Author: İrem Duman, University of Ege Department of Bioengineering
As the years pass by technology has been developed with it. Diagnosis and cure of the diseases which are affecting human health have been developing by scientists. However, the amount of money which spent on the R&D studies for new drug developments or diagnostic methods have been too much high. In addition, seeing the effects of those drugs takes time. These studies have the possibility of failure after all that time and cost. Trials of drugs or diagnostic kits; starts to be developed in a laboratory and concludes with animal tests followed by clinical trials.
In both cases, there are some limitations. The most important negative factor for working with the cell culture in vitro is that; the cells are growing in an artificial environment, not in the human body. This may cause the cells to request the intracellular conditions where they are accustomed to earlier, and the cells can grow stressed in vitro. Intracellular conditions can hardly be achieved in artificial environments emulating the human body provides them with their natural environment. This may cause challenges about the expected results.
In animal testing, depending on the species, the disease agent or immune response to the drug may be varied. In that case, human immune response would be different because of the kind of the species. So how do we fight effectively against the microorganisms or cancer that threaten human health if we have limitations with current methods? How can we develop more efficient and cheaper drugs? Could we create artificial environments that enable us to observe the in vitro conditions, shorten our project time and also can we observe cells alike inside the human body?
What are the organ-on-a-chip systems?
Organ-on-a-chip systems have been developing as biomimetic systems of original tissue architecture. One of the key points in this system is the cell layer architecture. It is working for the cells which they can feel same inside the human body. Basically, it is a home for the cells in vitro. The aim of this system is instead of creating a new organ in a laboratory, it is forming a small functional assembly by the help of the multidisciplinary scientific expertise to provide the mimic of some layers of original tissue systems.
The aim of lab-on-a-chip tissue devices is to incorporate minimal functional units that can mimic functions at the tissue and organ level. Micro-channel systems are improving the functionality of the 3D organ models compared to traditional 2D culture methods with the physicochemical interactions in multi-cell structures and tissue interfaces. These devices can provide control over many system parameters that cannot be easily controlled in 2D static cultures or bioreactors. A wide range of physiological events and high-resolution real-time visualization are applicable as well. Organ-on-a-chip systems have a lot of different functions, such as usability in drug development, toxicity testing, biomarker identification and so on.
Various versions have been developed in the literature; liver-on-a-chip, heart-on-a-chip, kidney-on-a-chip and moreover including bones, brain, eye, and skin.
Fabrication of tissue chips
Now the real question is; ‘How to produce these chips?’ In its simplest form, the system is a microchannel platform in which a cultured cell exhibiting functions of a tissue type. When the method becomes more complicated, like increasing types of cells, a higher number of micro-channels porous connections are required to carry out communication between cell layers.
Photolithography is the most used technology for the manufacture of the chip molds. It is the process that transfers channel architecture from computer design to the photoresist on the surface of a silicon wafer using focused UV light. The photoresist mold is used to form microchip using materials, such as PDMS (poly-dimethylsiloxane) by pouring onto. To close the device, the microchannel layer is bond with another layer of PDMS, glass or any other suitable material.
Lung on a chip as an example
One of the most impressive examples is lung-on-a-chip, first developed by Donald E. Ingber and Dongeun Huh. The device was developed by using human lung epithelial cells and vascular endothelial cells. It can also mimic the inflammatory response induced by microbial pathogens by showing the passing of white blood cells across cell layers inside the chip. The main usage can be for testing the environmental toxins or antibacterials in the future.
The chip constitutes 3 microchannels and a flexible membrane in the center. While airflow has applied from the lung epithelial part of the chip, blood flow like liquid is sent within the channel of blood vessel mimicking part. The third microchannel is on a side for vacuum generation to provide mechanical resemblance of breathing. The system was tested with the E. coli bacteria. The microbial cell sample is given to the lung on a chip by airflow on the chip (upper part). Blood flow is also given at the same time (lower part). When the white blood cells detect the bacteria, they adhere to the cells. Activated white blood cells pass through the membrane and start fighting the E. coli. This simple but effective experimental proof of concept is a simulation of the inflammatory response that can occur in a body every minute.
Scientists do research on new treatment methods with the help of microchip technology. However, there are also challenges that have not yet been overcome. These are mimicking tissues thicker than 3mm, integrating micro-capillary circulation, usage of primary stem cells or immortalized cells, dynamic control of closed chips and more. Each system/organ has its own difficulty, additionally. For example, to simulate the heartbeat, it is necessary to design a chip that does not interfere with electrical activities. More importantly; we don't fully know the effects of polymers and chip conditions on cell behavior, like shear stress or adsorption on channel walls.
Although Organ-on-a-chip technology is a new method and has many challenges, it is promising for following the 3Rs rule (reduction, refinement, replacement) for model animal usage in scientific research.
- Bhatia, Sangeeta N., and Donald E. Ingber. "Microfluidic organs-on-chips" Nature Biotechnology 32.8 (2014): 760.
- Zheng, Fuyin, et al. "Organ‐on‐a‐Chip Systems: Microengineering to Biomimetic Living Systems" Small 12.17 (2016): 2253-2282.
- Lee, Jong Bum, and Jong Hwan Sung. "Organ‐on‐a‐chip technology and microfluidic whole‐body models for pharmacokinetic drug toxicity screening" Biotechnology journal 8.11 (2013): 1258-1266.
- Bhise, Nupura S., et al. "Organ-on-a-chip platforms for studying drug delivery systems." Journal of Controlled Release 190 (2014): 82-93.
- Zhang, Chi, et al. "Towards a human-on-chip: culturing multiple cell types on a chip with compartmentalized microenvironments." Lab on a Chip 9.22 (2009): 3185-3192.
- Baker, Monya. "Tissue models: a living system on a chip." Nature 471.7340 (2011): 661.
- Lee, Jihoon, et al. "Effect of thermal treatment on the chemical resistance of polydimethylsiloxane for microfluidic devices." Journal of Micromechanics and Microengineering 23.3 (2013): 035007.
- RE, C. "Lung-on-a-Chip Breathes New Life Into Drug Discovery." Science (2010): 1662.