Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity

Abstract

The lining of the gastrointestinal (GI) tract is the largest surface exposed to the external environment in the human body. One of the main functions of the small intestine is absorption, and intestinal absorption is a route used by essential nutrients, chemicals, and pharmaceuticals to enter the systemic circulation. Understanding the effects of digestion on a drug or chemical, how compounds interact with and are absorbed through the small intestinal epithelium, and how these compounds affect the rest of the body is critical for toxicological evaluation. Our goal is to create physiologically realistic in vitro models of the human GI tract that provide rapid, inexpensive, and accurate predictions of the body's response to orally delivered drugs and chemicals. Our group has developed an in vitro microscale cell culture analog (microCCA) of the GI tract that includes digestion, a mucus layer, and physiologically realistic cell populations. The GI tract microCCA, coupled with a multi-chamber silicon microCCA representing the systemic circulation, is described and challenged with acetaminophen. Proof of concept experiments showed that acetaminophen passes through and is metabolized by the in vitro intestinal epithelium and is further metabolized by liver cells, resulting in liver cell toxicity in a dose-dependent manner. The microCCA response is also consistent with in vivo measurements in mice. The system should be broadly useful for studies on orally delivered drugs or ingestion of chemicals with potential toxicity.

NutriChip: nutrition analysis meets microfluidics

“…In particular, we mention here the Ingber group at Harvard University, [14][15][16] who did pioneering work on ''organ-on-a-chip'' devices and the Shuler group at Cornell University who have pioneered the development of in vitro analogues to physiologically-based pharmacokinetic (PBPK) models. [17][18][19][20][21] Such micro-scale devices have the potential to accurately produce physiologically realistic parameters and can closely model the desired in vivo system to be tested. In a recent publication, Kim et al 16 reported a ''human gut-on-a-chip'' microdevice, which was composed of a confluent layer of intestinal epithelial (Caco-2) cells cultured on a porous membrane.…”

A living system on a chip

“…The intestines, a barrier that must be passed by all swallowed drugs, seem surprisingly easy to model (see 'Just cells'): using cell lines representing only the gut epithelium, mucin-secreting cells and lymphocytes, Shuler and his colleagues have been able to recreate the mucoid layer in the gut 5 . With the help of an absorbent polymer gel that can be used to build microscale scaffolding, the team has even crafted a collagen structure to represent the villi that line the intestinal wall 6 .…”

Modeling Life

“…Our most realistic tissue construct is the GI tract which contains cell lines that mimic three cell types in appropriate ratios. [12][13][14] A major component of the current call for proposals from DARPA, NIH, and DTRA is for more biologically authentic tissues. Colleagues with in-depth expertise in tissue engineering have much to contribute in this regard.…”

“…14 The GI tract model has been coupled with systemic circulation to observe interaction of the GI tract with a liver compartment in terms of acetaminophen toxicity. 13 The presence of the GI tract modulated the amount of acetaminophen delivered to the liver. Predictions of response to high concentration of acetaminophen were similar to that observed in rodent studies.…”