title: Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium.
abstract: A pH- and temperature-responsive, injectable hydrogel has been designed to take advantage of the acidic microenvironment of ischemic myocardium. This system can improve therapeutic angiogenesis methods by providing spatio-temporal control of angiogenic growth factor delivery. The pH- and temperature-responsive random copolymer, poly(N-isopropylacrylamide-co-propylacrylic acid-co-butyl acrylate) (p[NIPAAm-co-PAA-co-BA]), was synthesized by reversible addition fragmentation chain transfer polymerization. This polymer was a liquid at pH 7.4 and 37 °C but formed a physical gel at pH 6.8 and 37 °C. Retention of biotinylated basic fibroblast growth factor (bFGF) between 0 and 7 days after injection into infarcted rat myocardium was 10-fold higher with hydrogel delivery versus saline. Following 28 days of treatment in vivo, capillary and arteriolar densities were increased 30-40% by polymer + bFGF treatment versus saline + bFGF or polymer-only controls. Treatment with polymer + bFGF for 28 days resulted in a 2-fold improvement in relative blood flow to the infarct region versus day 0, whereas saline + bFGF or polymer-only had no effect. Fractional shortening determined by echocardiography was significantly higher following treatment with polymer + bFGF (30 ± 1.4%) versus saline (25 ± 1.2%) and polymer alone (25 ± 1.8%). By responding to local changes in pH- and temperature in an animal model of ischemia, this hydrogel system provided sustained, local delivery of bFGF, improved angiogenesis, and achieved therapeutic effects in regional blood flow and cardiac function.
authors.affiliation: Department of Bioengineering, University of Washington, 3720 15th Ave NE, Box 355061, Seattle, WA 98195, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Garbern
authors.forename: Elina
authors.initials: E
authors.lastname: Minami
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D001710:Biotin / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000494:pharmacology*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007267:Injections; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D013599:Systole / Q000187:drug effects / Q000502:physiology; D014463:Ultrasonography
chemical_list: D000178:Acrylamides; C512582:poly(N-isopropylacrylamide-co-propylacrylic acid); D016222:Fibroblast Growth Factor 2; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D001710:Biotin