Methods and compositions for enhancing vascular access

• US 9,023,377 B2
• Filed: 11/02/2012
• Issued: 05/05/2015
• Est. Priority Date: 06/21/2005
• Status: Active Grant

• Current Assignee: Shire Regenerative Medicine Incorporated (Shire plc)
• Original Assignee: Shire Regenerative Medicine Incorporated (Shire plc)
• Inventors: Nugent, Helen Marie, Edelman, Elazer
• Primary Examiner(s): Fox, Allison
• Assistant Examiner(s): Pyla, Yvonne
• Application Number:
  US13/667,227
• Publication Number:
  US 20130210142A1
• Time in Patent Office: 914 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61L 27/3808 Endothelial cells
• CPC Class Codes: C12N 5/069 Vascular Endothelial cells

Abstract

Disclosed is an implantable material comprising a biocompatible matrix and cells which, when provided to a vascular access structure, can promote functionality generally. For example, implantable material of the present invention can enhance maturation of an arteriovenous native fistula as well as prolong the fistula in a mature, functional state suitable for dialysis. Additionally, the present invention can promote formation of a functional arteriovenous graft suitable for dialysis as well as promote formation of a functional peripheral bypass graft. Implantable material can be configured as a flexible planar form or a flowable composition with shape-retaining properties suitable for implantation at, adjacent or in the vicinity of an anastomoses or arteriovenous graft. According to the methods disclosed herein, the implantable material is provided to an exterior surface of a blood vessel. Certain embodiments of the flexible planar form define a slot. The materials and methods of the present invention comprise cells, preferably endothelial cells or cells having an endothelial-like phenotype.

Claims

1. An implantable material prepared by a method comprising the steps of:

cryopreserving at −

4°

C. to −

160°

C. for at least 1 month a population of vascular endothelial cells having an inhibitory phenotype such that they are capable of inhibiting or interfering with vascular smooth muscle cell proliferation, said cells attached via cell to matrix interactions to a flexible planar or flowable biocompatible substrate, wherein said inhibitory phenotype is selected from the group consisting of;

expression of heparin sulfate of at least 200 ng/mL/day, expression of TGF-beta of at least 300 pg/mL/day, and expression of b-FGF of no more than 300 pg/mL/day; and

wherein said population of cells is at least 80% viable prior to and following cryopreservation; and

thawing said cryopreserved implantable material in a transport media composition comprising EGM-2 supplemented with an amount of VEGF sufficient to maintain both cell viability and said inhibitory phenotype for an extended period of time when said implantable material is stored at temperatures below the cells'"'"' standard cell culture temperature.

2. The implantable material of claim 1 wherein said material has been cryopreserved at −

4°

C. to −

160°

C. for at least 6 months.

3. The implantable material of claim 1 wherein said material has been cryopreserved at −

4°

C. to −

160°

C. for at least 12 months.

4. The implantable material of claim 1 wherein said material is in a non-frozen state for up to 7 days.

5. The implantable material of claim 1 wherein said material is in a non-frozen state for at least 14 days.

6. The implantable material of claim 1 wherein said material is in a non-frozen state for at least 21 days.

7. The implantable material of claim 1 wherein said material is in a non-frozen state for at least 28 days.

8. The implantable material of claim 1 wherein said material is stored at or below 37°

C.

9. The implantable material of claim 1 wherein said material is stored at 15-25°

C.

10. The implantable material of claim 1 wherein said population of cells is not immortalized.

11. The implantable material of claim 1 wherein the amount of VEGF is 2 ng/mL to 4 ng/mL and the extended period is one week.

12. A composition for treatment comprising the implantable material of claim 1, characterized in that said composition is implanted in a patient in need thereof in a non-frozen state.

13. The composition of claim 12 wherein said composition is implanted 1 week to 1 year after a non-frozen state is achieved.

14. A cryopreserved implantable material comprising:

a biocompatible matrix engrafted with a population of near-confluent, confluent, or post-confluent vascular endothelial cells, wherein the implantable material is cryopreserved at −

4°

C. to −

160°

C. for at least 1 month, and wherein the cells are at least 80% viable and exhibit a phenotype comprising heparan sulfate production of at least 200 ng/mL/day, TGF-β

1 production of at least 300 pg/mL/day, and b-FGF production of no more than 300 pg/mL/day, prior to and following cryopreservation; and

, a transport media composition comprising EGM-2 supplemented with an amount of VEGF sufficient to maintain both cell viability and said inhibitory phenotype for an extended period of time when said implantable material is stored at temperatures below the cells'"'"' standard cell culture temperature.

15. The cryopreserved implantable material of claim 14 wherein the material is cryopreserved at −

4°

C. to −

160°

C. for at least 6 months.

16. The cryopreserved implantable material of claim 14 wherein the material is cryopreserved at −

4°

C. to −

160°

C. for at least 12 months.

17. The cryopreserved implantable material of claim 14 wherein the amount of VEGF is 2 ng/mL to 4 ng/mL and the extended period is one week.