Summary
Despite recent advances in tissue engineering and regenerative medicine, heart failure (HF) following myocardial
infarction (MI) continues to be the leading cause of death in the U.S., and the rest of the western world. One of
our goals is the development of new, minimally invasive tissue-engineered therapies for the treatment of MI.
While cell therapies have been extensively studied for the treatment of MI and HF, meta-analyses of initial cell
therapy trials suggest only a modest effect on cardiac function. Injectable biomaterials that stimulate endogenous
repair are an attractive, potentially more effective alternative since therapies could still be delivered minimally
invasively via catheter, yet could be off the shelf and have significantly reduced costs and complications
compared to cell products. The PI’s lab developed the first cardiac specific injectable hydrogel, a myocardial
matrix hydrogel, which is derived from decellularized porcine myocardial extracellular matrix (ECM) and is
deliverable via a transendocardial injection catheter. This material is liquid at room temperature and forms a
porous and fibrous scaffold upon injection, which we have shown promotes pro-remodeling immune cell
polarization, other endogenous cell infiltration and cardiac repair in subacute and chronic MI models. This initial
work led to a successful Phase I clinical trial in post-MI patients. However, this approach is not amenable to
treating acute MI patients because of safety issues related to transendocardial injections. Therefore, significant
damage and remodeling of the heart will occur before a patient is even eligible for this therapy. In contrast to
transendocardial delivery, intracoronary infusion can be performed in acute MI patients as interventional
cardiologists are already performing a balloon angioplasty. We therefore recently developed a new infusible form
of ECM (iECM) that can be delivered via intracoronary infusion to coat and fill gaps of damaged vasculature to
heal the tissue. We have already shown this is effective when delivered immediately post-reperfusion in a rat
acute MI model and in a pilot pig study. In acute MI, we hypothesize that iECM promotes endothelial cell survival
and polarization of infiltrating immune cells to a pro-remodeling phenotype, which secondarily along with an
already demonstrated reduction in vascular permeability results in improved cardiomyocyte survival. Our
preliminary results provide strong support for the use of our new iECM technology for treating acute MI. In this
proposal, we will better understand the immunomodulatory and regenerative potential of our iECM technology
and perform translational studies with the goal of developing a novel therapy for acute MI.