Hydrogel engineering for myocardial infarction repair: from material design to functional mechanisms and translational perspectives.

Abstract

Myocardial infarction (MI) remains a leading cause of cardiovascular-related morbidity and mortality worldwide. Its primary pathophysiological cascade involves the ischemic and hypoxic necrosis of cardiomyocytes (CMs), the degradation of the extracellular matrix (ECM), and the subsequent formation of fibrotic scar, which collectively drive the progression toward terminal heart failure. Current clinical interventions, which predominantly include pharmacotherapy, device implantation and reperfusion strategies, are largely palliative and mainly focus on restoring blood perfusion or alleviating symptoms. Consequently, they fail to fundamentally reverse the permanent loss of functional CMs and the structural devastation of the ECM post-MI. In recent years, hydrogels have emerged as highly promising platforms for myocardial tissue repair and regeneration, owing to their excellent biocompatibility, tunable mechanical properties, inherent biodegradability, and highly biomimetic three-dimensional (3D) network architectures. This review systematically summarizes recent advances in hydrogel engineering for MI repair, analyzing these systems from the dual perspectives of material composition and functional mechanisms. First, we highlight the design strategies underlying major material platforms, including stimuli-responsive systems, cell-engineered platforms and RNA/miRNA-loaded hydrogels. Second, we elucidate the mechanistic roles of hydrogels in myocardial repair, emphasizing mechanical support, microenvironmental modulation, and multifunctional integration. Finally, we critically evaluate the translational barriers facing hydrogel-based therapies and outline prospective future directions. Ultimately, this review aims to provide critical insights and a strategic roadmap for the fundamental research and clinical translation of hydrogels in cardiovascular regenerative medicine. STATEMENT OF SIGNIFICANCE: Myocardial infarction leads to irreversible cardiac injury and high cardiovascular mortality, with conventional therapies unable to restore heart function. Hydrogels represent promising repair materials with tunable mechanics, favorable biocompatibility and biomimetic microenvironments. This review systematically integrates hydrogel design and cardiac pathophysiology, classifying responsive hydrogels, evaluating cell/cell-free platforms, analyzing repair mechanisms, and outlining translational hurdles. It summarizes cutting-edge advances and provides valuable references for biomaterials and cardiovascular researchers exploring infarct repair hydrogels.