Thrombin and Fibrin Foam
               A number of wound management projects were developed in the Department of Physical Chemistry at Harvard Medical School during World War II.   These included thrombin, fibrin foam, and fibrin film.  Minot and Taylor (1) used thrombin as a hemostatic agent in hemophilia A.  Thrombin was used more commonly in combination with fibrinogen but in a manner different from the current fibrin sealant products.   Three products were developed including fibrin foam, fibrin film, and fibrinogen plastics.   This section address the past and present of fibrin foam; fibrin film and fibrinogen plastics will be addressed in future sections.
               Fibrin foam was described by Bering in 1944(2,3) in a process which takes human Cohn Fraction I in solution which is mixed in a Waring Blender followed by the addition of thrombin.   The resulting foam is cut into pieces and dried by lyophilization, air drying, or by solvent replacement with ethanol followed by air drying.   Each method provides a product with somewhat different physical characteristics.   The dried product can be sterilized by dry heat; such drying destroys the residual thrombin activity and changes the physical properties of the dried foam.   The dried foam could be rehydrated in saline or in saline containing thrombin if additional hemostatic effect was desired; additional thrombin was needed if the sterilized product was used.   The presence of fibrinolytic activity in the product resulted in rapid dissolution of the product after reconstitution which might be desirable; the sterilized product was be much less susceptible to such degradation.   The sterilized material appears to have been product of choice since a two-component system (thrombin and fibrin foam) was provided (4) to investigators.  It is reasonable to assume that a fair amount of technical skill was required for the preparation of the fibrin foam component.
               The fibrin foam product was developed for neurosurgical use (5-7); the various investigators did note the earlier observations of Grey (8) on the use of fibrin as a hemostatic agent in neurosurgery.   Fibrin foam also was demonstrated to prevent meningocerebral adhesions (7).   Quinby and Landsteiner (9) used fibrin foam as a hemostatic plug in the cavity left by removal of the prostate.  One of the advantages of fibrin foam is that it is "space-filling" on placement and subject to cellular infiltration and resolution.   Fallon and Croskery (10) reviewed their extensive experience in the use of fibrin foam and thrombin as a hemostatic agent, as a space-filling material, and as a wound dressing material.   There was considerable success with the space-filling material and as a wound-dressing material and more problematic as a hemostatic agent.  Spangler (11) described 17 years of experience in use of a fibrin foam suspension in the treatment of depressed scars considering this material to be more successful than silicone.  It should be noted that Fibrin gel analogous to fibrin foams serves as 3-dimensional matrices for cell culture serving organized structure development (12-14).  Tünnerhoff and Schwabe (15) earlier suggested the use of fibrin foam as matrix for the formation of connective tissue.  The other area of application for fibrin foam was in oral surgery (4, 16-19).  There was sporadic use of this material into the early 1950's both in the United States and Europe (12.   It would appear the transmission of hepatitis by human thrombin preparations  (5,20) led to discontinuation of use this material in fibrin-based product.   There was increased use of bovine thrombin (21)  and gelatin sponge (Gelfoam®) (22,23)     Fibrospum, a fibrin foam product derived from bovine plasma was introduced in Europe during the 1950's.(24) but I cannot find any indication of current manufacture or use.   Fibrinol® is a bovine fibrin foam product which is/was available in Brazil (25).   Hemofibrine® is a product which has been used in Europe (26) but does not appear to available and/or marketed at the current time.   I assume that Fibrinol® is still available in Brazil; there is a Fibrinol® in the United States which appears to describe a naturopathic material. The study on Hemofibrine® described an allergic reaction secondary to the use of this material in oral surgery.  A consideration of the literature suggests that allergic responses to implanted bovine thrombin are somewhat rare.   That said, there are animal studies which suggest the successful resolution does depend on species compatibility with heterologous fibrin implants eliciting an immunological response (27,28). 
               There has been increased interest in fibrin foam products (also referred to as fibrin sponges) including several patent applications.   This likely reflects the ability of "safe" thrombin derived either from human plasma or by recombinant DNA technology reduces the risk of infectious disease previously associated with the thrombin product (5,18).   The ability of fibrin gel to support complex cellular development  (mentioned above) provides considerable opportunity for tissue engineering (29-32) .  It is noted that a recent publication described the formation of "fibrin foam" from aeration of fibrin sealant product (33).
               Finally, whenever possible I have consulted the original literature.  Some of the Fibrinol® information is in Portuguese with which I am not familar so such is not included.  I could work with the original material in German; however, if there are mistakes, it is my error in translation, not that of the author.
1. Minot, G.R. and Taylor, F.H.L., Hemophilia: The clinical use of antihemophilic globulin,  Ann.Int.Med. 26, 363-367, 1947.
2.  Bering, E.A., Jr., Chemical, clinical, and immunological studies on the products of human plasma fractionation. XX. A development of fibrin foam as a hemostatic agent and for use in conjunction with human thrombin, J.Clin.Invest. 23, 586-590, 1944.
3.  Bering, E.A., Jr., Fibrin foam, US Patent 2,492,458 (December 27, 1949).
4.  Mitchell, D.F., Products of human blood fractionation and their uses in dentistry,  J.A.D.A. 33. 1287-1291,  1946.
5. Anon, Byproducts of plasma fractionation, in Blood Program in World War II, ed. D.B. Kendrick, Chapter 13, pps. 360-369, U.S Government Printing Office, Washington, DC, USA, 1964.
6.  Bailey, O.T. and Ingraham, F.D., Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXI The use of fibrin foam as a hemostatic agent in neurosurgery: clinical and pathological studies, J.Clin.Invest. 23, 591-596, 1944.
7.  Ingraham, F.D. and Bailey, O.T., The use of products prepared from human fibrinogen and human thrombin in neurosurgery. Fibrin foams as hemostatic agents: Fibrin films in repair of dural defects and in prevention of meningocerebral adhesions, J.Neurosurg. 1, 23-24, 1944.
8. Grey, E.G., Fibrin as a haemostaticin cerebral surgery, Surg.Gynecol.Obstet. 21, 452-454, 1915.
9.  Quinby, W.C. and Landsteiner, E.K., Fibrin foam as a hemostatic agent in suprapubic prostectomy, New Engl.J.Med. 233, 267-268, 1945.
10. Fallon, J. and Croskery, W.F., Plasma fractions - "Fibrin foam," thrombin, and "Fraction No. 1" - in general surgery, Surg.Gynecol.Obstet. 84, 361-365, 1947.
11. Spangler, H.S., Treatment of depressed scars with fibrin foam - Seventeen years of experience, J.Derm.Surg. 1(4), 65-69, 1975.
12. Kalos, M. and O'Neal, R.M. Organ tissue culture on a three-dimensional matrix of human fibrin foam, Arch.Pathol. 86, 52-59, 1968.
13. Janney, P.A., Winer, J.P., and Weisel, J.W., Fibrin gels and their clinical and bioengineering applications, J.R.Soc.Interface 6, 1-10,2006.
14. Eyrich, D., Wiese, H., Maier, G., et al., In vitro and in vivo cartilage engineering using a combination of chrondrocyte-seeded long-term stable fibrin gels and polycaprolactone-based polyurethane scaffolds, Tissue Engineer. 13, 2207-2218, 2007.
15. Tünnerhoff, F.-K. and Schwabe, H.K., Tierexperimentelle untersuchungen zur frage struktureller veränderungen an implantierem fibrin, zugleich ein beitrag zur frage der möglichkeit künstlicher bindegewebsbildung. 1. Milleilung, Arzneimittal Forschg.Drug Res. 5, 201-204, 1955.
16. Weiner, L. and Wald, A.H., Fibrin foam and thrombin as used in the surgical removal of a large fibromyxoma of the mandible, J.Am.Dent.Assoc. 33, 731-745, 1945.
17. Henry, T.C., Clinical application of fibrin foam and thrombin in oral surgery, Brit.Dent.J. 83, 235-238, 1947.
18.  Bradley, J.L., Fibrin foam and thrombin in oral surgery, J.Dent.Res. 26, 339, 1947.
19. State, D., Use of human fibrin foam and thrombin solution as hemostatic agents in general surgery, Arch.Surg. 58, 284-290, 1949.
20.  Lesses, M.F. and Hamolsky, M.W., Epidemic of serum hepatitis  apparently caused by human thrombin, J.Am.Med.Assoc. 147, 727-730, 1951
21.  Seegers, W.H., Warner, E.D., Brinkhous, K.M., and Smith, H.P., The use of purified thrombin as an hemostatic agents, Science  89, 86, 1939.
22.  Light, R.V. and Prentice, H.R., Gelatin sponge. Surgical investigation of a new material used in conjunction with thrombin in hemostasis, Arch.Surg. 51, 69-80, 1945.
23. Senturia, B.H., Ogura, J.H., and Walsh, T.E., The use of thrombin and absorbable sponge for hemostasis in otolaryngology, The Laryngoscope 59, 1068-1083, 1949.
24. Kraus, H.H., Die verwendung von Fibrospum and gelatinetampons zur stillung parenchymatöser Blutungen, Zentralblatt für Gynäkologie 3, 114-116, 1953.
25.  Zaccaro Scelza, M.F., de Silva Pierre, V.S., Chagas, M.A., et al., Evolution of inflammatory response of EDTA, EDTA-T, and citric acid in animal model, J.Endodontics 36, 515-519, 2010.
26. Wüthrich, B., Biandri,-Kusch, E., and Johnsson, S.G.O., Allergic uticaria and angioedema caused by a hemostatic sponge of bovine fibrin used in tooth extraction, Allergy 51, 49-51, 1996.
27.  Bannerjee, S.K. and Glynn, L.E., Reaction to homologous and heterologous fibrin implants in experimental animals, Ann.N.Y.Acad.Sci. 86, 1064-1074, 1960.
28.  Dumonde, D.C., and Glynn, L.E., Reaction of guinea pigs to autologous and heterologous fibrin implants, J.Path.Bacteriol. 90, 649-676, 1965.
29.  Syedain, Z.H., Meier, L.A., Bjork, J.W., et al., Implantable arterial grafts from human fibroblasts and fibrin using a multi-graft pulsed flow-stretch bioreactor witn noninvasive strength monitoring, Biomaterials 32, 714-722, 2010.
30.  Davis, H.E., Miller, S.L., Case, E.M., and Leach, J.K., Supplmentation of fibringels with sodium chloride enhances physical properties and ensuing osteogenic response, Acta Biomat. 7, 691-699, 2011.
31.  Evers, R., Khait, L., and Birla, R.K., Fabrication of functional cardiac, skeletal, and smooth muscle pumps in vitro, Artif.Organs 35, 69-74, 2011.
32. Kniazeva, E., Kachgal, S.,  and Putman, A.J., Effects of extracellular matrix density and  mesenchymal stem cells on neovascularization in vivo, Tissue Eng.Part A,  in press, 2011.
33. Kheirabad, B.S., Sieber, J., Bukhari, T., et al., High-pressure fibrin sealant foams: an effective hemostatic agent for treating severe parenchymal hemorrhage,  J.Surg.Res. 144, 145-150, 2008.