Controlled release of growth factors and signaling molecules for promoting angiogenesis
The present invention comprises compositions, methods, and devices for delivering angiogenic factors and signaling molecules to a target tissue, and controlling the release of these factors and signaling molecules to spatially and temporally restrict their release and dissemination, for the purpose of promoting angiogenesis in target tissues.
1. A method of inducing growth of new blood vessels either from existing blood vessels, or creation of de novo vessels, or a combination thereof, in a target tissue of a mammal, comprising contacting a mammalian cell by injecting into a tissue a device comprising an alginate hydrogel scaffold composition comprising N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and vascular endothelial growth factor (VEGF), wherein said scaffold composition temporally controls release of the DAPT and the VEGF, wherein the VEGF said bioactive composition induces angiogenesis, arteriogenesis, or vasculogenesis, and wherein the VEGF comprises VEGF 121 , VEGF 145 , VEGF 165 , VEGF 189 , or VEGF 206 .
2. The method of claim 1 , wherein the DAPT is released before the VEGF.
3. The method of claim 1 , wherein said VEGF is released over a period of weeks and said DAPT is released over a period of less than one week.
4. The method of claim 1 , wherein said mammal is a human.
5. The method of claim 1 , wherein said mammal has diabetes.
6. The method of claim 1 , wherein said hydrogel scaffold comprises nanopores.
7. The method of claim 1 , wherein the DAPT is released from the scaffold composition at a first rate and the VEGF is released from the scaffold composition at a second rate, and wherein the second rate is slower than the first rate.
8. The method of claim 7 , wherein the VEGF exits from the scaffold composition for a time period of one or more weeks.
9. The method of claim 7 , wherein the DAPT exits from the scaffold composition for a period of one or more days.
10. The method of claim 1 , wherein the device comprises a molar ratio of 1:1 to 1:200 for VEGF 165 to DAPT.
11. The method of claim 10 , wherein the device comprises a molar ratio of 1:31 for VEGF 165 to DAPT.
12. The method of claim 1 , wherein the mammal has coronary arterial disease (CAD) or peripheral arterial disease (PAD).
13. The method of claim 1 , wherein the mammal has acute or chronic ischemia due to peripheral arterial disease (PAD).
14. The method of claim 1 , wherein the mammal has a diabetic ulcer or a wound due to peripheral arterial disease (PAD).
15. A method of inducing growth of new blood vessels either from existing blood vessels, or creation of de novo vessels, or a combination thereof, in a target tissue of a mammal, comprising contacting a mammalian cell by injecting into a tissue a device comprising an alginate hydrogel scaffold composition comprising N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and a bioactive composition selected from the group consisting of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), wherein said scaffold composition temporally controls release of the DAPT and the bioactive composition, wherein the bioactive composition induces angiogenesis, arteriogenesis, or vasculogenesis, and wherein the VEGF comprises VEGF 121 , VEGF 145 , VEGF 165 , VEGF 189 , or VEGF 206 .
16. The method of claim 15 , wherein said DAPT is released within 1-3 days and said VEGF or PDGF is released within 7-60 days.
17. The method of claim 15 , wherein the DAPT is released before the bioactive composition.
18. The method of claim 15 , wherein the PDGF comprises PDGF-BB.
19. The method of claim 15 , wherein the device comprises a molar ratio of 1:1 to 1:200 for VEGF 165 to DAPT, or 1:1 to 1:200 for PDGF-BB to DAPT.
20. The method of claim 19 , wherein the device comprises a molar ratio of 1.8:31 for PDGF-BB to DAPT.
21. The method of claim 15 , wherein the mammal has coronary arterial disease (CAD) or peripheral arterial disease (PAD).
22. The method of claim 15 , wherein the mammal has acute or chronic ischemia due to peripheral arterial disease (PAD).
23. The method of claim 15 , wherein the mammal has a diabetic ulcer or a wound due to peripheral arterial disease (PAD).
24. A method of inducing growth of new blood vessels either from existing blood vessels, or creation of de novo vessels, or a combination thereof, in a target tissue of a mammal, comprising contacting a mammalian cell by injecting into a tissue a device comprising a hydrogel scaffold composition comprising N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), wherein said scaffold composition temporally controls release of the DAPT, VEGF, and PDGF, and wherein the VEGF and PDGF induce angiogenesis, arteriogenesis, or vasculogenesis.
25. The method of claim 24 , wherein the device comprises a molar ratio of 1:0.1:1 to 1:10:200 for VEGF 165 , PDGF-BB and DAPT.
26. The method of claim 25 , wherein the device comprises a molar ratio of 1:1.8:31 for VEGF 165 , PDGF-BB and DAPT.
27. The method of claim 24 , wherein the mammal has coronary arterial disease (CAD) or peripheral arterial disease (PAD).
28. The method of claim 24 , wherein the mammal has acute or chronic ischemia due to peripheral arterial disease (PAD).
29. The method of claim 24 , wherein the mammal has a diabetic ulcer or a wound due to peripheral arterial disease (PAD).