Novel cellular factor-containing solution compositions

Abstract

The invention is directed to novel cellular factor-containing solution compositions (referred to herein as “CFS” compositions), including novel sustained-release cellular factor-containing solution compositions (referred to herein as “SR-CFS” compositions), methods of making such novel compositions and uses thereof.

1 . An extraembryonic cell-derived cellular cytokine solution composition comprising physiologic concentrations of:
 a) at least one factor selected from VEGF, TGFβ2, Angiogenin and PDGF; and   b) at least one MMP inhibitor.   
     
     
         2 . The composition of  claim 1  wherein the MMP inhibitor is TIMP-1 and/or TIMP-2 
     
     
         3 . The composition of  claim 1  comprising physiologic concentrations of:
 a) at least two factors selected from VEGF, TGFβ2, Angiogenin and PDGF; and   b) at least one MMP inhibitor.   
     
     
         4 . The composition of  claim 1  comprising physiologic concentrations of:
 a) at least three factors selected from VEGF, TGFβ2, Angiogenin and PDGF; and   b) at least one MMP inhibitor.   
     
     
         5 . The composition of  claim 1  comprising physiologic concentrations of VEGF, TGFβ2, Angiogenin, PDGF and TIMP-1. 
     
     
         6 . The composition of  claim 1  comprising physiologic concentrations of VEGF, TGFβ2, Angiogenin, PDGF and TIMP-2. 
     
     
         7 . The composition of  claim 1  comprising physiologic concentrations of VEGF, TGFβ2, Angiogenin, PDGF, TIMP-1 and TIMP-2. 
     
     
         8 . The composition of  claim 1  wherein the cellular factor-containing solution composition is amnion-derived cellular cytokine solution. 
     
     
         9 . The composition of  claim 8  wherein the amnion-derived cellular cytokine solution comprises physiologic concentrations of VEGF, TGFβ2, Angiogenin, PDGF, TIMP-1 and TIMP-2. 
     
     
         10 . A sustained-release composition comprising the extraembryonic cell-derived cellular cytokine solution of  claim 1 . 
     
     
         11 . The sustained-release composition of  claim 10  wherein the extraembryonic cell-derived cellular cytokine solution is amnion-derived cellular cytokine solution. 
     
     
         12 . A method of making an amnion-derived cellular cytokine solution comprising
 a) isolating amnion epithelial cells from the amnion of a placenta,   b) selecting AMP cells from the amnion epithelial cells,   c) culturing the AMP cells until they reach confluence,   d) changing the culture medium,   e) culturing the cells in the medium, and   f) collecting the culture medium of step (e) to obtain amnion-derived cellular cytokine solution.   
     
     
         13 . The method of  claim 12  in which step (f) is repeated a plurality of times and the amnion-derived cellular cytokine solution obtained in each step (f) is combined to create a pooled amnion-derived cellular cytokine solution. 
     
     
         14 . The amnion-derived cellular cytokine solution made by the method of  claim 13 . 
     
     
         15 . The amnion-derived cellular cytokine solution of  claim 14  wherein the solution comprises the factors VEGF, TGFβ2, Angiogenin, PDGF, TIMP-1 and/or TIMP-2 at physiological concentrations. 
     
     
         16 . The composition of  claim 1 ,  3 ,  4 ,  5 ,  6 ,  7  or  9  -wherein the physiologic concentration is ˜5.0-16 ng/mL for VEGF, ˜3.5-4.5 ng/mL for Angiogenin, ˜100-165 pg/mL for PDGF, ˜2.5-2.7 ng/mL for TGFβ2, ˜0.68 μg mL for TIMP-1 and ˜1.04 μg/mL for TIMP-2. 
     
     
         17 . A physiologic cytokine solution composition comprising a therapeutic component consisting essentially of physiologic concentrations of:
 a) one or more factors selected from VEGF, TGFβ2, Angiogenin and PDGF;   b) at least one MMP inhibitor; and   c) a carrier, wherein the physiologic concentration is ˜5.0-16 ng/mL for VEGF, ˜3.5-4.5 ng/mL for Angiogenin, ˜100-165 pg/mL for PDGF, ˜2.5-2.7 ng/mL for TGFβ2, ˜0.68 μg mL for TIMP-1 and ˜1.04 μg/mL for TIMP-2, and wherein the carrier is normal saline, PBS, lactated Ringer's solution or cell culture medium.   
     
     
         18 . The composition of  claim 17  wherein the MMP inhibitor is TIMP-1 and/or TIMP-2 
     
     
         19 . The composition of  claim 17  comprising a therapeutic component consisting essentially of physiologic concentrations of:
 a) VEGF, TGFβ2, Angiogenin and PDGF;   b) TIMP-1 and/or TIMP-2; and   c) a carrier; wherein the physiologic concentration is ˜5.0-16 ng/mL for VEGF, ˜3.5-4.5 ng/mL for Angiogenin, ˜100-165 pg/mL for PDGF, ˜2.5-2.7 ng/mL for TGFβ2, ˜0.68 μg mL for TIMP-1 and ˜1.04 μg/mL for TIMP-2, and wherein the carrier is normal saline, PBS, lactated Ringer's solution or cell culture medium.   
     
     
         20 . A physiologic cytokine solution composition comprising a therapeutic component consisting essentially of a composition selected from the group consisting of: Composition A: VEGF and TIMP-1; Composition B: VEGF, Angiogenin and TIMP-1; Composition C: VEGF, Angiogenin, PDGF-BB and TIMP-1; Composition D: VEGF, Angiogenin, PDGF-BB, TGFβ2 and TIMP-1; Composition E: VEGF and TIMP-2; Composition F: VEGF, Angiogenin and TIMP-2; Composition G: VEGF, Angiogenin, PDGF-BB and TIMP-2; Composition H: VEGF, Angiogenin, PDGF-BB, TGFβ2 and TIMP-2; Composition I: VEGF, TIMP-1 and TIMP-2; Composition J: VEGF, Angiogenin, TIMP-1 and TIMP-2; Composition K: VEGF, Angiogenin, PDGF-BB, TIMP-1 and TIMP-2; Composition L: VEGF, Angiogenin, PDGF-BB, TGFβ2, TIMP-1 and TIMP-2; Composition M: Angiogenin and TIMP-1; Composition N: Angiogenin, PDGF-BB and TIMP-1; Composition O: Angiogenin, PDGF-BB, TGFβ2 and TIMP-1; Composition P: Angiogenin and TIMP-2; Composition Q: Angiogenin, PDGF-BB and TIMP-2; Composition R: Angiogenin, PDGF-BB, TGFβ2 and TIMP-2; Composition S: Angiogenin, PDGF-BB, TGFβ2, TIMP-1 and TIMP-2; Composition T: PDGF-BB and TIMP-1; Composition U: PDGF-BB, TGFβ2and TIMP-1; Composition V: PDGF-BB and TIMP-2; Composition W: PDGF-BB, TGFβ2 and TIMP-2; Composition X: PDGF-BB, TIMP-1 and TIMP-2; and Composition Y: PDGF-BB, TGFβ2, TIMP-1 and TIMP-2; and a carrier, wherein VEGF, Angiogenin, PDGF-BB, TGFβ2, TIMP-1 and TIMP-2 are at ˜5-16 ng/mL for VEGF, ˜3.5-4.5 ng/mL for Angiogenin, ˜100-165 pg/mL for PDGF, ˜2.5-2.7 ng/mL for TGFβ2, ˜0.68 μg mL for TIMP-1 and ˜1.04 μg/mL for TIMP-2, and wherein the carrier is normal saline, PBS, lactated Ringer's solution or cell culture medium. 
     
     
         21 . A sustained-release composition comprising the composition of  claim 17 ,  19  or  20 . 
     
     
         22 . The sustained-release composition of  claim 21  further comprising an agent capable of effecting sustained-release of the extraembryonic cell-derived cellular cytokine solution, wherein the agent is selected from polymers, blended polymers, hyaluronic acid particles, microencapsulation materials or nanoparticles. 
     
     
         23 . A method of making a sustained-release composition comprising the steps of combining a cellular factor-containing solution composition with an agent capable of effecting sustained-release of the cellular factor-containing solution composition. 
     
     
         24 . A sustained-release composition made by the method of  claim 23 .