars).

[0189] In one embodiment, the drying step y) is characterized in that it comprises at least one freeze-drying step.

[0190] In one embodiment, freeze-drying is carried out under the following conditions:

[0191] a two-stage freezing:

[0192] the first freezing stage being carried out at an acclimatization temperature chosen so as not to damage the structural, functional and biological integrity of the umbilical cord wall,

[0193] the second freezing stage taking place at the final freezing temperature which is lower than the acclimatization temperature;

[0194] and, a freeze-drying process in two main stages, called primary and secondary:

[0195] the primary freeze-drying step being carried out by applying a vacuum of approximately 200 microbars and an ascending temperature profile;

[0196] the secondary freeze-drying step being carried out by applying a vacuum of about 50 microbars and a descending temperature profile.

[0197] In one embodiment the acclimatization temperature is between -5 and -20°C and the final freezing temperature is between -40 and -60°C.

[0198] The ascending temperature profile is advantageously a profile in which the freeze-drying temperature is initially set at a low initial temperature and then increased to a final primary freeze-drying temperature, in one or more intermediate ascending temperature steps. The descending temperature profile is advantageously a profile in which the freeze-drying temperature is initially set at a temperature higher than the final temperature of the primary freeze-drying step and then decreased to a final secondary freeze-drying temperature higher than the initial temperature of the primary freeze-drying step.

[0199] For the purposes of the present invention, "freeze-drying" means a technique for drying a previously frozen product by sublimation. More specifically, the liquid to be removed from the product is first transformed into a solid (ice) by freezing; then, through primary drying under vacuum, the solid is sublimated; finally, through secondary drying, the water molecules on the surface of the product are extracted by desorption.

[0200] In one embodiment, the process according to the invention is characterized in that it further comprises a sterilization step z) after step c), or when these steps are carried out, after step c') or y).

[0201] Sterilization may be carried out by any method classically known to a person skilled in the art.

[0202] In one embodiment, the sterilization step z) is carried out by irradiation.

[0203] In one embodiment, the sterilization step z) is carried out by irradiation with gamma radiation.

[0204] In one embodiment, the sterilization step z) is carried out by irradiation with gamma radiation at a dose in the range of 25 to 35 kGrays (25 kGrays < dose < 35 kGrays).

[0205] In one embodiment, the process according to the invention is characterized in that it is carried out under aseptic conditions.

[0206] In one embodiment, the process according to the present invention is characterized in that it further comprises a step x) of cutting the umbilical cord wall obtained at the end of any one of the steps of the process.

[0207] In one embodiment, the cutting step x) is characterized in that it is carried out at the end of any one of the steps a), b) and / or c).

[0208] In one embodiment, the cutting step x) is characterized in that it is carried out at the end of any one of the steps a), a'), b), b'), c), c'), y) and / or z).

[0209] In one embodiment, the cutting step x) is characterized in that it is carried out using an instrument and / or apparatus selected from the group including: a scalpel, a pair of surgical scissors, a microtome, an electric scalpel, surgical forceps, a surgical laser, a razor blade, an oscillating saw, a biopsy perforator and / or cutting forceps.

[0210] In one embodiment, the cutting step x) is characterized in that it is carried out using a laser.

[0211] In one embodiment, the cutting step x) is characterized in that it is carried out using a surgical laser or an industrial cutting laser.

[0212] In one embodiment, the cutting step x) is characterized in that it is carried out using a laser selected from the group comprising: a CO2 laser, an excimer laser, a diode laser, an Nd laser, an Er laser, a KTP laser, an argon laser, a holmium laser, a femtosecond laser and / or a thulium laser.

[0213] In one embodiment, the cutting step x) is characterized in that it is carried out using a femtosecond laser.

[0214] In one embodiment, the cutting step x) is characterized in that it is carried out using an industrial cutting laser of the femtosecond laser type.

[0215] By femtosecond laser is meant a light source, capable of emitting a LASER beam in the form of ultra-short pulses, the duration of which is between 1 femtosecond and 100 picoseconds.

[0216] In one embodiment, the cutting step x) is characterized in that it is carried out using a surgical laser of the femtosecond laser type as described in application WO2016055539 (Al).

[0217] The present invention also relates to an implantable device obtained by the process according to the present invention.

[0218] In one embodiment, the implantable device obtained by the process according to the present invention has a thickness of the umbilical cord wall layer between 0.3 and 3 millimeters.

[0219] In one embodiment, the implantable device obtained by the process according to the present invention has a thickness of the umbilical cord wall layer between 0.3 and 1 millimeter.

[0220] In one embodiment, the implantable device obtained by the process according to the present invention has a thickness of the umbilical cord wall layer between 1 and 3 millimeters.

[0221] The implantable device may be a biological lens, also called a "bandage lens," used in particular for medical applications, for example in the treatment of ocular surfaces. For the sake of brevity, only the term "lens" will be used below.

[0222] Due to its thickness, the lens does not require a support structure or double-layer mounting to perform its function.

[0223] In one embodiment of the method according to the invention, the implantable device is a biological lens.

[0224] In one embodiment, the process for manufacturing an implantable device according to the invention, said implantable device being a lens, is characterized in that the cutting step x) is implemented to give a disc shape, substantially circular, substantially oval or elliptical.

[0225] Disc shapes, substantially circular, substantially oval or elliptical, have an equivalent diameter. By "equivalent diameter" is meant one of the definitions below, depending on the shape of the umbilical cord wall.

[0226] For the disk shape, the equivalent diameter is the diameter of the circle representing the circumference of the disk.

[0227] For the elliptical shape, the equivalent diameter is between twice the length of the minor axis, also called the minor radius, and twice the length of the major axis, also called the major radius, of the ellipse.

[0228] For the substantially oval shape, that is to say a closed convex plane curve, the equivalent diameter is less than or equal to the length of the axis of symmetry when the closed convex plane curve has a single axis of symmetry; and the equivalent diameter is between the length of the longest axis of symmetry and the length of the shortest axis of symmetry, when the closed convex plane curve has two orthogonal axes of symmetry.

[0229] Preferably, the equivalent diameter of the cut is less than or equal to the average diameter of an adult human eye.

[0230] In one embodiment, the equivalent diameter of the cut is within a range of 0.5 to 3 cm.

[0231] In one embodiment, the equivalent diameter of the cut is within a range of 1 to 2.5 cm.

[0232] In one embodiment, the process for manufacturing an implantable device according to the invention, said implantable device being a lens, is characterized in that step c) of crosslinking is carried out on a dome-shaped support.

[0233] In one embodiment, the dome-shaped support has a curvature similar to that of the cornea.

[0234] In one embodiment, the dome-shaped support is as described in application WO2020 / 245324 (Al).

[0235] In one embodiment, the method for manufacturing an implantable device according to the invention, said implantable device being a lens, is characterized in that the crosslinking step is carried out on a dome-shaped support, the umbilical cord wall being arranged so that the epithelium of the umbilical cord wall is on the concave side.

[0236] The invention also relates to a lens made of umbilical cord wall having undergone at least one treatment step with a strong base for a period of at least one hour and at least one crosslinking step, said umbilical cord wall not being treated with proteases and / or collagenases.

[0237] In the embodiment, the crosslinking is as previously described.

[0238] In the embodiment, treatment with a strong base for a duration of at minus one hour is as previously described.

[0239] In one embodiment, the lens according to the invention is characterized in that it is viro-inactivated.

[0240] In one embodiment, the lens according to the invention is characterized in that it is sterile.

[0241] In one embodiment, the lens according to the invention is characterized in that it is desiccated.

[0242] In one embodiment, lens according to the invention is characterized in that it is obtained by the process according to the invention.

[0243] Another object of the present invention relates to the lens according to the invention for its therapeutic use.

[0244] Another object of the present invention relates to the lens according to the invention for its use in the treatment of eye lesions and / or dry eyes.

[0245] In one embodiment, eye lesions and / or dry eyes are chosen from the group comprising inflammatory diseases of the conjunctiva and / or cornea, infections of the conjunctiva and / or cornea, destruction of the surface of the conjunctiva and / or cornea, corneal ulcers, Stevens-Johnson syndrome, Lyell's syndrome and / or immune, allergic, inflammatory and / or traumatic keratoconjunctivitis.

[0246] In one embodiment, the lens according to the invention is intended to be used in the treatment of eye lesions and / or dry eyes.

[0247] The present invention also relates to a method for treating an eye injury and / or dry eye in a subject requiring such treatment, said method comprising the following steps:

[0248] a) identify the eye injury and / or dry eye in said subject;

[0249] b) provide a lens according to the invention;

[0250] c) apply the lens according to the invention according to the invention on said eye injury and / or dry eye.

[0251] The implantable device can also be a guide for nerve, ligament and / or tendon regeneration.

[0252] The nerve, ligament and / or tendon regeneration guide according to the present invention can be used in surgery by optionally cutting it dry, such that The device should be at least approximately 1 centimeter longer than the length of the gap to be bridged between the proximal and distal ends of the tissue to be repaired, which may be a peripheral nervous system nerve, tendon, or ligament. The tissue to be repaired is prepared so that the cut is clean.

[0253] The nerve, ligament and / or tendon regeneration guide according to the invention is handled dry. One end (proximal or distal) of the tissue to be repaired is inserted inside the sterile, lyophilized, virus-inactivated allograft material, and the latter is slid over the end of the tissue.

[0254] Both ends of the nerve, proximal end and distal end, are sutured and / or fixed.

[0255] In the event of severe loss of substance, the tissue to be repaired is introduced into the implantable device at each end and stabilized by suture, the implantable device acting as a guide.

[0256] The nerve, ligament and / or tendon regeneration guide according to the invention is slid beyond the suture, positioning it on either side of it, with the edges equidistant from the suture line.

[0257] The nerve, ligament and / or tendon regeneration guide according to the invention is naturally rehydrated by the surrounding organic tissues and becomes more flexible.

[0258] As previously stated, the nerve, ligament, and / or tendon regeneration guide according to the invention can be manipulated dry. Alternatively, the device is sufficiently rigid to be manipulated under an arthroscope after rehydration.

[0259] The nerve, ligament and / or tendon regeneration guide according to the invention can also be used when using an embedding technique, for example when the nerve is injured but not severed or when access to the implantation site is difficult.

[0260] These technical advantages conferred by an implantable device are difficult to obtain from a product that is little or not deformable, such as, for example, synthetic or collagen neurotubes, because the tubular structure will be too solid to allow the passage of a curved suture needle through the lumen of said neurotube.

[0261] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the invention is intended to be used by a technique of coating the injured structure.

[0262] The nerve, ligament and / or tendon regeneration guide according to the invention also has the advantage of being sufficiently translucent to allow the surgeon to see and possibly the tissue to be repaired through the guide during the surgical procedure and thus control and possibly reposition it.

[0263] The nerve, ligament and / or tendon regeneration guide is also characterized in that said rigidity of the guide allows a certain flexibility to be able to slide along the structure to be treated and bend during its implantation, as well as during the motor movements of the patient who has undergone the implantation, while being sufficiently rigid to reduce the risks of collapse in vivo.

[0264] The applicant has demonstrated, through observation of histological sections, that a nerve, ligament and / or tendon regeneration guide according to the invention has a porous structure attached to the internal surface of the guide which is particularly appreciated in tissue regeneration.

[0265] This rigidity of the nerve, ligament and / or tendon regeneration guide according to the invention therefore allows the reduction of the risks of collapse, while providing the tissue intended to regenerate within said guide with a longitudinal porous network conducive to its biological development.

[0266] It also has the advantage of having a larger internal diameter than the internal diameters of devices known in the prior art.

[0267] In one embodiment of the method according to the invention, the implantable device is a nerve, ligament and / or tendon regeneration guide.

[0268] In one embodiment, the process for manufacturing an implantable device, said implantable device being a nerve, ligament and / or tendon regeneration guide, is characterized in that the cutting step x) is implemented so as to produce a strip shape.

[0269] In one embodiment, the process for manufacturing an implantable device, said implantable device being a nerve, ligament and / or tendon regeneration guide, is characterized in that the cutting step x) is implemented so as to produce a strip shape between 1 and 12 cm in length.

[0270] In one embodiment, the process for manufacturing an implantable device, said implantable device being a nerve, ligament and / or tendon regeneration guide, is characterized in that the cutting step x) is implemented so as to produce a strip shape of 1 to 5 cm in width.

[0271] In one embodiment, the process for manufacturing an implantable device, said implantable device being a nerve, ligament and / or tendon regeneration guide, is characterized in that the cutting step x) is carried out so as to produce a strip shape between 1 and 12 cm in length and 1 to 5 cm in width.

[0272] In one embodiment, the process for manufacturing an implantable device, said implantable device being a nerve, ligament and / or tendon regeneration guide is characterized in that the crosslinking step is preceded by a step w) of winding the umbilical cord wall around a tubular, or substantially tubular, shaped support.

[0273] For the purposes of the present invention, "tubular" means a circular or substantially circular cross-section of a conduit, tube or cylinder.

[0274] For the purposes of the present invention, "substantially circular" means a slightly ovoid shape or a slightly flattened circle. When the shape is substantially circular, it will be defined by an equivalent diameter.

[0275] In one embodiment, the tubular or substantially tubular support used in step w) is characterized by a diameter of 1 to 30 mm.

[0276] In one embodiment, the tubular or substantially tubular support used in step w) is characterized by a diameter of 3 to 25 mm.

[0277] In one embodiment, the tubular or substantially tubular support used in step w) is characterized by a diameter of 5 to 20 mm.

[0278] In one embodiment, the tubular or substantially tubular support used in step w) is characterized by a diameter of 7 to 12 mm.

[0279] According to a preferred embodiment, the tubular or substantially tubular support used in step w) is made of PETG (polyethylene terephthalate glycolysate), or PET (polyethylene terephthalate), or PLGA (poly(lactic-co-glycolic acid)), or poly(α-hydroxy esters), in particular of polylactic acid (PLA) and polyglycolic acid (PGA), or various polyethylenes.

[0280] The present invention also relates to a nerve, ligament and / or tendon regeneration guide made of umbilical cord wall having undergone at least one treatment step with a strong base for a period of at least one hour and at least one cross-linking step, said umbilical cord wall not being treated with proteases and / or collagenases.

[0281] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that it is obtained by the process as previously described.

[0282] In the embodiment, the crosslinking is as previously described.

[0283] In the embodiment, treatment with a strong base for a duration of at minus one hour is as previously described.

[0284] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that it is viro-inactivated.

[0285] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that it is sterile.

[0286] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that it is lyophilized.

[0287] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that it is desiccated.

[0288] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that it has a non-collapsible tubular shape.

[0289] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that the diameter of its lumen is between 1.5 and 25 mm.

[0290] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that the diameter of its lumen is between 5 and 20 mm.

[0291] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that the diameter of its lumen is between 7 and 12 mm.

[0292] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the present invention is characterized in that the diameter of its length is between 1 and 12 centimeters.

[0293] In one embodiment, the nerve, ligament and / or tendon regeneration guide according to the invention is characterized in that it is intended to be used as an allograft material selected from the group consisting of nerve regeneration guide grafting, tendon regeneration guide grafting, and ligament regeneration guide grafting.

[0294] In one embodiment, the nerve, ligament and / or tendon regeneration guide is characterized in that it is intended to be used as an allograft material selected from the group consisting of peripheral nervous system nerve repair, tendon repair, ligament repair.

[0295] The present invention also relates to a method for treating a nerve, ligament and / or tendon injury in a subject requiring such treatment, said method comprising the following steps:

[0296] a) identify the nerve, ligament and / or tendon lesion in said subject;

[0297] b) provide a guide for nerve, ligament and / or tendon regeneration according to the invention;

[0298] c) apply the nerve, ligament and / or tendon regeneration guide according to the invention to said lesion.

[0299] In one embodiment, said method of treating a nerve, ligament and / or tendon injury according to the invention is characterized in that step c) of application is carried out by coating the lesion.

[0300] In one embodiment, said method for treating a nerve, ligament and / or tendon injury according to the invention further comprises, after step c), step d) fix the nerve, ligament and / or tendon regeneration guide according to the invention around the nerve, ligament and / or tendon lesion

[0301] In one embodiment, the nerve injury is chosen from the group comprising traumatic or excisional nerve sections, neuritis, neurotmesis, axonotmesis and / or neurapraxias.

[0302] In one embodiment, the ligament injury is chosen from the group comprising sprains and / or total or partial ligament ruptures.

[0303] In one embodiment, the tendon injury is chosen from the group comprising tendinitis, tendinosis, tendon ruptures, enthesopathies and / or calcific tendinitis.

[0304] The implantable device may be an intracorneal implant consisting of a ring or a ring segment.

[0305] Intracorneal corneal ring segments are medical devices used in ophthalmic surgery, primarily to treat corneal abnormalities such as keratoconus. They are designed to be inserted into the human cornea to modify its curvature and correct refractive errors of the eye. They have a shaped and configured arc to surround a portion of the cornea during implantation.

[0306] In one embodiment of the method according to the invention, the implantable device is an intracorneal implant consisting of a ring or a ring segment.

[0307] In one embodiment of the method according to the invention, the implantable device is an intracorneal implant consisting of a ring.

[0308] The ring shape can be cut extemporaneously by the practitioner so as to be adapted to the pathology being treated.

[0309] In one embodiment of the method according to the invention, the implantable device is an intracorneal implant consisting of a ring segment.

[0310] For the purposes of the present invention, "ring segment" means an incomplete circular structure of less than 360° continuously.

[0311] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring segment, is characterized in that at least one cutting step x) includes cutting at least one ring segment with an arc length of 90° to 350° continuously.

[0312] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring segment, is characterized in that at least one cutting step x) comprises cutting at least one ring segment with an arc length of 120° to 325° continuously.

[0313] In one embodiment, the process of manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring segment is characterized in that at least one cutting step x) includes cutting at least one ring segment with an arc length of 160° to 320° continuously.

[0314] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring segment, is characterized in that at least one cutting step x) comprises cutting at least one ring segment with an arc length of 210° to 260° continuously.

[0315] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring segment, is characterized in that at least one cutting step x) comprises cutting at least one ring segment with an arc length of 90°, 120°, 160°, 210°, 260° or 320° continuously.

[0316] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring or a ring segment, is characterized in that at least one cutting step x) includes cutting at least one ring or a ring segment with an external diameter in a range of 3 to 10 mm.

[0317] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring or a ring segment, is characterized in that at least one cutting step x) includes cutting at least one ring or a ring segment with an external diameter within a range of 4 to 7 mm.

[0318] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring or a ring segment, is characterized in that at least one cutting step x) includes cutting at least one ring or a ring segment with an external diameter within a range of 5 to 6 mm.

[0319] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring or a ring segment, is characterized in that at least one cutting step x) includes cutting at least one ring or ring segment with a thickness in a range from 150 pm to 500 pm.

[0320] In one embodiment, the method for manufacturing an implantable device, said implantable device being an intracorneal implant consisting of a ring or a ring segment, is characterized in that at least one cutting step x) includes cutting at least one ring segment of increasing thickness in a clockwise or counterclockwise direction.

[0321] In one embodiment, the process of manufacturing an implantable device according to the invention, said implantable device being an intracorneal implant consisting of a ring or ring segment, is characterized in that the crosslinking step is carried out on a dome-shaped support.

[0322] In one embodiment, the dome-shaped support has a curvature similar to that of the inner cornea.

[0323] In one embodiment, the dome-shaped support is as described in application WO2020 / 245324 (Al).

[0324] In one embodiment, the method for manufacturing an implantable device according to the invention, said implantable device being an intracorneal implant consisting of a ring or a ring segment, is characterized in that the crosslinking step is carried out on a dome-shaped support, the umbilical cord wall being arranged so that the epithelium of the umbilical cord wall is on the concave side.

[0325] The present invention also relates to an intracorneal implant consisting of a ring or a ring segment made of umbilical cord wall.

[0326] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that the umbilical cord wall is reticulated.

[0327] In the embodiment, the crosslinking is as previously described.

[0328] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that the umbilical cord wall is treated with a strong base for a period of at least one hour.

[0329] In the embodiment, the treatment with a strong base for a period of at least one hour is as previously described.

[0330] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that the umbilical cord wall is treated with a strong base for a period of at least one hour and then cross-linked.

[0331] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that it is viro-inactivated.

[0332] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that it is sterile.

[0333] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that it is lyophilized.

[0334] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that it is desiccated.

[0335] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized in that the umbilical cord wall has undergone at least one treatment step with a strong base during a duration of at least one hour and at least one cross-linking step, said umbilical cord wall not being treated with proteases and / or collagenases.

[0336] In the embodiment, the intracorneal implant consisting of a ring segment according to the present invention is characterized by an arc length of 90° to 350° continuously.

[0337] In the embodiment, the intracorneal implant consisting of a ring segment according to the present invention is characterized by an arc length of 120° to 325° continuously.

[0338] In the embodiment, the intracorneal implant consisting of a ring segment according to the present invention is characterized by an arc length of 160° to 320° continuously.

[0339] In the embodiment, the intracorneal implant consisting of a ring segment according to the present invention is characterized by an arc length of 210° to 260° continuously.

[0340] In the embodiment, the intracorneal implant consisting of a ring segment according to the present invention is characterized by an arc length of 90°, 120°, 160°, 210°, 260° or 320° continuously

[0341] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized by a thickness within a range from 150 pm to 500 pm.

[0342] In one embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized by a thickness increasing in the clockwise or counterclockwise direction.

[0343] In the embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized by an external diameter of 3 to 12 mm.

[0344] In the embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized by an external diameter of 4 to 7 mm.

[0345] In the embodiment, the intracorneal implant consisting of a ring or a ring segment according to the present invention is characterized by an external diameter of 5 to 6 mm.

[0346] The present invention also relates to a method for treating keratoconus in a subject requiring such treatment, said method comprising the following steps:

[0347] a) identify the irregularity of the cornea;

[0348] b) provide an intracorneal implant consisting of a ring or a ring segment according to the present invention;

[0349] c) prepare the intracomean thickening site; and

[0350] d) implant the intracorneal implant consisting of a ring or a ring segment according to the present invention on said irregularity.

[0351] The implantable device may also be an artificial heart valve.

[0352] In one embodiment of the method according to the invention, the implantable device is an artificial heart valve.

[0353] In one embodiment of the method according to the invention, the implantable device is an artificial heart valve selected from the group comprising: an aortic valve, a pulmonary valve, a mitral valve and / or a tricuspid valve.

[0354] In one embodiment, the process for manufacturing an implantable device, said implantable device being an artificial heart valve, is characterized in that step c) of crosslinking is preceded by a shaping step w') comprising the substeps of:

[0355] w'i) selection of a tubular segment of umbilical cord wall (1) whose diameter is adapted to the cardiac valve to be reproduced, and closure (2) at a non-terminal point of said tubular segment of umbilical cord wall,

[0356] w'2) insertion of a support (3) inside the umbilical cord wall segment (1), the closure zone (2) of the cord wall segment (1) being centered at the end of the support (3), said support (3) comprising at its end impressions (4) corresponding to the leaflets of the heart valve to be reproduced,

[0357] w'3) mass deposition of marking (5) on the surface so as to recreate the shape and / or the curvature of the heart valve leaflets to be reproduced.

[0358] The sub-steps of the formatting step w') are in particular shown in figures [Fig.4] and [Fig.5].

[0359] In one embodiment, the closing step w'i) (2) includes at least one step of knotting, suturing and / or gluing the umbilical cord wall.

[0360] In one embodiment, the closing step w'i) (2) includes at least one knotting step of the umbilical cord wall in which the knot is made using a suture thread.

[0361] In one embodiment, the support inserted in step w'2) is characterized in that the support (3) has an external diameter adapted to the size of the heart valve to be reproduced.

[0362] In one embodiment, the shaping step w') further includes a substep w'4) of cutting the leaflets of the heart valve to be reproduced.

[0363] Alternatively, the step of cutting the leaflets of the heart valve to be reproduced can be carried out after the crosslinking step.

[0364] The present invention also relates to an artificial heart valve made of umbilical cord wall.

[0365] In one embodiment, the artificial heart valve according to the present invention is characterized in that the umbilical cord wall at the level of the valve segments is cross-linked.

[0366] In the embodiment, the crosslinking is as previously described.

[0367] In one embodiment, the artificial heart valve according to the present invention is characterized in that the umbilical cord wall subject to cross-linking is treated with a strong base for a period of at least one hour.

[0368] In the embodiment, the treatment with a strong base for a period of at least one hour is as previously described.

[0369] In one embodiment, the artificial heart valve according to the present invention is characterized in that the umbilical cord wall is treated with a strong base for a period of at least one hour and then cross-linked.

[0370] In one embodiment, the artificial heart valve according to the present invention is characterized in that it is viro-inactivated.

[0371] In one embodiment, the artificial heart valve according to the present invention is characterized in that it is sterile.

[0372] In one embodiment, the artificial heart valve according to the present invention is characterized in that it is lyophilized.

[0373] In one embodiment, the artificial heart valve according to the present invention is characterized in that it is desiccated.

[0374] In one embodiment, the artificial heart valve according to the present invention is characterized in that the umbilical cord wall has undergone at least one treatment step with a strong base for a duration of at least one hour and at least one crosslinking step, said umbilical cord wall not being treated with proteases and / or collagenases.

[0375] In one embodiment, the artificial heart valve according to the present invention is obtained by the process according to the present invention.

[0376] In the examples, all percentages are given by weight unless otherwise stated, temperature is expressed in degrees Celsius unless otherwise stated, tests are carried out at room temperature, i.e. about 23°C, unless otherwise stated, and pressure is atmospheric pressure unless otherwise stated.

[0377] EXAMPLES

[0378] Example 1: Preparation process.

[0379] Example La. Example of a method for preparing an implantable device consisting of a reticulated umbilical cord wall.

[0380] A properly informed and consenting donor, in accordance with the requirements of the Declaration of Helsinki, donates umbilical cord blood from a childbirth. Due to health requirements for donations of human tissues and cells, prior screening of the donor is mandatory. This screening includes testing for HIV, hepatitis B, C, HTLV, and the bacterium Treponema pallidum, which causes syphilis.

[0381] The umbilical cord is retrieved as soon as possible in the delivery room. It is placed in a sterile container containing a NaCl solution at +4°C.

[0382] In the laboratory, in a sterile room, the following procedure is applied:

[0383] The umbilical cord is cut lengthwise and then opened.

[0384] The umbilical vessels are removed manually so as to retain only the cord wall.

[0385] In a first cutting step, strips 10 to 30 mm wide are cut lengthwise from the umbilical cord wall.

[0386] The tissues are dry-frozen before processing.

[0387] The strips are placed in a bath of purified water at room temperature for approximately 3 hours.

[0388] Then, they are transferred into a decontaminating bath composed of an aqueous solution of 70% v / v ethanol at room temperature for about 1 hour.

[0389] A wash is carried out in purified water for about 15 minutes at room temperature to remove the ethanol.

[0390] In order to ensure the second decontaminating treatment step, the umbilical cord wall is transferred into a bath composed of 30% w / v hydrogen peroxide at room temperature for approximately 15 minutes.

[0391] Then the umbilical cord wall strips are transferred into a decontaminating bath composed of a 3% w / v aqueous hydrogen peroxide solution at room temperature for about 1 hour.

[0392] The chemical action is neutralized in two baths comprising basic buffer diluted around a pH of 8.5. The neutralization baths are carried out at room temperature for about 15 minutes.

[0393] In a second cutting step, the umbilical cord wall strips are cut into homogeneous discs of approximately 10 to 12 mm in diameter.

[0394] Umbilical cord wall discs are treated with 1 molar sodium hydroxide for 19 hours in Falcon tubes.

[0395] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the structures obtained are transferred into two successive baths of PBS buffer at room temperature for about 15 minutes in order to ensure its physiological rebalancing.

[0396] The discs are then immersed in a riboflavin solution at a concentration of 0.1 g / L for 7 minutes, and the resulting structures are placed on a mold simulating a cornea. The assembly is then subjected to UV-A radiation of 14.4 joules for two 15-minute periods.

[0397] In order to ensure a rebalancing of the pH and to best eliminate the organic residues detaching from the tissue of interest, the umbilical cord wall is rinsed several times in sterile water in order to ensure a physiological rebalancing.

[0398] The reticulated umbilical cord wall obtained is subjected to a drying step by desiccation under the following conditions.

[0399] Temperature of 8.0°C for 5 minutes,

[0400] Temperature of 8.0° for 120 minutes,

[0401] Temperature of 10.0°C for 30 minutes under a vacuum pressure of 400 pbar,

[0402] Temperature of 15.0°C for 30 minutes under a vacuum pressure of 400 pbar,

[0403] Temperature of 20.0°C for 30 minutes under a vacuum pressure of 400 pbar,

[0404] Temperature of 25.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0405] Temperature of 30.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0406] Temperature of 35.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0407] End of cycle by a return to normal atmosphere and ambient temperature for a period of 5 minutes.

[0408] Outside the sterile room, a final sterilization step of the implantable device consisting of a reticulated umbilical cord wall is carried out by exposing it to gamma radiation at 25-32 kGrays.

[0409] Example lb Example of a method for preparing a bandage lens consisting of a reticulated umbilical cord wall.

[0410] A properly informed and consenting donor, in accordance with the requirements of the Declaration of Helsinki, donates umbilical cord blood from a childbirth. Due to health requirements for donations of human tissues and cells, prior screening of the donor is mandatory. This screening includes testing for HIV, hepatitis B, C, HTLV, and the bacterium Treponema pallidum, which causes syphilis.

[0411] The umbilical cord is retrieved as soon as possible in the delivery room. It is placed in a sterile container containing a NaCl solution at +4°C.

[0412] In the laboratory, in a sterile room, the following procedure is applied under aseptic conditions:

[0413] The umbilical cord is opened and then cut with a dermatome to a thickness of 0.5 mm in the length direction.

[0414] The umbilical vessels are removed manually so as to retain only the cord wall. In a first cutting step, strips 10 to 12 mm wide are cut lengthwise from the umbilical cord wall.

[0415] The tissues are dry-frozen before processing

[0416] Initially, the strips are placed in a bath of purified water at room temperature for approximately 3 hours.

[0417] Then, they are transferred into a decontaminating bath composed of an aqueous solution of 70% v / v ethanol at room temperature for about 1 hour.

[0418] A wash is carried out in purified water for about 15 minutes at room temperature to remove the ethanol.

[0419] In order to ensure the second decontaminating treatment step, the strips are transferred into a bath composed of 30% w / v hydrogen peroxide at room temperature for approximately 15 minutes.

[0420] Then they are transferred to a decontaminating bath composed of a 3% w / v aqueous hydrogen peroxide solution at room temperature for about 1 hour.

[0421] The chemical action is neutralized in two baths of dilute basic buffer around a pH of 8.5. The neutralization baths are carried out at room temperature for about 15 minutes.

[0422] In a second cutting step, the umbilical cord wall strips are cut into substantially homogeneous circular discs of about 10 to 12 mm.

[0423] Umbilical cord wall discs are treated with 1 molar sodium hydroxide for 19 hours in Falcon tubes.

[0424] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, they are transferred into two successive baths of PBS buffer at room temperature for about 15 minutes in order to ensure its physiological rebalancing.

[0425] The structures obtained are arranged flat so as to be totally immersed on a UV-A transparent support, in the shape of a dome containing a riboflavin solution at a concentration of 0.1 g / L. The assembly is then subjected to UV-A radiation of 14.4 joules for two times 15 minutes.

[0426] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the structures obtained are rinsed several times in a solution comprising sterile water and 5% dextran in order to ensure physiological rebalancing.

[0427] The umbilical cord wall is transferred into a final bath of purified water, at room temperature, for 2 times 15 minutes.

[0428] The dressing lens consisting of a reticulated umbilical cord wall obtained is kept in a dextran solution.

[0429] The photograph of the dressing lens consisting of a reticulated umbilical cord wall thus obtained is shown in [Fig.1].

[0430] Example Le. Example of a method for preparing a nerve, ligament and / or tendon regeneration guide consisting of a reticulated umbilical cord wall.

[0431] A properly informed and consenting donor, in accordance with the requirements of the Declaration of Helsinki, donates umbilical cord blood from a childbirth. Due to health requirements for donations of human tissues and cells, prior screening of the donor is mandatory. This screening includes testing for HIV, hepatitis B, C, HTLV, and the bacterium Treponema pallidum, which causes syphilis.

[0432] The umbilical cord is retrieved as soon as possible in the delivery room. It is placed in a sterile container containing an aqueous NaCl solution at +4°C.

[0433] In the laboratory, in a sterile room, the following procedure is applied:

[0434] The umbilical cord is cut lengthwise and then opened.

[0435] The umbilical vessels are removed manually so as to retain only the cord wall. In a first cutting step, strips are made.

[0436] The strips are frozen at -80°C in a dry state.

[0437] The strips are placed in a bath of purified water at room temperature for approximately 3 hours.

[0438] Then, they are transferred into a decontaminating bath composed of an aqueous solution of 70% v / v ethanol at room temperature for about 1 hour.

[0439] A wash is carried out in purified water for about 15 minutes at room temperature to remove the ethanol.

[0440] In order to ensure the second decontaminating treatment step, the strips are transferred into a bath composed of 30% w / v hydrogen peroxide at room temperature for approximately 15 minutes.

[0441] Then the strips are transferred into a decontaminating bath composed of a 3% w / v aqueous hydrogen peroxide solution at room temperature for about 1 hour.

[0442] The applied chemical action is neutralized in two baths comprising basic buffer diluted around a pH of 8.5. The neutralization baths are carried out at room temperature for about 15 minutes.

[0443] Umbilical cord wall strips are treated with 1 molar sodium hydroxide for 19 hours in Falcon tubes.

[0444] To ensure pH rebalancing and to best eliminate organic residues

[0445] detaching from the tissue of interest, the strips are transferred to two successive baths of PBS buffer at room temperature for approximately 15 minutes to ensure physiological rebalancing. The strips are cut into rectangles of a size adapted for the different

[0446] indications. The resulting structures are partially wound around a UV-A transparent guide

[0447] slightly larger than the desired diameter for the guide on the amniotic membrane side. The assembly is immersed in an aqueous riboflavin solution at a concentration of 0.1 g / L such that the ends of the opening created during partial winding are not immersed. The assembly is then subjected to UV-A radiation of 14,4 joules for two 15-minute intervals. To ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the structures obtained are rinsed several times in a solution comprising sterile water and 5% dextran to ensure physiological rebalancing. They are then collected and subjected to freeze-drying under the following conditions. Temperature of -10.0°C for 5 minutes,

[0451] Temperature of -15.0°C for 90 minutes,

[0452] Temperature of -45.0°C for 5 minutes,

[0453] Temperature of -45.0°C for 90 minutes,

[0454] Temperature of 10.0°C for 180 minutes under a vacuum pressure of 200

[0455] pbar, Freezing temperature -40°C,

[0456] Vacuuming to a pressure of 300 pbar,

[0457] Temperature of 10.0°C for 210 minutes under a vacuum pressure of 200

[0458] pbar, Temperature of 25.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0459] Temperature of 25.0°C for 120 minutes under a vacuum pressure of 200 pbar,

[0460] Temperature of 35.0°C for 60 minutes under a vacuum pressure of 50 pbar,

[0461] Temperature of 35.0°C for 90 minutes under a vacuum pressure of 50 pbar,

[0462] Temperature of 25.0°C for 40 minutes under a vacuum pressure of 50 pbar,

[0463] Temperature of 25.0°C for 20 minutes under a vacuum pressure of 50 pbar,

[0464] End of the cycle by returning to normal atmosphere and ambient temperature for a period of 5 minutes.

[0465] Outside the sterile room, a final sterilization step of the nerve, ligament and / or tendon regeneration guide consisting of a reticulated umbilical cord wall is carried out by exposing it to gamma radiation at 25-32 kGrays.

[0466] The photograph of the nerve, ligament and / or tendon regeneration guide consisting of a reticulated umbilical cord wall thus obtained is shown in [Fig.2].

[0467] Example ld Example of a process for preparing a ring segment formed from an umbilical cord wall.

[0468] A properly informed and consenting donor, in accordance with the requirements of the Declaration of Helsinki, donates umbilical cord blood from a childbirth. Due to health requirements for donations of human tissues and cells, prior screening of the donor is mandatory. This screening includes testing for HIV, hepatitis B, C, HTLV, and the bacterium Treponema pallidum, which causes syphilis.

[0469] The umbilical cord is retrieved as soon as possible in the delivery room. It is placed in a sterile container containing an aqueous NaCl solution at +4°C.

[0470] In the laboratory, in a sterile room, the following procedure is applied:

[0471] The umbilical cord is cut lengthwise and then opened.

[0472] The umbilical cord wall is isolated from the other components of the umbilical cord.

[0473] In a first cutting step, strips 10 to 12 mm wide are cut lengthwise from the umbilical cord wall.

[0474] They are placed in a bath of purified water at room temperature for approximately 3 hours.

[0475] Then, they are transferred into a decontaminating bath composed of an aqueous solution of 70% v / v ethanol at room temperature for about 1 hour.

[0476] A wash is carried out in purified water for about 15 minutes at room temperature to remove the ethanol.

[0477] In order to ensure the second decontaminating treatment step, the umbilical cord wall strips are transferred into a bath composed of 30% w / v hydrogen peroxide at room temperature for approximately 15 minutes.

[0478] Then they are transferred to a decontaminating bath composed of a 3% w / v aqueous hydrogen peroxide solution at room temperature for about 1 hour.

[0479] The applied chemical action is neutralized in two baths of dilute basic buffer having a pH of about 8.5. The neutralization baths are carried out at room temperature for about 15 minutes.

[0480] In a second cutting step, the umbilical cord wall strips are cut into substantially homogeneous circular discs of about 10 to 12 mm.

[0481] Umbilical cord wall discs are treated with 1 molar sodium hydroxide for 19 hours in Falcon tubes.

[0482] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the umbilical cord wall discs are transferred into two successive baths of PBS buffer at room temperature for about 15 minutes to ensure its physiological rebalancing.

[0483] The structures obtained are arranged flat so as to be totally immersed on a support transparent to UV-A light, in the shape of a dome with a curvature similar to that of an inner cornea containing an aqueous solution of riboflavin at a concentration of 0.2 g / L. The assembly is then subjected to UV-A radiation of 14.4 joules for 30 minutes.

[0484] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the structures obtained are rinsed several times in a solution comprising sterile water and 5% dextran in order to ensure physiological rebalancing.

[0485] The structures obtained are cut using a femtosecond laser into several ring segments, with continuous arc lengths from 160° to 260°, diameters varying between 5 and 6 mm, and thicknesses ranging from 150 pm to 500 pm.

[0486] The ring segments are then subjected to a drying step by desiccation under the following conditions.

[0487] Temperature of 8.0°C for 5 minutes,

[0488] Temperature of 8.0° for 120 minutes,

[0489] Temperature of 10.0°C for 30 minutes under a vacuum pressure of 400 pbar,

[0490] Temperature of 15.0°C for 30 minutes under a vacuum pressure of 400 pbar,

[0491] Temperature of 20.0°C for 30 minutes under a vacuum pressure of 400 pbar,

[0492] Temperature of 25.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0493] Temperature of 30.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0494] Temperature of 35.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0495] End of cycle by a return to normal atmosphere and ambient temperature for a period of 5 minutes.

[0496] The structures are cut using a scalpel into ring segments of the following different dimensions:

[0497] Arc length of 120°, 160°, 210°, 260° or 320° continuously,

[0498] External diameter: 4 to 7 mm,

[0499] Thickness 150 pm to 500 pm.

[0500] Outside the sterile room, a final sterilization step of the ring segment formed from an umbilical cord wall is carried out by exposing it to gamma radiation at 25-32 kGrays.

[0501] Example Le. Example of a method for preparing a heart valve made from umbilical cord wall.

[0502] An informed and consenting donor, in accordance with the requirements of the Declaration of Helsinki, donates umbilical cord blood from a childbirth. Due to health requirements for donations of human tissues and cells, prior screening of the donor is mandatory. This screening includes testing for HIV, hepatitis B, C, HTLV, and the bacterium Treponema pallidum, which causes syphilis.

[0503] The umbilical cord is retrieved as soon as possible in the delivery room. It is placed in a sterile container containing an aqueous NaCl solution at +4°C.

[0504] In the laboratory, in a sterile room, the following procedure is applied:

[0505] The umbilical vessels are removed manually so as to retain only the cord wall.

[0506] The umbilical cord wall is placed in a bath of purified water at room temperature for approximately 3 hours.

[0507] Then, the umbilical cord wall is transferred into a decontaminating bath composed of an aqueous solution of 70% v / v ethanol at room temperature for approximately 1 hour.

[0508] A wash is carried out in purified water for about 15 minutes at room temperature to remove the ethanol.

[0509] In order to ensure the second decontaminating treatment step, the umbilical cord wall is transferred into a bath composed of a 30% w / v aqueous hydrogen peroxide solution at room temperature for approximately 15 minutes.

[0510] Then the umbilical cord wall is transferred into a decontaminating bath composed of a 3% w / v aqueous hydrogen peroxide solution at room temperature for about 1 hour.

[0511] The chemical action applied to the umbilical cord wall is neutralized in two baths comprising dilute basic buffer having a pH of about 8.5. The neutralization baths are carried out at room temperature for about 15 minutes.

[0512] The umbilical cord wall is treated with a 1 molar aqueous sodium hydroxide solution for 19 hours in Falcon tubes.

[0513] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the umbilical cord wall is transferred into two successive baths of PBS buffer at room temperature for approximately 15 minutes to ensure its physiological rebalancing.

[0514] The shaping of the umbilical cord wall is schematically shown in [Fig.4] and [Fig.5].

[0515] The treated cord wall (1) is closed by a knot (2) using a suture thread at a central point along the length of the umbilical cord wall (1).

[0516] A support (3) with valve segment-shaped impressions (4) at the end is inserted inside the closed umbilical cord wall (1) so that the closure area (2) of the cord wall (1) is centered at the end of the support (3).

[0517] Three marking masses (5) are deposited on the closed upper surface of the cord wall (1) opposite the impressions (4) of the support (3) so as to recreate the shape and curvature of the leaflets of a tricuspid valve.

[0518] The valve part to be formed is covered with a riboflavin solution at a concentration of 0.1 g / L such that the lower ends opposite the valve ends are not immersed.

[0519] The cuts of the valvular segments are made.

[0520] The assembly is then subjected to UV-A radiation of 14.4 joules for 30 minutes.

[0521] In order to ensure pH rebalancing and to best eliminate organic residues detaching from the tissue of interest, the reticulated umbilical cord wall obtained is rinsed several times in a solution comprising sterile water and 5% dextran in order to ensure physiological rebalancing.

[0522] It is recovered and subjected to freeze-drying under the following conditions.

[0523] Temperature of -10.0°C for 5 minutes,

[0524] Temperature of -15.0°C for 90 minutes,

[0525] Temperature of -45.0°C for 5 minutes,

[0526] Temperature of -45.0°C for 90 minutes,

[0527] Temperature of 10.0°C for 180 minutes under a vacuum pressure of 200 pbar,

[0528] Freezing temperature -40°C,

[0529] Vacuum sealing to a pressure of 300 pbar,

[0530] Temperature of 10.0°C for 210 minutes under a vacuum pressure of 200 pbar,

[0531] Temperature of 25.0°C for 30 minutes under a vacuum pressure of 200 pbar,

[0532] Temperature of 25.0°C for 120 minutes under a vacuum pressure of 200 pbar,

[0533] Temperature of 35.0°C for 60 minutes under a vacuum pressure of 50 pbar,

[0534] Temperature of 35.0°C for 90 minutes under a vacuum pressure of 50 pbar.

[0535] Temperature of 25.0°C for 40 minutes under a vacuum pressure of 50 pbar,

[0536] Temperature of 25.0°C for 20 minutes under a vacuum pressure of 50 pbar,

[0537] End of cycle by a return to normal atmosphere and ambient temperature for a period of 5 minutes.

[0538] Outside the sterile room, a final sterilization step of the artificial tricuspid heart valve is carried out by exposing it to gamma radiation at 25-32 kGrays.

[0539] The photograph of the artificial tricuspid heart valves thus obtained is shown in [Fig.3].

Claims

Demands

1. A method for manufacturing an implantable device characterized in that it comprises the steps of: a) Having an umbilical cord wall, b) Treating the umbilical cord wall with a strong base for a period of at least one hour, c) Carrying out at least one crosslinking step, d) Obtaining an implantable device consisting of a crosslinked umbilical cord wall, said method not comprising a step of treating the umbilical cord wall with proteases and / or collagenases.

2. Method according to claim 1, characterized in that the implantable device is selected from the group comprising a biological lens, an intracorneal implant consisting of a ring or ring segment, a nerve, ligament and / or tendon regeneration guide, and / or an artificial heart valve.

3. A method according to any one of the preceding claims, wherein step b) is characterized in that the strong base is an aqueous solution of an alkali salt selected from the group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, barium hydroxide, strontium hydroxide.

4. A method according to any one of the preceding claims, characterized in that it further comprises a step a') of viro-inactivation of the umbilical cord wall following step a).

5. A process according to any one of the preceding claims, characterized in that it further comprises a step b') of pH neutralization before step c) of crosslinking.

6. A method according to any one of the preceding claims, characterized in that it further comprises a rinsing step c') following step c).

7. A method according to any one of the preceding claims, characterized in that it further comprises a drying step (y) following step (c), or alternatively (c') when that step is put implemented.

8. A method according to any one of the preceding claims, characterized in that it further comprises a sterilization step z) after step c), or when these steps are carried out, after step c') or y).

9. A method according to any one of the preceding claims, characterized in that it further comprises a step x) of cutting the umbilical cord wall obtained at the end of any one of the steps of the method.

10. Implantable device obtained by the method according to any one of the preceding claims.

11. Lens characterized in that it is made up of umbilical cord wall having undergone at least one treatment step with a strong base for a duration of at least one hour and at least one crosslinking step, said umbilical cord wall not being treated with proteases and / or collagenases.

12. Nerve, ligament and / or tendon regeneration guide characterized in that it consists of umbilical cord wall having undergone at least one treatment step with a strong base for a duration of at least one hour and at least one crosslinking step, said umbilical cord wall not being treated with proteases and / or collagenases.

13. Intracomean implant consisting of a ring or ring segment characterized in that it is made of umbilical cord wall and in that the umbilical cord wall has undergone at least one treatment step with a strong base for a duration of at least one hour and at least one crosslinking step, said umbilical cord wall not being treated with proteases and / or collagenases.

14. Artificial heart valve characterized in that it is made of umbilical cord wall and in that the umbilical cord wall has undergone at least one treatment step with a strong base for a duration of at least one hour and at least one crosslinking step, said umbilical cord wall not being treated with proteases and / or collagenases.

Images