Ultrasound-triggerable agents for tissue engineering
The present invention is directed to compositions and methods for delivering a tissue scaffold comprising ultrasound-triggerable agents to an individual.
1. A method of delivering an effective amount of a therapeutic agent to an individual in need thereof comprising administering to the individual a device comprising:
(a) a hydrogel scaffold having a density of polymer within the hydrogel scaffold of about 1 mg/mL to about 50 mg/mL; and
(b) an emulsion comprising a first population of perfluorocarbon (PFC) droplets comprising a first therapeutic agent in the interior thereof, said first population of PFC droplets being within the hydrogel scaffold and having the property of vaporizing at a first ultrasound frequency and/or acoustic pressure threshold; the device further comprising
a second population of PFC droplets comprising a second therapeutic agent in the interior thereof, said second population of PFC droplets being within the hydrogel scaffold and having the property of vaporizing at a second ultrasound frequency and/or acoustic pressure threshold that is different than the first ultrasound frequency and/or acoustic pressure threshold, and
exposing the hydrogel scaffold to the first ultrasound frequency and/or acoustic pressure threshold to deliver the first therapeutic agent,
wherein the concentration of the first population of PFC droplets is sufficient to result in acoustic shadowing upon exposure of the first population of PFC droplets to ultrasound.
2. The method of claim 1 , wherein the device further comprises a progenitor cell.
3. The method of claim 2 wherein the progenitor cell is a fibroblast, a chondrocyte, an osteoblast, a skeletal myocyte, a cardiac myocyte, a mesenchymal progenitor cell, a hematopoietic progenitor cell, a satellite cell, a neural progenitor cell, a pancreatic progenitor cell, a blast cell or a combination thereof.
4. The method of claim 1 wherein the emulsion is a double emulsion comprising a primary emulsion and a secondary emulsion.
5. The method of claim 4 wherein the primary emulsion comprises water-in-PFC, and the secondary emulsion comprises water-in-PFC-in-water.
6. The method of claim 5 , wherein the device further comprises a surfactant.
7. The method of claim 6 , wherein a first surfactant stabilizing the primary emulsion is a triblock copolymer, and a second surfactant stabilizing the secondary emulsion is an aqueous soluble surfactant.
8. The method of claim 7 wherein the triblock copolymer comprises a perfluoroether and polyethylene glycol.
9. The method of claim 7 wherein the aqueous soluble surfactant is selected from the group consisting of a protein, a lipid, an ionic copolymer and a non-ionic copolymer.
10. The method of claim 1 wherein initial pore size of the hydrogel scaffold is at least about 100 nanometers (nm).
11. The method of claim 1 wherein vaporization of the PFC droplet results in a final pore size within the hydrogel scaffold of at least about 40 μm and up to about 5 millimeters (mm).
12. The method of claim 1 , wherein the density of the hydrogel scaffold is between about 1 mg/mL to about 20 mg/ml fibrinogen.
13. The method of claim 1 wherein the device is implantable.
14. The method of claim 1 wherein the device is topical.
15. The method of claim 1 wherein the first and/or second therapeutic agent is selected from the group consisting of a polypeptide, a peptide, a polynucleotide, a viral particle, a gas, a contrast agent and a small molecule.
16. The method of claim 1 wherein release of the first and/or second therapeutic agent is controlled spatially.
17. The method of claim 1 wherein release of the first and/or second therapeutic agent is controlled temporally.
18. The method of claim 1 wherein the first therapeutic agent and the second therapeutic agent are different.
19. The method of claim 1 wherein the device is administered to the individual by implantation.
20. The method of claim 19 wherein the implantation is subcutaneous or intramuscular.
21. The method of claim 1 wherein the volume fraction of the hydrogel scaffold that is taken up by all PFC droplets is from about 1% to about 10%, wherein the volume fraction of the first population of PFC droplets is at least 0.1%.
22. The method of claim 21 wherein the average diameter of the PFC droplets is from about 1 μm to about 100 μm.
23. The method of claim 21 wherein the average diameter of the PFC droplets is from about 0.1 μm to about 50 μm.
24. The method of claim 22 wherein the average diameter of the PFC droplets is about 5 μm, about 10 μm, about 15 μm, about 20 μm, or about 50 μm.
25. The method of claim 1 , further comprising exposing the hydrogel scaffold to the second ultrasound frequency and/or acoustic pressure threshold to deliver the second therapeutic agent.