Fibrin porous structure

Details Fibrin porous structure Fibrin porous structure

2000-05-08

2003-07-29

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S443000, C424S423000, C424S424000, C424S426000

Reexamination Certificate

active

06599515

ABSTRACT:

TECHNICAL FIELD
This invention provides a fibrin porous structure material and particularly a fibrin porous structure having good resistance to compression and a porosity formed by large cells.
BACKGROUND ART
Fibrin sponges are known from U.S. Pat. No. 4,442,655 and WO99/15209. The fibrin sponges have a porous structure and have substantially no compression strength. After hydration, the sponges have cells having a cross section area of less than about 100 &mgr;m
2
, i.e., a porosity which is different from the porosity of a natural human bone.
As explained in the '655 patent, the sponge structure is obtained by freeze-drying a reaction mixture containing fibrinogen, fibrin and a catalytic amount of thrombin. None of the examples of the '655 patent relates to the freeze-drying of a solution containing fibrin partially cross-linked due to the presence of an anticoagulant increasing the clotting time.
It has now been found that, after lyophilizing a solution containing fibrin partially cross-linked due to the presence of a sufficient amount of a calcium inhibiting or blocking agent, preferably an anticoagulant, it was possible to obtain a solid porous structure having an open cross section of more than 500 &mgr;m
2
and/or a wall thickness between channels of at least 10 &mgr;m. Those skilled in the art were unable to predict that it would be able to prepare fibrin porous structure having a good resistance to compression and a porosity formed by large cells, such as in the natural human bone.
BRIEF DESCRIPTION OF THE INVENTION
The invention relates to a porous structure comprising fibrin or fibrinogen material, and possibly other compounds, the structure having:
in its substantially dry form, a compression strain of less than about 8%, preferably less than about 7%, and most preferably from about 6 and to about 7%, and a creep modulus higher than 1.5×10
6
Pa, advantageously higher than 1.7×10
6
Pa, most preferably from about 1.8×10
6
Pa to about 2.5×10
6
Pa, said compression strain and creep modulus being measured for a sample having a diameter of 5 mm on which a compression of 2500 milli Newtons is exerted with a compression ramp of 500 milli Newtons per minute, after a compression release step following an initial compression of 2500 milli Newtons with a compression ramp of 500 milli Newtons per minute, and
after hydration, such a porosity that at least about 50% by volume of the total porosity is formed by channels with an open cross section of more than 500 &mgr;m
2
.
These large pores are suitable for the attachment of cells on the structure. Moreover, according to an embodiment, such large pores are similar to the pores of human natural bones.
Advantageously, the mechanical properties of the porous structure of the invention are kept after successive compression steps, separated the one from another by a release step. Advantageously, the structure, in its substantially dry form, has a compression strain of less than about 8%, more preferably less than about 7%, most preferably from about 6% to about 7%, and a creep modulus higher than 1.5×10
6
Pa, advantageously higher than 1.7×10
6
Pa, for example between about 1.8×10
6
Pa to about 2.5×10
6
Pa, the compression strain and creep modulus being measured for a sample having a diameter of 5 mm on which a compression of 2500 milli Newtons is exerted with a compression ramp of 500 milli Newtons per minute, after ten cycles consisting of a compression step of 2500 milli Newtons with a compression ramp of 500 milli Newtons per minute followed by a compression release step.
It has also been observed that it was interesting to adjust the atomic ratio of calcium and phosphorus (Ca/P) of the structure, preferably between 1 and 2, most preferably between 1.67 and 1.95, for the formation of hydroxyapatite.
The structure of the invention can be used, after grinding, as a powder. Such a powder can, for example, be added to a liquid or to form a liquid glue.
The structure of the invention that has a good compression resistance and larger pores can be used as support for a skin layer and/or for a sponge structure, especially a fibrin sponge structure.
A titanium support can also be provided with a layer of the porous structure of the invention, or with a layer of a powder of the porous structure of the invention, or with a layer containing a powder of the structure of the invention. Preparation processes of such titanium supports will be disclosed after the description of processes of preparation of the structure of the invention.
The present invention further provides a process for preparing a porous structure of the invention. The process provides the steps of (1) providing a solution containing fibrin or fibrinogen materials (advantageously at least 3 mg/ml), (2) polymerizing the fibrin or fibrinogen, preferably a polymerization with at least partial cross-linking of the fibrin or fibrinogen materials in the presence of a calcium blocking or inhibiting agent (preferably an anticoagulant), and (3) lyophilizing the polymerized fibrin or fibrinogen. The calcium blocking or inhibiting agent should be present in the solution in an amount sufficient for preparing a porous structure. The resulting fibrin or fibrinogen material should have:
in its substantially dry form, a compression strain of less than about 8%, preferably less than about 7%, and more preferably from about 6% to about 7%, and a creep modulus higher than 1.5×10
6
Pa, more preferably higher than 1.7×10
6
Pa, most preferably from about 1.8×10
6
Pa to about 2.5×10
6
Pa, the compression strain and creep modulus being measured for a sample having a diameter of 5 mm on which a compression of 2500 milli Newtons is exerted with a compression ramp of 500 milli Newtons per minute, after a compression release step following an initial compression of 2500 milli Newtons with a compression ramp of 500 milli Newtons per minute, and
after hydration, such a porosity that at least 50% by volume of the total porosity is formed by channels with an open cross section of more than about 500 &mgr;m
2
.
Calcium inhibiting agent means an agent suitable for inhibiting at least partly the functionality of one or more calcium sites of the fibrin or fibrinogen material. The calcium inhibiting agent is preferably a calcium blocking agent, most preferably an anticoagulant.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a porous structure comprising fibrin or fibrinogen material, and possibly other compounds, the structure having:
in its substantially dry form, a compression strain of less than about 8%, preferably less than about 7%, and more preferably from about 6% to about 7%, and a creep modulus higher than 1.5×10
6
Pa, more preferably higher than 1.7×10
6
Pa, most preferably from about 1.8×10
6
Pa to about 2.5×10
6
Pa, the compression strain and creep modulus being measured for a sample having a diameter of 5 mm on which a compression of 2500 milli Newtons is exerted with a compression ramp of 500 milli Newtons per minute, after a compression release step following an initial compression of 2500 milli Newtons with a compression ramp of 500 milli Newtons per minute, and
after hydration, such a porosity that at least 50% by volume of the total porosity is formed by channels with an open cross section of more than about 500 &mgr;m
2
.
In the present specification, the wordings “substantially dry form” mean a residual moisture level of less than about 1%, and more preferably of less than about 0.5%.
The structure of the invention has advantageously a low moisture content, for example a moisture content of less than about 7.5%, preferably of less than about 2%, most preferably of less than about 1%, and more specifically less than about 0.5%. In the event the moisture content of the structure of the invention is greater than 1%, for the determination of the mechanical properties of the structure of the invention in its substantially dry form, the moisture content h

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