How body-on-a-chip devices can help foster drug development: an outline of strategies

Microphysiologic Cell Culture Systems are microfluidic platforms on which multiple in vitro tissues can communicate with each other via soluble metabolites that re-circulate through a medium stream. The systems are also referred to as body-on-a-chip systems or micro cell culture analogs (µCCAs).

My research combines tissue engineering and microfabrication to construct microphysiological systems and to examine how cooperative interactions of organs result in the overall functioning of the human body. The collective effects of inter-organ metabolic exchanges are not only directly relevant to evaluating new drugs, they also raise a number of fascinating Systems Biology questions concerning the mechanisms of communication between organs that lead to the overall response of the human body to chemical and biological challenges.

Here is a paper that reviews some of the literature regarding micro physiological systems and outlines their possibilities for research:

Mandy B. Esch, Alec Smith, Jean-Mathew Prot, Charlotta Oleaga Sancho, James Hickman, Michael L. Shuler, How Multi-Organ Microdevices Can Help Foster Drug Development. Advanced Drug Delivery Reviews, 201469/70, 158-169.

Here are two papers that present a micro physiological system with GI tract  and liver tissues:

Mandy B. Esch, Gretchen J. Mahler, Michael L. Shuler, Body-on-a-Chip simulation with gastrointestinal and liver tissue suggests that ingested nanoparticles have the potential to cause liver injury. Lab on a Chip, 2014, 14, 3081-3092. doi: 10.1039/c41c00371c

Mahler, G.J., Esch M.B., Shuler, M.L. “Characterization of a Gastrointestinal Tract Microscale Cell Culture Analog Used to Predict Drug Toxicity ”, Biotechnol & Bioeng, 2009, 104(1), 193-205.

3D tissue scaffold for on-chip gut: microfabrication and integration into fluidic cell culture platform


Esch, M.B., Sung, J.H., Yang, J. Yu, J., March, J.C., Shuler, M.L. “On Chip Porous Polymer Membranes for Integration of Gastrointestinal Tract Epithelium with Microfluidic ‘Body-on-a-Chip’ Devices”, Biomedical Microdevices, 2012, 14 (5), 895-906.

We have developed a method to fabricate porous polymer membranes that are shaped in 3D to form 50 x 50 μm tall villi. This membrane was used as a scaffold to culture gut cells (Caco-2 and primary gut cells) on silicon within microfluidic systems. The 3D cell cultures can be used to simulate the oral uptake and absorption of nutrients, drugs, and drug carriers.  When incorporated into a microfluidic system that facilitates the recirculation of medium the tissue can also be combined with other on-chip tissues such as liver tissue to simulate the first pass metabolism. First pass metabolism refers to the absorption of ingested substances through intestinal tissue and their immediate transfer to the liver where enzymes can metabolize them before they enter the systemic circulation. The process considerably decreases the bioavailability of ingested substances and is of interest to drug developers, toxicologists, and nutrition scientists.

Tissue Engineering A: 50 micrometer in vitro microvasculature (endothelial lining) establishes adherents junctions even on the sidewalls of channels

microvasculature results 2-01Esch, M.B., Post, D., Shuler, M.L., Stokol, T. “Characterization of Small Diameter In Vitro Endothelial Linings of the Microvasculature,” Tissue Engineering A, 2011, 17, 2965-2971

In vitro microvascular endothelial linings cultured in 50 µm wide, 50 µm high microfluidic vessels establish tight junctions that allow us to use them to investigate biophysical and molecular mechanisms that play a role in circulatory disease phenomena. In vivo, endothelial cells grow on the inner surface of blood vessels and are confined by its geometry. In the smallest vessels of the microvasculature, this confinement leads to a significant bend within each cell. To imitate these geometric constraints within an in vitro model of the endothelial lining, we have fabricated small microfluidic channels (50 µm wide, 50 µm high) and cultured human umbilical vein endothelial cells (HUVECs) within them. We have characterized the developed model and our results show that the cells are capable of establishing adherents junctions (shown in the picture in red) even at the sidewalls of the channels.

Pittcon: Paper-based microfluidics for the detection of C. parvum mRNA in 30 min

Esch, M.B.; Bäumner, A.; Durst, R.A. “Rapid Visual Detection of Viable Cryptosporidium parvum on Test Strips using Oligonucleotide-tagged Liposomes” Analytical Chemistry, 2001, 73(13), 3162-3167

Paper-based microfluidics are the basis for pregnancy test strips that detect hormones via antibodies that are immobilized on a paper test strip. We employed the same principle to detect the RNA of a pathogen (Cryptosporidium parvum).  We immobilized synthetic DNA that is complementary to the RNA and placed it on the test strip. While the sample moves up the strip via capillary forces, the RNA in the sample comes into very close contact with the immobilized DNA. In our assay, the RNA competes with a second dye-conjugated synthetic DNA with the same sequence. This dye-conjugated DNA was initially added to the sample. In this competitive assay format, no color on the strip means the pathogen RNA was present.

Biopolymers: Relaxation of water confirms experimentally that water is bound to hydrogels via non-covalent forces


Esch, M.B.; Sukhorukov, V.L.; Kürschner, M.; Zimmermann, U. “Dielectric Properties of Alginate Beads and Bound Water Relaxation Studied by Electrorotation” Biopolymers, 1999, 50, 227-237

The association of water with polysaccharides is the basis for the survival of cells within hydrogels. Hydrogel-encapsulated cells are important because they could replace native cells that have experienced a loss of function, for example insensitivity to insulin-needs of the body. Here we proved experimentally that water is bound non-covalently to hydrogels. To prove this, we used four microelectrodes to create a rotating electric field in which we placed 400 micrometer large alginate beads. We measured how fast the beads rotated in fields of varying frequency and in medium of varying conductivity. A broad internal dispersion of the hydrogel centered between 20 and 40 MHz. We attribute this dispersion to the relaxation of water bound to the polysaccharide matrix of the beads.