The Future of Medicine on a Chip

Written by: Benjamin Yu

Edited by: Leila Torres Garcia, Daniel Siahaan, Jessica Kim

Illustrated by: Elvan Eren

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Many modern cell culture protocols and animal models often fail to replicate human physiology due to their 2D growth dynamics or dissimilar features. For example, the transition from animal models to clinical trials in cancer has a success rate of less than 8% [1]. As a result, many of these current approaches are limited in their application to humans. By more closely mimicking the environment of human organs, organ-on-a-chip (OoC) platforms can produce more accurate data on how cells respond to drugs and diseases. In return, this improves the chances of successful translation to human trials. More recently, OoC platforms have emerged as a groundbreaking piece of biotechnology that integrates tissue engineering, microfluidics, and biomaterials to mimic the environment of a human organ [2].

In order to create OoCs, multiple cell types resembling human organ functions and structures must be cultured. Many researchers use induced pluripotent stem cells (iPSCs), which are adult cells reprogrammed to behave like embryonic stem cells, as they can be differentiated into almost every type of cell in the body. Some common iPSC-differentiated cells in OoCs include endothelial cells, macrophages, and tissue-specific fibroblasts. Endothelial cells line the inside of blood vessels, allowing for vascularization—the creation of blood vessels—and delivery of nutrients throughout the entire body. Macrophages, on the other hand, are white blood cells of the immune system that remove harmful or mutated cells and microorganisms in the body. Fibroblasts, specific to certain types of tissues, support tissue structure and repair, and help with cell-to-cell connection and compaction. Moreover, each tissue must contain specific cell types that mimic the organ’s natural function, such as cardiomyocytes for the heart or hepatocytes for the liver [3]. 

Vascularization, the process of creating blood vessels in tissues, is performed specifically using endothelial cells. By seeding endothelial cells throughout tissues, they congregate to form miniature blood vessels that allow for the transportation of nutrients into the center of the tissue. Vascularization allows for all parts of the tissue to receive the essential nutrients rather than just the outside of the tissue. The process of vascularization typically goes hand-in-hand with microfluidics or the study of fluids on a microscopic level, typically through miniature channels. As vascularization takes place, a nutrient-rich solution called cell media flows through the microchannels created by the endothelial cells. Since microfluidics deal with extremely small amounts of liquid, tiny electronic pumps are often used to push the liquid through these channels. Together, vascularization and microfluidics help to simulate the flow of blood throughout the human body [4]. 

It is fairly difficult to create structures that can hold the nutrient-rich cell culture medium, electronic pumps, and other components of OoCs in a sterile and effective manner. OoCs utilize biomaterial scaffolds to provide structural support and maintain tissue formation. One common example is polydimethylsiloxane (PDMS), a synthetic, biocompatible scaffold that helps to hold the tissue in place while organizing and supporting cellular formation to mimic the extracellular matrix that exists in real tissues. Although PDMS is limited by its hydrophobicity (its ability to repel water), various methods, such as plasma treatment, allow PDMS to produce a hydrophilic surface [5]. This is important because a hydrophilic surface improves cell attachment and nutrient flow, helping PDMS better mimic the extracellular matrix (ECM) found in real tissues. Alternatively, other biomaterials, such as GelMA hydrogels (or soft water-containing materials), are hydrophilic and can be used as scaffolds to overcome the limitations of PDMS [6]. By integrating these biomaterials with microfluidics and vascularization techniques, researchers can create the OoC. 

OoCs can integrate anywhere from a single organ to multiple organs across various organ systems [7]. This allows for the creation of complex models that can simulate interactions between human organs and provide a more accurate representation of human physiology. Multi-organ OoCs are particularly useful in studying cancer development and how various drugs or diseases affect different systems simultaneously [8]. Additionally, multi-organ OoCs can be used to study organ-organ interactions, such as how the liver can process drugs that affect the heart, which are difficult to obtain from single-organ models. 

Despite their promise, organ-on-a-chip systems still face several challenges. These include difficulties in producing life-sized tissues, ensuring long-term cell viability, and accurately replicating the full complexity of human organs [2]. Additionally, variability in materials and fabrication methods can lead to inconsistent results across studies [2]. These limitations can be seen in many studies involving OoCs. 

An impressive study involving OoCs was conducted by Dr. Gordana Vunjak-Novakovic’s lab at Columbia University’s Department of Biomedical Engineering. The researchers designed a multi-organ chip to integrate 4 different organs linked by vascular flow, including compartments for heart, liver, bone, and skin tissues [9]. These tissues were created through the differentiation of iPSCs, and to ensure that each cell type was differentiated correctly, researchers evaluated the phenotypes—observable characteristics such as cell shape and function—of each cell over 4 weeks. Heart tissues were electronically matured and stimulated into simultaneous beating, while liver tissues exhibited active metabolism and production of albumin. Albumin is a protein specific to the liver that helps maintain blood volume and pressure by keeping fluid from leaking out of blood vessels. Bone tissues displayed high amounts of bone-specific protein and exhibited physical features similar to a real bone. Skin tissues were verified as they displayed barrier function similar to human skin implants. Underneath each tissue, there was an elastic mesh covered by an endothelial barrier that allowed for vascularization. 

These organ compartments were not just simply connected through medium flow but also by communication through cytokines (chemical signals used for communication), circulating cells, and exosomes (tiny particles released by cells to exchange information). When the researchers exposed the OoC to 30 uM of doxorubicin, a dosage known to induce cardiotoxicity, the system accurately replicated the drug’s pharmacokinetics and pharmacodynamics. Cardiotoxicity, or damage to the heart muscle, can lead to impaired heart function. This is a critical side effect of certain chemotherapy drugs like doxorubicin that limits their safe dosage in patients.

The liver metabolized doxorubicin into its active form, just as it would in the human body. As a result, the heart showed signs of cardiotoxicity, such as beating less effectively (reduced excitability) and releasing more cardiac troponin I, a protein that signals heart damage. However, there are certain limitations to this system. The PDMS pillars absorbed some of the doxorubicin in the heart chamber, leading to lower amounts of the drug reaching the heart. This absorption reduces the accuracy of the model, as it underestimates the drug’s effects, making it harder to replicate real-life drug exposure. Furthermore, only a single high dosage of doxorubicin was implemented instead of various doses over longer periods of time or different drug formulations, as the goal was to model doxorubicin-induced heart dysfunction using a clinically relevant dose known to be a primary cause of heart damage in patients. 

As biomedical technology continues to advance, OoCs show great promise for improving drug testing and disease modeling in a simulated human organ environment. Remarkably, OoCs are capable of accurately simulating the environments of multiple human organs, not just one, but up to four. By integrating multiple organ systems, OoCs help researchers understand the complex interaction between human organs, which are difficult to perceive with common cell culture and animal model techniques. The continued refinement and testing of OoC technology could revolutionize how drugs are developed and tested, leading to safer and more effective therapies in the future. 

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References

[1] Mak, I. W., Evaniew, N., & Ghert, M. (2014). Lost in translation: animal models and clinical trials in cancer treatment. American journal of translational research, 6(2), 114–118.

[2] Leung, C. M., de Haan, P., Ronaldson-Bouchard, K., et al. (2022). A guide to the organ-on-a-chip. Nature Reviews Methods Primers, 2(33). https://doi.org/10.1038/s43586-022-00118-6

[3] Vunjak-Novakovic, G., Ronaldson-Bouchard, K., & Radisic, M. (2021). Organs-on-a-chip models for biological research. Cell, 184(18), 4597-4611. https://doi.org/10.1016/j.cell.2021.08.017

[4] Yang, G., Mahadik, B., Choi, J. Y., & Fisher, J. P. (2020). Vascularization in tissue engineering: fundamentals and state-of-art. Progress in biomedical engineering (Bristol, England), 2(1), 012002. https://doi.org/10.1088/2516-1091/ab5637

[5] Trantidou, T., Elani, Y., Parsons, E., & Ces, O. (2017). Hydrophilic surface modification of PDMS for droplet microfluidics using a simple, quick, and robust method via PVA deposition. Microsystems & Nanoengineering, 3, 16091. https://doi.org/10.1038/micronano.2016.91

[6] Piao, Y., You, H., Xu, T., Bei, H., Piwko, I. Z., Kwan, Y. Y., & Zhao, X. (2021). Biomedical applications of gelatin methacryloyl hydrogels. Engineered Regeneration, 2, 47–56. https://doi.org/10.1016/j.engreg.2021.03.002

[7] Farhang Doost, N., & Srivastava, S. K. (2024). A Comprehensive Review of Organ-on-a-Chip Technology and Its Applications. Biosensors, 14(5), 225. https://doi.org/10.3390/bios14050225

[8] Ingber, D. E. (2022). Human organs-on-chips for disease modelling, drug development and personalized medicine. Nature Reviews Genetics, 23(8), 467–491. https://doi.org/10.1038/s41576-022-00466-9

[9] Ronaldson-Bouchard, K., Teles, D., Yeager, K., et al. (2022). A multi-organ chip with matured tissue niches linked by vascular flow. Nature Biomedical Engineering, 6(4), 351–371. https://doi.org/10.1038/s41551-022-00882-6