Title of Invention

"SOLID DRESSING FOR TREATING WOUNDED TISSUE"

Abstract

Disclosed are solid dressings for treated wounded tissue in mammalian patients, such as a human, comprising a haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed from a single aqueous solution containing the fibrinogen component and the fibrinogen activator. Also disclosed are methods for treating wounded tissue using these dressings and frozen compositions useful for preparing the haemostatic layer(s) of these dressings.

Full Text

SOLID DRESSENG FOR TREATING WOUNDED TISSUE FIELD OF THE INVENTION The present invention relates to a solid dressing for treating wounded tissue in a mammalian patient, such as a human. BACKGROUND OF THE INVENTION The materials and methods available to stop bleeding in pre-hospital care (gauze dressings, direct pressure, and tourniquets) have, unfortunately, not changed significantly in the past 2000 years. See L. Zimmerman et a/., Great Ideas in the History of Surgery (San Francisco, Calif.: Norman Publishing; 1993), 31. Even in trained hands they are not uniformly effective, and the occurrence of excessive bleeding or fatal hemorrhage from an accessible site is not uncommon. See J. M. Rocko et al.,). Trauma 22:635 (1982). Mortality data from Vietnam indicates that 10% of combat deaths were due to uncontrolled extremity hemorrhage. See SAS/STAT Users Guide, 4th ed. (Cary, N.C.: SAS Institute Inc; 1990). Up to one third of the deaths from ex-sanguination during the Vietnam War could have been prevented by the use of effective field hemorrhage control methods. See SAS/STAT Users Guide, 4th ed. (Cary, N.C.: SAS Institute Inc; 1990). Although civilian trauma mortality statistics do not provide exact numbers for prehospital deaths from extremity hemorrhage, case and anecdotal reports indicate similar occurrences. See J. M. Rocko et at.. These data suggest that a substantial increase in survival can be affected by the pre-hospital use of a simple and effective method of hemorrhage control. There are now in use a number of newer haemostatic agents that have been developed to overcome the deficiencies of traditional gauze bandages. These haemostatic agents include the following: • Microporous polysaccharide particles (TraumaDEX®, Medafor Inc., Minneapolis, MN); • Zeolite (QuikClot®, Z-Medica Corp, Wallington, CT); • Acetylated poly-N-acetyl glucosamine (Rapid Deployment Hemostat™ (RDM), Marine Polymer Technologies, Danvers, MA); • Chitosan (HemCon® bandage, HemCon Medical Technologies inc., Portland OR); • Liquid Fibrin Sealants (Tisseel VH, Baxter, Deerfield, EL) • Human fibrinogen and thrombin on equine collagen (TachoComb-S, Hafslund Nycomed Pharma, Linz, Austria); • Microdispersed oxidized cellulose (m»doc™, Alltracel Group, Dublin, Ireland); • Propyl gallate (Hemostatin™, Analytical Control Systems Inc., Fishers, EN); • Epsilon aminocaproic acid and thrombin (Hemarrest™ patch, Clarion Pharmaceuticals, Inc); • Purified bovine corium collagen (Avitene® sheets (non-woven web or Avitene Microfibrillar Collagen Hemostat (MCH), DavoL, Inc., Cranston, Rl); • Controlled oxidation of regenerated cellulose (Surgicel®, Ediicon Inc., Somerville, NJ); • Aluminum sulfate with an ethyl cellulose coating (Sorbastace Microcaps, Hemostace, LLC, New Orleans, LA); • Microporous hydrogel-forming polyacrylamide (BioHemostat, Hemodyne, Inc., Richmond VA); and • Recombinant activated factor VTI (NovoSeven®, NovoNordisk Inc., Princeton, NJ). These agents have met with varying degrees of success when used in animal models of traumatic injuries and/or in the field. One such agent is a starch-based haemostatic agent sold under the trade name TraumaDEX™. This product comprises microporous polysaccharide particles that are poured directly into or onto a wound. The particles appear to exert their haemostatic effect by absorbing water from the blood and plasma in the wound, resulting in the accumulation and concentration of clotting factors and platelets. In two studies of a lethal groin wound model, however, this agent showed no meaningful benefit over standard gauze dressings. See McManus et a!., Business Briefing: Emergency Medical Review 2005, pp. 76-79 (presently available on-line at www.touchbdiefings.com/pdf/ 1334/Wedmore.pdf). Another particle-based agent is QuickClot™ powder, a zeolite granular haemostatic agent that is poured directly into or onto a wound. The zeolite particles also appear to exert their haemostatic effect through fluid absorption, which cause the accumulation and concentration of clotting factors and platelets. Although this agent has been used successfully in some animal studies, there remains concern about the exothermic process of fluid absorption by the particles. Some studies have shown this reaction to produce temperatures in excess of 143°C in vitro and in excess of 50 deg C in vivo, which is severe enough to cause third-degree burns. See McManus et a/., Business Briefing: Emergency Medical Review 2005, at 77. The exothermic reaction of QuikClot™ has also been observed to result in gross and histological tissue changes of unknown clinical significance. Acheson et a/., J. Trauma 59:865-874 (2005). Unlike these particle-based agents, the Rapid Deployment Hemostat™ appears to exert its haemostatic effect through red blood cell aggregation, platelet activation, clotting cascade activation and local vasoconstriction. The Rapid Deployment Hemostat™ is an algae-derived dressing composed of poly-N-acetyl-glucosamine. While the original dressing design was effective in reducing minor bleeding, it was necessary to add gauze backing in order to reduce blood loss in swine models of aortic and liver injury. See McManus et aL, Business Briefing: Emergency Medical Review 2005, at 78. Another poly-N-acetyl-glucosarnine-derived dressing is the HemCon™ Chitosan Bandage, which is a freeze-dried chitosan dressing purportedly designed to optimize the mucoadhesive surface density and structural integrity of the chitosan at the site of the wound. The HemCon™ Chitosan Bandage apparently exerts its haemostatic effects primarily through adhesion to the wound, although there is evidence suggesting it may also enhance platelet function and incorporate red blood cells into the clot it forms on the wound. This bandage has shown improved hemostasis and reduced blood loss in several animal models of arterial hemorrhage, but a marked variability was observed between bandages, including the failure of some due to inadequate adherence to the wound. See McManus et aL, Business Briefing: Emergency Medical Review 2005, at 79. Liquid fibrin sealants, such as Tisseel VH, have been used for years as an operating room adjunct for hemorrhage control. See]. L. Garza et aL, J. Trauma 30:512-513 (1990); H. B. Kram et aL, J. Trauma 30:97-101(1990); M. G. Ochsner et aL, J. Trauma 30:884-887 (1990); T. L. Matthew et aL, Ann. Thorac. Surg. 50:40-44 (1990); H. Jakob et aL,]. Vase. Surg., 1:171-180 (1984). The first mention of tissue glue used for hemostasis dates back to 1909. See Current Trends in Surgical Tissue Adhesives: Proceedings of the First International Symposium on Surgical Adhesives, M. J. MacPhee etaL, eds. (Lancaster, Pa.: Technomic Publishing Co; 1995). Liquid fibrin sealants are typically composed of fibrinogen and thrombin, but may also contain Factor Xlll/Xllla, either as a by-product of fibrinogen purification or as an added ingredient (in certain applications, it is therefore not necessary that Factor XIII/Factor Xllla be present in the fibrin sealant because there is sufficient Factor XIII /Xllla, or other transaminase, endogenously present to induce fibrin formation). As liquids, however, these fibrin sealants have not proved useful for treating traumatic injuries in the field. Dry fibrinogen-thrombin dressings having a collagen support {e.g. TachoComb™, TachoComb™ H and TachoSil available from Hafslund Nycomed Pharma, Linz, Austria) are also available for operating room use in many European countries. See U. Schiele et al., Clin. Materials 9:169-177 (1992). While these fibrinogen-thrombin dressings do not require the pre-mixing needed by liquid fibrin sealants, their utility for field applications is limited by a requirement for storage at 4°C and the necessity for pre-wetting with saline solution prior to application to the wound. These dressings are also not effective against high pressure, high volume bleeding. See Sondeen et al.,). Trauma 54:280-285 (2003). A dry fibrinogen/thrombin dressing for treating wounded tissue is also available from the American Red Cross (ARC). As disclosed in U.S. Patent No. 6,762,336, this particular dressing is composed of a backing material and a plurality of layers, the outer two of which contain fibrinogen (but no thrombin) while the inner layer contains thrombin and calcium chloride (but no fibrinogen). While this dressing has shown great success in several animal models of hemorrhage, the bandage is fragile, inflexible, and has a tendency to break apart when handled. See McManus et al, Business Briefing: Emergency Medical Review 2005, at 78.; Kheirabadi et al.,]. Trauma 59:25-35 (2005). Other fibrinogen/thrombin-based dressings have also been proposed. For example, U.S. Patent No. 4,683,142 discloses a resorptive sheet material for closing and healing wounds which consists of a glycoprotein matrix, such as collagen, containing coagulation proteins, such as fibrinogen and thrombin. U.S. Patent No. 5,702,715 discloses a reinforced biological sealant composed of separate layers of fibrinogen and thrombin, at least one of which also contains a reinforcement filler such as PEG, PVP, BSA, mannitol, FICOLL, dextran, myo-inositol or sodium chlorate. U.S. Patent No. 6,056,970 discloses dressings composed of a bioabsorbable polymer, such as hyaluronic acid or carboxymethylcellulose, and a haemostatic composition composed of powdered thrombin and/or powdered fibrinogen. U.S. Patent No. 7,189,410 discloses a bandage composed of a backing material having thereon: (i) particles of fibrinogen; (ii) particles of thrombin; and (iu) calcium chloride. U.S. Patent Application Publication No. US 2006/0155234 Al discloses a dressing composed of a backing material and a plurality of fibrinogen layers which have discrete areas of thrombin between them. To date, none of these dressings have been approved for use or are available commercially. In addition, past efforts to prepare fibrinogen/thrombin solid dressings have always been hampered by the very property that makes them desirable ingredients for treating wounds - their inherent ability to rapidly react under aqueous conditions to form fibrin. The presence of Factor XIII results in the mixture results in further conversion of fibrin la into cross-linked fibrin II. The overall coagulation process for a human is shown in Figure 1. As depicted therein, the conversion of fibrinogen into fibrin I involves the cleavage of two small peptides (A and B) from the alpha (a) and beta (ß) chains of fibrinogen respectively. These small peptides are difficult to detect and monitor directly; the decrease in the molecular weight of the alpha and beta chains, however, resulting from this cleavage can be monitored by gel electrophoresis. Similarly, the conversion of fibrin I to cross-linked fibrin II can be followed by the disappearance on gels of the gamma (γ ) chain monomer of fibrinogen (as it is converted into γ-γ dimers by the action of Factor XIII upon the γ chain monomers). To avoid premature reaction, previous attempts to manufacture fibrinogen/thrombin solid dressings have emphasized the separation of the fibrinogen and thrombin components as much as possible in order to prevent them from forming too much fibrin prior to use of the dressing. For example, the fibrinogen-thrombin dressings having a collagen support {e.g. TachoComb™, TachoComb™ H and TachoSil) available from Hafslund Nycomed Pharma are prepared by suspending particles of fibrinogen and thrombin in a non-aqueous liquid and then spraying the suspension onto the collagen base. The use of a non-aqueous environment, as opposed to an aqueous one, is intended to prevent excessive interaction between the fibrinogen and thrombin. Alternatives to this process have been proposed, each similarly designed to maintain the fibrinogen and thrombin as separately as possible. For example, the fibrinogen/thrombin solid dressing disclosed in U.S. Patent No. 7.189,410 was prepared by mixing powdered fibrinogen and powdered thrombin in the absence of any solvent and then applying the dry powder mixture to the adhesive side of a backing material. The fibrinogen/thrombin solid dressings disclosed in U.S. Patent No. 6,762,336 and U.S. Patent Application Publication No. US 2006/0155234 Al contain separate and discrete layers of fibrinogen or thrombin, each substantially free of the other. These approaches, however, have not been completely successful. In order to function properly, a fibrinogen/thrombin-based solid dressing must meet several criteria. To begin with, the fibrinogen and thrombin must be able to successfully interact to form a clot and the more this clot adheres to the wound, the better the dressing performs. Grossly, the dressing must have a high degree of integrity, as the loss of active ingredients due to cracking, flaking and the like will ultimately result in decreased performance and meet with poor user acceptance. There have been reports that known fibrinogen/thrombin solid dressings are deficient in one or more of these characteristics. Furthermore, the dressing must be homogenous, as all areas of the dressing must function equally well in order to assure its successful use. The dressing must also hydrate rapidly and without significant or special efforts. Relatively flat dressings are generally preferred, with curling or irregular, non-planar structures to be avoided if possible (these ten to interfere with effective application and, in some instances, may result in poor performance). Flexibility is another characteristic that is greatly preferred, both to improve performance and to increase the number of wound geometries and locations that can be treated effectively. Although known fibrinogen/ thrombin solid dressings may be flexible when hydrated, they do not possess sufficient moisture content prior to hydration to be flexible. See, e.g., Sondeen et aL, J. Trauma 54:280-285 (2003) ); Holcomb et al;. J. Trauma, 55 518-526; McManus & Wedmore, Emergency Medicine Review, pp76-79, 2005. The amount of fibrin present in the dressing prior to use, particularly insoluble, cross-linked fibrin II, must be relatively small. This latter characteristic is important for several reasons. First, the presence of insoluble fibrin during manufacture normally results in poor quality dressings, which can exhibit decreased integrity, lack of homogeneity and difficult/slow hydration. These consequences can usually be detected visually by one of skill in the art. For example, the presence of pre-formed fibrin in a fibrinogen/thrombin-based solid dressing can be detected visually by deviations from a homogenous surface appearance. In particular, a rough or lumpy appearance frequently signals that there are significant masses of fibrin that have formed during manufacture and will likely impede future performance. Solid, smooth & glossy "sheets" on the surface of solid dressings are also signs of fibrin that will tend to slow (or even block) hydration during use. Excessive curling-up of a solid dressing is another sign that a significant amount of fibrin has formed during manufacture. Upon addition of water or an aqueous solution, dressings with excessive fibrin content are slow to hydrate and often require forceful application of the liquid, sometimes with mechanical penetration of the surface, in order to initiate hydration. Moreover, once hydrated, dressings with a significant amount of pre-formed fibrin usually have a mottled and distinctly non-homogenous appearance. The amount of pre-formed fibrin can also be assessed by various biochemical assays, such as the method described in U.S. Patent Application Publication No. US 2006/0155234 Al. According to this assay, the conversion of the fibrinogen γ chains to cross-linked γ-γ dimers is used as an indication of the presence of fibrin (the proportion of γ chain that is converted to γ-γ dirtier being a measure of the amount of fibrin produced). Other assays could assess changes in the other component chains of fibrinogen, such as the conversion of the Aa chain into free a chain and fibrinopeptide A or the conversion of the Bß chain into free (3 chain and fibrinopeptide B. These changes can be monitored by gel electrophoresis in a similar manner to the γ to γ-γ conversion described in U.S. Patent Application Publication No. US 2006/0155234 Al. Interestingly, in U.S. Patent Application Publication No. US 2006/0155234 Al, relatively high levels of γ-γ dimewation (up to 10%) were reported, indicating that these dressings included substantial amounts of fibrin prior to use. This observation may account for the delamination and/or cracking observed in some of these dressings. For a properly functioning fibrinogen/thrombin-based solid dressing, hydration should normally be completed within a few seconds and require nothing more than applying water (or some aqueous solution) onto the dressing. This solution could be blood or another bodily fluid from an injury site that the dressing is applied to, or it may be from some external source, such as a saline or other physiologically acceptable aqueous liquid applied to the dressing while it is on the wound to be treated. Longer hydration times, i.e. generally greater than 5 seconds, will impede the dressing's performance as portions of the dressing may be lost or shed into the fluids which will continue to freely flow prior to formation of sufficient cross-linked fibrin. Given the potentially fatal consequences of continued bleeding, any delay in dressing hydration during use is highly undesirable. In addition, the performance of dressings with excessive fibrin content are usually poor, as reflected by decreased scores in the EVPA and Adherence assays described herein, as well as during in nvo tests and clinical use. Accordingly, there remains a need in the art for a solid dressing that can be used to treat wounded tissue, particularly wounded tissue resulting from traumatic injury in the field. SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a solid dressing that can treat wounded mammalian tissue, particularly wounded tissue resulting from a traumatic injury. It is further an object of the present invention to provide a method of treating wounded mammalian tissue, particularly human tissue. Other objects, features and advantages of the present invention will be set forth in the detailed description of preferred embodiments that follows, and will in part be apparent from that description and/or may be learned by practice of the present invention. These objects and advantages will be realized and attained by the compositions and methods described in this specification and particularly pointed out in the claims that follow. In accordance with these and other objects, a first embodiment of the present invention is direct to a solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed from a single aqueous solution containing the fibrinogen component and the fibrinogen activator. Another embodiment is directed to a solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed as a single piece. Another embodiment is directed to a method of treating wounded tissue using a solid dressing comprising at least one haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed from a single aqueous solution containing the fibrinogen component and the fibrinogen activator. Another embodiment is directed to a method of treating wounded tissue using a solid dressing comprising at least one haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed as a single piece. Another embodiment is directed to a composition consisting essentially of a mixture of a fibrinogen component, a fibrinogen activator and water, wherein the composition is frozen and is stable at reduced temperature for at least 24 hours. It is to be understood that the foregoing general description and the following detailed description of preferred embodiments are exemplary and explanatory only and are intended to provide further explanation, but not limitation, of the invention as claimed herein. BRIEF DESCRIPTION OF DRAWINGS Figure 1 is an overview of the human clotting cascade as provided by ERL's website (www.enzymeresearch.co.uk/coag.htm). Figure 2 is a diagram of the set-up for the ex vivo porcine arteriotomoy assay described herein. Figures 3A-3C are graphs showing the results achieved in Example 1. Figure 4A and Figure 4B are graphs depicting the results of the EVPA and Adherence Assays for the dressings made in Examples 6-12. Figures 5A and 5B are graphs showing the performance characteristics of frozen compositions stored at -80 deg C as shown in Example 13. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference. As used herein, use of a singular article such as "a," "an," and "the" is not intended to excluded pluralities of the article's object unless the context clearly and unambiguously dictates otherwise. "Patient" as used herein refers to human or animal individuals in need of medical care and/or treatment "Wound" as used herein refers to any damage to any tissue of a patient which results in the loss of blood from the circulatory system and/ or any other fluid from the patient's body. The tissue may be an internal tissue, such as an organ or blood vessel, or an external tissue, such as the skin. The loss of blood may be internal, such as from a ruptured organ, or external, such as from a laceration. A wound may be in a soft tissue, such as an organ, or in hard tissue, such as bone. The damage may have been caused by any agent or source, including traumatic injury, infection or surgical intervention. "Resorbable material" as used herein refers to a material that is broken down spontaneously and/or by the mammalian body into components which are consumed or eliminated in such a manner as not to interfere significantly with wound healing and/or tissue regeneration, and without causing any significant metabolic disturbance. "Stability" as used herein refers to the retention of those characteristics of a material that determine activity and/ or function. "Suitable" as used herein is intended to mean that a material does not adversely affect the stability of the dressings or any component thereof. "Binding agent" as used herein refers to a compound or mixture of compounds that improves the adherence and/or cohesion of the components of the haemostatic layer(s) of the dressings. "Solubilizing agent" as used herein refers to a compound or mixture of compounds that improves the dissolution of a protein or proteins in aqueous solvent "Filler" as used herein refers to a compound or mixture of compounds that provide bulk and/or porosity to the haemostatic layer(s) of a dressing. "Release agent" as used herein refers to a compound or mixture of compounds that facilitates removal of a dressing from a manufacturing mold. "Foaming agent" as used herein refers to a compound or mixture of compounds that produces gas when hydrated under suitable conditions. "Solid" as used herein is intended to mean that the dressing will not substantially change in shape or form when placed on a rigid surface, wound-facing side down, and men left to stand at room temperature for 24 hours. "Frozen" as used herein is intended to mean that the composition will not substantially change in shape or form when placed on a rigid surface, wound-facing side down, and then left to stand at -40 deg C for 24 hours, but will substantially change in shape or form when placed on a rigid surface, wound-facing side down, and then left at room temperature for 24 hours. Thus, in the context of the present invention, a "solid" dressing is not "frozen" and a "frozen" composition is not "solid". A first preferred embodiment of the present invention is directed to a solid dressing for treating wounded tissue in a patient which comprises a haemostatic layer consisting of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed from a single aqueous solution containing the fibrinogen component and the fibrinogen activator. Another embodiment of the present invention is directed to a solid dressing for treating wounded tissue in a patient which comprises a haemostatic layer consisting of a fibrinogen component and a fibrinogen activator, wherein the haemostatic layer(s) is cast or formed as single piece. As used herein, "consisting essentially of is intended to mean that the fibrinogen component and the fibrinogen activator are the only necessary and essential ingredients of the haemostatic layer(s) of the solid dressing when it is used as intended to treat wounded tissue. Accordingly, the haemostatic layer may contain other ingredients in addition to the fibrinogen component and the fibrinogen activator as desired for a particular application, but these other ingredients are not required for the solid dressing to function as intended under normal conditions, i.e. these other ingredients are not necessary for the fibrinogen component and fibrinogen activator to react and form enough fibrin to reduce the flow of blood and/ or fluid from normal wounded tissue when that dressing is applied to that tissue under the intended conditions of use. If, however, the conditions of use in a particular situation are not normal, for example the patient is a hemophiliac suffering from Factor XIII deficiency, then the appropriate additional components, such as Factor Xlll/Xllla or some other transaminase, may be added to the haemostatic layer(s) without deviating from the spirit of the present invention. Similarly, the solid dressing of the present invention may contain one or more of these haemostatic layers as well as one or more other layers, such as one or more support layers (e.g. a backing material or an internal support material) and release layers. Other preferred embodiments of the present invention are directed to methods for treating wounded tissue in a mammal, comprising placing a solid dressing of the present invention to wounded tissue and applying sufficient pressure to the dressing for a sufficient time for enough fibrin to form to reduce the loss of blood and/or other fluid from the wound. Still other preferred embodiments are directed to compositions consisting essentially of a mixture of a fibrinogen component, a fibrinogen activator and water, wherein these compositions are frozen and are stable at reduced temperature for at least 24 hours. Such compositions are particularly useful for preparing the haemostatic layer(s) of the inventive solid dressings. According to certain embodiments of the present invention, the haemostatic layer(s) of the solid dressing is formed or cast as a single piece. According to certain other embodiments of the present invention, the haemostatic layer is made or formed into or from a single source, e.g. an aqueous solution containing a mixture of the fibrinogen and the fibrinogen activator. With each of these embodiments of the present invention, the haemostatic layer(s) is preferably substantially homogeneous throughout According to certain preferred embodiments, the haemostatic layer(s) of the solid dressing may also contain a binding agent to facilitate or improve the adherence of the layer(s) to one another and/or to any support layer(s). Illustrative examples of suitable binding agents include, but are not limited to, sucrose, mannitol, sorbitol, gelatin, hyaluron and its derivatives, such as hyaluronic acid, maltose, povidone, starch, chitosan and its derivatives, and cellulose derivatives, such as carboxymediylcellulose, as well as mixtures of two or more thereof. The haemostatic layer(s) of the solid dressing may also optionally contain one or more suitable fillers, such as sucrose, lactose, maltose, silk, fibrin, collagen, albumin, polysorbate (Tween™), chitin, chitosan and its derivatives {e.g. NOCC-chitosan), alginic acid and salts thereof, cellulose and derivatives thereof, proteoglycans, hyaluron and its derivatives, such as hyaluronic acid, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co-polymers, and mixtures of two or more thereof. The haemostatic layer of the solid dressing may also optionally contain one or more suitable solubilizing agents, such as sucrose, dextrose, mannose, trehalose, mannitol, sorbitol, albumin, hyaluron and its derivatives, such as hyaluronic acid, sorbate, polysorbate (Tween™), sorbitan (SPAN™) and mixtures of two or more thereof. The haemostatic layer of the solid dressing may also optionally contain one or more suitable foaming agents, such as a mixture of a physiologically acceptable acid (e.g. citric acid or acetic acid) and a physiologically suitable base (e.g. sodium bicarbonate or calcium carbonate). Other suitable foaming agents include, but are not limited to, dry particles containing pressurized gas, such as sugar particles containing carbon dioxide (see, e.g., U.S. Patent No. 3,012,893) or other physiologically acceptable gases (e.g. Nitrogen or Argon), and pharmacologically acceptable peroxides. Such a foaming agent may be introduced into the aqueous mixture of the fibrinogen component and the fibrinogen activator, or may be introduced into an aqueous solution of the fibrinogen component and/or an aqueous solution of the fibrinogen activator prior to mixing. The haemostatic layer(s) of the solid dressing may also optionally contain a suitable source of calcium ions, such as calcium chloride, and/or a fibrin cross-linker, such as a transaminase (e.g. Factor XIII /Xllla) or glutaraldehyde. The haemostatic layer of the solid dressing is preferably prepared by mixing aqueous solutions of the fibrinogen component and the fibrinogen activator under conditions which minimize the activation of the fibrinogen component by the fibrinogen activator. The mixture of aqueous solutions is then subjected to a process such as lyophilization or free-drying to reduce the moisture content to the desired level, i.e. to a level where the dressing is solid and therefore will not substantially change in shape or form upon standing, wound-facing surface down, at room temperature for 24 hours. Similar processes that achieve the same result, such as drying, spray- drying, vacuum drying and vitrification, may also be employed. As used herein, "moisture content" refers to the amount freely-available water in the dressing. "Freely-available" means the water is not bound to or complexed with one or more of the non-liquid components of the dressing. The moisture content referenced herein refers to levels determined by procedures substantially similar to the FDA-approved, modified Karl Fischer method (Meyer and Boyd, Analytical Chem., 31:215-219, 1959; May et al.,]. Biol. Standardization, 10:249- 259, 1982; Centers for Biologies Evaluation and Research, FDA, Docket No. 89D-0140, 83-93; 1990) or by near infrared spectroscopy. Suitable moisture contends) for a particular solid dressing may be determined empirically by one skilled in the art depending upon the intended application(s) thereof. For example, in certain embodiments of the present invention, higher moisture contents are associated with more flexible solid dressings. Thus, in solid dressings intended for extremity wounds, it may be preferred to have a moisture content of at least 6% and even more preferably in the range of 6% to 44%. Similarly, in other embodiments of the present invention, lower moisture contents are associated with more rigid solid dressings. Thus, in solid dressings intended for flat wounds, such as wounds to the abdomen or chest, it may be preferred to have a moisture content of less than 6% and even more preferably in the range of 1% to 6%. Accordingly, illustrative examples of suitable moisture contents for solid dressings include, but are not limited to, the following (each value being ± 0.9%): less than 53%; less than 44%; less than 28%; less than 24%; less than 16%; less than 12%; less than 6%; less than 5%; less than 4%; less than 3%; less than 2.5%; less than 2%; less than 1.4%; between 0 and 12%, non-inclusive; between 0 and 6%; between 0 and 4%; between 0 and 3%; between 0 and 2%; between 0 and 1%; between 1 and 16%; between 1 and 11%; between 1 and 8%; between 1 and 6%; between 1 and 4%; between 1 and 3%; between 1 and 2%; and between 2 and 4%. The fibrinogen component in the haemostatic layer(s) of the solid dressings may be any suitable fibrinogen known and available to those skilled in the art. The fibrinogen component may also be a functional derivative or metabolite of a fibrinogen, such the fibrinogen a, (3 and/or γ chains, soluble fibrin I or fibrin II, or a mixture of two or more thereof. A specific fibrinogen (or functional derivative or metabolite) for a particular application may be selected empirically by one skilled in the art As used herein, the term "fibrinogen" is intended to include mixtures of fibrinogen and small mounts of Factor XIII/Factor Xllla, or some other such transaminase. Such small amounts are generally recognized by those skilled in the art as usually being found in mammalian fibrinogen after it has been purified according to the methods and techniques presently known and available in the art, and typically range from 0.1 to 20 Units/ml. Preferably, the fibrinogen employed as the fibrinogen component of the solid dressing is a purified fibrinogen suitable for introduction into a mammal. Typically, such fibrinogen is a part of a mixture of human plasma proteins which include Factor Xlll/Xllla and have been purified to an appropriate level and virally inactivated. A preferred aqueous solution of fibrinogen for preparation of a solid dressing contains around 37.5 mg/mL fibrinogen at a pH of around 7.4 ±0.1. Suitable fibrinogen for use as the fibrinogen component has been described in the art, e.g. U.S. Patent No. 5,716,645, and similar materials are commercially available, e.g. from sources such as Sigma-Aldrich, Enzyme Research Laboratories, Haematologic Technologies and Aniara. Preferably, the fibrinogen component is present in an amount of from about 1.5 to about 13.0 mg (± 0.9 mg) of fibrinogen per square centimeter of solid dressing, and more preferably from about 3.0 to about 13.0 mg/cm2. Greater or lesser amounts, however, may be employed depending upon the particular application intended for the solid dressing. For example, according to certain embodiments where increased adherence is desired, the fibrinogen component is present in an amount of from about 11.0 to about 13.0 mg (± 0.9 mg) of fibrinogen per square centimeter of solid dressing, likewise, according to certain embodiments which are intended for treating low pressure-containing vessels, lower levels of the fibrinogen component may be employed. The fibrinogen activator employed in the haemostatic layer(s) of the solid dressing may be any of the substances or mixtures of substances known by those skilled in the art to convert fibrinogen into fibrin. Illustrative examples of suitable fibrinogen activators include, but are not limited to, the following: thrombins, such as human thrombin or bovine thrombin, and prothrombins, such as human prothrombin or prothrombin complex concentrate (a mixture of Factors II, VII, EX and X); snake venoms, such as batroxobin, reptilase (a mixture of batroxobin and Factor Xllla), bothrombin, calobin, fibrozyme, and enzymes isolated from the venom of Bothrops jararacussu; and mixtures of any two or more of these. See, e.g., Dascombe et al, Thromb. Haemost. 78:947-51 (1997); Hahn etal.,}. Biochem. (Tokyo) 119:835-43 (1996); Fortova et aL,). Chromatogr. S. Biomed. Appl. 694:49-53 (1997); and Andriao-Escarso et al., Toxicon. 35: 1043-52 (1997). Preferably, the fibrinogen activator is a thrombin. More preferably, the fibrinogen activator is a mammalian thrombin, although bird and/or fish thrombin may also be employed in appropriate circumstances. While any suitable mammalian thrombin may be used in the solid dressing, the thrombin employed in the haemostatic layer is preferably a lyophilized mixture of human plasma proteins which has been sufficiently purified and virally inactivated for the intended use of the solid dressing. Suitable thrombin is available commercially from sources such as Sigma- Aldrich, Enzyme Research Laboratories, Haematologic Technologies and Biomol International. A particularly preferred aqueous solution of thrombin for preparing a solid dressing contains thrombin at a potency of between 10 and 2000 ± 50 International Units/mL, and more preferred at a potency of 25 ± 2.5 International Units/mL . Other constituents may include albumin (generally about 0.1 mg/mL) and glycine (generally about 100 mM ± 0.1 mM). The pH of this particularly preferred aqueous solution of thrombin is generally in the range of 6.5-7.8, and preferably 7.4± 0.1, although a pH in the range of 5.5-8.5 may be acceptable. In addition to the haemostatic layer(s), the solid dressing may optionally further comprise one or more support layers. As used herein, a "support layer" refers to a material that sustains or improves the structural integrity of the solid dressing and/ or the fibrin dot formed when such a dressing is applied to wounded tissue. According to certain preferred embodiments of the present invention the support layer comprises a backing material on the side of the dressing opposite the side to be applied to wounded tissue. Such a backing material may be affixed with a physiologically-acceptable adhesive or may be self-adhering (e.g. by having a sufficient surface static charge). The backing material may comprise one or more resorbable materials or one or more non-resorbable materials or mixtures thereof. Preferably, the backing material is a single resorbable material. Any suitable resqrbable material known and available to those skilled in the art may be employed in the present invention. For example, the resorbable material may be a proteinaceous substance, such as silk, fibrin, keratin, collagen and/or gelatin. Alternatively, the resorbable material may be a carbohydrate substance, such as alginates, chitin, cellulose, proteoglycans (e.g. poly-N- acetyl glucosamine), glycolic acid polymers, lactic acid polymers, or glycolic acid/lactic acid copolymers. The resorbable material may also comprise a mixture of proteinaceous substances or a mixture of carbohydrate substances or a mixture of both proteinaceous substances and carbohydrate substances. Specific resorbable material(s) may be selected empirically by those skilled in the art depending upon the intended use of the solid dressing. According to certain preferred embodiments of the present invention, the resorbable material is a carbohydrate substance. Illustrative examples of particularly preferred resorbable materials include, but are not limited to, the materials sold under the trade names VICRYL™ (a glycolic acid/lactic acid copolymer) and DEXON™ (a glycolic acid polymer). Any suitable non-resorbable material known and available to those skilled in the art may be employed as the backing material. Illustrative examples of suitable non-resorbable materials include, but are not limited to, plastics, silicone polymers, paper and paper products, latex, gauze and the like. According to other preferred embodiments, the support layer comprises an internal support material. Such an internal support material is preferably fully contained within a haemostatic layer of the solid dressing., although it may be placed between two adjacent haemostatic layers in certain embodiments. As with the backing material, the internal support material may be a resorbable material or a non-resorbable material, or a mixture thereof, such as a mixture of two or more resorbable materials or a mixture of two or more non-resorbable materials or a mixture of resorbable material(s) and non-resorbable material(s). According to still other preferred embodiments, the support layer may comprise a front support material on the wound-facing side of the dressing, Le. the side to be applied to wounded tissue. As with the backing material and the internal support material, the front support material may be a resorbable material or a non-resorbable material, or a mixture thereof, such as a mixture of two or more resorbable materials or a mixture of two or more non-resorbable materials or a mixture of resorbable material(s) and non-resorbable material(s). According to still other preferred embodiments, the solid dressing comprises both a backing material and an internal support material in addition to the haemostatic layer(s), Le. the solid dressing comprises two support layers in addition to the haemostatic layer (s). According to still other preferred embodiments, the solid dressing comprises both a front support material and an internal support material in addition to the haemostatic layer(s). According to still other preferred embodiments, the solid dressing comprises a backing material, a front support material and an internal support material in addition to the haemostatic layer(s). According to certain embodiments of the present invention, particularly where the solid dressing is manufactured using a mold, the solid dressings may also optionally further comprise a release layer in addition to the haemostatic layer(s) and support layer(s). As used herein, a "release layer" refers to a layer containing one or more agents ("release agents") which promote or facilitate removal of the solid dressing from a mold in which it has been manufactured. A preferred such agent is sucrose, but other suitable release agents include gelatin, hyaluron and its derivatives, including hyaluronic acid, mannitol, sorbitol and glucose. Alternatively, such one or more release agents may be contained in the haemostatic layer. The various layers of the inventive dressings may be affixed to one another by any suitable means known and available to those skilled in the art. For example, a physiologically- acceptable adhesive may be applied to a backing material (when present), and the haemostatic layer(s) subsequently affixed thereto. In certain embodiments of the present invention, the physiologically-acceptable adhesive has a shear strength and/or structure such that the backing material can be separated from the fibrin clot formed by the haemostatic layer after application of the dressing to wounded tissue. In other embodiments, the physiologically-acceptable adhesive has a shear strength and/or structure such that the backing material cannot be separated from the fibrin clot after application of the bandage to wounded tissue. Suitable fibrinogens and suitable fibrinogen activators for the haemostatic layer(s) of the solid dressing may be obtained from any appropriate source known and available to those skilled in the art, including, but not limited to, the following: from commercial vendors, such as Sigma- Aldrich and Enzyme Research Laboratories; by extraction and purification from human or mammalian plasma by any of the methods known and available to those skilled in the art; from supernatants or pastes derived from plasma or recombinant tissue culture, viruses, yeast, bacteria, or the like that contain a gene that expresses a human or mammalian plasma protein which has been introduced according to standard recombinant DNA techniques; and/or from the fluids {e.g. blood, milk, lymph, urine or the like) of transgenic mammals {e.g. goats, sheep, cows) that contain a gene which has been introduced according to standard transgenic techniques and that expresses the desired fibrinogen and/or desired fibrinogen activator. According to certain preferred embodiments of the present invention, the fibrinogen is a mammalian fibrinogen such as bovine fibrinogen, porcine fibrinogen, ovine fibrinogen, equine fibrinogen,, caprine fibrinogen, feline fibrinogen, canine fibrinogen, murine fibrinogen or human fibrinogen. According to other embodiments, the fibrinogen is bird fibrinogen or fish fibrinogen. According to any of these embodiments, the fibrinogen may be recombinantly produced fibrinogen or transgenic fibrinogen. According to certain preferred embodiments of the present invention, the fibrinogen activator is a mammalian thrombin, such as bovine thrombin, porcine thrombin, ovine thrombin, equine thrombin, caprine thrombin, feline thrombin, canine thrombin, murine thrombin and human thrombin. According to other embodiments, the thrombin is bird thrombin or fish dirombin. According to any of these embodiments, the thrombin may be recombinantly produced thrombin or transgenic thrombin. As a general proposition, the purity of the fibrinogen and/or the fibrinogen activator for use in the solid dressing will be a purity known to one of ordinary skill in the relevant art to lead to the optimal efficacy and stability of the protein(s). Preferably, the fibrinogen and/or the fibrinogen activator has been subjected to multiple purification steps, such as precipitation, concentration, diafiltration and affinity chromatography (preferably immunoaffinity chromatography), to remove substances which cause fragmentation, activation and/or degradation of the fibrinogen and/or the fibrinogen activator during manufacture, storage and/or use of the solid dressing. Illustrative examples of such substances that are preferably removed by purification include: protein contaminants, such as inter-alpha trypsin inhibitor and pre-alpha trypsin inhibitor; non-protein contaminants, such as lipids; and mixtures of protein and non-protein contaminants, such as lipoproteins. The amount of the fibrinogen activator employed in the solid dressing is preferably selected to optimize both the efficacy and stability thereof. As such, a suitable concentration for a particular application of the solid dressing may be determined empirically by one skilled in the relevant art. According to certain preferred embodiments of the present invention, when the fibrinogen activator is human thrombin, the amount of human thrombin employed is between 2.50 Units/mg of fibrinogen component and 0.025 Units/mg of the fibrinogen (all values being ± 0.009). Other preferred embodiments are directed to similar solid dressings wherein the amount of thrombin is between 0.250 Units/mg of fibrinogen and 0.062 Units/mg of fibrinogen and solid dressings wherein the amount of thrombin is between 0.125 Units/mg of fibrinogen and 0.080 Units/mg of fibrinogen. During use of the solid dressing, the fibrinogen and the fibrinogen activator are preferably activated at the rime the dressing is applied to the wounded tissue by the endogenous fluids of the patient escaping from the hemorrhaging wound. Alternatively, in situations where fluid loss from the wounded tissue is insufficient to provide adequate hydration of the protein layers, the fibrinogen component and/or the thrombin may be activated by a suitable, physiologically- acceptable liquid, optionally containing any necessary co-factors and/or enzymes, prior to or during application of the dressing to the wounded tissue. In some embodiments of the present invention, the haemostatic layer(s) may also contain one or more supplements, such as growth factors, drugs, polyclonal and monoclonal antibodies and other compounds. Illustrative examples of such supplements include, but are not limited to, the following: fibrinolysis inhibitors, such as aprotonin, tranexamic acid and epsilon- amino-caproic acid; antibiotics, such as tetracycline and ciprofloxacin, amoxicillin, and metronidazole; anticoagulants, such as activated protein C, heparin, prostacyclins, prostaglandins (particularly (PGI2), leukotrienes, antithrombin III, ADPase, and plasminogen activator; steroids, such as dexamethasone, inhibitors of prostacyclin, prostaglandins, leukotrienes and/or kinins to inhibit inflammation; cardiovascular drugs, such as calcium channel blockers, vasodilators and vasoconstrictors; chemoattractants; local anesthetics such as bupivacaine; and antiproliferative/antitumor drugs such as 5-fluorouracil (5-FU), taxol and/or taxotere; antivirals, such as gangcyclovir, zidovudine, amantadine, vidarabine, ribaravin, trifluridine, acyclovir, dideoxyuridine and antibodies to viral components or gene products; cytokines, such as alpha- or beta- or gamma-lnterferon, alpha- or beta-tumor necrosis factor, and interleukins; colony stimulating factors; erythropoietin; antifungals, such as diflucan, ketaconizole and nystatin; antiparasitic gents, such as pentamidine; anti-inflammatory agents, such as alpha-1 -anti- trypsin and alpha-1-antichymotrypsin; anesthetics, such as bupivacaine; analgesics; antiseptics; hormones; vitamins and other nutritional supplements; glycoproteins; fibronectin; peptides and proteins; carbohydrates (both simple and/or complex); proteoglycans; antiangiogenins; antigens; lipids or liposomes; oligonucleotides (sense and/or antisense DNA and/or RNA); and gene therapy reagents. In other embodiments of the present invention, the backing layer and/or the internal support layer, if present, may contain one or more supplements. According to certain preferred embodiments of the present invention, the therapeutic supplement is present in an amount greater than its solubility limit in fibrin. The following examples are illustrative only and are not intended to limit the scope of the invention as defined by the appended claims. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. EXAMPLES The ability of the dressings to seal an injured blood vessel was determined by an ex vivo porcine arteriotomy (EVPA) performance test, which was first described in U.S. Patent No. 6,762,336. The EVPA performance test evaluates the ability of a dressing to stop fluid flow through a hole in a porcine artery. While the procedure described in U.S. Patent No. 6,762,336 has been shown to be useful for evaluating haemostatic dressings, it failed to replicate faithfully the requirements for success in vivo. More specifically, the procedure disclosed in U.S. Patent No. 6,762,336 required testing at 37°C, whereas, in the real world, wounds are typically cooler than that. This decreased temperature can significantly reduce the rate of fibrin formation and its haemostatic efficacy in trauma victims. See, e.g., Acheson et ai, J. Trauma 59:865-874 (2005). The test in U.S. Patent No. 6,762,336 also failed to require a high degree of adherence of the dressing to the injured tissue. A failure mode in which fibrin forms but the dressing fails to attach tightly to the tissue would, therefore, not be detected by this tesL Additionally, the pressure utilized in the procedure (20OmHg) may be exceeded during therapy for some trauma patients. The overall result of this is that numerous animal tests, typically involving small animals (such as rats and rabbits), must be conducted to accurately predict dressing performance in large animal, realistic trauma studies and in the clinical environment. In order to minimize the amount of time and the number of animal studies required to develop the present invention, an improved ex vivo testing procedure was developed. To accomplish this, the basic conditions under which the dressing test was conducted were changed, and the severity of the test parameters was increased to include testing at lower temperatures (i.e. 29- 33 deg C vs. 37 deg C, representing the real physiologic challenge at realistic wound temperatures (Acheson et aL, J. Trauma 59:865-874 (2005)), higher pressures (i.e. 250 mmHg vs. 200 mmHg), a longer test period (3 minutes vs. 2 minutes) and larger sized arterial injuries (U.S. Patent No. 6,762,336 used an 18 gauge needle puncture, whereas the revised procedure used puncture holes ranging from 2.8mm to 4mm x 6mm). In addition, a new test was derived to directly measure adherence of the dressing to the injured tissue. Both these tests showed greatly improved stringency and are thus capable of surpassing the previous ex vivo test and replacing many in vivo tests for efficacy. The following is a list of acronyms used in the Examples below: CFB: Complete Fibrinogen Buffer (10OmM Sodium Chloride, llmM Calcium Chloride, 1OmM Tris, 1OmM Sodium Citrate, 1.5% Sucrose, Human Serum Albumin (80mg/g of total protein) and Tween™ 80 (animal source) 15mg/g total protein) CTB: Complete Thrombin Buffer (15OmM Sodium Chloride, 4OmM Calcium Chloride, 1OmM Tris and 10OmM L-Lysine with the addition of HSA at lOOug/ml) ERL: Enzyme Research Laboratories EVPA: Ex Vivo Porcine Arteriotomy FD: Inventive haemostatic dressing HSA: Human Serum Albumin HD: A "sandwich" fibrin sealant haemostatic dressing as disclosed in U.S. Patent No. 6,762,336 IFB: Incomplete Fibrinogen Buffer.; CFB without HSA and Tween PETG: Glycol-modified Polyethlylenetetrapthalate PPG: Polypropylene PVC: Poly vinyl chloride TRIS: trishydroxymethylaminomethane (2-amino-2-hydroxymethyl-l,3-propanediol) Example 1 Backing material (DEXON™) was cut and placed into each PETG 2.4 X 2.4cm mold. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. Fibrinogen (Enzyme Research Laboratories™) was formulated in CFB. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentrations were adjusted to 37.5, 31.7, 25.9, 20.16, 14.4, 8.64, and 4.3mg/ml. When 2ml of fibrinogen was delivered into the molds, this would result in a fibrinogen dose of 13, 11, 9, 7, 5, 3 or 1.5mg/cm2. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. The concentrations of thrombin were adjusted so that when mixed with the fibrinogen solutions as described below, the combination would produce a solution that contained 0.1 units/mg of Fibrinogen. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Molds were removed from the -80 deg C freezer and placed on a copper plate that was placed on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was rilled with thrombin. Two ml of fibrinogen and 300 micro liters of thrombin were dispensed simultaneously into each mold. Once the molds were filled they were allowed to freeze and then returned to the -80 deg C freezer for at least two hours. The frozen dressings were then placed into a pre-cooled Genesis™ lyophylizer (Virus, Gardiner, NY). The chamber was sealed and the temperature equilibrated. The chamber was then evacuated and the dressings lyophilized via a primary and secondary drying cycle. The dressings were removed from the lyophylizer, sealed in foil pouches and stored at room temperature until testing. Subsequently, the dressings were evaluated in the EVPA, Adherence and Weight Assays. The results are given in the following Table and depicted graphically in Figures 3A-3C. (Table Removed) Example 2 Monolithic dressings were manufactured as follows: backing material was cut and placed into each PETG 2.4 X 2.4cm mold. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. For all dressings, ERL fibrinogen lot 3114 was formulated in CFB. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. The thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml thrombin. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Molds were removed from the -80 deg C freezer and placed on a copper plate that was placed on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Simultaneously 2ml of fibrinogen and 300 micro liters of thrombin were dispensed into each mold. Once the molds were filled they were returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. Dressings were then lyophilized as described above. Once complete the dressings were stored in low moisture transmission foil bags containing 5 grams of desiccant. Trilayer dressings were manufactured as described previouslyl, using the same materials as described above.Subsequently, the dressings were placed under conditions of 100% relative humidity at 37°C for various times in order to increase their relative moisture content to desired levels. The dressings were evaluated visually and for their handling and other physical characteristics. Following this evaluation, a sample of each of the dressings was tested to determine their moisture content. The remaining dressings were performance tested in the EVPA, Adherence and Weight Held assays. Results The results of the assays are given in the Tables below: Table 1: Performance Data of Inventive Solid Dressings (Table Removed) Table 2: Performance Data for Tri-layer Dressings (Table Removed) Table 3: Integrity and Handling Characteristics of Inventive Solid Dressings (Table Removed) Table 4: Integrity and Handling Characteristics of Trilayer Dressings (Table Removed) Conclusions: The monolithic dressings were fully functional at very high levels of moisture. As much as 28% moisture was found to retain complete functionality. When the moisture levels rose to 44%, the dressings were still functional, however some of their activity was reduced Higher levels of moisture may also retain some function. The original dressings, at 2.5% moisture content, were not flexible, but had all the other desired properties including appearance, a flat surface, integrity, rapid and uncomplicated hydration and a smooth appearance post hydration. Once the moisture content was increased to 5.8%, the monolithic dressings became flexible, while retaining their functionality and desirable characteristics. They retained their flexibility, without curling or losing their integrity or appearing to form excessive amounts of fibrin prior to hydration. This contrasted with the tri-layer dressings, which began to lose their desirable characteristics upon the addition of moisture, and lost them entirely by the time moisture had increased to 33%. Example 3 For dressings utilizing a backing, the backing material was cut and placed into each PETG 2.4 X 2.4cm mold. Twenty- five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. For dressings without backing material, PETG 2.4 X 2.4cm molds were placed in a -80 deg C freezer for at least 60 minutes. For all dressings, ERL fibrinogen lot 3114 was formulated in CFB. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. The thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml thrombin. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Molds were removed from the -80 deg C freezer and placed on a copper plate that was placed on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Simultaneously 2ml of fibrinogen and 300 micro liters of thrombin were dispensed into each mold. Once the molds were filled they were returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. Dressings were then lyophylized as described below. Both groups were performance tested in the EVPA assay. In addition, the group which had a backing was also tested in the Adherence and Weight Held assays. Results: (Table Removed) Conclusions: Dressings formulated with backing material performed well, with all dressings passing the EVPA test, and high values for adherence and weight held. Dressings without backing material were not quite as effective in the EVPA assay, however, surprisingly 75% of them passed the EVPA test. Without the backing the other tests could not be performed. The ability of the dressings made without a backing to succeed in the EVPA assay indicates that these dressings would be effective in treating arterial injuries and even more effective in treating venous and small vessel injuries. Example 4 For all dressings, ERL fibrinogen lot 3130 was formulated in CFB. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. The thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml thrombin. For the group with shredded VICRYL™ mesh dispersed within, this support material was cut into approximately Imm x Imm pieces and dispersed within the thrombin solution prior to filling the molds. Once prepared the dirombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Cylindrical molds made of 10 or 3 ml polypropylene syringes (Becton Dickinson) with the luer-lock end removed were used. The plungers were withdrawn to the 6 ml and 2 ml mark respectively. For dressings utilizing a backing, the support material was cut and placed into each mold and pushed down until it was adjacent to the plunger. Once prepared the molds were placed upright and surrounded by dry ice, leaving the opening exposed at the top. 1 ml of fibrinogen and 0.15 mL of thrombin (widi or without backing material dispersed within) were dispensed into the 1OmL molds and 1 ml of fibrinogen and 0.15 ml of thrombin (with or without support material dispersed within) were dispensed into the 3mL molds, which were allowed to freeze for 5 minutes. The molds were then placed into the -80 deg C freezer for at least two hours before being placed into the freeze dryer and lyophylized as described above. Upon removal from the lyophylizer, both groups were performance tested in a modified EVPA assay. Briefly, a plastic foam form was slipped over the artery. This covering had a hole in it that corresponded to the hole in the artery and the surrounding tissue. Warm saline was added to the surface of the dressing and the mold was immediately passed down thru the hole in the foam to the artery surface. The plunger was then depressed and held by hand for 3 minutes, after which the mold was withdrawn as the plunger was depressed further. At this point the artery was pressurized and the assay continued as before. Results (Table Removed) Conclusions: Dressings that included no backing or a DEXON™ mesh backing performed well, with all passing the EVPA test at 250 mmHg. When the support material was dispersed throughout the composition, the dressings also performed well, with the large size (1OmL mold) dressings holding the full 250mmHg of pressure, while the smaller held up to 150 mmHg of pressure. This indicates that the use of a support material may be optional, and it's location may be on the Taack' of the dressing, or dispersed throughout the composition, as desired. Example 5 Dressings made with a support material on the "back" (i.e. the non wound-facing side) of the dressing were manufactured by first cutting the mesh support material and placing it into each PETG 10 X 10cm mold. Twenty- five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. For dressings made with a support material on the "front" {i.e. the wound-facing side) of the dressing, these were manufactured without any support material in the mold. The support mesh was placed atop the dressing immediately after dispensing of the fibrinogen and thrombin into the mold (see below), and lightly pressing it into the surface prior to its freezing. In all other ways the manufacture of the dressings was similar as described below. For all dressings, ERL fibrinogen lot 3114 was formulated in CFB. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. The thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml thrombin. Once prepared the dirombin was placed on ice until use. The thrombin was adjusted to deliver 0.1 units/mg of Fibrinogen or 25 Units/ml dirombin. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. The mold was removed from the -80 deg C freezer and placed on an aluminum plate diat was placed on top of dry ice. The aluminum plate had a 0.25 inch hole drilled in the center and a fitting attached so that a piece of tubing could be attached to a vacuum source. The mold was centered over the hole in the aluminum plate and vacuum was turned on. The vacuum served two purposes it prevented the mold from moving and it held it flat against the aluminum plate. Thirty-five milliliters of fibrinogen and 5.25 milliliters of Thrombin were placed in 50ml test tube, inverted three times and poured into the mold. Once the molds were filled and the support material applied as described above, they were returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. Dressings were then lyophylized as described previously. Both groups were performance tested in the EVPA assay. In addition, the group which had a backing was also tested in the Adherence and Weight Held assays. Results: (Table Removed) Conclusions: Dressings formulated with backing material in either orientation well, with all dressings passing the EVPA test, and high values for adherence and weight held. This indicates that the location of a support material may be on the 'back1 of the dressing, or the 'front', of the composition as desired. Example 6 Backing material (DEXON™) was placed into 2.4 X 2.4cm PETG molds. Twenty- five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. Fibrinogen (Enzyme Research Laboratories™ (ERL) lot 3114) was formulated in CFB. The fibrinogen concentration was adjusted to 37.5mg/ml using CFB. The final pH of the fibrinogen was 7.4 ±0.1. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ± 0 1 The thrombin concentrations were adjusted with CFB to produce 12.5 units/mg of Fibrinogen (upon mixing), which corresponded to 3120 Units/ml thrombin pnor to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin pnor to dispensing was 4°C ± 2°C Molds were removed from the -80 deg C freezer and placed on a copper plate that was precooled on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Two ml of fibrinogen and 300 micro liters of thrombin were dispensed simultaneously into each mold. Once the molds were filled they were returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. The results are shown in Figures 4A and 4B. Example 7 Backing material was placed into each 1 5 X 1.5cm PVC molds. Fifteen microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was fitted on top of the 1.5 X 1.5 molds and held in place. This formed a closed mold. The molds were then placed in a -80 deg C freezer for at least 60 minutes. Fibrinogen (ERL lot 3100) was formulated in CFB. The fibrinogen concentration was adjusted to 37.5mg/ml using CFB. The final pH of the fibrinogen was 7.4 ± 0.1. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. The thrombin concentrations were adjusted using CTB to deliver the following amounts 2.5, 0.25, 0.1, 0.05, 0.025, 0.016, 0.0125 and 0.01 units/mg of Fibrinogen (upon mixing), which corresponded to 624, 62.4, 25, 12.5, 6.24, 3.99, 3.12, and 2.5 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and dirombin prior to dispensing was 4°C ± 2°C. Molds were then removed from the -80 deg C freezer and placed on an aluminum plate that was pre-cooled on top of dry ice. Three holes were punched at the top of the mold using an 18 gauge needle. One hole was used for injecting fibrinogen, the second for injecting thrombin, and the third hole served as a vent to release air that was displaced from inside the mold. A pipette was then filled with fibrinogen and a second pipette with thrombin. Simultaneously 0.78ml of fibrinogen and 0.17ml of dirombin were injected via these pipettes into each mold. Once filled the molds were placed on top of a pool of liquid nitrogen for thirty seconds and then returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. Example 8 Backing material was placed into 2.4 X 2.4cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. Fibrinogen (ERL lot 3100) was formulated in CFB. The fibrinogen concentration was adjusted to 37.5mg/ml using CFB. The final pH of the fibrinogen was 7.4 ±0,1. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ± 0.1. Using CTB, the thrombin concentrations were adjusted to deliver the following amounts 0.125, 0.025, 0.0125, 0.00625 and 0.0031 units/mg of Fibrinogen upon mixing, which corresponded to 31.2, 6.24, 3.12, 1.56 and 0.78 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. The molds were removed from the -80 deg C freezer and placed on an aluminum plate that that was precooled on top of dry ice. A 3ml syringe fitted with an 18 gauge needle was filled with 2ml of fibrinogen and a second, Iml, syringe fitted with a 22 gauge needle was filled with 0.3ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the - 80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. Example 9 Backing material was placed into PVC 2.4 X 2.4cm molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four comers of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. A vial containing 3 grams of Fibrinogen (Sigma™ Lot# F-3879) was removed the -20 deg C freezer and placed at 4°C for 18 hours. The bottle was then removed from the freezer and allowed to come to room temperature for 60 minutes. To the bottle, 60ml of 37°C water was added and allowed to mix for 15 minutes at 37°C. Once in solution the fibrinogen was dialyzed against incomplete fibrinogen buffer (IFB, which was CFB without HSA and Tween™) for 4 hours at room temperature. At the end of the four hours HSA was added to a concentration of 80mg/g of total protein, and Tween™ 80 (animal source) was added to a concentration of 15mg/g total protein. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was then adjusted to 37.5mg/m with CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ± 0.1. Using CTB, the thrombin concentrations were adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.083 and 0.0625 units/mg of Fibrinogen (upon mixing) which corresponded to 624, 62.4, 31.2, 20.8 and 15.6 Units/ml thrombin prior to mixing. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Molds were removed from the -80 deg C freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3ml syringe fitted with an 18 gauge needle was filled with 2ml of fibrinogen and a second Iml syringe fitted with a 22 gauge needle was filled with 0.3ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. Example 10 Backing material was placed into 2.4 X 2.4cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the molds and held in place by clips located at each end of the mold, producing closed molds. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. Fibrinogen (ERL lot 3060 was formulated in CFB. The final pH of the fibrinogen was 7.4 ± 0.1. The fibrinogen concentration was adjusted to 37.5mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. Using CTB, thrombin concentrations were adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.083 and 0.062 units/mg of Fibrinogen (after mixing), which corresponded to 624, 62.4, 31.2, 20.8, and 15.6 Units/ml thrombin (prior to mixing). Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Molds were removed from the -80 deg C freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3ml syringe fitted with an 18 gauge needle was filled with 2ml of fibrinogen and a second, Iml, syringe fitted with a 22 gauge needle was filled with 0.3ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. Example 11 Backing material was placed into 2.4 X 2.4cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the 2.4 X 2.4 molds and held in place by the use of clips located at each end of the mold to create closed molds. The molds were then placed in a -80 deg C freezer for at least 60 minutes. A vial containing 3 grams of Fibrinogen (Sigma Lo t# F-3879) was removed the -20 deg C freezer and placed at 4°C for 18 hours. The bottle was then removed from the freezer and allowed to come to room temperature for 60 minutes. To the bottle, 60ml of 37°C water was added and allowed to mix for 15 minutes at 37°C. Once in solution the fibrinogen was dialyzed against IFB. At the end of the four hours HSA was added to a concentration of 80mg/g of total protein, and Tween™ 80 (animal source) was added to a concentration of 15mg/g total protein. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was adjusted to 37.5mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ± 0.1. Thrombin concentration was adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.1 and 0.083 units/mg of Fibrinogen (upon mixing), which corresponded to 624, 62.4, 31.2, 24.96 and 20.79 Units/ml thrombin (before mixing). Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C, Molds were removed from the -80 deg C freezer and placed on an aluminum plate that was that was pre-cooled on top of dry ice. A 3ml syringe fitted with an 18 gauge needle was filled with 2ml of fibrinogen and a second, Iml, syringe fitted with a 22 gauge needle was filled with 0.3ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. Example 12 Backing material was placed into 2.4 x 2.4cm PVC molds. Twenty-five microliters of 2% sucrose was pipetted on top of each of the four corners of the backing material. A second piece of PETG plastic was cut to fit on top of the molds and held in place by the use of clips located at each end of the mold to create closed molds. Once completed, the molds were placed in a -80 deg C freezer for at least 60 minutes. A vial containing 3 grains of Fibrinogen (Sigma™ Lot# F-3879) was removed from the -20 deg C freezer and placed at 4°C for 18 hours. The bottle was then allowed to come to room temperature for 60 minutes. To the bottle, 60ml of 37°C water was added and allowed to mix for 20 minutes at 37°C. Once in solution, the fibrinogen was dialyzed against IFB. At the end of the four hours, human serum albumin (HSA) was added to a concentration of 80mg/g of total protein, and Tween™ 80 (animal source) was added to a concentration of 15mg/g total protein. The final pH of the fibrinogen was 7.4 ±0.1. The fibrinogen concentration was adjusted to 37.5mg/ml using CFB. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in CTB. The final pH of the thrombin was 7.4 ±0.1. Thrombin was adjusted to deliver the following amounts 2.5, 0.25, 0.125, 0.08 and 0.06 units/mg of Fibrinogen (after mixing), which corresponded to 624, 62.4, 31.2, 20.8 and 15.6 Units/ml thrombin (prior to mixing). Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C ± 2°C. Molds were removed from the -80 deg C freezer and placed on an aluminum plate that was that was precooled on top of dry ice. A 3ml syringe fitted with an 18 gauge needle was filled with 2ml of fibrinogen and a second, Iml, syringe fitted with a 22 gauge needle was filled with 0.3ml of thrombin. The contents of both syringes were dispensed simultaneously into each mold. Once filled the molds were placed on top of liquid nitrogen for thirty seconds and then returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. They were then lyophilized as described below, and performance tested using the EVPA and Adherence Assays as described below. Trilayer (Sandwich) Dressings Trilayer dressings were produced using the process described in US Patent 6,762,336, using the same sources of fibrinogen and thrombin as utilized to produce the monolithic dressings above. Results The results of the EVPA and Adherence Assays are shown in Figures 4A and 4B, respectively. Conclusions (Examples 6-12): Dressings produced with between 2.5 to 0.025 thrombin Units/mg of fibrinogen were active in both assays, while those with greater or lesser ratios of thrombin to fibrinogen were not. Significantly greater activity was seen over the range of 2.5 to 0.05 thrombin Units/mg of fibrinogen. Greatly improved performance was seen between the ranges of 0.25 to 0.062 thrombin Units/mg of fibrinogen, while optimum performance was seen between the ranges of 0.125 to 0.08 thrombin Units/mg of fibrinogen. This contrasted with the dressings produced using the process described in U.S. Patent No. 6,762,336 which reached full performance at 12.5 thrombin Units/mg of fibrinogen, with unacceptable performance occurring as the thrombin concentration was diminished below 12.5 thrombin Units/mg of fibrinogen, with essentially no activity remaining at 1.4 thrombin Units/mg of fibrinogen. This difference in both the limits of performance and the optimum levels is all the more profound given that the performance of the trilayer dressings from U.S. Patent No. 6,762,336 was decreased by the use of decreasing amounts of thrombin, while the dressing described herein showed an increased activity over this range. Example 13 Backing material was cut and placed into each PETG 2.4 X 2.4cm mold. Twenty- five microliters of 2% sucrose was pipeted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80°C freezer for at least 60 minutes. Enzyme Research Laboratories (ERL) fibrinogen lot 3114 was formulated in CFB. In addition, HSA was added to 80mg/g of total protein and Tween 80 (animal source) was added to 15mg/g total protein. The final pH of the fibrinogen was 7.4 +/- 0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Once prepared the fibrinogen was placed on ice until use. Thrombin was formulated in 150mM Sodium Chloride, 4OmM Calcium Chloride, 10mM Tris and 10OmM L-Lysine with the addition of Human Serum Albumin at lOOug/mL The final pH of the thrombin was 7.4 +/- 0.1. The thrombin was adjusted to deliver 0.1 units/mg of fibrinogen or 25 Units/ml thrombin. Once prepared the thrombin was placed on ice until use. The temperature of the fibrinogen and thrombin prior to dispensing was 4°C +/- 2°C. Molds were removed from the -80 deg C freezer and placed on an aluminum plate that was placed on top of dry ice. A repeat pipettor was filled with fibrinogen and second repeat pipettor was filled with thrombin. Simultaneously 2ml of fibrinogen and 300 micro liters of thrombin were dispensed into each mold. Once the molds were filled they were returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. One group of dressings was lyophylized on day 0, while the remainders were kept frozen at -80 deg C. A second group of dressings were lyophylized on day seven and a third group was lyophylized on day fourteen. Once all the dressings had been lyophylized, they were tested using the EVPA, Adherence, and Weight Assays described herein. Results: (Table Removed) Conclusions: The compositions of fully mixed, frozen fibrinogen and thrombin remained stable and functional for 7 and 14 days, with no apparent degradation in their performance. Longer storage would be expected to produce similar results. These results are shown graphically in Figures 5A and 5B. Example 14 Backing material was cut and placed into each PETG 2.4 X 2.4cm mold. Twenty- five microliters of 2% sucrose was pipeted on top of each of the four corners of the backing material. Once completed the molds were placed in a -80 deg C freezer for at least 60 minutes. Dressings Group 1 (no Albumin, no Tween 80): Enzyme Research Laboratories (ERL) Fibrinogen lot 3130 was formulated in 10OmM Sodium Chloride, LlmM Calcium Chloride, 1OmM Trjs, 1OmM Sodium Citrate, and 1.5% Sucrose. The final pH of the fibrinogen was 7.4 +/- 0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Dressings Group 2 (no Albumin, Tween 80): ERL Fibrinogen was formulated in 10OmM Sodium Chloride, I.ImM Calcium Chloride, 1OmM Tris, 1OmM Sodium Citrate, and 1.5% Sucrose. Tween 80 (animal source) was added to 15mg/g total protein. The final pH of the fibrinogen was 7.4 +/- 0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Dressings Group 3 (Albumin, no Tween 80): ERL Fibrinogen was formulated in 10OmM Sodium Chloride, I.ImM Calcium Chloride, 1OmM Tris, 1OmM Sodium Citrate, and 1.5% Sucrose. HSA was added to 80mg/g of total protein. The final pH of the fibrinogen was 7.4 +/- 0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Dressings group 4 (Albumin, Tween 80): ERL Fibrinogen was formulated in 100mM Sodium Chloride, I.ImM Calcium Chloride, 1OmM Tris, 1OmM Sodium Citrate, and 1.5% Sucrose (Fibrinogen complete buffer). In addition, HSA was added to 80mg/g of total protein and Tween 80 (animal source) was added to 15mg/g total protein. The final pH of the fibrinogen was 7.4 +/- 0.1. The fibrinogen concentration was adjusted to 37.5mg/ml. Once prepared, the fibrinogen solutions were placed on ice until use. Thrombin was formulated in 15OmM Sodium Chloride, 4OmM Calcium Chloride, 1OmM Tris and 100mM L-Lysine with the addition of HSA at 100ug/ml. The final pH of the thrombin was 7.4 +/- 0.1. The thrombin was adjusted to deliver 0.1 Units/mg of fibrinogen or 25 Units/ml thrombin. Once prepared the thrombin solution was placed on ice until use. The temperature of the fibrinogen and thrombin solutions prior to dispensing was 4°C +/- 2°C. Molds were removed from the -80 deg C freezer and placed on an aluminum plate that was placed on top of dry ice. A repeat pipetor was filled with fibrinogen solution and second repeat pipetor was filled with thrombin solution. Simultaneously 2ml of fibrinogen solution and 300 micro liters of thrombin solution were dispensed into each mold. Once the molds were filled they were returned to the -80 deg C freezer for at least two hours before being placed into the freeze dryer. Results: (Table Removed) Conclusions: The results show that the addition of Albumin improved dressing performance. The addition of Tween improved performance even further. The combination of both resulted in the best performance. EVPA Performance Testing Equipment and Supplies: In-line high pressure transducer(Ashcroft Duralife™ or equivalent) Peristaltic pump (Pharmacia Biotech™, Model P-l or equivalent) Voltmeter (Craftsman™ Professional Model 82324 or equivalent) Computer equipped with software for recording pressure or voltage information Tygon™ tubing (assorted sizes) with attachments Water bath (Baxter Durabath™ or equivalent), preset to 37 deg C Incubation chamber (VWR™, Model 1400G or equivalent), preset to 37 degC. Thermometer to monitor temperatures of both water bath and oven Assorted forceps, hemostats, and scissors 10cc. and 20cc. syringes with an approximately 0.6 cm hole drilled in center and smaller hole drilled through both syringe and plunger. This hole, drilled into the end of the syringe, will be used to keep the plunger drawn back and stationary. O-rings (size 10 and 13) Plastic Shields to fit the 10cc and 20cc syringes (approximately 3.5 cm in length) P-1000 Pipetman™ with tips Sphygmomanometer with neonatal size cuff and bladder Programmable Logic Controller (PLC) to control the pumps to maintain the desired pressure profile (Optional. Manual control may be used if desired.) 1. Materials and Chemicals Porcine descending aortas (Pel-Freez Biologicals™, Catalog # 59402- 2 or equivalent) Cyanoacrylate glue (Vetbond™, 3M or equivalent) 18-gauge needle(s) 0.9% Saline, maintained at 37 deg C Red food coloring Vascular Punch(es), 2.8mm or other Plastic Wrap 2. Artery Cleaning and Storage 1. Store arteries at -20 deg C until used. 2. Thaw arteries at 37°C in H2O bath. 3. Clean fat and connective tissue from exterior surface of artery. 4. Cut the arteries into —5cm segments. 5. The arteries may be refrozen to -2O deg C and stored until use. 3. Artery Preparation for Assay 1. Turn the artery inside-out so that the smooth, interior wall is facing outwards. 2. Stretch a size 13 O-ring over a 20cc syringe or a size 10 O-ring over a 1Occ syringe with an approximately 0,6 cm (0.25 in) hole drilled into one side. 3. Pull the artery onto the syringe, taking care not to tear the artery or have a too loose fit The artery should fit snugly to the syringe. Slide another O-ring of the same size onto the bottom of the syringe 4. Carefully pull both 0-rings over the ends of the artery. The distance between the O-rings should be at least 3.5 cm 5. Using the blade of some surgical scissors, gently scrape the surface of the artery in order to roughen the surface of the artery. 6. Use a 18-gauge needle to poke a hole through the artery over the site of the hole in the syringe barrel (see note above) 7. The tip of the biopsy punch is inserted through the hole in the artery. Depress the punch's plunger to make an open hole in the artery. Repeat a couple of times to ensure that the hole is open and free of connective tissue. 8. Patch holes left by collateral arteries. Generally this is done by cutting a patch from a latex glove and gluing it over the hole with cyanoacrylate glue. Allow the glue to cure for at least 10 minutes. 9. Place the artery in the warmed, moistened container and place in the incubation chamber. Allow the arteries to warm for at least 30 minutes. 4. Solution and Equipment Preparation 1. Check to see that the water bath and incubation chamber are maintained at 29-33°C. 2. Make sure that there is sufficient 0.9% saline in the pump's reservoir for completion of the day's assays. Add more if needed. 3. Place 0.9% saline and 0.9% saline with a few drops of red food coloring added into containers in a water bath so that the solutions will be warmed prior to performing the assay. 4. Prepare the container for warming the arteries in the incubation chamber by lining with Kim Wipes™ and adding a small amount of water to keep the arteries moist. 5. Check the tubing for air bubbles. If bubbles exist, turn on the pump and allow the 0.9% saline to flow until all bubbles are removed. 5. Application of the Dressing 1. Open the haemostatic dressing pouch and remove haemostatic dressing 2. Place the haemostatic dressing, mesh backing side UP, over the hole in the artery 3. Slowly wet the haemostatic dressing with an amount of saline appropriate for the article being tested NOTE: A standard (13-15 tag/ cm2 of fibrinogen) 2.4 x 2.4 cm haemostatic dressing should be wet with 800 µl of saline or other blood substitute. The amount of saline used can be adjusted depending on the requirements of the particular experiment being performed; however, any changes should be noted on the data collection forms. NOTE: Wet the haemostatic dressing drop wise with 0.9% saline warmed to 29-33°C or other blood substitute, taking care to keep the saline from running off the edges. Any obvious differences in wetting characteristics from the positive control should be noted on data collection forms. 4. Place the shield gently onto the haemostatic dressing, taking care that it lies flat between the O-rings. Press lightly to secure in place 5. Wrap the artery and haemostatic dressing with plastic wrap 6. Wrap with blood pressure cuff, taking care that the bladder is adjacent to the haemostatic dressing. 7. Pump up the bladder to 100-120 mmHg, and monitor the pressure and pump again if it falls below 100 mmHg. Maintain pressure for 5 minutes. NOTE: Time and pressure can be altered according to the requirements of the experiment; changes from the standard conditions should be noted on the data collection forms. 8. After polymerization, carefully unwrap the artery and note the condition of the haemostatic dressing. Any variation from the positive control should be noted on the data collection form. EXCLUSION CRITERION: The mesh backing must remain over the hole in the artery. If it has shifted during the polymerization and does not completely cover the hole the haemostatic dressing must be excluded. Testing Procedure 1. Diagram of testing equipment set-up The set-up of the testing equipment is shown in Figure 2. Some additional, unshown components may be utilized to read out (pressure gauge) or control the pressure within the system. 2. Equipment and Artery Assembly Fill the artery and syringe with red 0.9% saline warmed to 37°C, taking care to minimize the amount of air bubbles within the syringe & artery. Filling the artery with the opening uppermost can assist with this. Attach the artery and syringe to the testing apparatus, making sure that there are as few air bubbles in the tubing as possible. The peristaltic pump should be calibrated so that it delivers approximately 3 ml/min. If available, the PLC should be operated according to a pre-determined range of pressures and hold times as appropriate for the article being tested. If under manual control, the pressure/time profile to be followed is attained by manually turning the pump on and off while referencing the system pressure as read out by one or more pressure-reading components of the system. Following the conclusion of testing, the haemostatic dressing is subjectively assessed with regard to adhesion to the artery and formation of a plug in the artery hole. Any variations from the positive control should be noted on the data coDection form. Success Criteria Haemostatic dressings that are able to withstand pressures for 3 minutes are considered to have passed the assay. When a haemostatic dressing has successfully passed the assay the data collection should be stopped immediately so that the natural decrease in pressure that occurs in the artery once the test is ended isn't included on the graphs. Should the operator fail to stop data collection, these points can be deleted from the data file to avoid confusing the natural pressure decay that occurs post-test with an actual dressing failure. The entire testing period from application of the haemostatic dressing to completion must fall within pre-established criteria. The maximum pressure reached should be recorded on the data collection form. NOTE: Typical challenge is 250 mmHg for three minutes in one step, but that may be altered based on the article being tested. Changes from the standard procedure should be noted on the data collection forms. Failure Criteria Haemostatic dressings that start leaking saline at any point during testing are considered to have failed the assay. NOTE: Build failures that are caused by artery swelling can be ignored and the test continued or re-started (as long as the total testing time doesn't fall beyond the established limit). When leakage does occur, the pressure should be allowed to fall ~20 mmHg before data collection is stopped so that the failure is easily observed on the graphs. The pressures at which leakage occurred should be recorded on the data collection form. Should the data collection stop in the middle of the experiment due to equipment failure the data can be collected by hand at 5 second intervals until the end of the test or haemostatic dressing failure, whichever happens first. The data points should be recorded on the back of the data collection form, clearly labeled, and entered by hand into the data tables. Exclusion Criteria If the total testing period exceeds the maximum allowed for that procedure, regardless of cause, results must be excluded. If there are leaks from collaterals that can't be fixed either by patching or finger pressure the results must be excluded. If the test fails because of leaks at the O-rings, the results must be excluded. If the mesh backing does not completely cover the hole in the artery, the results must be excluded. Adherence Performance Testing 1. Equipment and Supplies Hemostat(s), Porcine artery and haemostatic dressing (usually after completion of the EVPA Assay although it does not need to be performed to do the Adherence Assay) I. Preparation of the Artery + Dressing After application of the dressing without completion of the EVPA Assay, the dressing is ready for the Adherence Assay and Weight limit Test (if applicable). After application of the dressing and subsequent EVPA Analysis, the artery and syringe system is then disconnected slowly from the pump so that solution does not spray everywhere. The warmed, red saline solution from the EVPA Assay remains in the syringe until the Adherence Assay and Weight limit Test (if applicable) is completed. Performance of the Adherence Assay 1. After preparation of the artery and dressing (with or widiout EVPA analysis), gently lift the corner of the mesh and attach a hemostat of known mass to the corner. NOTE: If the FD developed a channel leak during the performance of the EVPA Assay, test the adherence on the opposite of the haemostatic dressing to obtain a more accurate assessment of the overall adherence. 2. Gently let go of the hemostat, taking care not to allow the hemostat to drop or twist. Turn the syringe so mat the hemostat is near the top and allow the hemostat to peel back the dressing as far as the dressing will permit. This usually occurs within 10 seconds. After the hemostat has stopped peeling back the dressing, rate the adherence of the bandage according to the following scale. (Table Removed) Exclusion Criteria The mesh backing must remain over the hole in the artery. If it has shifted during the polymerization and does not completely cover the hole the haemostatic dressing must be excluded. Success Criteria Dressings that are given an adherence score of 3 are considered to have passed the assay. Failure Catena If a dressing does not adhere to the artery after application and/or prior to performing the EVPA assay, it is given a score of 0 and fails the adherence test. If a dressing receives a score ≤2, the dressing is considered to have failed the Adherence Assay. Weight Held Performance Assay After the initial scoring of the "Adherence Test", weights may then be added to the hemostat in an incremental manner until the mesh backing is pulled entirely off of the artery. The maximum weight that the dressing holds is then recorded as a measure of the amount of weight the dressing could hold attached to the artery. Moisture Assay Moisture determinations were carried out using a Bπnkman Metrohm Moisture Analyzer System. The system contains the following individual components, 774 Oven Sample Processor, 774SC Controller, 836 Titrando, 5rnl and 50ml 800 Dosino Units and a 801 Stirrer. The system was connected to a computer using the Bdnkman Tiamo software for data collection, analysis and storage. The moisture system is set-up and run according to the manufactures recommendations and specifications to measure the moisture content of lyophilized samples using the Karl Fischer method. All components were turned on and allowed to reach operating temperature prior to use. Lactose and water were run as standards and to calibrate the instrument. Once the machine was successfully calibrated, samples were prepared as follows. Dressing pieces weighing at least 30mg were placed into vials and capped. The vials were placed in the 774 Oven Sample Processor in numerical order, and one empty capped vial is placed in the conditioning space. The machine was then run to determine the moisture content (residual moisture) in the controls and samples. SDS-PAGE Gel Electrophoresis Each dressing is cut into VA 'S, approximately 50 mg per section, and a section is then placed into a 15 ml conical tube. For the production control (ie Time 0), 1.0 mL of Okuda Dissolving Solution (10 M Urea, 0.1% Sodium Dodecyl Sulfate, 0.1% ß-Mercaptoethanol) is added. For the remaining 3 pieces, 80 µL of 0.9% Saline is added to wet the dressing. The pieces are then incubated at 37°C for 2, 5, and 10 minutes or such time as desired. To stop the reaction at the desired time, 1.0 mL of the Okuda Dissolving solution is added. The samples are then incubated at room temperature overnight, and men incubated at 7O deg C for 30 minutes. To prepare the samples for loading onto the gel, the samples which were previously dissolved in the Okuda Dissolving Solution were added to Sample buffer so that a 20 µL aliquot contains 10 µg. One µL of 0.1 M Dithiothreitol was men added to each sample. Twenty µL of each diluted sample is then loaded onto an 8% Tηs-Glycine gel (Invitrogen), 1.0 mm thick, 10 wells. The gels were then run at 140V until the dye front reached the end of the gel. They were then removed and placed into Coomassie Blue Stain (50% v/v Methanol, 0.25% w/v Coomassie Brilliant Blue, 10% w/v Acetic Acid in ddH2O) on a shaking platform for a minimum of 1 hour. The gel is then transferred to the Destain Solution (25% Medianol, 10% Acetic Acid, 65% ddH2O) on a shaking platform until the background is nearly colorless. After destaining, the gels were scanned, and the γ-γ dimer bands and the Aa, and BP bands analyzed by Scion densitometry software in order to determine the amount of conversion that occurred. We Claim: 1. A solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein said haemostatic layer is formed from a single aqueous solution containing said fibrinogen component and said fibrinogen activator. 2. A solid dressing for treating wounded tissue in a mammal comprising at least one haemostatic layer consisting essentially of a fibrinogen component and a fibrinogen activator, wherein said haemostatic layer is cast as a single piece. 3. The solid dressing of claim 1 or 2, further comprising at least one support layer. 4. The solid dressing of claim 3, wherein said support layer comprises a backing material. 5. The solid dressing of claim 3, wherein said support layer comprises an internal support material. 6. The solid dressing of claim 3, wherein said support layer comprises a resorbable material. 7. The solid dressing of claim 3, wherein said support layer comprises a non-resorbable material. 8. The solid dressing of claim 7, wherein said non-resorbable material is selected from the group consisting of silcone polymers, paper, gauze and latexes. 9. The solid dressing of claim 3, further comprising at least physiologically acceptable adhesive between said haemostatic layer and said backing layer. 10. The solid dressing of claim 6, wherein said resorbable material is selected from the group consisting of proteinaceous materials and carbohydrate substances. 11. The solid dressing of claim 10, wherein said proteinaceous material is at least one substance selected from the group consisting of keratin, silk, fibrin, collagen and gelatin. 12. The solid dressing of claim 10, wherein said carbohydrate substance is selected from the group consisting of alginic acid and salts thereof, chitin, chitosan, cellulose, n-acetyl glucosamine, proteoglycans, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co- polymers and mixtures of two or more thereof. 13. The solid dressing of claim 1 or 2, wherein said haemostatic layer also contains a fibrin cross-linker and/or a source of calcium ions. 14. The solid dressing of claim 1 or 2, wherein said haemostatic layer also contains one or more of the following: at least one filler; at least one solubilizing agent; at least one foaming agent; and at least one release agent 15. The solid dressing of claim 14, wherein said filler is selected from the group consisting of sucrose, lactose, maltose, keratin, silk, fibrin, collagen, gelatin, albumin, polysorbate, chitin, chitosan., alginic acid and salts thereof, cellulose, proteoglycans, glycolic acid polymers, lactic acid polymers, glycolic acid/lactic acid co-polymers, and mixtures of two or more thereof. 16. The solid dressing of claim 14, wherein said solubilizing agent is selected from the group consisting of sucrose, lactose, maltose, dextrose, mannose, trehalose, mannitol, sorbitol, albumin, sorbate, polysorbate, and mixtures of two or more thereof. 17. The solid dressing of claim 14, wherein said release agent is selected from the group consisting of gelatin, mannitol, sorbitol, polysorbate, sorbitan, lactose, maltose, trehalose, sorbate, glucose and mixtures of two or more thereof. 18. The solid dressing of claim 14, wherein said foaming agent is selected from the group consisting of mixtures of sodium bicarbonate/citric acid, sodium bicarbonate/acetic acid, calcium carbonate/citric acid and calcium carbonate/acetic acid. 19. The solid dressing of claim 1 or 2, wherein said haemostatic layer also contains at least one therapeutic supplement selected from the group consisting of antibiotics, anticoagulants, steroids, cardiovascular drugs, growth factors, antibodies (poly and mono), chemoattractants, anesthetics, antiproliferatives/antitumor agents, antivirals, cytokines, colony stimulating factors, antifungals, antiparasitics, antiinflammatories, antiseptics, hormones, vitamins, glycoproteins, fibronectin, peptides, proteins, carbohydrates, proteoglycans, antiangiogeruns, antigens, nucleotides, lipids, liposomes, fibrinolysis inhibitors and gene therapy reagents. 20. The solid dressing of claim 19, wherein said therapeutic supplement is present in an amount equal to or greater than its solubility limit in fibrin. 21. The solid dressing of claim 3, wherein said haemostatic layer further contains at least one binding agent in an amount effective to improve the adherence of said haemostatic layer to said support layer. 22. The solid dressing of claim 21, wherein said binding agent is selected from the group consisting of sucrose, mannitol, sorbitol, gelatin, maltose, povidone, chitosan and carboxymethylcellulose.. 23. The solid dressing of claim 1 or 2, wherein said haemostatic layer is substantially homogeneous throughout. 24. The solid dressing of claim 1 or 2, wherein said haemostatic layer is a monolith. 25. The solid dressing of claim 1 or 2, wherein said haemostatic layer has been lyophilized. 26. The solid dressing of claim 1 or 2, wherein said haemostatic layer has moisture content of at least 6%. 27. The solid dressing of claim 1 or 2, wherein said haemostatic layer has moisture content of less than 6%. 28. The solid dressing of claim 1 or 2, wherein said fibrinogen component is a mammalian fibrinogen. 29. The solid dressing of claim 28, wherein said mammalian fibrinogen is selected from the group consisting of bovine fibrinogen, porcine fibrinogen, ovine fibrinogen, equine fibrinogen,, caprine fibrinogen, feline fibrinogen, canine fibrinogen, murine fibrinogen and human fibrinogen. 30. The solid dressing of claim 1 or 2, wherein said fibrinogen component is selected from the group consisting of bird fibrinogen and fish fibrinogen. 31. The solid dressing of claim 1 or 2, wherein said fibrinogen component is selected from the group consisting of human fibrinogen, human fibrin I, human fibrin II, human fibrinogen a chain, human fibrinogen ß chain, human fibrinogen γ chain, and mixtures of two or more thereof. 32. The solid dressing of claim 28, 30 or 31, wherein said fibrinogen is selected from the group consisting of recombinantly produced fibrinogen and transgenic fibrinogen. 33. The solid dressing of claim 28, wherein said mammalian fibrinogen is present in an amount between 1.5 mg/cm2 of the wound-facing surface of said dressing and 13.0 mg/cm2 of the wound- facing surface of said dressing. 34. The solid dressing of claim 1 or 2, wherein said fibrinogen activator is selected from the group consisting of thrombins, prothrombins, snake venoms, and mixtures of any two or more thereof. 35. The solid dressing of claim 34, wherein said thrombin is mammalian thrombin. 36. The solid dressing of claim 35, wherein said mammalian thrombin is selected from the group consisting of bovine thrombin, porcine thrombin, ovine thrombin, equine thrombin, caprine thrombin, feline thrombin, canine thrombin, murine thrombin and human thrombin. 37. The solid dressing of claim 34, wherein said thrombin is selected from the group consisting of bird thrombin and fish thrombin. 38. The solid dressing of claim 35 or 37, wherein said thrombin is selected from the group consisting of recombinantly produced thrombin and transgenic thrombin. 39. The solid dressing of claim 34, wherein said thrombin is present in an amount between 2.50 Units/mg of said fibrinogen component and 0.025 Units/mg of said fibrinogen component. 40. A method of treating wounded tissue in a mammal, comprising placing a solid dressing of claim 1 or 2 to said wounded tissue and applying sufficient pressure to said dressing for a sufficient time for enough fibrin to form to reduce the loss of blood and/or other fluid from said wounded tissue. 41. A composition of matter consisting essentially of a mixture of fibrinogen component, a fibrinogen activator and water, wherein said mixture is frozen and is stable at a temperature of less than 0°C for at least 24 hours. 42. The composition of claim 41, wherein said mixture also contains one or more of the following: at least one binding agent, at least one filler; at least one solubilizing agent; at least one foaming agent; and at least one release agent 43. The composition of claim 41, wherein said mixture also contains at least one therapeutic supplement selected from the group consisting of antibiotics, anticoagulants, steroids, cardiovascular drugs, growth factors, antibodies (poly and mono), chemoattractants, anesthetics, antiproliferatives/antitumor agents, antivirals, cytokines, colony stimulating factors, antifungals, antiparasitics, antiinflammatories, antiseptics, hormones, vitamins, glycoproteins, fibronectin, peptides, proteins, carbohydrates, proteoglycans, antiangiogenins, antigens, nucleotides, lipids, liposomes, fibrinolysis inhibitors and gene therapy reagents. 44. A solid dressing for treating wounded tissue substantially as hereinbefore described with reference to the accompnaying drawings.

Documents:

1394-delnp-2009-abstract.pdf

1394-delnp-2009-Claims-(21-07-2014).pdf

1394-delnp-2009-claims.pdf

1394-delnp-2009-Correspondence Others-(11-08-2014).pdf

1394-delnp-2009-Correspondence Others-(21-07-2014).pdf

1394-delnp-2009-Correspondence Others-(22-07-2014).pdf

1394-DELNP-2009-Correspondence-181214.pdf

1394-delnp-2009-correspondence-others.pdf

1394-delnp-2009-description (complete).pdf

1394-delnp-2009-drawings.pdf

1394-delnp-2009-form-1.pdf

1394-delnp-2009-Form-13-(21-07-2014).pdf

1394-delnp-2009-form-18.pdf

1394-delnp-2009-form-2.pdf

1394-delnp-2009-Form-3-(21-07-2014).pdf

1394-delnp-2009-form-3.pdf

1394-delnp-2009-form-5.pdf

1394-delnp-2009-pct-210.pdf

1394-delnp-2009-pct-237.pdf

1394-delnp-2009-pct-304.pdf