Histologic Evaluation of Therapeutic Responses in Ischemic Myocardium Elicited by Dual Growth Factor Delivery from Composite Glycosaminoglycan Hydrogels

44 Pages Posted: 28 Mar 2019

See all articles by Alexander A. Xu

Alexander A. Xu

Tufts Medical Center - Department of Surgery

Kayle S. Shapero

Tufts Medical Center - Department of Surgery

Jared A. Geibig

Tufts Medical Center - Department of Surgery

Hsiang-Wei K. Ma

Tufts Medical Center - Department of Surgery

Alex R. Jones

Tufts Medical Center - Department of Surgery

Marina Hanna

Tufts Medical Center - Department of Surgery

Daniel R. Pitts

Tufts Medical Center - Department of Surgery

Elaine Hillas

University of Utah - Department of Surgery

Matthew A. Firpo

University of Utah - Department of Surgery

Robert A. Peattie

Tufts Medical Center - Department of Surgery

Date Written: March 23, 2019

Abstract

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

Suggested Citation

Xu, Alexander A. and Shapero, Kayle S. and Geibig, Jared A. and Ma, Hsiang-Wei K. and Jones, Alex R. and Hanna, Marina and Pitts, Daniel R. and Hillas, Elaine and Firpo, Matthew A. and Peattie, Robert A., Histologic Evaluation of Therapeutic Responses in Ischemic Myocardium Elicited by Dual Growth Factor Delivery from Composite Glycosaminoglycan Hydrogels (March 23, 2019). Available at SSRN: https://ssrn.com/abstract=3360259 or http://dx.doi.org/10.2139/ssrn.3360259

Alexander A. Xu

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Kayle S. Shapero

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Jared A. Geibig

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Hsiang-Wei K. Ma

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Alex R. Jones

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Marina Hanna

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Daniel R. Pitts

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

Elaine Hillas

University of Utah - Department of Surgery

1645 E. Campus Center
Salt Lake City, UT 84112
United States

Matthew A. Firpo

University of Utah - Department of Surgery

1645 E. Campus Center
Salt Lake City, UT 84112
United States

Robert A. Peattie (Contact Author)

Tufts Medical Center - Department of Surgery

800 Washington St
Boston, MA 02111
United States

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