Dual Delivery of Hepatocyte and Vascular Endothelial Growth Factors via a Protease-Degradable Hydrogel Improves Cardiac Function in Rats

Apoorva S Salimath,Edward A Phelps,Archana V Boopathy,Pao-Lin Che,Michael E Davis,Andrés J García,Milton Brown,Patrick Ching-Ho Hsieh

doi:10.1371/journal.pone.0050980

Abstract

Acute myocardial infarction (MI) caused by ischemia and reperfusion (IR) is the most common cause of cardiac dysfunction due to local cell death and a temporally regulated inflammatory response. Current therapeutics are limited by delivery vehicles that do not address spatial and temporal aspects of healing. The aim of this study was to engineer biotherapeutic delivery materials to harness endogenous cell repair to enhance myocardial repair and function. We have previously engineered poly(ethylene glycol) (PEG)-based hydrogels to present cell adhesive motifs and deliver VEGF to promote vascularization in vivo. In the current study, bioactive hydrogels with a protease-degradable crosslinker were loaded with hepatocyte and vascular endothelial growth factors (HGF and VEGF, respectively) and delivered to the infarcted myocardium of rats. Release of both growth factors was accelerated in the presence of collagenase due to hydrogel degradation. When delivered to the border zones following ischemia-reperfusion injury, there was no acute effect on cardiac function as measured by echocardiography. Over time there was a significant increase in angiogenesis, stem cell recruitment, and a decrease in fibrosis in the dual growth factor delivery group that was significant compared with single growth factor therapy. This led to an improvement in chronic function as measured by both invasive hemodynamics and echocardiography. These data demonstrate that dual growth factor release of HGF and VEGF from a bioactive hydrogel has the capacity to significantly improve cardiac remodeling and function following IR injury.

Highlights

Cardiovascular disease is the leading cause of death in the United States, with estimates indicating 1 death every 39 seconds
To determine release of vascular endothelial growth factor (VEGF) (Figure 1B) and hepatocyte growth factor (HGF) (Figure 1C) in vitro, fluorescently-labeled growth factors were chemically incorporated into poly(ethylene glycol) (PEG)-MAL hydrogels
PBS treated samples released protein much more slowly. These results show the rate of release of growth factors is dependent upon protease-mediated degradation of the hydrogel due to the protease-degradable crosslinking peptides

Summary

Introduction

Cardiovascular disease is the leading cause of death in the United States, with estimates indicating 1 death every 39 seconds. Myocardial infarctions (MI), accounts for 1 of every 6 deaths in the Unites States with over 1 million new, recurrent, and silent MI annually [1]. The ischemia and subsequent reperfusion (IR) induces massive regional necrosis and apoptosis, with billions of myocytes being lost over the first few days [3,4,5]. These lost cells are not replaced and a non-contractile scar is laid down, which will eventually lead to heart failure. New therapies to treat this progressive disease and improve cardiac function are greatly needed

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