Written by: Jamie Saito ‘25
Edited by: Melinda Li ‘22
A promising new modeling system may help scientists better understand human physiological responses. Organs-on-Chips (OoC), or “tissue chips”, are microfluidic devices containing human cells that can model physiological environments in vitro. Though this technology is relatively new, recent research has shown promising results that may change the way we understand human physiology, treat rare diseases, and test drug delivery systems.
Ranging from the size of a USB to a 96-well laboratory plate, OoCs are microfluidic cell culture devices that integrate living human organ cells to model the 3-D structure of tissues. Biomechanical forces, such as compression forces applied to organs on a daily basis, can then be integrated into this system to create a device that captures realistic physiological responses [1]. Scientists can control the types and structure of the cells on these devices, allowing them to mimic the functionality of organs. OoCs have thus been applied to understand human pathophysiology.
To design these systems, scientists rely on a reverse engineering process, which focuses on identifying “the minimal set of design principles that are necessary to reconstitute relevant functions of the whole” [2]. To mimic a human organ, OoCs should include parenchymal tissue, such as nerve tissue; vascular tissue, or blood vessels; and biomechanical forces, such as stresses and strains that act on tissues and fluids in the body. Disassembling the basic structure of human organs allows researchers to design devices that can mimic organ systems, such as the lung, intestine, and heart. Scientists are looking to integrate other fields of research, such as 3D bioprinting, to assemble these models, which allow for control over cell distribution and structure. However, an incomplete current understanding of human physiological systems may limit future design of these devices.
These single-organ systems have been able to provide scientists with in vitro insight into human pathophysiology. One of the earliest applications of this technology was in the development of a lung-on-a-chip device. Scientists used a vacuum system to create breathing movements that mimicked the forces applied to a lung [3]. These researchers later discovered that the mechanical breathing motions applied in their OoC model increased the likelihood of pulmonary edema, or excess fluid in the lungs [4]. The inclusion of biomechanical forces and intercellular communication has the potential to provide scientists with more complete insight into human physiology, which may not be possible using other modeling systems.
While single-organ systems are promising models for tissue-specific diseases, the linkage of multiple OoC models may further broaden the range of applications of this technology. Scientists have been successful in creating a four organ chip that integrated small intestine, skin, liver, and kidney equivalent systems [5]. Tissue structure was effectively maintained for 28 days, and metabolic analysis established that this chip was able to achieve a sustained balanced internal (homeostatic) environment, providing evidence that these devices are able to mimic the biological processes that occur within our bodies. These studies therefore suggest that complex, multi-organ chips may be designed to “study signal transfer between different organs and to analyze physiological human organ-organ coupling in vitro,” which can better inform researchers on large-scale biological processes [2].
Furthermore, scientists are looking for ways to maximize the customizability of these devices. Instead of using healthy cells, OoCs may be adapted to treat rare diseases by using induced pluripotent stem cells (iPS) from patients. By this method, using cell samples from patients, scientists can engineer individual-specific stem cells that are immunologically identical to the patient. A 2014 study used patient-derived iPS cells to create a heart-on-a-chip model that was then used to study Barth syndrome, a rare condition [6]. By combining OoC and Cas-9 gene editing technology, researchers were able to conduct an in-depth study of the pathway of this disease. Thus, this customizability may be used to create in vitro models that effectively mimic rare, idiopathic conditions which would be hard to study otherwise.
Because these chips are able to mimic physiological processes and tissue-tissue interactions, they may also be applied to study drug delivery systems and toxicity. Currently, about 80% of developmental drugs fail in clinical testing [1]. Scientists often rely on animal models, which might not be entirely effective at mimicking human physiological responses. Researchers have found that lung-on-chips models produced with rat, dog, and human cells have different drug-induced toxicity responses, suggesting that species-specific modeling is necessary to create effective delivery systems [7]. OoCs thus have the potential to become a gold standard in pharmaceutical development.
While these small devices hold a lot of potential, there are still limitations that may hinder the widespread use of OoCs. Because they rely on a reverse-engineering approach, our incomplete understanding of human physiological systems may prove challenging for rapid development. Furthermore, to effectively mimic the biomechanical structure of the body, scientists need to optimize the materials used to produce these devices, which may limit functionality [1]. While there is still a lot of research to be done on this technology, organs-on-chips are promising models to study human physiology, disease pathways, and drug delivery systems.
Works Cited
1. Low LA, Mummery C, Berridge BR, Austin CP, Tagle DA. Organs-on-chips: into the next decade. Nat Rev Drug Discov. 2021 May;20(5):345–61.
2. Ingber DE. Reverse Engineering Human Pathophysiology with Organs-on-Chips. Cell. 2016 Mar 10;164(6):1105–9.
3. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Reconstituting Organ-Level Lung Functions on a Chip. Science. 2010 Jun 25;328(5986):1662–8.
4. Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, et al. A human disease model of drug toxicity–induced pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med. 2012 Nov 7;4(159):159ra147.
5. Maschmeyer I, Lorenz AK, Schimek K, Hasenberg T, Ramme AP, Hübner J, et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip. 2015;15(12):2688–99.
6. Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med. 2014 Jun;20(6):616–23.
7. Jang KJ, Otieno MA, Ronxhi J, Lim HK, Ewart L, Kodella KR, et al. Reproducing human and cross-species drug toxicities using a Liver-Chip. Sci Transl Med. 2019 Nov 6;11(517):eaax5516.
[Image citation] The Wyss Institute’s gut-on-a-chip constricts and relaxes, just as in the human body, producing finger-like projections called villi [Internet] [cited May 7 2022] Available from:https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/human-organ-chips-radiation-countermeasure-development