Biomechanical design principles of intestine-on-chip models: past, present and future directions

Human intestine is a complex organ that performs critical roles in nutrient absorption, immune regulation, and host-microbiome interactions. Traditional 2D and 3D in vitro models, while useful for some applications, fall short in replicating the dynamic and multifaceted environment of the small intestine. In recent years, Intestine-on-Chip (IoC) technologies have emerged as promising platforms that integrate microfluidics, biomechanical cues, and tissue engineering to better simulate intestinal structure and function. This review provides a comprehensive overview of IoC devices, covering their underlying principles, historical development, design elements, and key functional capabilities, with special emphasis on the incorporation of mechanical strain and peristalsis-like motion. We also discuss the limitations of current models, including application of constant uniaxial strain, scale constraints, material challenges, biological complexity, and lack of standardization as well as prospective directions for advancing this field. By addressing these gaps, next-generation IoC systems can pave the way for more predictive disease models, advanced drug testing platforms, and personalized medicine applications.