Synthetic Organs on a Chip, by Manuel Escanciano and Chris Lowe

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Synthetic Organs on a Chip

Actual Lung on a Chip

Background

Organs on chips are devices that contain living cells, meant to mimic the behavior of actual human organs. The functions depicted by the chips don’t account for all the functions of an organ just the most vital ones. The chips simulate the structure, the microenvironment, and the mechanical behavior of an organ, to be able to study the effects of diseases, toxins, and pharmaceuticals.

Motivation

The organs on a chip were created because they can provide more accurate and faster results on human drug testing when compared to the conventional methods. The two methods for drug testing are to test them on animals or on engineered cells. Both methods are highly expensive, since the current drug testing expense is roughly 1.5 billion US dollars [1].

Currently there’s a high failure rate with new pharmaceuticals, and animal testing can be inefficient since the responses that are exhibited by animals might not be the same responses in human organs. The pace at which you can collect results is also very slow in animals testing, while on the other hand using a chip you can observe in real time how the organs react to different drugs or diseases.

Animal Testing and Three Dimensional Tissue

At the moment animal testing is the most recognized and best method to test drugs in vivo. But many people are against it due to the loss of life of the animal test subjects, as well as the high price of the process. More importantly the results obtained in animal testing might not indicate good results when the drug is introduced into the human body, therefore complications are always present.

Three dimensional tissue models such as hydrogel or other cell seeded scaffolds systems can provide greater insight into cellular behaviors due to increased cell-cell signaling and migration that can take place in three dimensional cultures. These systems have been demonstrated by various groups to model various cell and tissue types; however their long term viability is limited by transport of nutrients, oxygen and other vital compounds to cellular survival in a full organ or tissue system due to the inability to successfully incorporate vessels approaching natural occurring vasculature [2].

Organs on a Chip

Lung on a Chip

The Lung on a Chip was developed in 2010 by Doctor Donald Ingber and other researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Specifics

Representation of a Lung on a Chip

The lung on a chip is constructed primarily of poly(dimethylsiloxane) (PDMS), a soft, partially elastic polymer, that has been patterned through soft lithography techniques typical of nanotechnology and microfluidic devices. Two pieces of a PDMS slab are patterned with three different channels about ten microns in width. These two PDMS slabs are sandwiched around a thin PDMS membrane that has been patterned with pentagonal pores. The three pieces of PDMS are fused together to create three microfluidic channels that are divided down the middle by the porous PDMS membrane. The outermost channels are exposed to a PDMS etching compound that etches away part of the exposed PDMS surface, including the entire membrane. These outermost channels are the vacuum channels that will cause the PDMS chip to expand and contract similar to natural lung tissue. The middle channel that remains with its porous membrane intact is where the gas exchange takes place. Human lung epithelial cells are seeded onto the top layer of the chip and they adhere to the sides of this channel including the porous PDMS membrane while they are exposed to air. On the opposite side of the membrane, human endothelial cells are seeded on to the membrane and channel surface while a blood modeling media is flowed through. The vacuum channels will be connected to a computer driven vacuum pump that will cause the central channel and it’s membrane to expand and contract, while microfluidic pumps model the flow of air and blood through the central channel on either side of the membrane [3].

Initial Experiments

Two experiments were carried out using the lung on a chip model and its response compared to results in animal models, the two experiments were bacterial lung infection, and the inhalation of nanoparticles.

Gut on a Chip

The gut on a chip contains intestinal epithelial cells that mimic peristalsis. Peristalsis is the contractions and relaxations in a wave-like manner, which can be observed in the digestive system as it pushes food through[4]. On the gut on a chip this is achieved by vacuums that force the membrane, which the cells adhere to, to contract and relax. The gut on a chip is a far better way to study intestinal cells since it has been observed that the cells create villi structures, which are a finger like structure that helps absorb nutrients, while on a dish this feature has not been observed. Researchers have also been able to support intestinal microbial inhabitants on the surface of the cells, creating even more similarities to an actual gut, which can give great insight into Cronh’s Disease, which is an inflammation of the intestines.

Kidney on a Chip

The Kidney on a chip contains renal tubular cells attached to a porous membrane. Renal tubular cells are in charged of filtering blood and produce urine. The chip is bisected by the membrane resulting in a inner flow and an outer flow; the inner flow being filled with a fluid that mimics urine, and the outer flow being filled with a blood like substance [6].

Bone Marrow on a Chip

Bone marrow on a chip consists of a cylindrical hole in which bone-inducing material is induced. The chip contains hematopoietic cells which produces the blood cells of the human body. The membrane is made out of poly-dimethylsiloxane, and currently it has only been used with laboratory mice’s bone marrow [7].

Other Chips

Liver on a Chip – carries out protein synthesis

Heart on a Chip – used to study pace makers

Spleen on a Chip

Brain on a Chip

Future Research

Research groups like the Wyss Institute want to be able to add more functions to the organs on a chip instead of only one or two specific functions. Once this technology is full understood they hope to make chips that are specific to individuals, in that sense they could even be used for individuals with genetic mutations.

The main goal of this research is to be able to connect everything, create a body on a chip [9]. Scientists hope to connect all organs on a chip in series, to be able to observe the effects toxins, diseases, or pharmaceuticals have on the whole body rather than just one organ (funded by the Defense Advanced Research Project Agency with 37 millions U.S. Dollars).

References

[1] Canadian Medical Association. Journal of the Canadian Medical Association. ”Drug Devlopment Cost Estimates Hard to Swallow”. 2009. 180 (3) 279-280.

[2] Pampaloni, F., Reynaud, E.G, Stelzer, E.H.K., Nature Reviews: Molecular and Cell Biology. 2007 8. 839-845

[3] žJohnson, Carolyn Y. National Effort to Create Organs on a Chip to Speed Development of Safe Medications. Harvard University Press. http://www.boston.com/whitecoatnotes/2012/07/24/national-effort-create-organs-chip-speed-development-safe-medications/e23fYPgraAquOTBHUCCTaN/story.html

[4] žMoyer, Melinda Wenner. Organs-on-a-Chip for Faster Drug Development. Scientific American. [Online] http://www.scientificamerican.com/article.cfm?id=organs-on-a-chip

[5] žBennett, Drake. Making Human Organs on a Chip. Businessweek Technology. [Online] http://www.businessweek.com/articles/2012-06-27/making-human-organs-on-a-chip

[6] žKidney on a Chip. Chemical Biology. RSC Publishing. [Online] http://www.rsc.org/Publishing/Journals/cb/Volume/2009/10/Kidney_chip.asp

[7] žYu-suke Torisawa; Catherine S. Spina; James J. Collins; Donald E. Ingber. Bone Marrow-on-a-chip. [Online] http://www.rsc.org/images/loc/2012/pdf/M.3.96.pdf

[8] žWilliamson, Adam; Singh Sukhdeep; Schober, Andreas. Lab on a Chip. RSC Publishing. http://pubs.rsc.org/en/content/articlepdf/2013/lc/c3lc50237f

[9] žGammon. Organs On A Chip Might Soon Simulate The Entire Human Body. Co. Exist. [Online] http://www.fastcoexist.com/1681357/organs-on-a-chip-might-soon-simulate-the-entire-human-body