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1. WO2000025838 - ELEMENT PROVIDED WITH A FIBRIN LAYER, PREPARATION AND USE THEREOF

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[ EN ]

CLAIMS

1. An element provided with a layer based on fibrin- or fibrinogen-containing material, said element comprising (a) a hydrophobic or substantially hydrophobic support, which has a porous part with a thickness of 0.1 to 5 mm, and whose pores, extending across its thickness have a node spacing of 5 to 100 μm, one face of said porous part being treated with a compound based on fibrin and/or a fibrinogen-containing material, and (b) a fibrin-based layer covering said treated surface of the support, characterized in that said fibrin-based layer is substantially uniform and homogeneous on said treated surface, and that the fibrin layer and at least the face of the support in contact with the fibrin layer are substantially free of fibrinogen.
2. An element as claimed in claim 1, characterized in that the fibrin layer and at least a support layer extending across a thickness of 10 μm contains less than 1% by weight, advantageously less than 0.5%, preferably less than 0.1% by weight of fibrinogen which has not reacted, with respect to the weight of the fibrin layer.
3. An element as claimed in claim 1 or 2, characterized in that fibrin extends across the thickness of the treated porous part of the support, from said treated face to a depth of at least 2 μm, both through the pores having an average diameter of 10 to 20 μm and through the pores having an average diameter of more than 20 μm.
4. An element as claimed in any preceding claim, wherein the porous part of the support has a substantially homogeneous and uniform porosity over the treated face, characterized in that some fibrin extends homogeneously and uniformly across the thickness of the porous part of the support to a depth of at least 10 μm.
5. An element as claimed in claim 2 , characterized in that the porous support contains fibrinogen in a layer which is at a distance of more than 10 μm from the face in contact with the fibrin layer.
6. An element as claimed in claim 5 , characterized in that fibrinogen extends across the thickness of the support to a depth of at least 20 μm.
7. An element as claimed in any preceding claim, characterized in that at least the face of the fibrin layer opposite to the one contacting the porous support is stabilized.
8. An element as claimed in claim 7, characterized in that said fibrin-based layer is at least partially cross-linked, to form a network of adjacent alveoli.
9. An element as claimed in any preceding claim, characterized in that said layer is provided with cells and/or proteins, particularly with proteins mediating cell-fibrin bonds.
10. An element as claimed in any preceding claim, characterized in that the cross-linked fibrin-based layer which covers the porous part of the support, when measured in the dry state, is 0.5 to 100 μm thick, preferably 2.5 to 50 μm thick, with alveoli being formed between the cross-linked fibrin-based molecules or bonds, or fibers, said alveoli having a volume of 5 to 25 μm3, the average thickness or height of said alveoli being of 1 to 5 μm, particularly of 1 to 3 μm.
11. An element as claimed in any preceding claim, characterized in that the pores of the support part, covered by said fibrin layer have inner faces at least partially covered by a water-soluble or substantially water-soluble protein.
12. An element as claimed in claim 11, characterized in that the support face opposite to the treated face is at least partially covered by a water-soluble or substantially water-soluble protein.
13. An element as claimed in any preceding claim, characterized in that at least the pores of the porous part of the support are covered by a water-soluble or miscible polar organic additive.
14. An element as claimed in claim 13 , characterized in that the network of cross-linked fibrin fibers is at least partially covered by and/or contains a water-soluble or miscible polar additive, preferably an additive selected in the group comprising glycerol, sugars and mixtures thereof .
15. An element as claimed in any preceding claim, characterized in that it has a moisture content of less than 0.5% by weight, preferably of less than 0.1% by weight .
16. An element as claimed in any preceding claim, characterized in that fibronectin is attached to the fibrin layer, the fibronectin content, as compared to the fibrin and fibronectin weight in the layer being of 0.5 to 15%.
17. An element as claimed in any preceding claim, characterized in that the fibrin layer contains calcium in the order of 1 to 100 μg, preferably of 1 to 50 μg of calcium per cm3 of the fibrin layer volume.
18. An element as claimed in claim 14, characterized in that calcium takes the form of calcium chloride .

19. An element as claimed in any preceding claim, characterized in that the support has two superposed fibrin layers, the layer in contact with the support having alveoli with larger volumes as compared with the alveoli of the layer which covers the fibrin layer in contact with the support .
20. An element as claimed in any preceding claim, characterized in that the support is biocompatible and/or biodegradable .
21. A process for preparing an element as claimed in any claim 1 to 20, wherein at least one porous part of a first face of a porous support is placed in contact with an aqueous solution containing fibrin or a fibrinogen-containing material, wherein the face of the porous part of the support opposite to said first face is homogeneously and uniformly submitted to a suction force to suck the solution, at least partly, through said porous part, thus ensuring the deposition of a layer based on fibrin or on fibrinogen-containing materials, homogeneously and uniformly with respect to said porous part, and the diffusion of at least the solution water through the porous part of the porous support as well as the penetration of fibrin or fibrinogen through the porous support .
22. A process as claimed in claim 21, wherein the face of the support opposite to said first face, is submitted to a pressure of less than 0.8 105 Pa, and wherein a pressure difference is created between the two faces of the porous part of at least 0.3 105 Pa.
23. A process as claimed in claim 22, characterized in that the support face opposite to said first face is submitted to a pressure of less than 0.5 10s, preferably less than or equal to 0.4 105 Pa.

24. A process as claimed in claim 22 or 23, characterized in that the support face opposite to the first face is intermittently submitted to a first pressure, of less than 0.8 105 Pa, preferably less than 0.4 105 Pa, and to a second pressure of less than 0.8 10s Pa, preferably less than 0.4 105 Pa, the first pressure being at least 5% higher than the second pressure.
25. A process as claimed in any claim 22 to 24, wherein the face of the porous support opposite to said first face is submitted to a pressure of less than 0.8 10s Pa, and exposed to a temperature of 0 to 100°C, preferably to a temperature of 15 to 60°C.
26. A process as claimed in claim 21, wherein the face of the porous support opposite to said first face is submitted to a solution selected so as to create a reverse osmosis, causing the diffusion of at least the solution water in contact with the first face through the porous part of the support .
27. A process as claimed in any claim 21 to 26, characterized in that a solution is used which contains 5 to 20 mg/ml of fibrinogen-containing materials.
28. A process as claimed in claim 27, characterized in that a solution is used which contains 5 to 20 mg/ml of fibrinogen-containing materials and 0.01 to 10 units of thrombin per ml.
29. A process as claimed in claim 28, characterized in that a solution is used which contains 5 to 20 mg/ml of fibrinogen-containing materials, factor XIII, and 0.01 to 2 units of thrombin per ml.
30. A process as claimed in claim 29, characterized in that a solution is used which contains 0.1 to 10 units of factor XIII per ml.

31. A process as claimed in any claim 27 to 30, characterized in that the solution contains 1 to 40 millimoles of calcium chloride per ml.
32. A process as claimed in any claim 27 to 31, characterized in that the solution contains 0 to 20% by weight, advantageously 3 to 15%, preferably 5 to 10% of a water-soluble or miscible polar organic additive.
33. A process as claimed in claim 32, characterized in that the additive is glycerol.
34. A process as claimed in any claim 21 to

33, characterized in that, during a first step, at least one portion of a first face of a porous support is placed in contact with a solution containing fibrin and/or fibrinogen-containing materials, wherein the face of the porous support opposite to said first face is submitted to a suction force, thus ensuring a diffusion of at least the solution water across the thickness of the porous support and a penetration of fibrin or fibrinogen across the thickness of the porous support, homogeneously and uniformly with respect to said porous part of the first face and in that, during a second step, the fibrin and/or fibrinogen layer is stabilized.
35. A process as claimed in any claim 21 to

34, characterized in that a contact is provided between said part of the first face and a moving aqueous solution.
36. A process as claimed in any claim 21 to

35, characterized in that an aqueous solution is used which contains a wetting agent to fill the pores of the porous support before placing said support in contact with the solution containing fibrin or fibrinogen-containing materials .

37. A process as claimed in any claim 21 to 36, characterized in that the fibrin layer is submitted to a drying step, possibly preceded by a washing step.
38. A process as claimed in claim 37, characterized in that this drying operation is effected at least partially by lyophilization, advantageously at a temperature of -30°C and -100°C, preferably at a temperature of -40°C to -70°C.
39. A process as claimed in any claim 28 to 38, characterized in that at least for a part of the deposit of the layer based on fibrin or on fibrinogen-containing materials, the concentration of fibrin or fibrinogen-containing materials in the solution in contact with the first face is controlled in order to ensure a substantially constant water diffusion through the support .
40. A process as claimed in any claim 21 to

39, characterized in that a biocompatible and/or biodegradable porous support is used.
41. A process as claimed in any claim 21 to

40, characterized in that the porous part is treated with an aqueous solution which advantageously contains a wetting agent, a protein or a polar organic additive, or a mixture thereof, before bringing the solution containing fibrin and/or fibrinogen-containing materials in contact with said porous part .
42. A filter including a membrane consisting of an element as claimed in any claim 1 to 20.
43. A bioreactor including a membrane consisting of an element as claimed in any claim 1 to 20.
44. An implant consisting of an element as claimed in any claim 1 to 20.

45 . An artificial skin produced from an element as claimed in any claim 1 to 20 .