A revolutionary microchip-based human disease model for testing drugs
Reporter: Ritu Saxena, Ph.D.
Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, have developed lung-on-a-microfluid chip and shown that it mimic human lung function in response to Interluekin-2 (IL-2) and mechanical strain. Authors describe it as “a “lung-on-a-chip” that reconstituted the alveolar-capillary interface of the human lung and exposed it to physiological mechanical deformation and flow; in other words, it breathed rhythmically much like a living lung”.
The model was developed by Hu et al and reported earlier in the journal Science in 2010. The group has now been successful in demonstrating that lung-on-a-chip can act as a drug-testing model for pulmonary edema. Infact, Hu et al were able to predict the activity of a new drug, GSK2193874, for edema. Authors stated “These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.” The findings have been published recently in the November 7 issue of Science Translational Medicine.
Research
To recreate lung on the microchip, the authors cultured two toes of human lung cells in parallel microchannels separated by a thin membrane. It was observed that the upper channel (alveolar) was filled with air, while the lower channel (microvascular) was filled with liquid. The observation was similar to what occurs in human lung. Breathing motion of the lung was mimicked on the chip by applying vacuum cyclically to the sides of the channels.
Mimicking pulmonary edema
Pulmonary edema is a condition characterized by the abnormal buildup of fluid in the air sacs of the lungs, which leads to shortness of breath. It is often caused when the heart is not able to pump blood to the body efficiently, it can back up into the veins that take blood through the lungs to the left side of the heart. As the pressure in these blood vessels increases, fluid is pushed into the air spaces (alveoli) in the lungs. This fluid reduces normal oxygen movement through the lungs. This and the increased pressure can lead to shortness of breath.
Hu and colleagues observed that when IL-2 was added to the microvascular channel, the fluid started to leak into the alveolar compartment of the chip. This process is a reproduction of what happens in edema. Further, adding cyclic mechanical strain along with IL-2 compromised the pulmonary barrier even further and leading to a threefold increase in leakage.
Drug-testing model
Once the authors established the pulmonary disease model on the microchip, they tested against a novel pharmacological agent, GSK2193874, which blocks certain ion channels activated by mechanical strain. This drug was able to inhibit leakage suggesting that it might be a viable treatment option for patients with pulmonary edema who are being mechanically ventilated. A major advantage of using this model is avoiding the use of animal models for research.
Future perspective
The lung-on-a-chip model developed by Hu et al could be used to test novel agents for pulmonary edema.
Editorial note on the article in Science translational medicine article states “The next step is to hook this lung up to other chip-based organs− heart, liver, pancreas, etc.−with the goal of one day being able to rapidly screen many drugs and conditions that could affect patient health.”
Source:
Journal articles
Hul D, et al. A Human Disease Model of Drug Toxicity−Induced Pulmonary Edema in aLung-on-a-Chip. Microdevice Sci Transl Med. 2012 Nov 7;4(159):159ra147.http://www.ncbi.nlm.nih.gov/pubmed/23136042
Hul D et al Reconstituting organ-level lung functions on a chip. Science. 2010 Jun 25;328(5986):1662-8. http://www.ncbi.nlm.nih.gov/pubmed/20576885
News brief
Video link to lung-on-a-chip http://wyss.harvard.edu/viewpage/240/
Sciencedaily report, November 7, 2012 http://www.sciencedaily.com/releases/2012/11/121107141044.htm
Thank you Dr. Sanexa. The video link was wonderful! I would be very interested to see what other systems could be designed and what other organs can be mimicked. It would also be interesting to have different type of cocultured cells to see interactions between blood flow, hypoxia, and other microenvironmental changes to the biochemical changes occurring in these cells. In addition I can see possibilites of developing micrometastases models in a physiologically relevant system.
Very Interesting
Dr. Ritu,
Thank you for this fascinating post on new prototyping technology in drug development. It is a new area you are exploring your interests and applying your fine scientific writing skills. You are pursuing the Lung disease from many angles and disease etiology, a shift from lung cancer to pulmonary edema, great breath and widening the focus of research.
We may wish to consider that a forthcoming e-Book on Nano Technology in Drug Delivery will take a broader scope to include chapter(s) on Nascent modalities for Drug Testing, thus, allowing this post into the e-Book to be Edited by our Dr. Tilda.
I suspect that the project was funded by GSK and it was a pioneering attempt to develop a prototype for drug testing by using this model instead of animal testing. A Solution “must-to-be-found-ASAP” to lower the cost and the time involved in new drug development.
It will be interesting to follow if success will be achieved in the planning to hook this lung up to other chip-based organs− heart, liver, pancreas, etc.− with the goal of one day being able to rapidly screen many drugs and conditions that could affect patient health.”
Great work.
Dr. Williams, I am glad you liked the report. Someone on linkedin pointed out that the lung-on-the-chip model is part of a DTRA effort to put about 10 organ like samples interacting with each other on a chip to give a better diagnosis of infectious agent and drug interactions. I guess, the refinement of the chip and its standardization could enable further studies in different conditions and drugs. Endless possibilities!
Dear Aviva,
Thanks for the comment. Yes, I too realized that I have written quite a few posts based on lung diseases and therapy.
I agree with you that this post would make a good addition in the forthcoming book on Nanotechnology edited by Dr. Tilda. The post would require addition of follow up studies because I am assuming some progress would be made in this research by the time we get down to writing the book on nanotechnology.
The work was funded by the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), Defense Advanced Research Projects Agency (DARPA), and the Wyss Institute for Biologically Inspired Engineering at Harvard University. http://wyss.harvard.edu/viewpressrelease/99/
Editors of ALL books, must contact AUTHORS and solicit Updates,
ALL Authors are responsible, when their name appears in a Table of Contents to make all changes due PRIOR to e-Book completion.
All Authors should have alist of the posts going into EACH e-Book fo rupdates. Ritu, in your own case, You are Author in 5 e-Bookd and Editor of and Editor of 2 e-Books — BRAVO
Mitichondria – eBook on Cardiovascular
Lung – eBook Cancer
Lung e-Book Nano
Liver – eBoom Metabolism
NO – NO e-Book