Graft materials containing bioactive substances, and methods for their manufacture

Abstract

Described are packaged, sterile medical graft products containing controlled levels of a growth factor such as Fibroblast Growth Factor-2 (FGF-2). Also described are methods of manufacturing medical graft products wherein processing, including sterilization, is controlled and monitored to provide medical graft products having modulated, known levels of a extracellular matrix factor, such as a growth factor, e.g. FGF-2. Preferred graft materials are extracellular matrix materials isolated from human or animal donors, particularly submucosa-containing extracellular matrix materials. Further described are ECM compositions that are or are useful for preparing gels, and related methods for preparation and use.

1 - 60 . (canceled) 
     
     
         61 . A medical product, comprising:
 a fluid composition comprising solubilized or suspended collagenous extracellular matrix material;   said fluid composition comprising FGF-2 at a level of about 0.1 ng/ml to about 100 ng/ml.   
     
     
         62 . The medical product of  claim 61 , wherein said fluid composition is a gelable composition. 
     
     
         63 - 105 . (canceled) 
     
     
         106 . A composition comprising: (a) lyophilized extracellular matrix derived from a mammalian tissue and digested with an acid protease, and (b) the acid protease, wherein the composition after addition of water is a liquid at a temperature of about 4° C. to 25° C. and gels at a temperature greater than 25° C. 
     
     
         107 . The composition of  claim 106 , wherein the extracellular matrix is comminuted. 
     
     
         108 . The composition of  claim 106 , wherein the mammalian tissue comprises cardiac tissue. 
     
     
         109 . The composition of  claim 106 , wherein the composition has a pH between 7.2 and 7.8. 
     
     
         110 . The composition of  claim 106 , wherein the protease is pepsin. 
     
     
         111 . The composition of  claim 106 , wherein the composition is injectable through a needle. 
     
     
         112 . The composition of  claim 106 , wherein the composition is chemically cross-linked. 
     
     
         113 . The composition of  claim 106 , wherein the extracellular matrix comprises collagen and glycosaminoglycan. 
     
     
         114 . The composition of  claim 106 , wherein the composition further comprises a biocompatible material, a cell, a drug, a growth factor or an antibiotic. 
     
     
         115 . The composition of  claim 106 , wherein the extracellular matrix is a non-dialyzed extracellular matrix. 
     
     
         116 . The composition of  claim 106 , wherein the composition is a liquid. 
     
     
         117 . The composition of  claim 116 , wherein the composition transitions to a gel form at a physiological temperature. 
     
     
         118 . The composition of  claim 116 , wherein the extracellular matrix is suspended in the liquid. 
     
     
         119 . The composition of  claim 116 , wherein the extracellular matrix is solubilized in the liquid. 
     
     
         120 . A composition comprising: (a) extracellular matrix derived from a mammalian tissue and digested with an acid protease, and (b) the acid protease, wherein the composition is chemically crosslinked. 
     
     
         121 . A method for correcting a disease-induced tissue defect in a subject in need of repair or augmentation of said tissue defect comprising administering to said subject an effective amount of the composition of  claim 106 . 
     
     
         122 . The method of  claim 121 , wherein the extracellular matrix is comminuted. 
     
     
         123 . The method of  claim 121 , wherein the mammalian tissue comprises cardiac tissue. 
     
     
         124 . The method of  claim 121 , wherein the composition has a pH between 7.2 and 7.8. 
     
     
         125 . The method of  claim 121 , wherein the protease is pepsin. 
     
     
         126 . The method of  claim 121 , wherein the composition is injectable through a needle. 
     
     
         127 . The method of  claim 121 , wherein the composition is chemically cross-linked. 
     
     
         128 . The method of  claim 121 , wherein the extracellular matrix comprises collagen and glycosaminoglycan. 
     
     
         129 . The method of  claim 121 , wherein the composition further comprises a biocompatible material, a cell, a drug, a growth factor or an antibiotic. 
     
     
         130 . The method of  claim 121 , wherein the extracellular matrix is a non-dialyzed extracellular matrix. 
     
     
         131 . The method of  claim 121 , wherein the composition is a liquid. 
     
     
         132 . The method of  claim 131 , wherein the composition transitions to a gel form at a physiological temperature. 
     
     
         133 . The method of  claim 131 , wherein the extracellular matrix is suspended in the liquid. 
     
     
         134 . The method of  claim 131 , wherein the extracellular matrix is solubilized in the liquid. 
     
     
         135 . The composition of  claim 106 , wherein the composition after addition of water is a liquid at room temperature and gels at a temperature of about 37° C. 
     
     
         136 . The composition of  claim 106 , wherein the composition after addition of water does not gel or gels only very slowly at temperatures below 37° C. 
     
     
         137 . The composition of  claim 106 , wherein the composition after addition of water does not gel at temperatures below 37° C. 
     
     
         138 . A composition comprising: (a) lyophilized extracellular matrix derived from a mammalian tissue and digested with pepsin, and (b) the pepsin, wherein the composition after addition of water gels at a temperature of about 37° C. 
     
     
         139 . The composition of  claim 138 , wherein the extracellular matrix is a non-dialyzed extracellular matrix. 
     
     
         140 . The composition of  claim 138 , wherein the composition is a liquid and transitions to a gel form at a physiological temperature. 
     
     
         141 . The composition of  claim 140 , wherein the extracellular matrix is suspended or solubilized in the liquid. 
     
     
         142 . A method for correcting a disease-induced tissue defect in a subject in need of repair or augmentation of said tissue defect comprising administering to said subject an effective amount of the composition of  claim 138 . 
     
     
         143 . The method of  claim 142 , wherein the composition has a pH between 7.2 and 7.8. 
     
     
         144 . The method of  claim 142 , wherein the composition is injectable through a needle. 
     
     
         145 . The method of  claim 142 , wherein the extracellular matrix comprises collagen and glycosaminoglycan. 
     
     
         146 . The method of  claim 142 , wherein the extracellular matrix is a non-dialyzed extracellular matrix. 
     
     
         147 . The method of  claim 142 , wherein the composition is a liquid and transitions to a gel form at a physiological temperature. 
     
     
         148 . The method of  claim 147 , wherein the extracellular matrix is suspended or solubilized in the liquid.