title: Tissue-engineered, hydrogel-based endothelial progenitor cell therapy robustly revascularizes ischemic myocardium and preserves ventricular function.
abstract: OBJECTIVE
  Cell-based angiogenic therapy for ischemic heart failure has had limited clinical impact, likely related to low cell retention (<1%) and dispersion. We developed a novel, tissue-engineered, hydrogel-based cell-delivery strategy to overcome these limitations and provide prolonged regional retention of myocardial endothelial progenitor cells at high cell dosage.
  
  
  METHODS
  Endothelial progenitor cells were isolated from Wistar rats and encapsulated in fibrin gels. In vitro viability was quantified using a fluorescent live-dead stain of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells. Endothelial progenitor cell-laden constructs were implanted onto ischemic rat myocardium in a model of acute myocardial infarction (left anterior descending ligation) for 4 weeks. Intramyocardial cell injection (2 × 10(6) endothelial progenitor cells), empty fibrin, and isolated left anterior descending ligation groups served as controls. Hemodynamics were quantified using echocardiography, Doppler flow analysis, and intraventricular pressure-volume analysis. Vasculogenesis and ventricular geometry were quantified. Endothelial progenitor cell migration was analyzed by using endothelial progenitor cells from transgenic enhanced green fluorescent protein(+) rodents.
  
  
  RESULTS
  Endothelial progenitor cells demonstrated an overall 88.7% viability for all matrix and cell conditions investigated after 48 hours. Histologic assessment of 1-week implants demonstrated significant migration of transgenic enhanced green fluorescent protein(+) endothelial progenitor cells from the fibrin matrix to the infarcted myocardium compared with intramyocardial cell injection (28 ± 12.3 cells/high power field vs 2.4 ± 2.1 cells/high power field, P = .0001). We also observed a marked increase in vasculogenesis at the implant site. Significant improvements in ventricular hemodynamics and geometry were present after endothelial progenitor cell-hydrogel therapy compared with control.
  
  
  CONCLUSIONS
  We present a tissue-engineered, hydrogel-based endothelial progenitor cell-mediated therapy to enhance cell delivery, cell retention, vasculogenesis, and preservation of myocardial structure and function.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Pavan
authors.initials: P
authors.lastname: Atluri
authors.affiliation: Department of Bioengineering, Rice University, Houston, Tex.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Emery
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: George
authors.initials: G
authors.lastname: Hung
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Alen
authors.initials: A
authors.lastname: Trubelja
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Cohen
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Lloyd
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Jason
authors.initials: J
authors.lastname: Han
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Gaffey
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.
authors.forename: John W
authors.initials: JW
authors.lastname: MacArthur
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Mass.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif. Electronic address: joswoo@stanford.edu.
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation*; D005337:Fibrin / Q000378:metabolism; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics; D020100:Hydrogels; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D051381:Rats; D017208:Rats, Wistar; D033581:Stem Cell Transplantation; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D014162:Transfection; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D020100:Hydrogels; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005337:Fibrin