Mechanical force in organoid and organ-on-a-chip systems: Design principles, biological effects, and translational applications

Organoid and Organ-on-a-Chip (OoC) are transformative <em>in vitro</em> platforms for biomedical research. A critical determinant of their physiological relevance is the faithful recapitulation of the native mechanical microenvironment, which governs cell behavior, morphogenesis, and maturation. Despite its recognized importance, a comprehensive review dedicated to the principles, design, and application of mechanical stimuli in these advanced systems remains limited. This review provides a systematic overview of this crucial aspect. We first elucidate the fundamental principles of mechanobiology, detailing how cells perceive and transduce mechanical cues such as fluid shear stress, substrate stiffness, and tensile strain. Subsequently, we analyze the implementation of mechanical control across diverse organoid culture methodologies, including scaffold-based, microcarrier, and advanced scaffold-free techniques. The review's core examines the application of engineered mechanical forces in various OoC models (e.g., lung, gut, heart, tumor), demonstrating how simulating physiological forces like cyclic stretching and peristalsis enhances biomimetic fidelity and functional maturation. Finally, we address key challenges and future prospects, including multi-scale stimuli integration, smart responsive materials, and mechanically coupled multi-organ systems. This work underscores the indispensable role of mechanical engineering in advancing organoid and OoC technologies for basic research and clinical applications. This review not only systematically synthesizes current progress but also proposes mechanobiological frameworks for the next generation of organoid and OoC systems.