title: Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair.
abstract: Myocardial infarction (MI) causes myocardial necrosis, triggers chronic inflammatory responses, and leads to pathological remodeling. Controlled delivery of a combination of angiogenic and immunoregulatory proteins may be a promising therapeutic approach for MI. We investigated the bioactivity and therapeutic potential of an injectable, heparin-based coacervate co-delivering an angiogenic factor, fibroblast growth factor-2 (FGF2), and an anti-inflammatory cytokine, Interleukin-10 (IL-10) in a spatially and temporally controlled manner. Coacervate delivery of FGF2 and IL-10 preserved their bioactivities on cardiac stromal cell proliferation in vitro. Upon intramyocardial injection into a mouse MI model, echocardiography revealed that FGF2/IL-10 coacervate treated groups showed significantly improved long-term LV contractile function and ameliorated LV dilatation. FGF2/IL-10 coacervate substantially augmented LV myocardial elasticity. Additionally, FGF2/IL-10 coacervate notably enhanced long-term revascularization, especially at the infarct area. In addition, coacervate loaded with 500 ng FGF2 and 500 ng IL-10 significantly reduced LV fibrosis, considerably preserved infarct wall thickness, and markedly inhibited chronic inflammation at the infarct area. These results indicate that FGF2/IL-10 coacervate has notably greater therapeutic potential than coacervate containing only FGF2. Overall, our data suggest therapeutically synergistic effects of FGF-2/IL-10 coacervate, particularly coacervate with FGF2 and 500 ng IL-10, for the treatment of ischemic heart disease.
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Stem Cell Research Center, Department of Orthopaedic Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
authors.forename: William C W
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Brandon G
authors.initials: BG
authors.lastname: Lee
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh School of Medicine, PA, 15260, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15213, USA.
authors.forename: Dae Woo
authors.initials: DW
authors.lastname: Park
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon, South Korea.
authors.forename: Kyobum
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Hunghao
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh School of Medicine, PA, 15260, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, 15219, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Kim
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, 15219, USA.
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, 15219, USA; Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA; Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA. Electronic address: yaw20@pitt.edu.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations; D004357:Drug Synergism; D004548:Elasticity / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology*; D005355:Fibrosis; D006493:Heparin / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016753:Interleukin-10 / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008807:Mice, Inbred BALB C; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D009204:Myocardial Revascularization; D009206:Myocardium / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D003692:Delayed-Action Preparations; D016222:Fibroblast Growth Factor 2; D016753:Interleukin-10; D006493:Heparin
keywords: Angiogenesis; Anti-inflammation; Coacervate; Controlled release; Fibroblast growth factor-2; Interleukin-10; Myocardial infarction