Injectable formulations for organ augmentation

Abstract

The present invention concerns therapeutic formulations containing active agents, such bioactive cell populations, and methods of making and using the same.

1 . An injectable formulation comprising bioactive cells and a temperature-sensitive cell-stabilizing biomaterial that maintains
 (i) a substantially solid state at about 8° C. or below, and   (ii) a substantially liquid state at about ambient temperature or above.   
     
     
         2 . The formulation of  claim 1 , wherein the bioactive cells comprise renal cells. 
     
     
         3 . The formulation of  claim 1 , wherein the bioactive cells are substantially uniformly dispersed throughout the volume of the cell-stabilizing biomaterial. 
     
     
         4 . The formulation of  claim 1 , wherein the biomaterial comprises a solid-to-liquid transitional state between about 8° C. and about ambient temperature or above. 
     
     
         5 . The formulation of  claim 1 , wherein the substantially solid state is a gel state. 
     
     
         6 . The formulation of  claim 1 , wherein the cell-stabilizing biomaterial comprises a hydrogel. 
     
     
         7 . The formulation of  claim 6 , wherein the hydrogel comprises gelatin. 
     
     
         8 . The formulation of  claim 7 , wherein the gelatin is present in the formulation at about 0.5% to about 1% (w/v). 
     
     
         9 . The formulation of  claim 7 , wherein the gelatin is present in the formulation at about 0.75% (w/v). 
     
     
         10 . The formulation of  claim 1 , further comprising a cell viability agent. 
     
     
         11 . The formulation of  claim 10 , wherein the cell viability agent comprises an agent selected from the group consisting of an antioxidant, an oxygen carrier, an immunomodulatory factor, a cell recruitment factor, a cell attachment factor, an anti-inflammatory agent, an immunosuppressant, an angiogenic factor, and a wound healing factor. 
     
     
         12 . (canceled) 
     
     
         13 . The formulation of  claim 11 , wherein the antioxidant is 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. 
     
     
         14 . The formulation of  claim 13 , wherein the 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid is present at about 50 μM to about 150 μM. 
     
     
         15 - 16 . (canceled) 
     
     
         17 . The formulation of  claim 11 , wherein the oxygen carrier is a perfluorocarbon. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . An injectable formulation comprising bioactive renal cells, about 0.75% (w/v) gelatin, and about 100 μM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, wherein the formulation has
 (i) a substantially solid state at about 8° C. or below, and 
 (ii) a substantially liquid state at ambient temperature or above. 
 
     
     
         21 - 29 . (canceled) 
     
     
         30 . The formulation of  claim 1 , further comprising biocompatible beads comprising a biomaterial. 
     
     
         31 . The formulation of  claim 30 , wherein the beads are crosslinked. 
     
     
         32 . The formulation of  claim 31 , wherein the crosslinked beads have a reduced susceptibility to enzymatic degradation as compared to non-crosslinked biocompatible beads. 
     
     
         33 . The formulation of  claim 31 , wherein the crosslinked beads are carbodiimide-crosslinked beads. 
     
     
         34 . The formulation of  claim 33 , wherein the carbodiimide is selected from the group consisting of 1-Ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC), DCC—N,N′-dicyclohexylcarbodiimide (DCC), and N,N′-Diisopropylcarbodiimide (DIPC). 
     
     
         35 . (canceled) 
     
     
         36 . The formulation of  claim 32 , wherein the crosslinked beads comprise a reduced number of free primary amines as compared to non-crosslinked beads. 
     
     
         37 . (canceled) 
     
     
         38 . The formulation of  claim 30 , wherein the beads are seeded with the bioactive cells. 
     
     
         39 . The formulation of  claim 38 , wherein the bioactive cells are renal cells. 
     
     
         40 . The formulation of  claim 30 , further comprising additional biocompatible beads that comprise a temperature-sensitive biomaterial that maintains
 (i) a substantially solid state at ambient temperature or below, and   (ii) a substantially liquid state at about 37° C. or above.   
     
     
         41 . The formulation of  claim 40 , wherein the biomaterial of the beads comprises a solid-to-liquid transitional state between ambient temperature and about 37° C. 
     
     
         42 . The formulation of  claim 40 , wherein the substantially solid state is a gel state. 
     
     
         43 . The formulation of  claim 40 , wherein the biomaterial of the beads comprises a hydrogel. 
     
     
         44 . The formulation of  claim 43 , wherein the hydrogel comprises gelatin. 
     
     
         45 . The formulation of  claim 44 , wherein the beads comprise gelatin at about 5% (w/v) to about 10% (w/v). 
     
     
         46 . The formulation of  claim 40 , wherein the additional biocompatible beads are spacer beads. 
     
     
         47 . The formulation of  claim 46 , wherein the spacer beads are not seeded with bioactive cells. 
     
     
         48 . The formulation of  claim 1 , further comprising products secreted by a renal cell population. 
     
     
         49 . The formulation of  claim 48 , wherein the secreted products are selected from the group consisting of paracrine factors, endocrine factors, juxtacrine factors, vesicles, microvessicles, exosomes and RNA. 
     
     
         50 - 54 . (canceled) 
     
     
         55 . The formulation of  claim 49 , wherein the vesicles comprise a secreted product selected from the group consisting of paracrine factors, endocrine factors, juxtacrine factors, and RNA.