A Bioengineered Hydrogel System Enables Targeted and Sustained Intramyocardial Delivery of Neuregulin, Activating the Cardiomyocyte Cell Cycle and Enhancing Ventricular Function in a Murine Model of Ischemic Cardiomyopathy
Background—Neuregulin (NRG) is a member of the epidermal growth factor family possessing a critical role in cardiomyocyte development and proliferation. Systemic administration of NRG demonstrated efficacy in cardiomyopathy animal models, leading to clinical trials employing daily NRG infusions. This approach is hindered by requiring daily infusions and off-target exposure. Therefore, this study aimed to encapsulate NRG in a hydrogel (HG) to be directly delivered to the myocardium, accomplishing sustained localized NRG delivery.
Methods and Results—NRG was encapsulated in HG and release over 14 days confirmed by ELISA in vitro. Sprague-Dawly rats were utilized for cardiomyocyte isolation. Cells were stimulated by PBS, NRG, HG, or NRG-HG and evaluated for proliferation. Cardiomyocytes demonstrated EdU and phosphorylated histone-H3 (PH3) positivity in the NRG-HG group only. For in vivo studies, 2 month old mice (n=60) underwent LAD ligation and were randomized to the 4 treatment groups mentioned. Only NRG-HG treated mice demonstrated PH3 and Ki67 positivity along with decreased caspase-3 activity compared to all controls. NRG was detected in myocardium 6 days following injection without evidence of off-target exposure in NRG-HG animals. At 2 weeks, the NRG-HG group exhibited enhanced LVEF, decreased LV area, and augmented borderzone thickness.
Conclusions—Targeted and sustained delivery of NRG directly to the myocardial borderzone augments cardiomyocyte mitotic activity, decreases apoptosis, and greatly enhances LV function in a model of ICM. This novel approach to NRG administration avoids off-target exposure and represents a clinically translatable strategy in myocardial regenerative therapeutics.
- Received December 12, 2013.
- Accepted May 27, 2014.