Collagen-based therapeutic delivery systems
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.
1. A collagen-based therapeutic delivery device, comprising:
a controlled release collagen-based therapeutic delivery device, the device including:
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 types of non-oligomeric soluble collagen molecules; and
a first active agent dispersed throughout the collagen-fibril matrix or within a portion of the collagen-fibril matrix;
wherein the first active agent is present in a biologically active amount;
wherein the collagen-fibril matrix exhibits a stiffness of at least 5 Pa; and
wherein the microstructure of the collagen-fibril matrix controls the release kinetics of the first active agent in the collagen-based therapeutic delivery device, and wherein the device does not include cells.
2. The therapeutic delivery device of claim 1 , wherein the collagen-fibril matrix comprises type I collagen.
3. The therapeutic delivery device of claim 1 , wherein the collagen-based therapeutic delivery device is a tissue graft.
4. The therapeutic delivery device of claim 1 , wherein the collagen-based therapeutic delivery device is lyophilized.
5. The therapeutic delivery device of claim 1 , wherein the collagen-fibril matrix comprises a polymerization product of a mixture of more than 0 but less than 100 percent soluble oligomeric collagen with more than 0 but less than 100 percent of one or more types of non-oligomeric soluble collagen molecules.
6. The therapeutic delivery device of claim 5 , wherein the collagen-fibril matrix comprises a polymerization product of a mixture of soluble oligomeric collagen with one or more types of non-oligomeric soluble collagen molecules and wherein the oligomeric collagen and non-oligomeric soluble collagen molecules are in a ratio within a range selected from the group consisting of 5:95 to 10:90, 10:90 to 15:85, 15:85 to 20:80, 20:80to 25:75, 25:75 to 50:50, and 50:50 to 75:25.
7. The therapeutic delivery device of claim 1 , further comprising a second active agent dispersed throughout the collagen-fibril matrix or within a portion of the collagen-fibril matrix.
8. The therapeutic delivery device of claim 7 , wherein each of the first and second active agents is a growth factor or a drug.
9. The therapeutic delivery device of claim 1 , wherein the collagen-fibril matrix includes a first portion having a first fibril density and a second portion having a second fibril density; wherein the first fibril density is different than the second fibril density.
10. The therapeutic delivery device of claim 1 , wherein the collagen-fibril matrix includes a first portion having dispersed therein the first active agent and a second portion having dispersed therein a second active agent, wherein the therapeutic delivery device exhibits a first release profile for the first active agent and a second release profile for the second active agent, and wherein the first release profile is different than the second release profile.
11. The therapeutic delivery device of claim 1 , wherein the first active is present in in a biologically active amount sufficient to act as a chemotherapeutic agent, an oncostate, a hemapoietic modulator, an immune modulator, or an osteoinductant.
12. The therapeutic delivery device of claim 1 , wherein the collagen-fibril matrix includes a first portion having a first fibril microstructure and a second portion having a second fibril microstructure.
13. The therapeutic delivery device of claim 1 , wherein the polymerization product includes at least one of telocollagen and atelocollagen.