Cardiac microtissues for myocardial repair: working in a dream

Myocardial infarction results not only in the loss of cardiomyocytes (CMs) but also in the breakdown of myocardial structure, including non-contractile cell populations. Current treatments are directed mainly at achieving early CM salvage, yet the subsequent formation of a necrotic scar remains largely unaddressed. Efforts to restore the lost myocardium have proven to be a formidable challenge, with limited success to date. Consequently, restoring functional myocardium remains a major unmet clinical need in cardiovascular medicine. This review explores the progress of cardiac microtissues (CMTs) as an emerging approach in cardiac regenerative therapy. Cell-based strategies—such as transplantation of pluripotent stem cell-derived CMs—have shown encouraging potential, but their translation remains hampered by poor cell retention, low engraftment efficiency, and increased risk of arrhythmias. CMTs, including spheroids and organoids, consist of three-dimensional aggregates of CMs with or without supporting cell types, and have emerged as a novel therapeutic approach. Their organized structure offers key advantages over single-CM suspensions, including improved survival, better integration with host myocardium, and a reduced risk of arrhythmias. Preclinical studies in both small and large animal models have recently demonstrated their promise, showing enhanced remuscularization and cardiac function at lower effective cell doses. Key challenges remain for the translation of CMTs from bench to bedside. These include elucidating the primary mechanisms of action, defining optimal dosing, refining delivery strategies and timing, and ensuring long-term safety, particularly regarding arrhythmic risks. In parallel with biological validation, robust efforts in clinical-grade manufacturing are essential. The clinical translation of CMTs requires scalable, xeno-free, automated, and good manufacturing practice (GMP)-compliant production processes, along with optimized protocols for storage, transport, and delivery CMTs represent a promising approach in myocardial regenerative therapy, with the potential to improve biological performance while mitigating some limitations associated with single-cell delivery. Nonetheless, their successful translation from bench to bedside will require coordinated multidisciplinary efforts to resolve remaining biological, technical, and manufacturing challenges, ultimately enabling safe and effective myocardial repair in patients with ischemic heart disease.