Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb.
OBJECTIVE
We hypothesized that sustained delivery of vascular endothelial growth factor (VEGF) using a polymer [85:15 poly(lactide-co-glycolide) (PLG)] would enhance angiogenesis and improve perfusion of ischemic tissue.


METHODS
C57BL/6J mice (n = 20/group) underwent unilateral hind limb ischemia surgery and were randomized to groups of no scaffold implantation (0-Implant), unloaded scaffold implantation (Empty-PLG), or implantation of scaffolds incorporating 3 microg of VEGF165 (PLG-VEGF). Endpoints included laser Doppler perfusion imaging (LDPI, ischemic/nonischemic limb, %), local vessel counts, immunohistochemistry for CD31, and alpha-smooth muscle actin. In vitro release kinetics of VEGF from PLG was also measured.


RESULTS
PLG-VEGF resulted in improved lower extremity perfusion vs. controls as measured by LDPI% at 7, 14, 21, and 28 days (p < 0.05). PLG-VEGF was associated with significantly greater percentage of vessels staining for CD31 and alpha-smooth muscle actin compared to the Empty-PLG or 0-Implant (p < 0.05 for both).


CONCLUSIONS
The PLG-VEGF scaffolds resulted in sustained VEGF delivery, improved tissue perfusion, greater capillary density, and more mature vasculature compared to the controls. The sustained-release PLG polymer vehicle is a promising delivery system for therapeutic neovascularization applications.
Sun
Qinghua
Q
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Hospitals and Health System, Ann Arbor, Michigan 48109-0311, USA.
Chen
Ruth R
RR
Shen
Yuechun
Y
Mooney
David J
DJ
Rajagopalan
Sanjay
S
Grossman
P Michael
PM
D000199:Actins / Q000378:metabolism; D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage; D002196:Capillaries / Q000254:growth & development; D004195:Disease Models, Animal; D004337:Drug Carriers; D006614:Hindlimb / Q000098:blood supply / Q000503:physiopathology; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D019344:Lactic Acid / Q000008:administration & dosage*; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010477:Perfusion; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
D000199:Actins; D001672:Biocompatible Materials; D004337:Drug Carriers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011108:Polymers; D042461:Vascular Endothelial Growth Factor A; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid