Key functions of the small intestine — nutrient absorption, barrier protection, and immune regulation — arise from its complex microenvironment characteristics, including fluid flow and extracellular matrix.
The shear stress induced by flow has a significant impact on physiological functions and presents spatial differences due to the macroscopic structure of the small intestine, particularly the circular folds. Reproducing this complexity in vitro is crucial for regenerative medicine, drug development, and disease model research. However, most models only simulate microenvironment signals while neglecting the role of large-scale structures in shaping spatial shear patterns.
Combining biomimetic structural features with controllable fluid dynamics is essential for achieving physiologically relevant models, yet existing systems often lack this capability. For instance, organ-on-a-chip technologies typically simulate uniform flow and shear stress in two-dimensional or 2.5D environments, while three-dimensional engineered small intestine models with villi or circular folds often rely on static culture, lacking mechanical stimulation. Therefore, reproducing the functional regulation of human intestinal spatial shear stress in tissue models remains a significant challenge, limiting the authenticity of models simulating natural intestinal functions.
To address this issue, Professor Zhou Hongzhao’s research group from Zhejiang University and Shen Luqi from Westlake University have developed a three-dimensional bioprinted small intestine model that integrates biomimetic macrostructures with physiologically relevant dynamic flow. By employing an embedded extrusion printing strategy, they constructed high-fidelity thin-walled tubular structures that accurately preserve the geometric shape of the lumen to control the flow field.
The anatomically designed circular folds simulate natural architectural features, creating shear gradients that establish region-specific microenvironments under perfusion. This biomimetic platform reveals shear-dependent transcriptomic patterns, including the partitioned regulation of tight junctions, secretory capabilities, and transport proteins, guiding epithelial specialization towards barrier or absorptive types. High shear regions enhance proliferation and barrier integrity, while low shear regions maintain absorptive functions; these results are validated at both transcript and protein levels, demonstrating long-term functional stability.
The physiological relevance of the model is further supported by studies on host-microbiome interactions. Co-culturing with Lactobacillus plantarum formed colonies with spatial distribution differences, activating local immune responses and remodeling epithelial functions, thereby recapitulating in vivo dynamic characteristics. Additionally, nutrient and drug absorption experiments demonstrated flow-regulated transcellular and paracellular uptake patterns — a feature typically absent in traditional static models. Quantitative assessments of drug absorption showed a strong correlation between in vitro and in vivo, reinforcing the model’s potential in pharmacokinetics and translational applications.
By integrating anatomical precision, mechanical partitioning, and biological validation, this platform bridges critical gaps in intestinal modeling. It can be used to study shear-regulated epithelial functions, regional microbiome interactions, and absorption behaviors, providing a scalable and physiologically relevant system for drug testing, microbiome research, and personalized medicine.