title: Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats.
abstract: Acute myocardial infarction (MI) caused by ischemia and reperfusion (IR) is the most common cause of cardiac dysfunction due to local cell death and a temporally regulated inflammatory response. Current therapeutics are limited by delivery vehicles that do not address spatial and temporal aspects of healing. The aim of this study was to engineer biotherapeutic delivery materials to harness endogenous cell repair to enhance myocardial repair and function. We have previously engineered poly(ethylene glycol) (PEG)-based hydrogels to present cell adhesive motifs and deliver VEGF to promote vascularization in vivo. In the current study, bioactive hydrogels with a protease-degradable crosslinker were loaded with hepatocyte and vascular endothelial growth factors (HGF and VEGF, respectively) and delivered to the infarcted myocardium of rats. Release of both growth factors was accelerated in the presence of collagenase due to hydrogel degradation. When delivered to the border zones following ischemia-reperfusion injury, there was no acute effect on cardiac function as measured by echocardiography. Over time there was a significant increase in angiogenesis, stem cell recruitment, and a decrease in fibrosis in the dual growth factor delivery group that was significant compared with single growth factor therapy. This led to an improvement in chronic function as measured by both invasive hemodynamics and echocardiography. These data demonstrate that dual growth factor release of HGF and VEGF from a bioactive hydrogel has the capacity to significantly improve cardiac remodeling and function following IR injury.
authors.affiliation: Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Apoorva S
authors.initials: AS
authors.lastname: Salimath
authors.forename: Edward A
authors.initials: EA
authors.lastname: Phelps
authors.forename: Archana V
authors.initials: AV
authors.lastname: Boopathy
authors.forename: Pao-lin
authors.initials: PL
authors.lastname: Che
authors.forename: Milton
authors.initials: M
authors.lastname: Brown
authors.forename: Andrés J
authors.initials: AJ
authors.lastname: García
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D002465:Cell Movement / Q000187:drug effects; D002469:Cell Separation; D016503:Drug Delivery Systems / Q000379:methods*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage* / Q000494:pharmacology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010447:Peptide Hydrolases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D001672:Biocompatible Materials; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D017228:Hepatocyte Growth Factor; D010447:Peptide Hydrolases