Although cardiovascular disease remains a major global health burden, many preclinical systems still struggle to predict how drug candidates will perform in the human heart. Although rodent models are limited by species differences, traditional two-dimensional cell cultures cannot fully reproduce the structure, mechanics, electrical activity, metabolism, and cellular communication of human heart tissue. In a review published in the studyIn , researchers from Shanghai University and collaborating institutions highlight how 3D cardiac constructs are emerging as a more clinically relevant platform for cardiovascular drug discovery and safety assessment.
3D cardiac constructs are typically generated from human pluripotent stem cells and assembled through scaffold-based systems, suspension cultures, microfluidic devices, or self-assembly protocols. Better capture cardiac contractility, electrophysiology, metabolic activity, and multicellular interactions compared to 2D culture. This review compares major model types including engineered heart tissue, heart-on-a-chip systems, scaffold-free cardiac microtissues, and cardiac organoids. Each serves a different purpose. Synthetic tissues are powerful tools for contractility and tissue-level functional testing. The heart-on-chip system allows for controlled flow and dynamic stimulation. Microtissues support scalable screening. Cardiac organoids are particularly useful for modeling early cardiac development and genetic diseases.
For disease modeling, patient-derived induced pluripotent stem cells allow researchers to preserve disease-associated genetic variation and build models for dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, and other inherited diseases. Non-genetic conditions can also be modeled by applying metabolic stress, inflammatory factors, environmental toxins, or hypoxic stimuli. These approaches allow 3D cardiac systems to reproduce oxidative stress, inflammation, vascular dysfunction, contractile abnormalities, and other clinically relevant phenotypes, creating a more informative setting for drug response testing.
This review highlights that the value of 3D heart models depends not only on their resemblance to cardiac tissue but also on whether they provide stable quantitative functional readouts. Key measurements include electrophysiology, action potentials, calcium signaling, contractility, myocardial metabolism, and genetic profiling. Technologies such as multi-electrode arrays, patch-clamp recording, optical mapping, calcium imaging, contractility analysis, extracellular flux analysis, and multi-omics profiling can help determine whether drugs affect rhythm, contraction, energy use, and cardiotoxicity. However, many of the current assays were originally designed for 2D systems, and the field still requires standardized functional platforms tailored to intact 3D tissues.
Biomaterials and artificial intelligence are accelerating the transition of 3D cardiac structures from experimental models to drug discovery platforms. Conductive materials improve electrical coupling between cardiac muscle cells. Hydrogels provide matrix-like support. And 3D bioprinting using biocompatible and supportive materials enables spatial organization of multiple cell types. AI is increasingly being used for image-based phenotyping, cell type annotation, and model design. 3D cardiac systems can be costly and time-consuming to generate, so AI-assisted workflows can help narrow down candidate compounds before functional validation and accelerate drug discovery.
Despite this progress, significant barriers remain. Many stem cell-derived cardiomyocytes still resemble fetal or neonatal cells rather than adult myocardium, with effects on sarcomere organization, calcium handling, metabolism, electrophysiology, and drug response. Limited angiogenesis limits construct size, long-term culture, and cell survival in deep regions. Reproducibility also remains a challenge, as results can vary depending on cell source, differentiation efficiency, culture batch, cell type ratio, and assay workflow. This review argues that 3D cardiac structures should complement, rather than replace, existing animal and in vitro models. Their wider adoption will depend on improvements in maturation, angiogenesis, immune cell integration, standardization, scalable manufacturing, cost control, and clearer regulatory pathways.
sauce:
Science and Technology Review Publishing
Reference magazines:
Liu, C. others. (2026). 3D cardiac constructs in drug discovery: current advances and future challenges. the studyDOI:10.34133/research.1165. https://spj.science.org/doi/10.34133/research.1165
