MRI Evaluation of Injectable Hyaluronic Acid Hydrogel Therapy to Attenuate Myocardial Infarct Remodeling

Left ventricular (LV) remodeling following myocardial infarction (MI) leads to maladaptive processes that often progress to heart failure. Injectable biomaterials can alter the mechanical signaling post-MI to limit this progression. To design optimal therapies, noninvasive techniques are needed to elucidate the reciprocal interaction between the injected material and the surrounding myocardial tissue. Towards this goal, the general hypothesis of this dissertation was that magnetic resonance imaging (MRI) can be used to characterize the properties of injectable materials once delivered to the myocardium and evaluate the temporal effects of injectable materials on myocardial tissue properties post-MI. To test this hypothesis, injectable hyaluronic acid (HA) hydrogels were developed with a range of gelation, degradation and mechanical properties by altering the initiator concentration, macromer modification, and macromer concentration, respectively. Non-contrast MRI was then used to characterize the properties (e.g., distribution, chemical composition) of injectable HA hydrogels in myocardial explants. Altering hydrogel gelation led to differences in distribution in myocardial tissue, as quantified by T2-weighted MRI. As an alternative to conventional (i.e.T2-weighted) MRI where contrast depends on differences in MR properties and thus, is non-specific for the material, chemical exchange saturation transfer (CEST) MRI was used to specifically image hydrogels based on their functional (i.e. exchangeable proton) groups. CEST contrast correlated with changes in material properties, specifically macromer concentration. Furthermore, CEST MRI was shown to simultaneously visualize and discriminate between different injectable materials based on their unique chemistry. Finally, the effect of injectable HA hydrogels on myocardial tissue properties was temporally evaluated in a porcine infarct model up to 12 weeks post-MI. Outcome assessment using MRI (e.g. cine, lategadolinium enhancement, and spatial modulation of magnetization MRI) and finite element (FE) modeling demonstrated that hydrogel therapy led to improved global LV structure and function, increased wall thickness, preserved borderzone contractility, and increased infarct stiffness, respectively. This work demonstrates that MRI can be used to simultaneously study hydrogel properties after injection into the myocardium and evaluate the ability of injectable hydrogels to alter myocardial tissue properties to ultimately improve cardiac outcomes and enable future optimization of biomaterial therapies to attenuate adverse remodeling post-MI. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Bioengineering First Advisor Jason A. Burdick This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1046