Hydrogel-Based Strategies for Metabolic Modulation After Myocardial Infarction

Following myocardial infarction (MI), the injured myocardium undergoes substantial metabolic changes that contribute to cardiomyocyte death, adverse ventricular remodeling, and impaired cardiac function. Both ischemia and the restoration of blood flow through reperfusion contribute to these changes, which include disrupted oxidative phosphorylation, increased reactive oxygen species production, mitochondrial dysfunction, ferroptosis, and alterations in glucose and reactive carbonyl metabolism. Although therapies have been developed to target these pathways, their effectiveness is often limited by poor myocardial retention and an inability to respond to changes within the infarct environment. Injectable hydrogels provide a way to deliver these therapies locally, prolong their activity, and incorporate stimulus-responsive properties that allow for more controlled release. This review examines hydrogel-based approaches designed to reduce oxidative stress, alleviate hypoxia, preserve or replace damaged mitochondria, inhibit ferroptosis, regulate glycolysis, and limit methylglyoxal-associated damage following MI. The different biological rationales and material designs are discussed, along with their effects on cardiac repair. Finally, the challenges associated with translating these systems into clinical applications are considered, including the need for more representative preclinical models, practical delivery methods, and therapeutic strategies that account for the changing post-infarct environment.