Minimally invasive delivery of engineered heart tissues restores cardiac function in rats with chronic myocardial infarction

Background Myocardial infarction leads to irreversible cardiomyocyte loss and adverse ventricular remodeling, often culminating in heart failure. Transplantation of functional cardiac patches offers a promising avenue for myocardial repair, yet current delivery methods typically require open-chest surgery and suturing of the graft, limiting their applicability in patients with severe heart failure. Methods We developed an engineered heart tissue composed of human induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, and fibroblasts seeded on a durable, flexible scaffold. The scaffold was made of intertwined poly lactide-co-glycolide nano- and microfiber hybrid aerogels coated with gelatin of shape-recoverable property, ensuring mechanical resilience and flexibility for thoracoscopic delivery. Engineered heart tissues were loaded with pro-angiogenic factors including fibroblast growth factor 1 and CHIR99021. After in vitro characterization and optimization, engineered heart tissues were delivered to rats via thoracoscopy at 28 days after myocardial infarction induction. Echocardiography and histological analysis were used to assess cardiac function and heart remodeling. Results Engineered heart tissues exhibited structural integrity under mechanical compression. Thoracoscopy-based epicardial engineered heart tissue transplantation to rats with chronic myocardial infarction significantly improved left ventricular ejection fraction and fractional shortening, concomitant with reduced fibrosis, cardiomyocyte apoptosis, and inflammation, as well as enhanced vascularization. Furthermore, engineered heart tissues modulated the immune response by decreasing neutrophil and macrophage infiltration. Conclusions These findings establish the feasibility of a minimally invasive approach for delivery of engineered heart tissues, eliminating the need for suturing and offering a less invasive alternative to transplantation, thereby broadening the clinical potential of engineered heart tissue-based therapy for heart failure. STATEMENT OF SIGNIFICANCE: Transplantation of engineered heart tissues emerges as a promising approach for regenerating myocardium and improving cardiac function in preclinical models of heart failure. However, clinical translation remains challenged due to the invasive nature of current delivery methods, which often involve open-chest procedures that pose significant risks, particularly for patients with severe heart failure. This study introduces an engineered heart tissue (EHT) made from human induced pluripotent stem cells-derived cardiac cells on a flexible scaffold, and shows that EHTs can be delivered to animal models of chronic myocardial infarction using a minimally invasive, video-assisted thoracoscopic approach. This approach offers a safer alternative to open-chest surgery for EHT treatment of patients with end-stage heart failure.