Resources Contact Us Home Browse by: INVENTOR PATENT HOLDER PATENT NUMBER DATE     Supplemented and unsupplemented tissue sealants, methods of their production and use RE39298 Supplemented and unsupplemented tissue sealants, methods of their production and use Patent Drawings: Inventor: MacPhee, et al. Date Issued: September 19, 2006 Application: 10/465,860 Filed: June 20, 2003 Inventors: MacPhee; Martin J. (Montgomery Village, MD) Drohan; William N. (Springfield, VA) Liau; Gene (Darnestown, MD) Nunez; Hernan (Derwood, MD) Burgess; Wilson H. (Clifton, VA) Maciag; Thomas (Freeport, ME) Singh; Manish (San Diego, CA) Assignee: The American National Red Cross (Rockville, MD) Primary Examiner: Witz; Jean C. Assistant Examiner: Attorney Or Agent: Sterne, Kessler, Goldstein, & Fox P.L.L.C. U.S. Class: 424/426; 424/400; 424/422; 424/423; 424/425; 424/488; 424/499; 424/78.06; 424/78.07; 530/380; 530/381; 530/382 Field Of Search: 424/426; 424/78.06; 424/78.07; 424/400; 424/422; 424/423; 424/425; 424/488; 424/499; 530/380; 530/381; 530/382; 623/16; 623/18; 623/19; 623/20; 623/21; 623/22; 623/23 International Class: A61K 35/14; A61F 2/28; A61K 31/74 U.S Patent Documents: 2492458; 2533004; 3089815; 3523807; 3723244; 4265233; 4298598; 4321711; 4359049; 4362567; 4373519; 4377159; 4377572; 4393041; 4394370; 4407787; 4414976; 4427650; 4427651; 4442655; 4453939; 4472840; 4516276; 4548736; 4597960; 4600574; 4606337; 4617293; 4619913; 4619989; 4627879; 4631055; 4642120; 4650678; 4708861; 4714457; 4717717; 4761471; 4789732; 4816339; 4820626; 4837379; 4853225; 4861757; 4874746; 4904259; 4909251; 4928603; 4952403; RE33375; 4969880; 4983581; 4997425; 5019559; 5023082; 5024742; 5030215; 5034375; 5035887; 5059123; 5100396; 5124155; 5139527; 5171318; 5171579; 5176916; 5185001; 5206023; 5209776; 5219328; 5226877; 5260420; 5290552; 5294314; 5306311; 5364839; 5366958; 5368858; 5395923; 5407671; 5411894; 5420250; 5428014; 5431790; 5464471; 5505945; 5534557; 5549904; 5552452; 5607694; 5612456; 5716645; 5763411; 5962420; 6117425; 6124273; 6197325 Foreign Patent Documents: B-83581/82; B-43122/85; 554041; B-75097/87; 576365; B-91093/91; 1119516; 1 168 982; 3037270; 231 987; 0 081 990; 0 312 208; 0 341 007; 0 443 724; 0 485 210; 0 562 864; 1 584 080; 2 041 942; 2 042 556; 2 102 811; 2 137 209; 2 102 811; 2 185 747; 54-104687; 55-104687; 55-110556; 55-110557; 57-153645; 58-38216; 58-38217; 59-192364; 60-204725; 62-246370; 63-24951; 63-115564; 64-86974; 1-99565; 2-114; 2-71750; 2-167234; 81/00516; 86/00526; 86/01814; 86/03122; WO 88/03409; WO 89/05656; WO 89/11293; WO 90/01331; WO 91/00046; WO 91/00046; 91/09573; 91/17744; WO 92/09301; 92/09697; WO 92/13547; WO 92/13565; WO 92/17206; 92/22312; WO 93/05067; WO 94/20133; WO 96/17633 Other References: MacPhee, M., "Fibrin Sealant Based Bandages and Foam: Hemostatic Devices for Treatment of Combat Casualties on the Battlefield," Presented atthe Advanced Technology Applications to Combat Casualty Care (ATACCC) conference (May 1995). cited by examiner. 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Abstract: This invention provides methods for the localized delivery of supplemented tissue sealants, wherein the supplemented tissue sealants comprise at least one composition which is selected from one or more antibodies, analgesics, anticoagulants, anti-inflammatory compounds, antimicrobial compositions, antiproliferatives, cytokines, cytotoxins, drugs, growth factors, interferons, hormones, lipids, demineralized bone or bone morphogenetic proteins, cartilage inducing factors, oligonucleotides polymers, polysaccharides, polypeptides, protease inhibitors, vasoconstrictors or vasodilators, vitamins, minerals, stabilizers and the like. Further provided are methods of using the site-specific supplemented tissue sealants, including preparation of a biomaterial. Claim: What is claimed is: 1. A method of localized sustained delivery of a supplement to promote generation or regeneration of bone and/or cartilage, said method comprising: (a) preparing abiocompatible, supplemented tissue sealant composition comprising: (i) at least one supplement selected from the group consisting of a cytotoxin or cell proliferation inhibiting compound, an osteogenic compound, an osteo-conductive compound, a cartilageinducing compound, an oligonucleotide or polynucleotide, a compound that inhibits the differentiation of cells involved in the formation or metabolism of bone, a compound that induces the differentiation of cells involved in the formation or metabolismof bone, and a compound that prevents resorption of bone, in an amount which promotes generation or regeneration of bone and/or cartilage; and (ii) fibrinogen, or a derivative or metabolite thereof selected from the group consisting of fibrin I andfibrin II, in an amount which forms a fibrin matrix in the presence of thrombin and Ca.sup.++ and water; and (b) applying said composition of step (a) to a site in need of newly formed bone and/or cartilage under conditions which induce formation of afibrin matrix at a concentration which provides sustained delivery of an amount of said supplement effective to promote the generation or regeneration of bone and/or cartilage, wherein said amount of said supplement is greater than the amount which issoluble in said fibrin matrix; and wherein said fibrin matrix provides a scaffold that determines the shape and location of said newly formed bone and/or cartilage; and further wherein said sustained delivery is for a period greater than the periodobtained according to simple diffusion kinetics. 2. A method of localized sustained delivery of a supplement to promote generation or regeneration of bone and/or cartilage, said method comprising: (a) preparing a biocompatible, supplemented tissue sealant composition comprising: (i) at leastone growth factor supplement in an amount which promotes generation or regeneration of bone and/or cartilage; and (ii) fibrinogen, or a derivative or metabolite thereof selected from the group consisting of fibrin I and fibrin II, in an amount whichforms a fibrin matrix in the presence of thrombin and Ca.sup.++ and water; and (b) applying said composition of step (a) to a site in need of newly formed bone and/or cartilage under conditions which induce formation of a fibrin matrix at aconcentration which provides sustained delivery of an amount of said growth factor supplement effective to promote the generation or regeneration of bone and/or cartilage; wherein said fibrin matrix provides a scaffold that determines the shape andlocation of said newly formed bone and/or cartilage; and further wherein said sustained delivery is for a period greater than the period obtained according to simple diffusion kinetics. 3. A method of localized sustained delivery of a supplement to promote generation or regeneration of bone and/or cartilage, said method comprising: (a) preparing a biocompatible, supplemented tissue sealant composition comprising: (i) at leastone supplement selected from the group consisting of an osteogenic protein, an osteoconductive protein, a cartilage inducing protein, a polypeptide, a hormone, a cytokine, a cytotoxin or cell proliferation inhibiting protein, a protein that inhibits thedifferentiation of cells involved in the formation or metabolism of bone, a protein that induces the differentiation of cells involved in the formation or metabolism of bone, and a protein that prevents resorption of bone, in an amount which promotesgeneration or regeneration of bone and/or cartilage; and (ii) fibrinogen, or a derivative or metabolite thereof selected from the group consisting of fibrin I and fibrin II, in an amount which forms a fibrin matrix in the presence of thrombin andCa.sup.++ and water; and (b) applying said composition of step (a) to a site in need of newly formed bone and/or cartilage under conditions which induce formation of a fibrin matrix at a concentration which provides sustained delivery of an amount ofsaid supplement effective to promote the generation or regeneration of bone and/or cartilage; wherein said fibrin matrix provides a scaffold that determines the shape and location of said newly formed bone and/or cartilage; and further wherein saidsustained delivery is for a period greater than the period obtained according to simple diffusion kinetics. 4. The method of claim 1, wherein said supplement is an oligonucleotide or polynucleotide. 5. The method of claim 1, wherein said supplement is a cytotoxin or cell proliferation inhibiting compound. 6. The method of claim 1, wherein said supplement is an osteogenic compound or a cartilage inducing compound. 7. The method of claim 2, wherein said supplement is a lipid or liposome. 8. The method of claim 3, wherein said growth factor is selected from the group consisting of: fibroblast growth factors; platelet-derived growth factors; insulin-binding growth factors; epidermal growth factors; transforming growthfactors; cartilage-inducing factors; osteoid-inducing factors; osteogenin; bone growth factors; bone morphogenetic growth factors; collagen growth factors; and heparin-binding growth factors. 9. The method of claim 8, wherein said biocompatible, supplemented tissue sealant composition further comprises at least one regulatory compound selected from the group consisting of inhibiting compounds and potentiating compounds, wherein saidinhibiting compounds inhibit biochemical activities of one or more factors interfering with a biological function of said supplement, while said potentiating compounds potentiate and/or mediate biological activity of said supplement. 10. The method of claim 9, wherein said regulatory compound potentiates and/or mediates the biological activity of said supplement, while simultaneously inhibiting the biochemical activity of one or more factors that interfere with thebiological activity of said supplement. 11. The method of claim 9, wherein said regulatory compound is heparin. 12. The method of claim 9, wherein said regulatory compound interacts with said supplement and/or said fibrin matrix, such that degradation of said fibrin matrix is reduced. 13. The method of claim 3, wherein said supplement is a cytokine. 14. The method of claim 3, wherein said supplement is a hormone. 15. The method of claim 3, wherein said supplement is a polypeptide. 16. The method of claim 3, wherein said supplement is an osteogenic protein, an osteoconductive protein or a cartilage inducing protein. 17. The method of claim 16, wherein said osteogenic protein, osteoconductive protein or cartilage inducing protein is selected from the group consisting of cartilage-inducing factors; osteoid-inducing factors; osteogenin; bone growth factorswhich modulate the proliferation, migration and/or attraction of progenitor bone cells; bone morphogenetic growth factors; demineralized bone matrix; and interleukin. 18. The method of claim 1, 2 or 3, wherein said biocompatible, supplemented tissue sealant composition further comprises a polysaccharide selected from the group consisting of chitin, chitosan and N,O-carboxymethyl chitosan. 19. The method of claim 1, 2 or 3, wherein said biocompatible, supplemented tissue sealant composition is applied to a biomaterial. 20. The method of claim 19, wherein said biomaterial is an indwelling medical device. 21. The method of claim 19, wherein said biomaterial is a resorbable biomaterial. 22. The method of claim 21, wherein said resorbable biomaterial is selected from the group consisting of hydroxyapaptite, coral and collagen. 23. The method of claim 19, wherein said biomaterial is a non-resorbable biomaterial. 24. The method of claim 23, wherein said non-resorbable biomaterial is steel or titanium. 25. The method of claim 1, 2 or 3, wherein said supplement is in solid form. 26. The method of claim 1, 2 or 3, wherein said supplement is introduced in solution in a carrier, said carrier having a higher rate of dissolution or diffusion in said fibrin matrix than said supplement, so that said supplement is depositedwithin said fibrin matrix as a solid precipitate. 27. The method of claim 1, 2 or 3, wherein said supplement is introduced as an emulsion. 28. The method of claim 1, 2 or 3, wherein said supplement interacts with said fibrin matrix and/or said environment of use, such that degradation of said fibrin matrix is reduced. 29. The method of claim 28, wherein said supplement interacts with the body fluids and/or cells of the patient. 30. The method of claim 29, wherein said interaction is pH dependent. 31. The method of claim 1, 2 or 3, wherein said supplement is first dissolved in a carrier which is then introduced as an emulsion. 32. The method of claim 31, wherein said carrier is a lipid. 33. The method of claim 32, wherein said carrier is a lipid-based structure. 34. The method of claim 1, 2 or 3, wherein said biocompatible tissue sealant composition further comprises thrombin. 35. The method of claim 34, wherein said thrombin is recombinantly-produced human thrombin. 36. The method of claim 1, 2 or 3, wherein said biocompatible tissue sealant composition further comprises Factor XIII. 37. The method of claim 36, wherein said Factor XIII is recombinantly-produced human Factor XIII. 38. The method of claim 1, 2 or 3, wherein said biocompatible tissue sealant composition further comprises Ca.sup.++. 39. The method of claim 1, 2 or 3, wherein said fibrinogen is recombinantly-produced human fibrinogen. 40. The method of claim 1, 2 or 3, wherein said biocompatible, supplemented tissue sealant composition further comprises an effective amount of at least one additional supplement selected from the group consisting of an analgesic, ananesthetic, an antimicrobial compound, an antibiotic, an antibody, an anticoagulant, an antifungal agent, an anti-inflammatory compound, an antiparasitic agent, an antiseptic compound, an antiviral compound, a cardiovascular drug, a cytokine, a cytotoxinor cell proliferation inhibiting compound, a chemotherapeutic drug, a growth factor, a hormone, an interferon, a lipid or liposome, an oligonucleotide or polynucleotide, an osteogenic compound, a cartilage inducing compound, a polysaccharide, a proteaseinhibitor, a proteoglycan, a polypeptide, a steroid, a vasoconstrictor, a vasodilator, a vitamin, a nutritional supplement, and a mineral. 41. The method of claim 1, 2 or 3, wherein said site in need of newly formed bone and/or cartilage is a site in a mammalian body. 42. The method of claim 1, 2 or 3, wherein said fibrinogen, or derivative or metabolite thereof, forms a fibrin matrix prior to step (b). 43. The method of claim 1, 2 or 3, wherein said fibrinogen, or derivative or metabolite thereof, forms a fibrin matrix after step (b). 44. The method of claim 1, 2 or 3, wherein said fibrinogen, or derivative or metabolite thereof, forms a fibrin matrix during step (b). 45. The method of claim 1, 2 or 3, wherein said composition of step (a) is dried prior to step (b). 46. The method of claim 45, wherein said fibrin matrix is lyophilized prior to step (b). 47. The method of claim 45, wherein said fibrin matrix is dried prior to step (b). 48. The method of claim 1, 2 or 3, wherein said composition of step (a) is lyophilized prior to step (b). Description: FIELD OF INVENTION This invention is directed to unsupplemented and supplemented Tissue Sealants (TS), such as fibrin glue (FG), as well as to methods of their production and use. In one embodiment, this invention is directed to TSs which do not inhibitfull-thickness skin wound healing. In another embodiment, this invention is directed to TSs which have been supplemented with a growth factor(s) and/or a drug(s), as well as to methods of their production and use. The particular growth factor(s) anddrug(s) that is selected is a function of its use. BACKGROUND OF THE INVENTION A. Wound Healing and Growth Factors Wound healing, the repair of lesions, begins almost instantly after injury. It requires the successive coordinated function of a variety of cells and the close regulation of degradative and regenerative steps. The proliferation, differentiationand migration of cells are important biological processes which underlie wound healing, which also involves fibrin clot formation, resorption of the clot, tissue remodeling, such as fibrosis, endothelialization and epithelialization. Wound healinginvolves the formation of highly vascularized tissue that contains numerous capillaries, many active fibroblasts, and abundant collagen fibrils, but not the formation of specialized skin structures. The process of wound healing can be initiated by thromboplastin which flows out of injured cells. Thromboplastin contacts plasma factor VII to form factor X activator, which then, with factor V and in a complex with phospholipids and calcium,converts prothrombin into thrombin. Thrombin catalyzes the release of fibrinopeptides A and B from fibrinogen to produce fibrin monomers, which aggregate to form fibrin filaments. Thrombin also activates the transglutaminase, factor XIIIa, whichcatalyzes the formation of isopeptide bonds to covalently cross-link the fibrin filaments. Alpha.sub.2-antiplasmin is then bound by factor XIII onto the fibrin filaments to thereby protect the filaments from degradation by plasmin (see, for example,Doolittle et al., Ann. Rev. Biochem. 53:195-229 (1984)). When a tissue is injured, polypeptide growth factors, which exhibit an array of biological activities, are released into the wound where they play a crucial role in healing (see, e.g., Hormonal Proteins and Peptides (Li, C. H., ed.) Volume 7,Academic Press, Inc., New York, N.Y. pp. 231-277 (1979) and Brunt et al., Biotechnology 6:25-30 (1988)). These activities include recruiting cells, such as leukocytes and fibroblasts, into the injured area, and inducing cell proliferation anddifferentiation. Growth factors that may participate in wound healing include, but are not limited to: platelet-derived growth factors (PDGFs); insulin-binding growth factor-1 (IGF-1); insulin-binding growth factor-2 (IGF-2); epidermal growth factor(EGF); transforming growth factor-.alpha. (TGF-.alpha.); transforming growth factor-.beta. (TGF-.beta.); platelet factor 4 (PF4); and heparin binding growth factors one and two (HBGF-1 and HBGF-2, respectively). PDGFs are stored in the alpha granules of circulating platelets and are released at wound sites during blood clotting (see, e.g., Lynch et al., J. Clin. Invest. 84:640-646 (1989)). PDGFs include: PDGF; platelet derived angiogenesis factor(PDAF); TGF-.beta.; and PF4, which is a chemoattractant for neutrophils (Knighton et al., in Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications, Alan R. Liss, Inc., New York, N.Y., pp. 319-329 (1988)). PDGF is amitogen, chemoattractant and a stimulator of protein synthesis in cells of mesenchymal origin, including fibroblasts and smooth muscle cells. PDGF is also a nonmitogenic chemoattractant for endothelial cells (see, for example, Adelmann-Grill et al.,Eur. J. Cell Biol. 51:322-326 (1990)). IGF-1 acts in combination with PDGF to promote mitogenesis and protein synthesis in mesenchymal cells in culture. Application of either PDGF or IGF-1 alone to skin wounds does not enhance healing, but application of both factors together appearsto promote connective tissue and epithelial tissue growth (Lynch et al., Proc. Natl. Acad. Sci. 76:1279-1283 (1987)). TGF-.beta. is a chemoattractant for macrophages and monocytes. Depending upon the presence or absence of other growth factors, TGF-.beta. may stimulate or inhibit the growth of many cell types. For example, when applied in vivo TGF-.beta. increases the tensile strength of healing dermal wounds. TGF-.beta. also inhibits endothelial cell mitosis, and stimulates collagen and glycosaminoglycan synthesis by fibroblasts. Other growth factors, such as EGF, TGF-.alpha., the HBGFs and osteogenin are also important in wound healing. EGF, which is found in gastric secretions and saliva, and TGF-.alpha., which is made by both normal and transformed cells, arestructurally related and may recognize the same receptors. These receptors mediate proliferation of epithelial cells. Both factors accelerate reepithelialization of skin wounds. Exogenous EGF promotes wound healing by stimulating the proliferation ofkeratinocytes and dermal fibroblasts (Nanney et al., J. Invest. Dermatol. 83:385-393 (1984) and Coffey et al., Nature 328:817-820 (1987)). Topical application of EGF accelerates the rate of healing of partial thickness wounds in humans (Schultz etal., Science 235:350-352 (1987)). Osteogenin, which has been purified from demineralized bone, appears to promote bone growth (see, e.g., Luyten et al., J. Biol. Chem. 264:13377 (1989)). In addition, platelet-derived wound healing formula, a plateletextract which is in the form of a salve or ointment for topical application, has been described (see, e.g., Knighton et al., Ann. Surg. 204:322-330 (1986)). The Heparin Binding Growth Factors (HBGFs), also known as Fibroblast Growth Factors (FGFs), which include acidic HBGF (aHBGF also known as HBFG-1 or FGF-1) and basic HBGF (bHBGF also known as HBGF-2 or FGF-2), are potent mitogens for cells ofmesodermal and neuro-ectodermal lineages, including endothelial cells (see, e.g., Burgess et al., Ann. Rev. Biochem. 58:575-606 (1989)). In addition, HBGF-1 is chemotactic for endothelial cells and astroglial cells. Both HBGF-1 and HBGF-2 bind toheparin, which protects them from proteolytic degradation. The array of biological activities exhibited by the HBGFs suggests that they play an important role in wound healing. Basic fibroblast growth factor (FGF-2) is a potent stimulator of angiogenesis and the migration and proliferation of fibroblasts (see, for example, Gospodarowicz et al., Mol. Cell. Endocinol. 46:187-204 (1986) and Gospodarowicz et al., Endo. Rev. 8:95-114 (1985)). Acidic fibroblast growth factor (FGF-1) has been shown to be a potent angiogenic factor for endothelial cells (Burgess et al., supra, 1989). However, it has not been established if any FGF growth factor is chemotactic forfibroblasts. Growth factors are, therefore, potentially useful for specifically promoting wound healing and tissue repair. However, their use to promote wound healing has yielded inconsistent results (see, e.g., Carter et al., in Growth Factors and OtherAspects of Wound Healing: Biological and Clinical Implications, Alan R. Liss, Inc., New York, New York, pp. 303-317 (1988)). For example, PDGF, IGF-1, EGF, TGF-.alpha., TGF-.beta. and FGF (also known as HBGF) applied separately to standardized skinwounds in swine had little effect on the regeneration of connective tissue or epithelium in the wounds (Lynch et al., J. Clin. Invest. 84:640-646 (1989)). Of the factors tested, TGF-.beta. stimulated the greatest response alone. However, acombination of factors, such as PDGF-bb homodimer and IGF-1 or TGF-.alpha. produced a dramatic increase in connective tissue regeneration and epithelialization. (Id.) Tsuboi et al. have reported that the daily application of bFGF to an open woundstimulated wound healing in healing-impaired mice but not in normal mice (J. Exp. Med. 172:245-251 (1990)). On the other hand, the application to human skin wounds of crude preparations of porcine or bovine platelet lysate, which presumably containedgrowth factors, increased the rate at which the wounds closed, the number of cells in the healing area, the growth of blood vessels, the total rate of collagen deposition and the strength of the scar tissue (Carter et al., supra). The reasons for such inconsistent results are not known, but might be the result of difficulty in applying growth factors to a wound in a manner in which they can exhibit their normal array of biological activities. For example, it appears thatsome growth factor receptors must be occupied for at least 12 hours to produce a maximal biologic effect (Presta et al., Cell Regul. 2:719-726 (1991) and Rusnati et al., J. Cell Physiol. 154:152-161 (1993)). Because of such inconsistent results, therole played by exogenously applied growth factors in stimulating wound healing is not clear. Further, a means by which growth factors might be applied to wounds to produce prolonged contact between the wound and the growth factor(s) is not presentlyknown. B. TSs Surgical adhesives and TSs which contain plasma proteins are used for sealing internal and external wounds, such as in bones and skin, to reduce blood loss and maintain hemostasis. Such TSs contain blood clotting factors and other bloodproteins. FG, also called fibrin sealant, is a gel similar to a natural clot which is prepared from plasma. The precise components of each FG are a function of the particular plasma fraction which is used as a starting material. Fractionation ofplasma components can be effected by standard protein purification methods, such as ethanol, polyethylene glycol, and ammonium sulfate precipitation, ion exchange, and gel filtration chromatography. Typically FG contains a mixture of proteins includingtraces of albumin, fibronectin and plasminogen. In Canada, Europe and possibly elsewhere, commercially available FG typically also contains aprotinin as a stabilizer. FGs generally are prepared from: (1) a fibrinogen concentrate, which contains fibronectin, Factor XIII, and von Willebrand factor: (2) dried human or bovine thrombin; and (3) calcium ions. Commercially prepared FGs generally contain bovinecomponents. The fibrinogen concentrate can be prepared from plasma by cryoprecipitation followed by fractionation, to yield a composition that forms a sealant or clot upon mixture with thrombin and an activator of thrombin such as calcium ions. Thefibrinogen and thrombin concentrates are prepared in lyophilized form and are mixed with a solution of calcium chloride immediately prior to use. Upon mixing, the components are applied to a tissue where they coagulate on the tissue surface and form aclot that includes cross-linked fibrin. Factor XIII, which is present in the fibrinogen concentrate, catalyzes the cross-linking. Australian Patent 75097/87 describes a one-component adhesive, which contains an aqueous solution of fibrinogen, factor XIII, a thrombin inhibitor, such as antithrombin III, prothrombin factors, calcium ions, and, if necessary, a plasmininhibitor. Stroetmann, U.S. Pat. Nos. 4,427,650 and 4,427,651, describes the preparation of an enriched plasma derivative in the form of a powder or sprayable preparation for enhanced wound closure and healing that contains fibrinogen, thrombinand/or prothrombin, and a fibrinolysis inhibitor, and may also contain other ingredients, such as a platelet extract. Rose et al., U.S. Pat. Nos. 4,627,879 and 4,928,603, disclose methods for preparing cryoprecipitated suspensions that containfibrinogen and Factor XIII and their use to prepare a FG. JP 1-99565 discloses a kit for the preparation of fibrin adhesives for wound healing. Alterbaum (U.S. Pat. NO. 4,714,457) and Morse et al. (U.S. Pat. No. 5,030,215) disclose methods toproduce autologous FG. In addition, improved FG delivery systems have been disclosed elsewhere (Miller et al., U.S. Pat. No. 4,932,942 and Morse et al., PCT Application WO 91/09641). IMMUNO AG (Vienna, Austria) and BEHRINGWERKE AG (Germany) (Gibble et al., Transfusion 30:741-747 (1990)) presently have FGs on the market in Europe and elsewhere (see, e.g., U.S. Pat. Nos. 4,377,572 and 4,298,598, which are owned by IMMUNOAG). TSs are not commercially available in the U.S. However, the American National Red Cross and BAXTER/HYLAND (Los Angeles, Calif.) have recently co-developed a FG (ARC/BH FG) which is now in clinical studies. The TSs which are used clinically outside of the U.S. pose certain clinical risks and have not been approved by the Food and Drug Administration for use in the USA. For example, the TSs available in Europe contain proteins of non-human originsuch as aprotinin and bovine thrombin. Since these proteins are of non-human origin, people may develop allergic reactions to them. In Europe heat inactivation is used to inactivate viruses which may be present in the components of the FG. However,this heat inactivation method may produce denatured proteins in the FG which may also be allergenic. In addition, there is concern that this inactivation method will not inactivate prions which cause bovine spongiform encephalopathy, "mad cow disease,"which may be present in the TS due to the use of bovine proteins therein. Since this disease appears to have already crossed from sheep, in which it is called "scrapies," to cows, it is not an insignificant concern that it could infect humans. The ARC/BH FG has advantages over the TSs available in Europe because it does not contain bovine proteins. For example, the ARC/BH TS contains human thrombin instead of bovine thrombin and does not contain aprotinin. Since the ARC/BH FG doesnot contain bovine proteins it should be less allergenic in humans than those TSs available in Europe. In addition, the ARC/BH FG is virally inactivated by a solvent detergent method which produces fewer denatured proteins and thus is less allergenicthan those available in Europe. Therefore, the ARC/BH FG possesses advantages over the TSs which are now commercially available in other countries. FG is primarily formulated for clinical topical application and is used to control bleeding, maintain hemostasis and promote wound healing. The clinical uses of FG have recently been reviewed (Gibble et al., Transfusion 30:741-747 (1990); Lerneret al., J. Surg. Res. 48:165-181 (1990)). By sealing tissues FG prevents air or fluid leaks, induces hemostasis, and may contribute to wound healing indirectly by reducing or preventing events which may interfere with wound healing such as bleeding,hematomas, infections, etc. Although FG maintains hemostasis and reduces blood loss, it has not yet been shown to possess true wound healing properties. Because FG is suitable for both internal and external injuries, such as bone and skin injuries, andis useful to maintain hemostasis, it is desirable to enhance its wound healing properties. FG with a fibrinogen concentration of approximately 39 g/l and a thrombin concentration of 200-600 U/ml has produced clots with significantly increased stress, energy absorption and elasticity values (Byrne et al., Br. J. Surg. 78:841-843(1991)). Perforated Teflon cylinders filled with fibrin clot (5 mg/ml) and implanted subcutaneously stimulated the formation of granulation tissue, including an increased precipitation of collagen, when compared to empty cylinders (Hedelin et al., Eur. Surg. Res. 15:312 (1983)). C. Bone Wounds and Their Repair The sequence of bone induction was first described by Urist et al. using demineralized cortical bone matrix (Clin. Orthop. Rel. Res. 71:271 (1970) and Proc. Natl. Acad. Sci. USA 70:3511 (1973)). Implanted subcutaneously in allogeneicrecipients, demineralized cortical bone matrix releases factors which act as local mitogens to stimulate the proliferation of mesenchymal cells (Rath et al., Nature (Lond.) 278:855 (1979)). New bone formation occurs between 12 and 18 dayspostimplantation. Ossicle development replete with hematopoietic marrow lineage occurred by day 21 (Reddi, A., In Extracellular Matrix Biochemistry (Piez et aL, ed.) Elsevier, New York, N.Y., pp. 375-412 (1984)). Demineralized bone matrix (DBM) is a source of osteoinductive proteins known as bone morphogenetic proteins (BMP), and growth factors which modulate the proliferation of progenitor bone cells (see, e.g., Hauschka et al., J. Biol. Chem.261:12665-12674 (1986) and Canalis et al., J. Clin. Invest. 81:277-281 (1988)). Eight BMPs have now been identified and are abbreviated BMP-1 through BMP-8. BMP-3 and BMP-7 are also known as osteogenin and osteogenic protein-1 (OP-1), respectively. Unfortunately, DBM materials have little clinical use unless combined with particulate marrow autografts. There is a limit to the quantity of DBM that can be surgically placed into a recipient's bone to produce a therapeutic effect. Inaddition, resorption has been reported to be at least 49% (Toriumi et al., Arch. Otolaryngo. Head Neck Surg. 116:676-680 (1990)). DBM powder and osteogenin may be washed away by tissue fluids before their osteoinductive potential is expressed. In addition, seepage of tissue fluids into DBM-packed bone cavities or soft-tissue collapse into the wound bed are two factors thatmay significantly affect the osteoinductive properties of DBM and osteogenin. Soft-tissue collapse into the wound bed may likewise inhibit the proper migration of osteocompetent stem cells into the wound bed. Human DBM in powder form is currently used by American dentists to pack jaw bone cavities created during oral surgery. However, DBM in powder form is difficult to use. Purified BMPs have osteoinductive effects in animals when delivered by a variety of means including FG (Hattori, T., Nippon. Seikeigeka, Gakkai, Zasshi. 64:824-834 (1990); Kawamura et al., Clin. Orthop. Rel. Res. 235:302-310 (1988); Schlaget al., Clin. Orthop. Rel. Res. 227:269-285 (1988) and Schwarz et al., Clin. Orthop. Rel. Res. 238:282-287 (1989)) and whole blood clots (Wang et al., J. Cell. Biochem. 15F:Q20 Abstract (1990)). However, Schwarz et al. (supra.) demonstratedneither a clear positive or negative effect of FG on ectopic osteoinduction or BMP-dependent osteoregeneration. Kawamura et al. (supra.) found a synergistic effect when partially purified BMP in FG was tested in an ectopic non-bony site. Therefore,these results are inconsistent and confusing. TS also can serve as a "scaffold" which cells can use to move into a wounded area to generate new tissues. However, commercially available preparations of FG and other TSs are too dense to allow cell migration into and through them. This limitstheir effectiveness in some in vivo uses. In one type of bone wound, called bone nonunion defects, there is a minimal gap above which no new bone formation occurs naturally. Clinically, the treatment for these situations is bone grafting. However, the source of bone autografts isusually limited and the use of allgeneic bones involves a high risk of viral contamination. Because of this situation, the use of demineralized, virally inactivated bone powder is an attractive solution. D. Vascular Prostheses Artificial vascular prostheses are frequently made out of polytetrafluoroethylene (PTFE) and are used to replace diseased blood vessels in humans and other animals. To maximize patency rates and minimize the thrombogenicity of vascularprostheses various techniques have been used including seeding of nonautologous endothelial cells onto the prothesis. Various substrates which adhere both to the vascular graft and endothelial cells have been investigated as an intermediate substrate toincrease endothelial cell seeding. These substrates include preclotted blood (Herring et al., Surgery 84:498-504 (1978)), FG (Rosenmann et al., J. Vasc. Surg. 2:778-784 (1985); Schrenk et al., Thorac. Cardiovasc. Surg. 35:6-10 (1986); Koveker etal., Thorac. Cardiovasc. Surgeon 34: 49-51 (1986) and Zilla et al., Surgery 105:515-522 (1989)), fibronectin (see, e.g., Kesler et al., J. Vasc. Surg. 3:58-64 (1986); Macarak et al., J. Cell Physiol. 116:76-86 (1983) and Ramalanjeona et al., J.Vasc. Surg. 3:264-272 (1986)), or collagen (Williams et al., J. Surg. Res. 38:618-629 (1985)). However, one general problem with these techniques is that nonautologous cells were used for the seeding (see, e.g., Schrenk et al., supra) thus raisingthe possibility of tissue rejection. In addition, a confluent endothelium is usually never established and requires months to do so if it is. As a result of this delay, there is a high occlusion rate of vascular prostheses (see, e.g., Zilla et al.,supra). E. Angiogenesis Angiogenesis is the induction of new blood vessels. Certain growth factors such as HBGF-1 and HBGF-2 are angiogenic. However, their in vivo administration attached to: collagen sponges (Thompson et al., Science 241:1349-1352 (1988)); beads(Hayek et al., Biochem. Biophys. Res. Commun. 147:876-880 (1987)); solid PTFE fibers coated with collagen arranged in a sponge-like structure (Thompson et al., Proc. Natl. Acad. Sci. USA 86:7928-7932 (1989)); or by infusion (Puumala et al., BrainRes. 534:283-286 (1990)) resulted in the generation of random, disorganized blood vessels. These growth factors have not been used successfully to direct the growth of a new blood vessel(s) at a given site in vivo. In addition, fibrin gels (0.5-10mg/ml) implanted subcutaneously in plexiglass chambers induce angiogenesis within 4 days of implantation, compared to empty chambers, or chambers filled with sterile culture medium (Dvorak et al., Lab. Invest. 57:673 (1987)). F. Site-Directed, Localized Drug Delivery An efficacious, site-directed, drug delivery system is greatly needed in several areas of medicine. For example, localized drug delivery is needed in the treatment of local infections, such as in periodontitis, where the systemic administrationof antimicrobial agents is ineffective. The problem after systemic administration usually lies in the low concentration of the antimicrobial agent which can be achieved at the target site. To raise the local concentration a systemic dose increase maybe effective but also may produce toxicity, microbial resistance and drug incompatibility. To circumvent some of these problems, several alternative methods have been devised but none are ideal. For example, collagen and/or fibrinogen dispersed in anaqueous medium as an amorphous flowable mass, and a proteinaceous matrix composition which is capable of stable placement, have also been shown to locally deliver drugs (Luck et al., U.S. Reissue Pat. No. 33,375; Luck et al., U.S. Pat. No.4,978,332). A variety of antibiotics (AB) have been reported to be released from FG, but only at relatively low concentrations and for relatively short periods of time ranging from a few hours to a few days (Kram et al., J. Surg. Res. 50:175-178 (1991)). Most of the ABs have been in freely water soluble forms and have been added into the TS while it was being prepared. However, the incorporation of tetracycline hydrochloride tetracycline hydrochloride (TET HCl) and other freely water soluble forms ofABs into FG has interfered with fibrin polymerization during the formation of the AB-supplemented FG (Schlag et al., Biomaterials 4:29-32 (1983)). This interference limited the amount and concentration of the TET HCl that could be achieved in the AB-FGmixture and appeared to be AB concentration dependent. The relatively short release time of the AB from the FG may reflect the relatively short life of the AB-supplemented TS or the form and/or quantity of the AB in the AB-TS. G. Controlled Drug Release From TSs For some clinical applications controlled, localized drug release is desirable. As discussed above, some drugs, especially ABs, have been incorporated into and been released from TSs such as FG. However, there is little or no control over theduration of the drug release which apparently is at least partially a reflection of the relatively short life of the drug-supplemented FG. Therefore, a means to stabilize FG and other TSs to allow to extended, localized drug release is desirable andneeded, as are new techniques for the incorporation and extended release of other supplements from TS. H. The Disclosed TS Preparations Provide Life-Saving Emergency Treatment for Trauma Wounds Despite continued advances in trauma care, a significant percentage of the population, both military and civilian, suffer fatal or severe hemorrhage every year. An alarming number of fatalities are preventable since the occur in the presence ofthose who could achieve life-saving control of their wounds given adequate tools and training. The availability of the herein-disclosed TS satisfies the long-felt need for a advanced, easy-to-use, field-ready hemostatic preparation, to permit not onlytrained medical personnel, but even untrained individuals to rapidly reduce bleeding in trauma victims. Utilization of the disclosed TS preparations will result in a two-fold benefit: the reduction of trauma death, and the decreased demand upon theavailable blood supply. The disclosed technology would also be available for the treatment of massed casualities in disaster situation. When severe natural or man-made disasters occur, local hospitals and clinics may be overwhelmed by the number of individualsrequiring trauma care. Combined with the isolating effects of such disasters, the resulting demand for blood and blood products often exceeds the locally available supplies. In many cases, the demand upon the local medical personnel also exceeds theavailed number of trained individuals. As a result, less seriously injured persons may be turned-away or given sub-optimal care. The availability of the easy-to-use, self-contained TS preparations disclosed below will permit local medical personnel anddisaster relief workers to provide the injured with temporary treatment until definitive care becomes available. Moreover, the disclosed TS preparations will permit self-treatment in disaster victims, until medical assistance can be provided. Often the only form of medical treatment that can be applied under such circumstances to prevent death due to blood loss is pressure dressings, tourniquets and pressure points. Unfortunately, however, each of these treatments requires continuousmonitoring and attention. Since such attention is not always possible in emergency or disaster situations, there is a clear need in the art for a simple, fast-acting, first-aid treatment which can successfully control excessive blood loss. The application of the disclosed TS preparations to the military is readily apparent, particularly in isolated battlefield situations. The single greatest cause of death on the battlefield is exsanguination, which until now has accounted for upto 50% of all combat casualties. SUMMARY OF THE INVENTION In one embodiment, this invention provides a composition of matter, comprising a TS, wherein the sealant does not inhibit full-thickness skin wound healing. In another embodiment, this invention provides a composition of matter, comprising: a TS, wherein the total protein concentration of the sealant is less than 30 mg/ml. In another embodiment, this invention provides a composition of matter comprising a supplemented TS wherein the total protein concentration is less than 30 mg/ml and the supplement is a growth factor(s) and/or a drug(s). In another embodiment, this invention provides a composition of matter comprising a supplemented TS wherein the total protein concentration is greater than 30 mg/ml and the supplement is a growth factor(s) and/or a drug(s). In another embodiment, this invention provides a composition of matter that promotes the directed migration of animal cells, comprising: a TS; and an effective concentration of at least one growth factor, wherein the concentration of the growthfactor is effective in promoting the directed migration of the animal cells. In another embodiment, the present invention provides a composition of matter that promotes wound healing, comprising: a TS; and an effective concentration of at least one growth factor, wherein the concentration is effective in promoting woundhealing. In another embodiment, the present invention provides a composition of matter that promotes the endothelialization of a vascular prosthesis, comprising: a TS; and an effective concentration of at least one growth factor, wherein the concentrationis effective in promoting the endothelialization of a vascular prosthesis. In another embodiment, the present invention provides a composition of matter that promotes the proliferation and/or differentiation of animal cells, comprising: a TS; and an effective concentration of at least one growth factor, wherein theconcentration is effective in promoting proliferation and/or differentiation of animal cells. In another embodiment, the present invention provides a composition of matter that promotes the localized delivery of at least one drug, comprising: a TS; and at least one drug. In another embodiment, the present invention provides a composition of matter that promotes the localized delivery of at least one growth factor, comprising: a TS; and at least one growth factor. In another embodiment, the present invention provides a process for promoting the healing of wounds, comprising applying to the wound, a composition that contains a TS and an effective concentration of at least one growth factor, wherein theconcentration is effective to promote wound healing. In another embodiment, the present invention provides a process for promoting the endothelialization of a vascular prosthesis, comprising applying to the vascular prosthesis a composition that contains a TS and an effective concentration of atleast one growth factor, wherein the concentration is effective to promote the endothelialization of a vascular prothesis. In another embodiment, the present invention provides a process for promoting the proliferation and/or differentiation of animal cells, comprising placing the cells in sufficient proximity to a TS which contains an effective concentration of atleast one growth factor, wherein the concentration is effective in promoting the proliferation and/or differentiation of the cells. In a further embodiment, the present invention provides a process for the localized delivery of at least one drug to a tissue, comprising applying to the tissue a TS which contains at least one drug. In another embodiment, the present invention provides a process for the localized delivery of at least one growth factor to a tissue, comprising applying to the tissue a TS which contains at least one growth factor. In another embodiment, this invention provides a process for producing the directed migration of animal cells, comprising: placing in sufficient proximity to the cells, a TS which contains an effective concentration of at least one growth factor,wherein the concentration is effective to produce the desired directed migration of said cells. In another embodiment, this invention provides a simple to use, fast acting, field-ready fibrin bandage for applying a tissue sealing composition to wounded tissue in a patient, comprising an occlusive backing, affixed to which is a layer of drymaterials comprising an effective amount, in combination, of (a) dry, virally-inactivated, purified fibrinogen, (b) dry, virally-inactivated, purified thrombin, and as necessary (c) effective amounts of calcium and/or Factor XIII to produce atissue-sealing fibrin clot upon hydration. In a further embodiment, this invention provides a method of treating wounded tissue in a patient by applying to said wound a fibrin bandage, comprising: (1) a occlusive backing, affixed to which is a layer of dry material comprising an effectiveamount, in combination, of (a) dry, virally-inactivated, purified fibrinogen, (b) dry, virally-inactivated, purified thrombin; and as necessary (c) effective amounts of calcium and/or Factor XIII to produce a tissue-sealing fibrin clot upon hydration. In yet another embodiment, this invention provides a simple to use, fast acting, field-ready fibrin dressing for treating wounded tissue in a patient, is formulated as an expandable foam comprising an effective amount, in combination, of (1)virally-inactivated, purified fibrinogen, (2) virally-inactivated, purified thrombin, and as necessary (3) calcium and/or Factor XIII; wherein said composition does not significantly inhibit full-thickness skin wound healing. While in a further embodiment, this invention provides a method of treating wounded tissue in a patient by applying to said wound a tissue sealant expandable foam dressing, comprising an effective amount, in combination, of (1)virally-inactivated, purified fibrinogen, (2) virally-inactivated, purified thrombin, and as necessary (3) calcium and/or Factor XIII; wherein said composition does not significantly inhibit full-thickness skin wound healing. In the embodiments of this invention, the TS may be FG. In the various embodiments of the invention FG may be made from the mixing of topical fibrinogen complex (TFC), human thrombin and calcium chloride. Varying the concentration of the TFC has the most significant effect upon the density of thefinal FG matrix. Varying the concentration of the thrombin has an insignificant effect upon the total protein concentration of the final FG, but has a profound effect upon the time required for the polymerization of the fibrinogen component of the TFCinto fibrin. While this effect is well known, it is not generally appreciated that it may be used to maximize the effectiveness of the FG, when it is used alone or supplemented. Because of this effect one can alter the time between the mixing of the FGcomponents and the setting of the FG. Thus, one can allow the FG to flow more freely into deep crevices in a wound, permitting it to fill the wound completely before the FG sets. Alternatively, one can allow the FG to set quickly enough to prevent itfrom exiting the wound site, especially if the wound is leaking fluid under pressure (i.e., blood, lymph, intercellular fluid, etc). This property is also important to keep the FG from clogging delivery devices with long passages, i.e., catheters,endoscopes, etc., which is important to allow the application of the FG or supplemented FG to sites in the body that are only accessible by surgery. This effect is also important in keeping the insoluble supplements in suspension and preventing themfrom settling in the applicator or in the tissue site. As used herein, TFC is a lyophilized mixture of human plasma proteins which have been purified and virally inactivated. When reconstituted TFC contains: Total Protein: 100-130 mg/ml Fibrinogen: (as clottable protein) 80% of total protein(minimum) Albumin (Human): 5-25 mg/ml Plasminogen: 5 mg/ml Factor XIII: 1040 Units/ml Polysorbate-80: 0.3% (maximum) pH: 7.1-7.5. The reconstituted TFC may also contain trace amounts of fibronectin. As used herein, human thrombin is a lyophilized mixture of human plasma proteins, which have been purified and virally inactivated. When reconstituted it contains: Thrombin Potency: 300.+-.50 International Units/ml Albumin (Human): 5 mg/mlGlycine: 0.3M.+-.05 M pH: 6.5-7.1. Calcium chloride is added in sufficient concentration to activate the thrombin. As long as there is sufficient calcium, its concentration is not important. In the compositions of this invention containing a growth factor, the composition may contain an inhibiting compound (s) and/or potentiating compound(s), wherein the inhibiting compound(s) inhibit the activities of the sealant that interfere withany of the biological activities of the growth factor, the potentiating compound(s) potentiate, mediate or enhance any of the biological activities of the growth factor, and wherein the concentration of the inhibiting or potentiating compound iseffective for achieving the inhibition, potentiation, mediation or enhancement. The growth factor-supplemented TSs of this invention are useful for promoting the healing of wounds, especially those that do not readily heal, such as skin ulcers in diabetic individuals, and for delivering growth factors including, but notlimited to, FGF-1, FGF-2, FGF4, PDGFs, EGFs, IGFs, PDGF-bb, BMP-1, BMP-2, OP-1, TGF-.beta., cartilage-inducing factor-A (CIF-A), cartilage-inducing factor-B (CIF-B), osteoid-inducing factor (OIF), angiogenin(s), endothelins, hepatocyte growth factor andkeratinocyte growth factor, and providing a medium for prolonged contact between a wound site and the growth factor(s). The growth factor-supplemented TS may be used to treat burns and other skin wounds and may comprise a TS and, in addition to thegrowth factor(s), an antibiotic(s) and/or an analgesic(s), etc. The growth factor-supplemented TS may be used to aid in the engraftment of a natural or artificial graft, such as skin to a skin wound. They may also be used cosmetically, for example inhair transplants, where the TS might contain FGF, EGF, antibiotics and minoxidil, as well as other compounds. An additional cosmetic use for the compositions of this invention is to treat wrinkles and scars instead of using silicone or other compoundsto do so. In this embodiment, for example, the TS may contain FGF-1, FGF4, and/or PDGFs, and fat cells. The growth factor-supplemented TSs may be applied to surgical wounds, broken bones or gastric ulcers and other such internal wounds in order topromote healing thereof. The TSs of this invention may be used to aid the integration of a graft, whether artificial or natural, into an animal's body as for example when the graft is composed of natural tissue. The TSs of this invention can be used tocombat some of the major problems associated with certain conditions such as periodontitis, namely persistent infection, bone resorption, loss of ligaments and premature re-epithelialization of the dental pocket. In another embodiment, this invention provides a mixture of FG, DBM and/or purified BMP's. This mixture provides a matrix that allows the cellular components of the body to migrate into it and thus produce osteoinduction where needed. Thematrix composition in terms of proteins (such as fibrinogen and Factor XIII), enzymes (such as thrombin and plasmin), BMPs, growth factors and DBM and their concentrations are adequately formulated to optimize the longevity of this temporal scaffoldingstructure and the osteoinduction which needs to occur. All the FG components are biodegradable but during osteogenesis the mixture provides a non-collapsible scaffold that can determine the shape and location of the newly formed bone. Soft tissuecollapse into the bony nonunion defect, which is a problem in bone reconstructive surgery, will thus be avoided. The use of TS supplemented with growth factors such as CIF-A and CIF-B, infra, which promote cartilage development, will be useful in thereconstruction of lost or damaged cartilage and/or damaged bone. In a preferred embodiment, an effective concentration of HBGF-1 is added to a FG in order to provide a growth factor-supplemented TS that possesses the ability to promote wound healing. In another preferred embodiment, an effective amount of aplatelet-derived extract is added to a FG. In other preferred embodiments, an effective concentration of a mixture of at least two growth factors are added to FG and an effective amount of the growth factor(s)-supplemented FG is applied to the woundedtissue. In addition to growth factors, drugs, polyclonal and monoclonal antibodies and other compounds, including, but not limited to, DBM and BMPs may be added to the TS. They accelerate wound healing, combat infection, neoplasia, and/or other diseaseprocesses, mediate or enhance the activity of the growth factor in the TS, and/or interfere with TS components which inhibit the activities of the growth factor in the TS. These drugs may include, but are not limited to: antibiotics, such astetracycline and ciprofloxacin; antiproliferative/cytotoxic drugs, such as 5-fluorouracil (5-FU), taxol and/or taxotere; antivirals, such as gangcyclovir, zidovudine, amantidine, vidarabine, ribaravin, trifluridine, acyclovir, dideoxyuridine andantibodies to viral components or gene products; cytokines, such as .alpha.- or .beta.- or .gamma.-Interferon, .alpha.- or .beta.-tumor necrosis factor, and interleukins; colony stimulating factors; erythropoietin; antifungals, such as diflucan,ketaconizole and nystatin; antiparasitic agents, such as pentamidine; anti-inflammatory agents, such as .alpha.-1-anti-trypsin and .alpha.-1-antichymotrypsin; steroids; anesthetics; analgesics; and hormones. Other compounds which may be added to the TSinclude, but are not limited to: vitamins and other nutritional supplements; hormone; glycoproteins; fibronectin; peptides and proteins; carbohydrates (both simple and/or complex); proteoglycans; antiangiogenins; antigens; oligonucleotides (sense and/orantisense DNA and/or RNA); BMPs; DBM; antibodies (for example, to infectious agents, tumors, drugs or hormones); and gene therapy reagents. Genetically altered cells and/or other cells may also be included in the TSs of this invention. Theosteoinductive compounds which can be used in practicing this invention include, but are not limited to: osteogenin (BMP3); BMP-2; OP-1; BMP-2A, -2B, and -7; TGF-.beta., HBGF-1 and -2; and FGF-1 and 4. In addition, anything which does not destroy the TScan be added to the TSs of this invention. The studies reported herein unexpectedly demonstrate that the inclusion of compounds such as the free base TET or ciprofloxacin (CIP) HCl, in FG or the treatment of FG therewith confers extended longevity to the supplemented FG. This phenomenoncan be exploited to increase the duration of a drug's release from the TS. Alternatively, this phenomenon can be exploited to modulate the release of another drug(s) other than the compound used to stabilize the FG, which is (are) also incorporated intothe TET-FG, and/or to cause the FG to persist for a greater period in vivo or in vitro. In general, poorly water soluble forms of a drug, such as the free base of TET, increase the delivery of the drug from the TS more than freely water soluble forms thereof. Therefore, the drug may be bound to an insoluble carrier, such asfibrinogen or activated charcoal, within the TS to prolong the delivery of the drug from the supplemented TS. In another embodiment, the supplemented TS can be used in organoids and could contain, for example, growth factors such as FGF-1, FGF-2, FGF4 and OP-1. In another embodiment, this invention provides a composition that promotes the localized delivery of a poorly water soluble form of an antibiotic(s), such as the free base form of TET, and other drug(s), comprising a TS and an effectiveconcentration of at least one poorly water soluble form of an antibiotic. Similar delivery methods are also applied to other drugs, antibodies, oligonucleotides, cytotoxins, cell proliferation inhibitors, osteogenic or cartilage inducing compounds,growth factors or other supplements herein disclosed. The present invention has several advantages over the previously used TS compositions and methods. The first advantage is that the growth factor- and/or drug-supplemented TSs of the present invention have many of the characteristics of an idealbiodegradable carrier, namely: they can be formulated to contain only human proteins thus eliminating or minimizing immunogenicity problems and foreign-body reactions; their administration is versatile; and their removal from the host's tissues is notrequired because they are degraded by the host's own natural fibrinolytic system. A second advantage is that the present invention provides a good way to effectively deliver growth factors and/or drugs for a prolonged period of time to an internal or external wound. It appears that some growt