Engineering Cardiobundles with Dynamic Microenvironmental Control as Advanced Cardiac Modeling for Heart‐on‐a‐Chip

Abstract Advancing cardioprotective therapies requires physiologically relevant preclinical models, yet conventional approaches—including 2D cell cultures, 3D spheroids, and animal models—fail to fully recapitulate the structural complexity and dynamic microenvironment of native cardiac tissue, often facing species‐specific discrepancies and ethical concerns. Organ‐on‐a‐chip (OoC) technology, a microfluidic‐based biomimetic system, offers real‐time organ‐level physiology and disease progression monitoring. In this study, a heart‐on‐a‐chip (HoC) platform is developed by integrating cardiobundles—engineered 3D cardiac tissues—with microfluidic technology. Using a fibrinogen‐Matrigel hydrogel system, aligned cardiobundles are fabricated that mimic the native myocardial architecture and function. The HoC system demonstrates enhanced cardiomyocyte differentiation, intercellular connectivity, calcium handling, and contractility. Furthermore, the effects of oxygen and nutrient circulation, as well as dynamic microenvironmental conditions, are systematically assessed on cardiobundle performance, highlighting the platform's physiological relevance. This biomimetic HoC represents a promising tool for drug screening, disease modeling, and personalised medicine, offering a physiologically relevant alternative to traditional cardiac models in preclinical research.