Applications and Challenges of Stage-Specific Microenvironment-Responsive Hydrogels for Myocardial Infarction

Myocardial infarction (MI) progresses through a series of distinct pathological stages, from acute ischemia and reperfusion injury to chronic inflammation, fibrotic proliferation, and ventricular remodeling, each characterized by a unique combination of microenvironmental cues and therapeutic demands. Traditional injectable hydrogels, designed primarily as passive mechanical fillers, largely fail to adapt to these stage-specific needs: their fixed degradation, mechanics, and drug release profiles cannot match the dynamic post-MI milieu. Microenvironment-responsive hydrogels, by sensing signals such as reactive oxygen species (ROS), pH changes, and matrix metalloproteinases (MMPs), offer a means to align hydrogel behavior more closely with pathological progression. While existing reviews have catalogued these systems by their response mechanisms, this review takes a pathology-driven perspective. We first analyze the evolving microenvironmental characteristics and repair requirements across the major phases of MI. Then, rather than organizing the discussion by stimulus type, we examine how hydrogel properties, including responsiveness, mechanical support, electrical conductivity, and degradation, can be rationally combined with appropriate delivery formats (injectable hydrogels, cardiac patches, and composite constructs) and clinical workflows to address phase-specific therapeutic objectives. Finally, we identify bottlenecks that currently prevent these materials from reaching clinical application and outline practical strategies for overcoming them. By linking material design directly to stage-specific pathology, this review aims to offer a more clinically relevant framework for developing next-generation responsive hydrogels for MI repair. STATEMENT OF SIGNIFICANCE: Myocardial infarction (MI) is a leading cause of heart failure. Revascularization improves survival, yet reperfusion injury and remodeling drive long-term mortality. Traditional injectable hydrogels are passive fillers that cannot adapt to the post-infarction microenvironment. Most reviews classify responsive hydrogels by chemical trigger, separating material design from clinical pathology. We take a different view, linking hydrogel design to the four phases of MI healing. For each phase we identify the microenvironmental signals, then show how reactive oxygen species (ROS), pH and matrix metalloproteinase (MMP) responsiveness, mechanics, conductivity, and degradation can be combined for stage-specific therapy. We also examine how injectable hydrogels, epicardial patches, and composite constructs integrate with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) workflows. This pathology-matched framework highlights translational bottlenecks and strategies to bridge materials science and clinical application.