title: Therapeutic angiogenesis induced by controlled release of fibroblast growth factor-2 from injectable chitosan/non-anticoagulant heparin hydrogel in a rat hindlimb ischemia model.
abstract: The addition of non-anticoagulant heparin [periodate-oxidized (IO4) heparin] and fibroblast growth factor (FGF)-2 to a viscous water-soluble chitosan (CH-LA) aqueous solution produces an injectable FGF-2/CH-LA/IO4-heparin hydrogel. The purpose of this study was to examine the ability of the injected FGF-2/CH-LA/IO4-heparin hydrogel to induce vascularization and fibrous tissue formation. FGF-2/CH-LA/IO4-heparin hydrogels (100 microL of hydrogel consisting of 20 mg/mL of CH-LA, 2 mg/mL of IO4-heparin, and 50 microg/mL of FGF-2) were subcutaneously injected into the backs of wound healing-impaired diabetic (db/db) mice. Furthermore, the effect of percutaneous injection of FGF-2/CH-LA/IO4-heparin hydrogel at eight sites (25 microL/site) into ischemic left lower limbs of rats was examined from day 4 to at least day 28 postinjection. The injection of FGF-2/CH-LA/IO4-heparin hydrogels into the backs of db/db mice resulted in significant increases in blood vessel formation, significant vascularization, and fibrous tissue formation near the injection site. Injection of FGF-2/CH-LA/IO4-heparin hydrogel into ischemic left lower limbs of rats also significantly recovered and increased blood flow and blood oxygen in the calf and thigh. These results indicate that the controlled release of biologically active FGF-2 molecules from FGF-2/CH-LA/IO4-heparin induces angiogenesis and possibly collateral circulation in db/db mice and the ischemic limbs of rats.
authors.affiliation: Department of Medical Engineering, National Defense Medical College, Saitama, Japan. BXB01424@nifty.ne.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishihara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kiyohaya
authors.initials: K
authors.lastname: Obara
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kanatani
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morimoto
authors.forename: Bonpei
authors.initials: B
authors.lastname: Takase
authors.forename: Takemi
authors.initials: T
authors.lastname: Matsui
authors.forename: Makoto
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Maehara
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D048271:Chitosan; D003097:Collateral Circulation / Q000187:drug effects; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D006493:Heparin / Q000031:analogs & derivatives; D006614:Hindlimb / Q000098:blood supply*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D007273:Injections, Intramuscular; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D016222:Fibroblast Growth Factor 2; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D006493:Heparin; D048271:Chitosan