Surgery: splint – brace – or bandage – Bandage structure
Reexamination Certificate
1999-11-05
2001-10-30
Yu, Mickey (Department: 3764)
Surgery: splint, brace, or bandage
Bandage structure
C602S042000, C602S043000, C602S044000, C602S045000, C602S046000, C602S047000, C602S048000
Reexamination Certificate
active
06310267
ABSTRACT:
The invention relates to a flexible, biodegradable fibrin web for wound healing, and its production. Web materials of this type can be employed for hemostasis on internal and external wounds and also as carrier materials for biological factors.
It is known that surgical interventions on internal organs are accompanied by problems of wound closure, caused by the strong blood flow and softness of the tissue. A frequently used method for the closure of internal wounds is electrocoagulation of the blood vessels, which in most cases leads to postoperative adhesions which are painful for the patient. Moreover, it is only of limited suitability for the closure of posttraumatic organ ruptures. A good alternative is fibrin adhesive, with which the wound is closed by means of preceding reaction of a number of endogenous, human clotting factors. The clot in this case formed on the wound is distinguished by a high compatibility and rapid hemostasis. Less advantageous is the longer preparation time preceding the application of the fibrin adhesive and the somewhat involved application, especially in minimally invasive surgery, where a special applicator is needed for the endoscope. Therefore attempts have also already been made to develop a biodegradable wound covering based on fibrin, which is available ready-for-use and can be applied to the wound without special preparation. A web material of this type is disclosed in European Patent Application 0 068 149, which is directed at a fibrinogen-containing dry preparation which has a foam or web structure achieved by freeze-drying and, in addition to thrombin in at least catalytically active amounts, consists essentially of approximately 10 to 95% by weight of fibrin and approximately 5 to 90% by weight of fibrinogen. In the production of a web-like wound covering, fibrin is in this case first produced in a fibrinogen- and thrombin-containing aqueous solution and the resulting reaction mixture is deep-frozen and lyophilized. This material is especially intended as a wound care material, as a filling material for bone cavities and/or as a carrier material for further active compounds. A serious disadvantage of this wound covering consists, however, in the fact that what is concerned here is a rigid and fragile web, which maintains its rigidity even after contact with water or blood. As a result, the application possibilities of a fibrin web of this type are extremely restricted. Moreover, an absorbable, multilayer sheet material which contains at least one thrombin-free and at least one fibrinogen-free component layer, which in each case have a glycoprotein matrix, is disclosed in German Patent 32 14 337. As a result of the spatial separation of thrombin and fibrinogen, in this case the formation of a fibrin web is prevented.
There has therefore been no lack of attempts to develop more suitable wound coverings from other biological materials. Webs are found on the market which consist of a biological material such as collagen, which is mainly obtained from animal connective tissue from cattle, from horses or from pigs. Thus EP-A 0 485 210, for example, has proposed a fibrin-containing collagen membrane.
Materials of this type, however, require virus inactivation and particular safety measures in order to avoid potential transmission of the BSE infective agents. Moreover, cases of patients with hypersensitivity reactions to bovine collagen have been reported in the literature. Therefore it has already been thought of making available collagen webs of human material, for example of collagen which is obtained from the placenta. Although this could admittedly have a better biocompatibility, it is likewise affected by the problem of virus safety. The idea has therefore also already been expressed of employing recombinant or transgenic human collagen for the production of wound coverings, but collagen of this type, even in the present state of development, is still not competitive for reasons of cost. Finally, in U.S. Pat. No. 2,492,458 a fibrin foam is disclosed which can be introduced permanently into a wound for hemostasis.
Finally, it has also already been thought of employing synthetically prepared, biodegradable materials, such as polyhydroxycarboxylic acids or polyamino acids, for the production of degradable wound coverings.
Although these materials admittedly offer a more economical alternative to recombinant collagen, their use is restricted, as they are not very suitable for hemostasis in heavily bleeding and soft tissues. Moreover, they are more poorly compatible, as during their use products which can cause inflammatory reactions in the body are formed by degradation processes.
The object was therefore to develop a biodegradable wound covering which avoids the known disadvantages of the wound coverings customary until now. This object is achieved according to the invention by means of a biodegradable wound covering based on fibrin, which as a result of particular process steps used in its production has a high flexibility and is therefore outstandingly suitable as a web for the covering and closure of bleeding wounds.
It has now been found that a biodegradable, flexible wound covering based on fibrin, in which the wound covering is a fibrin web or contains a fibrin web which is largely or completely free of dialyzable constituents, meets these demands. In this case, the fibrin web is preferably firmly combined with a biodegradable carrier material. A fibrin web is particularly suitable which contains 10-80% by weight of glycerol per fibrin unit.
A wound covering of this type based on fibrin can be produced according to the invention by a process in which a fibrinogen solution is subjected to a single-stage or multistage dialysis, then a flexible fibrin web is formed by action of an aqueous thrombin solution on the fibrinogen solution and this is subsequently subjected to freeze-drying.
As a result of the single-stage or multistage dialysis of the fibrinogen solution, its composition is crucially changed and the concentrations of salts and amino acids customarily contained in it are considerably reduced. It is assumed that this is the crucial prerequisite for the production of a flexible fibrin web. The dialysis of the fibrinogen solution can be carried out in various ways. With a single-stage solution, the fibrinogen solution is treated in a dialysis bath which simultaneously contains an organic complexing agent and physiologically compatible inorganic salts. The single-stage dialysis, however, can also be carried out using a dialysis bath which exclusively contains organic complexing agents. Then, after completion of the dialysis, the physiologically compatible inorganic salt, as a rule NaCl, is added to the fibrinogen solution in an amount of 0.05 to 0.5 percent by weight.
Organic complexing agents added in the dialysis are especially alkali metal salts of ethylenediaminetetraacetic acid, of oxalic acid or of citric acid. The concentration of the organic complexing agent in the dialysis bath is in general 1 to 20 mM, preferably 1 to 5 mM.
However, it is also possible to carry out the dialysis in two stages. In this case, in the first dialysis step the fibrinogen solution is dialyzed with an aqueous solution of one of the abovementioned complex salts and subsequently in a second dialysis bath the dialysis with an NaCl solution or the solution of another physiologically tolerable inorganic salt is carried out.
The fibrinogen thus freed of dialyzable concomitants, which can also still contain the addition of factor XIII customary in fibrin adhesive preparations, is an outstandingly suitable starting substance for the production of a flexible fibrin web. This is produced by mixing the dialyzed fibrinogen solution with an aqueous solution of thrombin and calcium chloride. In this process, the water-soluble calcium salt is present, as a rule, in an amount from 0.5 to 40 mM. In general, the fibrinogen is employed for the production of the fibrin web in an amount from 10 to 25 g/l and the thrombin is employed in an amount of up to 100 I.U./ml
Aventis Behring GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
Hamilton Lalita M.
Yu Mickey
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