title: Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction.
abstract: Treatment of ischemia through therapeutic angiogenesis faces significant challenges. Growth factor (GF)-based therapies can be more effective when concerns such as GF spatiotemporal presentation, bioactivity, bioavailability, and localization are addressed. During angiogenesis, vascular endothelial GF (VEGF) is required early to initiate neovessel formation while platelet-derived GF (PDGF-BB) is needed later to stabilize the neovessels. The spatiotemporal delivery of multiple bioactive GFs involved in angiogenesis, in a close mimic to physiological cues, holds great potential to treat ischemic diseases. To achieve sequential release of VEGF and PDGF, we embed VEGF in fibrin gel and PDGF in a heparin-based coacervate that is distributed in the same fibrin gel. In vitro, we show the benefits of this controlled delivery approach on cell proliferation, chemotaxis, and capillary formation. A rat myocardial infarction (MI) model demonstrated the effectiveness of this delivery system in improving cardiac function, ventricular wall thickness, angiogenesis, cardiac muscle survival, and reducing fibrosis and inflammation in the infarct zone compared to saline, empty vehicle, and free GFs. Collectively, our results show that this delivery approach mitigated the injury caused by MI and may serve as a new therapy to treat ischemic hearts pending further examination.
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Hassan K
authors.initials: HK
authors.lastname: Awada
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Noah R
authors.initials: NR
authors.lastname: Johnson
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: yaw20@pitt.edu.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D002633:Chemotaxis / Q000187:drug effects; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers; D004338:Drug Combinations; D005337:Fibrin / Q000737:chemistry; D005355:Fibrosis; D005782:Gels; D006493:Heparin / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010215:Papio; D020574:Proto-Oncogene Proteins c-sis / Q000008:administration & dosage* / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004338:Drug Combinations; D005782:Gels; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D005337:Fibrin; D006493:Heparin
keywords: Coacervate; Controlled release; Fibrin gel; Growth factors; Myocardial infarction; Therapeutic angiogenesis
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