title: Sustained release of engineered stromal cell-derived factor 1-α from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction.
abstract: BACKGROUND
  Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.
  
  
  RESULTS
  Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.
  
  
  CONCLUSIONS
  We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA (J.W.M., Y.S., J.E.C., A.F., A.T., J.P., P.H., E.Y., K.L., W.H., P.A., Y.J.W.); and Department of Bioengineering, University of Pennsylvania, Philadelphia, PA (B.P.P., J.A.B.).
authors.forename: John W
authors.initials: JW
authors.lastname: MacArthur
authors.forename: Brendan P
authors.initials: BP
authors.lastname: Purcell
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shudo
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Cohen
authors.forename: Alex
authors.initials: A
authors.lastname: Fairman
authors.forename: Alen
authors.initials: A
authors.lastname: Trubelja
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: Philip
authors.initials: P
authors.lastname: Hsiao
authors.forename: Elaine
authors.initials: E
authors.lastname: Yang
authors.forename: Kelsey
authors.initials: K
authors.lastname: Lloyd
authors.forename: William
authors.initials: W
authors.lastname: Hiesinger
authors.forename: Pavan
authors.initials: P
authors.lastname: Atluri
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12 / Q000008:administration & dosage / Q000502:physiology*; D003692:Delayed-Action Preparations; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020100:Hydrogels; D007267:Injections; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; D003692:Delayed-Action Preparations; D020100:Hydrogels
keywords: angiogenesis; endothelial progenitor cell; injectable hydrogels; myocardial infarction
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