Significance Microfluidic chips incorporate basic operation units such as sample preparation, reaction, separation, and detection on a microchip, revealing great potential in the chemical and biological analysis. Compared with the traditional macroscopic large-volume systems, microfluidic chips feature the advantages of high efficiency, low loss, high safety factor, and high sensitivity. As a high-throughput micro-scale analysis device, the microfluidic chip system has shown significant potential in the highly sensitive detection of various chemical and biological molecules. So far, several detection methods such as ultraviolet-visible absorption, plasma atomic emission spectrometry, inductive coupling, mass spectrometry, chemiluminescence, laser-induced fluorescence, thermal lens microscopy, and biosensors, have been successfully applied to microfluidic systems. Among them, the surface enhanced Raman scattering (SERS) method as a unique detection technology was also introduced to the detection of microfluidic chips and rapidly developed in the past decade. Because SERS is a fingerprint feature map with rich spectral lines, it has high sensitivity, fast speed, and non-contact. Combined with the characteristics of the microfluidic chip, the SERS detection method shows several unique advantages: the laser spot is small and can be directly focused on the tiny channel of the microfluidic chip; the high sensitivity is especially suitable for the requirement of a small amount of reagents in the microfluidic chip; it has no direct contact with the reaction reagents, and it has no interference to the reaction system; with fingerprint spectral characteristics, it can be used to analyze and identify the mixture in the reaction system.

Progress In this review, we will discuss and study the development of SERS microfluidic chips from two parts. The first part is the preparation of microfluidic chip channels and integrated SERS substrates. The second one is the application of SERS integrated microfluidic chips. Figure 1 shows the overall discussion ideas of this article. For the preparation of microfluidic channels, two preparation methods are mainly introduced: wet etching assisted femtosecond laser direct writing and soft lithography. The first method is more complicated and requires multiple processing steps, but the preparation accuracy and detection results are relatively ideal. As a digital processing method, there is no need to replace different templates, especially for the unique advantages of the preparation of the three-dimensional channel. The second method is relatively simple, but two problems need to be addressed. The first is to control the hardness of the PDMS, as the excessive softness will affect the fluidity of the liquid in the channel; the second is to optimize the channel structure to make the device have higher repeatability and stability. The preparation and integration of SERS substrates include the following four methods: colloidal self-assembly, femtosecond laser direct writing (FsLDW) induced metal ion reduction, dual-beam interference, and light scribing. These methods have their pros and cons. The cost of the colloidal self-assembly method is relatively low, the method is relatively simple, but its dispersion uniformity is poor. Femtosecond laser direct writing has obvious advantages in processing accuracy, but the processing time is too long and it is thorny for large-area preparation of the substrate. Dual-beam interference has successfully solved the problem of slow processing speed, but the complexity of the processing pattern and topography of the substrate need to be strengthened. Light scribing meets the requirements of rapid processing and patterned preparation, but there is room for further enhancement in preparation accuracy. In addition to the above-mentioned preparation methods, there are also many methods to prepare SERS microfluidic chips, such as two-photon polymerization, AAO template method for preparing nanostructures, and built-in optical fiber SERS probes. We analyzed the advantages and disadvantages of various methods and summarized the detailed data of the typical research work in this part, and compared them in Table 1. In terms of application, it focuses on the analysis and detection of harmful substances, in-situ monitoring of chemical reactions, biomolecular detection and immunoassay, and cell metabolite detection and analysis of SERS microfluidic chip. We summarized the typical research work of this part in Table 2 and proved that this technology has broad applications in many aspects. However, behind the rapid development of technology, there are still some problems. For example, in biological detection, due to the significant differences in the pH tolerance, life span and size of different types of cells, each chip can only detect corresponding one or several kinds of cells. The current preparation methods of such SERS substrates are mostly colloidal self-assembly methods, which is a huge challenge for the popularization and application of SERS microfluidic chips in this direction.

Conclusion and Prospect With the support of the above content, promoting the development of portable applications of SERS detection microfluidic chips has become a major challenge. To realize the portability of the microfluidic SERS detection system, current research focuses mainly on the transition from active liquid driving to liquid self-driving. For liquid self-driving, the capillary effect is mainly used to replace equipment such as injection pumps that need to add liquid to the chip multiple times. By using this technology, we can reduce the use of pumps and even replace the role of pumps. In addition, with the rapid development of a new generation of manufacturing technology, the production efficiency, accuracy, and stability of microfluidic chips will be significantly improved, and people will gradually solve the problems of long time and high cost in the manufacturing process. With the help of new technologies, microfluidic technology will achieve more functions, and it will be more integrated with SERS detection, various performance indicators will be more excellent, and various devices will be highly integrated. We look forward to the continuous development of this technology and its early use, making contributions to people's daily life, industrial production, and biological testing.