Faculty Editor: Professor Jeffrey DaCosta
When researchers aim to evaluate the effects of an experimental drug or explore the virulence of a dangerous pathogen without the use of human subjects, several avenues are available. Given the abundance of homologies between humans and other mammals, tests such as these have been conducted on animal subjects for hundreds of years5. While animal testing is still a prevalent form of experimentation, the use of isolated cell cultures continues to provide ground-breaking insights into our cellular biology1,5.
However, animal testing and cell cultures are not without their flaws. Aside from the many ethical issues raised by animal testing, the genetic and phenotypic variation between animal subjects and humans is to such a degree that it limits the reliability of any data collected in these tests. Simply put: animals are not humans, and their physiological reactions to drugs, chemicals, and pathogens may differ greatly from our own1,3,5. While conventional cell cultures can be derived from human cells, they also have shortcomings. Most importantly, due to their simplicity they are often unable to recapitulate the complex physiological processes that occur within and between tissues,5.
As they seek more reliable approaches to studying human physiology, more and more researchers are turning their eyes to a technology with the potential to upend the status quo for in vitro medical research: microphysiological systems (MPSs)1,4,5. MPS are chip-sized models of human organs that use viable tissue to replicate organ function, commonly referred to as “organs-on-chips”2,4. These innovative chips strike a balance between conventional methods, granting the convenience and control of a cell culture while offering a complexity on par with animal models. The primary application of MPS is as a means of recapitulation, i.e. the authentic reproduction of an organ’s structure, function, and response to stimuli4,5. Using immortalized cell tissue in conjunction with integrated sensors, MPS allow researchers to collect a breadth of data on the effects that drugs, toxins, diseases, and other foreign agents have on organ function4.
While MPS promise an array of advances for life science research, industries are hesitant to adopt this new technology due to concerns over its reliability and robustness3,4. These devices remain largely unproven, and questions regarding their applications and transferability continue to persist. Industry professionals are particularly concerned with low reproducibility beyond the confines of the MPS manufacturer’s lab. In an effort to bolster confidence in MPS and legitimize these devices as reliable research platforms, a number of research teams have conducted studies illustrating the performance of MPS in comparison with conventional cell cultures and animal testing.
One such effort was a collaboration between researchers from Texas A&M University, North Carolina State University, and the University of Washington that compared the nephrotoxicity of several compounds using both an MPS and a traditional cell culture3. Both platforms involved the use of epithelial cells resected from human renal proximal tubules, structures critical to healthy kidney function. While the research team is ultimately interested in characterizing the effects of chemical compounds on these renal tubules, the goal of this study was to test the transferability and reproducibility of the data they collected using the MPS. If MPS are to achieve widespread acceptance, their reliability must be proven beyond their developers’ laboratories. To this end, the group of researchers strove to validate the tissue chip developer’s results in an independent setting3.
In order to back up the developer’s results, the researchers used a microfluidic MPS platform made from specialized glass and plastic containing a small channel for conducting fluid through and a chamber for cell growth. Renal proximal tubule epithelial cells (RPTECs) were cultured in the growth area of the microfluidic platforms, with some models containing RPTECs from the MPS developer and others from a commercial supplier. Though these cells were cultured at identical temperatures and C02 levels, conditions like growth medium and supplements differed between the cultivation methods used by the two cell sources3. The cells within the microfluidic platforms were then immortalized to maintain their viability for the duration of the study. Throughout the study, the cells within the MPS were compared to those being cultured in conventional 384-well plates. While cell cultures in the plates remained static, cells within the MPS were subjected to the continual flow of fluid passing through the central channel3. Both the cells within the 3D microfluidic platforms and those within the 2D well plates were subjected to the same battery of nephrotoxins, namely polymyxin B, cisplatin, gentamicin, and cadmium. Using the two opposing platforms, data was collected and subsequently compared to the developer’s endpoints chosen prior to the start of the study3.
After nearly a month of observation and analysis, the researchers arrived at a nuanced conclusion. The MPS were successful in terms of more authentic recapitulation and overall transferability, lending support for their widespread implementation as legitimate research platforms. However, there was a caveat: the reproducibility of the data depended heavily on the source of the epithelial cells used in the study. When integrated with the MPS, freshly isolated cells from the developer’s lab produced different results when compared to cells from a different vendor3. While the study proved promising for the future of microphysiological systems, the researchers concluded that future MPS platforms “should be joined with a commercially-available well-characterized cell population” to ensure reproducibility. If MPS are to succeed in supplanting traditional cell cultures, end-users must have access to the same cell source used by the developer3.
Ultimately, the study bears further testimony to the use of MPS in mainstream research. Though still relatively nascent in their development, MPS offer an exciting range of applications that go far beyond the limitations of traditional in vitro platforms2,4. Moreover, as these devices increase in precision and sophistication, they may very well eliminate the need for animal testing1. With momentum growing behind this new technology, it would be reasonable to expect microphysiological systems to become an important resource as the biological sciences continue to progress forward.
1. About MPS. Micropysiological Systems Web site. http://mps.amegroups.com/about. Updated 2009. Accessed Oct 4, 2018.
2. Burrows L. 3-D printed heart-on-a-chip with integrated sensors. Harvard John A. Paulson School of Engineering and Applied Sciences Web site. https://www.seas.harvard.edu/news/2016/10/3d-printed-heart-on-chip-with-integrated-sensors. Updated 2016. Accessed Oct 5, 2018.
3. Courtney Sakolish, Elijah J Weber, Edward J Kelly, et al. Technology transfer of the microphysiological systems: A case study of the human proximal tubule tissue chip. Scientific reports. 2018;8(1):14882. https://www.ncbi.nlm.nih.gov/pubmed/30291268. doi: 10.1038/s41598-018-33099-2.
4. Ringeisen B. Microphysiological systems (MPS). Defense Advanced Research Programs Agency Web site. https://www.darpa.mil/program/microphysiological-systems. Accessed 10/02/, 2018.5.
5. Wikswo JP. The relevance and potential roles of microphysiological systems in biology and medicine. Experimental Biology and Medicine. 2014;239(9):1061-1072. https://journals.sagepub.com/doi/full/10.1177/1535370214542068. doi: 10.1177/1535370214542068.