Mennella, Raffaele (2024) Intestine-on-chip for dissecting shear stress, topography and microbiome influence on epithelial morphogenesis and permeability. [Tesi di dottorato]

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Abstract

At the convergence between engineering and biology, the organ-on-chip technology has been extensively employed for reproducing the native physiological intestinal ecosystem in vitro. Continuous advances in this field have allowed the generation of progressively sophisticated models that include microfabrication strategies, multicell culture, controllable biophysical and biochemical signalling or on-line and off-line measurements of processes typically performed by the gut barrier. Nevertheless, significant challenges still hinder a broader application of these platforms in clinical nutrition and pharmacology. To this aim, this thesis presents approaches to facilitate market implementation, ensuring higher biological fidelity, microbial crosstalk and practical functionalities. A novel methodology is presented to reconstruct the microscale villar organization in a microfluidic chip predisposed to grant transepithelial absorption studies. This involves the customization of the characteristic microporous membrane that separates the areas allocated for the lumen and the bloodstream. Authenticating better morphological and structural resemblance with the original tissue, a comprehensive study, conducted to elucidate the influence of external perturbations on the selective barrier properties, reveal functional readaptation of intestinal epithelial cells when subjected to a range of increasing physical forces. Finally, incrementing model complexity, the typical anaerobic state of the gut lumen is computationally and experimentally validated to allow microbial-host interplay examination. As such, it contributes to master reliant in vitro alternatives and design new clinical interventions in human health.

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