title: Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel.
abstract: Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor therapy is promising, the retention in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. VEGF and ANG-1 were incorporated in PF hydrogels and their in vitro characteristics were studied. Acute MI was generated in a rodent model with rats randomly assigned to 4 groups; sham, saline, PF and PF-VEGF-ANG1 (n=10 each group). Saline or hydrogel was injected in infarct and peri-infarct areas of the myocardium. After 4weeks, myocardial function was assessed using echocardiography. Tissue samples were harvested for Hematoxylin and Eosin, Masson Trichrome and capillary staining to assess the extent of fibrotic scar and arteriogenesis. Both VEGF and ANG-1 were released in a sustained and controlled manner over 30days. PF-VEGF-ANG1 treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI. The utility of this synergistic, biomaterial-based growth factor delivery may have clinical implications in the prevention of post-MI cardiac dysfunction.
  
  
  
  Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. Treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI.
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Abdul Jalil
authors.initials: AJ
authors.lastname: Rufaihah
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Nurul Azizah
authors.initials: NA
authors.lastname: Johari
authors.affiliation: Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, Singapore.
authors.forename: Srirangam Ramanujam
authors.initials: SR
authors.lastname: Vaibavi
authors.affiliation: Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, Singapore.
authors.forename: Marian
authors.initials: M
authors.lastname: Plotkin
authors.affiliation: Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, Singapore.
authors.forename: Do Thi
authors.initials: DT
authors.lastname: Di Thien
authors.affiliation: Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, National University Health System, Singapore. Electronic address: surtk@nus.edu.sg.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kofidis
authors.affiliation: Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel; Nanoscience and Nanotechnology Initiative, Faculty of Engineering, National University of Singapore, Singapore. Electronic address: dror@nm.technion.ac.il.
authors.forename: Dror
authors.initials: D
authors.lastname: Seliktar
mesh_terms: D042683:Angiopoietin-1 / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005340:Fibrinogen / Q000737:chemistry; D005455:Fluorescent Antibody Technique; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007700:Kinetics; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D011092:Polyethylene Glycols / Q000737:chemistry; D017208:Rats, Wistar; D013194:Staining and Labeling; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011092:Polyethylene Glycols; D005340:Fibrinogen
keywords: Biomaterials; Growth factor delivery; Heart attack; Myocardial infarction; PEG-fibrinogen