Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis.
Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half-life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 mug) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE(-/-)) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm(-2)). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long-term in vivo therapeutic benefit (localized bioactive VEGF for 1-2 weeks) with minimally invasive delivery.
Silva
E A
EA
Division of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02139, USA.
Mooney
D J
DJ
D000464:Alginates / Q000737:chemistry; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006614:Hindlimb; D006801:Humans; D020100:Hydrogels; D007267:Injections; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects; D015203:Reproducibility of Results; D012995:Solubility; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000464:Alginates; D043925:Angiogenesis Inducing Agents; D001057:Apolipoproteins E; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A