Neointimal hyperplasia is a response to injury in vascular tissues which promotes abnormal thickening of vascular walls with luminal narrowing. In the clinical setting, this luminal narrowing in response to mechanical injury can promote renarrowing or restenosis of balloon-dilated arteries. In vascular surgery, small diameter vascular grafts fail at clinically unacceptable rates because of uncontrolled, injury-induced neointimal hyperplasia. Antagonists of beta3 and alphaV integrins delivered locally to balloon-injured arteries have been shown by the investigator and others to significantly reduce neointimal hyperplasia by limiting smooth muscle cell migration. This drug class has also been shown to effectively limit clinical restenosis following coronary arterial balloon angioplasty. In the proposed study, it is hypothesized that under optimal conditions, locally delivered alphaV integrin antagonist cyclic RGD peptide (cyclic GPENGRGDSPCA) will limit neointimal hyperplasia in implanted small diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts. Further, this locally delivered peptide will limit neointimal hyperplasia without affecting EC retention and function in EC-sodden grafts. One major goal of this study will be to develop a polymeric drug delivery formulation that can be loaded with cyclic RGD peptide, impregnated into a small diameter ePTFE graft, and deliver cyclic RGD peptide at an optimal rate for maximal reduction of graft hyperplasia. To achieve this goal, a well characterized degradable, gel-forming co-polyester family and degradable crystalline, polymeric cation exchanger microparticles will be utilized to develop biocompatible formulations that provide a broad range of in vitro release rates for cyclic RGD. Peptide-loaded formulations that have a desirable range of release rates will then be impregnated in ePTFE grafts and evaluated for their effect on hyperplasia in a well defined rat aorta small diameter ePTFE graft model. A second goal of this project will be to determine how locally delivered cyclic RGD peptide that is optimized for reducing graft hyperplasia will influence endothelial cell (EC) retention and function in EC-sodded grafts. The effects of local drug delivery on EC retention will be assessed in vitro and in vivo in sodded grafts. Cyclic RGD-mediated effects on EC pro- and anticoagulant activity in EC-sodded grafts will also be determined in vitro. The development of efficacious local drug therapies may be critical for reducing progressive neointimal thickening to tolerable levels in small diameter synthetic vascular grafts so that clinically acceptable failure rates can be realized.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060450-06
Application #
6537399
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M1))
Program Officer
Lundberg, Martha
Project Start
1998-07-10
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2002
Total Cost
$202,500
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
188435911
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Ehteshami, Gholamreza; Brune, Daniel C; Lopez, John C et al. (2005) A bioconjugate of Lys and Arg mimics biological activity of the Arg-Gly-Asp peptide sequence. Acta Biomater 1:85-91
Trudel, J; Massia, S P (2002) Assessment of the cytotoxicity of photocrosslinked dextran and hyaluronan-based hydrogels to vascular smooth muscle cells. Biomaterials 23:3299-307
Massia, S P; Stark, J (2001) Immobilized RGD peptides on surface-grafted dextran promote biospecific cell attachment. J Biomed Mater Res 56:390-9
Massia, S P; Stark, J; Letbetter, D S (2000) Surface-immobilized dextran limits cell adhesion and spreading. Biomaterials 21:2253-61