Compositions Comprising Citrate and Applications Thereof

Abstract

In one aspect, methods of promoting bone growth are described herein. In some embodiments, a method of promoting bone growth described herein comprises promoting cell differentiation or phenotype progression in a population of bone cells by providing a citrate-presenting composition to the population of bone cells. In some embodiments, the citrate-presenting composition is provided to the bone cells at a first stage of cell development selected to obtain a first cell differentiation or phenotype progression. Additionally, in some cases, a second citrate-presenting composition is further provided to the bone cells at a second stage of cell development selected to obtain a second cell differentiation or phenotype progression.

That which is claimed is: 
     
         1 . A method for promoting bone growth, said method comprising providing to a subject in need thereof free citric acid or citrate at a concentration of between about 20 μM and about 2000 μM, thereby promoting bone growth in said subject. 
     
     
         2 . The method of  claim 1 , wherein providing to the subject free citric acid or citrate comprises administering to the subject a citrate-presenting composition, wherein free citric acid or citrate is released from said citrate-presenting composition. 
     
     
         3 . The method of  claim 2 , wherein said citrate-presenting composition comprises a polymer or oligomer comprising a citrate moiety. 
     
     
         4 . The method of  claim 3 , wherein said citrate moiety comprises a moiety having the structure of Formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , and R 3  are independently —H, —CH 3 , —CH 2 CH 3 , M + , or a point of attachment to the remainder of the polymer or oligomer; 
 R 4  is —H or a point of attachment to the remainder of the polymer or oligomer; and 
 M +  is a cation such as Na +  or K + , provided that at least one of R 1 , R 2 , R 3 , and R 4  is a point of attachment to the remainder of the polymer or oligomer. 
 
     
     
         5 . The method of  claim 4 , wherein said polymer or oligomer comprises the reaction product of (i) citric acid, or an ester of citric acid with (ii) a polyol. 
     
     
         6 . The method of  claim 5 , wherein said ester of citric acid is triethyl citrate. 
     
     
         7 . The method of  claim 5 , wherein said polyol is a diol. 
     
     
         8 . The method of  claim 5 , wherein said polymer or oligomer is formed from one or more monomers of Formula (A) and one or more monomers of Formula (B) or (B′): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , and R 3  are independently —H, —CH 3 , —CH 2 CH 3 , or M + ; 
 R 4  is —H; 
 R 5  is —H, —OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , or —CH 2 CH 3 ; 
 R 6  is —H, —CH 3 , or —CH 2 CH 3 ; 
 M +  is a cation such as Na +  or K + ; and 
 n and m are independently integers ranging from 1 to 20. 
 
     
     
         9 . The method of  claim 8 , wherein R 1 , R 2 , and R 3  are —H, R 5  is —OH, and R 6  is —H. 
     
     
         10 . The method of  claim 5 , wherein said polymer or oligomer is formed from one or more monomers of Formula (A), one or more monomers of Formula (B) or (B′), and one or more monomers of Formula (C): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , and R 3  are independently —H, —CH 3 , —CH 2 CH 3 , or M + ; 
 R 4  is —H; 
 R 5  is —H, —OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , or —CH 2 CH 3 ; 
 R 6  is —H, —CH 3 , or —CH 2 CH 3 ; 
 M +  is a cation such as Na +  or K + ; 
 n and m are independently integers ranging from 1 to 20; and 
 p is an integer ranging from 1 to 10. 
 
     
     
         11 . The method of  claim 10 , wherein R 1 , R 2 , and R 3  are —H, or —CH 2 CH 3 , R 5  is —OH, R 6  is —H, n is 2 to 6, m is 2 to 8, and p is 2 to 6. 
     
     
         12 . The method of  claim 5 , wherein said citrate-presenting composition comprises:
 a first polymer or oligomer having the structure of Formula (I):   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —H, —OC(O)NH , or  ; 
    represents an additional chain of repeating units having the structure of Formula (I); and 
 m, n, and p are 8; and 
 q is 6; and 
 
       a second polymer or oligomer having the structure of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is —H or  ; 
    represents an additional chain of repeating units having the structure of Formula (II); and 
 m, n, and p are 8, 
 
       wherein the first polymer or oligomer is blended with the second polymer or oligomer, and 
       wherein the first polymer or oligomer and the second polymer or oligomer are cross linked with one another to form a polymer network. 
     
     
         13 . The method of  claim 1 , wherein the citrate-presenting composition further comprises a particulate material dispersed in the polymer network. 
     
     
         14 . The method of  claim 13 , wherein said particulate material comprises one or more of hydroxyapatite, tricalcium phosphate, biphasic calcium phosphate, bioglass, ceramic, magnesium powder, magnesium alloy, and decellularized bone tissue particles. 
     
     
         15 . The method of  claim 1 , the citrate-presenting composition promotes osteoblast phenotype progression in the population of bone cells or at least partially inhibits the growth of cancer cells present among the population of bone cells. 
     
     
         16 . The composition for use according to  claim 15 , wherein the bone cells comprise stem cells.