METHOD OF MANUFACTURING AN IMPLANTABLE FILM AND PROTHESIS COMPRISING SUCH A FILM

Abstract

A method for manufacturing an implantable film and a prosthesis comprising such a film The present invention relates to a method for manufacturing a non porous film intended to be implanted in the human body, said method comprising the following steps: preparation of a first film, called intermediate film, via gelling of a starting solution comprising at least one polymer selected in the group consisting of collagen, glycosaminoglycans, and mixtures thereof, immersion of said intermediate film in an alkaline composition comprising at least one C.sub.1-C.sub.4 alcohol, drying of the film obtained at the end of the immersing step. The invention also relates to a method for manufacturing a prosthesis comprising a textile support and such a film.

Claims

1-14. (canceled)

15. A method for manufacturing a non porous film intended to be implanted in the human body, said method comprising the following steps: a) preparing an intermediate film via gelling of a starting solution comprising at least one polymer selected in the group consisting of collagen, glycosaminoglycans, and mixtures thereof, b) immersing said intermediate film in an alkaline composition comprising at least one C.sub.1-C.sub.4 alcohol, c) drying said intermediate film obtained at an end of said immersing step.

16. The method according to claim 15, wherein said starting solution comprises oxidized collagen.

17. The method according to claim 16, wherein said starting solution further comprises glycerol.

18. The method according to claim 15, wherein said C.sub.1-C.sub.4 alcohol is selected from methanol, ethanol, propanol, 1,2 propanediol, isopropanol, butanol and mixtures thereof.

19. The method according to claim 15, wherein said C.sub.1-C.sub.4 alcohol comprises ethanol.

20. The method according to claim 15, wherein an amount of the C.sub.1-C.sub.4 alcohol ranges from 85% to 99% by weight, with respect to a weight of said alkaline composition.

21. The method according to claim 15, wherein an amount of the C.sub.1-C.sub.4 alcohol ranges from 90% to 91% by weight, with respect to a weight of said alkaline composition.

22. The method according to claim 15, wherein said alkaline composition further comprises sodium hydroxide.

23. The method according to claim 22, wherein said sodium hydroxide is present in said alkaline composition in an amount ranging from 0.010 to 0.030 mol/L.

24. The method according to claim 22, wherein said alkaline composition further comprises at least one plasticizer.

25. The method according to claim 24, wherein said at least one plasticizer comprises glycerol.

26. The method according to claim 15, wherein immersing said intermediate film in said alkaline composition comprises an immersing time ranging from about 60 min to about 180 min.

27. The method according to claim 15, wherein said starting solution comprises an acidic pH ranging from 3.4 to 3.6.

28. The method according to claim 15, wherein said intermediate film is first dried under a laminar flow before said step of immersing said intermediate film in said alkaline composition.

29. The method according to claim 15, wherein drying said intermediate film obtained at said end of the immersing step is carried out by subjecting said intermediate film to a laminar flow.

30. The method according to claim 15, further comprising sterilizing said intermediate film, obtained after said drying step, by gamma irradiation.

31. The method according to claim 15, further comprising washing said intermediate film obtained at an end of said immersing step and before said drying step.

32. A method for manufacturing a prosthesis comprising a textile support and a non porous film associated with a face of said textile support comprising the following steps: i) preparing an intermediate film via gelling of a starting solution comprising at least one polymer selected in the group consisting of collagen, glycosaminoglycans, and mixtures thereof, and applying a face of said textile support on said intermediate film before an end of the gelling in order to associate said textile support with said intermediate film, ii) immersing said intermediate film associated with said textile support in an alkaline composition comprising at least one C.sub.1-C.sub.4 alcohol,) iii) drying said intermediate film associated with said textile support obtained at an end of said immersing step.

33. The method according to claim 32, wherein said starting solution comprises oxidized collagen and glycerol, and an acidic pH ranging from 3.4 to 3.6.

34. The method according to claim 32, wherein said C.sub.1-C.sub.4 alcohol comprises ethanol and said alkaline composition further comprises sodium hydroxide.

35. The method according to claim 32, further comprising sterilizing by gamma irradiation said intermediate film obtained after said drying step, wherein drying step is carried out by subjecting said intermediate film to a laminar flow.

Description

EXAMPLE 1

[0058] Two films were prepared as follows:

[0059] A solution of solubilized oxidized collagen at 2.7% (w/w) is prepared, with 0.55% (w/w) of glycerol, and a pH of 3.5. About 70% of the volume of the solution is spread over an inert support to form a first layer. After leaving this first layer to dry for about 1 h and until it is in gel form, the 30% of the remaining volume of the starting solution is applied to form a second layer. This second layer is left to dry for about 1 h.

[0060] The films are then submitted to a drying step under a laminar flow of 1 m/s, 37 C. and 40% of humidity, for 20 h.

[0061] The first (comparative) film, hereinafter called F1, is submitted to a sterilization by gamma irradiation (radiation ranging from 25 kGy to 40 kGy) then is left for three days in an oven at 40 C.

[0062] The second film (according to the invention), hereinafter called F2, is immersed in an alkaline composition A of the following formulation:

TABLE-US-00001 Composition A % By weight, with respect to the Component weight of the composition Ethanol 90.50 Glycerol 5.91 Water 2.36 Sodium hydroxide 1N 1.23

[0063] The film F2 is immersed in this composition for about 60 min.

[0064] During this step, a portion of the water present in the film is expelled from the film by ethanol.

[0065] After this step, the film F2 therefore holds less humidity and occupies a smaller volume. It is thus found that the film F2 has lost 30% of its thickness during this step.

[0066] The film F2 is then washed with water in order to remove the residual salts.

[0067] Then, the film F2 is again submitted to a drying step under laminar flow of 1 m/s, 37 C. and 40% of humidity, for 20 h.

[0068] The film F2 is then submitted to a sterilization by gamma irradiation (radiation ranging from 25 kGy to 40 kGy) and then left for three days in an oven at 40 C., in the same way as for the comparative film F1.

[0069] The maximum elastic force was then measured for a linear behavior of the films F1 and F2, that is, the force at 18% of deformation, by submitting these films to the mechanic tensile strength test according to the following protocol:

[0070] Test samples of dog bone shape type of 11.5 cm0.5 cm are cut for each film.

[0071] Each test sample is then tested on a tensile bench HT 400 Pneumatic Grip Controller ECME 0702

[0072] The measurement parameters are as follows:

[0073] Scale F: 5N

[0074] Scale D: 100 mm

[0075] Speed: 50 mm/min

[0076] Elongation length: 40 mm

[0077] Elongation 1: 20%

[0078] Elongation 2: 18%

[0079] Breaking Sensor: 100%

[0080] Preload: 0,005N

[0081] For this test, the test sample is placed in a gripper and then immersed in a solution of sodium chloride at 0.9% for a time ranging from 5 to 7 min. The test sample is placed between the jaw and the gripper. The apparatus then moves the jaw away from the gripper. The force is measured until the test sample breaks.

[0082] The results are given in the following table:

TABLE-US-00002 Force at 18% of deformation in Film N + standard deviation F1 (comparative) 0.19 0.018 F2 (invention) 0.344 0.042

[0083] Thus, the film F2 obtained by the method according to the invention has a tensile strength much greater than that of the film F1 of the prior art.

[0084] The film F2 has a smooth, non-porous aspect. The film F2 can be directly used and implanted in the human body, as a reinforcement member of a suture area of another implant. Alternatively, it may be associated with a biocompatible textile support to form a barrier for the prevention of post-surgical adhesions for a prosthesis for repairing a hernia, for example.

EXAMPLE 2

[0085] Films of the invention were manufactured by the same method as in Example 1, by varying the composition of the alkaline composition A, by preparing the compositions A1, A2, A3 and A4 as indicated in the table below (the amounts are given in percent by weight, with respect to the weight of the composition):

TABLE-US-00003 Composition A1 A2 A3 A4 Ethanol 90.48 90.46 90.44 90.46 Glycerol 5.90 5.90 5.90 5.90 Water 1.77 1.18 0.59 0.00 Sodium 1.84 2.46 3.07 3.68 hydroxide 1N

[0086] The immersing time of the film in each composition is identical, namely about 60 min.

[0087] The resulting film after immersion in the composition Ai, for i ranging from 1 to 4, is called FAi.

[0088] The concentration in mol/L of sodium hydroxide (NaOH) used in the alkaline composition used for the different films F2 (Example 1) and FAi is as indicated in the following table:

TABLE-US-00004 NaOH concentration in mol/L in the Film alkaline composition F2 (Example 1) 0.010 FA1 0.015 FA2 0.020 FA3 0.025 FA4 0.030

[0089] The films FA1-FA4 were submitted to the mechanical tensile strength test described in the Example 1. The results are the following:

TABLE-US-00005 Force at 18% of deformation in N+ Film standard deviation F2 (Example 1) 0.344 0.042 FA1 0.513 0.004 FA2 0.692 0.042 FA3 1.073 0.059 FA4 1.217 0.048

[0090] Thus, the variation of the molar concentration of sodium hydroxide in the alkaline composition of the immersing step of the method according to the invention allows varying the mechanical properties of the resulting film.

[0091] The films FA1-FA4 have a smooth and non-porous aspect. They can be directly used and implanted in the human body as members of reinforcement of a suture area of another implant. Alternatively, they may be associated with a biocompatible textile support to form a barrier for the prevention of post-surgical adhesions for a prosthesis for repairing a hernia, for example.

EXAMPLE 3

[0092] A solution of solubilized oxidized collagen at 2.7% (w/w) was prepared, with 0.55% (w/w) of glycerol, and a pH of 3.5. About 70% of the volume of the solution is spread over an inert support to form a first layer. When this first layer is gelled, the 30% of the remaining volume of the starting solution is applied to form a second layer.

[0093] A textile, for example of monofilament of polyethylene terephthalate (PET), is then deposited on this second layer before the end of the gelling of this second layer. The textile therefore becomes superficially anchored in the second layer of the film while it is in the process of gelling.

[0094] The prosthesis consisting of the film associated with the textile is then dried under a laminar flow of 1 m/s, 37 C. and 40% of humidity, for at least 16 h.

[0095] The prosthesis is then immersed in an alkaline composition B of the following composition:

TABLE-US-00006 Composition B % By weight, with respect to the Component weight of the composition Ethanol 90.50 Glycerol 5.91 Water 2.36 sodium hydroxide 1N 1.23

[0096] The prosthesis is immersed in this composition for about 60 min.

[0097] During this step, a portion of the water present in the film of the prosthesis is expelled from the film by the ethanol.

[0098] After this step, the film holds thus less humidity and occupies a smaller volume. It is noted that the film thickness was reduced by about 30%. The prosthesis is then washed with water in order to remove residual salts therefrom until obtaining a washing solution having a pH compatible with an implantation of the prosthesis in the human body. The prosthesis is then dried under a laminar flow of 1 m/s, 37 C. and 40% of humidity, for at least 16 h.

[0099] The prosthesis is then submitted to a step of sterilization by gamma irradiation (radiation ranging from 25 kGy to 40 kGy).

[0100] After sterilization, the prosthesis is left three days at a temperature of 40 C. for the structuration of the film. It is assumed that during this step, the polymer chains are reorganized, further reinforcing the mechanical properties of the final film.

[0101] A prosthesis usable as abdominal wall reinforcement is obtained, which is particularly effective for the prevention of post-surgical adhesions on the face of the textile provided with the non porous film obtained by the method according to the invention.