Collagen-based therapeutic delivery systems

Abstract

A collagen-based therapeutic delivery device includes an insoluble synthetic collagen-fibril matrix comprising a polymerization product of soluble oligomeric collagen or a polymerization product of a mixture of soluble oligomeric collagen with one or more type of non-oligomeric soluble collagen molecules, such as, for example, soluble telocollagen and/or soluble atelocollagen, and an active agent dispersed throughout the collagen-fibril matrix or within a portion of the collagen-fibril matrix. A pre-matrix composition includes an aqueous solution including soluble collagen-fibril building blocks and an active agent in the aqueous solution. The soluble collagen-fibril building blocks include soluble oligomeric collagen or a mixture of soluble oligomeric collagen with non-oligomeric soluble collagen molecules. The building blocks are operable to self-assemble into a macromolecular synthetic collagen-fibril matrix in the absence of an exogenous cross-linking agent. Methods of making and using the pre-matrix composition and the device are also provided.

What is claimed is: 
     
         1 - 10 . (canceled) 
     
     
         11 . A method for making a therapeutic delivery device, comprising:
 forming an aqueous solution comprising a first quantity of soluble collagen-fibril building blocks;   causing the building blocks to polymerize by self-assembly, thereby forming an insoluble synthetic collagen-fibril matrix; and   either including a second quantity of an active agent in the aqueous solution whereby said causing forms the insoluble synthetic collagen-fibril matrix having the active agent dispersed therein or contacting the insoluble synthetic collagen-fibril matrix with the second quantity of the active agent to form a collagen-fibril matrix having the active agent dispersed therein;   wherein the first quantity of building blocks comprises soluble oligomeric collagen molecules; and   wherein the collagen-fibril matrix exhibits a stiffness of at least 5 Pa.   
     
     
         12 . The method of  claim 11 , wherein the first quantity of building blocks further comprises soluble non-oligomeric collagen molecules. 
     
     
         13 . The method of  claim 11 , further comprising compressing the insoluble synthetic collagen-fibril matrix to form a condensed insoluble synthetic collagen-fibril matrix. 
     
     
         14 . The method of  claim 13 , wherein said compressing comprises subjecting the insoluble synthetic collagen-fibril matrix to confined compression. 
     
     
         15 . The method of  claim 11 , further comprising, after said causing, lyophilizing the insoluble synthetic collagen-fibril matrix. 
     
     
         16 . A pre-matrix composition comprising an aqueous solution including a first quantity of soluble collagen-fibril building blocks and a second quantity of an active agent in the aqueous solution, wherein the first quantity of soluble collagen-fibril building blocks includes soluble oligomeric collagen or a mixture of soluble oligomeric collagen with one or more other type of non-oligomeric soluble collagen molecules, wherein the building blocks are operable to self-assemble into a macromolecular insoluble synthetic collagen-fibril matrix having a stiffness of at least 5 Pa in the absence of an exogenous cross-linking agent. 
     
     
         17 . The pre-matrix composition of  claim 16 , wherein the one or more other type of non-oligomeric soluble collagen molecules comprises one or both of soluble telocollagen molecules and soluble atelocollagen molecules. 
     
     
         18 . The pre-matrix composition of  claim 16 , wherein the oligomeric collagen comprises type I collagen. 
     
     
         19 . The pre-matrix composition of  claim 16 , wherein the active agent is a growth factor or a drug. 
     
     
         20 . The pre-matrix composition of  claim 16 , wherein the active agent is covalently attached to one or more of the building blocks. 
     
     
         21 . The pre-matrix composition of  claim 16 , wherein the pre-matrix composition comprises the oligomeric collagen and non-oligomeric soluble collagen molecules in a ratio within a range selected from the group consisting of 0:100 to 5:95, 5:95 to 10:90, 10:90 to 15:85, 15:85 to 20:80, 20:80 to 25:75, 25:75 to 50:50, 50:50 to 75:25 and 75:25 to 100:0. 
     
     
         22 . The pre-matrix composition of  claim 16 , wherein the pre-matrix composition is capable of being modulated to achieve a nonsoluble synthetic collagen-fibril matrix that exhibits an optimized active agent release profile for the active agent. 
     
     
         23 . A method for delivering an active agent, comprising positioning at an in situ position:
 a pre-matrix composition comprising an aqueous solution including a first quantity of soluble collagen-fibril building blocks and a second quantity of an active agent in the aqueous solution, wherein the first quantity of soluble collagen-fibril building blocks includes soluble oligomeric collagen or a mixture of soluble oligomeric collagen with one or more type of soluble non-oligomeric collagen molecules, wherein the building blocks are operable to self-assemble into an insoluble synthetic macromolecular collagen-fibril matrix having a stiffness of at least 5 Pa in situ in the absence of an exogenous cross-linking agent; or   a collagen-based therapeutic delivery device comprising an insoluble synthetic collagen-fibril matrix comprising a polymerization product of soluble oligomeric collagen or a polymerization product of a mixture of soluble oligomeric collagen with one or more type of soluble non-oligomeric collagen molecules; and a first active agent dispersed throughout the collagen-fibril matrix or within a portion of the collagen-fibril matrix; wherein the collagen-fibril matrix exhibits a stiffness of at least 5 Pa.   
     
     
         24 . The method of  claim 23 , wherein the pre-matrix composition is positioned in situ by injection. 
     
     
         25 . The method of  claim 23 , wherein the collagen-based therapeutic delivery device is a tissue graft.