How often do you have an opportunity to help shift a paradigm? Here might be one: our research team wants to create alternatives for animal experiments. We build microphysiologic body-on-a-chip systems that can mimic the human metabolism.
When new drugs are tested on patients, we count on animal experiments to predict the outcome. Often though, those predictions miss the mark: drugs are less effective or more toxic than hoped for. That’s because human metabolic pathways can differ from those in animals. The resulting metabolites can inflict unanticipated injuries.
Microphysiologic body-on-a-chip systems provide a way to test drugs in the presence of human metabolic pathways. Those pathways are created by placing human tissues into tissue culture chambers that are interconnected via microfluidic channels. If one tissues’ enzymes convert a drug to a toxic metabolite, the fluidic channels distribute it to all other tissues. The effects of a toxic metabolite are easy to spot when tissues start to lose their function or die.
Current microphysiologic systems contain 2 - 14 human organ compartments. In proof of concept experiments, the systems have been challenged with painkillers and known toxicants. They are capable of predicting acute toxicity to the lung, kidney, and liver, and drug-induced weakened heart muscle contractions. The systems can also generate physiologic concentrations of orally taken painkillers. Advanced microphysiological systems have been operated with primary cells and stem-cell derived tissues, providing more authentic environments for drug action.
Our research team is a group of postdocs, graduate students, and undergraduate students who are passionate about developing microphysiologic systems. Our laboratory is located on the NIST campus in Gaithersburg, MD. We have access to first-class nanofabrication facilities (CNST) and the expertise of scientists at NIST. We collaborate with many other academic groups in the US (University of Maryland, University of Illinois at Urbana-Champaign) as well as abroad (Gunma University, Japan).
To ready microphysiologic systems for drug testing in commercial settings, we are currently addressing the following challenges:
1. Drug toxicity depends on drug concentrations (or drug metabolite concentrations). To create physiologic drug metabolite concentrations, the systems must reflect human physiology. That means, the systems must replicate organ size ratios, blood flow rates, and drug residence times accurately.
2. The enzymes within the tissues must reach near-physiologic activity levels.
3. The systems must have integrated sensors for continuous tissue health monitoring.
4. The systems must run for 30 days or longer so that chronic drug exposures can be simulated.
5. At the end of an experiment, it must be possible to recover tissues for further examination.
6. We need to develop a cell culture medium that will adequately supply all tissues in the system with nutrients.
7. The routine addition of undefined animal serum to cell culture medium causes high experiment-to-experiment variability. A cell culture medium that does not contain animal serum would aid in making results more reproducible.
8. In the future, iPS cell-derived tissues might also make it possible to create a microphysiologic system that represents a particular group of patients. To advance precision medicine, the systems must support human primary cells or stem-cell derived tissues.
We encourage you to apply to work with us on those challenges.
Esch MB, Smith A, JProt JM, Sancho CO, Hickman J, Shuler ML: How Multi-Organ Microdevices Can Help Foster Drug Development. Advanced Drug Delivery Rev. 2014, 69, 158-169
Miller PG, Shuler ML: Design and demonstration of a pumpless 14 compartment microphysiological system. Biotechnology and Bioengineering 113(10): 2213-2227, 2016
Mahler GJ, Esch MB, Shuler ML: Characterization of a Gastrointestinal Tract –Liver Microscale Cell Culture Analog Used to Predict Drug Toxicity. Biotechnology and Bioengineering 104(1): 193-205, 2009
Bernabini C, Oleaga C, Smith AT, Srinivasan B, McLamb W, Platt V, Bridges R, Cai Y, Santhanam N, Berry B, Najjar S, Guo NAXG, Martin C, Ekam G, Esch MB, Langer J, Ouedraogo G, Cotovio J, Breton L, Shuler ML, Hickman JJ: Multi-Organ toxicity demonstration in a functional four organ pumpless in vitro system. Scientific Reports 6(1): 20030, 2016
Esch MB, Ueno H, Applegate D, Shuler ML: Modular, pumpless body-on-a-chip platform for the co-culture of GI tract epithelium and 3D primary liver tissue. Lab on a Chip 16(14): 2719-2729, 2016
Smith AST, Long CJ, Berry BJ, McAleer C, Stancescu M, Molnar P, Miller PG, Esch MB, Prot JM, Hickman JJ, Michael L. Shuler ML: Microphysiological systems and low-cost microfluidic platform with analytics. Stem Cell Research & Therapy 4 (1): 11, 2013
1. Companies work on commercializing such systems: Hµrel Corporation, Hesperos, and Emulate
2. Patents related to body-on-a-chip devices: US patent 5,612,188
3. NIH “tissue chips” program website: https://ncats.nih.gov/tissuechip/projects/2014.
Body-on-a-chip; Organ-on-a-chip; Microfluidics, microphysiologic systems; Biosensors; Nanofabrication; Liver; Toxicity; Drug;