The effects of controlled HGF delivery from an affinity-binding alginate biomaterial on angiogenesis and blood perfusion in a hindlimb ischemia model.
Enhancing tissue self-repair through the use of active acellular biomaterials is one of the main goals of regenerative medicine. We now describe the features of an injectable alginate biomaterial designed to affinity-bind heparin-binding proteins and release them at a rate reflected by their association constant to alginate-sulfate. The interactions of hepatocyte growth factor (HGF) with alginate-sulfate resulted in factor protection from proteolysis, as shown by mass spectroscopy analysis after trypsin digestion. When the HGF/alginate-sulfate bioconjugate was incorporated into alginate hydrogel, HGF release was sustained by a factor of 3, as compared to the release rate from non-modified hydrogel. The released factor retained activity, as shown by its induction of ERK1/2 activation and affording cytoprotection in rat neonatal cardiomyocyte cultures. In vivo, an injectable form of the affinity-binding alginate system extended by 10-fold, as compared to a saline-treated group, retention of HGF in myocardial tissue when delivered immediately after myocardial infarction. In a severe murine hindlimb ischemia model, HGF delivery from the affinity-binding system improved tissue blood perfusion and induced mature blood vessel network formation. The therapeutic efficacy of the affinity-binding system, as well as its ease of delivery by injection, provides a proof-of-concept for the potential use of this bioactive biomaterial strategy in cardiovascular repair.
Ruvinov
Emil
E
Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Leor
Jonathan
J
Cohen
Smadar
S
D000464:Alginates / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D020723:Glucuronic Acid / Q000737:chemistry / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000494:pharmacology; D006603:Hexuronic Acids / Q000737:chemistry / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000378:metabolism; D007267:Injections; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000464:Alginates; D001672:Biocompatible Materials; D004337:Drug Carriers; D006603:Hexuronic Acids; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D017228:Hepatocyte Growth Factor; D020723:Glucuronic Acid