Cardiac microphysiological systems in cardiovascular research: Construction paradigms, maturation trajectories, and...

Cardiovascular diseases remain the leading cause of global mortality, yet traditional preclinical models fail to accurately capture the physiological and genetic complexity of the human heart, hindering the development of targeted therapies. Cardiac microphysiological systems (cardiac MPS), including self-organizing human cardiac organoids and engineered cardiac tissue models, have emerged as promising human-relevant platforms for recapitulating selected aspects of cardiac development, tissue organization, and function. This review evaluates current strategies for the construction of these cardiac microphysiological systems through a systematic comparison of two major approaches: development-driven self-organization based on intrinsic stem-cell programs, and engineering-driven assembly supported by bioactive materials, 3D bioprinting, and microfluidic technologies. To address key bottlenecks limiting translational utility, we outline a multidimensional maturity assessment framework encompassing sarcomeric ultrastructural organization, the fidelity of electromechanical coupling, and metabolic reprogramming toward fatty acid β-oxidation. Furthermore, we discuss the translational applications of cardiac microphysiological systems in elucidating early cardiogenesis, modeling complex genetic and ischemic cardiovascular diseases, and enabling high-throughput cardiotoxicity screening. Despite persistent challenges in building perfusable multi-scale vascular networks, reducing batch-to-batch variability, and modeling multi-organ crosstalk, the integration of cardiac microphysiological systems with spatial multi-omics, next-generation biomaterials, and artificial intelligence-assisted culture systems may enhance their translational relevance, provided that these approaches are supported by rigorous benchmarking and cross-laboratory validation.