Supplemented and unsupplemented tissue sealants, methods of their production and use

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.

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 a biocompatible, 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 cartilage inducing 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 metabolism of 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 and fibrin II, in an amount which forms a fibrin matrix in the presence of thrombin and Ca ++  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 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 is soluble 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 period obtained 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 least one 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 which forms a fibrin matrix in the presence of thrombin and Ca ++  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 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 and location 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 least one 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 the differentiation 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 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 which forms a fibrin matrix in the presence of thrombin and Ca ++  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 of said 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 said sustained 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 growth factors; 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 said inhibiting 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 the biological 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 factors which 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 deposited within 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 ++ . 
     
     
       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, an anesthetic, 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 cytotoxin or 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 protease inhibitor, 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).