Pavan Atluri1, Jordan S Miller2, Robert J Emery1, George Hung1, Alen Trubelja1, Jeffrey E Cohen3, Kelsey Lloyd1, Jason Han1, Ann C Gaffey1, John W MacArthur1, Christopher S Chen4, Y Joseph Woo5. 1. Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa. 2. Department of Bioengineering, Rice University, Houston, Tex. 3. Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif. 4. Department of Biomedical Engineering, Boston University, Boston, Mass. 5. Department of Cardiothoracic Surgery, Stanford University, Stanford, Calif. Electronic address: joswoo@stanford.edu.
Abstract
OBJECTIVES: 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.
OBJECTIVES: 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 ischemicrat 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: M Kulkarni; A O'Loughlin; R Vazquez; K Mashayekhi; P Rooney; U Greiser; E O'Toole; T O'Brien; Maria M Malagon; A Pandit Journal: Biomaterials Date: 2013-12-10 Impact factor: 12.479
Authors: Ahmad Y Sheikh; Bruno C Huber; Kazim H Narsinh; Joshua M Spin; Koen van der Bogt; Patricia E de Almeida; Katherine J Ransohoff; Daniel L Kraft; Giovanni Fajardo; Diego Ardigo; Julia Ransohoff; Daniel Bernstein; Michael P Fischbein; Robert C Robbins; Joseph C Wu Journal: Arterioscler Thromb Vasc Biol Date: 2011-10-27 Impact factor: 8.311
Authors: Y Joseph Woo; Corinna M Panlilio; Richard K Cheng; George P Liao; Pavan Atluri; Vivian M Hsu; Jeffrey E Cohen; Hina W Chaudhry Journal: Circulation Date: 2006-07-04 Impact factor: 29.690
Authors: Volker Schächinger; Sandra Erbs; Albrecht Elsässer; Werner Haberbosch; Rainer Hambrecht; Hans Hölschermann; Jiangtao Yu; Roberto Corti; Detlef G Mathey; Christian W Hamm; Tim Süselbeck; Birgit Assmus; Torsten Tonn; Stefanie Dimmeler; Andreas M Zeiher Journal: N Engl J Med Date: 2006-09-21 Impact factor: 91.245
Authors: John R Frederick; J Raymond Fitzpatrick; Ryan C McCormick; David A Harris; Ah-Young Kim; Jeffrey R Muenzer; Nicole Marotta; Maximilian J Smith; Jeffrey E Cohen; William Hiesinger; Pavan Atluri; Y Joseph Woo Journal: Circulation Date: 2010-09-14 Impact factor: 29.690
Authors: Michael Hofmann; Kai C Wollert; Gerd P Meyer; Alix Menke; Lubomir Arseniev; Bernd Hertenstein; Arnold Ganser; Wolfram H Knapp; Helmut Drexler Journal: Circulation Date: 2005-04-25 Impact factor: 29.690
Authors: Vasant Jayasankar; Timothy J Pirolli; Lawrence T Bish; Mark F Berry; Jeffrey Burdick; Todd Grand; Y Joseph Woo Journal: J Mol Cell Cardiol Date: 2004-04 Impact factor: 5.000
Authors: Marc Ruel; Roger J Laham; J Anthony Parker; Mark J Post; J Anthony Ware; Michael Simons; Frank W Sellke Journal: J Thorac Cardiovasc Surg Date: 2002-07 Impact factor: 5.209
Authors: Pavan Atluri; Alen Trubelja; Alexander S Fairman; Philip Hsiao; John W MacArthur; Jeffrey E Cohen; Yasuhiro Shudo; John R Frederick; Y Joseph Woo Journal: Circulation Date: 2013-09-10 Impact factor: 29.690
Authors: Andreas Brandl; Quan Yuan; Anja M Boos; Justus P Beier; Andreas Arkudas; Ulrich Kneser; Raymund E Horch; Oliver Bleiziffer Journal: BMC Cell Biol Date: 2014-03-26 Impact factor: 4.241
Authors: Renganaden Sooppan; Samantha J Paulsen; Jason Han; Anderson H Ta; Patrick Dinh; Ann C Gaffey; Chantel Venkataraman; Alen Trubelja; George Hung; Jordan S Miller; Pavan Atluri Journal: Tissue Eng Part C Methods Date: 2015-12-14 Impact factor: 3.056
Authors: Ann C Gaffey; Minna H Chen; Chantel M Venkataraman; Alen Trubelja; Christopher B Rodell; Patrick V Dinh; George Hung; John W MacArthur; Renganaden V Soopan; Jason A Burdick; Pavan Atluri Journal: J Thorac Cardiovasc Surg Date: 2015-07-17 Impact factor: 5.209
Authors: Ann C Gaffey; Minna H Chen; Alen Trubelja; Chantel M Venkataraman; Carol W Chen; Jennifer J Chung; Susan Schultz; Chandra M Sehgal; Jason A Burdick; Pavan Atluri Journal: J Thorac Cardiovasc Surg Date: 2018-11-14 Impact factor: 5.209
Authors: Lei Cai; Ruby E Dewi; Andrew B Goldstone; Jeffrey E Cohen; Amanda N Steele; Y Joseph Woo; Sarah C Heilshorn Journal: Adv Healthc Mater Date: 2016-10-06 Impact factor: 9.933
Authors: Carol W Chen; Leo L Wang; Samir Zaman; Jon Gordon; Maria F Arisi; Chantel M Venkataraman; Jennifer J Chung; George Hung; Ann C Gaffey; Lynn A Spruce; Hossein Fazelinia; Robert C Gorman; Steven H Seeholzer; Jason A Burdick; Pavan Atluri Journal: Cardiovasc Res Date: 2018-06-01 Impact factor: 10.787
Authors: Ze-Wei Tao; Dillon K Jarrell; Andrew Robinson; Elizabeth M Cosgriff-Hernandez; Jeffrey G Jacot Journal: Adv Healthc Mater Date: 2021-10-08 Impact factor: 9.933
Authors: Jennifer J Chung; Jason Han; Leo L Wang; Maria F Arisi; Samir Zaman; Jonathan Gordon; Elizabeth Li; Samuel T Kim; Zoe Tran; Carol W Chen; Ann C Gaffey; Jason A Burdick; Pavan Atluri Journal: J Thorac Cardiovasc Surg Date: 2019-06-18 Impact factor: 6.439