Cardiovascular disease (CVD) is ranked the second leading cause of death in Canada, with 53,704 heart disease-related deaths documented in 2020 alone. After a patient sustains cardiac injury, such as a myocardial infarction (MI), the heart is often unable to undergo sufficient self-recovery for healthy cardiac regeneration and repair; this is largely attributed to fibrotic tissue development at the injury site and subsequent pathological ventricular remodeling. The prevalence of MI events has created a considerable demand to develop novel strategies for effective and safe post-MI therapies. Research has indicated that post-MI modifications interfere with endogenous cardiac repair mechanisms, resulting in a pathological state. After an infarction, there is an accumulation of methylglyoxal (MG) at the site of injury. It has been suggested that MG contributes to ventricular fibrotic development, however its underlying mechanism remains unclear. Additionally, the effects that the post-MI cardiac environment, specifically MG accumulation, has on post-MI therapies and biomaterials has not been sufficiently established. Accordingly, the primary focus of this research project is to elucidate the effects of MG on the collagen-rich extracellular matrix (ECM) of the heart and key cardiac cells involved in the repair process. Further, the interaction between MG and a promising collagen-based hydrogel therapy is investigated, exploring the effects of MG on the hydrogel’s degradative process. It was found that the MG modification of hydrogels did not alter the degradation rate. Additionally, the degradation products of hydrogels, and MG-modified substrates did not affect the properties and formation of myofibroblasts.