Abstract 13112: A Bioengineered Hydrogel System Enables Targeted and Sustained Intramyocardial Delivery of Neuregulin, Activating the Cardiomyocyte Cell Cycle and Enhancing Ventricular Function in Ischemic Cardiomyopathy
Introduction: Neuregulin (NRG) is a member of the epidermal growth factor family possessing a critical role in the development and proliferation of cardiomyocytes. Systemic administration of NRG has shown efficacy in animal models of ischemic cardiomyopathy (ICM), leading to early clinical trials employing daily NRG infusions. This approach is hindered by requiring daily infusions and off-target exposure. Therefore, this study aimed to provide sustained localized delivery of NRG by utilizing a bioengineered hydrogel encapsulating NRG.
Methods: NRG was encapsulated in a hydrogel (H) and release analyzed by ELISA over 14 days. For in vivo studies, 2 month old male C57BL mice were anesthetized, underwent LAD ligation (n=42), and were randomized to 4 treatment groups: PBS, H, NRG, and NRG-H. Immunohistochemistry was performed at 5 and 14 days for phospho-histone H3 (H3P) presence at the borderzone. ECHO and Masson’s Trichrome staining were performed at 14 days for functional and histologic evaluation.
Results: Sustained release of NRG from H was demonstrated in vitro by ELISA for 14 days. At 5 days, 100% (5/5) of NRG-H mice exhibited positive H3P activity compared to 0% in the H group. At 14 days, 62.5% (5/8) of NRG-H mice were positive for H3P compared to 0% in the other three groups. ECHO at 14 days demonstrated a significantly enhanced EF in the NRG-H group (37.5 ± 3.6%) compared to PBS (20.2 ± 3.2%, p<0.01), H (17.2 ± 3.7%, p<0.01), and NRG (20.1 ± 4.7%, p<0.01). End diastolic left ventricular (LV) geometry was analyzed by ECHO at 14 days revealing significantly reduced LV area at the papillary level in the NRG-H group (0.18 ± 0.02 cm2) compared to PBS (0.29 ± 0.02 cm2, p<0.01), H (0.30 ± 0.04 cm2, p<0.01), and NRG (0.33 ± 0.04 cm2, p<0.01). Histologic analysis at 14 days exhibited augmented borderzone thickness in the NRG-H group (0.65 ± 0.07 mm) compared to PBS (0.27 ± 0.05 mm, p<0.01), H (0.26 ± 0.05 mm, p<0.01), and NRG (0.30 ± 0.05 mm, p<0.01).
Conclusions: Targeted and sustained delivery of NRG directly to the myocardial borderzone augments cardiomyocyte mitotic activity and greatly enhances LV function in a model of ICM. This novel approach to NRG administration represents a clinically translatable strategy in myocardial regenerative therapeutics.
- © 2013 by American Heart Association, Inc.