Elastogenic cues and methods for using same
Disclosed are elastogenic cues that can be utilized to encourage growth and development of elastin-containing cellular constructs. The elastogenic cues include hyaluronan fragments and oligomers, optionally in conjunction with growth factors and/or a source of copper ions. The elastogenic cues can up-regulate elastin matrix synthesis and by vascular smooth muscle cells. In addition to encouraging synthesis of elastin in a cellular matrix and organization into elastic fibers, the elastogenic cues can also stabilize the formed ECM matrix through suppression of elastin-laminin receptor (ELR). In addition, the elastogenic cues can inhibit cell hyper-proliferation (e.g., hyperplasia) common in inflammatory vascular disease.
1. An elastogenic composition comprising:
hyaluronic acid fragments, the hyaluronic acid fragments of the composition having a number average molecular weight of less than about 2×10 6 Daltons;
nanoparticles formed of copper, the nanoparticles formed of copper being present in the elastogenic composition at a concentration that delivers copper ions from the nanoparticles in an aqueous environment at a concentration of between about 0.1 μM and about 0.1M; and
a delivery vehicle for delivering the hyaluronic acid fragments and the nanoparticles formed of copper to a cellular construct including elastin producing cells.
2. The elastogenic composition of claim 1 , wherein the hyaluronic acid oligomers of the composition are less than 12 monomer units in length.
3. The elastogenic composition of claim 1 , further comprising a growth factor.
4. The elastogenic composition of claim 3 , wherein the growth factor is TGF-β.
5. The elastogenic composition of claim 3 , wherein the growth factor is IGF-1.
6. The elastogenic composition of claim 1 , wherein the delivery vehicle is a tissue engineering scaffold.
7. The elastogenic composition of claim 6 , wherein the hyaluronic acid fragments are tethered to the tissue engineering scaffold.
8. The elastogenic composition of claim 1 , wherein the delivery vehicle is a sustained release delivery vehicle.
9. The elastogenic composition of claim 1 , wherein the nanoparticles are formed of only copper.
10. The elastogenic composition of claim 1 , wherein the hyaluronic acid fragments have a molecular weight of between about 0.6 kDa and about 1 kDa.
11. A method for upregulating elastin synthesis by elastin producing cells comprising contacting a cellular construct including elastin producing cells with the elastogenic composition of claim 1 .
12. The method according to claim 11 , wherein the elastin producing cells are smooth muscle cells.
13. The method according to claim 11 , wherein the cellular construct is a natural tissue.
14. The method according to claim 11 , wherein the cellular construct is a synthetic cellular construct.
15. An elastogenic composition comprising:
hyaluronic acid fragments, the hyaluronic acid fragments of the composition having a number average molecular weight of between about 0.6 kDa and about 1 kDa; and
nanoparticles formed of copper, the nanoparticles formed of copper being present in the elastogenic composition at a concentration that delivers copper ions from the nanoparticles in an aqueous environment at a concentration of between about 0.1 μM and about 0.1M; wherein
the elastogenic composition is a component of a perivascular or endovascular delivery vehicle placeable adjacent a blood vessel wall.
16. The elastogenic composition of claim 15 , wherein the perivascular or endovascular delivery vehicle comprises a tubular member.
17. The elastogenic composition of claim 15 , wherein the perivascular or endovascular delivery vehicle is a stent.
18. The elastogenic composition of claim 15 , wherein the perivascular or endovascular delivery vehicle comprises a sustained-release matrix.
19. The elastogenic composition of claim 15 , wherein the perivascular or endovascular delivery vehicle comprises a hydrogel.
20. The elastogenic composition of claim 15 , wherein the hyaluronic acid fragments of the composition are less than 12 monomer units in length.
21. The elastogenic composition of claim 15 , further comprising a growth factor.
22. The elastogenic composition of claim 21 , wherein the growth factor is TGF-β or IGF-1.