A US study that successfully used a “lung-on-a-chip” to mimic a chemotherapy drug side effect brings closer the day when drug developers use “organ-on-a-chip” methods to replace more traditional approaches like animal testing and cell cultures, which are costly and time consuming.
Senior author Donald Ingber, founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, and colleagues, write in the 7 November online issue of Science Translational Medicine, how they developed their “lung-on-a-chip” to study pulmonary edema, a major toxic side effect of the cancer chemotherapy drug interleukin-2 (IL-2).
Ingber says in a statement:
“Major pharmaceutical companies spend a lot of time and a huge amount of money on cell cultures and animal testing to develop new drugs, but these methods often fail to predict the effects of these agents when they reach humans.”
In their paper, Ingber and colleagues write how their study provides “proof of principle for using a biomimetic microdevice” that works sufficiently like a lung to mimic pulmonary edema.
The microdevice, which the team first wrote about two years ago, is a crystal clear, flexible polymer about the size of a memory stick, containing hollow channels.
They lined the channels with layers of living human cells to create a “microfluidic device” that replicates the “alveolar-capillary interface” in human lungs. This interface is where oxygen from the air passes through the walls of tiny air sacs into the fine blood vessels of the lungs and thence into the bloodstream.
The key part of the device has a thin, flexible, porous membrane as the wall between two channels. On one side it is lined with human lung cells from the air sac and exposed to air (the air channel), while the other side holds human capillary blood cells with medium flowing over them (the blood channel).
The cells experience air flow and fluid flow, and a cyclic “mechanical strain” that mimics normal breathing motions. To create the mechanical strain, a vacuum is applied to side channels: this deforms the tissue-tissue interface and re-creates the way lung tissue expands and retracts during breathing.
Ingber and colleagues used their microdevice to test pulmonary edema, a major side effect of the chemotherapy drug IL-2. Pulmonary edema is a deadly condition where the lungs fill with fluid and blood clots.
When they injected IL-2 into the blood channel, fluid leaked across the membrane that separated it from the air channel, reducing its air supply and thereby reducing the amount of oxygen that moves into the blood cells. This is exactly what happens in the lungs of human patients receiving equivalent doses of IL-2, and over the same timescale, say the researchers.
Blood plasma proteins also crossed over into the air channel, causing blood clots to form in the air space, as it does in humans treated with IL-2.
However, the researchers were surprised by one particular result: the physical act of breathing seems to boost the effect of IL-2 in pulmonary edema. Ingber says this was “something that clinicians and scientists never suspected”.
They discovered this when they turned on the vacuum generator to simulate the mechanical breathing: fluid leakage increased more than three-fold when treated with the relevant IL-2 dose. The team confirmed the same response occurs in an animal model of pulmonary edema.
This surprising result would suggest doctors giving IL-2 to patients on a respirator should consider lowering the tidal volume of air being pushed into the lungs. This could reduce the negative side effects of the drug, say the researchers.
The study also offers exciting prospects for drug developers, in that, as Ingber explains, “this on-chip model of human pulmonary edema can be used to identify new potential therapeutic agents in vitro“.
The researchers suggest the pulmonary edema symptoms could be prevented by treating the tissues with a new class of drug, a transient receptor potential vanilloid 4 (TRPV4) channel blocker.
TRPV4 is already under development by GlaxoSmithKline (GSK), and is the subject of a separate study, by GSK researchers, in the same issue of Science Translational Medicine. In that study, the GSK team writes how they independently confirmed the ability of TRPV4 to reduce pulmonary edema using animal models of the condition caused by heart failure.
Ingber says in just over two years they have gone from revealing the initial design of their lung-on-a-chip to showing it can model a complex human disease, and give a glimpse of what drug discoverers and developers will be doing in the future.
Some of the funding for the study came from the NIH Division of Program Coordination, Planning, and Strategic Initiatives, through the Common Fund’s Regulatory Science program. The director of that division is James M. Anderson, who says:
“Organs-on-a-chip represents a new approach to model the structure, biology, and function of human organs, as evidenced by the complex breathing action of this engineered lung. This breathing action was key to providing new insight into the etiology of pulmonary edema.”
“These results provide support for the broader use of such microsystems in studying disease pathology and hopefully for identifying new therapeutic targets,” he adds.
Written by Catharine Paddock PhD