Histologic Evaluation of Therapeutic Responses in Ischemic Myocardium Elicited by Dual Growth Factor Delivery from Composite Glycosaminoglycan Hydrogels
44 Pages Posted: 28 Mar 2019 First Look: Preprint
In this project, the ability of dual growth factor-preloaded, silk-reinforced, composite hyaluronic acid-based hydrogels to elicit advantageous therapeutic responses when secured to ischemic myocardium was evaluated in vivo. Reinforced hydrogels containing both Vascular Endothelial Growth Factor (VEGF) and Platelet-derived Growth Factor (PDGF) were prepared by crosslinking chemically modified hyaluronic acid and heparin with poly(ethylene glycol)-diacrylate around a reinforcing silk mesh. Composite patches were sutured to the ventricular surface of ischemic myocardium in Sprague-Dawley rats, and the resulting angiogenic response was followed for 28 days. The gross appearance of treated hearts showed significantly reduced ischemic area and fibrous deposition compared to untreated control hearts. Histologic evaluation showed growth factor delivery to restore myofiber orientation to pre-surgical levels and to significantly increase elicited microvessel density and maturity by day 28 in ischemic myocardial tissue (p < 0.05). In addition, growth factor delivery reduced cell apoptosis, decreased the density of elicited mast cells and pro-inflammatory M1 macrophages and increased the density of elicited anti-inflammatory M2 macrophages. These findings suggest that HA-based, dual growth factor-loaded hydrogels can successfully induce a series of beneficial responses in ischemic myocardium, and offer the potential for therapeutic improvement of ischemic myocardial remodeling.
Keywords: Myocardial ischemia, Hyaluronic acid hydrogels, Growth factors, Vascular endothelial growth factor, Angiogenesis, Apoptosis, Mast cell, M1 and M2 macrophage
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