Patient-Derived 3D Bioprinted Cardiac Organoid Constructs Reveal Key Pathological Features of Duchenne Muscular Dystrophy

This study developed patient-derived 3D cardiac organoids and 3D bioprinted cardiac organoid constructs to model Duchenne muscular dystrophy-associated cardiomyopathy using DMD hiPSCs, a CRISPR-corrected isogenic control, and healthy control hiPSCs. By day 15 of cardiac differentiation, DMD cardiac organoids showed significantly increased cardiomyocyte death, apoptosis, ROS accumulation, NOX4 upregulation, elevated NADPH-dependent ROS production, abnormal calcium transient dynamics, and increased mechanical stiffness relative to controls. The team then embedded organoids into a 7% alginate and 5% gelatin bioink to generate bioprinted constructs that supported organoid fusion, maintained beating, increased connexin 43 expression, and reduced NKX2.5 levels. By day 14 post-bioprinting, dystrophic bioprinted constructs showed higher cell death and apoptosis, reduced expression of multiple cardiac structural markers, substantial collagen deposition, and mesenchymal drift-associated transcriptional changes, reproducing key features of DMD cardiomyopathy. The work establishes both standard and bioprinted cardiac organoids as human 3D disease models for mechanistic study and preclinical therapeutic screening in DMD cardiomyopathy.