Chips in Nucleic Acid Detection

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Since the outbreak of the new crown epidemic in 2020, the epidemic has repeatedly jumped between the outbreak and its control. Whether it is in the community or in the hospital, people can see long queues in front of the nucleic acid testing sampling points, and the “pain mask” of being stabbed by doctors Scenes. According to the National Bureau of Statistics, by the end of 2021, a total of 11,937 medical and health institutions across the country provided nucleic acid testing services for the new coronavirus, with a total testing capacity of 41.68 million copies per day. More than 400 million people have been tested. It can be said that nucleic acid testing has become a part of people’s lives.

In addition to nucleic acid testing, there are methods such as antigen testing and antibody testing that can test for the new coronavirus. A few days ago, some pharmacies and online shopping platforms put some antigen testing kits on the shelves for residents to self-test at home, but only nucleic acid testing is The “gold standard” for testing the new crown virus is also most related to chips. After reading this article, you will know:

1. What is nucleic acid testing?

2. What is the industry chain like?

3. Which chips are used in it?

What is nucleic acid testing?

What is the nucleic acid testing industry chain like?

Before nucleic acid detection, we must first understand the word “in vitro diagnosis (IVD)”. There are four main detection methods: biochemical diagnosis, immunodiagnosis, molecular diagnosis, and bedside detection. To put it simply, in vitro diagnosis is to use machines to test samples of human blood, body fluids, tissues, etc., and judge whether we are sick according to the test results. Therefore, in vitro diagnosis is also called “doctor’s eyes”. Does this process sound? Much like nucleic acid testing? Yes, nucleic acid testing is a type of molecular diagnosis.

The main steps of nucleic acid detection are: nucleic acid sampling, nucleic acid extraction, nucleic acid amplification, and nucleic acid detection. Nucleic acid sampling can be understood as the process of being poked in the nose and throat in hospitals and communities, mainly to collect our body fluid samples, nucleic acid Extraction is to extract the nucleic acid (DNA, RNA) in the sample through the magnetic beads and magnetic rods in the nucleic acid extractor. The results are compared to determine whether we are infected.

Before the epidemic, nucleic acid detection had been widely used, such as HIV, hepatitis B virus, hepatitis C virus, and avian influenza A virus. Song Haibo, president of the Medical Laboratory Industry Branch of the National Health Industry Enterprise Management Association, said that in the past, due to limited conditions, molecular diagnosis was basically performed in large hospitals. The main reason is that molecular diagnosis has three major pain points: expensive laboratories, expensive equipment, and strict requirements for staff. After the outbreak, my country’s nucleic acid testing institutions have developed rapidly. According to the National Bureau of Statistics, by the end of 2021, a total of 11,937 medical and health institutions across the country will provide new coronavirus nucleic acid testing services. Therefore, Song Haibo believes: “Now that the laboratory is established and the instruments and equipment are available, there should be no problem in carrying out more testing items.”

Nucleic acid detection methods mainly include PCR method, constant temperature amplification method, gene sequencing method and so on. In 1983, American scientist Kelly Mullis invented PCR (polymerase chain reaction). Due to its simple operation and high sensitivity, PCR is the most widely used method. It can be said that PCR method is the most mature molecular diagnosis or nucleic acid detection. technology.

The difference between the constant temperature amplification method and PCR is that the temperature is kept constant during nucleic acid amplification, and multiple pathogens can be detected at one time. It has the characteristics of strong integration ability, short detection time, and low reagent consumption. However, through the continuous innovation of technology, PCR has higher detection accuracy, so PCR is still the best choice for nucleic acid detection. Only a small number of enterprises have put into production the rest of the methods, and their applications are less.

Nucleic acid detection industry chain

The traditional nucleic acid detection industry chain consists of upstream raw material suppliers (Fepeng Biotech, Novozyme, etc.), diagnostic instrument manufacturers (Roche, Illumina, Berry, Daan Gene, Huada Gene, Qiagen of Germany, Bioneer of South Korea, Thermo Fisher, etc.), midstream reagent manufacturers (BGI, Mingde Biotech, Mike Biotech, etc.), and downstream demand side (hospitals, third-party testing institutions, etc.).

From the perspective of upstream raw materials, there are few domestic manufacturers that can provide upstream raw materials, mainly dominated by foreign companies such as Roche. In terms of nucleic acid detection instruments, after the outbreak of the epidemic, the nucleic acid detection market has grown rapidly. Many reagent manufacturers located in the middle reaches of the industrial chain have also started the research and development and production of nucleic acid detection instruments. Molecular diagnostic instruments mainly include nucleic acid extractors, PCR amplification instruments, etc. Multiplier, Nucleic Acid Molecular Hybridization Instrument, Gene Chip Instrument, Gene Sequencer, etc.

In terms of nucleic acid extractors, domestic instruments are generally superior to foreign instruments in terms of throughput and processing time, and the price is more affordable. Domestic nucleic acid extractors generally cost hundreds of thousands, while foreign nucleic acid extractors cost hundreds of thousands more. about. In terms of PCR amplification instruments, the prices of domestic manufacturers are generally lower, and the performance can reach the level of foreign brands. Nucleic acid molecule hybridization instruments and gene chip instruments have also been fully localized. In terms of gene sequencers, in the past, it was mainly monopolized by foreign manufacturers such as Illumina, Thermo Fisher, Roche, etc., but in recent years, many products in my country have been approved by the State Food and Drug Administration, such as the gene sequencers of BGI, Berry and other companies. instrument.

At present, many enterprises in my country have entered the upstream of the industrial chain, such as Daan Gene, Shengxiang Bio, Zhijiang Bio, Shuo Shi Bio, Kaipu Bio, Mingde Biology and other manufacturers. The official website of the product center has different quantities and types of testing instruments. .

In recent years, due to the increasing demand for nucleic acid detection, many nucleic acid detection integrated instruments have appeared, such as the GeneXpert Dx molecular diagnostic system of the United States, Roche’s fully automatic new coronavirus detection instrument, etc., and domestic nucleic acid detection analyzers such as Shengxiang , Rendu’s fully automatic nucleic acid detection and analysis system, Wondfo Bio’s fully automatic nucleic acid detection and analysis system, etc., all try their best to break through the limitations of nucleic acid detection application scenarios, and integrate the functions of multiple instruments in nucleic acid detection into one machine. It can be seen that the current upstream product pattern of nucleic acid detection is also changing.


From the perspective of reagents in the midstream, in the mid-to-late 1990s, some domestic companies seized the opportunity to act as an agent for Roche and other companies to import PCR instruments, developed matching nucleic acid detection reagent products, and realized the localization of nucleic acid detection reagents very early. The data shows that in May 2021, the production capacity of Da’an Gene has reached 1 million servings per day, ranking first among domestic molecular diagnostic companies in 2021 with a revenue of 7.63 billion yuan, followed by Shengxiang Biotechnology 45.05 100 million, Zhijiang Bio 2.021 billion, Mingde Bio (first three quarters) 1.938 billion, Shuo Shi Bio 2.172 billion.

From the downstream perspective, Roche, Danaher, Siemens Healthcare, and Abbott, the four major foreign capital giants, put reagents and instruments into the market in a closed mode, monopolizing high-end markets such as tertiary hospitals. And China’s domestic in vitro diagnostic equipment companies have also started to catch up with technology, and seized the market in secondary hospitals, primary hospitals, third-party independent laboratories and other fields.

Taking Shengxiang Biotech as an example, from 2015 to 2019, Sanxiang Biotech’s PCR-related instruments only sold less than 1,000 units, but in 2020, it sold more than 6,000 units, and the epidemic has greatly increased. Fast acting. On the whole, the nucleic acid detection industry chain has been quietly changing, and the market structure of my country’s molecular diagnosis industry has basically taken shape.

Which chips are used in each link of detection?

As mentioned above, the process of nucleic acid detection mainly includes four steps: nucleic acid sampling, nucleic acid extraction, nucleic acid amplification, and nucleic acid detection. The steps that need to use chips are mainly in nucleic acid extraction and nucleic acid amplification. The main application of nucleic acid amplification is Microfluidic chips, current drivers, temperature sensors, etc., and corresponding molecular diagnostic instruments include PCR amplifiers, constant temperature amplification microfluidic chip nucleic acid analyzers, etc. In terms of nucleic acid extraction, the chips mainly used include wifi chips, power management chips, etc., corresponding to instruments such as nucleic acid extractors.

The PCR microfluidic chip in the PCR amplification instrument is to integrate PCR technology on the chip through microfluidic technology. According to the number of samples tested in one experiment, the PCR chip can be divided into low-throughput and high-throughput, low- The number of detections of the throughput PCR chip is limited, while the high-throughput can detect hundreds or thousands of samples at the same time. Representative manufacturers include Thermo Fisher Scientific and Roche. At present, PCR chip technology has been widely used in many fields such as biotechnology, disease detection and clinical medicine.

The principle of the constant temperature amplification microfluidic chip nucleic acid analyzer is to combine the constant temperature amplification technology with the microfluidic chip technology, amplify the sample at a constant temperature (41 degrees), and then use specific fluorescent probes for real-time analysis. Fluorescence detection results. At the beginning of the epidemic in 2020, academician Zhong Nanshan announced at the New Coronary Pneumonia Multidisciplinary Forum that China has developed a new crown pneumonia nucleic acid detection method (constant temperature amplification chip method), which can distinguish new crown pneumonia from influenza A and B.

The portable quick nucleic acid detection cartridge also uses microfluidic chip technology, which integrates reagents, amplification equipment, and detection devices in a matchbox-sized sealed cartridge to automatically complete nucleic acid detection. The dean of West China Hospital of Sichuan University introduced: “It It is as big as a lighter, and the result can be obtained within 40 minutes after the test, which is very convenient.” However, the product is currently in the application stage and has not yet been launched for sale.

The home-use new crown self-test system was jointly developed by Zhang Yan of Tianjin University and Harvard University and other scientific research institutions. This product uses microfluidic chip technology, which can detect the result within 5 minutes at the fastest, and provides the naked eye with intuitive color contrast. Visible results, but its detection accuracy is still not as good as the correct nucleic acid detection. Currently, the system is in the research and development stage and has not been marketed.

In addition to the above microfluidic chip technology, there is also a gene chip method to detect the new coronary pneumonia virus. The prototype of the gene chip was proposed in the mid-1980s, that is, the method of determining the nucleic acid sequence by hybridizing with a set of known sequence nucleic acid probes. The corresponding instruments include gene chip instruments, etc. The nucleic acid detection method is still the PCR method.

A blogger analyzed the nucleic acid amplification instrument and found that during the PCR amplification process, the instrument needs to use a thermoelectric cooler to adjust the temperature, which will use LED drivers, current drivers, operational amplifiers, temperature sensors and other components.

It can be seen that TI’s TLV9061 operational amplifier is used. This chip is mainly used in electric bicycles, smoke detectors, motor control, refrigerators, notebook computers, sensor signal conditioning, power modules and other fields. The current price of the chip is about 20 around yuan.

In the heating and cooling unit of the instrument, TI’s sensor TMP117, LED driver TPS54201 and motor driver DRV8873 are also used. Among them, TMP117 is mainly used in electronic thermometers, wireless environmental sensors, thermostats, automotive test equipment, gas meters and heat meters. . The TPS54201 is mainly used in the fields of IR LED with adjustable day/night vision, LED display and lighting. DRV8873 is mainly used in H-bridge motor drivers, automobiles, current mirrors for output current detection, configurable control interfaces and other fields. It is mainly used in H-bridge motor drivers in nucleic acid detection epidemics, and forms a heating and cooling system with TPS54201 and TMP117 .

There is also a digital-to-analog converter DDC112 that controls current input and a series voltage reference component REF3040. REF3040 is mainly used in temperature and pressure transmitters, data acquisition systems, medical equipment and other fields. According to TI’s official website, in addition to DDC112 showing that it is in stock, TLV9061, TMP117, TPS54201, DRV8873, REF3040 and other series components are mostly out of stock.

In addition, there is news that the sensor EESX1081 released by Omron has also been applied to the nucleic acid amplification instrument, which is mainly used to detect whether there is a test tube in the nucleic acid detector and whether the position of the test tube is placed correctly.

Many chips are also needed in the nucleic acid extractor. The manual of a certain brand of 96-channel automatic nucleic acid extractor shows that the network communication, remote control, power supply and other functions all need chips to realize.


Chips in nucleic acid detection

Both the wireless wifi function of network communication and the function of app remote monitoring instruments need to use wifi chips. Representative manufacturers include Broadcom, Qualcomm, Marvell Technology, TI, Realtek, etc. The power management chip that the power supply needs to use represents manufacturers such as TI, Qualcomm, and ADI.

The domestic epidemic situation is repeated, and the express delivery from Hong Kong to the mainland is out of service. At the front end, chips are stuck in Shenzhen and Hong Kong (for details, please refer to the recommended reading at the end of the article). Although the Huaqiangbei market has been partially unblocked, the chips in Shenzhen have been released. However, the IC people fighting on the front line and the terminal manufacturers downstream of the semiconductor industry chain are still worried, and they are suffering unspeakably from the epidemic.

The chips that deal with us every day have made great contributions to the prevention and control of the epidemic. Both biochips and microfluidic chips have made great contributions in many fields such as medicine and life sciences. Among the 15 key technology projects listed in the “10th Five-Year Plan of Medical Biotechnology and 2015 Plan”, eight projects will use biochips, and microfluidic chip technology is rated by Forbes as the 15th project that will affect the future of mankind. one of the most important inventions. And all kinds of products closely related to our life, ranging from airplanes and high-speed trains to PCs, mobile phones, remote controls, U disks, etc., cannot be separated from the shadow of chips.

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