Fibrin Sealants

Most FS products used clinically outside of the U. S. pose certain risks and, as a result, have not been approved by the Food and Drug Administration for use in the U. S. A. For example the FS products available in Europe contain proteins of non-human origin, e. g., aprotinin and bovine thrombin. Consequently, certain individuals are at risk of developing allergic reactions to such non-human protein additives. U. S. Patent No. 6,183, 498 reports that the use of biomedical adhesives have been observed to induce inflammatory tissue reactions.
Both liquefaction processes, however, are associated with significant effort and a considerable time lag before the product can be used in FS products, which can place an already injured patient into a life-threatening situation. Therefore, significant effort has been undertaken to improve the solubility of lyophilized fibrinogen preparations. For example, one manufacturer requires the use of a magnetic stirrer added to the vials of protein to provide significant agitation while heating. This results in dissolution times which are faster than those obtained for the same product without significant mixing, but it still requires 30-60 minutes of preparation time simply to get the fibrinogen ready to use.
Moreover, when heat inactivation is used to inactivate any viruses that may be present in the FS, the process may result in the formation of denatured proteins, which may also be allergenic. For example, the European heat inactivation methods do not inactivate prions which cause bovine spongiform encephalopathy ("mad cow disease"), which has been epidemic recently in bovine herds in European, and hence disease could be carried in the bovine proteins used in the foreign FS products, risking human infection when those products are used for their intended purpose.
Nevertheless, at a sufficiently high fibrinogen concentration, FS preparations provide safe hemostasis, good adherence of the seal to the wound and/or tissue areas, high strength of the adhesions and/or wound sealing, and complete resorbability of the adhesive in the course of the wound healing process (Byrne et al., Br. J. Surg. 78: 841-843 (1991) ). For optimal adhesion, a concentration of fibrinogen of about 15 to 60 mg/ml is required in a ready-to-use tissue adhesive solution (MacPhee, personal communication). The clinical uses of FS products have been reviewed (e. g., by Brennan, Blood Reviews 5: 240-244 (1991) ; Gibble et al., Transfusion 30: 741-747 (1990); Matras, J. Oral Maxillofac. Surg. 43: 605-611 (1985); Lemer et al., J Surg. Res. 48: 165-181 (1990)).
Baxter/Hyland (Los Angeles, Calif.) in conjunction with The American National Red Cross have co-developed Tisseel, the first commercial fibrin sealant to be approved in the United States (see, e. g., U. S. Patent Nos. 6,054, 122; 6,117, 425; and 6,197, 325 (MacPhee et al.). This FS product has advantages over those available in Europe because it is free of bovine proteins. For example, it contains human thrombin, and it contains no aprotinin, thereby reducing the potential for allergenicity. In addition, it is virally inactivated by a solvent detergent method, which produces fewer allergenic denatured proteins.
However, not only does the need to slowly liquefy the protein components cause a significant delay in the formation of the FS preparation, a significant problem arises once fibrinogen is solubilized because its instability results in a tendency to prematurely self- coagulate. In fact, once prepared, the Baxter instructions indicate that the reconstituted solutions can be kept in their respective vials or syringes for a maximum of only 4 hours, after which any unused sealant must be discarded. As a result, the Baxter FS cannot be stored in a ready-to-use condition for any useful length of time.