A team from Harvard University have designed a device that can mimic lung function. Published in Science, the ‘lung-on-a-chip’ device designed by Donald Ingber and his group, gives some crucial new evidence on how nano-sized particles are taken up by the body. This could be the first step to a laboratory tool that will allow us to predict responses to drugs and toxins more accurately.
Ingber’s group at Harvard’s Wyss Institute for Biologically Inspired Engineering, have designed a device that can reproduce many of the properties of the air sacks (alveoli) within a human lung including their interface with surrounding capillaries.
The silicone device contains two closely placed 1mm channels separated by a 10 micrometre (ten millionth of a metre) porous flexible membrane. The entire device is between 1-2 cm in length: small enough to be integrated into a more complex microdevice in the future.
The membrane is coated on one side with alveolar cells to mimic the alveolar surface. On the other side, the membrane is coated with cells from the lining of the capillaries that surround the lung. Air is introduced to the alveolar channel to reproduce the air-liquid interface found in the human lung.
A key advance in this device is its ability to replicate breathing, particularly the stretching of the alveolar surface and adjacent capillary walls. The device does this using two additional microchambers either side of the main microchannels. When a vacuum is applied to these chambers, the porous silicone membrane and the attached tissue layers are stretched. This action can be cycled to replicate the effect of breathing.
Ingber’s team tried to further reproduce lung behaviour by adding immune cells to the capillary microchannel fluid. They wanted to try and induce an inflammation response. The mechanism involved is multistep, but ultimately leads to the movement of white blood cells into the alveoli.
Within several minutes of introducing cell-signalling proteins (cytokines) to the alveolar microchannel, the team saw migration of white blood cells from the capillary microchannel. They crossed the porous membrane to emerge on the alveolar surface. Similar experiments using E. coli showed that within five hours white blood cells reached the alveolar surface and started to engulf the bacteria.
The Harvard team went on to investigate if the device would replicate the lungs response to nanoparticles. Results using 12 nm silica showed that whilst in static mode, little response was triggered, but when ‘breathing’, a significant immune response was produced within several hours.
The breathing movement appears to accelerate toxicity and Ingber suggests that this is because it increases uptake of nanoparticles into the lung membrane. This was confirmed using confocal microscopy, which showed that 70% of cells contained nanoparticles when experiments were carried out in ‘breathing’ mode, a factor of 10 more than when the device had been static.
The device offers a low-cost route to toxicity screening but ultimately, moves us one step closer to the goal of a miniaturised whole-body model that could predict the human physiological responses to a range of substances entering our bodies.
Reconstituting Organ-Level Lung Functions on a Chip, D Huh, B D Matthews, A Mammoto, M Montoya-Zavala, H Y Hsin, D E Ingber, Science. 328, 1662 (2010)