Injectable hydrogels for local protein delivery to engineer myocardial remodeling

The endogenous tissue remodeling events that occur following a myocardial infarction (MI) are inadequate to maintain left ventricular (LV) function, and the progression towards heart failure is often inevitable. Our increased understanding of protein regulators of post MI remodeling provides the opportunity to intervene and engineer tissue remodeling through exogenous protein delivery. The global hypothesis of this dissertation was that the local delivery of therapeutic proteins (SDF-1alpha and TIMP-3) from injectable hyaluronic acid (HA) hydrogels attenuates adverse post MI remodeling processes by providing sustained concentrations of bioactive signals within the remodeling myocardium. To test this hypothesis, HA based hydrogels were designed with crosslinking chemistries to allow hydrogel formation and protein encapsulation in situ upon injection through a syringe, negatively charged polymer backbones to bind encapsulated proteins through electrostatic interactions and sustain protein release, and degradable crosslinks to release proteins in a controlled fashion. Using these injectable hydrogel systems, adverse post MI remodeling events were attenuated following experimental MI in animals by enhancing endogenous cell homing to the myocardium through SDF-1alpha delivery and inhibiting matrix metalloproteinase activity through TIMP-3 delivery. Our results demonstrate the utility of implantable biomaterials to localize and sustain biological signals to engineer tissue remodeling processes, and provide insight into novel biological therapeutics to treat LV remodeling following MI