Microfluidic based-3D spheroid models for drug development studies: a review

Microfluidic based-3D spheroid models for drug development studies: a review
Marziye Soleimani,^1,* Zeinab Bagheri,²
1. Faculty of life science and biotechnology, Shahid Beheshti University, Tehran, Iran
2. Faculty of life science and biotechnology, Shahid Beheshti University, Tehran, Iran
Introduction: Monolayer or two-dimensional (2D) cell cultures are the primary test platform in biomedical research that supports conventional assays and high-throughput screening. In addition, 2D cell cultures are easy to use and very widespread, but cannot mimic the in vivo physiological state of natural tissues, so many of the results do not apply to clinical application. This lack of similarity between in vivo and in vitro conditions increases the cost and time invested in research, particularly in drug development studies. Research has shown, for example, that most cancer drugs that are effective in 2D cell cultures cannot work properly in the human body and yet less than 5 percent of the drugs reach the clinic. To overcome the gap, using animal models are common but they have some drawbacks such as being costly and time-consuming in addition to having physiological differences with humans. Subsequently, 3D cellular models have developed and attracted a lot of attention to narrow the gap between pre-clinical and clinical studies. Among 3D cell cultures, spheroids are one of the best cellular models especially for cancer research and solid tumor studies. They are widely used due to their diverse, easy, and cost-effective preparation methods. In recent years, microfluidic systems which can control the physiological condition and mimic the perfusion of metabolites and wastes by incorporating flow dynamics became an interesting alternative to traditional methods in 3D cell culturing. They are suitable platforms for spheroid cultivation or analysis.
Methods: Kwapiszewska et al. developed a microfluidic chip to culture tumor spheroids for in vitro drug screening. In their work, a microfluidic device by PDMS was designed and fabricated. The chip was composed of a concentration gradient generator (CGG) as a mixing channel which enables the formation of spheroids and analysis of drug screening results in a controlled fluid flow rate. After the device fabrication, HT-29 human colon carcinoma cells and Hep-G2 human liver carcinoma cell lines were cultured separately, and then their suspension was introduced to the microfluidic device using syringe pumps to form the spheroids. The drug screening was performed by long-term monitoring of the viability of spheroids exposed to different dosages of 5-fluorouracil (5-FU) drug. In another study, Lim et al. introduced a microfluidic spheroid culture device (µFSCD) for high-throughput cancer drug screening. their µFSCD has a concentration gradient generator (CGG) for a parallel screening. After the formation of colon cancer cell (HCT116) spheroids in chip microwells, the drug (irinotecan) was injected into the device. Finally, live/dead Staining and Cell Viability Measurements were performed.
Results: The results from different spheroids which were exposed to different drug concentrations were collected and compared. This comparison can investigate drug efficiency. For instance, in the first research mentioned above, it was observed that low concentrations of 5-FU are more effective when the dose is repeated. Also, Lim et al. showed that the cell viability in different microwells containing more concentrations of irinotecan was lower and vice versa which was following the observations of spheroids roundness.
Conclusion: Using this combinational approach for drug development studies especially for nano-drug delivery to solid tumors is a new method to reduce the time and costs of preclinical researches, in addition, to reduce the gap between in vitro and in vivo studies. It’s expected that a well-designed microfluidic-based spheroid culture system is a powerful tool for drug development researches as a 3D in vitro tumor model.
Keywords: Microfluidic systems; 3D cell culture; spheroid; drug development