The Cornell researchers collaborated with the University of Maryland, John Hopkins University, and the National University of Singapore on the study. They 3D printed an artificial small intestine system on the microscale, which actually mimics the topography of the gut surface and the necessary fluid flow that epithelial cells need to grow, function, and reproduce. The team states that this is the first small intestine model that has accurately recreated peristaltic fluid flow.
“The intestine is home to most of our immune system and it is also where all of our nutrients are absorbed, so to function as a human being or any multicellular animal, our gut is the centerpiece of our interactions with the outside world. The more we understand about how our guts work, the more we can develop therapies and gain insights into the evolution of human biology,” explained John C. March, professor and chair of Cornell’s Department of Biological and Environmental Engineering.
As part of the study, which was funded by the National Institutes of Health (NIH), the researchers published a paper on their new system earlier this month in Scientific Reports, titled “Microscale Bioreactors for in situ characterization of GI epithelial cell physiology.”
March is senior author on the paper, and a research associate from his lab, Cait M. Costello, the first author; other co-authors include Mikkel B. Phillipsen, Leonard M. Hartmanis, Marek A. Kwasnica, Victor Chen, David Hackam, Matthew W. Chang, and William E. Bentley.
The abstract reads, “The development of in vitro artificial small intestines that realistically mimic in vivo systems will enable vast improvement of our understanding of the human gut and its impact on human health. Synthetic in vitro models can control specific parameters, including (but not limited to) cell types, fluid flow, nutrient profiles and gaseous exchange. They are also ‘open’ systems, enabling access to chemical and physiological information. In this work, we demonstrate the importance of gut surface topography and fluid flow dynamics which are shown to impact epithelial cell growth, proliferation and intestinal cell function. We have constructed a small intestinal bioreactor using 3-D printing and polymeric scaffolds that mimic the 3-D topography of the intestine and its fluid flow. Our results indicate that TEER measurements, which are typically high in static 2-D Transwell apparatuses, is lower in the presence of liquid sheer and 3-D topography compared to a flat scaffold and static conditions. There was also increased cell proliferation and discovered localized regions of elevated apoptosis, specifically at the tips of the villi, where there is highest sheer. Similarly, glucose was actively transported (as opposed to passive) and at higher rates under flow.”
In the paper, the researchers explain that epithelial cells grown in a 3D villus environment on scaffolds are able to get different nutrient gradients, such as oxygen, than cells grown on flat surfaces. The team used their 3D printed bioreactor system to get an in-depth understanding of fluid flow dynamics inside the small intestine; even if a person is fasting, an intermittent flow in their intestine exposes its cells to shear stresses, so it’s important to be able to recreate this motion.
AutoCAD Inventor was used to design the bioreactors, which were then 3D printed on a Stratasys Objet30 Pro with a clear material. The study illustrated that cells could realistically grow the same as they would in a living intestine by recreating peristaltic flow in the 3D printed model. If the fluid flows properly inside the organ, cells will selectively die off near the villi tips. However, if this flow is not there, the cells will self-destruct.
The researchers were also able to study the dynamics of bacterial populations in the small intestine, thanks to the accurate fluid flow in their 3D printed bioreactor.
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