WINDOW INTO THE GUT: IN VIVO ANALYSIS AND MODULATION OF THE GASTROINTESTINAL ENVIRONMENT

Abstract

The gastrointestinal (GI) tract plays a key role in maintaining homeostasis, regulating digestion, microbiota environment, and has bidirectional communication to the brain. As such, dysregulation of the system leads to serious functional gastrointestinal diseases (FGIDs) that affect over a quarter of the world’s population. A significant impediment in designing FGID therapies that can address many of these diseases is the lack of a clear method to visualize the impact of such therapies. In this dissertation, I have tackled this problem by designing surgical methods to visualize the upper and lower GI tract in vivo through the use of window technologies. The first technology used a titanium window and an implantable 2-pronged insert that stabilized the intestine. A graphene electrode was fused to the borosilicate glass surface, with electrodes leading to a recording platform. Using transgenic mouse models, I was able to both image enteric nervous system (ENS) activity, while also recording local field potentials (LFP) emanating from the surface of the gut. This provided the first ever glance into the enteric changes of a living mouse, and how it changes over the course of several weeks. This technology was then explored further as I created a novel metal 3D-printed surgical window that allowed the live animal imaging of the colon. To overcome the vast expansion of the colon, a ferromagnetic steel implant was designed to press the colon to the gut surface without causing blockage of food passage and a novel gut motility image analysis pipeline was used to isolate individual neuron in ganglia. This was used to visualize the impact of a variety of sacral nerve stimulation (SNS) electrotherapies on the colon. SNS is a widely used medical technique to treat FGIDs, but this is the first system that can provide instant feedback with high spatiotemporal resolution on the efficacy of the therapy.