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.
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.


METHODS AND 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.
['MacArthur|John W|JW|', 'Purcell|Brendan P|BP|', 'Shudo|Yasuhiro|Y|', 'Cohen|Jeffrey E|JE|', 'Fairman|Alex|A|', 'Trubelja|Alen|A|', 'Patel|Jay|J|', 'Hsiao|Philip|P|', 'Yang|Elaine|E|', 'Lloyd|Kelsey|K|', 'Hiesinger|William|W|', 'Atluri|Pavan|P|', 'Burdick|Jason A|JA|', 'Woo|Y Joseph|YJ|']
D000818:Animals D002465:Cell Movement D054377:Chemokine CXCL12 D003692:Delayed-Action Preparations D042783:Endothelial Cells D020100:Hydrogels D007267:Injections D008297:Male D009203:Myocardial Infarction D051381:Rats D017208:Rats, Wistar D013234:Stem Cells D016277:Ventricular Function, Left
injectable hydrogels endothelial progenitor cell myocardial infarction angiogenesis