title: A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction.
abstract: After myocardial infarction (MI), the heart undergoes fibrotic pathological remodeling instead of repair and regeneration. With multiple pathologies developing after MI, treatment using several proteins is expected to address this range of pathologies more effectively than a single-agent therapy. A factorial design of experiments study guided us to combine three complementary factors in one injection: tissue inhibitor of metalloproteinases-3 (TIMP-3) was embedded in a fibrin gel for signaling in the initial phase of the treatment, while basic fibroblast growth factor (FGF-2) and stromal cell-derived factor 1-alpha (SDF-1α) were embedded in heparin-based coacervates for sustained release and distributed within the same fibrin gel to exert their effects over a longer period. The gel was then tested in a rat model of myocardial infarction. Contractility of rat hearts treated with the protein coacervate-gel composite stabilized and slightly improved after the first week while contractility continued to decrease in rats treated with free proteins or saline over the 8 week study period. Hearts receiving the protein coacervate-gel composite treatment also exhibited reduced ventricular dilation, inflammation, fibrosis, and extracellular matrix (ECM) degradation. Revascularization, cardiomyocyte preservation, stem cell homing, and increased myocardial strain likely all contributed to the repair. This study demonstrates the potential of a multifactorial therapeutic approach in MI, using three complementary proteins delivered sequentially for comprehensive healing. The study also shows the necessity of controlled delivery for growth factors and cytokines to be an effective treatment.
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: H 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: D W
authors.initials: DW
authors.lastname: Long
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
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: M P
authors.initials: MP
authors.lastname: Hwang
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Heart and Vascular Institute, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh School of Medicine, PA 15260, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kim
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; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: yaw20@pitt.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000737:chemistry; D003102:Colloids; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004655:Emulsions; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry*; D015552:Injections, Intralesional; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D010316:Particle Size; D044367:Phase Transition; D011506:Proteins / Q000008:administration & dosage*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects*; D016896:Treatment Outcome; D014783:Viscosity
chemical_list: D002316:Cardiotonic Agents; D003102:Colloids; D003692:Delayed-Action Preparations; D004655:Emulsions; D020100:Hydrogels; D053769:Nanocapsules; D011506:Proteins
keywords: Cardiac repair; Coacervate; Controlled release; Fibrin gel; Myocardial infarction; Proteins