Optimization of small-intestine-on-chip

Hyoann Choi. Biological Engineering

Title:Optimization of small-intestine-on-chip

Mentor: Professor Esak Lee, Biomedical Engineering


Organ-on-chip is an in vitro model that uses microfluidic principles to recapitulate

dynamic physiological environment of tissues and organs. Among various organ-on-chips for a human body, the intestine-on-chip has been developed to reconstitute the villi structure, cell composition, and barrier function of the intestinal epithelium. However, the small intestine lymphatic capillaries, referred to as lacteals, are yet to be modeled in vitro on a microfluidic chip.

In the small intestine, the epithelium is exposed to various food molecules and microbes. The metabolic and immunological information from the gut from this exposure regulates the metabolic and immune responses both locally and systemically. Thus, the intestine is important for maintaining the homeostasis not only at the local site, but also throughout the body. Disruption of the intestinal homeostasis can lead to various metabolic and inflammatory diseases, including inflammatory bowel disease, colorectal cancer, and obesity. Although deciphering how the intestine maintains its homeostasis is critical for developing therapeutics and interventions for multiple metabolic and inflammatory diseases, the underlying mechanisms are poorly understood due to the complexity of conventional animal models and a lack of physiologically relevant in vitro models.

Lacteals play an important role in maintaining the intestinal homeostasis by regulating the interstitial pressure of the intestinal lamina propria. They also contribute to delivering the intestine-derived metabolic and immunological information to other parts of the body by transporting fat molecules and immunological components, including immune cells and antigens. Given the previous findings that lacteal integrity is disrupted during the metabolic and inflammatory diseases in addition to during the intestinal microbial dysbiosis, I hypothesize that the recovery of lacteal integrity helps resolve the intestinal barrier dysfunction and local inflammation by clearing out the inflammatory molecules that may lead to microbial dysbiosis and immune diseases. Moreover, I hypothesize that a better understanding of lacteal integrity in various levels of luminal fat molecules reveals mechanisms of dysregulation in fat absorption, transport, and metabolism as well as the onset of inflammation during obesity. Finally, I hypothesize that understanding of how the transport of fat molecules and immune cells by the lacteals relays the local responses to the systemic responses in various diseases can suggest new therapeutic targets.

Given the advantages of organ-on-chips to better mimic the dynamic physiological environments, I suggest that the development of gut-lacteals-on-chip will help to understand how lacteals are affected in various conditions and how the intestinal epithelium and lacteals interact with each other. In my research, I aimed to optimize the microfluidic small-intestine-on-chip to provide the foundation for the ultimate development of more relevant human gut models. The main objective is to create a 3D cylindrical system of double cell layers using a microfluidic chip design. The cylindrical system will allow authentic 3D analysis of how the luminal contents are absorbed by the intestine from all directions of 360 degrees compared to the previous chip models with flat cell layers. Although I could not finish developing a complete model due to the COVID-19 pandemic, my experimental attempts left critical suggestions for future development of the gut-lacteals-on-chip model.