Research advances of high-throughput cell-based drug screening systems based on microfluidic technique

Drug screening is the process of screening new drugs or leading compounds with biological activity from natural products or synthetic compounds, and it plays an essential role in drug discovery. The discovery of innovative drugs requires the screening of a large number of compounds with appropriate drug targets. With the development of genomics, proteomics, metabolomics, combinatorial chemistry, and other disciplines, the library of drug molecules has been largely expanded, and the number of drug targets is continuously increasing. High-throughput screening systems enable the parallel analysis of thousands of reactions through automated operation, thereby enhancing the experimental scale and efficiency of drug screening. Among them, cell-based high-throughput drug screening has become the main screening mode because it can provide a microenvironment similar to human physiological conditions. However, the current high-throughput screening systems are mainly built based on multiwell plates, which have several disadvantages such as simple cell culture conditions, laborious and time-consuming operation, and high reagent consumption. In addition, it is difficult to achieve complex drug combination screening. Therefore, there is an urgent need for rapid and low-cost drug screening methods to reduce the time and cost of drug development. Microfluidic techniques, which can manipulate and control microfluids in microscale channels, have the advantages of low consumption, high efficiency, high throughput, and automation. It can overcome the shortcomings of screening systems based on multi-well plates and provide an efficient and reliable technical solution for establishing high-throughput cell-based screening systems. Moreover, microfluidic systems can be flexibly changed in terms of cell culture materials, chip structure design, and fluid control methods to enable better control and simulation of cell growth microenvironment. Operations such as cell seeding, culture medium replacement or addition, drug addition and cleaning, and cell staining reagent addition are usually involved in cell-based microfluidic screening systems. These operations are all based on the manipulation of microfluids. This paper reviews the research advances in cell-based microfluidic screening systems using different microfluidic manipulation modes, namely perfusion flow mode, droplet mode, and microarray mode. In addition, the advantages and disadvantages of these systems are summarized. Moreover, the development prospects of high-throughput screening systems based on microfluidic techniques has been looked forward. Furthermore, the current problems in this field and the directions to overcome these problems are discussed.