Building Barrier Tissues for a “Body-On-A-Chip”

We seek to understand the response of the human body to various pharmaceuticals. Our platform technology is an in vitro system that combines microfabrication and cell cultures and is guided by a computer model of the body. We called this in vitro system a micro cell culture analog (microCCA) or a "Body-on-a-Chip". A microCCA device contains mammalian cells cultured in interconnected micro-chambers to represent key body organs linked through the circulatory system and is a physical representation of a physiologically based pharmacokinetic model. MicroCCAs can reveal toxic effects that result from interactions between organs as well as provide realistic, inexpensive, accurate, rapid throughput toxicological studies that do not require animals. The advantages of operating on a microscale include the ability to mimic physiological relationships more accurately as the natural length scale is order of 10 to 100 microns. The basic concept has been described.⁽¹⁾

We will describe the basic concept of a "Body-on-a-Chip" and then discuss how to build models of barrier tissues (e.g. GI tract, lung, blood brain barrier, skin, etc.) that interact with the systemic circulation. This talk will focus on the GI tract. We have built a model using a mixture of epithelial cells (Caco-2), mucus producing goblet like cells (HT29-MTX) and an M cell mimic (using co-culture with Raji B-lymphocytes) responsible for uptake of particles.(2) Proof-of-concept experiments with acetaminophen as model drug demonstrate that the "liver" compartment responds in a dose-dependent manner to drug delivered "orally" that passes through the model GI tract.(3) We also present data on the effects of in vitro "oral" uptake of nanoparticles and compare the response to that observed in vivo using chicks. All of these results taken together suggest that combining "barrier" tissue models with models of systemic circulation is feasible and yields predictions consistent with in vivo observations.

References:

1. Sung, J. H., M.L. Shuler. 2010. In vitro microscale systems for systematic drug toxicity study, Bioprocess and Biosystems Engineering, 33: 5-19.
2. Mahler, G.J., M.L. Shuler, and R.P. Glahn. 2009. Characterization of Caco-2 and HT29-MTX co-cultures in an in vitro digestion/cell culture model used to predict iron bioavailability. J. Nutr. Biochem. 20:494-502.
3. Mahler, G.J., M.B. Esch, R.P. Glahn, and M.L. Shuler. 2009. Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity. Biotechnol. Bioeng. 104:193-205.