Dynamic Biological Hydrogels to Modulate Cardiac Remodeling Following Myocardial Infarction - Summary: Heart disease is the leading cause of death in the United States and there are currently over 5 million people in the U.S. affected by heart failure (HF). One potential therapeutic that is currently undergoing Phase I clinical trials is the injection of solubilized cardiac extracellular matrix (cECM) derived from adult porcine left ventricle. Healthy porcine cECM mimics the native binding sites available to cells and has been shown to promote functional repair in a pre-clinical model of MI, but cECM alone is limited in terms of the ability to mechanically stabilize the infarct during remodeling as the gels formed by cECM are softer than normal myocardium (~3-7 kPa). This is important because hydrogels with a higher stiffness than native myocardium injected into the infarct have been shown to reduce pathological remodeling, indicating that modulation of stiffness may be an important tool to regulating healing response. The protein composition of the ECM also has a profound effect on cells and we, and others, have demonstrated significant changes to the cardiac ECM protein composition in normal development and in disease, which modulates cardiac cell proliferation, progenitor/stem cell differentiation, cell traction force against the ECM and paracrine signaling from stem cells in the infarct environment, among other effects. In particular, our lab has demonstrated the potential utility of ECM derived from younger developmental ages in promoting a more regenerative healing response, and preliminary data indicates that this also occurs in the context of adult injury as well. As younger animals have the capability of regenerating their hearts to a greater degree, a logical hypothesis is that this difference in regeneration potential is at least partially derived from the remodeling of the ECM in which the cells reside at that point in development. We propose the development and use of biomaterials that can dynamically change to mimic a more developmentally regenerative niche for cardiac tissue repair. Our central hypothesis is that injectable, highly elastic silk-cECM composite hydrogels containing fetal heart derived cECM will provide a means for mechanical stabilization of the infarcted ventricular wall while promoting more favorable remodeling by cardiac cells, leading to improved repair and the minimization of diastolic dysfunction. To assess this hypothesis, we will use combinations of silk-based crosslinked hydrogels and a series of relevant chemical modifications to achieve physiologically relevant mechanical properties with a range of dynamics. The samples will be characterized for their physicochemical properties and evaluated both in vitro and in vivo. We will then assess the impact of the incorporation of young developmental age cECM to our dynamic silk hydrogels on cardiac cells in vitro and cardiac remodeling in vivo. We hypothesize that optimized silk-cECM based formulations will enhance diastolic heart function and reduce ventricular wall thinning following injection 1-week post-MI. Weekly functional assessment (echo) and endpoint hemodynamic functional assessment (PV loops) will be used to monitor cardiac function over an 8-week repair timeline in rats.
